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Ancient Science of Life  1986;6(1):42-46.
This article attempts to trace the origin of the systems concerned as cosmology and humorology. The three elements Earth, Water and Fire formulated as the first cosmology are essential to human lives which are interpreted scientifically here.
PMCID: PMC3331399  PMID: 22557547
2.  Evolution of Minimal Specificity and Promiscuity in Steroid Hormone Receptors 
PLoS Genetics  2012;8(11):e1003072.
Most proteins are regulated by physical interactions with other molecules; some are highly specific, but others interact with many partners. Despite much speculation, we know little about how and why specificity/promiscuity evolves in natural proteins. It is widely assumed that specific proteins evolved from more promiscuous ancient forms and that most proteins' specificity has been tuned to an optimal state by selection. Here we use ancestral protein reconstruction to trace the evolutionary history of ligand recognition in the steroid hormone receptors (SRs), a family of hormone-regulated animal transcription factors. We resurrected the deepest ancestral proteins in the SR family and characterized the structure-activity relationships by which they distinguished among ligands. We found that that the most ancient split in SR evolution involved a discrete switch from an ancient receptor for aromatized estrogens—including xenobiotics—to a derived receptor that recognized non-aromatized progestagens and corticosteroids. The family's history, viewed in relation to the evolution of their ligands, suggests that SRs evolved according to a principle of minimal specificity: at each point in time, receptors evolved ligand recognition criteria that were just specific enough to parse the set of endogenous substances to which they were exposed. By studying the atomic structures of resurrected SR proteins, we found that their promiscuity evolved because the ancestral binding cavity was larger than the primary ligand and contained excess hydrogen bonding capacity, allowing adventitious recognition of larger molecules with additional functional groups. Our findings provide an historical explanation for the sensitivity of modern SRs to natural and synthetic ligands—including endocrine-disrupting drugs and pollutants—and show that knowledge of history can contribute to ligand prediction. They suggest that SR promiscuity may reflect the limited power of selection within real biological systems to discriminate between perfect and “good enough.”
Author Summary
The functions of most proteins are defined by their interactions with other biological substances, such as DNA, nutrients, hormones, or other proteins. Some proteins are highly specific, but others are more promiscuous and can interact with a variety of natural substances, as well as drugs and pollutants. Understanding molecular interactions is a key goal in pharmacology and toxicology, but there are few general principles to help explain or predict protein specificity. Because every biological entity is the result of evolution, understanding a protein's history might help explain why it interacts with the substances to which it is sensitive. In this paper, we used ancestral protein reconstruction to experimentally trace how specificity evolved in an ancient group of proteins, the steroid hormone receptors (SRs), a family of proteins that regulate reproduction and other biological processes in animals. We show that SRs evolved according to a principle of minimal specificity: at each point in time, these proteins evolved to be specific enough to distinguish among the substances to which they were naturally exposed, but not more so. Our findings provide an historical explanation for modern SRs' diverse sensitivities to natural and man-made substances; they show that knowledge of history can contribute to predicting the ligands to which a modern protein will respond and indicate that promiscuity reflects the limited power of natural selection to discriminate between perfect and “good enough.”
PMCID: PMC3499368  PMID: 23166518
3.  A comprehensive review of Cataract (Kaphaja Linganasha) and its Surgical Treatment in Ayurvedic Literature 
Ayu  2010;31(1):93-100.
Ayurveda the science of life, since its origin is serving the mankind throughout in health & disease state of life. Shalakyatantra, one of its specialized branch deals with the science of Ophthalmology, Otorhinolaryngology, Orodental surgery & Head; was contributed and developed by Rajrishi Nimi, the King of Videha, who was a colleague of Atreya, Punarvasu, Dhanwantri, Bharadwaja, Kashyapa etc. The available literature related to this speciality is reproduced from original text of Nimitantra in Uttartantra of Sushruta samhita. So Rajrishi Nimi deserves all the credit and regards for Shalakyatantra and for being the first eye surgeon on this earth. The fact regarding the technique of cataract surgery adopted by ancient surgeons is still a matter of debate. Most of the medical fraternity accepts cataract surgery of ancient surgeons as couching procedure but after going through forth coming pages, the prevailing concept will prove to be a myth. It started with extra capsular extraction through small incision during the period of Sushruta Samhita but later shifted to couching like technique by Acharya Vagbhatta. Secondly, the objective of this literary research paper is to find proper co-relation of the disease cataract to those mentioned in Ancient Ayurvedic classic. Linganasha has been inadvertently taken as cataract but this is neither logical nor in accordance with classics. We find detailed description of cataract's differential diagnosis, indications, contra- indications, pre/intra/post operative procedures and complication in ancient texts of Ayurveda. Not only this, vivid description of treatment of various complications of cataract surgery are also given. Needless to say, no other surgically treatable diseases & its complications except Kaphaja Linganasha are given this much attention.
PMCID: PMC3215330  PMID: 22131692
Linganasha; Shalaka; Vedhana; Daivakrita; Lekhana; Aschyotana; Lepa; Seka
4.  Re-Examination of Globally Flat Space-Time 
PLoS ONE  2013;8(11):e78114.
In the following, we offer a novel approach to modeling the observed effects currently attributed to the theoretical concepts of “dark energy,” “dark matter,” and “dark flow.” Instead of assuming the existence of these theoretical concepts, we take an alternative route and choose to redefine what we consider to be inertial motion as well as what constitutes an inertial frame of reference in flat space-time. We adopt none of the features of our current cosmological models except for the requirement that special and general relativity be local approximations within our revised definition of inertial systems. Implicit in our ideas is the assumption that at “large enough” scales one can treat objects within these inertial systems as point-particles having an insignificant effect on the curvature of space-time. We then proceed under the assumption that time and space are fundamentally intertwined such that time- and spatial-translational invariance are not inherent symmetries of flat space-time (i.e., observable clock rates depend upon both relative velocity and spatial position within these inertial systems) and take the geodesics of this theory in the radial Rindler chart as the proper characterization of inertial motion. With this commitment, we are able to model solely with inertial motion the observed effects expected to be the result of “dark energy,” “dark matter,” and “dark flow.” In addition, we examine the potential observable implications of our theory in a gravitational system located within a confined region of an inertial reference frame, subsequently interpreting the Pioneer anomaly as support for our redefinition of inertial motion. As well, we extend our analysis into quantum mechanics by quantizing for a real scalar field and find a possible explanation for the asymmetry between matter and antimatter within the framework of these redefined inertial systems.
PMCID: PMC3826743  PMID: 24250790
5.  The cosmological model of eternal inflation and the transition from chance to biological evolution in the history of life 
Biology Direct  2007;2:15.
Recent developments in cosmology radically change the conception of the universe as well as the very notions of "probable" and "possible". The model of eternal inflation implies that all macroscopic histories permitted by laws of physics are repeated an infinite number of times in the infinite multiverse. In contrast to the traditional cosmological models of a single, finite universe, this worldview provides for the origin of an infinite number of complex systems by chance, even as the probability of complexity emerging in any given region of the multiverse is extremely low. This change in perspective has profound implications for the history of any phenomenon, and life on earth cannot be an exception.
Origin of life is a chicken and egg problem: for biological evolution that is governed, primarily, by natural selection, to take off, efficient systems for replication and translation are required, but even barebones cores of these systems appear to be products of extensive selection. The currently favored (partial) solution is an RNA world without proteins in which replication is catalyzed by ribozymes and which serves as the cradle for the translation system. However, the RNA world faces its own hard problems as ribozyme-catalyzed RNA replication remains a hypothesis and the selective pressures behind the origin of translation remain mysterious. Eternal inflation offers a viable alternative that is untenable in a finite universe, i.e., that a coupled system of translation and replication emerged by chance, and became the breakthrough stage from which biological evolution, centered around Darwinian selection, took off. A corollary of this hypothesis is that an RNA world, as a diverse population of replicating RNA molecules, might have never existed. In this model, the stage for Darwinian selection is set by anthropic selection of complex systems that rarely but inevitably emerge by chance in the infinite universe (multiverse).
The plausibility of different models for the origin of life on earth directly depends on the adopted cosmological scenario. In an infinite universe (multiverse), emergence of highly complex systems by chance is inevitable. Therefore, under this cosmology, an entity as complex as a coupled translation-replication system should be considered a viable breakthrough stage for the onset of biological evolution.
This article was reviewed by Eric Bapteste, David Krakauer, Sergei Maslov, and Itai Yanai.
PMCID: PMC1892545  PMID: 17540027
6.  Types of Nasal Delivery Drugs and Medications in Iranian Traditional Medicine to Treatment of Headache 
Headache is a common symptom throughout the world. The main purpose of patient-centered approaches is the utilization of useful and simple treatment. Nowadays, there is a rising propensity toward herbal remedies. Nasal route is one of the ancient and topical prescriptions used in headache. In Iranian traditional medicine, physicians such as Avicenna were prescribing herbal drugs through the nose to treat a variety of central nervous system diseases like headache.
In this review paper, authors have attempted to introduce different types of nasal administrations which were used in Iranian traditional medicine for the treatment of headaches.
Evidence Acquisition:
Initially, we studied two different types of Canon and separated all herbs used in the treatment of headache. Next, all plants were classified according to the method of prescription. Then, we pick out all the plants which were nasally utilized in the treatment of headache and divided them based on the method of administration. In order to find scientific names of herbs, we used two different botany references. Moreover, we conducted various researches in scientific databases with the aim of finding results concerning the analgesic and antinociceptive effects of herbs. Throughout the research, key terms were “analgesic” and “antinociceptive “with the scientific names of all herbs separately. The databases searched included PubMed, Scopus, Cochrane library and SID.
35 plants were prescribed for the treatment of headaches, which were all nasally used. These plants took either the form of powder, liquid or gas (steam). They were divided in to six categories according to the method of prescription. The Percentage of usage for each method was as follows: 62% Saoot (nasal drop), 25% Shamoom (smell), 17% Inkabab (vapor), 11% Nafookh (snuff), 11% Nashooq (inhaling) and 2% Bokhoor (smoke).
Medications that are used via nasal delivery have greater effect than oral medications. Iranian physicians were fully aware of systemic effects of topical medications, including prescription drugs through the nose. The study of ancient medical texts helps us in identification of herbal medicine and the investigation of new way for the preparation of drugs.
PMCID: PMC4102976  PMID: 25068043
Headache; Herbal Medicine; Nose; Analgesics
7.  A Landau-Squire nanojet 
Nano letters  2013;13(11):5141-5146.
Fluid jets are found in nature at all length scales – microscopic to cosmological. Here we report on an electroosmotically driven jet from a single glass nanopore about 75 nm in radius with a maximum flow rate ~ 30 pL/s. A novel anemometry technique allows us to map out the vorticity and velocity fields which show excellent agreement with the classical Landau-Squire solution of the Navier Stokes equations for a point jet. We observe a phenomenon that we call flow rectification: an asymmetry in the flow rate with respect to voltage reversal. Such a nanojet could potentially find applications in micro manipulation, nano patterning, and as a diode in microfluidic circuits.
PMCID: PMC3897716  PMID: 24124664
nanojet; microfluidics; nanopore; flow rectification
8.  The Biological Big Bang model for the major transitions in evolution 
Biology Direct  2007;2:21.
Major transitions in biological evolution show the same pattern of sudden emergence of diverse forms at a new level of complexity. The relationships between major groups within an emergent new class of biological entities are hard to decipher and do not seem to fit the tree pattern that, following Darwin's original proposal, remains the dominant description of biological evolution. The cases in point include the origin of complex RNA molecules and protein folds; major groups of viruses; archaea and bacteria, and the principal lineages within each of these prokaryotic domains; eukaryotic supergroups; and animal phyla. In each of these pivotal nexuses in life's history, the principal "types" seem to appear rapidly and fully equipped with the signature features of the respective new level of biological organization. No intermediate "grades" or intermediate forms between different types are detectable. Usually, this pattern is attributed to cladogenesis compressed in time, combined with the inevitable erosion of the phylogenetic signal.
I propose that most or all major evolutionary transitions that show the "explosive" pattern of emergence of new types of biological entities correspond to a boundary between two qualitatively distinct evolutionary phases. The first, inflationary phase is characterized by extremely rapid evolution driven by various processes of genetic information exchange, such as horizontal gene transfer, recombination, fusion, fission, and spread of mobile elements. These processes give rise to a vast diversity of forms from which the main classes of entities at the new level of complexity emerge independently, through a sampling process. In the second phase, evolution dramatically slows down, the respective process of genetic information exchange tapers off, and multiple lineages of the new type of entities emerge, each of them evolving in a tree-like fashion from that point on. This biphasic model of evolution incorporates the previously developed concepts of the emergence of protein folds by recombination of small structural units and origin of viruses and cells from a pre-cellular compartmentalized pool of recombining genetic elements. The model is extended to encompass other major transitions. It is proposed that bacterial and archaeal phyla emerged independently from two distinct populations of primordial cells that, originally, possessed leaky membranes, which made the cells prone to rampant gene exchange; and that the eukaryotic supergroups emerged through distinct, secondary endosymbiotic events (as opposed to the primary, mitochondrial endosymbiosis). This biphasic model of evolution is substantially analogous to the scenario of the origin of universes in the eternal inflation version of modern cosmology. Under this model, universes like ours emerge in the infinite multiverse when the eternal process of exponential expansion, known as inflation, ceases in a particular region as a result of false vacuum decay, a first order phase transition process. The result is the nucleation of a new universe, which is traditionally denoted Big Bang, although this scenario is radically different from the Big Bang of the traditional model of an expanding universe. Hence I denote the phase transitions at the end of each inflationary epoch in the history of life Biological Big Bangs (BBB).
A Biological Big Bang (BBB) model is proposed for the major transitions in life's evolution. According to this model, each transition is a BBB such that new classes of biological entities emerge at the end of a rapid phase of evolution (inflation) that is characterized by extensive exchange of genetic information which takes distinct forms for different BBBs. The major types of new forms emerge independently, via a sampling process, from the pool of recombining entities of the preceding generation. This process is envisaged as being qualitatively different from tree-pattern cladogenesis.
This article was reviewed by William Martin, Sergei Maslov, and Leonid Mirny.
PMCID: PMC1973067  PMID: 17708768
9.  Questioning the preclinical paradigm: natural, extreme biology as an alternative discovery platform 
Aging (Albany NY)  2014;6(11):913-920.
The pace at which science continues to advance is astonishing. From cosmology, microprocessors, structural engineering, and DNA sequencing our lives are continually affected by science-based technology. However, progress in treating human ailments, especially age-related conditions such as cancer and Alzheimer's disease, moves at a relative snail's pace. Given that the amount of investment is not disproportionately low, one has to question why our hopes for the development of efficacious drugs for such grievous illnesses have been frustratingly unrealized. Here we discuss one aspect of drug development –rodent models – and propose an alternative approach to discovery research rooted in evolutionary experimentation. Our goal is to accelerate the conversation around how we can move towards more translative preclinical work.
PMCID: PMC4276785  PMID: 25553771
preclinical models; extremophiles; grizzly bear; insulin sensitivity; obesity; cardiac function; naked mole-rat; aging; cancer resistance
10.  Ancient Chinese medicine and mechanistic evidence of acupuncture physiology 
Pflugers Archiv  2011;462(5):645-653.
Acupuncture has been widely used in China for three millennia as an art of healing. Yet, its physiology is not yet understood. The current interest in acupuncture started in 1971. Soon afterward, extensive research led to the concept of neural signaling with possible involvement of opioid peptides, glutamate, adenosine and identifying responsive parts in the central nervous system. In the last decade scientists began investigating the subject with anatomical and molecular imaging. It was found that mechanical movements of the needle, ignored in the past, appear to be central to the method and intracellular calcium ions may play a pivotal role. In this review, we trace the technique of clinical treatment from the first written record about 2,200 years ago to the modern time. The ancient texts have been used to introduce the concepts of yin, yang, qi, de qi, and meridians, the traditional foundation of acupuncture. We explore the sequence of the physiological process, from the turning of the needle, the mechanical wave activation of calcium ion channel to beta-endorphin secretion. By using modern terminology to re-interpret the ancient texts, we have found that the 2nd century b.c. physiologists were meticulous investigators and their explanation fits well with the mechanistic model derived from magnetic resonance imaging (MRI) and confocal microscopy. In conclusion, the ancient model appears to have withstood the test of time surprisingly well confirming the popular axiom that the old wine is better than the new.
PMCID: PMC3192271  PMID: 21870056
Acupuncture; Acoustic wave; Ca2+ ion channels; Calcium waves; Meridians; Chinese traditional medicine
11.  The traditional knowledge on stingless bees (Apidae: Meliponina) used by the Enawene-Nawe tribe in western Brazil 
This paper presents the Enawene-Nawe Society's traditional knowledge about stingless bees. The Enawene-Nawe are an Aruak speaking people, indigenous to the Meridian Amazon. Specifically, they live in the Jurema River hydrological basin, located in the northwestern region of the Mato Grosso state.
The stingless bees were sampled from two ecologically similar regions in the interior of Enawene-Nawe Land. The first sampling took place around the village, i.e., adjacent to houses, by the edge of the Iquê River, next to food leftovers, around human excrement, and simply when the insects were found flying or reposing on a human body. The second round of sampling happened from 29/10 to 02/11/94, during an expedition for honey collection that took place throughout the ciliar bushes of the Papagaio River, an important tributary of Juruena River. We sampled bees adjacent to their nests following the beehive inspection or during the honey extraction.
In this work, the main bee species of the sub tribe Meliponina, which were handled by the Enawene-Nawe, was identified, and a brief ethnographic description of the honey collection expeditions and its social-cosmologic meaning for the group was done.
Results and Discussion
Similar to other indigenous people in Brazil, the Enawene-Nawe recognized 48 stingless bee species. They identified each bee species by name and specified each one's ecological niche. A brief ethnographic description of the honey collection expeditions and bees' social-cosmologic meaning for the group is included.
We concluded that, as an example of other indigenous people, the Enawene-Nawe classify and identify the bees based not only on their structure and morphological aspects but also on the ecological, etiological, and social characteristics of the species.
PMCID: PMC2562997  PMID: 18793393
12.  Use and trade of bitumen in antiquity and prehistory: molecular archaeology reveals secrets of past civilizations 
Natural asphalt (or bitumen) deposits, oil seepage and liquid oil shows are widespread in the Middle East, especially in the Zagros mountains of Iran. Ancient people from northern Iraq, south-west Iran and the Dead Sea area extensively used this ubiquitous natural resource until the Neolithic period (7000 to 6000 BC). Evidence of earlier use has been recently documented in the Syrian desert near El Kown, where bitumen-coated flint implements, dated to 40,000 BC (Mousterian period), have been unearthed. This discovery at least proves that bitumen was used by Neanderthal populations as hafting material to fix handles to their flint tools. Numerous testimonies, proving the importance of this petroleum-based material in Ancient civilizations, were brought to light by the excavations conducted in the Near East as of the beginning of the century. Bitumen remains show a wide range of uses that can be classified under several headings. First of all, bitumen was largely used in Mesopotamia and Elam as mortar in the construction of palaces (e.g. the Darius Palace in Susa), temples, ziggurats (e.g. the so-called 'Tower of Babel' in Babylon), terraces (e.g. the famous 'Hanging Gardens of Babylon') and exceptionally for roadway coating (e.g. the processional way of Babylon). Since the Neolithic, bitumen served to waterproof containers (baskets, earthenware jars, storage pits), wooden posts, palace grounds (e.g. in Mari and Haradum), reserves of lustral waters, bathrooms, palm roofs, etc. Mats, sarcophagi, coffins and jars, used for funeral practices, were often covered and sealed with bitumen. Reed and wood boats were also caulked with bitumen. Abundant lumps of bituminous mixtures used for that particular purpose have been found in storage rooms of houses at Ra's al-Junayz in Oman. Bitumen was also a widespread adhesive in antiquity and served to repair broken ceramics, fix eyes and horns on statues (e.g. at Tell al-Ubaid around 2500 BC). Beautiful decorations with stones, shells, mother of pearl, on palm trees, cups, ostrich eggs, musical instruments (e.g. the Queen's lyre) and other items, such as rings, jewellery and games, have been excavated from the Royal tombs in Ur. They are on view in the British Museum. With a special enigmatic material, commonly referred to as 'bitumen mastic', the inhabitants of Susa sculpted masterpieces of art which are today exhibited in the Louvre Museum in Paris. This unique collection is presented in a book by Connan and Deschesne (1996). Last, bitumen was also considered as a powerful remedy in medical practice, especially as a disinfectant and insecticide, and was used by the ancient Egyptians to prepare mixtures to embalm the corpses of their dead. Modern analytical techniques, currently applied in the field of petroleum geochemistry, have been adapted to the study of numerous archaeological bituminous mixtures found in excavations. More than 700 bituminous samples have been analysed during the last decade, using gas chromatography alone and gas chromatography coupled with mass spectrometry and isotopic chemistry (carbon and hydrogen mainly). These powerful tools, focused on the detailed analysis of biomarkers in hydrocarbon fractions, were calibrated on various well-known natural sources of bitumen in Iraq, Syria, Iran, Bahrain and Kuwait. These reference studies have made it possible to establish the origins of bitumen from numerous archaeological sites and to document the bitumen trade routes in the Middle East and the Arabo-Persian Gulf. Using a well-documented case history, Tell el 'Oueili (5800 to 3500 BC) in South Mesopotamia, we will illustrate in this paper how these new molecular and isotopic tools can help us to recognize different sources of bitumen and to trace the ancient trade routes through time. These import routes were found to vary with major cultural and political changes in the area under study. A second example, referring to the prehistoric period, describes bitumen traces on flint implements, dated from Mousterian times. This discovery, from the Umm El Tlel excavations near El Kown in Syria, was reported in 1996 in Boëda et al. At that time, the origin of the bitumen had not been elucidated due to contamination problems. Last year, a ball of natural oil-stained sands, unearthed from the same archaeological layer, allowed us to determine the source of the bitumen used. This source is regional and located in the Jebel Bichri, nearly 40 km from the archaeological site. The last case history was selected to illustrate another aspect of the investigations carried out. Recent geochemical studies on more than 20 balms from Egyptian mummies from the Intermediate, Ptolemaic and Roman periods have revealed that these balms are composed of various mixtures of bitumen, conifer resins, grease and beeswax. Bitumen occurs with the other ingredients and the balms studied show a great variety of molecular compositions. Bitumen from the Dead Sea area is the most common source but some other sources (Hit in Iraq?) are also revealed by different molecular patterns. The absolute amount of bitumen in balms varies from almost zero to 30% per weight.
PMCID: PMC1692448
13.  Reconstruction of Ancestral Metabolic Enzymes Reveals Molecular Mechanisms Underlying Evolutionary Innovation through Gene Duplication 
PLoS Biology  2012;10(12):e1001446.
Resurrection of ancient fungal maltase enzymes uncovers the molecular details of how repeated gene duplications allow the evolution of protein variants with different functions.
Gene duplications are believed to facilitate evolutionary innovation. However, the mechanisms shaping the fate of duplicated genes remain heavily debated because the molecular processes and evolutionary forces involved are difficult to reconstruct. Here, we study a large family of fungal glucosidase genes that underwent several duplication events. We reconstruct all key ancestral enzymes and show that the very first preduplication enzyme was primarily active on maltose-like substrates, with trace activity for isomaltose-like sugars. Structural analysis and activity measurements on resurrected and present-day enzymes suggest that both activities cannot be fully optimized in a single enzyme. However, gene duplications repeatedly spawned daughter genes in which mutations optimized either isomaltase or maltase activity. Interestingly, similar shifts in enzyme activity were reached multiple times via different evolutionary routes. Together, our results provide a detailed picture of the molecular mechanisms that drove divergence of these duplicated enzymes and show that whereas the classic models of dosage, sub-, and neofunctionalization are helpful to conceptualize the implications of gene duplication, the three mechanisms co-occur and intertwine.
Author Summary
Darwin's theory of evolution is one of gradual change, yet evolution sometimes takes remarkable leaps. Such evolutionary innovations are often linked to gene duplication through one of three basic scenarios: an extra copy can increase protein levels, different ancestral subfunctions can be split over the copies and evolve distinct regulation, or one of the duplicates can develop a novel function. Although there are numerous examples for all these trajectories, the underlying molecular mechanisms remain obscure, mostly because the preduplication genes and proteins no longer exist. Here, we study a family of fungal metabolic enzymes that hydrolyze disaccharides, and that all originated from the same ancestral gene through repeated duplications. By resurrecting the ancient genes and proteins using high-confidence predictions from many fungal genome sequences available, we show that the very first preduplication enzyme was promiscuous, preferring maltose-like substrates but also showing trace activity towards isomaltose-like sugars. After duplication, specific mutations near the active site of one copy optimized the minor activity at the expense of the major ancestral activity, while the other copy further specialized in maltose and lost the minor activity. Together, our results reveal how the three basic trajectories for gene duplicates cannot be separated easily, but instead intertwine into a complex evolutionary path that leads to innovation.
PMCID: PMC3519909  PMID: 23239941
14.  The Epidemiologic Vocabulary of the West and the Former Soviet Union: Different Sides of the Same Science 
The purpose of this project was to develop an English-Russian Epidemiology Dictionary, which is needed for improved international collaboration in public health surveillance.
As part of the US Department of Defense strategy to counter biological threats, the Defense Threat Reduction Agency’s Cooperative Biological Engagement Program is enhancing the capabilities of countries in the former Soviet Union (FSU) to detect, diagnose, and report endemic and epidemic, man-made or natural cases of especially dangerous pathogens. During these engagements, it was noted that Western-trained and Soviet-trained epidemiologists have difficulty, beyond that of simple translation, in exchanging ideas.
The Soviet public health system and epidemiology developed independently of that of other nations. Whereas epidemiology in the West is thought of in terms of disease determinants in populations and relies on statistics to make inferences, classical Soviet epidemiology is founded on a more ecological view with the main focus on infectious diseases’ spread theory. Consequently many fundamental Soviet terms and concepts lack simple correlates in English and other languages outside the Soviet sphere; the same is true when attempting to translate from English to Russian and other languages of the FSU. Systematic review of the differences in FSU and Western epidemiologic concepts and terminology is therefore needed for strengthening understanding and collaboration in disease surveillance, pandemic preparedness, response to biological terrorism, etc.
Following an extensive search of the Russian and English literature by a working group of Western and FSU epidemiologists, we created a matrix containing English and Russian definitions of key epidemiologic terms found in FSU and Western epidemiology manuals and dictionaries, such as A Dictionary of Epidemiology (1), Epidemiology Manual (2) and many other sources. Particular emphasis was placed on terms relating to infectious disease surveillance, analysis of surveillance data, and outbreak investigation. In order to compare the definitions of each term and to elucidate differences in usage and existing gaps, all definitions were translated into English and Russian so that the definitions could be compared side by side and discussed by the working group.
Six hundred and thirty one terms from 27 English and 51 Russian sources were chosen for inclusion based on their importance in applied epidemiology in either the West or the FSU. Review of the definitions showed that many terms within biosurveillance and infectious disease public health practice are used differently, and some concepts are lacking altogether in the Russian or English literature. Significant gaps in FSU epidemiology are in the areas of biostatistics and epidemiologic study designs. There are distinctive differences in FSU and Western epidemiology in the conceptualization and classification of disease transmission, surveillance practices, and control measures.
Epidemiologic concepts and definitions significantly differed in the FSU and Western literature. To improve biosurveillance and international collaboration, recognition of these differences must occur. Detailed analysis of epidemiology terminology differences will be discussed in the presentation and paper. Major limitations of the work were scarcity of prior research on the subject and lack of bilingual epidemiologists with the good understanding of FSU and Western approaches. A bilingual reference in the form of a dictionary will greatly improve mutual comprehension and collaboration in the areas of biosurveillance and public health practice.
PMCID: PMC3692890
Surveillance; Dictionary; Collaboration
15.  ‘Swapna’ in the Indian classics: Mythology or science? 
Ayu  2010;31(2):170-174.
There are many concepts in Ayurveda as well as the ancient sciences that are untouched or unexplored. One such concept is that of the Swapna (dreams). Being an abstract phenomenon it makes it difficult to be explained and understood; probably because of this the descriptions related to Swapna in the Indian classics are supported by mythology, to make them acceptable. Variations in these explanations are seen according to the objective of the school of thought; that is, in the ancient texts where dreams are used to delve into the knowledge of the Atman and are related to spirituality, its description in the Ayurvedic texts evolves around the Sharira and Manas. Although all these explanations seem to be shrouded in uncertainty and mythology; there definitely seems to be a logical and rational science behind these quotations. They only need research, investigation, and explanation on the basis of logic, and a laboratory.
PMCID: PMC3215360  PMID: 22131706
Indian classics; mythology; science; Swapna; dreams; ayurveda; upanishad
16.  Nursing identity and patient-centredness in scholarly health services research: a computational text analysis of PubMed abstracts 1986–2013 
The most important and contested element of nursing identity may be the patient-centredness of nursing, though this concept is not well-treated in the nursing identity literature. More conceptually-based mapping of nursing identity constructs are needed to help nurses shape their identity. The field of computational text analytics offers new opportunities to scrutinise how growing disciplines such as health services research construct nursing identity. This paper maps the conceptual content of scholarly health services research in PubMed as it relates to the patient-centeredness of nursing.
Computational text analytics software was used to analyse all health services abstracts in the database PubMed since 1986. Abstracts were treated as indicative of the content of health services research. The database PubMed was searched for all research papers using the term “service” or “services” in the abstract or keywords for the period 01/01/1986 to 30/06/2013. A total of 234,926 abstracts were obtained. Leximancer software was used in 1) mapping of 4,144,458 instances of 107 concepts; 2) analysis of 106 paired concept co-occurrences for the nursing concept; and 3) sentiment analysis of the nursing concept versus patient, family and community concepts, and clinical concepts.
Nursing is constructed within quality assurance or service implementation or workforce development concepts. It is relatively disconnected from patient, family or community care concepts.
For those who agree that patient-centredness should be a part of nursing identity in practice, this study suggests that there is a need for development of health services research into both the nature of the caring construct in nursing identity and its expression in practice. More fundamentally, the study raises questions about whether health services research cultures even value the politically popular idea of nurses as patient-centred caregivers and whether they should.
PMCID: PMC4312431  PMID: 25608677
Nursing identity; Health services research; Patient-centredness; Computational linguistics
17.  The chicken IL-1 family: evolution in the context of the studied vertebrate lineage 
Immunogenetics  2014;66(7-8):427-438.
The interleukin-1 gene family encodes a group of related proteins that exhibit a remarkable pleiotropy in the context of health and disease. The set of indispensable functions they control suggests that these genes should be found in all eukaryotic species. The ligands and receptors of this family have been primarily characterised in man and mouse. The genomes of most non-mammalian animal species sequenced so far possess all of the IL-1 receptor genes found in mammals. Yet, strikingly, very few of the ligands are identifiable in non-mammalian genomes. Our recent identification of two further IL-1 ligands in the chicken warranted a critical reappraisal of the evolution of this vitally important cytokine family. This review presents substantial data gathered across multiple, divergent metazoan genomes to unambiguously trace the origin of these genes. With the hypothesis that all of these genes, both ligands and receptors, were formed in a single ancient ancestor, extensive database mining revealed sufficient evidence to confirm this. It therefore suggests that the emergence of mammals is unrelated to the expansion of the IL-1 family. A thorough review of this cytokine family in the chicken, the most extensively studied amongst non-mammalian species, is also presented.
Electronic supplementary material
The online version of this article (doi:10.1007/s00251-014-0780-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4090809  PMID: 24863340
Interleukin-1; Interleukin-1 receptor; Interleukin-36; Evolution; Synteny; Chicken
18.  Experiences with Policing among People Who Inject Drugs in Bangkok, Thailand: A Qualitative Study 
PLoS Medicine  2013;10(12):e1001570.
Using thematic analysis, Kerr and colleagues document the experiences of policing among people who inject drugs in Bangkok and examine how interactions with police can affect drug-using behaviors and health care access.
Please see later in the article for the Editors' Summary
Despite Thailand's commitment to treating people who use drugs as “patients” not “criminals,” Thai authorities continue to emphasize criminal law enforcement for drug control. In 2003, Thailand's drug war received international criticism due to extensive human rights violations. However, few studies have since investigated the impact of policing on drug-using populations. Therefore, we sought to examine experiences with policing among people who inject drugs (PWID) in Bangkok, Thailand, between 2008 and 2012.
Methods and Findings
Between July 2011 and June 2012, semi-structured, in-depth interviews were conducted with 42 community-recruited PWID participating in the Mitsampan Community Research Project in Bangkok. Interviews explored PWID's encounters with police during the past three years. Audio-recorded interviews were transcribed verbatim, and a thematic analysis was conducted to document the character of PWID's experiences with police. Respondents indicated that policing activities had noticeably intensified since rapid urine toxicology screening became available to police. Respondents reported various forms of police misconduct, including false accusations, coercion of confessions, excessive use of force, and extortion of money. However, respondents were reluctant to report misconduct to the authorities in the face of social and structural barriers to seeking justice. Respondents' strategies to avoid police impeded access to health care and facilitated transitions towards the misuse of prescribed pharmaceuticals. The study's limitations relate to the transferability of the findings, including the potential biases associated with the small convenience sample.
This study suggests that policing in Bangkok has involved injustices, human rights abuses, and corruption, and policing practices in this setting appeared to have increased PWID's vulnerability to poor health through various pathways. Novel to this study are findings pertaining to the use of urine drug testing by police, which highlight the potential for widespread abuse of this emerging technology. These findings raise concern about ongoing policing practices in this setting.
Please see later in the article for the Editors' Summary
Editors' Summary
In many countries, the dominant strategy used to control illegal drugs such as heroin and methamphetamine is criminal law enforcement, a strategy that sometimes results in human rights abuses such as ill-treatment by police, extrajudicial killings, and arbitrary detention. Moreover, growing evidence suggests that aggressive policing of illicit drug use can have adverse public-health consequences. For example, the fear engendered by intensive policing may cause people who inject drugs (PWID) to avoid services such as needle exchanges, thereby contributing to the HIV/AIDS epidemic. One country with major epidemics of illicit drug use and of HIV/AIDS among PWID is Thailand. Although Thailand reclassified drug users as “patients” instead of “criminals” in 2002, possession and consumption of illicit drugs remain criminal offenses. The 2002 legislation also created a system of compulsory drug detention centers, most of which lack evidence-based addiction treatment services. In 2003, the Thai government launched a campaign to suppress drug trafficking and to enrol 300,000 people who use drugs into treatment. This campaign received international criticism because it involved extensive human rights violations, including more than 2,800 extrajudicial killings of suspected drug users and dealers.
Why Was This Study Done?
Drug-related arrests and compulsory detention of drug users are increasing in Thailand but what is the impact of current policing practices on drug users and on public health? In this qualitative study (a study that aims for an in-depth understanding of human behavior), the researchers use thematic analysis informed by the Rhodes' Risk Environment Framework to document the social and structural factors that led to encounters with the police among PWID in Bangkok between 2008 and 2012, the policing tactics employed during these encounters, and the associated health consequences of these encounters. The Risk Environment Framework posits that a range of social, political, economic, and physical environmental factors interact with each other and shape the production of drug-related harm.
What Did the Researchers Do and Find?
Between July 2011 and June 2012, the researchers conducted in-depth interviews with a convenience sample (a non-random sample from a nearby population) of 42 participants in the Mitsampan Community Research Project, an investigation of drug-using behavior, health care access, and drug-related harms among PWID in Bangkok. Respondents reported that policing activities had intensified since rapid urine toxicology screening became widely available and since the initiation of a crackdown on drug users in 2011. They described various forms of violence and misconduct that they had experienced during confrontations with police, including false accusations, degrading stop and search procedures, and excessive use of force. Urine drug testing was identified as a key tool used by the police, with some respondents describing how police caused unnecessary humiliation by requesting urine samples in public places. It was also reported that the police used positive test results as a means of extortion. Finally, some respondents reported feeling powerless in relation to the police and cited fear of retaliation as an important barrier to obtaining redress for police corruption. Others reported that they had adopted strategies to avoid the police such as staying indoors, a strategy likely to impede access to health care, or changing their drug-using behavior by, for example, injecting midazolam rather than methamphetamine, a practice associated with an increased risk of injection-related complications.
What Do These Findings Mean?
These findings suggest that the policing of PWID in Bangkok between 2008 and 2012 involved injustices, human rights abuses, and corruption and highlight the potential for widespread misuse of urine drug testing. Moreover, they suggest that policing practices in this setting may have increased the vulnerability of PWID to poor health by impeding their access to health care and by increasing the occurrence of risky drug-using behaviors. Because this study involved a small convenience sample of PWID, these findings may not be generalizable to other areas of Bangkok or Thailand and do not indicate whether police misconduct and corruption is highly prevalent across the all police departments in Bangkok. Nevertheless, these findings suggest that multilevel structural changes and interventions are needed to mitigate the harm associated with policing of illicit drug use in Bangkok. These changes will need to ensure full accountability for police misconduct and access to legal services for victims of this misconduct. They will also need to include ethical guidelines for urine drug testing and the reform of policies that promote repressive policing and compulsory detention.
Additional Information
Please access these websites via the online version of this summary at
This study is further discussed in a PLOS Medicine Perspective by Burris and Koester
Human Rights Watch, a global organization dedicated to defending and protecting human rights, has information about drug policy and human rights, which includes information on Thailand
The Global Commission on Drug Policy published a report in June 2012 entitled “The War on Drugs and HIV/AIDS: How the Criminalization of Drug Use Fuels the Global Pandemic” (available in several languages)
The Global Commission on HIV and the Law published a report in July 2012 entitled “HIV and the Law: Risk, Rights and Health” (available in several languages), the Open Society Foundations have prepared a briefing on this report
More information about the Mitsampan Community Research Project is available
PMCID: PMC3858231  PMID: 24339753
19.  Review of Two Decades of Cholera Diagnostics – How Far Have We Really Come? 
Cholera, an ancient scourge, continues to inflict high rates of mortality today. The rising incidence of epidemics in areas of poor sanitation and crowding highlight the need for better epidemic prevention and early response. Such interventions require the availability of rapid and accurate diagnostic techniques to trigger timely response and mitigate the scale of the outbreak. The current gold standard of bacterial culture is inadequate for rapid diagnosis, highlighting the overarching neglect of field diagnostic needs. This paper was written to support the World Health Organisation's Global Task Force on Cholera Control mandated Cholera and diarrhoeal disease laboratory Network (CholdiNet) in devising a protocol for the validation of Rapid Diagnostic Tests (RDTs) for Vibrio cholerae. The status of diagnostic tools for Vibrio cholerae is assessed, describing products that have been commercialised over the last two decades and discussing their peer-reviewed evaluation.
Review of post-1990 peer-reviewed and grey literature on rapid diagnostic tests for Vibrio cholerae.
Since 1990, twenty four diagnostic tests have been developed for the detection of Vibrio cholerae in human faecal samples. Fourteen of these have also been described in the literature, with rapid chromatographic-immuno assays (CIA) featuring strongly. Polymerase chain reaction (PCR) assays maintain the ability to detect the lowest amount of bacteria; however CIAs achieve both low detection thresholds and high sensitivity and specificity, making them possible candidates for use in field conditions. Field and laboratory studies were performed in a wide range of settings demonstrating variability in performance, however only a few of these studies were sufficiently stringent, highlighting five RDTs that showed promise in field conditions; COAT, IP cholera dipstick, SMART, IP dipstick and Medicos. In light of non-independent reporting, the authors would like to see these five products undergoing additional studies, with further technical improvements if needed and commercial production. The authors hope that public health use of such a RDT in limited-resource field conditions on stool samples may contribute to effective reduction in cholera epidemic spread.
Author Summary
Rising prevalence of cholera outbreaks highlights the need for accurate detection tools. Diagnosing cholera early at the onset of an epidemic, at field level, should allow for a more timely response and a quick containment of the spread and thus a diminished case load. Currently the gold standard to identify the bacteria, Vibrio cholerae, from patient samples remains reliant on lengthy bacterial cultures and an array of biochemical tests. Furthermore, the need for highly-skilled operators and numerous laboratory resources underline the inadequacy of sophisticated tests for use in remote locations. Research to develop more appropriate tools has largely focused on rapid diagnostic tests and attempts to simplify existing technologies. This is yet to deliver evidence-based appropriate tools to address the burden-of-disease cholera inflicts. In light of this neglect we have taken the first step, assessing developments in commercialised diagnostic tools, reviewing previous evaluations undertaken in the literature since 1990. In doing so, we highlight evaluation study parameters that could benefit from stringent standardisation, and identify five tests that show promise for use in field conditions. The authors recommend an indipendent assessment of these products, including technical improvements as required and production to trigger early detection of cholera epidemics.
PMCID: PMC3469466  PMID: 23071851
Ancient Science of Life  1987;6(4):192-202.
The author probes in this study the maternity or obsterics and gynaecology in Ancient Indian medicine by interpreting various classical texts in Ayurveda, Sociology and Religion.
PMCID: PMC3331425  PMID: 22557571
21.  Mycobacterium leprae genomes from a British medieval leprosy hospital: towards understanding an ancient epidemic 
BMC Genomics  2014;15:270.
Leprosy has afflicted humankind throughout history leaving evidence in both early texts and the archaeological record. In Britain, leprosy was widespread throughout the Middle Ages until its gradual and unexplained decline between the 14th and 16th centuries. The nature of this ancient endemic leprosy and its relationship to modern strains is only partly understood. Modern leprosy strains are currently divided into 5 phylogenetic groups, types 0 to 4, each with strong geographical links. Until recently, European strains, both ancient and modern, were thought to be exclusively type 3 strains. However, evidence for type 2 strains, a group normally associated with Central Asia and the Middle East, has recently been found in archaeological samples in Scandinavia and from two skeletons from the medieval leprosy hospital (or leprosarium) of St Mary Magdalen, near Winchester, England.
Here we report the genotypic analysis and whole genome sequencing of two further ancient M. leprae genomes extracted from the remains of two individuals, Sk14 and Sk27, that were excavated from 10th-12th century burials at the leprosarium of St Mary Magdalen. DNA was extracted from the surfaces of bones showing osteological signs of leprosy. Known M. leprae polymorphisms were PCR amplified and Sanger sequenced, while draft genomes were generated by enriching for M. leprae DNA, and Illumina sequencing. SNP-typing and phylogenetic analysis of the draft genomes placed both of these ancient strains in the conserved type 2 group, with very few novel SNPs compared to other ancient or modern strains.
The genomes of the two newly sequenced M. leprae strains group firmly with other type 2F strains. Moreover, the M. leprae strain most closely related to one of the strains, Sk14, in the worldwide phylogeny is a contemporaneous ancient St Magdalen skeleton, vividly illustrating the epidemic and clonal nature of leprosy at this site. The prevalence of these type 2 strains indicates that type 2F strains, in contrast to later European and associated North American type 3 isolates, may have been the co-dominant or even the predominant genotype at this location during the 11th century.
PMCID: PMC4234520  PMID: 24708363
Mycobacterium leprae; SNP; Leprosy; Genome; Ancient DNA; Middle Ages; Bioarchaeology
22.  A New Family of Lysozyme Inhibitors Contributing to Lysozyme Tolerance in Gram-Negative Bacteria 
PLoS Pathogens  2008;4(3):e1000019.
Lysozymes are ancient and important components of the innate immune system of animals that hydrolyze peptidoglycan, the major bacterial cell wall polymer. Bacteria engaging in commensal or pathogenic interactions with an animal host have evolved various strategies to evade this bactericidal enzyme, one recently proposed strategy being the production of lysozyme inhibitors. We here report the discovery of a novel family of bacterial lysozyme inhibitors with widespread homologs in gram-negative bacteria. First, a lysozyme inhibitor was isolated by affinity chromatography from a periplasmic extract of Salmonella Enteritidis, identified by mass spectrometry and correspondingly designated as PliC (periplasmic lysozyme inhibitor of c-type lysozyme). A pliC knock-out mutant no longer produced lysozyme inhibitory activity and showed increased lysozyme sensitivity in the presence of the outer membrane permeabilizing protein lactoferrin. PliC lacks similarity with the previously described Escherichia coli lysozyme inhibitor Ivy, but is related to a group of proteins with a common conserved COG3895 domain, some of them predicted to be lipoproteins. No function has yet been assigned to these proteins, although they are widely spread among the Proteobacteria. We demonstrate that at least two representatives of this group, MliC (membrane bound lysozyme inhibitor of c-type lysozyme) of E. coli and Pseudomonas aeruginosa, also possess lysozyme inhibitory activity and confer increased lysozyme tolerance upon expression in E. coli. Interestingly, mliC of Salmonella Typhi was picked up earlier in a screen for genes induced during residence in macrophages, and knockout of mliC was shown to reduce macrophage survival of S. Typhi. Based on these observations, we suggest that the COG3895 domain is a common feature of a novel and widespread family of bacterial lysozyme inhibitors in gram-negative bacteria that may function as colonization or virulence factors in bacteria interacting with an animal host.
Author Summary
Lysozyme is an ancient bactericidal enzyme that is part of the antibacterial defense system of vertebrate and invertebrate animals. Bacteria colonizing or infecting an animal host have developed various ways to overcome lysozyme action, a recently proposed mechanism being the production of lysozyme inhibitors. However, the only high affinity bacterial lysozyme inhibitor known thus far is produced only in few bacteria, and this raised questions about their wider relevance in bacteria–host interactions. We here report the discovery of a novel and distinct family of bacterial lysozyme inhibitors that is widely distributed among the Proteobacteria, including several major pathogens. The family comprises periplasmic as well as membrane-bound inhibitors, and both types contribute to lysozyme tolerance of bacterial cells, as we experimentally demonstrate for the periplasmic inhibitor from Salmonella Typhimurium and the membrane-bound inhibitors from Escherichia coli and Pseudomonas aeruginosa. Interestingly, a gene encoding one of the newly identified inhibitors has been previously found to promote macrophage survival of Salmonella Typhi. The widespread occurrence of lysozyme inhibitors in bacteria is likely to reflect their functional importance in a wide range of bacteria–host interactions. As such, they are also attractive novel targets for antibacterial drug development.
PMCID: PMC2267010  PMID: 18369469
23.  Hybrid methods for improving information access in clinical documents: concept, assertion, and relation identification 
This paper describes the approaches the authors developed while participating in the i2b2/VA 2010 challenge to automatically extract medical concepts and annotate assertions on concepts and relations between concepts.
The authors'approaches rely on both rule-based and machine-learning methods. Natural language processing is used to extract features from the input texts; these features are then used in the authors' machine-learning approaches. The authors used Conditional Random Fields for concept extraction, and Support Vector Machines for assertion and relation annotation. Depending on the task, the authors tested various combinations of rule-based and machine-learning methods.
The authors'assertion annotation system obtained an F-measure of 0.931, ranking fifth out of 21 participants at the i2b2/VA 2010 challenge. The authors' relation annotation system ranked third out of 16 participants with a 0.709 F-measure. The 0.773 F-measure the authors obtained on concept extraction did not make it to the top 10.
On the one hand, the authors confirm that the use of only machine-learning methods is highly dependent on the annotated training data, and thus obtained better results for well-represented classes. On the other hand, the use of only a rule-based method was not sufficient to deal with new types of data. Finally, the use of hybrid approaches combining machine-learning and rule-based approaches yielded higher scores.
PMCID: PMC3168313  PMID: 21597105
NLP; controlled terminologies and vocabularies; discovery and text and data mining methods; natural-language processing; automated learning; natural language processing; medical Informatics
24.  A Conceptual Muddle: An Empirical Analysis of the Use of ‘Sex’ and ‘Gender’ in ‘Gender-Specific Medicine’ Journals 
PLoS ONE  2012;7(4):e34193.
At the same time as there is increasing awareness in medicine of the risks of exaggerating differences between men and women, there is a growing professional movement of ‘gender-specific medicine’ which is directed towards analysing ‘sex’ and ‘gender’ differences. The aim of this article is to empirically explore how the concepts of ‘sex’ and ‘gender’ are used in the new field of ‘gender-specific medicine’, as reflected in two medical journals which are foundational to this relatively new field.
Method and Principal Findings
The data consist of all articles from the first issue of each journal in 2004 and an issue published three years later (n = 43). In addition, all editorials over this period were included (n = 61). Quantitative and qualitative content analyses were undertaken by the authors.
Less than half of the 104 papers used the concepts of ‘sex’ and ‘gender’. Less than 1 in 10 papers attempted any definition of the concepts. Overall, the given definitions were simple, unspecific and created dualisms between men and women. Almost all papers which used the two concepts did so interchangeably, with any possible interplay between ‘sex’ and gender’ referred to only in six of the papers.
The use of the concepts of ‘sex’ and gender’ in ‘gender-specific medicine’ is conceptually muddled. The simple, dualistic and individualised use of these concepts increases the risk of essentialism and reductivist thinking. It therefore highlights the need to clarify the use of the terms ‘sex’ and ‘gender’ in medical research and to develop more effective ways of conceptualising the interplay between ‘sex’ and ‘gender’ in relation to different diseases.
PMCID: PMC3329526  PMID: 22529907
25.  Literature Mining for the Discovery of Hidden Connections between Drugs, Genes and Diseases 
PLoS Computational Biology  2010;6(9):e1000943.
The scientific literature represents a rich source for retrieval of knowledge on associations between biomedical concepts such as genes, diseases and cellular processes. A commonly used method to establish relationships between biomedical concepts from literature is co-occurrence. Apart from its use in knowledge retrieval, the co-occurrence method is also well-suited to discover new, hidden relationships between biomedical concepts following a simple ABC-principle, in which A and C have no direct relationship, but are connected via shared B-intermediates. In this paper we describe CoPub Discovery, a tool that mines the literature for new relationships between biomedical concepts. Statistical analysis using ROC curves showed that CoPub Discovery performed well over a wide range of settings and keyword thesauri. We subsequently used CoPub Discovery to search for new relationships between genes, drugs, pathways and diseases. Several of the newly found relationships were validated using independent literature sources. In addition, new predicted relationships between compounds and cell proliferation were validated and confirmed experimentally in an in vitro cell proliferation assay. The results show that CoPub Discovery is able to identify novel associations between genes, drugs, pathways and diseases that have a high probability of being biologically valid. This makes CoPub Discovery a useful tool to unravel the mechanisms behind disease, to find novel drug targets, or to find novel applications for existing drugs.
Author Summary
The biomedical literature is an important source of knowledge on the function of genes and on the mechanisms by which these genes regulate cellular processes. Several text mining approaches have been developed to leverage this rich source of information by automatically extracting associations between concepts such as genes, diseases and drugs from a large body of text. Here, we describe a new method that extracts novel, not yet recognized associations between genes, diseases, drugs and cellular processes from the biomedical literature. Our method is built on the assumption that even if two concepts do not have a direct connection in literature, they may be functionally related if they are both connected to an overlapping set of concepts. Using this approach we predicted several novel connections between genes, diseases, drugs and pathways. Our results imply that our method is able to predict novel relationships from literature and, most importantly, that these newly identified relationships are biologically relevant. Our method can aid the drug discovery process where it can be used to find novel drug targets, increase insight in mode of action of a drug or find novel applications for known drugs.
PMCID: PMC2944780  PMID: 20885778

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