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Criminal offenders missing from police files limit the capacity to reconstruct criminal networks for criminological research and operational purposes. Recent studies show that forensic DNA databanks offer potential to address this problem, through large-scale analysis of DNA matches, many of which involve unidentified offenders. Applying social network analysis (SNA) to 18 years of DNA match data from Québec, Canada, we found that 1400 unknowns do not occupy more marginal positions in the network than 13,000 known offenders, and explain up to 18% of SNA values (e.g., betweenness centrality) for the latter while supporting 46% of their clustering values. Our results contrast with previous studies, showing moreover that unknown individuals who are positioned centrally in a network may have a larger impact than previously expected on investigation policing with implications for forensic intelligence., Competing Interests: Declarations of interest None., (Copyright © 2021 The Institution of Chemical Engineers. Published by Elsevier B.V. All rights reserved.)

Objectives: We describe a method to identify human remains excavated from unmarked graves in historical Québec cemeteries by combining parental-lineage genetic markers with the whole-population genealogy of Québec contained in the BALSAC database., Materials and Methods: The remains of six men were exhumed from four historical cemeteries in the province of Québec, Canada. DNA was extracted from the remains and genotyped to reveal their mitochondrial and Y-chromosome haplotypes, which were compared to a collection of haplotypes of genealogically-anchored modern volunteers. Maternal and paternal genealogies were searched in the BALSAC genealogical record for parental couples matching the mitochondrial and the Y-chromosome haplotypic signatures, to identify candidate sons from whom the remains could have originated., Results: Analysis of the matching genealogies identified the parents of one man inhumed in the cemetery of the investigated parish during its operating time. The candidate individual died in 1833 at the age of 58, a plausible age at death in light of osteological analysis of the remains., Discussion: This study demonstrates the promising potential of coupling genetic information from living individuals to genealogical data in BALSAC to identify historical human remains. If genetic coverage is increased, the genealogical information in BALSAC could enable the identification of 87% of the men (n = 178,435) married in Québec before 1850, with high discriminatory power in most cases since >75% of the parental couples have unique biparental signatures in most regions. Genotyping and identifying Québec's historical human remains are a key to reconstructing the genomes of the founders of Québec and reinhuming archeological remains with a marked grave., (© 2020 Wiley Periodicals, Inc.)

Probabilistic genotyping approaches are increasingly used for the interpretation of DNA mixtures. To explore the specificity of one of these systems (STRmix ™ ), we conducted an extensive study using 24 complex mixtures: all were known or apparent 4-person mixtures with at least one contributor representing less than 20% of total DNA, and all mixtures had at least one contributor with suboptimal DNA quantity. Those mixtures were either generated in-house or from casework. All the mixtures were compared to 300,000 virtual non-contributors, resulting in a dataset of 7.2 million comparisons. The great majority of the non-contributor comparisons led to a LR lower than 1 for a specificity of 99.1%. The effect of using replicate amplifications to calculate the LR of non-contributors was also assessed as triplicates were used and led to an increased specificity of 99.8%. The very large extent of the analyzed data shows that STRmix ™ has an excellent ability to discriminate non-contributors from complex DNA mixtures., (Crown Copyright © 2019. Published by Elsevier B.V. All rights reserved.)

Introduction: Animal studies suggested that NFKB1 , IKBKB , and SOCS3 genes could be involved in the association between overnutrition and obesity. This study aims to investigate interactions involving these genes and macronutrient intakes affecting obesity-related phenotypes. Methods: We used a traditional statistical method, logistic regression, and compared it to alternative statistical method, multifactor dimensionality reduction (MDR) and penalized logistic regression (PLR), to better detect genes/environment interactions in the Toronto Nutrigenomics and Health Study ( n = 1639) using dichotomized body mass index (BMI) and waist circumference as obesity-related phenotypes. Exposure variables included genotype on 54 single nucleotide polymorphisms ( NFKB1 : 18, IKBKB : 9, SOCS3 : 27), macronutrient (carbohydrates, protein, fat) and alcohol intakes and ethno-cultural background. Results: After correction for multiple testing, no interaction was found using logistic regression. MDR identified interactions between SOCS3 rs6501199 and rs4969172, and IKBKB rs3747811 affecting BMI in the Caucasian population; SOCS3 rs6501199 and NFKB1 rs1609798 affecting WC in the Caucasian population; and SOCS3 rs4436839 and IKBKB rs3747811 affecting WC in the South Asian population. PLR found a main effect of SOCS3 rs12944581 on BMI among the South Asian population. Conclusion: While MDR and PLR had discordant results, some models support results from previous studies. These results emphasize the need to use alternative statistical methods to investigate high-order interactions and suggest that variants in the nutrient-responsive hypothalamic IKKB/NF-kB signaling pathway may be involved in obesity pathogenesis.

Background: The interactive effect of the IGF pathway genes with the environment may contribute to childhood obesity. Such gene-environment interactions can take on complex forms. Detecting those relationships using longitudinal family studies requires simultaneously accounting for correlations within individuals and families., Methods: We studied three methods for detecting interaction effects in longitudinal family studies. The twin model and the nonparametric partition-based score test utilized individual outcome averages, whereas the linear mixed model used all available longitudinal data points. Simulation experiments were performed to evaluate the methods' power to detect different gene-environment interaction relationships. These methods were applied to the Quebec Newborn Twin Study data to test for interaction effects between the IGF pathway genes (IGF-1, IGFALS) and environmental factors (physical activity, daycare attendance and sleep duration) on body mass index outcomes., Results: For the simulated data, the twin model with the mean time summary statistic yielded good performance overall. Modelling an interaction as linear when the true model had a different relationship influenced power; for certain non-linear interactions, none of the three methods were effective. Our analysis of the IGF pathway genes showed suggestive association for the joint effect of IGF-1 variant at position 102,791,894 of chromosome 12 and physical activity. However, this association was not statistically significant after multiple testing correction., Conclusions: The analytical approaches considered in this study were not robust to different gene-environment interactions. Methodological innovations are needed to improve the current methods' performances for detecting non-linear interactions. More studies are needed in order to better understand the IGF pathway's role in childhood obesity development.

The light-switch mechanism of the complex [Ru(bpy) 2 (Br-dpqp)](PF 6 ) 2 (1, bpy = 2,2'-bipyridine, Br-dpqp = 12-bromo-14-ethoxydipyrido[3,2- a:2',3'- c]quinolino[3,2- h]phenazine), i.e., a light-up probe for the selective labeling of G-quadruplexes, is investigated by time-resolved transient absorption and emission spectroscopy. We show that, in contrast to the prototypical light-switch complex [Ru(bpy) 2 (dppz)](PF 6 ) 2 (2, dppz = dipyrido[3,2- a:2',3'- c]phenazine), a 3 ππ* state localized on the π-extended ligand is the state determining the excited-state properties in both protic and aprotic environments. In aprotic environments, emission originates from a bright 3 MLCT phen state, which is thermally accessible from the 3 ππ* state at ambient temperature. In the presence of water, i.e., in environments resembling in cellulo situations, the thermally accessible 3 MLCT state is altered and becomes close in energy to the 3 ππ* state, which induces a rapid excited-state deactivation of the 3 ππ* state and a comparably weak emission.

Increasing the efficiency of molecular artificial photosynthetic systems is mandatory for the construction of functional devices for solar fuel production. Decoupling the light-induced charge separation steps from the catalytic process is a promising strategy, which can be achieved thanks to the introduction of suitable electron relay units performing charge accumulation. We report here on a novel ruthenium tris-diimine complex able to temporarily store two electrons on a fused dipyridophenazine-pyridoquinolinone π-extended ligand upon visible-light irradiation in the presence of a sacrificial electron donor. Full characterization of this compound and of its singly and doubly reduced derivatives thanks to resonance Raman, EPR and (TD)DFT studies allowed us to localize the two electron-storage sites and to relate charge photoaccumulation with proton-coupled electron transfer processes.

A series of Ru II complexes exhibiting π-extended, acridine-based ancillary chelating heterocycles display high affinity and selectivity for DNA and RNA quadruplexes. The most promising candidates (3, 4) possess remarkable light-up luminophore properties (up to 330-fold luminescence enhancement upon interaction with quadruplexes), enabling them to discriminate quadruplexes from genomic DNA owing to a photochemical mechanism involving DNA protection against non-radiative decay (DAND), thus deviating from the other complexes of this series of ligands that exhibit an excited-state intramolecular proton transfer (ESIPT) that quenches their luminescence. The in vitro and preliminary in cellulo results shown here confirm the interest of this new family of fluorophores as invaluable molecular tools to detect G-quadruplexes in cells., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Three dyes for p-type dye-sensitised solar cells containing a novel doubly anchored pyrrole donor group were synthesised and their solar cell performances were evaluated. Dye 1 was comprised of a phenyl-thiophene linker and a maleonitrile acceptor, which has been established as an effective motif in other push-pull dyes. Two boron dipyrromethane analogues, dyes 2 and 3, were made with different linker groups to compare their effect on the behaviour of these dyes adsorbed onto nickel oxide (dye|NiO) under illumination. The photoexcited states of dye|NiO were probed using resonance Raman spectroscopy and compared to dyes anchored using the conventional 4-aminobenzoic acid moiety (P1 and 4). All three components, the anchor, the linker and the acceptor group were found to alter both the electronic structure following excitation and the overall solar cell performance. The bodipy acceptor gave a better performance than the maleonitrile acceptor when the pyrrole anchor was used, which is the opposite of the triphenylamine push-pull dyes. The linker group was found to have a large influence on the short-circuit current and efficiency of the p-type cells constructed., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The preparation and characterization of three series of novel ruthenium(ii) complexes are reported, each series differing by the nature of the ancillary ligands (2,2'-bipyridine - bpy, 1,10-phenanthroline - phen or 1,4,5,8-tetraazaphenanthrene - TAP). The third ligand was either the heptacyclic heterocycle dipyrido[3,2-a:2',3'-c]quinolino[3,2-h]phenazine (dpqp) substituted at position 12 by an hydroxyl (oxo), 2,2-dimethoxyethylamine (DMEA) or halogeno (Cl or Br) substituent, or the octacyclic dipyrido[3,2-a:2',3'-c]pyrido[2,3,4-de]quinolino[3,2-h]phenazine (dppqp), prepared by a multi-step "chemistry on the complex" strategy from [RuL 2 (oxo-dpqp)](PF 6 ) 2 . The three steps, halogenation, substitution by a dimethoxyethylamino group and cyclization in trifluoroacetic acid, were performed in reasonable to high yields depending on the nature of the ancillary ligands. Isolation and purification processes were facilitated by the ability to switch the solubility of the complex from aqueous to organic solvents, depending on the counter-ion. All new complexes were fully characterized; in particular their absorption properties were compared by UV-vis spectroscopy. Finally, π-stacking properties induced by these extended ligands were studied by 1 H NMR studies and quantum chemical calculations.

A series of photosensitizers for NiO-based dye-sensitized solar cells is presented. Three model compounds containing a triphenylamine donor appended to a boron dipyrromethene (bodipy) chromophore have been successfully prepared and characterised using emission spectroscopy, electrochemistry and spectroelectrochemistry, to ultimately direct the design of dyes with more complex structures. Carboxylic acid anchoring groups and thiophene spacers were appended to the model compounds to provide five dyes which were adsorbed onto NiO and integrated into dye-sensitized solar cells. Solar cells incorporating the simple Bodipy-CO₂H dye were surprisingly promising relative to the more complex dye 4. Cell performances were improved with dyes which had increased electronic communication between the donor and acceptor, achieved by incorporating a less hindered bodipy moiety. Further increases in performances were obtained from dyes which contained a thiophene spacer. Thus, the best performance was obtained for 7 which generated a very promising photocurrent density of 5.87 mA cm(-2) and an IPCE of 53%. Spectroelectrochemistry combined with time-resolved transient absorption spectroscopy were used to determine the identity and lifetime of excited state species. Short-lived (ps) transients were recorded for 4, 5 and 7 which are consistent with previous studies. Despite a longer lived (25 ns) charge-separated state for 6/NiO, there was no increase in the photocurrent generated by the corresponding solar cell.

The etiology of immune-related diseases or traits is often complex, involving many genetic and environmental factors and their interactions. While methodological approaches focusing on an outcome measured at one time point have succeeded in identifying genetic factors involved in immune-related traits, they fail to capture complex disease mechanisms that fluctuate over time. It is increasingly recognized that longitudinal studies, where an outcome is measured at multiple time points, have great potential to shed light on complex disease mechanisms involving genetic factors. However, longitudinal data require specialized statistical methods, especially in family studies where multiple sources of correlation in the data must be modeled. Using simulated data with known genetic effects, we examined the performance of different analytical methods for investigating associations between genetic factors and longitudinal phenotypes in twin data. The simulations were modeled on data from the Québec Newborn Twin Study, an ongoing population-based longitudinal study of twin births with multiple phenotypes, such as cortisol levels and body mass index, collected multiple times in infancy and early childhood and with sequencing data on immune-related genes and pathways. We compared approaches that we classify as (1) family-based methods applied to summaries of the observations over time, (2) longitudinal-based methods with simplifications of the familial correlation, and (3) Bayesian family-based method with simplifications of the temporal correlation. We found that for estimation of the genetic main and interaction effects, all methods gave estimates close to the true values and had similar power. If heritability estimation is desired, approaches of type (1) also provide heritability estimates close to the true value. Our work shows that the simpler approaches are likely adequate to detect genetic effects; however, interpretation of these effects is more challenging.

Background: Founder populations have an important role in the study of genetic diseases. Access to detailed genealogical records is often one of their advantages. These genealogical data provide unique information for researchers in evolutionary and population genetics, demography and genetic epidemiology. However, analyzing large genealogical datasets requires specialized methods and software. The GENLIB software was developed to study the large genealogies of the French Canadian population of Quebec, Canada. These genealogies are accessible through the BALSAC database, which contains over 3 million records covering the whole province of Quebec over four centuries. Using this resource, extended pedigrees of up to 17 generations can be constructed from a sample of present-day individuals., Results: We have extended and implemented GENLIB as a package in the R environment for statistical computing and graphics, thus allowing optimal flexibility for users. The GENLIB package includes basic functions to manage genealogical data allowing, for example, extraction of a part of a genealogy or selection of specific individuals. There are also many functions providing information to describe the size and complexity of genealogies as well as functions to compute standard measures such as kinship, inbreeding and genetic contribution. GENLIB also includes functions for gene-dropping simulations. The goal of this paper is to present the full functionalities of GENLIB. We used a sample of 140 individuals from the province of Quebec (Canada) to demonstrate GENLIB's functions. Ascending genealogies for these individuals were reconstructed using BALSAC, yielding a large pedigree of 41,523 individuals. Using GENLIB's functions, we provide a detailed description of these genealogical data in terms of completeness, genetic contribution of founders, relatedness, inbreeding and the overall complexity of the genealogical tree. We also present gene-dropping simulations based on the whole genealogy to investigate identical-by-descent sharing of alleles and chromosomal segments of different lengths and estimate probabilities of identical-by-descent sharing., Conclusions: The R package GENLIB provides a user friendly and flexible environment to analyze extensive genealogical data, allowing an efficient and easy integration of different types of data, analytical methods and additional developments and making this tool ideal for genealogical analysis.

A dyad built up of a zinc(II) porphyrin and the corresponding free base, [Zn-Fb], fused to N-heterocyclic carbene (NHCs) ligands, respectively acting as singlet energy donor and acceptor, and a bridging trans-PdI2 unit, along with the corresponding [Zn-Zn] and [Fb-Fb] dimers were prepared and investigated by absorption and emission spectroscopy and density functional computations. Despite favorable structural and spectroscopic parameters, unexpectedly slow singlet energy transfer rates are measured in comparison with the predicted values by the Förster theory and those observed for other structurally related dyads. This observation is rationalized by the lack of large molecular orbital (MO) overlaps between the frontier MOs of the donor and acceptor, thus preventing a double electron exchange through the trans-PdI2 bridge, and by an electronic shielding induced by the presence of this same linker preventing the two chromophores to fully interact via their transition dipoles., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In male mice, deficiency of hormone sensitive lipase (HSL, Lipe gene, E.C.3.1.1.3) causes deficient spermatogenesis, azoospermia, and infertility. Postmeiotic germ cells express a specific HSL isoform that includes a 313 amino acid N-terminus encoded by a testis-specific exon (exon T1). The remainder of testicular HSL is identical to adipocyte HSL. The amino acid sequence of the testis-specific exon is poorly conserved, showing only a 46% amino acid identity with orthologous human and rat sequences, compared with 87% over the remainder of the HSL coding sequence, providing no evidence in favor of a vital functional role for the testis-specific N-terminus of HSL. However, exon T1 is important for Lipe transcription; in mouse testicular mRNA, we identified 3 major Lipe transcription start sites, finding numerous testicular transcription factor binding motifs upstream of the transcription start site. We directly explored two possible mechanisms for the infertility of HSL-deficient mice, using mice that expressed mutant HSL transgenes only in postmeiotic germ cells on a HSL-deficient background. One transgene expressed human HSL lacking enzyme activity but containing the testis-specific N-terminus (HSL-/-muttg mice). The other transgene expressed catalytically inactive HSL with the testis-specific N-terminal peptide (HSL-/-atg mice). HSL-/-muttg mice were infertile, with abnormal histology of the seminiferous epithelium and absence of spermatozoa in the epididymal lumen. In contrast, HSL-/-atg mice had normal fertility and normal testicular morphology. In conclusion, whereas the catalytic function of HSL is necessary for spermatogenesis in mice, the presence of the N-terminal testis-specific fragment is not essential.

In genetics the ability to accurately describe the familial relationships among a group of individuals can be very useful. Recent statistical tools succeeded in assessing the degree of relatedness up to 6-7 generations with good power using dense genome-wide single-nucleotide polymorphism data to estimate the extent of identity-by-descent (IBD) sharing. It is therefore important to describe genome-wide patterns of IBD sharing for more remote and complex relatedness between individuals, such as that observed in a founder population like Quebec, Canada. Taking advantage of the extended genealogical records of the French Canadian founder population, we first compared different tools to identify regions of IBD in order to best describe genome-wide IBD sharing and its correlation with genealogical characteristics. Results showed that the extent of IBD sharing identified with FastIBD correlates best with relatedness measured using genealogical data. Total length of IBD sharing explained 85% of the genealogical kinship's variance. In addition, we observed significantly higher sharing in pairs of individuals with at least one inbred ancestor compared with those without any. Furthermore, patterns of IBD sharing and average sharing were different across regional populations, consistent with the settlement history of Quebec. Our results suggest that, as expected, the complex relatedness present in founder populations is reflected in patterns of IBD sharing. Using these patterns, it is thus possible to gain insight on the types of distant relationships in a sample from a founder population like Quebec.

The viability of applying bodipy sensitisers to NiO-based p-type dye-sensitised solar cells (p-DSCs) has been successfully demonstrated. The triphenylamine donor-bodipy acceptor design promotes a long-lived charge-separated state which is difficult to achieve with NiO-based devices. The current was above 3 mA cm(-2) and the IPCE was 28%.

The genetic diversity within an 11 kb segment of the MTMR8 gene in a sample of 111 sub-Saharan and 49 non-African X chromosomes was investigated to assess the early evolutionary history of sub-Saharan Africans and the out-of-Africa expansion. The analyses revealed a complex genetic structure of the Africans that contributed to the emergence of modern humans. We observed partitioning of two thirds of old lineages among southern, west/central and east African populations indicating ancient population stratification predating the out of Africa migration. Age estimates of these lineages, older than coalescence times of uniparentally inherited markers, raise the question whether contemporary humans originated from a single population or as an amalgamation of different populations separated by years of independent evolution, thus suggesting a greater antiquity of our species than generally assumed. While the oldest sub-Saharan lineages, ~500 thousand years, are found among Khoe-San from southern-Africa, a distinct haplotype found among Biaka is likely due to admixture from an even older population. An East African population that gave rise to non-Africans underwent a selective sweep affecting the subcentromeric region where MTMR8 is located. This and similar sweeps in four other regions of the X chromosome, documented in the literature, effectively reduced genetic diversity of non-African chromosomes and therefore may have exacerbated the effect of the demographic bottleneck usually ascribed to the out of Africa migration. Our data is suggestive, however, that a bottleneck, occurred in Africa before range expansion.

We report herein a detailed study of the use of porphyrins fused to imidazolium salts as precursors of N-heterocyclic carbene ligands 1 M. Rhodium(I) complexes 6 M-9 M were prepared by using 1 M ligands with different metal cations in the inner core of the porphyrin (M=Ni(II) , Zn(II) , Mn(III) , Al(III) , 2H). The electronic properties of the corresponding N-heterocyclic carbene ligands were investigated by monitoring the spectroscopic changes occurring in the cod and CO ancillary ligands of [(1 M)Rh(cod)Cl] and [(1 M)Rh(CO)2 Cl] complexes (cod=1,5-cyclooctadiene). Porphyrin-NHC ligands 1 M with a trivalent metal cation such as Mn(III) and Al(III) are overall poorer electron donors than porphyrin-NHC ligands with no metal cation or incorporating a divalent metal cation such as Ni(II) and Zn(II) . Imidazolium salts 3 M (M=Ni, Zn, Mn, 2H) have also been used as NHC precursors to catalyze the ring-opening polymerization of L-lactide. The results clearly show that the inner metal of the porphyrin has an important effect on the reactivity of the outer carbene., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

For years, studies of founder populations and genetic isolates represented the mainstream of genetic mapping in the effort to target genetic defects causing Mendelian disorders. The genetic homogeneity of such populations as well as relatively homogeneous environmental exposures were also seen as primary advantages in studies of genetic susceptibility loci that underlie complex diseases. European colonization of the St-Lawrence Valley by a small number of settlers, mainly from France, resulted in a founder effect reflected by the appearance of a number of population-specific disease-causing mutations in Quebec. The purported genetic homogeneity of this population was recently challenged by genealogical and genetic analyses. We studied one of the contributing factors to genetic heterogeneity, early Native American admixture that was never investigated in this population before. Consistent admixture estimates, in the order of one per cent, were obtained from genome-wide autosomal data using the ADMIXTURE and HAPMIX software, as well as with the fastIBD software evaluating the degree of the identity-by-descent between Quebec individuals and Native American populations. These genomic results correlated well with the genealogical estimates. Correlations are imperfect most likely because of incomplete records of Native founders' origin in genealogical data. Although the overall degree of admixture is modest, it contributed to the enrichment of the population diversity and to its demographic stratification. Because admixture greatly varies among regions of Quebec and among individuals, it could have significantly affected the homogeneity of the population, which is of importance in mapping studies, especially when rare genetic susceptibility variants are in play.

This review recalls the clinical, anatomic, physiopathological and etiological features necessary in the management of patients with neoplastic bile duct obstruction and exposes the current practice concerning endoscopic and radiologic palliative drainage. Clinical practice according to the clinical situations is explained. This review exposes complications management for patients having undergone an endoscopic or percutaneous drainage of the biliary ducts, the particular case of periportal stenosis, the respective indications of endoscopic and transhepatic percutaneous drainage, usual immediate evolution according to the type of the stenosis and the technique used as well as the management in case of stent obstruction.

Cleavage reactions of 2,3-diamino-meso-tetraarylporphyrins and meso-tetraarylporphyrins fused to imidazole rings afforded secochlorins including stable free base derivatives., (This journal is © The Royal Society of Chemistry 2012)

Identifying and understanding the impact of gene regulatory variation is of considerable importance in evolutionary and medical genetics; such variants are thought to be responsible for human-specific adaptation and to have an important role in genetic disease. Regulatory variation in cis is readily detected in individuals showing uneven expression of a transcript from its two allelic copies, an observation referred to as allelic imbalance (AI). Identifying individuals exhibiting AI allows mapping of regulatory DNA regions and the potential to identify the underlying causal genetic variant(s). However, existing mapping methods require knowledge of the haplotypes, which make them sensitive to phasing errors. In this study, we introduce a genotype-based mapping test that does not require haplotype-phase inference to locate regulatory regions. The test relies on partitioning genotypes of individuals exhibiting AI and those not expressing AI in a 2×3 contingency table. The performance of this test to detect linkage disequilibrium (LD) between a potential regulatory site and a SNP located in this region was examined by analyzing the simulated and the empirical AI datasets. In simulation experiments, the genotype-based test outperforms the haplotype-based tests with the increasing distance separating the regulatory region from its regulated transcript. The genotype-based test performed equally well with the experimental AI datasets, either from genome-wide cDNA hybridization arrays or from RNA sequencing. By avoiding the need of haplotype inference, the genotype-based test will suit AI analyses in population samples of unknown haplotype structure and will additionally facilitate the identification of cis-regulatory variants that are located far away from the regulated transcript.

Recent work on the Neandertal genome has raised the possibility of admixture between Neandertals and the expanding population of Homo sapiens who left Africa between 80 and 50 Kya (thousand years ago) to colonize the rest of the world. Here, we provide evidence of a notable presence (9% overall) of a Neandertal-derived X chromosome segment among all contemporary human populations outside Africa. Our analysis of 6,092 X-chromosomes from all inhabited continents supports earlier contentions that a mosaic of lineages of different time depths and different geographic provenance could have contributed to the genetic constitution of modern humans. It indicates a very early admixture between expanding African migrants and Neandertals prior to or very early on the route of the out-of-Africa expansion that led to the successful colonization of the planet.

A strategy for the stepwise annulation of pyrrolic rings of a porphyrin to imidazole rings is presented. Mono(imidazole), Janus and corner bis(imidazole), T-shaped tris(imidazole), and tetrakis(imidazole) porphyrins have been synthesized and characterized., (© 2011 American Chemical Society)

NHC ligands annulated to free-base porphyrins can be reversibly switched between electron-poor and electron-rich states upon protonation and deprotonation of the inner nitrogen atoms of the porphyrin. Metallation of the macrocycle with nickel(II) locks the peripheral NHC ligand in its electron-rich state.

Was the past genetic contribution of women and men to the current human population equal? Was polygyny (excess of breeding women) present among hominid lineages? We addressed these questions by measuring the ratio of population recombination rates between the X chromosome and the autosomes, rho(X)/rho(A). The X chromosome recombines only in female meiosis, whereas autosomes undergo crossovers in both sexes; thus, rho(X)/rho(A) reflects the female-to-male breeding ratio, beta. We estimated beta from rho(X)/rho(A) inferred from genomic diversity data and calibrated with recombination rates derived from pedigree data. For the HapMap populations, we obtained beta of 1.4 in the Yoruba from West Africa, 1.3 in Europeans, and 1.1 in East Asian samples. These values are consistent with a high prevalence of monogamy and limited polygyny in human populations. More mutations occur during male meiosis as compared to female meiosis at the rate ratio referred to as alpha. We show that at alpha not equal 1, the divergence rates and genetic diversities of the X chromosome relative to the autosomes are complex functions of both alpha and beta, making their independent estimation difficult. Because our estimator of beta does not require any knowledge of the mutation rates, our approach should allow us to dissociate the effects of alpha and beta on the genetic diversity and divergence rate ratios of the sex chromosomes to the autosomes., (Copyright 2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: Natural selection eliminates detrimental and favors advantageous phenotypes. This process leaves characteristic signatures in underlying genomic segments that can be recognized through deviations in allelic or haplotypic frequency spectra. To provide an identifiable signature of recent positive selection that can be detected by comparison with the background distribution, we introduced a new way of looking at genomic polymorphisms: haplotype allelic classes., Results: The model combines segregating sites and haplotypic information in order to reveal useful data characteristics. We developed a summary statistic, Svd, to compare the distribution of the haplotypes carrying the selected allele with the distribution of the remaining ones. Coalescence simulations are used to study the distributions under standard population models assuming neutrality, demographic scenarios and selection models. To test, in practice, haplotype allelic class performance and the derived statistic in capturing deviation from neutrality due to positive selection, we analyzed haplotypic variation in detail in the locus of lactase persistence in the three HapMap Phase II populations., Conclusions: We showed that the Svd statistic is less sensitive than other tests to confounding factors such as demography or recombination. Our approach succeeds in identifying candidate loci, such as the lactase-persistence locus, as targets of strong positive selection and provides a new tool complementary to other tests to study natural selection in genomic data.

Chlamydial infection of the upper genital tract after abortion is well recognized, but routine screening for infection before termination is rare, and few centres are aware of the prevalence of post-abortion complications in their patient population. Knowledge of the patient population is the best guide for developing screening strategies. The aim of this study was to determine the prevalence of chlamydial infection in patients presenting for legal termination of pregnancy, and to assess the presence of Chlamydia trachomatis by PCR on specimens collected in either PreservCyt (ThinPrep) or 2-sucrose phosphate (2-SP) transport medium. Two hundred and eleven single, sexually active women, aged 15-26 years, attending the Gynaecology and Obstetric Hospital, Amiens, France, for surgical termination of pregnancy were enrolled in this study from June 2002 to June 2003. C. trachomatis detection using a Cobas Amplicor PCR test (Roche Diagnostics) targeting a 207 bp segment of the common cryptic plasmid and a quantitative LightCycler real-time PCR (LC-PCR) (Roche Diagnostics) targeting a 123 bp fragment within the highly conserved constant domain 3 of the single-chromosome-copy ompA gene were performed on endocervical swabs in 2-SP, and on specimens collected using a cytobrush and placed in PreservCyt medium. The in-house LC-PCR was used as a chromosomal diagnosis method and to determine the load of C. trachomatis. This method was able to detect the mutant Swedish variant with a deletion of 377 bp in the target area in the cryptic plasmid, which is the region targeted by the Cobas Amplicor PCR test. C. trachomatis was detected in 19/211 patients (9 %) by both PCR methods. Among the 19 infected women, C. trachomatis was detected by the Cobas Amplicor PCR in 16 specimens in PreservCyt (7.6 %) and in 12 endocervical swabs in 2-SP (5.7 %). Specimens from only nine women were PCR-positive in both PreservCyt and 2-SP media by this method. Cobas Amplicor PCR revealed that 10.9 and 2.3 % of the PreservCyt and 2-SP samples, respectively, contained inhibitors. The same 19 infected women were LC-PCR positive in both PreservCyt and 2-SP samples. No additional infected women were found by this last method; thus, it was concluded that none of the samples contained the new variant of C. trachomatis. The load in each sample varied from 10(2) to 10(7) copies ml(-1).

Reverse transcription-polymerase chain reaction (RT-PCR) approaches have been used in a large proportion of transcriptome analyses published to date. The accuracy of the results obtained by this method strongly depends on accurate transcript normalization using stably expressed genes, known as references. Statistical algorithms have been developed recently to help validate reference genes, and most studies of gene expression in mammals, yeast and bacteria now include such validation. Surprisingly, this important approach is under-utilized in plant studies, where putative housekeeping genes tend to be used as references without any appropriate validation. Using quantitative RT-PCR, the expression stability of several genes commonly used as references was tested in various tissues of Arabidopsis thaliana and hybrid aspen (Populus tremula x Populus tremuloides). It was found that the expression of most of these genes was unstable, indicating that their use as references is inappropriate. The major impact of the use of such inappropriate references on the results obtained by RT-PCR is demonstrated in this study. Using aspen as a model, evidence is presented indicating that no gene can act as a universal reference, implying the need for a systematic validation of reference genes. For the first time, the extent to which the lack of a systematic validation of reference genes is a stumbling block to the reliability of results obtained by RT-PCR in plants is clearly shown.

In this article we present a new heuristic approach (informative recombinations, InfRec) to analyze recombination density at the sequence level. InfRec is intuitive and easy and combines previously developed methods that (i) resolve genotypes into haplotypes, (ii) estimate the minimum number of recombinations, and (iii) evaluate the fraction of informative recombinations. We tested this approach in its sliding-window version on 117 genes from the SeattleSNPs program, resequenced in 24 African-Americans (AAs) and 23 European-Americans (EAs). We obtained population recombination rate estimates (rho(obs)) of 0.85 and 0.37 kb(-1) in AAs and EAs, respectively. Coalescence simulations indicated that these values account for both the recombinations and the gene conversions in the history of the sample. The intensity of rho(obs) varied considerably along the sequence, revealing the presence of recombination hotspots. Overall, we observed approximately 80% of recombinations in one-third and approximately 50% in only 10% of the sequence. InfRec performance, tested on published simulated and additional experimental data sets, was similar to that of other hotspot detection methods. Fast, intuitive, and visual, InfRec is not constrained by sample size limitations. It facilitates understanding data and provides a simple and flexible tool to analyze recombination intensity along the sequence.

Genetic variability of the compound interrupted microsatellite DXS1238, in intron 44 of the dystrophin gene, provides evidence for a complex structure of the ancestral population that led to the emergence of modern humans. We sequenced DXS1238 in 600 X-chromosomes from all over the world. Forty four percent of African-specific chromosomes belong to the ancestral lineage that did not participate in the out-of-Africa expansion and subsequent colonization of other continents. Based on the coalescence analysis these lineages separated from those that contributed to the out-of-Africa expansion 366 +/- 136 thousands years ago (Kya). Independently, the analysis of the variance in the repeat length and of the decay of the ancestral alleles of the two DXS1238 repeats, GT and GA, dates this separation at more than 200 Kya. This suggests a complex demographic history and genetic structure of the African melting pot that led to the emergence of modern humans and their out-of-Africa migration. The subsequent subdivisions of human populations among different continents appear to be preceded by even more structured population history within Africa itself, which resulted from a restricted gene flow between lineages allowing for genetic differences to accumulate. If the transition to modern humans occurred during that time, it necessarily follows that genes associated with this transformation spread between subpopulations via gene flow. Otherwise, in spite of subsequent anatomical variation, Homo sapiens as a species could have emerged in Africa already between 300 and 200 Kya, i.e. before the mitochondrial DNA and well before the Y-chromosome most recent common ancestors.

It is likely that evolutionary differences among species are driven by sequence changes in regulatory regions. Likewise, polymorphisms in the promoter regions may be responsible for interindividual differences at the level of populations. We present an unbiased survey of genetic variation in 2-kb segments upstream of the transcription start sites of 28 protein-coding genes, characterized in five population groups of different geographic origin. On average, we found 9.1 polymorphisms and 8.8 haplotypes per segment with corresponding nucleotide and haplotype diversities of 0.082% and 58%, respectively. We characterized these segments through different summary statistics, Hardy-Weinberg equilibria fixation index (Fst) estimates, and neutrality tests, as well as by analyzing the distributions of haplotype allelic classes, introduced here to assess the departure from neutrality and examined by coalescent simulations under a simple population model, assuming recombinations or different demography. Our results suggest that genetic diversity in some of these regions could have been shaped by purifying selection and driven by adaptive changes in the other, thus explaining the relatively large variance in the corresponding genetic diversity indices loci. However, some of these effects could be also due to linkage with surrounding sequences, and the neutralists' explanations cannot be ruled out given uncertainty in the underlying demographic histories and the possibility of random effects due to the small size of the studied segments., (2007 Wiley-Liss, Inc.)