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1.  MicroRNAs down-regulate homologous recombination in the G1 phase of cycling cells to maintain genomic stability 
eLife  2014;3:e02445.
Homologous recombination (HR)-mediated repair of DNA double-strand break (DSB)s is restricted to the post-replicative phases of the cell cycle. Initiation of HR in the G1 phase blocks non-homologous end joining (NHEJ) impairing DSB repair. Completion of HR in G1 cells can lead to the loss-of-heterozygosity (LOH), which is potentially carcinogenic. We conducted a gain-of-function screen to identify miRNAs that regulate HR-mediated DSB repair, and of these miRNAs, miR-1255b, miR-148b*, and miR-193b* specifically suppress the HR-pathway in the G1 phase. These miRNAs target the transcripts of HR factors, BRCA1, BRCA2, and RAD51, and inhibiting miR-1255b, miR-148b*, and miR-193b* increases expression of BRCA1/BRCA2/RAD51 specifically in the G1-phase leading to impaired DSB repair. Depletion of CtIP, a BRCA1-associated DNA end resection protein, rescues this phenotype. Furthermore, deletion of miR-1255b, miR-148b*, and miR-193b* in independent cohorts of ovarian tumors correlates with significant increase in LOH events/chromosomal aberrations and BRCA1 expression.
DOI: http://dx.doi.org/10.7554/eLife.02445.001
eLife digest
The DNA in a cell is damaged thousands of times every day. One of the most serious types of damage involves something breaking both of the strands in the double helix. Such a double-strand break can delete genes or even kill the cell. In fact, conventional cancer therapy kills cancer cells by causing irreparable double-strand breaks. Conversely, a normal cell that is constantly exposed to DNA damaging agents can become a tumor if double-strand breaks are incorrectly repaired. An efficient and accurate double-strand break repair system needs to be in place to prevent this transformation. Therefore, an in-depth understanding of double-strand break repair and the factors involved are important for both gaining insight into the cause of cancer and to improve cancer therapy.
Cells have evolved several different ways to detect and repair double-strand breaks. A method called homologous recombination, for example, uses an undamaged DNA molecule as a template that can be copied to make new DNA. Since it needs a readily available DNA template, this method only works in phases of the cell growth cycle where there are many copies of DNA—that is, in the post-DNA replication phases. In particular, homologous recombination does not work during the pre-replication, G1 phase. If homologous recombination is attempted during G1, it will block the other methods employed by cells to repair broken strands of DNA.
An important challenge is to understand how homologous recombination is restricted to particular parts of the cell cycle. Although certain proteins associated with the early stages of double-strand repair are thought to determine the type of DNA repair that occurs, the details of this process are not fully understood.
One group of molecules that are thought to be involved are microRNAs, which normally limit the number of proteins produced from certain genes. However, since a single microRNA molecule can be associated with several proteins, and since a single protein can be associated with several microRNA molecules, it has proved difficult to establish the exact effects of a specific microRNA molecule.
Choi et al. now show that seven microRNA molecules can control homologous recombination, and three microRNAs in particular restrict homologous recombination during the G1 phase of the cell cycle. If these microRNAs are inhibited during the G1 phase, which allows homologous recombination to start, and counter-intuitively more double-stranded breaks are seen. However, if a gene involved in starting homologous repair–called CtIP—is silenced while the microRNAs are inhibited, then the DNA breaks are repaired. Exactly, how the microRNA molecules produce different effects during different phases of the cell cycle will be need to be investigated by future studies.
DOI: http://dx.doi.org/10.7554/eLife.02445.002
doi:10.7554/eLife.02445
PMCID: PMC4031983  PMID: 24843000
DNA repair; BRCA1; cell cycle; human; mouse
2.  P01.02. Positive Psychology: A Path to Greater Well-being 
Focus Area: Supporting Behavioral Change
In 1998, when Dr Martin Seligman was president of the American Psychological Association, he proposed a new approach to psychology. The thinking at that time led to a disease-based model in which the focus was on treating mental illness. Dr Seligman advocated, however, that the science should be expanded to include factors that contribute to optimal functioning and greater well-being. He, along with his colleague Dr Csikszentmihalyi, stated, “The exclusive focus on pathology that has dominated so much of our discipline results in a model of the human being lacking the positive features that make life worth living.” Since this time, a more complete and balanced scientific understanding of the human experience has begun to unfold, with human flourishing being the goal. The five pillars that significantly contribute to a flourishing life and greater well-being include positive emotions, engagement, relationships, meaning, and accomplishment. It is important to incorporate these pillars into our professional and personal lives, but in doing so, we must keep in mind the fundamental building blocks to getting there: responsibility, choice, and action. Even as far back as the ancient Greek philosophers, it was believed that “the good life” is not something that happens to us—it is not something the world owes us. There is nothing passive about it. Now, with the scientific model that Positive Psychology has given us, we have a path to follow that will move us in the direction of this “good life.”
doi:10.7453/gahmj.2013.097CP.P01.02
PMCID: PMC3875005
3.  A dedicated visual pathway for prey detection in larval zebrafish 
eLife  null;3:e04878.
Zebrafish larvae show characteristic prey capture behavior in response to small moving objects. The neural mechanism used to recognize objects as prey remains largely unknown. We devised a machine learning behavior classification system to quantify hunting kinematics in semi-restrained animals exposed to a range of virtual stimuli. Two-photon calcium imaging revealed a small visual area, AF7, that was activated specifically by the optimal prey stimulus. This pretectal region is innervated by two types of retinal ganglion cells, which also send collaterals to the optic tectum. Laser ablation of AF7 markedly reduced prey capture behavior. We identified neurons with arbors in AF7 and found that they projected to multiple sensory and premotor areas: the optic tectum, the nucleus of the medial longitudinal fasciculus (nMLF) and the hindbrain. These findings indicate that computations in the retina give rise to a visual stream which transforms sensory information into a directed prey capture response.
DOI: http://dx.doi.org/10.7554/eLife.04878.001
eLife digest
Our ability to recognize objects, and to respond instinctively to them, is something that is not fully understood. For example, seeing your favorite dessert could trigger an irresistible urge to eat it. Yet precisely how the image of the dessert could trigger an inner desire to indulge is a question that has so far eluded scientists. This compelling question also applies to the animal kingdom. Predators often demonstrate a typical hunting behavior upon seeing their prey from a distance. But just how the image of the prey triggers this hunting behavior is not known.
Semmelhack et al. have now investigated this question by looking at the hunting behavior of zebrafish larvae. The larvae's prey is a tiny microbe that resembles a small moving dot. When the larvae encounter something that looks like their prey, they demonstrate a hardwired hunting response towards it. The hunting behavior consists of a series of swimming maneuvers to help the larvae successfully capture their prey.
Semmelhack et al. used prey decoys to lure the zebrafish larvae, and video recordings to monitor the larvae's response. During the recordings, the larvae were embedded in a bed of jelly with only their tails free to move. The larvae's tail movements were recorded, and because the larvae are completely transparent, their brain activity could be visually monitored at the same time using calcium dyes.
Using this approach, Semmelhack et al. identified a specific area of the brain that is responsible for triggering the larvae's hunting behavior. It turns out that this brain region forms a circuit that directly connects the retina at the back of the eye to nerve centers that control hunting maneuvers. So when the larva sees its prey, this circuit could directly trigger the larva's hunting behavior. When the circuit was specifically destroyed with a laser, this instinctive hunting response was impaired.
These findings suggest that predators have a distinct brain circuit that hardwires their hunting response to images of their prey. Future studies would involve understanding precisely how this circuit coordinates the larvae's complex hunting behavior.
DOI: http://dx.doi.org/10.7554/eLife.04878.002
doi:10.7554/eLife.04878
PMCID: PMC4281881  PMID: 25490154
visual system; behavior; retinal ganglion cells; pretectum; optic tectum; Zebrafish
4.  Self-Referenced Memory, Social Cognition, and Symptom Presentation in Autism 
Background
We examined performance on a self-referenced memory (SRM) task for higher functioning children with autism (HFA) and a matched comparison group. SRM performance was examined in relation to symptom severity and social cognitive tests of mentalizing.
Method
Sixty-two children (31 HFA, 31 comparison; 8–16 years) completed a SRM task in which they read a list of words and decided whether the word described something about them, something about Harry Potter, or contained a certain number of letters. They then identified words that were familiar from a longer list. Dependent measures were memory performance (d′) in each of the three encoding conditions as well as a self-memory bias score (d′ self-d′ other). Children completed The Strange Stories Task and The Children’s Eyes Test as measures of social cognition. Parents completed the SCQ and ASSQ as measures of symptom severity.
Results
Children in the comparison sample showed the standard SRM effect in which they recognized significantly more self-referenced words relative to words in the other-referenced and letter conditions. In contrast, HFA children showed comparable rates of recognition for self- and other-referenced words. For all children, SRM performance improved with age and enhanced SRM performance was related to lower levels of social problems. These associations were not accounted for by performance on the mentalizing tasks.
Conclusions
Children with HFA did not show the standard enhanced processing of self- vs. other-relevant information. Individual differences in the tendency to preferentially process self-relevant information may be associated with social cognitive processes that serve to modify the expression of social symptoms in children with autism.
doi:10.1111/j.1469-7610.2008.02059.x
PMCID: PMC2697280  PMID: 19298471
5.  Portrait of a Leader in Immunotherapeutics 
Human Vaccines & Immunotherapeutics  2012;8(8):1018-1021.
When I heard about the concept of immunotherapeutics, I immediately loved it. Everything I had learned about medicine, cancer biology, genetics and oncology indicated to me that this was a potent approach, and at the time, completely untapped. I figured that since we had been unable to cure most metastatic solid tumors, something completely different needed to be employed. Realistically, “magic bullets” are not easy to find and therefore something that can be combined with other therapies, for enhanced synergy without overlapping adverse events, would be appealing.
doi:10.4161/hv.21699
PMCID: PMC3551870  PMID: 22914447
adenovirus; cancer; gene therapy; immunotherapy; oncolytic virus
6.  Effect of different forms of information produced for cancer patients on their use of the information, social support, and anxiety: randomised trial 
BMJ : British Medical Journal  2006;332(7547):942-948.
Objective To explore the hypothesis that different methods of selecting and printing information for cancer patients could improve emotional support by affecting interaction with others, and so lead to improved psychological wellbeing.
Design Randomised trial with eight groups (three factors, 2×2×2). Data collected at recruitment and three month follow-up.
Participants 400 patients starting radiotherapy, of whom 325 with breast or prostate cancer and complete anxiety and depression data were included in the analysis.
Interventions Printed booklets: half had only general information from CancerBACUP about each patient's cancer and half had personalised information from the patient's medical record plus selected general information; half were composed of information chosen interactively by the patient and half were produced automatically with a larger volume of material; and half had additional advice on anxiety management and half did not.
Main outcome measures Patients' views of the information, use of their booklets with others; change in reported social support; change in anxiety and depression.
Results The larger booklets produced automatically were more likely to be found useful and to tell patients something new and less likely to be seen as too limited than the booklets produced interactively, but they were also more likely to overwhelm some patients. Personalised booklets were more likely than general booklets to tell patients something new. There was no difference in patients' perceived understanding of their cancer by any of the intervention factors. Patients with personalised information were more likely to show their booklets to others and to think it helped in discussing their cancer or its treatment. There were no major differences in social support, anxiety, or depression by any intervention factors.
Conclusions Patients were more likely to show personalised information to their confidants than general information. Further research is needed into the effects of sharing information on patients' social support and anxiety.
Trial registration US Government Clinical Trials Database NCT00127465
doi:10.1136/bmj.38807.571042.68
PMCID: PMC1444811  PMID: 16597660
7.  United States Private-Sector Physicians and Pharmaceutical Contract Research: A Qualitative Study 
PLoS Medicine  2012;9(7):e1001271.
Jill Fisher and Corey Kalbaugh describe their findings from a qualitative research study evaluating the motivations of private-sector physicians conducting contract research for the pharmaceutical industry.
Background
There have been dramatic increases over the past 20 years in the number of nonacademic, private-sector physicians who serve as principal investigators on US clinical trials sponsored by the pharmaceutical industry. However, there has been little research on the implications of these investigators' role in clinical investigation. Our objective was to study private-sector clinics involved in US pharmaceutical clinical trials to understand the contract research arrangements supporting drug development, and specifically how private-sector physicians engaged in contract research describe their professional identities.
Methods and Findings
We conducted a qualitative study in 2003–2004 combining observation at 25 private-sector research organizations in the southwestern United States and 63 semi-structured interviews with physicians, research staff, and research participants at those clinics. We used grounded theory to analyze and interpret our data. The 11 private-sector physicians who participated in our study reported becoming principal investigators on industry clinical trials primarily because contract research provides an additional revenue stream. The physicians reported that they saw themselves as trial practitioners and as businesspeople rather than as scientists or researchers.
Conclusions
Our findings suggest that in addition to having financial motivation to participate in contract research, these US private-sector physicians have a professional identity aligned with an industry-based approach to research ethics. The generalizability of these findings and whether they have changed in the intervening years should be addressed in future studies.
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
Before a new drug can be used routinely by physicians, it must be investigated in clinical trials—studies that test the drug's safety and effectiveness in people. In the past, clinical trials were usually undertaken in academic medical centers (institutes where physicians provide clinical care, do research, and teach), but increasingly, clinical trials are being conducted in the private sector as part of a growing contract research system. In the US, for example, most clinical trials completed in the 1980s took place in academic medical centers, but nowadays, more than 70% of trials are conducted by nonacademic (community) physicians working under contract to pharmaceutical companies. The number of private-sector nonacademic physicians serving as principal investigators (PIs) for US clinical trials (the PI takes direct responsibility for completion of the trial) increased from 4,000 in 1990 to 20,250 in 2010, and research contracts for clinical trials are now worth more than USṩ11 billion annually.
Why Was This Study Done?
To date, there has been little research on the implications of this change in the conduct of clinical trials. Academic PIs are often involved in both laboratory and clinical research and are therefore likely to identify closely with the science of trials. By contrast, nonacademic PIs may see clinical trials more as a business opportunity—pharmaceutical contract research is profitable to US physicians because they get paid for every step of the trial process. As a result, pharmaceutical companies may now have more control over clinical trial data and more opportunities to suppress negative data through selective publication of study results than previously. In this qualitative study, the researchers explore the outsourcing of clinical trials to private-sector research clinics through observations of, and in-depth interviews with, physicians and other research staff involved in the US clinical trials industry. A qualitative study collects non-quantitative data such as how physicians feel about doing contract research and about their responsibilities to their patients.
What Did the Researchers Do and Find?
Between October 2003 and September 2004, the researchers observed the interactions between PIs, trial coordinators (individuals who undertake many of the trial activities such as blood collection), and trial participants at 25 US research organizations in the southwestern US and interviewed 63 informants (including 12 PIs) about the trials they were involved in and their reasons for becoming involved. The researchers found that private-sector physicians became PIs on industry-sponsored clinical trials primarily because contract research was financially lucrative. The physicians perceived their roles in terms of business rather than science and claimed that they offered something to the pharmaceutical industry that academics do not—the ability to carry out a diverse range of trials quickly and effectively, regardless of their medical specialty. Finally, the physicians saw their primary ethical responsibility as providing accurate data to the companies that hired them and did not explicitly refer to their ethical responsibility to trial participants. One possible reason for this shift in ethical concerns is the belief among private-sector physicians that pharmaceutical companies must be making scientifically and ethically sound decisions when designing trials because of the amount of money they invest in them.
What Do These Findings Mean?
These findings suggest that private-sector physicians participate as PIs in pharmaceutical clinical trials primarily for financial reasons and see themselves as trial practitioners and businesspeople rather than as scientists. The accuracy of these findings is likely to be limited by the small number of PIs interviewed and by the time that has elapsed since the researchers collected their qualitative data. Moreover, these findings may not be generalizable to other regions of the US or to other countries. Nevertheless, they have potentially troubling implications for drug development. By hiring private-sector physicians who see themselves as involved more with the business than the science of contract research, pharmaceutical companies may be able to exert more control over the conduct of clinical trials and the publication of trial results than previously. Compared to the traditional investigatorinitiated system of clinical research, this new system of contract research means that clinical trials now lack the independence that is at the heart of best science practices, a development that casts doubt on the robustness of the knowledge being produced about the safety and effectiveness of new drugs.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001271.
The ClinicalTrials.gov website is a searchable register of federally and privately supported clinical trials in the US; it provides information about all aspects of clinical trials
The US National Institutes of Health provides information about clinical trials, including personal stories about clinical trials from patients and researchers
The UK National Health Service Choices website has information for patients about clinical trials and medical research, including personal stories about participating in clinical trials
The UK Medical Research Council Clinical Trials Unit also provides information for patients about clinical trials and links to information on clinical trials provided by other organizations
MedlinePlus has links to further resources on clinical trials (in English and Spanish)
doi:10.1371/journal.pmed.1001271
PMCID: PMC3404112  PMID: 22911055
8.  PHL8/445: Internet Courses for Cancer Patients 
In September 1998 INKA started the first practical courses on the internet for cancer patients and their families in Germany. The aim was to show how they can use the internet to take more active control over the healing process. The project was open to all cancer patients and situated at the VHS Hamburg West (public adult education institute). Thanks to our sponsor the course fee was subsidised.85 participants took part. Most of them were cancer patients, with varying types of cancer. 2/3 were female and attended the course together with a family member or friend. They were aged 25-76 years and some of them even travelled from afar. 1/2 of the patients had a poor prognosis and a rare type of cancer. Asked why they took part they answered that they were either just curious, could not accept their poor prognosis, wanted to do something actively, thought INKA was a great project they wanted to join or were sent by their doctors to find out more information. Most of them were complete beginners with no internet experience, some without any computer knowledge. Apart from the technical introduction into the internet, its terms, retrieval methods etc. the participants had also enough opportunities for personal exchange within the group. Some keep in contact with each other and the project even now and 1/3 have their own internet access in the meantime. The patients and their families said that they were mostly dissatisfied with their interaction with their doctors and felt that the course was personally beneficial. The internet opened up a new dimension for them in the communication process, in that they learned that there is more and better information which they can print out and show to their doctors. They also liked to interact with experienced cancer survivors in the net. In general the course helped them to feel secure in their own healing decisions. Patients and institutions from all over Germany, Swiss and Austria showed interest and the conclusion is simple: there is a huge demand for this type of service. The project received a lot of press attention so that there were many multipliers in the health sector who now ask us for education material on this subject which INKA willing to provide in the future.
doi:10.2196/jmir.1.suppl1.e89
PMCID: PMC1761803
Cancer; Courses; Education; Patients; Public Adult Education
9.  Divergent kleisin subunits of cohesin specify mechanisms to tether and release meiotic chromosomes 
eLife  2014;3:e03467.
We show that multiple, functionally specialized cohesin complexes mediate the establishment and two-step release of sister chromatid cohesion that underlies the production of haploid gametes. In C. elegans, the kleisin subunits REC-8 and COH-3/4 differ between meiotic cohesins and endow them with distinctive properties that specify how cohesins load onto chromosomes and then trigger and release cohesion. Unlike REC-8 cohesin, COH-3/4 cohesin becomes cohesive through a replication-independent mechanism initiated by the DNA double-stranded breaks that induce crossover recombination. Thus, break-induced cohesion also tethers replicated meiotic chromosomes. Later, recombination stimulates separase-independent removal of REC-8 and COH-3/4 cohesins from reciprocal chromosomal territories flanking the crossover site. This region-specific removal likely underlies the two-step separation of homologs and sisters. Unexpectedly, COH-3/4 performs cohesion-independent functions in synaptonemal complex assembly. This new model for cohesin function diverges from that established in yeast but likely applies directly to plants and mammals, which utilize similar meiotic kleisins.
DOI: http://dx.doi.org/10.7554/eLife.03467.001
eLife digest
Most plant and animal cells have a pair of each chromosome: one copy is inherited from the father, the other from the mother. When a cell divides, each daughter cell must receive a copy of all of the original cell's genetic information. To this end, the chromosomes are replicated to form so-called ‘sister chromatids’, which are then segregated equally between the two daughter cells.
In contrast, sex cells such as eggs and sperm (also called gametes) have a single copy of each chromosome. When an egg and a sperm fuse to form a single cell (called a zygote), the zygote ends up with a full set of chromosomes. Gametes are formed by two successive rounds of cell division that occur after the chromosomes are replicated. The first round separates the pairs of chromosomes, and the second separates the sister chromatids to produce the gametes, each of which has half the original amount of genetic information.
If something goes awry in the production of gametes, a zygote can end up with the wrong number of chromosomes. Almost one-third of human zygotes inherit an aberrant complement of chromosomes, and many of these zygotes either fail to survive or develop into offspring with birth defects and developmental disorders.
To ensure that gametes receive the correct number of chromosomes, the sister chromatids remain bound together by a ring-shaped protein complex during the first cell division. Previous studies on how this protein complex—called cohesin—tethers the sister chromatids together were conducted on yeast and mammalian cells. Now, Severson and Meyer show that, in a microscopic worm called Caenorhabditis elegans, cohesin functions differently from how it functions in the simpler yeast cells.
Severson and Meyer found that rather than using a single cohesin complex like in yeast, the worms use multiple cohesin complexes that have different versions of one key protein subunit. Changing this single subunit has a major impact on cohesin's function. Consequently, each complex plays a specific role in tethering and then releasing sister chromatids. One of the cohesin complexes is triggered to tether the sister chromatids when the chromosomes replicate. Unexpectedly, another complex only tethers the sisters once breaks occur in the DNA. These breaks allow sister chromatids that are produced from maternally- and paternally-derived chromosomes to cross over and swap genetic material—which increases the genetic diversity of any future offspring. After these genetic swaps occur, the cohesin complexes are then selectively removed by different mechanisms, first to release the pairs of chromosomes and then the sister chromatids.
The findings of Severson and Meyer establish a new model for the mechanisms of chromosome segregation during gamete production. Further studies are now needed to determine the roles and regulation of these protein complexes in other species—including plants and mammals, which use similar cohesin complexes.
DOI: http://dx.doi.org/10.7554/eLife.03467.002
doi:10.7554/eLife.03467
PMCID: PMC4174578  PMID: 25171895
cohesin; sister chromatid cohesion; meiosis; gametogenesis; kleisin; aneuploidy; C. elegans
10.  Cortical regulation of cell size by a sizer cdr2p 
eLife  2014;3:e02040.
Cells can, in principle, control their size by growing to a specified size before commencing cell division. How any cell actually senses its own size remains poorly understood. The fission yeast Schizosaccharomyces pombe are rod-shaped cells that grow to ∼14 µm in length before entering mitosis. In this study, we provide evidence that these cells sense their surface area as part of this size control mechanism. We show that cells enter mitosis at a certain surface area, as opposed to a certain volume or length. A peripheral membrane protein kinase cdr2p has properties of a dose-dependent ‘sizer’ that controls mitotic entry. As cells grow, the local cdr2p concentration in nodes at the medial cortex accumulates as a measure of cell surface area. Our findings, which challenge a previously proposed pom1p gradient model, lead to a new model in which cells sense their size by using cdr2p to probe the surface area over the whole cell and relay this information to the medial cortex.
DOI: http://dx.doi.org/10.7554/eLife.02040.001
eLife digest
Although different types of cells come in a variety of shapes and sizes, most cells are able to maintain a fairly consistent size and shape as they grow and divide. For example, the rod-shaped cells of the fission yeast S. pombe grow to be 14 microns long before dividing in the middle to form two new cells. This prevents any single cell becoming too large or small.
A similar phenomenon has been observed in other types of cells, so it is clear that cells must be able to measure their own size, and then use that information to trigger cell division. A number of proteins that regulate cell size and cell division in fission yeast have now been identified. These proteins form a pathway in which a protein called pom1p inhibits another protein, cdr2p, which in turn causes a third protein, cdk1p, to start the process of cell division. However, the details of the measurement process and the property that the cells are actually measuring—surface area, volume, mass or something else—remain mysterious.
Pan et al. have now used imaging techniques and mathematical modeling to probe the distribution and movements of proteins in fission yeast cells. Their results do not support a previous model in which the cell uses the gradient of pom1p as a ruler to measure cell length. Rather, Pan et al. propose a new model in which the level of cdr2p is used to sense the size of the cell. Individual molecules of cdr2p come together to from clusters called nodes on the cell membrane. As the cell grows larger, more and more cdr2p proteins accumulate in these nodes, which are found in a band around the middle of the cell. When the cells reaches a critical cell size, the increased concentration of cdr2p at these nodes may help to trigger the start of cell division.
By examining cells that grow at different rates, Pan et al. show that the rate of accumulation of cdr2p in the nodes depends on how big the cells are, rather than on the length of time that has elapsed. Analysis of fission yeast cells of different shapes shows that cell division starts when the surface area of the cell grows to a certain value, as opposed to starting when the volume or length reach a given value.
Pan et al. also show that cdr2p binds to all parts of the cell membrane, not just to the nodes near the middle, and go on to provide a simple mathematical model showing how this property can allow cells to measure their surface area. However, as Pan et al. point out, this is probably just one component of a larger mechanism that tells cells when they need to divide.
DOI: http://dx.doi.org/10.7554/eLife.02040.002
doi:10.7554/eLife.02040
PMCID: PMC3956294  PMID: 24642412
cell size control; protein kinase; plasma membrane; cell cycle; S. pombe
11.  Structural rigidity of a large cavity-containing protein revealed by high-pressure crystallography 
Journal of molecular biology  2006;367(3):752-763.
Steric constraints, charged interactions and many other forces important to protein structure and function can be explored by mutagenic experiments. Research of this kind has led to a wealth of knowledge about what stabilizes proteins in their folded states. To gain a more complete picture requires that we perturb these structures in a continuous manner, something mutagenesis cannot achieve. With high pressure crystallographic methods it is now possible to explore the detailed properties of proteins while continuously varying thermodynamic parameters. In this paper, we detail the structural response of the cavity-containing mutant L99A of T4 lysozyme, as well as its pseudo wild-type (WT*) counterpart, to hydrostatic pressure. Surprisingly, the cavity has almost no effect on the pressure response: virtually the same changes are observed in WT* as in L99A under pressure. The cavity is most rigid, while other regions deform substantially. This implies that while some residues may increase the thermodynamic stability of a protein, they may also be structurally irrelevant. As recently shown, the cavity fills with water at pressures above 100 MPa while retaining its overall size. The resultant picture of the protein is one in which conformationally fluctuating side groups provide a liquid-like environment, but which also contribute to the rigidity of the peptide backbone.
doi:10.1016/j.jmb.2006.12.021
PMCID: PMC1853337  PMID: 17292912
12.  Preconceptional Folate Supplementation and the Risk of Spontaneous Preterm Birth: A Cohort Study 
PLoS Medicine  2009;6(5):e1000061.
In an analysis of a cohort of pregnant women, Radek Bukowski and colleagues describe an association between taking folic acid supplements and a reduction in the risk of preterm birth.
Background
Low plasma folate concentrations in pregnancy are associated with preterm birth. Here we show an association between preconceptional folate supplementation and the risk of spontaneous preterm birth.
Methods and Findings
In a cohort of 34,480 low-risk singleton pregnancies enrolled in a study of aneuploidy risk, preconceptional folate supplementation was prospectively recorded in the first trimester of pregnancy. Duration of pregnancy was estimated based on first trimester ultrasound examination. Natural length of pregnancy was defined as gestational age at delivery in pregnancies with no medical or obstetrical complications that may have constituted an indication for delivery. Spontaneous preterm birth was defined as duration of pregnancy between 20 and 37 wk without those complications. The association between preconceptional folate supplementation and the risk of spontaneous preterm birth was evaluated using survival analysis. Comparing to no supplementation, preconceptional folate supplementation for 1 y or longer was associated with a 70% decrease in the risk of spontaneous preterm delivery between 20 and 28 wk (41 [0.27%] versus 4 [0.04%] spontaneous preterm births, respectively; HR 0.22, 95% confidence interval [CI] 0.08–0.61, p = 0.004) and a 50% decrease in the risk of spontaneous preterm delivery between 28 and 32 wk (58 [0.38%] versus 12 [0.18%] preterm birth, respectively; HR 0.45, 95% CI 0.24–0.83, p = 0.010). Adjustment for maternal characteristics age, race, body mass index, education, marital status, smoking, parity, and history of prior preterm birth did not have a material effect on the association between folate supplementation for 1 y or longer and spontaneous preterm birth between 20 and 28, and 28 to 32 wk (adjusted HR 0.31, 95% CI 0.11–0.90, p = 0.031 and 0.53, 0.28–0.99, p = 0.046, respectively). Preconceptional folate supplementation was not significantly associated with the risk of spontaneous preterm birth beyond 32 wk. The association between shorter duration (<1 y) of preconceptional folate supplementation and the risk of spontaneous preterm birth was not significant after adjustment for maternal characteristics. However, the risk of spontaneous preterm birth decreased with the duration of preconceptional folate supplementation (test for trend of survivor functions, p = 0.01) and was the lowest in women who used folate supplementation for 1 y or longer. There was also no significant association with other complications of pregnancy studied after adjustment for maternal characteristics.
Conclusions
Preconceptional folate supplementation is associated with a 50%–70% reduction in the incidence of early spontaneous preterm birth. The risk of early spontaneous preterm birth is inversely proportional to the duration of preconceptional folate supplementation. Preconceptional folate supplementation was specifically related to early spontaneous preterm birth and not associated with other complications of pregnancy.
Editors' Summary
Background
Most pregnancies last about 40 weeks, but sometimes the new family member arrives early. Every year, half a million babies in the United States (12.5% of all babies) are born prematurely (before 37 completed weeks of pregnancy). Sadly, premature babies are more likely to die than full-term babies and many have short- and/or long-term health problems. Premature babies often have breathing problems, they are susceptible to life-threatening infections, and they are more likely to have learning and developmental disabilities than those born on time. The severity of these health problems depends on the degree of prematurity—preterm babies born between 34 and 36 weeks of pregnancy rarely develop severe disabilities, but a quarter of babies born before 28 weeks of pregnancy develop serious lasting disabilities and half have learning and behavioral problems. Although doctors have identified some risk factors for early delivery (for example, smoking), it is impossible to predict who will have an early birth and there is no effective way to prevent preterm births.
Why Was This Study Done?
Some researchers think that folate supplements may prevent preterm births. Folate (folic acid), a vitamin found in leafy green vegetables, fruits, and dried beans, helps to prevent neural tube birth defects. Consequently, women are encouraged to take folic acid supplements throughout (and preferably before) pregnancy and many governments now mandate that bread, pasta, and other grain products be fortified with folic acid to help women get sufficient folate. There is some evidence that women who deliver early have less folate in their blood than women who deliver at term. Furthermore, folate supplementation during pregnancy has increased the length of pregnancy in some but not all clinical trials. A possible explanation for these mixed results is that the duration of pregnancy reflects conditions in the earliest stages of pregnancy or before conception and that folate supplementation needs to start before conception to reduce the risk of preterm birth. In this study, the researchers test this idea by analyzing data collected from nearly 35,000 pregnant women enrolled in a study that was originally designed to investigate screening for Down's syndrome.
What Did the Researchers Do and Find?
During the first three months of their pregnancy, the women were asked whether they had taken folate supplements before conception. The duration of each pregnancy was estimated from ultrasound measurements taken early in the pregnancy and from the time of delivery. During the study, 1,658 women had spontaneous preterm deliveries before 37 weeks and 160 delivered before 32 weeks. After allowing for other maternal characteristics that might have affected the likelihood of preterm delivery, the risk of spontaneous preterm delivery between 20 and 28 weeks was 70% lower in women who took folate supplements for more than a year before becoming pregnant than in women who didn't take a supplement. Long-term folate supplementation also reduced the risk of preterm delivery between 28 and 32 weeks by 50% but did not affect the risk of preterm birth beyond 32 weeks. Folate supplementation for less than a year before conception did not reduce the risk of preterm birth, and folate supplementation was not associated with any other complications of pregnancy.
What Do These Findings Mean?
These findings show that folate supplementation for a year or more before conception is associated with a 50%–70% decrease in early (but not late) spontaneous preterm births and that the longer a woman takes folate supplements before becoming pregnant, the lower her risk of a preterm birth. Although the researchers allowed for maternal characteristics that might have affected the duration of pregnancy, it is possible that folate supplementation may not be responsible for the reduction in preterm birth risk seen in this study. For example, taking folate supplements may be a marker of healthy behavior and the women taking the supplements might have been doing something else that was reducing their risk of preterm birth. However, despite this and other limitations of this study, these findings suggest that long-term folate supplementation before conception is worth investigating further as a potential way to prevent preterm births.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000061.
This study is further discussed in a PLoS Medicine Perspective by Nicholas Fisk
The MedlinePlus encyclopedia contains a page on premature babies (in English and Spanish); MedlinePlus provides links to other information on premature babies (in English and Spanish)
The US National Institute of Child Health and Human Development provides information on preterm labor and birth
The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on preterm birth and on folic acid (in English and Spanish)
The Nemours Foundation, another nonprofit organization for child health, also provides information on premature babies (in English and Spanish)
The US Office of Dietary Supplements has a fact sheet on folate
doi:10.1371/journal.pmed.1000061
PMCID: PMC2671168  PMID: 19434228
13.  Defining the budding yeast chromatin-associated interactome 
We report here the first large-scale affinity purification and mass spectrometry (AP-MS) study of chromatin-associated protein, in which over 100 different baits involved in chromatin biology were studied by modified chromatin immunopurification (mChIP)-MS. In particular, focus was placed on poorly studied chromatin binding proteins, such as transcription factors, which have been underrepresented in previous AP-MS studies.mChIP-MS analysis of transcription factors identified dense networks of protein associated with chromatin that were composed of specific transcriptional co-activators, information not accessible through the use of classical AP-MS methods.Finally, we demonstrate that novel protein–protein interactions identified in study by mChIP have functional implications exemplified by the detailed study of both the ubiquitination of the proline isomerase Cpr1 and of histone chaperones involved in the regulation of the HTA1-HTB1 promoter.Our work demonstrates the value of targeted interactome studies, in which affinity purification methods are adapted to the needs of specific baits, as is the case for chromatin binding proteins.
The maintenance of cellular fitness requires living organisms to integrate multiple signals into coordinated outputs. Central to this process is the regulation of the expression of the genetic information encoded into DNA. As a result, there are numerous constraints imposed on gene expression. The access to DNA is restricted by the formation of nucleosomes, in which DNA is wrapped around histone octamers to form chromatin wherein the volume of DNA is considerably reduced. As such, nucleosome positioning is critical and must be defined precisely, particularly during transcription (Workman, 2006). Furthermore, nucleosomes can be actively assembled/disassembled by histone chaperones and can be made to ‘slide' along DNA by the actions of chromatin remodelers. Moreover, the histone proteins are heavily regulated at the expression level and by extensive post-translational modifications (PTMs) (Campos and Reinberg, 2009). Histone PTMs have also been shown to help recruit numerous chromatin-associated factors in accordance with the histone code (Strahl and Allis, 2000). Although our understanding of chromatin and its roles has improved, we still have limited knowledge of the chromatin-associated protein complexes and their interactions.
The characterization of biological systems and of specific subdomain within them, such as chromatin, remains a difficult task. An efficient approach to gain insight in the function of protein is to define its interactome. The underlying principle of protein interaction mapping is that proteins found to interact must be involved in common processes and localization, i.e., guilt by association. The large-scale mapping of proteins interactions allows to annotate protein of unknown functions, implicate protein of known functions in different processes and derive new hypothesis. This is possible because most proteins do not act in isolation but rather as part of complexes, and thus possess interaction partners that can now be detected with the right tools. AP-MS has emerged as a powerful tool for characterizing protein–protein interactions and biological systems in general (Gingras et al, 2007; Gstaiger and Aebersold, 2009).
Recently, we reported the development of a novel affinity purification approach termed mChIP, which was designed to improve the characterization of DNA binding proteins interactome (Lambert et al, 2009). The mChIP method consists of a single affinity purification step, whereby chromatin-associated proteins are isolated from mildly sonicated and gently clarified cellular extracts using magnetic beads coated with antibodies (Lambert et al, 2009; Figure 1A). As such, the mChIP approach maintains chromatin fragments in solution enabling their specific purification, something not previously possible in classical AP-MS methods (Lambert et al, 2009).
In this study, we report the utilization of mChIP followed by MS for the characterization of more than 100 proteins and their associated protein networks (Figure 1B). We initially focused on DNA-associated proteins that had been poorly characterized in past AP-MS studies, such as transcription factors. In addition, many histone modifiers, such as lysine acetyl transferases (KAT) and lysine methyl transferases, critical components of chromatin function and regulation, were also studied by mChIP. This resulted in raw non-redundant mChIP-MS data containing ∼9000 protein–protein interactions between ∼900 proteins. Following a two-step curation process designed to remove common contaminants and protein not specifically associated with the baits under study, a high confidence mChIP-MS data set was produced containing 2966 protein–protein interactions between 724 proteins (Figure 1B). It is important to note that our curation strategy was capable of maintaining the majority of the protein–protein interaction identified in previous AP-MS studies, while removing the bulk of protein–protein interaction not related to chromatin biology. Further analysis of the mChIP-MS data set revealed that for most bait tested, mChIP-MS resulted in the identification of more interaction partners than classical TAP-MS.
Visualization of the mChIP-MS data set was achieved by generating heat maps from two-dimensional hierarchical clustering of the bait–prey interactions. This revealed numerous clusters within our data set supporting functional relationship. For instance, mChIP analysis of the highly homologous heat-shock-inducible transcription factors Msn2 and Msn4 clustered with different transcriptional co-activators. Importantly, our analysis also revealed key differences in the co-activators associated with Msn2 and Msn4 relevant to their function. Another example that we explore in greater details is the Cpr1 proline isomerase, a known member of the Set3 complex (Pijnappel et al, 2001). mChIP-MS analysis of Cpr1 revealed an extended network of associated proteins, including the E3 ubiquitin ligase Bre1 and its association partner Lge1 (Figure 5A). This association raised the possibility of a direct action of Bre1/Lge1 on Cpr1 to ubiquitinate it. In targeted experiments, we observed that Cpr1 is in fact ubiquitinated in a process involving Bre1/Lge1 (Figure 5E), confirming their functional relationship. As such, mChIP is capable of uncovering novel protein–protein interactions with physiological impacts.
In this study, we report how the use of an AP-MS method designed for a given class of protein (chromatin-associated proteins) can help uncover numerous novel protein–protein interactions. Furthermore, our work detected dense chromatin-associated protein networks being co-purified with multiple transcription factors and other DNA binding proteins. The fact that even in the best-characterized model organism Saccharomyces cerevisiae, thousands of novel protein–protein interactions can be detected supports our view that targeted interactome studies are worthwhile and desirable. As such, the budding yeast interactome can still be consider incomplete and warrant further study.
We previously reported a novel affinity purification (AP) method termed modified chromatin immunopurification (mChIP), which permits selective enrichment of DNA-bound proteins along with their associated protein network. In this study, we report a large-scale study of the protein network of 102 chromatin-related proteins from budding yeast that were analyzed by mChIP coupled to mass spectrometry. This effort resulted in the detection of 2966 high confidence protein associations with 724 distinct preys. mChIP resulted in significantly improved interaction coverage as compared with classical AP methodology for ∼75% of the baits tested. Furthermore, mChIP successfully identified novel binding partners for many lower abundance transcription factors that previously failed using conventional AP methodologies. mChIP was also used to perform targeted studies, particularly of Asf1 and its associated proteins, to allow for a understanding of the physical interplay between Asf1 and two other histone chaperones, Rtt106 and the HIR complex, to be gained.
doi:10.1038/msb.2010.104
PMCID: PMC3018163  PMID: 21179020
affinity purification; chromatin-associated protein networks; mass spectrometry; nucleosome assembly factor Asf1; protein–DNA interaction
14.  Regulated aggregative multicellularity in a close unicellular relative of metazoa 
eLife  2013;2:e01287.
The evolution of metazoans from their unicellular ancestors was one of the most important events in the history of life. However, the cellular and genetic changes that ultimately led to the evolution of multicellularity are not known. In this study, we describe an aggregative multicellular stage in the protist Capsaspora owczarzaki, a close unicellular relative of metazoans. Remarkably, transition to the aggregative stage is associated with significant upregulation of orthologs of genes known to establish multicellularity and tissue architecture in metazoans. We further observe transitions in regulated alternative splicing during the C. owczarzaki life cycle, including the deployment of an exon network associated with signaling, a feature of splicing regulation so far only observed in metazoans. Our results reveal the existence of a highly regulated aggregative stage in C. owczarzaki and further suggest that features of aggregative behavior in an ancestral protist may had been co-opted to develop some multicellular properties currently seen in metazoans.
DOI: http://dx.doi.org/10.7554/eLife.01287.001
eLife digest
When living things made from many cells evolved from single-celled ancestors, it was a breakthrough in the history of life—and one that has occurred more than once. In fact, multicellular life has evolved independently at least 25 times, in groups as diverse as animals, fungi, plants, slime molds and seaweeds. There are broadly two ways to become multicellular. The most complex multicellular species, such as animals, will replicate a single cell, over and over, without separating the resultant cells. However, in species that are only occasionally multicellular, free-living cells tend instead to join together in one mass of many cells.
Evolution is constrained by its raw materials; so looking at the living relatives of a given species, or group, can lead to a better understanding of its evolution because its relatives contain clues about its ancestors. To gain insights into how animal multicellular life might have began; Sebé-Pedrós et al. studied the life cycle of the amoeboid organism Capsaspora owczarzaki. Found within the bodies of freshwater snails, this single-celled amoeba is a close relative of multicellular animals and could resemble one of their earliest ancestors.
At certain stages of the life cycle Sebé-Pedrós et al. noticed that individual amoebae gathered together to form a multicellular mass—something that had not been seen before in such a close relative of the animals. Moreover, the genes that ‘switched on’ when the amoebae began to aggregate are also found in animals; where, together with other genes, they control development and the formation of tissues. Sebé-Pedrós et al. suggest that the first multicellular animals could have recycled the genes that control the aggregation of single-celled species: in other words, genes that once controlled the changes that happen at different times in a life cycle, now control the changes that develop between different tissues at the same time.
Sebé-Pedrós et al. also observed that alternative splicing—a process that allows different proteins to be made from a single gene—occurs via two different mechanisms during the life cycle of Capsaspora. Most of the time Capsaspora employs a form of alternative splicing that is often seen in plants and fungi, and only rarely in animals; for the rest of the time it uses a form of alternative splicing similar to that used by animal cells.
The evolution of complex alternative splicing mechanisms is a hallmark feature of multicellular animals. The exploitation of two major forms of alternative splicing in Capsaspora could thus reflect an important transition during evolution that resulted in an increased diversity of proteins and in more complex gene regulation. Such a transition may ultimately have paved the way for the increased specialization of cell types seen in animals.
This glimpse into the possible transitions in gene regulation that contributed to the birth of multicellular animals indicates that the single-celled ancestor of the animals was likely more complex than previously thought. Future analyses of the animals’ close relatives may further improve our understanding of how single-celled organisms became multicellular animals.
DOI: http://dx.doi.org/10.7554/eLife.01287.002
doi:10.7554/eLife.01287
PMCID: PMC3870316  PMID: 24368732
opisthokonts; Capsaspora; alternative splicing; cell differentiation; evolutionary transitions; Other
15.  Cost-Effectiveness of Interventions to Promote Physical Activity: A Modelling Study 
PLoS Medicine  2009;6(7):e1000110.
Linda Cobiac and colleagues model the costs and health outcomes associated with interventions to improve physical activity in the population, and identify specific interventions that are likely to be cost-saving.
Background
Physical inactivity is a key risk factor for chronic disease, but a growing number of people are not achieving the recommended levels of physical activity necessary for good health. Australians are no exception; despite Australia's image as a sporting nation, with success at the elite level, the majority of Australians do not get enough physical activity. There are many options for intervention, from individually tailored advice, such as counselling from a general practitioner, to population-wide approaches, such as mass media campaigns, but the most cost-effective mix of interventions is unknown. In this study we evaluate the cost-effectiveness of interventions to promote physical activity.
Methods and Findings
From evidence of intervention efficacy in the physical activity literature and evaluation of the health sector costs of intervention and disease treatment, we model the cost impacts and health outcomes of six physical activity interventions, over the lifetime of the Australian population. We then determine cost-effectiveness of each intervention against current practice for physical activity intervention in Australia and derive the optimal pathway for implementation. Based on current evidence of intervention effectiveness, the intervention programs that encourage use of pedometers (Dominant) and mass media-based community campaigns (Dominant) are the most cost-effective strategies to implement and are very likely to be cost-saving. The internet-based intervention program (AUS$3,000/DALY), the GP physical activity prescription program (AUS$12,000/DALY), and the program to encourage more active transport (AUS$20,000/DALY), although less likely to be cost-saving, have a high probability of being under a AUS$50,000 per DALY threshold. GP referral to an exercise physiologist (AUS$79,000/DALY) is the least cost-effective option if high time and travel costs for patients in screening and consulting an exercise physiologist are considered.
Conclusions
Intervention to promote physical activity is recommended as a public health measure. Despite substantial variability in the quantity and quality of evidence on intervention effectiveness, and uncertainty about the long-term sustainability of behavioural changes, it is highly likely that as a package, all six interventions could lead to substantial improvement in population health at a cost saving to the health sector.
Please see later in the article for Editors' Summary
Editors' Summary
Background
The human body needs regular physical activity throughout life to stay healthy. Physical activity—any bodily movement produced by skeletal muscles that uses energy—helps to maintain a healthy body weight and to prevent or delay heart disease, stroke, type 2 diabetes, colon cancer, and breast cancer. In addition, physically active people feel better and live longer than physically inactive people. For an adult, 30 minutes of moderate physical activity—walking briskly, gardening, swimming, or cycling—at least five times a week is sufficient to promote and maintain health. But at least 60% of the world's population does not do even this modest amount of physical activity. The daily lives of people in both developed and developing countries are becoming increasingly sedentary. People are sitting at desks all day instead of doing manual labor; they are driving to work in cars instead of walking or cycling; and they are participating less in physical activities during their leisure time.
Why Was This Study Done?
In many countries, the chronic diseases that are associated with physical inactivity are now a major public-health problem; globally, physical inactivity causes 1.9 million deaths per year. Clearly, something has to be done about this situation. Luckily, there is no shortage of interventions designed to promote physical activity, ranging from individual counseling from general practitioners to mass-media campaigns. But which intervention or package of interventions will produce the optimal population health benefits relative to cost? Although some studies have examined the cost-effectiveness of individual interventions, different settings for analysis and use of different methods and assumptions make it difficult to compare results and identify which intervention approaches should be give priority by policy makers. Furthermore, little is known about the cost-effectiveness of packages of interventions. In this study, the researchers investigate the cost-effectiveness in Australia (where physical inactivity contributes to 10% of deaths) of a package of interventions designed to promote physical activity in adults using a standardized approach (ACE-Prevention) to the assessment of the cost-effectiveness of health-care interventions.
What Did the Researchers Do and Find?
The researchers selected six interventions for their study: general practitioner “prescription” of physical activity; general practitioner referral to an exercise physiologist; a mass-media campaign to promote physical activity; the TravelSmart car use reduction program; a campaign to encourage the use of pedometers to increase physical activity; and an internet-based program. Using published data on the effects of physical activity on the amount of illness and death caused by breast and colon cancer, heart disease, stroke, and type 2 diabetes and on the effectiveness of each intervention, the researchers calculated the health outcomes of each intervention in disability-adjusted life years (DALY; a year of healthy life lost because of premature death or disability) averted over the lifetime of the Australian population. They also calculated the costs associated with each intervention offset by the costs associated with the five conditions listed above. These analyses showed that the pedometer program and the mass-media campaign were likely to be the most cost-effective interventions. These interventions were also most likely to be cost-saving. Referral to an exercise physiologist was the least cost-effective intervention. The other three interventions, though unlikely to be cost-saving, were likely to be cost-effective. Finally, a package of all six interventions would be cost-effective and would avert 61,000 DALYs, a third of what could be achieved if every Australian did 30 minutes of physical activity five times a week.
What Do These Findings Mean?
As in all modeling studies, these findings depend on the quality of the data and on the assumptions included by the researchers in their calculations. Unfortunately, there was substantial variability in the quantity and quality of evidence on the effectiveness of each intervention and uncertainty about the long-term effects of each intervention. Nevertheless, the findings presented in this study suggest that the assessment of the cost-effectiveness of a combination of interventions designed to promote physical activity might provide policy makers with some guidance about the best way to reduce the burden of disease caused by physical inactivity. More specifically, for Australia, these findings suggest that the package of the six interventions considered here is likely to provide a cost-effective way to substantially improve the health of the nation.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000110.
The World Health Organization provides information about physical activity and health (in several languages); it also provides an explanation of DALYs
The US Centers for Disease Control and Prevention provides information on physical activity for different age groups and for health professionals
The UK National Health Service information source Choices also explains the benefits of regular physical activity
MedlinePlus has links to other resources about exercise and physical fitness (in English and Spanish)
The University of Queensland Web site has more information on ACE-Prevention (Assessing Cost-Effectiveness Prevention)
doi:10.1371/journal.pmed.1000110
PMCID: PMC2700960  PMID: 19597537
16.  Designing a Community Engagement Framework for a New Dengue Control Method: A Case Study from Central Vietnam 
Background
The Wolbachia strategy aims to manipulate mosquito populations to make them incapable of transmitting dengue viruses between people. To test its efficacy, this strategy requires field trials. Public consultation and engagement are recognized as critical to the future success of these programs, but questions remain regarding how to proceed. This paper reports on a case study where social research was used to design a community engagement framework for a new dengue control method, at a potential release site in central Vietnam.
Methodology/Principal Findings
The approach described here, draws on an anthropological methodology and uses both qualitative and quantitative methods to design an engagement framework tailored to the concerns, expectations, and socio-political setting of a potential trial release site for Wolbachia-infected Aedes aegypti mosquitoes. The process, research activities, key findings and how these were responded to are described. Safety of the method to humans and the environment was the most common and significant concern, followed by efficacy and impact on local lives. Residents expected to be fully informed and engaged about the science, the project, its safety, the release and who would be responsible should something go wrong. They desired a level of engagement that included regular updates and authorization from government and at least one member of every household at the release site.
Conclusions/Significance
Results demonstrate that social research can provide important and reliable insights into public concerns and expectations at a potential release site, as well as guidance on how these might be addressed. Findings support the argument that using research to develop more targeted, engagement frameworks can lead to more sensitive, thorough, culturally comprehensible and therefore ethical consultation processes. This approach has now been used successfully to seek public input and eventually support for releases Wolbachia-infected mosquitoes, in two different international settings - Australia and Vietnam.
Author Summary
In recent years, a number of new strategies using novel technologies for the control of dengue fever control have emerged. These strategies are notably different from their predecessors and not without controversy. Many also require open release field trials to test their efficacy. Public consultation and engagement are recognized as critical to the future success of these programs, but questions remain regarding how to proceed. In this paper we describe an approach to public engagement that uses social research to design an engagement framework and communication materials tailored to the concerns, expectations, and socio-political setting of potential trial release sites. This approach was developed and implemented in Australia (2008–2010) where the first publicly supported field trials occurred January 2011. We report here on the implementation of this approach in Vietnam (2009–2010) where the second release will occur in 2014. This paper describes the process, research activities, outcomes and key findings from the Vietnamese field site. It highlights key public concerns and expectations about engagement and authorization and shows how these were used to develop a more targeted, culturally appropriate and comprehensible engagement framework and communication materials. The paper demonstrates the viability of this approach to community engagement for new dengue control strategies, in a ‘developing’ country context.
doi:10.1371/journal.pntd.0002794
PMCID: PMC4031131  PMID: 24853391
17.  Ideas and Enhancements Related to Mobile Applications to Support Type 1 Diabetes 
JMIR mHealth and uHealth  2013;1(2):e12.
Background
Mobile devices have become increasingly important to young people who now use them to access a wide variety of health-related information. Research and policy related to the integration of health information and support with this technology do not effectively consider the viewpoint of a younger patient. Views of young people with type 1 diabetes are vital in developing quality services and improving their own health-related quality of life (HRQOL), yet research on their lifestyle and use of Web and mobile technology to support their condition and in non–health-related areas is sparse.
Objective
To develop insight into young people with type 1 diabetes and their current use of Web and mobile technology and its potential impact on HRQOL. This can be achieved by constructing an in-depth picture of their day-to-day experiences from qualitative interviewing and exploring how they make use of technology in their lives and in relation to their condition and treatment. The goal was then to build something to help them, using the researcher’s technical expertise and seeking users’ opinions during the design and build, utilizing sociotechnical design principles.
Methods
Data were collected by semistructured, in-depth qualitative interviews (N=9) of young people with type 1 diabetes aged 18-21. Interviews were transcribed and loaded onto NVivo for theme identification. Data analysis was undertaken during initial interviews (n=4) to locate potential ideas and enhancements for technical development. Latter interviews (n=5) assisted in the iterative sociotechnical design process of the development and provided additional developmental ideas.
Results
Six themes were identified providing an understanding of how participants lived with and experienced their condition and how they used technology. Four technological suggestions for improvement were taken forward for prototyping. One prototype was developed as a clinically approved app. A number of ideas for new mobile apps and enhancements to currently existing apps that did not satisfactorily cater to this age group’s requirements for use in terms of design and functionality were suggested by interviewees but were not prototyped.
Conclusions
This paper outlines the nonprototyped suggestions from interviewees and argues that young people with type 1 diabetes have a key role to play in the design and implementation of new technology to support them and improve HRQOL. It is vital to include and reflect on their suggestions as they have a radically different view of technology than either their parents or practitioners. We need to consider the relationship to technology that young people with type 1 diabetes have, and then reflect on how this might make a difference to them and when it might not be a suitable mechanism to use.
doi:10.2196/mhealth.2567
PMCID: PMC4114509  PMID: 25100684
patient education; type 1 diabetes; mobile; apps; sociotechnical design; lifeworld; humanising healthcare; patient voice; empathy; ideas; enhancements
18.  S28 peptidases: lessons from a seemingly 'dysfunctional' family of two 
BMC Biology  2010;8:87.
Abstract
A recent paper in BMC Structural Biology reports the crystal structure of human prolylcarboxypeptidase (PRCP), one of the two members of the S28 peptidase family. Comparison of the substrate-binding site of PRCP with that of its family partner, dipeptidyl dipeptidase 7 (DPP7), helps to explain the different enzymatic activities of these structurally similar proteins, and also reveals a novel apparent charge-relay system in PRCP involving the active-site catalytic histidine.
See research article: http://www.biomedcentral.com/1472-6807/10/16/
Commentary
The S28 serine peptidase family is something of an enzymatic odd couple. While showing low sequence similarity to all proteins except each other, the two known family members appear to be at odds functionally; one, prolylcarboxypeptidase (PRCP), is a carboxypeptidase that cleaves single hydrophobic residues from the carboxyl termini of proteins that end with a Pro-X motif (where X is any hydrophobic amino acid), while the other, human dipeptidyl peptidase (DPP7), is an aminopeptidase that cleaves amino-terminal X-Pro dipeptides. The structural basis of this orthogonal specificity would undoubtedly be interesting, and a recent report in BMC Structural Biology from the Merck Global Structural Biology group (Soisson et al. [1]) has now met that expectation. In addition they reveal a new wrinkle to the iconic catalytic triad common to most serine hydrolases.
The practical pharmaceutical interest in both these enzymes as potential drug targets is at present speculative. PRCP can inactivate a number of peptide hormones, such as angiotensin II, III and prekallikrein, implicating a role for the enzyme in hypertension, tissue proliferation and smooth-muscle growth. These properties suggest that this enzyme may well be a useful target for hypertension and anti-inflammatory therapy [2]. Another (non-S28 family) dipeptidyl dipeptidase (DPP4) is a major drug target in type 2 diabetes, and Merck has already developed a successful inhibitor of DPP4, the anti-hyperglycemic drug sitagliptin, for the treatment of type 2 diabetes. The DPP enzymes are rich in biological functions and other drug targets emerging from the group are possible [3].
doi:10.1186/1741-7007-8-87
PMCID: PMC2893137  PMID: 20598110
19.  Choice is not the issue. The misrepresentation of healthcare in bioethical discourse 
Journal of Medical Ethics  2010;37(4):212-215.
The principle of respect for autonomy has shaped much of the bioethics' discourse over the last 50 years, and is now most commonly used in the meaning of respecting autonomous choice. This is probably related to the influential concept of informed consent, which originated in research ethics and was soon also applied to the field of clinical medicine. But while available choices in medical research are well defined, this is rarely the case in healthcare. Consideration of ordinary medical practice reveals that the focus on patient choice does not properly grasp the moral aspects involved in healthcare. Medical decisions are often portrayed as if doctors and patients in confidence confront specific decisions about examinations or treatment, yet the reality often involves many different participants, with decisions being made over time and space. Indeed, most of the decisions are never even presented to patients, as it would be unethical to suggest something that is not medically justifiable. The options patients do confront are somewhat arbitrarily constructed within the narrow framework of both what is deemed to be medically appropriate and how the healthcare system is organised practically. While the autonomy discourse has proven valuable, a failure to distinguish between the fields of medical research and clinical medicine has generated a focus on patient choice that does not reflect what is really at stake in healthcare settings. This is alarming, because the current discourse misrepresents medical practice in a way that actually contributes to bioethical self-delusion.
doi:10.1136/jme.2010.039172
PMCID: PMC3063455  PMID: 21131609
Personal autonomy; bioethics; medical ethics; professional practice; delivery of healthcare; applied and professional ethics; philosophy of medicine; informed consent
20.  A Snapshot of the Population Structure of Branchiostoma lanceolatum in the Racou Beach, France, during Its Spawning Season 
PLoS ONE  2011;6(4):e18520.
A methodology for inducing spawning in captivity of the lancelet Branchiostoma lanceolatum has been developed recently with animals collected at the Racou beach, in the southern coast of France. An increasing amount of laboratories around the world are now working on the evolution of developmental mechanisms (Evo-Devo) using amphioxus collected in this site. Thus, today, the development of new aquaculture techniques for keeping amphioxus in captivity is needed and the study of the natural conditions at which amphioxus is exposed in the Racou beach during their spawning season becomes necessary. We have investigated the amphioxus distribution, size frequency, and population structure in the Racou beach during its natural spawning season using multivariate methods (redundancy analysis and multiple regression). We found a clear preference of amphioxus for sandy sites, something that seems to be a general behaviour of different amphioxus species around the world. We have also estimated the amphioxus growth rate and we show how the animals are preferentially localized in shallow waters during April and June.
doi:10.1371/journal.pone.0018520
PMCID: PMC3078106  PMID: 21525973
21.  Guidelines, Editors, Pharma And The Biological Paradigm Shift 
Mens Sana Monographs  2007;5(1):27-30.
Private investment in biomedical research has increased over the last few decades. At most places it has been welcomed as the next best thing to technology itself. Much of the intellectual talent from academic institutions is getting absorbed in lucrative positions in industry. Applied research finds willing collaborators in venture capital funded industry, so a symbiotic growth is ensured for both.
There are significant costs involved too. As academia interacts with industry, major areas of conflict of interest especially applicable to biomedical research have arisen. They are related to disputes over patents and royalty, hostile encounters between academia and industry, as also between public and private enterprise, legal tangles, research misconduct of various types, antagonistic press and patient-advocate lobbies and a general atmosphere in which commercial interest get precedence over patient welfare.
Pharma image stinks because of a number of errors of omission and commission. A recent example is suppression of negative findings about Bayer's Trasylol (Aprotinin) and the marketing maneuvers of Eli Lilly's Xigris (rhAPC). Whenever there is a conflict between patient vulnerability and profit motives, pharma often tends to tilt towards the latter. Moreover there are documents that bring to light how companies frequently cross the line between patient welfare and profit seeking behaviour.
A voluntary moratorium over pharma spending to pamper drug prescribers is necessary. A code of conduct adopted recently by OPPI in India to limit pharma company expenses over junkets and trinkets is a welcome step.
Clinical practice guidelines (CPG) are considered important as they guide the diagnostic/therapeutic regimen of a large number of medical professionals and hospitals and provide recommendations on drugs, their dosages and criteria for selection. Along with clinical trials, they are another area of growing influence by the pharmaceutical industry. For example, in a relatively recent survey of 2002, it was found that about 60% of 192 authors of clinical practice guidelines reported they had financial connections with the companies whose drugs were under consideration. There is a strong case for making CPGs based not just on effectivity but cost effectivity. The various ramifications of this need to be spelt out. Work of bodies like the Appraisal of Guidelines Research and Evaluation (AGREE) Collaboration and Guidelines Advisory Committee (GAC) are also worth a close look.
Even the actions of Foundations that work for disease amelioration have come under scrutiny. The process of setting up ‘Best Practices’ Guidelines for interactions between the pharmaceutical industry and clinicians has already begun and can have important consequences for patient care. Similarly, Good Publication Practice (GPP) for pharmaceutical companies have also been set up aimed at improving the behaviour of drug companies while reporting drug trials
The rapidly increasing trend toward influence and control by industry has become a concern for many. It is of such importance that the Association of American Medical Colleges has issued two relatively new documents - one, in 2001, on how to deal with individual conflicts of interest; and the other, in 2002, on how to deal with institutional conflicts of interest in the conduct of clinical research. Academic Medical Centers (AMCs), as also medical education and research institutions at other places, have to adopt means that minimize their conflicts of interest.
Both medical associations and research journal editors are getting concerned with individual and institutional conflicts of interest in the conduct of clinical research and documents are now available which address these issues. The 2001 ICMJE revision calls for full disclosure of the sponsor's role in research, as well as assurance that the investigators are independent of the sponsor, are fully accountable for the design and conduct of the trial, have independent access to all trial data and control all editorial and publication decisions. However the findings of a 2002 study suggest that academic institutions routinely participate in clinical research that does not adhere to ICMJE standards of accountability, access to data and control of publication.
There is an inevitable slant to produce not necessarily useful but marketable products which ensure the profitability of industry and research grants outflow to academia. Industry supports new, not traditional, therapies, irrespective of what is effective. Whatever traditional therapy is supported is most probably because the company concerned has a product with a big stake there, which has remained a ‘gold standard’ or which that player thinks has still some ‘juice’ left.
Industry sponsorship is mainly for potential medications, not for trying to determine whether there may be non-pharmacological interventions that may be equally good, if not better. In the paradigm shift towards biological psychiatry, the role of industry sponsorship is not overt but probably more pervasive than many have realised, or the right thinking may consider good, for the health of the branch in the long run.
An issue of major concern is protection of the interests of research subjects. Patients agree to become research subjects not only for personal medical benefit but, as an extension, to benefit the rest of the patient population and also advance medical research.
We all accept that industry profits have to be made, and investment in research and development by the pharma industry is massive. However, we must also accept there is a fundamental difference between marketing strategies for other entities and those for drugs.
The ultimate barometer is patient welfare and no drug that compromises it can stand the test of time. So, how does it make even commercial sense in the long term to market substandard products? The greatest mistake long-term players in industry may make is try to adopt the shady techniques of the upstart new entrant. Secrecy of marketing/sales tactics, of the process of manufacture, of other strategies and plans of business expansion, of strategies to tackle competition are fine business tactics. But it is critical that secrecy as a tactic not extend to reporting of research findings, especially those contrary to one's product.
Pharma has no option but to make a quality product, do comprehensive adverse reaction profiles, and market it only if it passes both tests.
Why does pharma adopt questionable tactics? The reasons are essentially two:
What with all the constraints, a drug comes to the pharmacy after huge investments. There are crippling overheads and infrastructure costs to be recovered. And there are massive profit margins to be maintained. If these were to be dependent only on genuine drug discoveries, that would be taking too great a risk.Industry players have to strike the right balance between profit making and credibility. In profit making, the marketing champions play their role. In credibility ratings, researchers and paid spokes-persons play their role. All is hunky dory till marketing is based on credibility. When there is nothing available to make for credibility, something is projected as one and marketing carried out, in the calculated hope that profits can accrue, since profit making must continue endlessly. That is what makes pharma adopt even questionable means to make profits.
Essentially, there are four types of drugs. First, drugs that work and have minimal side-effects; second, drugs which work but have serious side-effects; third, drugs that do not work and have minimal side-effects; and fourth, drugs which work minimally but have serious side-effects. It is the second and fourth types that create major hassles for industry. Often, industry may try to project the fourth type as the second to escape censure.
The major cat and mouse game being played by conscientious researchers is in exposing the third and fourth for what they are and not allowing industry to palm them off as the first and second type respectively. The other major game is in preventing the second type from being projected as the first. The third type are essentially harmless, so they attract censure all right and some merriment at the antics to market them. But they escape anything more than a light rap on the knuckles, except when they are projected as the first type.
What is necessary for industry captains and long-term players is to realise:
Their major propelling force can only be producing the first type. 2. They accept the second type only till they can lay their hands on the first. 3. The third type can be occasionally played around with to shore up profits, but never by projecting them as the first type. 4. The fourth type are the laggards, real threat to credibility and therefore do not deserve any market hype or promotion.
In finding out why most pharma indulges in questionable tactics, we are lead to some interesting solutions to prevent such tactics with the least amount of hassles for all concerned, even as both profits and credibility are kept intact.
doi:10.4103/0973-1229.32176
PMCID: PMC3192391  PMID: 22058616
Academia; Pharmaceutical Industry; Clinical Practice Guidelines; Best Practice Guidelines; Academic Medical Centers; Medical Associations; Research Journals; Clinical Research; Public Welfare; Pharma Image; Corporate Welfare; Biological Psychiatry; Law Suits Against Industry
22.  Diet and Physical Activity for the Prevention of Noncommunicable Diseases in Low- and Middle-Income Countries: A Systematic Policy Review 
PLoS Medicine  2013;10(6):e1001465.
Carl Lachat and colleagues evaluate policies in low- and middle-income countries addressing salt and fat consumption, fruit and vegetable intake, and physical activity, key risk factors for non-communicable diseases.
Please see later in the article for the Editors' Summary
Background
Diet-related noncommunicable diseases (NCDs) are increasing rapidly in low- and middle-income countries (LMICs) and constitute a leading cause of mortality. Although a call for global action has been resonating for years, the progress in national policy development in LMICs has not been assessed. This review of strategies to prevent NCDs in LMICs provides a benchmark against which policy response can be tracked over time.
Methods and Findings
We reviewed how government policies in LMICs outline actions that address salt consumption, fat consumption, fruit and vegetable intake, or physical activity. A structured content analysis of national nutrition, NCDs, and health policies published between 1 January 2004 and 1 January 2013 by 140 LMIC members of the World Health Organization (WHO) was carried out. We assessed availability of policies in 83% (116/140) of the countries. NCD strategies were found in 47% (54/116) of LMICs reviewed, but only a minority proposed actions to promote healthier diets and physical activity. The coverage of policies that specifically targeted at least one of the risk factors reviewed was lower in Africa, Europe, the Americas, and the Eastern Mediterranean compared to the other two World Health Organization regions, South-East Asia and Western Pacific. Of the countries reviewed, only 12% (14/116) proposed a policy that addressed all four risk factors, and 25% (29/116) addressed only one of the risk factors reviewed. Strategies targeting the private sector were less frequently encountered than strategies targeting the general public or policy makers.
Conclusions
This review indicates the disconnection between the burden of NCDs and national policy responses in LMICs. Policy makers urgently need to develop comprehensive and multi-stakeholder policies to improve dietary quality and physical activity.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Noncommunicable diseases (NCDs)—chronic medical conditions including cardiovascular diseases (heart disease and stroke), diabetes, cancer, and chronic respiratory diseases (chronic obstructive pulmonary disease and asthma)—are responsible for two-thirds of the world's deaths. Nearly 80% of NCD deaths, close to 30 million per year, occur in low- and middle-income countries (LMICs), where they are also rising most rapidly. Diet and lifestyle (including smoking, lack of exercise, and harmful alcohol consumption) influence a person's risk of developing an NCD and of dying from it. Because they can be modified, these risk factors have been at the center of strategies to combat NCDs. In 2004, the World Health Organization (WHO) adopted the Global Strategy on Diet, Physical Activity and Health. For diet, it recommended that individuals achieve energy balance and a healthy weight; limit energy intake from total fats and shift fat consumption away from saturated fats to unsaturated fats and towards the elimination of trans-fatty acids; increase consumption of fruits, vegetables, legumes, whole grains, and nuts; limit the intake of free sugars; and limit salt consumption from all sources and ensure that salt is iodized. For physical activity, it recommended at least 30 minutes of regular, moderate-intensity physical activity on most days throughout a person's life.
Why Was This Study Done?
By signing onto the Global Strategy in 2004, WHO member countries agreed to implement it with high priority. A first step of implementation is usually the development of local policies. Consequently, one of the four objectives of the WHO Global Strategy is “to encourage the development, strengthening and implementation of global, regional, national and community policies and action plans to improve diets and increase physical activity.” Along the same lines, in 2011 the United Nations held a high-level meeting in which the need to accelerate the policy response to the NCD epidemic was emphasized. This study was done to assess the existing national policies on NCD prevention in LMICs. Specifically, the researchers examined how well those policies matched the WHO recommendations for intake of salt, fat, and fruits and vegetables, as well as the recommendations for physical activity.
What Did the Researchers Do and Find?
The researchers searched the Internet (including websites of relevant ministries and departments) for all publicly available national policies related to diet, nutrition, NCDs, and health from all 140 WHO member countries classified as LMICs by the World Bank in 2011. For countries for which the search did not turn up policies, the researchers sent e-mail requests to the relevant national authorities, to the regional WHO offices, and to personal contacts. All documents dated from 1 January 2004 to 1 January 2013 that included national objectives and guidelines for action regarding diet, physical exercise, NCD prevention, or a combination of the three, were analyzed in detail.
Most of the policies obtained were not easy to find and access. For 24 countries, particularly in the Eastern Mediterranean, the researchers eventually gave up, unable to establish whether relevant national policies existed. Of the remaining 116 countries, 29 countries had no relevant policies, and another 30 had policies that failed to mention specifically any of the diet-related risk factors included in the analysis. Fifty-four of the 116 countries had NCD policies that addressed at least one of the risk factors. Thirty-six national policy documents contained strategies to increase fruit and vegetable intake, 20 addressed dietary fat consumption, 23 aimed to limit salt intake, and 35 had specific actions to promote physical activity. Only 14 countries, including Jamaica, the Philippines, Iran, and Mongolia, had policies that addressed all four risk factors. The policies of 27 countries mentioned only one of the four risk factors.
Policies primarily targeted consumers and government agencies and failed to address the roles of the business community or civil society. Consistent with this, most were missing plans, mechanisms, and incentives to drive collaborations between the different stakeholders.
What Do These Findings Mean?
More than eight years after the WHO Global Strategy was agreed upon, only a minority of the LMICs included in this analysis have comprehensive policies in place. Developing policies and making them widely accessible is a likely early step toward specific implementation and actions to prevent NCDs. These results therefore suggest that not enough emphasis is placed on NCD prevention in these countries through actions that have been proven to reduce known risk factors. That said, the more important question is what countries are actually doing to combat NCDs, something not directly addressed by this analysis.
In richer countries, NCDs have for decades been the leading cause of sickness and death, and the fact that public health strategies need to emphasize NCD prevention is now widely recognized. LMICs not only have more limited resources, they also continue to carry a large burden from infectious diseases. It is therefore not surprising that shifting resources towards NCD prevention is a difficult process, even if the human cost of these diseases is massive and increasing. That only about 3% of global health aid is aimed at NCD prevention does not help the situation.
The authors argue that one step toward improving the situation is better sharing of best practices and what works and what doesn't in policy development. They suggest that an open-access repository like one that exists for Europe could improve the situation. They offer to organize, host, and curate such a resource under the auspices of WHO, starting with the policies retrieved for this study, and they invite submission of additional policies and updates.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001465.
This study is further discussed in a PLOS Medicine Perspective by Stuckler and Basu
The WHO website on diet and physical activity contains links to various documents, including a diet and physical activity implementation toolbox that contains links to the 2004 Global Strategy document and a Framework to Monitor and Evaluate Implementation
There is a 2011 WHO primer on NCDs entitled Prioritizing a Preventable Epidemic
A recent PLOS Medicine editorial and call for papers addressing the global disparities in the burden from NCDs
A PLOS Blogs post entitled Politics and Global HealthAre We Missing the Obvious? and associated comments discuss the state of the fight against NCDs in early 2013
The NCD Alliance was founded by the Union for International Cancer Control, the International Diabetes Federation, the World Heart Federation, and the International Union Against Tuberculosis and Lung Disease; its mission is to combat the NCD epidemic by putting health at the center of all policies
The WHO European Database on Nutrition, Obesity and Physical Activity (NOPA) contains national and subnational surveillance data, policy documents, actions to implement policy, and examples of good practice in programs and interventions for the WHO European member states
doi:10.1371/journal.pmed.1001465
PMCID: PMC3679005  PMID: 23776415
23.  Tobacco: Its historical, cultural, oral, and periodontal health association 
This article provides information on the origin of tobacco and its subsequent spread throughout the world. In the era of the migration of communities, tobacco use gradually gained access and subsequently migrated along with the migrants, establishing in different locations. Probably at that time people were unaware of the health hazards and were using tobacco in treating certain ailments. Much has been known and written about tobacco in the context of oral and general health hazards but little has been explored and is known to many about where from and how this plant, which is now used in various forms, and speading widely. In what form, where, and how it had been served in religious rituals and considered for treatment or remedy of certain ailments in those days could not certainly be known. In the 21st century, people are considering hazardous tobacco as beneficial for their teeth, good for concentration of mind, and something which keeps them engaged. Even many professionals, though knowing the deleterious effects, are still using tobacco and gutkha in one or the other form. This article has been designed to revive the awareness for health hazards of tobacco and similar products. A pilot project questionnaire survey comprising this subject involving the educated mass has already been started and will be produced after analysis of data in part II of this paper.
doi:10.4103/2231-0762.115708
PMCID: PMC3894096  PMID: 24478974
Bidee; gutkha; naswar; paan; shisha; tobacco
24.  High temperature sensitivity is intrinsic to voltage-gated potassium channels 
eLife  2014;3:e03255.
Temperature-sensitive transient receptor potential (TRP) ion channels are members of the large tetrameric cation channels superfamily but are considered to be uniquely sensitive to heat, which has been presumed to be due to the existence of an unidentified temperature-sensing domain. Here we report that the homologous voltage-gated potassium (Kv) channels also exhibit high temperature sensitivity comparable to that of TRPV1, which is detectable under specific conditions when the voltage sensor is functionally decoupled from the activation gate through either intrinsic mechanisms or mutations. Interestingly, mutations could tune Shaker channel to be either heat-activated or heat-deactivated. Therefore, high temperature sensitivity is intrinsic to both TRP and Kv channels. Our findings suggest important physiological roles of heat-induced variation in Kv channel activities. Mechanistically our findings indicate that temperature-sensing TRP channels may not contain a specialized heat-sensor domain; instead, non-obligatory allosteric gating permits the intrinsic heat sensitivity to drive channel activation, allowing temperature-sensitive TRP channels to function as polymodal nociceptors.
DOI: http://dx.doi.org/10.7554/eLife.03255.001
eLife digest
If you touch something too hot, it can cause you pain and damage your skin. Sensing the heat given off by an object or the temperature of the environment is possible, at least in part, because of proteins called temperature-sensitive TRP ion channels. These proteins are found in the cell membranes of nerve endings that are underneath the skin; and they open in response to heat, allowing ions to flow into the nerve cell. This in turn triggers a nerve impulse that is sent to our central nervous system and is perceived as heat and/or pain.
The ability to sense heat was thought to be unique to these TRP ion channels, and it was believed that these ion channels contained an as-yet unidentified temperature-sensing domain. However, Yang and Zheng now report that similar ion channels, which open in response to changes in the voltage that exists across a cell's membrane, are also sensitive to changes in temperature.
The temperature response of these ‘voltage-gated channels’ had largely eluded the attention of researchers in the past. This is because parts of the ion channel—which act like a ‘voltage sensor’ and only shift when the membrane voltage changes—normally keep the channel closed and directly open the channel when they move. Like all other proteins, ion channels are made from smaller building blocks called amino acids; and by changing some of the amino acids in the voltage-gated channel Yang and Zheng could decouple these normally linked actions. The changes to the channel meant that it did not immediately open when the voltage sensor moved; and decreasing the concentration of calcium ions inside the cell had the same effect as changing these amino acids. Both approaches revealed that, after a change in membrane voltage caused the voltage sensor to move, the ion channel remained closed until a high temperature caused it to open. Yang and Zheng revealed that the response of the modified voltage-gated channel to temperature was comparable to that of a typical heat-sensitive TRP ion channel.
Further experiments showed that replacing some of the amino acids in the voltage-gated potassium ion channel with different amino acids could cause the channel to be either opened or closed by heat.
The findings of Yang and Zheng indicate that temperature-sensing TRP channels may not contain a specialized heat-sensor domain. Instead, as these TRP ion channels do not require other parts of the protein to move in order to open the channel, they can be activated by their own inherent sensitivity to heat.
DOI: http://dx.doi.org/10.7554/eLife.03255.002
doi:10.7554/eLife.03255
PMCID: PMC4123715  PMID: 25030910
TRP channel; potassium channel; temperature sensing; gating; conformational changes; allosteric coupling; none
25.  Probe Microphone Measurements: 20 Years of Progress 
Trends in Amplification  2001;5(2):35-68.
Probe-microphone testing was conducted in the laboratory as early as the 1940s (e.g., the classic work of Wiener and Ross, reported in 1946), however, it was not until the late 1970s that a “dispenser friendly” system was available for testing hearing aids in the real ear. In this case, the term “dispenser friendly,” is used somewhat loosely. The 1970s equipment that I'm referring to was first described in a paper that was presented by Earl Harford, Ph.D. in September of 1979 at the International Ear Clinics' Symposium in Minneapolis. At this meeting, Earl reported on his clinical experiences of testing hearing aids in the real ear using a miniature (by 1979 standards) Knowles microphone. The microphone was coupled to an interfacing impedance matching system (developed by David Preves, Ph.D., who at the time worked at Starkey Laboratories) which could be used with existing hearing aid analyzer systems (see Harford, 1980 for review of this early work). Unlike today's probe tube microphone systems, this early method of clinical real-ear measurement involved putting the entire microphone (about 4mm by 5mm by 2mm) in the ear canal down by the eardrum of the patient. If you think cerumen is a problem with probe-mic measurements today, you should have seen the condition of this microphone after a day's work!
While this early instrumentation was a bit cumbersome, we quickly learned the advantages that probe-microphone measures provided in the fitting of hearing aids. We frequently ran into calibration and equalization problems, not to mention a yelp or two from the patient, but the resulting information was worth the trouble.
Help soon arrived. In the early 1980s, the first computerized probe-tube microphone system, the Rastronics CCI-10 (developed in Denmark by Steen Rasmussen), entered the U.S. market (Nielsen and Rasmussen, 1984). This system had a silicone tube attached to the microphone (the transmission of sound through this tube was part of the calibration process), which eliminated the need to place the microphone itself in the ear canal. By early 1985, three or four different manufactures had introduced this new type of computerized probe-microphone equipment, and this hearing aid verification procedure became part of the standard protocol for many audiology clinics. At his time, the POGO (Prescription Of Gain and Output) and Libby 1/3 prescriptive fitting methods were at the peak of their popularity, and a revised NAL (National Acoustic Laboratories) procedure was just being introduced. All three of these methods were based on functional gain, but insertion gain easily could be substituted, and therefore, manufacturers included calculation of these prescriptive targets as part of the probe-microphone equipment software. Audiologists, frustrated with the tedious and unreliable functional gain procedure they had been using, soon developed a fascination with matching real-ear results to prescriptive targets on a computer monitor.
In some ways, not a lot has changed since those early days of probe-microphone measurements. Most people who use this equipment simply run a gain curve for a couple inputs and see if it's close to prescriptive target—something that could be accomplished using the equipment from 1985. Contrary to the predictions of many, probe-mic measures have not become the “standard hearing aid verification procedure.” (Mueller and Strouse, 1995). There also has been little or no increase in the use of this equipment in recent years. In 1998, I reported on a survey that was conducted by The Hearing Journal regarding the use of probe-microphone measures (Mueller, 1998). We first looked at what percent of people dispensing hearing aids own (or have immediate access to) probe-microphone equipment. Our results showed that 23% of hearing instrument specialists and 75% of audiologists have this equipment. Among audiologists, ownership varied among work settings: 91% for hospitals/clinics, 73% for audiologists working for physicians, and 69% for audiologists in private practice. But more importantly, and a bit puzzling, was the finding that showed that nearly one half of the people who fit hearing aids and have access to this equipment, seldom or never use it.
I doubt that the use rate of probe-microphone equipment has changed much in the last three years, and if anything, I suspect it has gone down. Why do I say that? As programmable hearing aids have become the standard fitting in many clinics, it is tempting to become enamoured with the simulated gain curves on the fitting screen, somehow believing that this is what really is happening in the real ear. Additionally, some dispensers have been told that you can't do reliable probe-mic testing with modern hearing aids—this of course is not true, and we'll address this issue in the Frequently Asked Questions portion of this paper.
The infrequent use of probe-mic testing among dispensers is discouraging, and let's hope that probe-mic equipment does not suffer the fate of the rowing machine stored in your garage. A lot has changed over the years with the equipment itself, and there are also expanded clinical applications and procedures. We have new manufacturers, procedures, acronyms and noises. We have test procedures that allow us to accurately predict the output of a hearing aid in an infant's ear. We now have digital hearing aids, which provide us the opportunity to conduct real-ear measures of the effects of digital noise reduction, speech enhancement, adaptive feedback, expansion, and all the other features. Directional microphone hearing aids have grown in popularity and what better way to assess the real-ear directivity than with probe-mic measures? The array of assistive listening devices has expanded, and so has the role of the real-ear assessment of these products. And finally, with today's PC -based systems, we can program our hearing aids and simultaneously observe the resulting real-ear effects on the same fitting screen, or even conduct an automated target fitting using earcanal monitoring of the output. There have been a lot of changes, and we'll talk about all of them in this issue of Trends.
doi:10.1177/108471380100500202
PMCID: PMC4168927  PMID: 25425897

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