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Background: With the exponential growth of publications in the field of investigator-initiated research/trials (IIRs/IITs), it has become necessary to employ text mining and bibliometric analysis as tools for gaining deeper insights into this area of study. By using these methods, researchers can effectively identify and analyze research topics within the field., Methods: This study retrieved relevant publications from the Web of Science Core Collection and conducted bioinformatics analysis. The latent Dirichlet allocation model, which is based on machine learning, was utilized to identify subfield research topics., Results: A total of 4315 articles related to IIRs/IITs were obtained from the Web of Science Core Collection. After excluding duplicates and articles with missing abstracts, a final dataset of 3333 articles was included for bibliometric analysis. The number of publications showed a steady increase over time, particularly since 2000. The United States, Germany, the United Kingdom, the Netherlands, Canada, Denmark, Japan, Switzerland, and France emerged as the most productive countries in terms of IIRs/IITs. The citation analysis revealed intriguing trends, with certain highly cited articles showing a significant increase in citation frequency in recent years. A model with 45 topics was deemed the best fit for characterizing the extensively researched fields within IIRs/IITs. Our analysis revealed 10 top topics that have garnered significant attention, spanning domains such as community health, cancer treatment, brain development and disease mechanisms, nursing research, and stem cell therapy. These top topics offer researchers valuable directions for further investigation and innovation. Additionally, we identified 12 hot topics, which represent the most cutting-edge and highly regarded research areas within the field., Conclusion: This study contributes to a comprehensive understanding of the current research landscape and provides valuable insights for researchers working in this domain., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Vaccination is one of the most efficient ways to control the spread of infectious diseases. Simulations are now widely used to assess how vaccination can limit disease spread as well as mitigate morbidity or mortality in susceptible populations. However, field studies investigating how much vaccines decrease the velocity of epizootic wave-fronts during outbreaks are rare. This study aimed at investigating the effect of vaccination on the propagation of bluetongue, a vector-borne disease of ruminants. We used data from the 2008 bluetongue virus serotype 1 (BTV-1) epizootic of southwest France. As the virus was newly introduced in this area, natural immunity of livestock was absent. This allowed determination of the role of vaccination in changing the velocity of bluetongue spread while accounting for environmental factors that possibly influenced it. The average estimated velocity across the country despite restriction on animal movements was 5.4 km/day, which is very similar to the velocity of spread of the bluetongue virus serotype 8 epizootic in France also estimated in a context of restrictions on animal movements. Vaccination significantly reduced the propagation velocity of BTV-1. In comparison to municipalities with no vaccine coverage, the velocity of BTV-1 spread decreased by 1.7 km/day in municipalities with immunized animals. For the first time, the effect of vaccination has been quantified using data from a real epizootic whilst accounting for environmental factors known to modify the velocity of bluetongue spread. Our findings emphasize the importance of vaccination in limiting disease spread across natural landscape. Finally, environmental factors, specifically those related to vector abundance and activity, were found to be good predictors of the velocity of BTV-1 spread, indicating that these variables need to be adequately accounted for when evaluating the role of vaccination on bluetongue spread. [ABSTRACT FROM AUTHOR]

Commuting data is increasingly used to describe population mobility in epidemic models. However, there is little evidence that the spatial spread of observed epidemics agrees with commuting. Here, using data from 25 epidemics for influenza-like illness in France (ILI) as seen by the Sentinelles network, we show that commuting volume is highly correlated with the spread of ILI. Next, we provide a systematic analysis of the spread of epidemics using commuting data in a mathematical model. We extract typical paths in the initial spread, related to the organization of the commuting network. These findings suggest that an alternative geographic distribution of GP accross France to the current one could be proposed. Finally, we show that change in commuting according to age (school or work commuting) impacts epidemic spread, and should be taken into account in realistic models. [ABSTRACT FROM AUTHOR]

The mandatory bovine abortion notification system in France aims to detect as soon as possible any resurgence of bovine brucellosis. However, under-reporting seems to be a major limitation of this system. We used a unilist capture-recapture approach to assess the sensitivity, i.e. the proportion of farmers who reported at least one abortion among those who detected such events, and representativeness of the system during 2006–2011. We implemented a zero-inflated Poisson model to estimate the proportion of farmers who detected at least one abortion, and among them, the proportion of farmers not reporting. We also applied a hurdle model to evaluate the effect of factors influencing the notification process. We found that the overall surveillance sensitivity was about 34%, and was higher in beef than dairy cattle farms. The observed increase in the proportion of notifying farmers from 2007 to 2009 resulted from an increase in the surveillance sensitivity in 2007/2008 and an increase in the proportion of farmers who detected at least one abortion in 2008/2009. These patterns suggest a raise in farmers’ awareness in 2007/2008 when the Bluetongue Virus (BTV) was detected in France, followed by an increase in the number of abortions in 2008/2009 as BTV spread across the country. Our study indicated a lack of sensitivity of the mandatory bovine abortion notification system, raising concerns about the ability to detect brucellosis outbreaks early. With the increasing need to survey the zoonotic Rift Valley Fever and Q fever diseases that may also cause bovine abortions, our approach is of primary interest for animal health stakeholders to develop information programs to increase abortion notifications. Our framework combining hurdle and ZIP models may also be applied to estimate the completeness of other clinical surveillance systems. [ABSTRACT FROM AUTHOR]

Abstract: The fourth Leon Thal Symposium (LTS2010) was convened in Toulouse, France, on November 3, 2010. This symposium reviewed design parameters that are necessary to develop comprehensive national databases on healthy aging. Such datasets offer the potential to serve as the foundation for a systems-approach to solve the dual public health problems of: (1) early detection of people who are at elevated risk for Alzheimer’s disease, and (2) the development of interventions to delay onset of, or prevent, late-life dementia. The symposium considered three interrelated components of a National Database for Longitudinal Studies on Healthy Aging as follows: (a) a registry of healthy aging adults; (b) refined computer-based assessments for data gathering, including assessments of behavioral/memory changes associated with aging that are appropriate for broad use in nonexpert settings; and (c) high performance computing/supercomputer-based approaches for health data modeling and mining. [Copyright &y& Elsevier]

Since December 2019, a novel coronavirus (COVID-19) has spread all over the world, causing unpredictable economic losses and public fear. Although vaccines against this virus have been developed and administered for months, many countries still suffer from secondary COVID-19 infections, including the United Kingdom, France, and Malaysia. Observations of COVID-19 infections in the United Kingdom and France and their governance measures showed a certain number of similarities. A further investigation of these countries' COVID-19 transmission patterns suggested that when a turning point appeared, the values of their stringency indices per population density (PSI) were nearly proportional to their absolute infection rate (AIR). To justify our assumptions, we developed a mathematical model named VSHR to predict the COVID-19 turning point for Malaysia. VSHR was first trained on 30-day infection records prior to the United Kingdom, Germany, France, and Belgium's known turning points. It was then transferred to Malaysian COVID-19 data to predict this nation's turning point. Given the estimated AIR parameter values in 5 days, we were now able to locate the turning point's appearance on June 2 nd , 2021. VSHR offered two improvements: (1) gathered countries into groups based on their SI patterns and (2) generated a model to identify the turning point for a target country within 5 days with 90% CI. Our research on COVID-19's turning point for a country is beneficial for governments and clinical systems against future COVID-19 infections., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2022 Xiang Yu et al.)

Simulating nationwide realistic individual movements with a detailed geographical structure can help optimise public health policies. However, existing tools have limited resolution or can only account for a limited number of agents. We introduce Epidemap, a new framework that can capture the daily movement of more than 60 million people in a country at a building-level resolution in a realistic and computationally efficient way. By applying it to the case of an infectious disease spreading in France, we uncover hitherto neglected effects, such as the emergence of two distinct peaks in the daily number of cases or the importance of local density in the timing of arrival of the epidemic. Finally, we show that the importance of super-spreading events strongly varies over time., Competing Interests: OT, SA, CB, MB, MS No competing interests declared, (© 2021, Thomine et al.)

The COVID-19 epidemic has forced most countries to impose contact-limiting restrictions at workplaces, universities, schools, and more broadly in our societies. Yet, the effectiveness of these unprecedented interventions in containing the virus spread remain largely unquantified. Here, we develop a simulation study to analyze COVID-19 outbreaks on three real-life contact networks stemming from a workplace, a primary school and a high school in France. Our study provides a fine-grained analysis of the impact of contact-limiting strategies at workplaces, schools and high schools, including: (1) Rotating strategies, in which workers are evenly split into two shifts that alternate on a daily or weekly basis; and (2) On-Off strategies, where the whole group alternates periods of normal work interactions with complete telecommuting. We model epidemics spread in these different setups using a stochastic discrete-time agent-based transmission model that includes the coronavirus most salient features: super-spreaders, infectious asymptomatic individuals, and pre-symptomatic infectious periods. Our study yields clear results: the ranking of the strategies, based on their ability to mitigate epidemic propagation in the network from a first index case, is the same for all network topologies (workplace, primary school and high school). Namely, from best to worst: Rotating week-by-week, Rotating day-by-day, On-Off week-by-week, and On-Off day-by-day. Moreover, our results show that below a certain threshold for the original local reproduction number [Formula: see text] within the network (< 1.52 for primary schools, < 1.30 for the workplace, < 1.38 for the high school, and < 1.55 for the random graph), all four strategies efficiently control outbreak by decreasing effective local reproduction number to [Formula: see text] < 1. These results can provide guidance for public health decisions related to telecommuting., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: L.O. has received research funding from Pfizer (through her research unit) on research related to meningococcal epidemiology and antimicrobial resistance. All other authors have declared that no competing interests exist.

The effective reproduction number Reff is a critical epidemiological parameter that characterizes the transmissibility of a pathogen. However, this parameter is difficult to estimate in the presence of silent transmission and/or significant temporal variation in case reporting. This variation can occur due to the lack of timely or appropriate testing, public health interventions and/or changes in human behavior during an epidemic. This is exactly the situation we are confronted with during this COVID-19 pandemic. In this work, we propose to estimate Reff for the SARS-CoV-2 (the etiological agent of the COVID-19), based on a model of its propagation considering a time-varying transmission rate. This rate is modeled by a Brownian diffusion process embedded in a stochastic model. The model is then fitted by Bayesian inference (particle Markov Chain Monte Carlo method) using multiple well-documented hospital datasets from several regions in France and in Ireland. This mechanistic modeling framework enables us to reconstruct the temporal evolution of the transmission rate of the COVID-19 based only on the available data. Except for the specific model structure, it is non-specifically assumed that the transmission rate follows a basic stochastic process constrained by the observations. This approach allows us to follow both the course of the COVID-19 epidemic and the temporal evolution of its Reff(t). Besides, it allows to assess and to interpret the evolution of transmission with respect to the mitigation strategies implemented to control the epidemic waves in France and in Ireland. We can thus estimate a reduction of more than 80% for the first wave in all the studied regions but a smaller reduction for the second wave when the epidemic was less active, around 45% in France but just 20% in Ireland. For the third wave in Ireland the reduction was again significant (>70%)., Competing Interests: The authors have declared that no competing interests exist.

In an epidemic, individuals can widely differ in the way they spread the infection depending on their age or on the number of days they have been infected for. In the absence of pharmaceutical interventions such as a vaccine or treatment, non-pharmaceutical interventions (e.g. physical or social distancing) are essential to mitigate the pandemic. We develop an original approach to identify the optimal age-stratified control strategy to implement as a function of the time since the onset of the epidemic. This is based on a model with a double continuous structure in terms of host age and time since infection. By applying optimal control theory to this model, we identify a solution that minimizes deaths and costs associated with the implementation of the control strategy itself. We also implement this strategy for three countries with contrasted age distributions (Burkina-Faso, France, and Vietnam). Overall, the optimal strategy varies throughout the epidemic, with a more intense control early on, and depending on host age, with a stronger control for the older population, except in the scenario where the cost associated with the control is low. In the latter scenario, we find strong differences across countries because the control extends to the younger population for France and Vietnam 2 to 3 months after the onset of the epidemic, but not for Burkina Faso. Finally, we show that the optimal control strategy strongly outperforms a constant uniform control exerted over the whole population or over its younger fraction. This improved understanding of the effect of age-based control interventions opens new perspectives for the field, especially for age-based contact tracing., Competing Interests: The authors have declared that no competing interests exist.

Background: The most common inherited peripheral neuropathy is Charcot-Marie-Tooth disease (CMT), with a prevalence of 1/2500. Other symptoms can be associated to the condition, such as hearing loss. Currently, no global hearing impairment assessment has been determined, and the physiopathology is not well known., Methods: The aim of the study was to analyze among a French series of 3,412 patients with inherited peripheral neuropathy (IPN), the ones who also suffer from hearing loss, to establish phenotype-genotype correlations. An NGS strategy for IPN one side and nonsyndromic hearing loss (NSHL) on the other side, were performed., Results: Hearing loss (HL) was present in only 44 patients (1.30%). The clinical data of 27 patients were usable. Demyelinating neuropathy was diagnosed in 15 cases and axonal neuropathy in 12 cases. HL varied from mild to profound. Five cases of auditory neuropathy were noticed. Diagnosis was made for 60% of these patients. Seven novel pathogenic variants were discovered in five different genes: PRPS1; MPZ; SH3TC2; NEFL; and ABHD12. Two patients with PMP22 variant, had also an additional variant in COCH and MYH14 respectively. No pathogenic variant was found at the DFNB1 locus. Genotype-phenotype correlations do exist, especially with SH3TC2, PRPS1, ABHD12, NEFL, and TRPV4., Conclusion: Involvement of PMP22 is not enough to explain hearing loss in patients suffering from IPN. HL can be due to cochlear impairment and/or auditory nerve dysfunction. HL is certainly underdiagnosed, and should be evaluated in every patient suffering from IPN., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Pseudomonas aeruginosa (P. aeruginosa) is an important cause of healthcare-associated infections, particularly in immunocompromised patients. Understanding how this multi-drug resistant pathogen is transmitted within intensive care units (ICUs) is crucial for devising and evaluating successful control strategies. While it is known that moist environments serve as natural reservoirs for P. aeruginosa, there is little quantitative evidence regarding the contribution of environmental contamination to its transmission within ICUs. Previous studies on other nosocomial pathogens rely on deploying specific values for environmental parameters derived from costly and laborious genotyping. Using solely longitudinal surveillance data, we estimated the relative importance of P. aeruginosa transmission routes by exploiting the fact that different routes cause different pattern of fluctuations in the prevalence. We developed a mathematical model including background transmission, cross-transmission and environmental contamination. Patients contribute to a pool of pathogens by shedding bacteria to the environment. Natural decay and cleaning of the environment lead to a reduction of that pool. By assigning the bacterial load shed during an ICU stay to cross-transmission, we were able to disentangle environmental contamination during and after a patient's stay. Based on a data-augmented Markov Chain Monte Carlo method the relative importance of the considered acquisition routes is determined for two ICUs of the University hospital in Besançon (France). We used information about the admission and discharge days, screening days and screening results of the ICU patients. Both background and cross-transmission play a significant role in the transmission process in both ICUs. In contrast, only about 1% of the total transmissions were due to environmental contamination after discharge. Based on longitudinal surveillance data, we conclude that cleaning improvement of the environment after discharge might have only a limited impact regarding the prevention of P.A. infections in the two considered ICUs of the University hospital in Besançon. Our model was developed for P. aeruginosa but can be easily applied to other pathogens as well., Competing Interests: The authors have declared that no competing interests exist.

Two Gram-stain-positive, small ellipsoidal cocci, non-motile, oxidase- and catalase-negative, and facultative anaerobic strains (UCMA15228 T and UCMA17102) were isolated in France, from fermented apple juices (ciders). The 16S rRNA gene sequence was identical between the two isolates and showed 97 % similarity with respect to the closest related species Oenococcus oeni and O. kitaharae. Therefore, the two isolates were classified within the genus Oenococcus. The phylogeny based on the pheS gene sequences also confirmed the position of the new taxon. DNA-DNA hybridizations based on in silico genome-to-genome comparisons (GGDC) and Average Nucleotide Identity (ANI) values, as well as species-specific PCR, validated the novelty of the taxon. Various phenotypic characteristics such as the optimum temperature and pH for growth, the ability to metabolise sugars, the aptitude to perform the malolactic fermentation, and the resistance to ethanol and NaCl, revealed that the two strains are distinguishable from the other members of the Oenococcus genus. The combined genotypic and phenotypic data support the classification of strains UCMA15228 T and UCMA17102 into a novel species of Oenococcus, for which the name O. sicerae sp. nov. is proposed. The type strain is UCMA15228 T (=DSM107163 T =CIRM-BIA2288 T )., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Metatranscriptome analysis relates to the transcriptome of microbial communities directly sampled in the environment. Accessing the mRNA pool in natural bacterial communities presents some technical challenges such as the RNA extraction, rRNA depletion, and the choice of the high-throughput sequencing technique. The lack of technical details in scientific articles is a major problem to correctly obtained mRNA from a microbial community and thus the corresponding sequencing data. In our study, we present the methodological procedure that was developed in order to access to the metatranscriptome of the microbial communities during two cyanobacterial blooms successively occurring in a freshwater eutrophic lake. Each procedure step was detailed and discussed with regard to the choices and difficulties encountered and to the recent literature. Finally, the two major limits for metatranscriptomic approaches targeting bacterial communities from natural environments were (i) the removal of rRNA in order to increase the putative mRNA reads number after sequencing, and (ii) for most of the bacterial communities living in natural environments, the lack of reference genomes in databases that leads to the non-assignation of numerous reads. Once these challenges overcome, we managed to access putative mRNA of dominant species, i.e. cyanobacteria (from 6 to 72 % of mRNA assigned), and of the surrounding bacteria (from 1 to 5 % of mRNA assigned).

Due to increased travel, climatic, and environmental changes, the incidence of tick-borne disease in both humans and animals is increasing throughout Europe. Therefore, extended surveillance tools are desirable. To accurately screen tick-borne pathogens (TBPs), a large scale epidemiological study was conducted on 7050 Ixodes ricinus nymphs collected from France, Denmark, and the Netherlands using a powerful new high-throughput approach. This advanced methodology permitted the simultaneous detection of 25 bacterial, and 12 parasitic species (including; Borrelia, Anaplasma, Ehrlichia, Rickettsia, Bartonella, Candidatus Neoehrlichia, Coxiella, Francisella, Babesia, and Theileria genus) across 94 samples. We successfully determined the prevalence of expected (Borrelia burgdorferi sensu lato, Anaplasma phagocytophilum, Rickettsia helvetica, Candidatus Neoehrlichia mikurensis, Babesia divergens, Babesia venatorum), unexpected (Borrelia miyamotoi), and rare (Bartonella henselae) pathogens in the three European countries. Moreover we detected Borrelia spielmanii, Borrelia miyamotoi, Babesia divergens, and Babesia venatorum for the first time in Danish ticks. This surveillance method represents a major improvement in epidemiological studies, able to facilitate comprehensive testing of TBPs, and which can also be customized to monitor emerging diseases.

Although CDKN2A is the most frequent high-risk melanoma susceptibility gene, the underlying genetic factors for most melanoma-prone families remain unknown. Using whole-exome sequencing, we identified a rare variant that arose as a founder mutation in the telomere shelterin gene POT1 (chromosome 7, g.124493086C>T; p.Ser270Asn) in five unrelated melanoma-prone families from Romagna, Italy. Carriers of this variant had increased telomere lengths and numbers of fragile telomeres, suggesting that this variant perturbs telomere maintenance. Two additional rare POT1 variants were identified in all cases sequenced in two separate Italian families, one variant per family, yielding a frequency for POT1 variants comparable to that for CDKN2A mutations in this population. These variants were not found in public databases or in 2,038 genotyped Italian controls. We also identified two rare recurrent POT1 variants in US and French familial melanoma cases. Our findings suggest that POT1 is a major susceptibility gene for familial melanoma in several populations.

Signalling through the Wnt family of secreted proteins originated in a common metazoan ancestor and greatly influenced the evolution of animal body plans. In bilaterians, Wnt signalling plays multiple fundamental roles during embryonic development and in adult tissues, notably in axial patterning, neural development and stem cell regulation. Studies in various cnidarian species have particularly highlighted the evolutionarily conserved role of the Wnt/β-catenin pathway in specification and patterning of the primary embryonic axis. However in another key non-bilaterian phylum, Ctenophora, Wnts are not involved in early establishment of the body axis during embryogenesis. We analysed the expression in the adult of the ctenophore Pleurobrachia pileus of 11 orthologues of Wnt signalling genes including all ctenophore Wnt ligands and Fz receptors and several members of the intracellular β-catenin pathway machinery. All genes are strongly expressed around the mouth margin at the oral pole, evoking the Wnt oral centre of cnidarians. This observation is consistent with primary axis polarisation by the Wnts being a universal metazoan feature, secondarily lost in ctenophores during early development but retained in the adult. In addition, local expression of Wnt signalling genes was seen in various anatomical structures of the body including in the locomotory comb rows, where their complex deployment suggests control by the Wnts of local comb polarity. Other important contexts of Wnt involvement which probably evolved before the ctenophore/cnidarian/bilaterian split include proliferating stem cells and progenitors irrespective of cell types, and developing as well as differentiated neuro-sensory structures.

Bluetongue (BT) is a commonly cited example of a disease with a distribution believed to have recently expanded in response to global warming. The BT virus is transmitted to ruminants by biting midges of the genus Culicoides, and it has been hypothesized that the emergence of BT in Mediterranean Europe during the last two decades is a consequence of the recent colonization of the region by Culicoides imicola and linked to climate change. To better understand the mechanism responsible for the northward spread of BT, we tested the hypothesis of a recent colonization of Italy by C. imicola, by obtaining samples from more than 60 localities across Italy, Corsica, Southern France, and Northern Africa (the hypothesized source point for the recent invasion of C. imicola), and by genotyping them with 10 newly identified microsatellite loci. The patterns of genetic variation within and among the sampled populations were characterized and used in a rigorous approximate Bayesian computation framework to compare three competing historical hypotheses related to the arrival and establishment of C. imicola in Italy. The hypothesis of an ancient presence of the insect vector was strongly favoured by this analysis, with an associated P ≥ 99%, suggesting that causes other than the northward range expansion of C. imicola may have supported the emergence of BT in southern Europe. Overall, this study illustrates the potential of molecular genetic markers for exploring the assumed link between climate change and the spread of diseases., (© 2013 Blackwell Publishing Ltd.)

Range expansion and contraction has occurred in the history of most species and can seriously impact patterns of genetic diversity. Historical data about range change are rare and generally appropriate for studies at large scales, whereas the individual pollen and seed dispersal events that form the basis of geneflow and colonization generally occur at a local scale. In this study, we investigated range change in Fagus sylvatica on Mont Ventoux, France, using historical data from 1838 to the present and approximate Bayesian computation (ABC) analyses of genetic data. From the historical data, we identified a population minimum in 1845 and located remnant populations at least 200 years old. The ABC analysis selected a demographic scenario with three populations, corresponding to two remnant populations and one area of recent expansion. It also identified expansion from a smaller ancestral population but did not find that this expansion followed a population bottleneck, as suggested by the historical data. Despite a strong support to the selected scenario for our data set, the ABC approach showed a low power to discriminate among scenarios on average and a low ability to accurately estimate effective population sizes and divergence dates, probably due to the temporal scale of the study. This study provides an unusual opportunity to test ABC analysis in a system with a well-documented demographic history and identify discrepancies between the results of historical, classical population genetic and ABC analyses. The results also provide valuable insights into genetic processes at work at a fine spatial and temporal scale in range change and colonization., (© 2011 Blackwell Publishing Ltd.)

Mutations in OPTN gene encoding optineurin have recently been identified at the homozygote and heterozygote state in Japanese families with slowly progressive amyotrophic lateral sclerosis (ALS). OPTN had previously been involved in adult primary open angle glaucoma (POAG). We sequenced the coding exons of OPTN in 126 French patients with familial ALS (FALS). We identified, at the heterozygote state, the nonsense c.382&#95;383insAG variant (also called 691&#95;692insAG), alternatively reported as a causative mutation for primary open angle glaucoma (POAG) or a rare polymorphism and the new p.Arg96Leu variant in a family with dominant ALS. Western blot experiments on the patients' lymphoblasts showed that the former variant led to a loss of function and the latter did not cause protein accumulation. Our results do not confirm the contribution of OPTN in ALS., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The island of Newfoundland, the first of England's overseas colonies, was settled from the 17th century onward by restricted numbers of English, Irish, and French immigrants, in small "outport" communities that have maintained geographic, religious, and linguistic isolation to the latest generations. To measure the extent of modification and loss of genetic variation through founder effect, drift, and inbreeding in this historically isolated population, we analyzed the complete mitochondrial DNA (mtDNA) genomes and 14 microsatellite loci from each of 27 individuals with matrilineal ancestries extending to the colonial period. Every individual has a unique mtDNA genome sequence. All but one of these genomes are assignable to one of five major (H,J,K,T, and U) or minor (I) European haplogroups. The possibility of homoplasy at single nucleotide polymorphism (SNP) sites that define subtypes within the H haplogroup is discussed. Observed haplogroup proportions do not differ significantly from those of western Europeans or between English and Irish Newfoundlanders. The exceptional individual is a member of haplogroup A2, who appears to be the descendant of a Mi'kmaq First Nations mother and a French father, a common marriage pattern in the early settlement of Newfoundland. Microsatellite diversity is high (HE = 0.763), unstructured with respect to mtDNA haplotype or ethnicity, and there is no evidence of linkage disequilibrium. There is a small but significant degree of inbreeding (FIS = 0.0174). Collection of whole mtDNA genome data was facilitated by the use of microarray sequencing, and we describe a simple algorithm that is 99.67% efficient for sequence recovery.

Adenoviral infections are typically acute, self-limiting, and not associated with death. However, we present the genomic and bioinformatics analysis of a novel recombinant human adenovirus (HAdV-D56) isolated in France that caused a rare neonatal fatality, and keratoconjunctivitis in three health care workers who cared for the neonate. Whole genome alignments revealed the expected diversity in the penton base, hexon, E3, and fiber coding regions, and provided evidence for extensive recombination. Bootscan analysis confirmed recombination between HAdV-D9, HAdV-D26, HAdV-D15, and HAdV-D29 in the penton base and hexon proteins, centered around hypervariable loops within the putative proteins. Protein structure analysis of the fiber coding region revealed similarity with HAdV-D8, HAdV-D9, and HAdV-D53, possibly accounting for the ocular tropism of the virus. Based on these data, this virus appears to be a new HAdV-D type (HAdV-D56), underscoring the importance of recombination events in human adenovirus evolution and the emergence of new adenovirus pathogens., (Copyright © 2010 Elsevier Inc. All rights reserved.)

In humans, the glycine N-acyltransferase enzyme (GLYAT) is thought to be important in the detoxification of endogenous and xenobiotic compounds which contain a carboxylic acid group, such as benzoic, isovaleric, or acetylsalicylic acids. The aim of this work was to report a comprehensive investigation of GLYAT genetic polymorphisms in DNA samples from 55 subjects of French Caucasian origin, using polymerase chain reaction-single-strand conformation polymorphism and sequencing strategies. Seven different polymorphisms of the GLYAT gene were identified, including two polymorphisms in the 5' flanking region of the gene (g.-8457C>T and g.-8010A>G), two polymorphisms in intron 5 (g.13931A>G and g.13944C>T) and three missense mutations in exon 2 (g.49T>A; p.Ser17Thr), exon 5 (g.13886A>G; p.Asn156Ser) and exon 6 (g.14435C>T; p.Arg199Cys). In addition to the wild-type allele GLYAT*1 (2.7%), four novel alleles were identified: GLYAT*2A (75.5%), *2B (4.5%), *3 (16.4%) and *4 (0.9%), and five different genotypes. Localisation of the p.Ser17Thr and p.Arg199Cys missense mutations in predicted secondary structures suggest that these variants might have a potential role on the GLYAT protein activity. These results could be helpful in investigating the potential association of GLYAT variants with an incidence of reduced efficiency in xenobiotic carboxylic acids detoxification in humans.

The results of several genome-wide association studies (GWASs) in the field of Alzheimer's disease (AD) have recently been published. Although these studies reported in detail on single-nucleotide polymorphisms (SNPs) and the neighboring genes with the strongest evidence of association with AD, little attention was paid to the rest of the genome. However, complementary statistical and bio-informatics approaches now enable the extraction of pertinent information from other SNPs and/or genes which are only nominally associated with the disease risk. Two different tools (the ALIGATOR and GenGen/KEGG software packages) were used to analyze a large GWAS dataset containing 2,032 AD cases and 5,328 controls. Convergent outputs from the two gene set enrichment approaches suggested an immune system dysfunction in AD. Furthermore, although these statistical approaches did not adopt a priori hypotheses concerning a biological function's putative role in the disease process, genes associated with AD risk were overrepresented in the "Alzheimer's disease" KEGG pathway. In conclusion, a systematic search for biological pathways using GWAS data set seems to comfort the primary causes already suspected but may specifically highlight the importance of the immune system in AD.

One of the major goals of evo-developmentalists is to understand how the genetic mechanisms controlling embryonic development have evolved to create the current diversity of bodyplans that we encounter in the animal kingdom. Tyrosine kinase receptors (RTKs) are transmembrane receptors present in all metazoans known to control several developmental processes. They act via the activation of various cytoplasmic signaling cascades, including the mitogen-activated protein kinase (MAPK), the PI3K/Akt, and the phospholipase C-gamma (PLCgamma)/protein kinase C (PKC) pathways. In order to address the evolution of these three pathways and their involvement during embryogenesis in chordates, we took advantage of the complete genome sequencing of a key evolutionarily positioned species, the cephalochordate amphioxus, and searched for the complete gene set of the three signaling pathways. We found that the amphioxus genome contains all of the most important modules of the RTK-activated cascades, and looked at the embryonic expression of two genes selected from each cascade. Our data suggest that although the PI3K/Akt pathway may have ubiquitous functions, the MAPK and the PLCgamma/PKC cascades may play specific roles in amphioxus development. Together with data known in vertebrates, the expression pattern of PKC in amphioxus suggests that the PLCgamma/PKC cascade was implicated in neural development in the ancestor of all chordates.

Eating disorders (EDs) are complex psychiatric diseases that include anorexia nervosa and bulimia nervosa, and have higher than 50% heritability. Previous studies have found association of BDNF and NTRK2 to ED, while animal models suggest that other neurotrophin genes might also be involved in eating behavior. We have performed a family-based association study with 151 TagSNPs covering 10 neurotrophin signaling genes: NGFB, BDNF, NTRK1, NGFR/p75, NTF4/5, NTRK2, NTF3, NTRK3, CNTF and CNTFR in 371 ED trios of Spanish, French and German origin. Besides several nominal associations, we found a strong significant association after correcting for multiple testing (P = 1.04 x 10(-4)) between ED and rs7180942, located in the NTRK3 gene, which followed an overdominant model of inheritance. Interestingly, HapMap unrelated individuals carrying the rs7180942 risk genotypes for ED showed higher levels of expression of NTRK3 in lymphoblastoid cell lines. Furthermore, higher expression of the orthologous murine Ntrk3 gene was also detected in the hypothalamus of the anx/anx mouse model of anorexia. Finally, variants in NGFB gene appear to modify the risk conferred by the NTRK3 rs7180942 risk genotypes (P = 4.0 x 10(-5)) showing a synergistic epistatic interaction. The reported data, in addition to the previous reported findings for BDNF and NTRK2, point neurotrophin signaling genes as key regulators of eating behavior and their altered cross-regulation as susceptibility factors for EDs.

Novel prognostic biomarkers are imperatively needed to help direct treatment decisions by typing subgroups of node-negative breast cancer patients. The current study has used a proteomic approach of SELDI-TOF-MS screening to identify differentially cytosolic expressed proteins with a prognostic impact in 30 node-negative breast cancer patients with no relapse versus 30 patients with metastatic relapse. The data analysis took into account 73 peaks, among which 2 proved, by means of univariate Cox regression, to have a good cumulative prognostic-informative power. Repeated random sampling (n = 500) was performed to ensure the reliability of the peaks. Optimized thresholds were then computed to use both peaks as risk factors and, adding them to the St. Gallen ones, improve the prognostic classification of node-negative breast cancer patients. Identification of ubiquitin and ferritin light chain (FLC), corresponding to the two peaks of interest, was obtained using ProteinChip LDI-Qq-TOF-MS. Differential expression of the two proteins was further confirmed by Western blotting analyses and immunohistochemistry. SELDI-TOF-MS protein profiling clearly showed that a high level of cytosolic ubiquitin and/or a low level of FLC were associated with a good prognosis in breast cancer.

Classical studies on protist diversity of freshwater environments worldwide have led to the idea that most species of microbial eukaryotes are known. One exemplary case would be constituted by the ciliates, which have been claimed to encompass a few thousands of ubiquitous species, most of them already described. Recently, molecular methods have revealed an unsuspected protist diversity, especially in oceanic as well as some extreme environments, suggesting the occurrence of a hidden diversity of eukaryotic lineages. In order to test if this holds also for freshwater environments, we have carried out a molecular survey of small subunit ribosomal RNA genes in water and sediment samples of two ponds, one oxic and another suboxic, from the same geographic area. Our results show that protist diversity is very high. The majority of phylotypes affiliated within a few well established eukaryotic kingdoms or phyla, including alveolates, cryptophytes, heterokonts, Cercozoa, Centroheliozoa and haptophytes, although a few sequences did not display a clear taxonomic affiliation. The diversity of sequences within groups was very large, particularly that of ciliates, and a number of them were very divergent from known species, which could define new intra-phylum groups. This suggests that, contrary to current ideas, the diversity of freshwater protists is far from being completely described.

Objective: In this paper we outline how Computational Integrative Physiology (CIP) can help unravel the mechanisms of normal and pathological biological processes. Our objective is to illustrate how CIP is firmly grounded on the life and computational sciences., Method: After describing a general theoretical frame-work for CIP, we will center our discussion on cardiac rhythmic disorders with a particular focus on the Long QT syndrome that will serve as a case example. Within this context, we will describe multi-scale processes in biological, medical and in general mathematical terms, starting from the control of gene expression to the electrical activity of the entire heart. We will therefore proceed from the smaller microscopic scales to the larger macroscopic ones. In doing so, we will illustrate, at least in a qualitative sense, how CIP can be accomplished by showing some of the relations that can exist between mathematical variables characterizing models of different space-scales., Conclusion: We will conclude by putting forth how CIP and the related fields of bioinformatics and medical informatics are necessary to derive meaningful knowledge from the huge and exponentially growing biological and medical data.

IMGT, the international ImMunoGeneTics database (http://imgt.cines.fr), is a high quality integrated information system specializing in Immunoglobulins (IG), T cell Receptors (TR) and Major Histocompatibility Complex (MHC) of human and other vertebrates, created in 1989, by LIGM, at the Université Montpellier II, CNRS, Montpellier, France. IMGT provides a common access to standardized data, which include nucleotide and protein sequences, oligonucleotide primers, gene maps, genetic polymorphisms, specificities, 2D and 3D structures. IMGT includes several databases (IMGT/LIGM-DB, IMGT/HLA-DB, IMGT/3Dstructure-DB), Web resources ('IMGT Marie-Paule page') which comprise IMGT Scientific Chart, IMGT Repertoire, IMGT Bloc-notes, IMGT Education, IMGT Aide-mémoire and IMGT Index, and interactive tools (IMGT/V-QUEST, IMGT/JunctionAnalysis). These expertly annotated data on the genome, proteome, genetics and structure of the IG, TR and MHC are of high value for comparative genome evolution studies of the adaptative immune response.