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1.  The cosmological model of eternal inflation and the transition from chance to biological evolution in the history of life 
Biology Direct  2007;2:15.
Background
Recent developments in cosmology radically change the conception of the universe as well as the very notions of "probable" and "possible". The model of eternal inflation implies that all macroscopic histories permitted by laws of physics are repeated an infinite number of times in the infinite multiverse. In contrast to the traditional cosmological models of a single, finite universe, this worldview provides for the origin of an infinite number of complex systems by chance, even as the probability of complexity emerging in any given region of the multiverse is extremely low. This change in perspective has profound implications for the history of any phenomenon, and life on earth cannot be an exception.
Hypothesis
Origin of life is a chicken and egg problem: for biological evolution that is governed, primarily, by natural selection, to take off, efficient systems for replication and translation are required, but even barebones cores of these systems appear to be products of extensive selection. The currently favored (partial) solution is an RNA world without proteins in which replication is catalyzed by ribozymes and which serves as the cradle for the translation system. However, the RNA world faces its own hard problems as ribozyme-catalyzed RNA replication remains a hypothesis and the selective pressures behind the origin of translation remain mysterious. Eternal inflation offers a viable alternative that is untenable in a finite universe, i.e., that a coupled system of translation and replication emerged by chance, and became the breakthrough stage from which biological evolution, centered around Darwinian selection, took off. A corollary of this hypothesis is that an RNA world, as a diverse population of replicating RNA molecules, might have never existed. In this model, the stage for Darwinian selection is set by anthropic selection of complex systems that rarely but inevitably emerge by chance in the infinite universe (multiverse).
Conclusion
The plausibility of different models for the origin of life on earth directly depends on the adopted cosmological scenario. In an infinite universe (multiverse), emergence of highly complex systems by chance is inevitable. Therefore, under this cosmology, an entity as complex as a coupled translation-replication system should be considered a viable breakthrough stage for the onset of biological evolution.
Reviewers
This article was reviewed by Eric Bapteste, David Krakauer, Sergei Maslov, and Itai Yanai.
doi:10.1186/1745-6150-2-15
PMCID: PMC1892545  PMID: 17540027
2.  Establishing the Scientific Validity of Tridosha part 1: Doshas, Subdoshas and Dosha Prakritis 
Ancient Science of Life  2010;29(3):6-18.
In traditional Ayurdev, basic concepts such as Tridosa are introduced didactically. Students of Ayurdeva learn to appreciate their practical value through experience; their validity is empirical. In an age where validity of concepts is judged by their scientific relevance, establishing the scientific validity of Tridosha is a program of significance. It requires translating concept and practical application into the idiom of modern biology and medicine. Four different complementary approaches have been proposed to do so: factor analysis of human physiology; systems analysis of organism function; correlation of Dosha and genomic variations - Ayugenomics; and correlation of Dosha and cellular function. Together these four independent approaches present compelling evidence that the family of Dosha based, Ayurveda fundamental concepts - the three Doshas, their fifteen subdoshas, innate Dosha balance in the individual (prakriti), and Dosha imbalances (vikriti) are scientifically valid. This paper concerns the first three. (I) The systems approach shows how Tridosha applies to every living organism from the first cells, and how it is inherited and diversified in the history of life. (2) Ayugenomics confirms Dosha's inheritance. (3) Each Dosha is responsible for regulating an essential aspect of organism function, connected to a recognised definition of life: Vata, Input/Output (homeostasis); Pitta, Turnover (negative entropy production); Kapha, Storage (inheritable structure).
PMCID: PMC3336287  PMID: 22557353
3.  The traditional knowledge on stingless bees (Apidae: Meliponina) used by the Enawene-Nawe tribe in western Brazil 
Background
This paper presents the Enawene-Nawe Society's traditional knowledge about stingless bees. The Enawene-Nawe are an Aruak speaking people, indigenous to the Meridian Amazon. Specifically, they live in the Jurema River hydrological basin, located in the northwestern region of the Mato Grosso state.
Methods
The stingless bees were sampled from two ecologically similar regions in the interior of Enawene-Nawe Land. The first sampling took place around the village, i.e., adjacent to houses, by the edge of the Iquê River, next to food leftovers, around human excrement, and simply when the insects were found flying or reposing on a human body. The second round of sampling happened from 29/10 to 02/11/94, during an expedition for honey collection that took place throughout the ciliar bushes of the Papagaio River, an important tributary of Juruena River. We sampled bees adjacent to their nests following the beehive inspection or during the honey extraction.
In this work, the main bee species of the sub tribe Meliponina, which were handled by the Enawene-Nawe, was identified, and a brief ethnographic description of the honey collection expeditions and its social-cosmologic meaning for the group was done.
Results and Discussion
Similar to other indigenous people in Brazil, the Enawene-Nawe recognized 48 stingless bee species. They identified each bee species by name and specified each one's ecological niche. A brief ethnographic description of the honey collection expeditions and bees' social-cosmologic meaning for the group is included.
Conclusion
We concluded that, as an example of other indigenous people, the Enawene-Nawe classify and identify the bees based not only on their structure and morphological aspects but also on the ecological, etiological, and social characteristics of the species.
doi:10.1186/1746-4269-4-19
PMCID: PMC2562997  PMID: 18793393
4.  The Biological Big Bang model for the major transitions in evolution 
Biology Direct  2007;2:21.
Background
Major transitions in biological evolution show the same pattern of sudden emergence of diverse forms at a new level of complexity. The relationships between major groups within an emergent new class of biological entities are hard to decipher and do not seem to fit the tree pattern that, following Darwin's original proposal, remains the dominant description of biological evolution. The cases in point include the origin of complex RNA molecules and protein folds; major groups of viruses; archaea and bacteria, and the principal lineages within each of these prokaryotic domains; eukaryotic supergroups; and animal phyla. In each of these pivotal nexuses in life's history, the principal "types" seem to appear rapidly and fully equipped with the signature features of the respective new level of biological organization. No intermediate "grades" or intermediate forms between different types are detectable. Usually, this pattern is attributed to cladogenesis compressed in time, combined with the inevitable erosion of the phylogenetic signal.
Hypothesis
I propose that most or all major evolutionary transitions that show the "explosive" pattern of emergence of new types of biological entities correspond to a boundary between two qualitatively distinct evolutionary phases. The first, inflationary phase is characterized by extremely rapid evolution driven by various processes of genetic information exchange, such as horizontal gene transfer, recombination, fusion, fission, and spread of mobile elements. These processes give rise to a vast diversity of forms from which the main classes of entities at the new level of complexity emerge independently, through a sampling process. In the second phase, evolution dramatically slows down, the respective process of genetic information exchange tapers off, and multiple lineages of the new type of entities emerge, each of them evolving in a tree-like fashion from that point on. This biphasic model of evolution incorporates the previously developed concepts of the emergence of protein folds by recombination of small structural units and origin of viruses and cells from a pre-cellular compartmentalized pool of recombining genetic elements. The model is extended to encompass other major transitions. It is proposed that bacterial and archaeal phyla emerged independently from two distinct populations of primordial cells that, originally, possessed leaky membranes, which made the cells prone to rampant gene exchange; and that the eukaryotic supergroups emerged through distinct, secondary endosymbiotic events (as opposed to the primary, mitochondrial endosymbiosis). This biphasic model of evolution is substantially analogous to the scenario of the origin of universes in the eternal inflation version of modern cosmology. Under this model, universes like ours emerge in the infinite multiverse when the eternal process of exponential expansion, known as inflation, ceases in a particular region as a result of false vacuum decay, a first order phase transition process. The result is the nucleation of a new universe, which is traditionally denoted Big Bang, although this scenario is radically different from the Big Bang of the traditional model of an expanding universe. Hence I denote the phase transitions at the end of each inflationary epoch in the history of life Biological Big Bangs (BBB).
Conclusion
A Biological Big Bang (BBB) model is proposed for the major transitions in life's evolution. According to this model, each transition is a BBB such that new classes of biological entities emerge at the end of a rapid phase of evolution (inflation) that is characterized by extensive exchange of genetic information which takes distinct forms for different BBBs. The major types of new forms emerge independently, via a sampling process, from the pool of recombining entities of the preceding generation. This process is envisaged as being qualitatively different from tree-pattern cladogenesis.
Reviewers
This article was reviewed by William Martin, Sergei Maslov, and Leonid Mirny.
doi:10.1186/1745-6150-2-21
PMCID: PMC1973067  PMID: 17708768
5.  On the Existence of Low-Mass Dark Matter and its Direct Detection 
Scientific Reports  2015;5:8058.
Dark Matter (DM) is an elusive form of matter which has been postulated to explain astronomical observations through its gravitational effects on stars and galaxies, gravitational lensing of light around these, and through its imprint on the Cosmic Microwave Background (CMB). This indirect evidence implies that DM accounts for as much as 84.5% of all matter in our Universe, yet it has so far evaded all attempts at direct detection, leaving such confirmation and the consequent discovery of its nature as one of the biggest challenges in modern physics. Here we present a novel form of low-mass DM χ that would have been missed by all experiments so far. While its large interaction strength might at first seem unlikely, neither constraints from particle physics nor cosmological/astronomical observations are sufficient to rule out this type of DM, and it motivates our proposal for direct detection by optomechanics technology which should soon be within reach, namely, through the precise position measurement of a levitated mesoscopic particle which will be perturbed by elastic collisions with χ particles. We show that a recently proposed nanoparticle matter-wave interferometer, originally conceived for tests of the quantum superposition principle, is sensitive to these collisions, too.
doi:10.1038/srep08058
PMCID: PMC4306971  PMID: 25622565
6.  THE TRIDOSHA DOCTRINE TRACED TO BREATH AS SOUL 
Ancient Science of Life  1989;9(1):25.
The author traces in this paper the clue of the Tridosha Doctrine consisting of Air, water and heat. Breath contains all the three. Probably the Tridosha doctrine arose while considering breath as soul.
PMCID: PMC3331300  PMID: 22557670
7.  THE QUALITATIVE STATUS OF THE ONKOI IN ASCLEPIADES' THEORY OF MATTER 
The medical and philosophical system of Asclepiades of Bithynia (fl. later second century BC)1 has been the subject of considerable controversy.2 His physical theory of anarmoi onkoi in particular has seen intense debate, and although many of its broader features appear to be fairly well established, many of its most fundamental details remain obscure. Perhaps somewhat paradoxically, some of the most important work carried out on Asclepiades has been explicitly focused instead on Heraclides of Pontus,3 the reconstruction of whose physical theory has often proceeded on the assumption that this was largely replicated by Asclepiades some two centuries later. But to a great extent the Asclepiadean debate has been framed in terms of the question of his intellectual debts to ancient atomism, and Epicureanism in particular, and in this respect the present study will be no different.4 The most recent scholarship has been sharply divided over this question. Vallance has emphasized the principally medical context of Asclepiades' system, and made the case that the frangibility of the onkoi marks such a fundamental divergence from Epicurus' atomism that any influence from Epicurean physics should be rejected, and that we should look instead especially to Erasistratus.5 Casadei, however, following on to a certain extent from the work of Pigeaud, has rightly drawn attention to the tendency in Vallance's exposition to suppress a number of fundamental elements of Asclepiades' doctrine which are undeniably also distinguishing features of Epicurean philosophy.6 The most significant of these include his particulate theory of matter, his antiteleological conception of nature, and his rejection of any theory of qualitative change. But these correspondences would certainly not be sufficient to qualify Asclepiades' system simply as a reproduction of Epicureanism, and there is clear evidence that Asclepiades stood in opposition to Epicurus in certain fundamental respects. In a recent study which has done much to establish Asclepiades' credentials as a philosopher, focusing especially on his philosophy of mind, Polito has underlined certain distinctly non-Epicurean elements in his system, such as his radical determinism and his denial of a localized ruling-part-of-the-soul.7 It thus seems clear that, despite some important parallels between their systems, Asclepiades cannot be regarded as an Epicurean physician. The evidence we have for his doctrine, and the authority which was accorded him by later writers, clearly attests to his status as an independent and innovative thinker in his own right. While Asclepiades' theory must, in my view, be analysed within the context of the Epicurean atomistic tradition, it must equally be acknowledged that any identifiable relationship between Epicurus and Asclepiades is likely to be one of considerable complexity.
In this paper I shall attempt to explore further the nature of the relationship between Epicurus and Asclepiades by examining some aspects of the latter's theory of matter. Given the widespread disagreement about his theory in general, I propose to focus on a fundamental question which I believe the extant evidence allows us to answer with a satisfactory degree of certainty, namely what Asclepiades' position was on the qualitative status of his onkoi. In Section I I shall analyse four passages which have a direct bearing on this question, from Caelius Aurelianus, Galen, Sextus Empiricus, and Calcidius respectively. I shall argue here that this position was in its details substantially the same as Epicurus' with regard to his atoms. It must be stressed that it is only in details that we can make such comparisons, since we have no surviving testimony which recounts Asclepiades' arguments or broader reasons for holding such a position. Nevertheless, in Section II I shall argue that these identifiable similarities in their respective doctrines on the qualities of their elements were more than superficial or incidental, and strongly suggest that Asclepiades and Epicurus shared certain premisses which were fundamental to their physics, which might then be used to contextualize and elucidate some of the more idiosyncratic and apparently unique parts of Asclepiades' system. This will lead me to suggest an interpretation of an important piece of evidence which may confirm that Asclepiades was reacting in a direct and critical way to certain aspects of Epicurus' physical doctrine.
PMCID: PMC2977080  PMID: 21076682
8.  Development and standardization of Mysore Tridosha scale 
Ayu  2011;32(3):308-314.
The authors have developed a personality scale to assess Tridoshas i.e. Vata, Pitta, and Kapha from psychological perspective in human beings. The Tridoshas are composed of the Pancha Mahabhutas, but one or the other Dosha is dominant singularly or in combination. There can never be a state when one or the other Pancha Mahabhutas and consequently the Tridoshas are absent totally. All five are essential to sustain life. Vata Dosha is composed of Akasa and Vayu Mahabhuta. Pitta Dosha is composed of Tejas or Agni and Ap Mahabhuta. Kapha Dosha is composed of Ap and Prithvi Mahabhuta. Although Tridosha is studied, understood, and applied in Ayurveda, the present authors have tried to validate the same from the domain of psychology. Since the authors are not from the domain of Ayurveda but of Psychology, there are some constructs that are not amenable for psychological testing which have been ignored. Only those constructs that can be used by psychologists to assess the psychological aspects of the Dosha Prakriti have been used to build items for the assessment of personality. In this process, the psychometric properties of the scale are established. The scale assesses the psychological manifestation of the Tridoshas, which was the basic objective. The standardization procedure involved in the development of the Mysore Psychological Tridosha Scale is herewith delineated.
doi:10.4103/0974-8520.93905
PMCID: PMC3326873  PMID: 22529642
Ayurveda; Kapha; Pitta; personality assessment; psychometric scale; Tridosha; Vata
9.  Questioning the preclinical paradigm: natural, extreme biology as an alternative discovery platform 
Aging (Albany NY)  2014;6(11):913-920.
The pace at which science continues to advance is astonishing. From cosmology, microprocessors, structural engineering, and DNA sequencing our lives are continually affected by science-based technology. However, progress in treating human ailments, especially age-related conditions such as cancer and Alzheimer's disease, moves at a relative snail's pace. Given that the amount of investment is not disproportionately low, one has to question why our hopes for the development of efficacious drugs for such grievous illnesses have been frustratingly unrealized. Here we discuss one aspect of drug development –rodent models – and propose an alternative approach to discovery research rooted in evolutionary experimentation. Our goal is to accelerate the conversation around how we can move towards more translative preclinical work.
PMCID: PMC4276785  PMID: 25553771
preclinical models; extremophiles; grizzly bear; insulin sensitivity; obesity; cardiac function; naked mole-rat; aging; cancer resistance
10.  Control of the conformations of ion Coulomb crystals in a Penning trap 
Nature Communications  2013;4:2571.
Laser-cooled atomic ions form ordered structures in radiofrequency ion traps and in Penning traps. Here we demonstrate in a Penning trap the creation and manipulation of a wide variety of ion Coulomb crystals formed from small numbers of ions. The configuration can be changed from a linear string, through intermediate geometries, to a planar structure. The transition from a linear string to a zigzag geometry is observed for the first time in a Penning trap. The conformations of the crystals are set by the applied trap potential and the laser parameters, and agree with simulations. These simulations indicate that the rotation frequency of a small crystal is mainly determined by the laser parameters, independent of the number of ions and the axial confinement strength. This system has potential applications for quantum simulation, quantum information processing and tests of fundamental physics models from quantum field theory to cosmology.
Ion traps form the core of many studies of fundamental physics and are a possible route to quantum computation. Using a Penning trap, Mavadia et al. demonstrate the formation and control of different configurations of ion Coulomb crystals, which may be useful for future ion-based applications.
doi:10.1038/ncomms3571
PMCID: PMC3806409  PMID: 24096901
11.  Insights into the Management of Emerging Infections: Regulating Variant Creutzfeldt-Jakob Disease Transfusion Risk in the UK and the US 
PLoS Medicine  2006;3(10):e342.
Background
Variant Creutzfeldt-Jakob disease (vCJD) is a human prion disease caused by infection with the agent of bovine spongiform encephalopathy. After the recognition of vCJD in the UK in 1996, many nations implemented policies intended to reduce the hypothetical risk of transfusion transmission of vCJD. This was despite the fact that no cases of transfusion transmission had yet been identified. In December 2003, however, the first case of vCJD in a recipient of blood from a vCJD-infected donor was announced. The aim of this study is to ascertain and compare the factors that influenced the motivation for and the design of regulations to prevent transfusion transmission of vCJD in the UK and US prior to the recognition of this case.
Methods and Findings
A document search was conducted to identify US and UK governmental policy statements and guidance, transcripts (or minutes when transcripts were not available) of scientific advisory committee meetings, research articles, and editorials published in medical and scientific journals on the topic of vCJD and blood transfusion transmission between March 1996 and December 2003. In addition, 40 interviews were conducted with individuals familiar with the decision-making process and/or the science involved. All documents and transcripts were coded and analyzed according to the methods and principles of grounded theory. Data showed that while resulting policies were based on the available science, social and historical factors played a major role in the motivation for and the design of regulations to protect against transfusion transmission of vCJD. First, recent experience with and collective guilt resulting from the transfusion-transmitted epidemics of HIV/AIDS in both countries served as a major, historically specific impetus for such policies. This history was brought to bear both by hemophilia activists and those charged with regulating blood products in the US and UK. Second, local specificities, such as the recall of blood products for possible vCJD contamination in the UK, contributed to a greater sense of urgency and a speedier implementation of regulations in that country. Third, while the results of scientific studies played a prominent role in the construction of regulations in both nations, this role was shaped by existing social and professional networks. In the UK, early focus on a European study implicating B-lymphocytes as the carrier of prion infectivity in blood led to the introduction of a policy that requires universal leukoreduction of blood components. In the US, early focus on an American study highlighting the ability of plasma to serve as a reservoir of prion infectivity led the FDA and its advisory panel to eschew similar measures.
Conclusions
The results of this study yield three important theoretical insights that pertain to the global management of emerging infectious diseases. First, because the perception and management of disease may be shaped by previous experience with disease, especially catastrophic experience, there is always the possibility for over-management of some possible routes of transmission and relative neglect of others. Second, local specificities within a given nation may influence the temporality of decision making, which in turn may influence the choice of disease management policies. Third, a preference for science-based risk management among nations will not necessarily lead to homogeneous policies. This is because the exposure to and interpretation of scientific results depends on the existing social and professional networks within a given nation. Together, these theoretical insights provide a framework for analyzing and anticipating potential conflicts in the international management of emerging infectious diseases. In addition, this study illustrates the utility of qualitative methods in investigating research questions that are difficult to assess through quantitative means.
A qualitative study of US and UK governmental policy statements on the topic of vCJD and blood transfusion transmission identified factors responsible for differences in the policies adopted.
Editors' Summary
Background.
In 1996 in the UK, a new type of human prion disease was seen for the first time. This is now known as variant Creutzfeldt-Jakob disease (vCJD). Prion diseases are rare brain diseases passed from individual to individual (or between animals) by a particular type of wrongly folded protein, and they are fatal. It was suspected that vCJD had passed to humans from cattle, and that the agent causing vCJD was the same as that causing bovine spongiform encephalopathy (or “mad cow disease”). Shortly after vCJD was recognized, authorities in many countries became concerned about the possibility that it could be transmitted from one person to another through contaminated blood supplies used for transfusion in hospitals. Even though there wasn't any evidence of actual transmission of the disease through blood before December 2003, authorities in the UK, US, and elsewhere set up regulations designed to reduce the chance of that happening. At this early stage in the epidemic, there was little in the way of scientific information about the transmission properties of the disease. Both the UK and US, however, sought to make decisions in a scientific manner. They made use of evidence as it was being produced, often before it had been published. Despite this, the UK and US decided on very different changes to their respective regulations on blood donation. Both countries chose to prevent certain people (who they thought would be at greater risk of having vCJD) from donating blood. In the UK, however, the decision was made to remove white blood cells from donated blood to reduce the risk of transmitting vCJD, while the US decided that such a step was not merited by the evidence.
Why Was This Study Done?
This researcher wanted to understand more clearly why the UK and US ended up with different policies: what role was played by science, and what role was played by non-scientific factors? She hoped that insights from this investigation would also be relevant to similar challenges in the future—for example, as many countries try to work out how to control the threat of avian flu.
What Did the Researcher Do and Find?
The researcher searched for all relevant official government documents from the US and UK, as well as scientific papers, published between the time vCJD was first identified (March 1996) and the first instance of vCJD carried through blood (December 2003). She also interviewed people who knew about vCJD management in the US and UK—for example, members of government agencies and the relevant advisory committees. From the documents and interviews, the researcher picked out and grouped shared ideas. Although these documents and interviews suggested that policy making was rooted in scientific evidence, many non-scientific factors were also important. The researcher found substantial uncertainty in the scientific evidence available at the time. The document search and interviews showed that policy makers felt guilty about a previous experience in which people had become infected with HIV/AIDS through contaminated blood and were concerned about repeating this experience. Finally, in the UK, the possibility of blood contamination was seen as a much more urgent problem than in the US, because BSE and vCJD were found there first and there were far more cases. This meant that when the UK made its decision about whether to remove white blood cells from donated blood, there was less scientific evidence available. In fact, the main study that was relied on at the time would later be questioned.
What Do These Findings Mean?
These findings show that for this particular case, science was not the only factor affecting government policies. Historical and social factors such as previous experience, sense of urgency, public pressure, and the relative importance of different scientific networks were also very important. The study predicts that in the future, infectious disease–related policy decisions are unlikely to be the same across different countries because the interpretation of scientific evidence depends, to a large extent, on social factors.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030342.
National Creutzfeldt-Jakob Disease Surveillance Unit, Edinburgh, UK
US Centers for Disease Control and Prevention pages about prion diseases
World Health Organization variant Creutzfeldt-Jakob disease fact sheet
US National Institute of Neurological Disorders and Stroke information about prion diseases
doi:10.1371/journal.pmed.0030342
PMCID: PMC1621089  PMID: 17076547
12.  Promotional Tone in Reviews of Menopausal Hormone Therapy After the Women's Health Initiative: An Analysis of Published Articles 
PLoS Medicine  2011;8(3):e1000425.
Adriane Fugh-Berman and colleagues analyzed a selection of published opinion pieces on hormone therapy and show that there may be a connection between receiving industry funding for speaking, consulting, or research and the tone of such opinion pieces.
Background
Even after the Women's Health Initiative (WHI) found that the risks of menopausal hormone therapy (hormone therapy) outweighed benefit for asymptomatic women, about half of gynecologists in the United States continued to believe that hormones benefited women's health. The pharmaceutical industry has supported publication of articles in medical journals for marketing purposes. It is unknown whether author relationships with industry affect promotional tone in articles on hormone therapy. The goal of this study was to determine whether promotional tone could be identified in narrative review articles regarding menopausal hormone therapy and whether articles identified as promotional were more likely to have been authored by those with conflicts of interest with manufacturers of menopausal hormone therapy.
Methods and Findings
We analyzed tone in opinion pieces on hormone therapy published in the four years after the estrogen-progestin arm of the WHI was stopped. First, we identified the ten authors with four or more MEDLINE-indexed reviews, editorials, comments, or letters on hormone replacement therapy or menopausal hormone therapy published between July 2002 and June 2006. Next, we conducted an additional search using the names of these authors to identify other relevant articles. Finally, after author names and affiliations were removed, 50 articles were evaluated by three readers for scientific accuracy and for tone. Scientific accuracy was assessed based on whether or not the findings of the WHI were accurately reported using two criteria: (1) Acknowledgment or lack of denial of the risk of breast cancer diagnosis associated with hormone therapy, and (2) acknowledgment that hormone therapy did not benefit cardiovascular disease endpoints. Determination of promotional tone was based on the assessment by each reader of whether the article appeared to promote hormone therapy. Analysis of inter-rater consistency found moderate agreement for scientific accuracy (κ = 0.57) and substantial agreement for promotional tone (κ = 0.65). After discussion, readers found 86% of the articles to be scientifically accurate and 64% to be promotional in tone. Themes that were common in articles considered promotional included attacks on the methodology of the WHI, arguments that clinical trial results should not guide treatment for individuals, and arguments that observational studies are as good as or better than randomized clinical trials for guiding clinical decisions. The promotional articles we identified also implied that the risks associated with hormone therapy have been exaggerated and that the benefits of hormone therapy have been or will be proven. Of the ten authors studied, eight were found to have declared payment for speaking or consulting on behalf of menopausal hormone manufacturers or for research support (seven of these eight were speakers or consultants). Thirty of 32 articles (90%) evaluated as promoting hormone therapy were authored by those with potential financial conflicts of interest, compared to 11 of 18 articles (61%) by those without such conflicts (p = 0.0025). Articles promoting the use of menopausal hormone therapy were 2.41 times (95% confidence interval 1.49–4.93) as likely to have been authored by authors with conflicts of interest as by authors without conflicts of interest. In articles from three authors with conflicts of interest some of the same text was repeated word-for-word in different articles.
Conclusion
There may be a connection between receiving industry funding for speaking, consulting, or research and the publication of promotional opinion pieces on menopausal hormone therapy.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Over the past three decades, menopausal hormones have been heavily promoted for preventing disease in women. However, the Women's Health Initiative (WHI) study—which enrolled more than 26,000 women in the US and which was published in 2004—found that estrogen-progestin and estrogen-only formulations (often prescribed to women around the age of menopause) increased the risk of stroke, deep vein thrombosis, dementia, and incontinence. Furthermore, this study found that the estrogen-progestin therapy increased rates of breast cancer. In fact, the estrogen-progestin arm of the WHI study was stopped in 2002 due to harmful findings, and the estrogen-only arm was stopped in 2004, also because of harmful findings. In addition, the study also found that neither therapy reduced cardiovascular risk or markedly benefited health-related quality of life measures.
Despite these results, two years after the results of WHI study were published, a survey of over 700 practicing gynecologists—the specialists who prescribe the majority of menopausal hormone therapies—in the US found that almost half did not find the findings of the WHI study convincing and that 48% disagreed with the decision to stop the trial early. Furthermore, follow-up surveys found similar results.
Why Was This Study Done?
It is unclear why gynecologists and other physicians continue to prescribe menopausal hormone therapies despite the results of the WHI. Some academics argue that published industry-funded reviews and commentaries may be designed to convey specific, but subtle, marketing messages and several academic analyses have used internal industry documents disclosed in litigation cases. So this study was conducted to investigate whether hormone therapy–promoting tone could be identified in narrative review articles and if so, whether these articles were more likely to have been authored by people who had accepted funding from hormone manufacturers.
What Did the Researchers Do and Find?
The researchers conducted a comprehensive literature search that identified 340 relevant articles published between July 2002 and June 2006—the four years following the cessation of the estrogen-progestin arm of the women's health initiative study. Ten authors had published four to six articles, 47 authored two or three articles, and 371 authored one article each. The researchers focused on authors who had published four or more articles in the four-year period under study and, after author names and affiliations were removed, 50 articles were evaluated by three readers for scientific accuracy and for tone. After individually analyzing a batch of articles, the readers met to provide their initial assessments, to discuss them, and to reach consensus on tone and scientific accuracy. Then after the papers were evaluated, each author was identified and the researchers searched for authors' potential financial conflicts of interest, defined as publicly disclosed information that the authors had received payment for research, speaking, or consulting on behalf of a manufacturer of menopausal hormone therapy.
Common themes in the 50 articles included arguments that clinical trial results should not guide treatment for individuals and suggestions that the risks associated with hormone therapy have been exaggerated and that the benefits of hormone therapy have been or will be proven. Furthermore, of the ten authors studied, eight were found to have received payment for research, speaking or consulting on behalf of menopause hormone manufacturers, and 30 of 32 articles evaluated as promoting hormone therapy were authored by those with potential financial conflicts of interest. Articles promoting the use of menopausal hormone therapy were more than twice as likely to have been written by authors with conflicts of interest as by authors without conflicts of interest. Furthermore, Three authors who were identified as having financial conflicts of interest were authors on articles where sections of their previously published articles were repeated word-for-word without citation.
What Do These Findings Mean?
The findings of this study suggest that there may be a link between receiving industry funding for speaking, consulting, or research and the publication of apparently promotional opinion pieces on menopausal hormone therapy. Furthermore, such publications may encourage physicians to continue prescribing these therapies to women of menopausal age. Therefore, physicians and other health care providers should interpret the content of review articles with caution. In addition, medical journals should follow the International Committee of Medical Journal Editors Uniform Requirements for Manuscripts, which require that all authors submit signed statements of their participation in authorship and full disclosure of any conflicts of interest.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000425.
The US National Heart, Lung, and Blood Institute has more information on the Womens Health Initiative
The US National Institutes of Health provide more information about the effects of menopausal hormone replacement therapy
The Office of Women's Health, U.S. Department of Health and Human Services provides information on menopausal hormone therapy
The International Committee of Medical Journal Editors Uniform Requirements for Manuscripts presents Uniform Requirements for Manuscripts published in biomedical journals
The National Womens Health Network, a consumer advocacy group that takes no industry money, has factsheets and articles about menopausal hormone therapy
PharmedOut, a Georgetown University Medical Center project, has many resources on pharmaceutical marketing practices
doi:10.1371/journal.pmed.1000425
PMCID: PMC3058057  PMID: 21423581
13.  THE ANCIENT MAN AND HIS FEW CONCEPTS PERTAINING TO DRUGS AND COSMOLOGY 
Ancient Science of Life  1985;5(2):98-103.
In this paper the author attempts to trace the ancient man and his conceptualism of drugs and cosmology by interpreting various classical texts related to that field.
PMCID: PMC3331453  PMID: 22557507
14.  The Emergence of Environmental Homeostasis in Complex Ecosystems 
PLoS Computational Biology  2013;9(5):e1003050.
The Earth, with its core-driven magnetic field, convective mantle, mobile lid tectonics, oceans of liquid water, dynamic climate and abundant life is arguably the most complex system in the known universe. This system has exhibited stability in the sense of, bar a number of notable exceptions, surface temperature remaining within the bounds required for liquid water and so a significant biosphere. Explanations for this range from anthropic principles in which the Earth was essentially lucky, to homeostatic Gaia in which the abiotic and biotic components of the Earth system self-organise into homeostatic states that are robust to a wide range of external perturbations. Here we present results from a conceptual model that demonstrates the emergence of homeostasis as a consequence of the feedback loop operating between life and its environment. Formulating the model in terms of Gaussian processes allows the development of novel computational methods in order to provide solutions. We find that the stability of this system will typically increase then remain constant with an increase in biological diversity and that the number of attractors within the phase space exponentially increases with the number of environmental variables while the probability of the system being in an attractor that lies within prescribed boundaries decreases approximately linearly. We argue that the cybernetic concept of rein control provides insights into how this model system, and potentially any system that is comprised of biological to environmental feedback loops, self-organises into homeostatic states.
Author Summary
Life on Earth is perhaps greater than three and a half billion years old and it would appear that once it started it never stopped. During this period a number of dramatic shocks and drivers have affected the Earth. These include the impacts of massive asteroids, runaway climate change and increases in brightness of the Sun. Has life on Earth simply been lucky in withstanding such perturbations? Are there any self-regulating or homeostatic processes operating in the Earth system that would reduce the severity of such perturbations? If such planetary processes exist, to what extent are they the result of the actions of life? In this study, we show how the regulation of environmental conditions can emerge as a consequence of life's effects. If life is both affected by and affects it environment, then this coupled system can self-organise into a robust control system that was first described during the early cybernetics movement around the middle of the twentieth century. Our findings are in principle applicable to a wide range of real world systems - from microbial mats to aquatic ecosystems up to and including the entire biosphere.
doi:10.1371/journal.pcbi.1003050
PMCID: PMC3656095  PMID: 23696719
15.  A LAGUERRE VORONOI BASED SCHEME FOR MESHING PARTICLE SYSTEMS 
We present Laguerre Voronoi based subdivision algorithms for the quadrilateral and hexahedral meshing of particle systems within a bounded region in two and three dimensions, respectively. Particles are smooth functions over circular or spherical domains. The algorithm first breaks the bounded region containing the particles into Voronoi cells that are then subsequently decomposed into an initial quadrilateral or an initial hexahedral scaffold conforming to individual particles. The scaffolds are subsequently refined via applications of recursive subdivision (splitting and averaging rules). Our choice of averaging rules yield a particle conforming quadrilateral/hexahedral mesh, of good quality, along with being smooth and differentiable in the limit. Extensions of the basic scheme to dynamic re-meshing in the case of addition, deletion, and moving particles are also discussed. Motivating applications of the use of these static and dynamic meshes for particle systems include the mechanics of epoxy/glass composite materials, bio-molecular force field calculations, and gas hydrodynamics simulations in cosmology
doi:10.1007/BF03167436
PMCID: PMC2865151  PMID: 20454544
circle and sphere Voronoi diagrams; subdivision; dynamic re-meshing; astrophysics; biophysics; composite materials
16.  What Can We Conclude from Death Registration? Improved Methods for Evaluating Completeness 
PLoS Medicine  2010;7(4):e1000262.
Julie Rajaratnam and colleagues evaluate the performance of a suite of demographic methods that estimate the fraction of deaths registered and counted by civil registration systems, and identify three variants that generally perform the best.
Background
One of the fundamental building blocks for determining the burden of disease in populations is to reliably measure the level and pattern of mortality by age and sex. Where well-functioning registration systems exist, this task is relatively straightforward. Results from many civil registration systems, however, remain uncertain because of a lack of confidence in the completeness of death registration. Incomplete registration systems mean not all deaths are counted, and resulting estimates of death rates for the population are then underestimated. Death distribution methods (DDMs) are a suite of demographic methods that attempt to estimate the fraction of deaths that are registered and counted by the civil registration system. Although widely applied and used, the methods have at least three types of limitations. First, a wide range of variants of these methods has been applied in practice with little scientific literature to guide their selection. Second, the methods have not been extensively validated in real population conditions where violations of the assumptions of the methods most certainly occur. Third, DDMs do not generate uncertainty intervals.
Methods and Findings
In this paper, we systematically evaluate the performance of 234 variants of DDM methods in three different validation environments where we know or have strong beliefs about the true level of completeness of death registration. Using these datasets, we identify three variants of the DDMs that generally perform the best. We also find that even these improved methods yield uncertainty intervals of roughly ± one-quarter of the estimate. Finally, we demonstrate the application of the optimal variants in eight countries.
Conclusions
There continues to be a role for partial vital registration data in measuring adult mortality levels and trends, but such results should only be interpreted alongside all other data sources on adult mortality and the uncertainty of the resulting levels, trends, and age-patterns of adult death considered.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Accurate worldwide information on the levels and patterns of mortality (deaths) is essential for planning and monitoring global public-health initiatives. The gold standard method for collecting such information is death registration. In high-income countries, death registration is effectively 100% complete, but the situation in many developing countries is very different. In most African countries, for example, less than one-quarter of deaths are officially recorded. Although other data sources such as household surveys can be used to estimate mortality levels in such countries, partial registration data could provide useful information about mortality levels in developing countries if its completeness could be evaluated. One way to do this is to use demographic methods called “death distribution methods” (DDMs). Demography is the study of the size, growth, and other characteristics of human populations; DDMs compare the age distribution of recorded deaths (the relative proportion of deaths in each age group) with the age distribution of the population in which they occurred to provide a correction factor that can be used to calculate corrected mortality levels from registered deaths. DDMs are used by the World Health Organization to monitor adult mortality in nearly 100 countries.
Why Was This Study Done?
Although widely used, few studies have compared the performance of the many available DDM variants, and DDMs have not been extensively validated by testing them in populations for which the completeness of death registration is known. In addition, because DDMs are mathematical in nature, they do not provide any indication of the uncertainty associated with the correction factors they yield. This means that public-health officials using estimates of mortality levels generated from partial registration data using DDMs have no idea of the limits between which the true mortality levels of their populations lie. In this study, the researchers systematically evaluate the performance of 234 DDM variants and use the optimal variants that they identify to analyze registration completeness over time in six developing countries.
What Did the Researchers Do and Find?
The researchers constructed 234 DDM variants by combining each of three general types of DDMs with 78 different “age trims”; demographers often age-trim—drop older and/or younger age groups—when using DDMs to estimate correction factors for observed death rates. The researchers then evaluated the performance of the variants in three “validation” datasets for which the completeness of death registration is known—a microsimulation of a population of 10 million people followed for 150 years, population data from US counties between 1990 and 2000, and population data from high-income OECD (Organisation for Economic Co-operation and Development) countries with populations of more than 5 million between 1950 and 2000. Detailed analyses of the performance of the DDM variants with all three datasets identified three optimal DDMs, one of each type. However, even with these optimal DDMs, the uncertainty intervals associated with estimates of relative completeness of registration were roughly +/− one-quarter of the estimate. Finally, the researchers applied their optimal DDMs to six developing countries over time. This analysis showed that death registration for adults has been relatively complete since 1970 in Mexico, for example, whereas in Tunisia, death registration has improved from nearly 50% in 1965 to complete by 1980. It also indicated that the three DDMs can give consistent results in some contexts.
What Do These Findings Mean?
By using multiple validation databases, these findings identify three optimal DDMs for the estimation of completeness of death registration. The researchers recommend that analysts apply all three methods when estimating the completeness of death registration data and look at the consistency of the results produced. They warn that the level of uncertainty associated with the estimation of completeness of registration means that results yielded by DDMs should be interpreted with considerable caution. In particular, they note that although correction factors provided by DDMs may be a good way of estimating mortality levels, the uncertainty in these factors may make them unsuitable for analyzing trends over time in mortality levels. Overall, the researchers conclude that partial death registration data have a role to play in measuring adult mortality levels, provided that they are analyzed alongside other data sources.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000262.
This study and two related PLoS Medicine Research Articles—by Obermeyer et al. and by Rajaratnam et al. —are further discussed in a PLoS Medicine Perspective by Mathers and Boerma
The Institute for Health Metrics and Evaluation makes available high-quality information on population health, its determinants, and the performance of health systems
Grand Challenges in Global Health provides information on research into better ways for developing countries to measure their health status
The World Health Organization Statistical Information System (WHOSIS) is an interactive database that brings together core health statistics for WHO member states, including information on vital registration of deaths; the WHO Health Metrics Network is a global collaboration focused on improving sources of vital statistics
doi:10.1371/journal.pmed.1000262
PMCID: PMC2854130  PMID: 20405002
17.  I love you with all my brain: laying aside the intellectually dull sword of biological determinism 
Background
By organizing and activating our passions with both hormones and experiences, the heart and mind of sexual behavior, sexual motivation, and sexual preference is the brain, the organ of learning. Despite decades of progress, this incontrovertible truth is somehow lost in the far-too-often biologically deterministic interpretation of genetic, hormonal, and anatomical scientific research into the biological origins of sexual motivation. Simplistic and polarized arguments are used in the media by both sides of the seemingly endless debate over sexual orientation, equality, and human rights with such catch phrases as ‘born gay’ contrasted against attempts of “reparative therapy” or “pray the gay away”. Though long abandoned in practically every other area of psychology, this remnant of the nature-nurture controversy remains despite its generally acknowledged insufficiency in explaining any adult aspect of the human condition within the scientific community.
Methods
This theoretical review article identifies three factors: 1) good intentions with regard to the argument from immutability; 2) false dichotomies limiting intellectual progress by oversimplification of theory and thus hypothesis, and most dangerously, interpretation and; 3) Tradition: a historical separation of the disciplines of biology and psychology, which, to this day, interferes with the effective translation of well-conducted science into good public understanding and policy.
Results
Studies clearly demonstrate that progress toward sexual-orientation equality is being made, if slowly, despite the apparent irrelevance of the “born gay” argument from immutability. Evidence is further provided supporting the inadequacy of polarized, dichotic theories of sexual development, particularly those pitting “blank slate learning” against a fated, deterministic biological perspective. Results of this review suggest that an emerging interactionist perspective will promote both better scientific progress and better public understanding, hopefully contributing to progress toward nondiscriminatory public policy.
Conclusion
Accepting that the brain is a highly plastic, modularly dimorphic, developmentally biased organ of learning, one which is organized and activated by both hormones and experiences across the lifespan, is essential for doing “good science” well. Interactionist theories of psychosexual development provide an empirically sound, strong, yet modifiable foundation for testable hypotheses exploring biologically biased sexual learning.
doi:10.3402/snp.v2i0.17334
PMCID: PMC3960069  PMID: 24693345
Brain; conditioning; controversy; dichotomy; differentiation; discrimination; equality; sex; sexual; orientation; learning; learned sexuality; born gay; hedonic evaluation; immutability; imprinting; incentive motivation; interactionism; predispositions; theory; therapy
18.  “Working the System”—British American Tobacco's Influence on the European Union Treaty and Its Implications for Policy: An Analysis of Internal Tobacco Industry Documents 
PLoS Medicine  2010;7(1):e1000202.
Katherine Smith and colleagues investigate the ways in which British American Tobacco influenced the European Union Treaty so that new EU policies advance the interests of major corporations, including those that produce products damaging to health.
Background
Impact assessment (IA) of all major European Union (EU) policies is now mandatory. The form of IA used has been criticised for favouring corporate interests by overemphasising economic impacts and failing to adequately assess health impacts. Our study sought to assess how, why, and in what ways corporations, and particularly the tobacco industry, influenced the EU's approach to IA.
Methods and Findings
In order to identify whether industry played a role in promoting this system of IA within the EU, we analysed internal documents from British American Tobacco (BAT) that were disclosed following a series of litigation cases in the United States. We combined this analysis with one of related literature and interviews with key informants. Our analysis demonstrates that from 1995 onwards BAT actively worked with other corporate actors to successfully promote a business-oriented form of IA that favoured large corporations. It appears that BAT favoured this form of IA because it could advance the company's European interests by establishing ground rules for policymaking that would: (i) provide an economic framework for evaluating all policy decisions, implicitly prioritising costs to businesses; (ii) secure early corporate involvement in policy discussions; (iii) bestow the corporate sector with a long-term advantage over other actors by increasing policymakers' dependence on information they supplied; and (iv) provide businesses with a persuasive means of challenging potential and existing legislation. The data reveal that an ensuing lobbying campaign, largely driven by BAT, helped secure binding changes to the EU Treaty via the Treaty of Amsterdam that required EU policymakers to minimise legislative burdens on businesses. Efforts subsequently focused on ensuring that these Treaty changes were translated into the application of a business orientated form of IA (cost–benefit analysis [CBA]) within EU policymaking procedures. Both the tobacco and chemical industries have since employed IA in apparent attempts to undermine key aspects of European policies designed to protect public health.
Conclusions
Our findings suggest that BAT and its corporate allies have fundamentally altered the way in which all EU policy is made by making a business-oriented form of IA mandatory. This increases the likelihood that the EU will produce policies that advance the interests of major corporations, including those that produce products damaging to health, rather than in the interests of its citizens. Given that the public health community, focusing on health IA, has largely welcomed the increasing policy interest in IA, this suggests that urgent consideration is required of the ways in which IA can be employed to undermine, as well as support, effective public health policies.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The primary goal of public health, the branch of medicine concerned with the health of communities, is to improve lives by preventing disease. Public-health groups do this by assessing and monitoring the health of communities, by ensuring that populations have access to appropriate and cost-effective health care, and by helping to formulate public policies that safeguard human health. Until recently, most of the world's major public-health concerns related to infectious diseases. Nowadays, however, many major public-health concerns are linked to the goods made and marketed by large corporations such as fast food, alcohol, tobacco, and chemicals. In Europe, these corporations are regulated by policies drawn up both by member states and by the European Commission, the executive organ of the European Union (EU; an economic and political partnership among 27 democratic European countries). Thus, for example, the tobacco industry, which is widely recognized as a driver of the smoking epidemic, is regulated by Europe-wide tobacco control policies and member state level policies.
Why Was This Study Done?
Since 1997, the European Commission has been required by law to assess the economic, social (including health), and environmental consequences of new policy initiatives using a process called an “impact assessment” (IA). Because different types of IA examine the likely effects of policies on different aspects of daily life—a health impact assessment, for example, focuses on a policy's effect on health—the choice of IA can lead to different decisions being taken about new policies. Although the IA tool adopted by the European Commission aims to assess economic, environmental and social impacts, independent experts suggest this tool does not adequately assess health impacts. Instead, economic impacts receive the most attention, a situation that may favour the interests of large businesses. In this study, the researchers seek to identify how and why the EU's approach to IA developed. More specifically, the researchers analyze internal documents from British American Tobacco (BAT), which have been disclosed because of US litigation cases, to find out whether industry has played a role in promoting the EU's system of IA.
What Did the Researchers Do and Find?
The researchers analyzed 714 BAT internal documents (identified by searching the Legacy Tobacco Documents Library, which contains more than 10 million internal tobacco company documents) that concerned attempts made by BAT to influence regulatory reforms in Europe. They also analyzed related literature from other sources (for example, academic publications) and interviewed 16 relevant people (including people who had worked at the European Commission). This analysis shows that from 1995, BAT worked with other businesses to promote European regulatory reforms (in particular, the establishment of a business-orientated form of IA) that favor large corporations. A lobbying campaign, initiated by BAT but involving a “policy network” of other companies, first helped to secure binding changes to the EU Treaty that require policymakers to minimize legislative burdens on businesses. The analysis shows that after achieving this goal, which BAT described as an “important victory,” further lobbying ensured that these treaty changes were translated into the implementation of a business-orientated form of IA within the EU. Both the tobacco industry and the chemical industry, the researchers argue, have since used the IA to delay and/or weaken EU legislation intended to protect public health.
What Do These Findings Mean?
These findings suggest that BAT and its corporate allies have fundamentally altered the way in which EU policy is made by ensuring that all significant EU policy decisions have to be assessed using a business-orientated IA. As the authors note, this situation increases the likelihood that the EU will produce policies that favor big business rather than the health of its citizens. Furthermore, these findings suggest that by establishing a network of other industries to help in lobbying for EU Treaty changes, BAT was able to distance itself from the push to establish a business-orientated IA to the extent that Commission officials were unaware of the involvement of the tobacco industry in campaigns for IA. Thus, in future, to safeguard public health, policymakers and public-health groups must pay more attention to corporate efforts to shape decision-making processes. In addition, public-health groups must take account of the ways in which IA can be used to undermine as well as support effective public-health policies and they must collaborate more closely in their efforts to ensure effective national and international policy.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/0.1371/journal.pmed.1000202.
Wikipedia has a page on public health (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
More information on the European Union (in several languages), on public health in the European Union, and on impact assessment by the European Commission is available
The Legacy Tobacco Documents Library is a public, searchable database of tobacco company internal documents detailing their advertising, manufacturing, marketing, sales, and scientific activities
The World Health Organization provides information about the dangers of tobacco (in several languages)
The Smoke Free Partnership contains more information about smoking prevalence in Europe and about European policies to tackle the public health issues associated with tobacco use
For more information about tobacco industry influence on policy see the 2009 World Health Organization report on tobacco industry interference with tobacco control
doi:10.1371/journal.pmed.1000202
PMCID: PMC2797088  PMID: 20084098
19.  GINS motion reveals replication fork progression is remarkably uniform throughout the yeast genome 
Time-resolved ChIP-chip can be utilized to monitor the genome-wide dynamics of the GINS complex, yielding quantitative information on replication fork movement.Replication forks progress at remarkably uniform rates across the genome, regardless of location.GINS progression appears to be arrested, albeit with very low frequency, at sites of highly transcribed genes.Comparison of simulation with data leads to novel biological insights regarding the dynamics of replication fork progression
In mitotic division, cells duplicate their DNA in S phase to ensure that the proper genetic material is passed on to their progeny. This process of DNA replication is initiated from several hundred specific sites, termed origins of replication, spaced across the genome. It is essential for replication to begin only after G1 and finish before the initiation of anaphase (Blow and Dutta, 2005; Machida et al, 2005). To ensure proper timing, the beginning stages of DNA replication are tightly coupled to the cell cycle through the activity of cyclin-dependent kinases (Nguyen et al, 2001; Masumoto et al, 2002; Sclafani and Holzen, 2007), which promote the accumulation of the pre-RC at the origins and initiate replication. Replication fork movement occurs subsequent to the firing of origins on recruitment of the replicative helicase and the other fork-associated proteins as the cell enters S phase (Diffley, 2004). The replication machinery itself (polymerases, PCNA, etc.) trails behind the helicase, copying the newly unwound DNA in the wake of the replication fork.
One component of the pre-RC, the GINS complex, consists of a highly conserved set of paralogous proteins (Psf1, Psf2, Psf3 and Sld5 (Kanemaki et al, 2003; Kubota et al, 2003; Takayama et al, 2003)). Previous work suggests that the GINS complex is an integral component of the replication fork and that its interaction with the genome correlates directly to the movement of the fork (reviewed in Labib and Gambus, 2007). Here, we used the GINS complex as a surrogate to measure features of the dynamics of replication—that is, to determine which origins in the genome are active, the timing of their firing and the rates of replication fork progression.
The timing of origin firing and the rates of fork progression have also been investigated by monitoring nascent DNA synthesis (Raghuraman et al, 2001; Yabuki et al, 2002). Origin firing was observed to occur as early as 14 min into the cell cycle and as late as 44 min (Raghuraman et al, 2001). A wide range of nucleotide incorporation rates (0.5–11 kb/min) were observed, with a mean of 2.9 kb/min (Raghuraman et al, 2001), whereas a second study reported a comparable mean rate of DNA duplication of 2.8±1.0 kb/min (Yabuki et al, 2002). In addition to these observations, replication has been inferred to progress asymmetrically from certain origins (Raghuraman et al, 2001). These data have been interpreted to mean that the dynamics of replication fork progression are strongly affected by local chromatin structure or architecture, and perhaps by interaction with the machineries controlling transcription, repair and epigenetic maintenance (Deshpande and Newlon, 1996; Rothstein et al, 2000; Raghuraman et al, 2001; Ivessa et al, 2003). In this study, we adopted a complementary ChIP-chip approach for assaying replication dynamics, in which we followed GINS complexes as they traverse the genome during the cell cycle (Figure 1). These data reveal that GINS binds to active replication origins and spreads bi-directionally and symmetrically as S phase progresses (Figure 3). The majority of origins appear to fire in the first ∼15 min of S phase. A small fraction (∼10%) of the origins to which GINS binds show no evidence of spreading (category 3 origins), although it remains possible that these peaks represent passively fired origins (Shirahige et al, 1998). Once an active origin fires, the GINS complex moves at an almost constant rate of 1.6±0.3 kb/min. Its movement through the inter-origin regions is consistent with that of a protein complex associated with a smoothly moving replication fork. This progression rate is considerably lower and more tightly distributed than those inferred from previous genome-wide measurements assayed through nascent DNA production (Raghuraman et al, 2001; Yabuki et al, 2002). Our study leads us to a different view of replication fork dynamics wherein fork progression is highly uniform in rate and little affected by genomic location.
In this work, we also observe a large number of low-intensity persistent features at sites of high transcriptional activity (e.g. tRNA genes). We were able to accurately simulate these features by assuming they are the result of low probability arrest of replication forks at these sites, rather than fork pausing (Deshpande and Newlon, 1996). The extremely low frequency of these events in wild-type cells suggests they are due to low probability stochastic occurrences during the replication process. It is hoped that future studies will resolve whether these persistent features indeed represent rare instances of fork arrest, or are the result of some alternative process. These may include, for example, the deposition of GINS complexes (or perhaps more specifically Psf2) once a pause has been resolved.
In this work, we have made extensive use of modeling to test a number of different hypotheses and assumptions. In particular, iterative modeling allowed us to infer that GINS progression is uniform and smooth throughout the genome. We have also demonstrated the potential of simulations for estimating firing efficiencies. In the future, extending such firing efficiency simulations to the whole genome should allow us to make correlations with chromosomal features such as nucleosome occupancy. Such correlations may help in determining factors that govern the probability of replication initiation throughout the genome.
Previous studies have led to a picture wherein the replication of DNA progresses at variable rates over different parts of the budding yeast genome. These prior experiments, focused on production of nascent DNA, have been interpreted to imply that the dynamics of replication fork progression are strongly affected by local chromatin structure/architecture, and by interaction with machineries controlling transcription, repair and epigenetic maintenance. Here, we adopted a complementary approach for assaying replication dynamics using whole genome time-resolved chromatin immunoprecipitation combined with microarray analysis of the GINS complex, an integral member of the replication fork. Surprisingly, our data show that this complex progresses at highly uniform rates regardless of genomic location, revealing that replication fork dynamics in yeast is simpler and more uniform than previously envisaged. In addition, we show how the synergistic use of experiment and modeling leads to novel biological insights. In particular, a parsimonious model allowed us to accurately simulate fork movement throughout the genome and also revealed a subtle phenomenon, which we interpret as arising from low-frequency fork arrest.
doi:10.1038/msb.2010.8
PMCID: PMC2858444  PMID: 20212525
cell cycle; ChIP-chip; DNA replication; replication fork; simulation
20.  THE FATE OF THE GIANT CELLS IN HEALING TUBERCULOUS TISSUE, AS OBSERVED IN A CASE OF HEALING TUBERCULOUS MENINGITIS 
From the foregoing description of the histological changes in the leptomeninx it is quite evident that we are dealing with a chronic, stationary, healing form of tuberculous inflammation. This statement is substantiated, in the first place, by the clinical history. The only reasonable interpretation of the symptoms would establish the duration of the process as four months. The imaginable contingency that there existed first a meningeal syphilitic lesion that was dispersed by the iodide of potassium only to be followed by a tuberculous infection is so remote and unlikely that it need not be discussed. At all events the tuberculous leptomeningitis, which presented a typical distribution, began insidiously, existed at times in a latent condition, and pursued a very anomalous course, marked by a relative mildness of all the symptoms, and thus it came about that when an apparent or real improvement followed the administration of iodide of potassium able observers were induced to make an erroneous diagnosis. Death occurred as a result of an intercurrent infection. The long duration of the process is also shown, anatomically, by the thick layer of firm, translucent and gelatinous material that matted together the structures at the base, and also by the evident adhesions between the pia and the brain. The histological examination furnishes proof positive of the correctness of the conclusion in regard to the peculiar character of this process because it shows: (1) That the tuberculous proliferation is uniform in development and has reached nearly the same stage of evolution throughout the entire extent of the leptomeninx involved; it is not a process that has advanced by exacerbations and irregular extensions; the lesions are, generally speaking, of nearly the same age everywhere and must have begun at about the same time. (2) That only a very limited degree of caseous degeneration is present, pointing to an early arrest of the activity of the tubercle bacillus or to a very decided diminution or attenuation of its virulence. (3) That the subendothelial intimal proliferations of epithelioid cells, so generally found in acute tuberculous leptomeningitis,* have in this case become more or less completely changed into distinct fibrous tissue in which but very slight, if any, direct evidence of its tuberculous origin can be found. It is only by recognizing that the chronic endarteritis is most marked in correspondence with the most advanced adventitial tuberculous changes, and by finding an imperfect, much altered giant cell in one district of intimal thickening, that we were able to establish the direct kinship of the endovascular changes with those of the pia in general. (4) That acute inflammatory changes, in the form of emigration of polymorphonuclear leucocytes and of fibrinous exudation, are entirely absent in all parts of the district involved. The presence of a turbid serous fluid is of course not at all inconsistent with the view that the anatomical changes are of long duration. (5) That the granulation tissue present is, in general, undergoing fibrillation and contains a rich supply of enabryonal capillary vessels as well as of larger blood-vessels of evidently new formation. The absence of any considerable extent of polymorphonuclear leucocytic infiltration in this tissue has already been referred to. The cells in the granulation tissue correspond to the cells of embryonal or formative connective tissue. Vacuolation is rarely present. (6) That the unusually large number of giant cells present are remarkably free from evidences of necrosis and degeneration of the character ordinarily observed in tuberculous proliferations, that they do not contain in demonstrable form tubercle bacilli, and that the majority of the giant cells seem to be separating into individual cells and smaller masses often with, but sometimes also without, evidences of nuclear disintegration. The possibility that these phenomena may signify fusion instead of the sundering of cells will be discussed below. For these reasons there can be no doubt that the general claim that we are dealing with an instance of chronic, healing tuberculous meningitis must be regarded as established beyond dispute. The growth of tubercle bacilli in the glycerine-agar tubes, inoculated with the fluid from the pial meshes, and the demonstration of tubercle bacilli, though in very small numbers, between the cells of the embryonal tissue, furnish the positive evidence that we are actually dealing with a tuberculous process due to living and not to dead bacilli. The degree of virulence of the cultures of tubercle bacilli was, unfortunately perhaps, not studied. The presence of living tubercle bacilli in a tissue free from active and acute changes characteristic of tuberculosis demonstrates that, whatever the actual degree of virulence of the bacilli may have been, the tissue in which they were found was at this time relatively immune from their action. The manner in which this immunity was produced, and in which the process of healing was initiated, need not be discussed at this time any further than to again direct attention to the fact that the bacilli lost their virulency as regards the cells in this leptomeninx before these cells underwent any marked degree of degeneration. The cells of the tuberculous proliferations survived the further action of the bacilli whose original effect it was to initiate cell accumulation or proliferation; the cells also retained sufficient vitality to develop, in some instances at any rate, into formative cells according as their origin would dictate, e. g. into fibroblasts. That fibroblasts are formed only by embryonal connective tissue cells, and not by wandering cells, such as the large mononuclear leucocytes, we are well aware, is possibly still a disputable assumption, and we do not consider it pertinent to discuss the question any further in connection with this study, but would only emphasize the point that some of the cells of tuberculous proliferations may, under favorable circumstances, become formative cells, and, furthermore, that the amount of formative tissue produced may be far in excess of what is actually needed for purposes of repair only. Surely the appearances here noted indicate that the bacillus of tuberculosis has the power to stimulate fixed cells to multiply, unless one assumes that all, or almost all, the formative cells here seen are derived from wandering cells attracted by the presence of the bacillus and its products. As to the ultimate fate of the formative and other cells in this healing tuberculous tissue no final statements can be made. It must be remembered that it is only one stage in the process of healing that is dealt with. The well marked evidences of fibrillation, the quite extensive formation of new vessels, the absence of evidences of degenerative changes in the uninuclear cells, all point to the production of new fibrous tissue as sure to occur, but it seems quite probable that occasional epithelioid cells may undergo or have undergone dropsical or other forms of degeneration, although it is certainly apparent that so far as the small cells are concerned the involution of the tuberculous tissue is not occurring through disintegration. Perhaps the most interesting feature in this case is the opportunity it affords to study the changes in the giant cells of healing, non-degenerated tuberculous tissue. In the first place, the large number of giant cells is quite remarkable. The general characters of the tissue in which they are found recall the fact that giant cells are regarded as quite constant elements in chronic mild tuberculosis; often the giant cells are the only cells that contain bacilli (Koch). In this instance the giant cells do not contain bacilli that are demonstrable by the usual methods; neither do they contain bodies that can be definitely interpreted as degenerate forms of bacilli such as those found by Metchnikoff, Stchastny, Weicker, and others, in the giant cells of Spermophilus guttatus, in avian and in human tuberculosis. Metchnikoff states, however, that he knows of the occurrence of such degenerate forms only in the Spermophilus guttatus under the circumstances mentioned, and in the rabbit and guinea-pig in mammalian tuberculosis, but not in man; consequently, the manner in which the giant cells rid themselves of the bacilli undoubtedly present in their interior at some time during their existence, must as yet remain without any explanation. In the description of the histological changes the various appearances presented by the giant cells are described somewhat minutely. The essential observations made concern, in my opinion, the further fate of giant cells which are still found to persist in healing nondegenerated tuberculous tissue. It was, I believe, quite conclusively shown that the consecutive changes appear to consist in the breaking up of the nuclei, the removal of the detritus by phagocytes, and the formation of a few apparently viable uninuclear cells in the case of more degenerated, exhausted giant cells, while other, and, as it would seem, better preserved or younger giant cells, separate into a number of individual, uninuclear cells with but little or no nuclear disintegration. Objection might be raised to this interpretation of the appearances in the giant cells. While no one could very well dispute the view that part of the giant cells are undergoing retrogressive and absorptive changes with the production of some viable cells, a question might well be raised concerning the nature of the process taking place in those giant cells that have been spoken of as splitting up or dividing into uninuclear cells and smaller multinucleated masses without much evidence of nuclear disintegration. It might be claimed that the process is one of fusion of many cells to form giant cells, and not one of division of fully formed giant cells into small cells. But a broad view of the processes described speaks against fusion. In the first place we are not dealing with a stage of tuberculous proliferation (Baumgarten), or cell accumulation (Metchnikoff), in which one would look for the production of giant cells, no matter which view concerning the histogenesis of tubercle be assumed as the correct one, because it has been demonstrated that, from whichever point of view the lesions are examined, the same positive conclusion that they are in the process of healing is reached; there is, therefore, no occasion for the formation of new giant cells in such wide-spread degree throughout the district involved. It might he claimed that the cells became arrested and, as it were, fixed in the act of fusion which was taking place in the early stage of the meningitis, but it would be difficult to understand the nature of the stimulus that could hold the cells together in such a peculiar manner for such a long time. It must be remembered that bacilli or bacillary detritus could not be found among the incomplete or in the complete giant cells. In the second place the difference between the cells that are undergoing disintegration and those regarded as dividing is essentially, to a certain extent at any rate, one of degree, because in the first instance there is not much, if any, doubt but that viable smaller cells are also formed, and in the second instance some, though often very slight, evidence of nuclear fragmentation is nearly always present; it would also be correct to infer that in advanced subdivision of a giant cell much, and perhaps all, of the nuclear detritus produced might have been removed up to the last trace; finally, the two extremes of these changes in the giant cells are connected by transition stages passing by gradation from the one to the other. Hence it is justifiable to conclude, for the time being, that in healing non-degenerated tuberculous tissue, the multinucleated giant cells may in part disintegrate and undergo absorption, in part form viable small cells; that both these changes may, and usually do, affect the same cell, but that in one class of cells—presumably the older or the more exhausted—the retrogressive process is predominant, while in a second class of cells—presumably the young and vigorous—the progressive changes are the more marked. In this connection it may be pointed out that while there cannot very well be any question but that we are dealing only with dividing and not coalescing cells, yet if this conclusion should be disputed and found incorrect, then the only remaining alternative would be to infer that this tissue furnished a unique and striking example of the formation of plasmodial masses by fusion in human tuberculosis, a conclusion to which many pathologists would refuse to subscribe, if for no other reason than because it is not in accordance with the almost universally accepted teachings of Baumgarten and Weigert in regard to the mode of formation of the giant cells in tuberculosis. Believing as I do that the giant cells under consideration are in the act of division and not at all of fusion, there remain to be discussed some of the histological and other features presented by the dividing cells. Many of the giant cells, perhaps the majority, contain larger and smaller vacuoles in the protoplasm. The exact significance of this vacuolation is not always clear. When the vacuolation accompanies an evident solution of the nucleus (karyolysis), there cannot be any doubt but that we are in the presence of a distinctly retrogressive process. Vacuoles are also most numerous in the giant cells that present other evidences of degeneration, such as coarseness of the granules in the protoplasm and extensive nuclear disintegration, but they occur as well around nuclei that stain deeply, around cells that seem to be separating from the giant cell, and even about nuclei that present mitoses. The formation of vacuoles seems to be responsible, to a certain extent at any rate, for the diminution in the volume of disintegrating and dividing giant cells, as shown by the clear spaces that form about them; these spaces are too large and occur too uniformly to be attributed solely to artificial shrinking produced by the hardening in alcohol. Further undoubted evidence of retrogression in certain giant cells is the occurrence of nuclear disintegration, or karyorhexis, which sets free larger and smaller chromatin masses that are recognized in the giant cell as well as in the interior of the phagocytes usually found around such cells. Almost all the polymorphonuclear leucocytes found in this tissue are met with around giant cells with broken-up nuclei. In many nuclei of disintegrating giant cells can be noted appearances that correspond well to certain stages in the complicated karyorhexis observed in anæmic necrosis by Schmaus and Albrecht; some of the nuclei with budding processes correspond particularly well with those in certain of their drawings; the interior of giant cells of tuberculous tissue may, it would seem, present conditions favorable to the development of this series of postnecrotic nuclear change. Vacuolation, karyolysis and karyorhexis are the essential steps that lead to destruction of the whole or parts of some of the giant cells; associated with these processes there is usually observed a splitting up of the body of the giant cell into irregular fragments with as well as without nuclei; and, as described, more or less phagocytosis of the resulting remnants of various kinds is seen. But evident degenerative and necrotic processes in a giant cell may be associated with progressive changes. While some nuclei undergo vacuolation or break up, others seem to become richer in chromatin and to stain more deeply at the same time that they seem to acquire cell bodies quite distinct from the protoplasm of the giant cells: this hyperchromatosis does not, therefore, seem to be a stage in karyorhexis. A very few but undoubted karyokinetic figures were found, together with evidences of division of the cell body formed in the giant cell protoplasm. Precisely similar changes are described by Klebs in healing pulmonary tuberculosis of the guinea-pig; the nuclei of the giant cells became rich in chromatin and karyokinetic figures occurred. Krückmann among others has found occasional mitoses in giant cells around foreign bodies, as well as elsewhere, but it would seem that such mitoses have always been interpreted as indicating the probable mode of formation of the giant cells rather than of their involution. The question of mitosis in existing multinucleated cells has recently been studied by Krompecher, who concludes that the individual nuclei of such cells may undoubtedly divide by mitosis, either simultaneously or at separate times. Division by amitosis can also occur, but mitosis is the only progressive form of division, amitosis being a retrogressive, disintegrating process that must be looked upon as an evidence of degeneration of the nucleus. Ziegler states that in division of giant cells whose nuclei have multiplied by mitosis it may happen that the separating cell remains enclosed in the protoplasm of the mother cell. A singular phase in the involution of the giant cells in this pia is to be found in the existence of progressive changes side by side with nuclear necrosis and with degeneration; this finding indicates that giant cells may contain many independent elements which, though apparently fused into one large cell, may preserve their individuality so that while some nuclei die, others proliferate and perhaps feed on the remnants of their dead brethren and form new, viable small cells. The nuclei in giant cells may be looked upon as representing independent centres, capable at times of existing even though the cell protoplasm is disintegrated. Many of the giant cells separate into individual cells, unaccompanied or unassociated with much evidence of necrosis. These cells may be regarded as the more vigorous forms. Here also are observed occasional mitoses—but on the whole extremely few—and very constantly an evident increase in the amount of chromatin in the nuclei of the new cells as compared with the amount ordinarily found in the nuclei of giant cells. These deductions concerning the persistence of the vitality of some of the nuclei, even in the presence of molecular and morphological changes in the cytoplasm and in other nuclei of the giant cell that lead to disintegration, are not entirely without the support of previous observations on cells, which, although made under different conditions, are nevertheless, it would seem, applicable to cells in general. Thus the brilliant investigations of Loeb upon the effects of various unfavorable surroundings, such as absence of oxygen or reduction of the amount of water, upon the cleavage of eggs of many kinds, show that the conditions which arrest development are qualitatively alike for nucleus and protoplasm, but quantitatively less for the protoplasm; when the irritability of the protoplasm is suspended the nucleus may segment without segmentation of the protoplasm, but upon re-establishment of favorable conditions the protoplasm may divide into about as many spheres as there are nuclei preformed—the nucleus persists, preserves the irritability of the cell and stimulates the protoplasm to segmentation. From the appearances of the giant cells here described it would seem, then, that some nuclei are able to maintain their vitality longer than others in the same cell, and under certain conditions to stimulate parts of the protoplasm to segment; in other cells all the nuclei have, as a rule, preserved their irritability. The groups of cells formed by the dividing of the giant cells can be traced by studying the process at the different stages in the different parts of the tissue. They assume an oval or spindle-shaped form, becoming more and more like the formative and endothelioid cells of young connective tissue, but their ultimate fate cannot be determined because it concerns essentially only one limited period in the involution of the tissue. It may be said with reasonable certainty, however, that the new cells do not form blood-vessels, but as regards their forming lymph-vessels nothing definite can be concluded. It would not be safe to draw any definite conclusions, from the appearances described, with regard to the origin and the mode of formation of the giant cells. The resulting small cells in general resemble very much endothelial and formative cells, but some of them are, at certain stages at any rate, not unlike large mononuclear leucocytes; their final fully developed or mature condition being unknown, no positive inference can be drawn as to their pre-giant-cell origin. The evidence points to the fact that the most probable origin of the giant cells, as indicated by their form and the apparent future career of their descendants, would be the fixed mesoblastic cells of the pia. In regard to the mode of formation of the giant cells it is quite clear that it must involve some process which is not incompatible with the viability of the small cells which may spring from the giant cells. Whether this would speak more in favor of formation by fusion than by karyokinesis of a single cell without division of the cell body cannot be well determined, and as long as authors are not agreed upon the question of the production of living, procreative cells by amitosis (direct segmentation, direct and indirect fragmentation) it would not be profitable to discuss the compatibility or incompatibility of the views of those investigators who trace the origin of giant cells to amitotic division, with the progressive changes that giant cells have been shown to be capable of. The fact that giant cells in tuberculous tissue, under certain conditions, undergo progressive changes and separate into small, living cells proves that they are not, as claimed by Baumgarten, Weigert and others, necrobiotic elements that are doomed to destruction from their very inception. On the other hand it lends more strength, if that were necessary, to the teleological view urged by Metchnikoff that they are living, defensive cells (whatever their origin may be), formed for the distinct purpose, like plasmodial masses in general, of isolating and removing foreign, harmful bodies, in this case the tubercle bacillus, and, having accomplished their object without being destroyed or exhausted, or the cause of their formation being removed or neutralized in some way, they, or their nuclei, may retain enough irritability to form a larger or smaller number of living, small, uninuclear cells.
PMCID: PMC2117963  PMID: 19866866
21.  Financial Conflicts of Interest and Reporting Bias Regarding the Association between Sugar-Sweetened Beverages and Weight Gain: A Systematic Review of Systematic Reviews 
PLoS Medicine  2013;10(12):e1001578.
Maira Bes-Rastrollo and colleagues examine whether financial conflicts of interest are likely to bias conclusions from systematic reviews that investigate the relationship between sugar-sweetened beverages and weight gain or obesity.
Please see later in the article for the Editors' Summary
Background
Industry sponsors' financial interests might bias the conclusions of scientific research. We examined whether financial industry funding or the disclosure of potential conflicts of interest influenced the results of published systematic reviews (SRs) conducted in the field of sugar-sweetened beverages (SSBs) and weight gain or obesity.
Methods and Findings
We conducted a search of the PubMed, Cochrane Library, and Scopus databases to identify published SRs from the inception of the databases to August 31, 2013, on the association between SSB consumption and weight gain or obesity. SR conclusions were independently classified by two researchers into two groups: those that found a positive association and those that did not. These two reviewers were blinded with respect to the stated source of funding and the disclosure of conflicts of interest.
We identified 17 SRs (with 18 conclusions). In six of the SRs a financial conflict of interest with some food industry was disclosed. Among those reviews without any reported conflict of interest, 83.3% of the conclusions (10/12) were that SSB consumption could be a potential risk factor for weight gain. In contrast, the same percentage of conclusions, 83.3% (5/6), of those SRs disclosing some financial conflict of interest with the food industry were that the scientific evidence was insufficient to support a positive association between SSB consumption and weight gain or obesity. Those reviews with conflicts of interest were five times more likely to present a conclusion of no positive association than those without them (relative risk: 5.0, 95% CI: 1.3–19.3).
An important limitation of this study is the impossibility of ruling out the existence of publication bias among those studies not declaring any conflict of interest. However, the best large randomized trials also support a direct association between SSB consumption and weight gain or obesity.
Conclusions
Financial conflicts of interest may bias conclusions from SRs on SSB consumption and weight gain or obesity.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In our daily lives, we frequently rely on the results of scientific research to make decisions about our health. If we are healthy, we may seek out scientific advice about how much exercise to do to reduce our risk of a heart attack, and we may follow dietary advice issued by public health bodies to help us maintain a healthy weight. If we are ill, we expect our treatment to be based on the results of clinical trials and other studies. We assume that the scientific research that underlies our decisions about health-related issues is unbiased and accurate. However, there is increasing evidence that the conclusions of industry-sponsored scientific research are sometimes biased. So, for example, reports of drug trials sponsored by pharmaceutical companies sometimes emphasize the positive results of trials and “hide” unwanted side effects deep within the report or omit them altogether.
Why Was This Study Done?
Although the effects of company sponsors on the conclusions of pharmaceutical research have been extensively examined, little is known about the effects of industry sponsorship on nutrition research, even though large commercial entities are increasingly involved in global food and drink production. It is important to know whether the scientific evidence about nutrition is free of bias because biased information might negatively affect the health of entire populations. Moreover, scientific evidence from nutrition research underlies the formulation of governmental dietary guidelines and food-related public health interventions. In this systematic review, the researchers investigate whether the disclosure of potential financial conflicts of interest (for example, research funding by a beverage company) has influenced the results of systematic reviews undertaken to examine the association between the consumption of highly lucrative sugar-sweetened beverages (SSBs) and weight gain or obesity. Systematic reviews identify all the research on a given topic using predefined criteria. In an ideal world, systematic reviews provide access to all the available evidence on specific exposure–disease associations, but publication bias related to authors' conflicts of interest may affect the reliability of the conclusions of such studies.
What Did the Researchers Do and Find?
The researchers identified 18 conclusions from 17 systematic reviews that had investigated the association between SSB consumption and weight gain or obesity. In six of these reviews, a financial conflict of interest with a food industry was disclosed. Among the reviews that reported having no conflict of interest, 83.3% of the conclusions were that SSB consumption could be a potential risk factor for weight gain. By contrast, the same percentage of reviews in which a potential financial conflict of interest was disclosed concluded that the scientific evidence was insufficient to support a positive association between SSB consumption and weight gain, or reported contradictory results and did not state any definitive conclusion about the association between SSB consumption and weight gain. Reviews in which a potential conflict of interest was disclosed were five times more likely to present a conclusion of no positive association between SSB consumption and weight gain than reviews that reported having no financial conflict of interest.
What Do These Findings Mean?
These findings indicate that systematic reviews that reported financial conflicts of interest or sponsorship from food or drink companies were more likely to reach a conclusion of no positive association between SSB consumption and weight gain than reviews that reported having no conflicts of interest. A major limitation of this study is that it cannot assess which interpretation of the available evidence is truly accurate. For example, the scientists involved in the systematic reviews that reported having no conflict of interest may have had preexisting prejudices that affected their interpretation of their findings. However, the interests of the food industry (increased sales of their products) are very different from those of most researchers (the honest pursuit of knowledge), and recent randomized trials support a positive association between SSB consumption and overweight/obesity. Thus, these findings draw attention to possible inaccuracies in scientific evidence from research funded by the food and drink industry. They do not imply that industry sponsorship of nutrition research should be avoided entirely. Rather, as in other research areas, clear guidelines and principles (for example, sponsors should sign contracts that state that they will not be involved in the interpretation of results) need to be established to avoid dangerous conflicts of interest.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001578.
The Research Ethics Program at the University of California, San Diego provides an overview of conflicts of interest for researchers and details of US regulations and guidelines
The PLOS Medicine series on Big Food examines the activities and influence of the food industry in global health
A PLOS Medicine Research Article by Basu et al. uses mathematical modeling to investigate whether SSB taxation would avert obesity and diabetes in India
A 2012 policy brief from the Yale Rudd Center for Food Policy and Obesity discusses current evidence regarding SSB taxes
The US National Institutes of Health has regulations on financial conflicts of interest for institutions applying to receive funding
Wikipedia has pages on conflict of interest, reporting bias, systematic review, and SSBs (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001578
PMCID: PMC3876974  PMID: 24391479
22.  Relationship between Funding Source and Conclusion among Nutrition-Related Scientific Articles 
PLoS Medicine  2007;4(1):e5.
Background
Industrial support of biomedical research may bias scientific conclusions, as demonstrated by recent analyses of pharmaceutical studies. However, this issue has not been systematically examined in the area of nutrition research. The purpose of this study is to characterize financial sponsorship of scientific articles addressing the health effects of three commonly consumed beverages, and to determine how sponsorship affects published conclusions.
Methods and Findings
Medline searches of worldwide literature were used to identify three article types (interventional studies, observational studies, and scientific reviews) about soft drinks, juice, and milk published between 1 January, 1999 and 31 December, 2003. Financial sponsorship and article conclusions were classified by independent groups of coinvestigators. The relationship between sponsorship and conclusions was explored by exact tests and regression analyses, controlling for covariates. 206 articles were included in the study, of which 111 declared financial sponsorship. Of these, 22% had all industry funding, 47% had no industry funding, and 32% had mixed funding. Funding source was significantly related to conclusions when considering all article types (p = 0.037). For interventional studies, the proportion with unfavorable conclusions was 0% for all industry funding versus 37% for no industry funding (p = 0.009). The odds ratio of a favorable versus unfavorable conclusion was 7.61 (95% confidence interval 1.27 to 45.73), comparing articles with all industry funding to no industry funding.
Conclusions
Industry funding of nutrition-related scientific articles may bias conclusions in favor of sponsors' products, with potentially significant implications for public health.
In 111 scientific articles on nonalcoholic beverages, articles with all industry funding were more than 7 times more likely to have favorable conclusions compared with articles with no industry funding.
Editors' Summary
Background.
Much of the money available for doing medical research comes from companies, as opposed to government agencies or charities. There is some evidence that when a research study is sponsored by an organization that has a financial interest in the outcome, the study is more likely to produce results that favor the funder (this is called “sponsorship bias”). This phenomenon is worrying, because if our knowledge about effectiveness and safety of medicines is based on biased findings, patients could suffer. However, it is not clear whether sponsorship bias extends beyond research into drugs, but also affects other types of research that is in the public interest. For example, research into the health benefits, or otherwise, of different types of food and drink may affect government guidelines, regulations, and the behavior patterns of members of the public. Were sponsorship bias also to exist in this area of research, the health of the wider public could be affected.
Why Was This Study Done?
There is not a great deal of evidence about whether sponsorship bias affects nutritional research (scientific studies that look at the relationship between food and/or drink, and health or disease states). Therefore, the group of researchers here set out to collect information from published nutritional research papers, to see if the type of sponsorship for the research studies was in any way linked with whether the main conclusions were favorable or unfavorable to the sponsor.
What Did the Researchers Do and Find?
The research study reported here used the scientific literature as a source of data. The researchers chose to examine one particular area of nutrition (nonalcoholic drinks including soft drinks, juices, and milk), so that their investigation would not be affected too much by variability between the different types of nutritional research. Using literature searches, the researchers identified all original research and scientific review articles published between January 1999 and December 2003 that examined soft drinks, juices, and milk; described research carried out in humans; and at the same time drew conclusions relevant to health or disease. Then, information from each published article was categorized: the conclusions were coded as either favorable, unfavorable, or neutral in relation to the health effects of the products being studied, and the article's funding was coded as either all industry (ie, food/drinks companies), no industry, or mixed. 206 published articles were analyzed and only 54% declared funding. The researchers found that, overall, there was a strong association between the type of funding available for these articles and the conclusions that were drawn. Articles sponsored exclusively by food/drinks companies were four to eight times more likely to have conclusions favorable to the financial interests of the sponsoring company than articles which were not sponsored by food or drinks companies.
What Do These Findings Mean?
These findings suggest that a high potential for bias exists in research into the health benefits or harms of nonalcoholic drinks. It is not clear from this research study why or how this bias comes about, but there are many different mechanisms that might cause it. The researchers suggest that certain initiatives might help to reduce bias, for example, increasing independent funding of nutrition research.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/doi:10.1371/journal.pmed.0040005.
Conflict of Interest definition from Wikipedia (Wikipedia is an internet encyclopedia that anyone can edit)
The International Committee of Medical Journal Editors provides standard guidelines for practices at medical journals, including a section on sponsorship, authorship, and accountability
The Committee on Publication Ethics is a forum for journal editors to discuss issues related to the integrity of the scientific record, and it provides guidelines for editors and case studies for reference
The Good Publication Practice guidelines outline standards for responsible publication of research sponsored by pharmaceutical companies
doi:10.1371/journal.pmed.0040005
PMCID: PMC1764435  PMID: 17214504
23.  The Meanings and Prospects of Primo Vascular System from the Viewpoint of Historical Context 
The aim of this overview is to evaluate the primo vascular system research in the context of the history of meridian theory and the modern meanings of it. The 12 meridian systems were naturally presupposed in the conventional study of the meridians and acupuncture. But the excavations of Mawang-tui old documents and Sichuan Mianyang wooden puppet revealed the primordial concepts of meridians uncolored by the numerological cosmology of Han era. Further, the meridian map of horse, cow and hawk show another resemblance to the primordial type of meridians. Modern meridian theory has been challenged by the material based scientific theory and the primo vascular theory presents the most radical answer for it. It aims to reveal the anatomical entity of meridians. However, the study of primo vascular system is unexpectedly opening the new horizon of scientific integration of East and West beyond the mere searching for anatomical entity of meridians. Conclusions we have drawn from the historical reviews are, (1) the surface structure of the body reflects the physiopathological changes of inside the body, (2) by stimulating specific sites on the surface, it is possible to acquire therapeutic effects of certain symptoms, and (3) numbers and locations of meridian acupoints are variable among traditional meridian theories.
doi:10.1155/2013/439508
PMCID: PMC3670526  PMID: 23762137
24.  EXPERIMENTAL NEPHRITIS IN THE FROG  
A summary of our findings is briefly made. A functional examination of the kidneys did not allow any differentiation between the results of vascular and parenchymal damage. This was true, as is emphasized in the arrangement of Charts 1 and 2, in the case of both glomerular and tubular dysfunction for it is seen that the type of functional derangement is identical in the two types of damage. Anatomical examination of the kidneys on the other hand showed definite differences in the state of the kidneys in the two types of damage, whether the dysfunction was glomerular or tubular. Certain points should be emphasized here. First, the validity of these results is not dependent on any particular interpretation of the significance of the functional phenomena observed. Whatever the anatomical relations between the two circulations in the kidney, whether urea, salts, dyes or water is excreted by one mechanism or another, no matter what part "filtration" or "absorption" may play in the elaboration of the final urine, the fact remains that the status of the function of these kidneys was identical, no matter how its functional state came into being, when an anatomical examination showed their actual condition to be significantly different. The fact that vascular disturbances, if of sufficient duration may in turn produce parenchymal changes complicates the problem still further, for in lesions that spontaneously develop in the kidney the mixture of vascular and parenchymal disturbances is so intimate that the functional results become infinitely more difficult of interpretation. Our previous studies have shown that even in the controlled extravital experiment conditions and relations of functional and structural response may thus become exceedingly complex (2). These complications were purposely avoided in the present study, however, by making the period of vascular disturbance short. Also, and again for the purpose of simplification, the toxic agent which caused the parenchymal disturbances was used in low enough concentration to produce only the less complex of the structural alterations that may follow its contact with the cells. And for the same reasons the simplicity of the general conditions existing in the perfusion experiments deserves special emphasis. Every element of the circulating fluid that is going to the kidneys is known and may be varied at will. Every constituent of the urine formed from this fluid can be accurately determined and compared with its condition in the circulating fluid. We have given in our experiments only rates of excretion but "concentration factors," "ratios," "clearances" or any other formulae might be calculated, without altering the conclusion that the functional status of the organs in the two types of damage, vascular and parenchymal, was identical. All these contrasts between the simplicity of our experiments and the complexity that must obtain when the problem is investigated in the living animal, particularly if mammals are used whose renal activity is only partially understood, add considerable weight to the conclusion that functional examination is unable to differentiate between two types of damage of very different significance, the one vascular, transient and reversible, the other parenchymal, permanent and, as far as the cells involved are concerned, irreparable. It might seem that a similar result is the proper conclusion to be drawn from the long series of similar attempts by clinical and experimental study to determine the condition of the kidneys from functional examinations. But it has been and apparently still is hoped, perhaps because in such examinations relations are so complex and involved that nothing seems beyond hope, that some refinement in method or the use of some selectively excreted substance, such as a dye or other foreign substance, may distinguish between the two conditions of vascular and parenchymal disturbance. The answer of our experiments is that the apparent similarity in the findings of the functional tests in the two cases is in fact an identity in the functional state in the two conditions though produced by different mechanisms; and there remains no reason to suppose that any procedure could distinguish between differences that in fact do not exist. The observation of the anatomical changes in the kidneys of our experiments allowed on the other hand a ready determination of the significance of the alteration that existed in the two conditions of damage, since the fate of the organ could be predicted directly from the structural alterations observed. In our experiments the observations were made by histological means; other methods which have been shown by postmortem pathological evidence to be valid and to give similar information, are however available (7). A final point in these experiments may be emphasized, well known perhaps, but often insufficiently appreciated, namely, a weakness in the anatomical approach to the problem. The morphologist is unable to describe even roughly the functional state of a kidney from its histological appearance. In certain cases of frank damage he may hazard a precarious guess, but severe functional disturbances may exist without any trace of structural derangement that can be seen by the eye. For all we know the converse may be true. And if such is the case in the simple and controlled conditions of our experiments, how can one venture to speculate on the significance or functional effects of inflamed glomeruli, abnormal tubules and sclerosed vessels as explaining some complicated clinical observation, the exact physiological basis of which is indeed unknown? Until the fundamental correlation of the two aspects of damage, functional derangement and structural change, has been made the whole problem of the abnormal kidney must remain not only unsolved but unsolvable.
PMCID: PMC2132086  PMID: 19869992
25.  Representation and Misrepresentation of Scientific Evidence in Contemporary Tobacco Regulation: A Review of Tobacco Industry Submissions to the UK Government Consultation on Standardised Packaging 
PLoS Medicine  2014;11(3):e1001629.
Selda Ulucanlar and colleagues analyze submissions by two tobacco companies to the UK government consultation on standardized packaging.
Please see later in the article for the Editors' Summary
Background
Standardised packaging (SP) of tobacco products is an innovative tobacco control measure opposed by transnational tobacco companies (TTCs) whose responses to the UK government's public consultation on SP argued that evidence was inadequate to support implementing the measure. The government's initial decision, announced 11 months after the consultation closed, was to wait for ‘more evidence’, but four months later a second ‘independent review’ was launched. In view of the centrality of evidence to debates over SP and TTCs' history of denying harms and manufacturing uncertainty about scientific evidence, we analysed their submissions to examine how they used evidence to oppose SP.
Methods and Findings
We purposively selected and analysed two TTC submissions using a verification-oriented cross-documentary method to ascertain how published studies were used and interpretive analysis with a constructivist grounded theory approach to examine the conceptual significance of TTC critiques. The companies' overall argument was that the SP evidence base was seriously flawed and did not warrant the introduction of SP. However, this argument was underpinned by three complementary techniques that misrepresented the evidence base. First, published studies were repeatedly misquoted, distorting the main messages. Second, ‘mimicked scientific critique’ was used to undermine evidence; this form of critique insisted on methodological perfection, rejected methodological pluralism, adopted a litigation (not scientific) model, and was not rigorous. Third, TTCs engaged in ‘evidential landscaping’, promoting a parallel evidence base to deflect attention from SP and excluding company-held evidence relevant to SP. The study's sample was limited to sub-sections of two out of four submissions, but leaked industry documents suggest at least one other company used a similar approach.
Conclusions
The TTCs' claim that SP will not lead to public health benefits is largely without foundation. The tools of Better Regulation, particularly stakeholder consultation, provide an opportunity for highly resourced corporations to slow, weaken, or prevent public health policies.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, about 6 million people die from tobacco-related diseases and, if current trends continue, annual tobacco-related deaths will increase to more than 8 million by 2030. To reduce this loss of life, national and international bodies have drawn up various conventions and directives designed to implement tobacco control measures such as the adoption of taxation policies aimed at reducing tobacco consumption and bans on tobacco advertising, promotion, and sponsorship. One innovative but largely unused tobacco control measure is standardised packaging of tobacco products. Standardised packaging aims to prevent the use of packaging as a marketing tool by removing all brand imagery and text (other than name) and by introducing packs of a standard shape and colour that include prominent pictorial health warnings. Standardised packaging was first suggested as a tobacco control measure in 1986 but has been consistently opposed by the tobacco industry.
Why Was This Study Done?
The UK is currently considering standardised packaging of tobacco products. In the UK, Better Regulation guidance obliges officials to seek the views of stakeholders, including corporations, on the government's cost and benefit estimates of regulatory measures such as standardised packaging and on the evidence underlying these estimates. In response to a public consultation about standardised packaging in July 2013, which considered submissions from several transnational tobacco companies (TTCs), the UK government announced that it would wait for the results of the standardised packaging legislation that Australia adopted in December 2012 before making its final decision about this tobacco control measure. Parliamentary debates and media statements have suggested that doubt over the adequacy of the evidence was the main reason for this ‘wait and see’ decision. Notably, TTCs have a history of manufacturing uncertainty about the scientific evidence related to the harms of tobacco. Given the centrality of evidence to the debate about standardised packaging, in this study, the researchers analyse submissions made by two TTCs, British American Tobacco (BAT) and Japan Tobacco International (JTI), to the first UK consultation on standardised packaging (a second review is currently underway and will report shortly) to examine how TTCs used evidence to oppose standardised packaging.
What Did the Researchers Do and Find?
The researchers analysed sub-sections of two of the four TTC submissions (those submitted by BAT and JTI) made to the public consultation using verification-oriented cross-documentary analysis, which compared references made to published sources with the original sources to ascertain how these sources had been used, and interpretative analysis to examine the conceptual significance of TTC critiques of the evidence on standardised packaging. The researchers report that the companies' overall argument was that the evidence base in support of standardised packaging was seriously flawed and did not warrant the introduction of such packaging. The researchers identified three ways in which the TTC reports misrepresented the evidence base. First, the TTCs misquoted published studies, thereby distorting the main messages of these studies. For example, the TTCs sometimes omitted important qualifying information when quoting from published studies. Second, the TTCs undermined evidence by employing experts to review published studies for methodological rigor and value in ways that did not conform to normal scientific critique approaches (‘mimicked scientific critique’). So, for example, the experts considered each piece of evidence in isolation for its ability to support standardised packaging rather than considering the cumulative weight of the evidence. Finally, the TTCs engaged in ‘evidential landscaping’. That is, they promoted research that deflected attention from standardised packaging (for example, research into social explanations of smoking behaviour) and omitted internal industry research on the role of packaging in marketing.
What Do These Findings Mean?
These findings suggest that the TTC critique of the evidence in favour of standardised packaging that was presented to the UK public consultation on this tobacco control measure is highly misleading. However, because the researchers' analysis only considered subsections of the submissions from two TTCs, these findings may not be applicable to the other submissions or to other TTCs. Moreover, their analysis only considered the efforts made by TTCs to influence public health policy and not the effectiveness of these efforts. Nevertheless, these findings suggest that the claim of TTCs that standardised packaging will not lead to public health benefits is largely without foundation. More generally, these findings highlight the possibility that the tools of Better Regulation, particularly stakeholder consultation, provide an opportunity for wealthy corporations to slow, weaken, or prevent the implementation of public health policies.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001629.
The World Health Organization provides information about the dangers of tobacco (in several languages) and an article about first experiences with Australia's tobacco plain packaging law; for information about the tobacco industry's influence on policy, see the 2009 World Health Organization report ‘Tobacco industry interference with tobacco control’
A UK parliamentary briefing on standardised packaging of tobacco products, a press release about the consultation, and a summary report of the consultation are available; the ideas behind the UK's Better Regulation guidance are described in a leaflet produced by the Better Regulation Task Force
Cancer Research UK (CRUK) has a web page with information on standardised packaging and includes videos
Wikipedia has a page on standardised packaging of tobacco products (note: Wikipedia is a free online encyclopaedia that anyone can edit; available in several languages)
The UK Centre for Tobacco Control Studies is a network of UK universities that undertakes original research, policy development, advocacy, and teaching and training in the field of tobacco control
TobaccoTactics.org, an online resource managed by the University of Bath, provides up-to-date information on the tobacco industry and the tactics it uses to influence tobacco regulation
SmokeFree, a website provided by the UK National Health Service, offers advice on quitting smoking and includes personal stories from people who have stopped smoking
Smokefree.gov, from the US National Cancer Institute, offers online tools and resources to help people quit smoking
doi:10.1371/journal.pmed.1001629
PMCID: PMC3965396  PMID: 24667150

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