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Corynebacterium striatum is an emerging nosocomial pathogen. This is the first report showing the presence of three distinct multidrug resistant lineages of C. striatum among patients in a UK hospital. The presence of ErmX, Tet(W), Bla and AmpC proteins, and mutations in gyrA gene are associated with the resistance to clindamycin, doxycycline, penicillin and moxifloxacin, respectively. These strains are equipped with several corynebacterial virulence genes including two SpaDEF-type and a novel pilus gene cluster, which needs further molecular characterisation. This study highlights a need of developing an active surveillance strategy for routine monitoring and preventing potential cross-transmission among susceptible patients. [ABSTRACT FROM AUTHOR]

In this paper, we defend two claims. First, we argue that a notion of contextuality that has been formalized in physics and psychology is applicable to linguistic contexts. Second, we propose that this formal apparatus is philosophically significant for the epistemology of language because it imposes homogeneous rational constraints on speakers. We propose a Contextuality Principle that explains and articulates these two claims. This principle states that speakers update contextual information by significantly reducing the space of probabilities and variables in a non-commutative way. Some contexts affect other contexts not merely in terms of the information they contain, but also on the basis of their sequential order. In particular, we argue that the Contextuality by Default (CBD) theory provides a formalism that helps explain the role of contextuality in rational linguistic exchanges. [ABSTRACT FROM AUTHOR]

Age at menarche (AAM) and age at natural menopause (ANM) are highly heritable traits and have been linked to various health outcomes. We aimed to identify circulating proteins associated with altered ANM and AAM using an unbiased two-sample Mendelian randomization (MR) and colocalization approach. By testing causal effects of 1,271 proteins on AAM, we identified 22 proteins causally associated with AAM in MR, among which 13 proteins (GCKR, FOXO3, SEMA3G, PATE4, AZGP1, NEGR1, LHB, DLK1, ANXA2, YWHAB, DNAJB12, RMDN1 and HPGDS) colocalized. Among 1,349 proteins tested for causal association with ANM using MR, we identified 19 causal proteins among which 7 proteins (CPNE1, TYMP, DNER, ADAMTS13, LCT, ARL and PLXNA1) colocalized. Follow-up pathway and gene enrichment analyses demonstrated links between AAM-related proteins and obesity and diabetes, and between AAM and ANM-related proteins and various types of cancer. In conclusion, we identified proteomic signatures of reproductive ageing in women, highlighting biological processes at both ends of the reproductive lifespan. Mendelian randomization and colocalization analyses identified 13 circulating proteins causally associated with age at menarche and 7 proteins associated with age at natural menopause, highlighting the proteomic signatures encompassing both ends of women's reproductive lifespans. [ABSTRACT FROM AUTHOR]

Clonal hematopoiesis (CH)—age-related expansion of mutated hematopoietic clones—can differ in frequency and cellular fitness by CH type (e.g., mutations in driver genes (CHIP), gains/losses and copy-neutral loss of chromosomal segments (mCAs), and loss of sex chromosomes). Co-occurring CH raises questions as to their origin, selection, and impact. We integrate sequence and genotype array data in up to 482,378 UK Biobank participants to demonstrate shared genetic architecture across CH types. Our analysis suggests a cellular evolutionary trade-off between different types of CH, with LOY occurring at lower rates in individuals carrying mutations in established CHIP genes. We observed co-occurrence of CHIP and mCAs with overlap at TET2, DNMT3A, and JAK2, in which CHIP precedes mCA acquisition. Furthermore, individuals carrying overlapping CH had high risk of future lymphoid and myeloid malignancies. Finally, we leverage shared genetic architecture of CH traits to identify 15 novel loci associated with leukemia risk. Types of clonal hematopoiesis (CH) differ in frequency and fitness. These findings uncover shared genetic architecture, suggest evolutionary trade-offs between CH types, and detail elevated leukemia risk in individuals with overlapping types of CH. [ABSTRACT FROM AUTHOR]

In this paper, we focus on some misconceptions about Critical Pragmatics, what it is, what it assumes and what it proposes. Doubtless, some of these misconceptions are due to clumsy writing on our part; perhaps others are due to inattentive reading. And some may be due to an effort to shield us from the apparent implausibility of what we said—and in fact meant. It does not matter much. We focus on those misunderstandings that most matter to us, either because, by repetition, they have ended up being annoying, even if they are not, perhaps, that important; or because they are substantial enough to represent a distortion of the basic picture of Critical Pragmatics and its theoretical foundations, namely, Critical Referentialism—also known as the Reflexive-referential Theory—and, more generally, Perry's fundamental views on meaning and content(s). [ABSTRACT FROM AUTHOR]

Higher cardiorespiratory fitness is associated with lower risk of type 2 diabetes. However, the causality of this relationship and the biological mechanisms that underlie it are unclear. Here, we examine genetic determinants of cardiorespiratory fitness in 450k European-ancestry individuals in UK Biobank, by leveraging the genetic overlap between fitness measured by an exercise test and resting heart rate. We identified 160 fitness-associated loci which we validated in an independent cohort, the Fenland study. Gene-based analyses prioritised candidate genes, such as CACNA1C, SCN10A, MYH11 and MYH6, that are enriched in biological processes related to cardiac muscle development and muscle contractility. In a Mendelian Randomisation framework, we demonstrate that higher genetically predicted fitness is causally associated with lower risk of type 2 diabetes independent of adiposity. Integration with proteomic data identified N-terminal pro B-type natriuretic peptide, hepatocyte growth factor-like protein and sex hormone-binding globulin as potential mediators of this relationship. Collectively, our findings provide insights into the biological mechanisms underpinning cardiorespiratory fitness and highlight the importance of improving fitness for diabetes prevention. Being fit has been linked to a lower risk of type 2 diabetes, but it is unclear whether this relationship is causal. Using large scale studies with genetic data and measurements of cardiorespiratory fitness, the authors show evidence that higher genetically predicted fitness is causally associated with lower risk of type 2 diabetes independent of adiposity. [ABSTRACT FROM AUTHOR]

A genomic and bioactivity informed analysis of the metabolome of the extremophile Amycolatopsis sp. DEM30355 has allowed for the discovery and isolation of the polyketide antibiotic tatiomicin. Identification of the biosynthetic gene cluster was confirmed by heterologous expression in Streptomyces coelicolor M1152. Structural elucidation, including absolute stereochemical assignment, was performed using complementary crystallographic, spectroscopic and computational methods. Tatiomicin shows antibiotic activity against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Cytological profiling experiments suggest a putative antibiotic mode-of-action, involving membrane depolarisation and chromosomal decondensation of the target bacteria. [ABSTRACT FROM AUTHOR]

Mosaic loss of chromosome Y (LOY) in leukocytes is the most common form of clonal mosaicism, caused by dysregulation in cell-cycle and DNA damage response pathways. Previous genetic studies have focussed on identifying common variants associated with LOY, which we now extend to rarer, protein-coding variation using exome sequences from 82,277 male UK Biobank participants. We find that loss of function of two genes—CHEK2 and GIGYF1—reach exome-wide significance. Rare alleles in GIGYF1 have not previously been implicated in any complex trait, but here loss-of-function carriers exhibit six-fold higher susceptibility to LOY (OR = 5.99 [3.04–11.81], p = 1.3 × 10−10). These same alleles are also associated with adverse metabolic health, including higher susceptibility to Type 2 Diabetes (OR = 6.10 [3.51–10.61], p = 1.8 × 10−12), 4 kg higher fat mass (p = 1.3 × 10−4), 2.32 nmol/L lower serum IGF1 levels (p = 1.5 × 10−4) and 4.5 kg lower handgrip strength (p = 4.7 × 10−7) consistent with proposed GIGYF1 enhancement of insulin and IGF-1 receptor signalling. These associations are mirrored by a common variant nearby associated with the expression of GIGYF1. Our observations highlight a potential direct connection between clonal mosaicism and metabolic health. Mosaic loss of chromosome Y (LOY) is a common form of clonal mosaicism in leukocytes. Here, the authors extend genetic association analyses to rare variation using exome-sequence data from 82,277 males, finding that loss-of-function alleles in GIGYF1 are associated with six-fold higher susceptibility to both LOY and Type 2 Diabetes. [ABSTRACT FROM AUTHOR]

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes. Sex differences in fasting glucose and insulin have been identified, but the genetic loci underlying these differences have not. Here, the authors perform a meta-analysis of genome-wide association studies to detect sex-specific and sex-dimorphic loci associated with fasting glucose and insulin. [ABSTRACT FROM AUTHOR]

The F4 algorithm re-imagines Buchberger's algorithm as the row reduction of a Macaulay matrix: each row corresponds to a polynomial; each reduction of one row by another corresponds to one step of reducing an S-polynomial; and any row that completes reduction with a new pivot position corresponds to a new element of the basis. On the other hand, each column corresponds to a term, so that while it is common in linear algebra to exchange a matrix's columns during row reduction, this has not been done in F4-style algorithms, as it runs the risk of producing an incorrect result. We show that it is possible to adapt an analogous, "dynamic" technique for Buchberger-style algorithms to F4-style algorithms, and we examine its behavior on some commonly referenced benchmark ideals. [ABSTRACT FROM AUTHOR]

Within the temporal psychology literature, evidence has been presented for a relationship between a variety of health indicators, including alcohol-related problems, as well as symptoms of anxiety and depression, and a variety of temporal constructs. Recently, it was claimed that the two factors of the Consideration of Future Consequences (CFC) Scale-14 (CFCS-14) were both practically and conceptually useful in understanding the relationship between CFC and various criterion variables. The present study examined the relationship between these two factors (consideration of immediate and consideration of future consequences) and symptoms of anxiety and depression, as well as problematic alcohol use. Participants were recruited from a University in the North West of England, and completed the CFCS-14, the Alcohol Use Disorders Identification Test, and the Hospital Anxiety and Depression Scale. Results offer support for the psychometric validity and internal consistency of the CFCS-14, and further reveal a modest relationship between its factors and criterion variables. Compared to temporal psychology measures focussing on time attitudes or time perspective, the clinical or practical utility of the CFCS-14 in understanding these health domains may be limited. [ABSTRACT FROM AUTHOR]

Singular terms without referents are called empty or vacuous terms. But not all of them are equally empty. In particular, not all proper names that fail to name an existing object fail in the same way: although they are all empty, they are not all equally vacuous. "Vulcan," "Jacob Horn," "Odysseus," and "Sherlock Holmes," for instance, are all empty. They have no referents. But they are not entirely vacuous or useless. Sometimes they are used in statements that are true or false. We are basically referentialists about proper names. The ordinary semantic function of a proper name is to refer to an object, and to do it directly, that is, without semantically providing any identifying condition that the object should meet to be the referent. To put it differently, we agree that statements containing proper names express singular propositions, i.e., that their truth-conditions involve the referent of the proper name, if it exists, and not any identifying condition of it. Now, since empty names lack a referent, and therefore would not express such a singular proposition, how do we explain that many, if not all, statements containing them have a truth-value? Answering this question for the case of fictional names, in particular, is the aim of this paper. [ABSTRACT FROM AUTHOR]

Photoplethysmographic imaging (PPG) is currently used to measure heart rate (HR) and the accuracy of PPG can be influenced by pigmentation of the skin; however, the effects of skin color-related artifacts on PPG during exercise remain unclear. This study aimed to assess the agreement between the Apple Watch photoplethysmography sensor and a criterion, for measuring heart rate across a range of intensities during exercise and to determine the influence of skin type on the accuracy of the measure. Forty-five males (20–43 y) completed the Fitzpatrick Skin Scale and were classified into three different skin type groups: a) types II (n = 15), III (n = 15) and IV (n = 15). Participants performed a graded incremental cycle-ergometer test while simultaneously wearing the Apple Watch and a Polar monitor as a criterion measure. Data from both devices were collected in 5-s epochs. Correlations between devices were very good (0.96–0.99 [95%CI: 0.94 to 0.99]). Significant differences were observed between skin types II and III when the intensity of the exercise was increased, albeit with trivial to small effect sizes (ES: 0.05 to 0.28). All significant differences corresponded to <2% of relative difference between both devices. Bland-Altman analyses showed a trivial but systematic underestimation of HR in the Apple Watch compared to Polar for all skin types during exercise. In conclusion, the Apple Watch accurately measures HR when cycling at different intensities and certain types of skin seem not to influence these measures, which may have important implications for controlling the intensity of exercise. [ABSTRACT FROM AUTHOR]

The negative impacts of social isolation and loneliness on health are well documented. However, little is known about their possible biological determinants. In up to 452,302 UK Biobank study participants, we perform genome-wide association study analyses for loneliness and regular participation in social activities. We identify 15 genomic loci (P <5 x 10-8) for loneliness, and demonstrate a likely causal association between adiposity and increased susceptibility to loneliness and depressive symptoms. Further loci were identified for regular attendance at a sports club or gym (N = 6 loci), pub or social club (N = 13) or religious group (N = 18). Across these traits there was strong enrichment for genes expressed in brain regions that control emotional expression and behaviour. We demonstrate aetiological mechanisms specific to each trait, in addition to identifying loci that are pleiotropic across multiple complex traits. Further study of these traits may identify novel modifiable risk factors associated with social withdrawal and isolation. [ABSTRACT FROM AUTHOR]

Population studies elucidating the genetic architecture of reproductive ageing have been largely limited to European ancestries, restricting the generalizability of the findings and overlooking possible key genes poorly captured by common European genetic variation. Here, we report 26 loci (all P < 5 × 10-8) for reproductive ageing, i.e. puberty timing or age at menopause, in a non-European population (up to 67,029 women of Japanese ancestry). Highlighted genes for menopause include GNRH1, which supports a primary, rather than passive, role for hypothalamic-pituitary GnRH signalling in the timing of menopause. For puberty timing, we demonstrate an aetiological role for receptor-like protein tyrosine phosphatases by combining evidence across population genetics and pre- and peri-pubertal changes in hypothalamic gene expression in rodent and primate models. Furthermore, our findings demonstrate widespread differences in allele frequencies and effect estimates between Japanese and European associated variants, highlighting the benefits and challenges of large-scale trans-ethnic approaches. [ABSTRACT FROM AUTHOR]

As age at pubertal onset declines and age at first pregnancy increases, the mechanisms that regulate female reproductive lifespan become increasingly relevant to population health. The timing of menarche and menopause can have profound effects not only on fertility but also on the risk of diseases such as type 2 diabetes mellitus, cardiovascular disease and breast cancer. Genetic studies have identified dozens of highly penetrant rare mutations associated with reproductive disorders, and also ∼175 common genetic variants associated with the timing of puberty or menopause. These findings, alongside other functional studies, have highlighted a diverse range of mechanisms involved in reproductive ageing, implicating core biological processes such as cell cycle regulation and energy homeostasis. The aim of this article is to review the contribution of such genetic findings to our understanding of the molecular regulation of reproductive timing, as well as the biological basis of the epidemiological links between reproductive ageing and disease risk. [ABSTRACT FROM AUTHOR]

Identifying genetic correlations between complex traits and diseases can provide useful etiological insights and help prioritize likely causal relationships. The major challenges preventing estimation of genetic correlation from genome-wide association study (GWAS) data with current methods are the lack of availability of individual-level genotype data and widespread sample overlap among meta-analyses. We circumvent these difficulties by introducing a technique-cross-trait LD Score regression-for estimating genetic correlation that requires only GWAS summary statistics and is not biased by sample overlap. We use this method to estimate 276 genetic correlations among 24 traits. The results include genetic correlations between anorexia nervosa and schizophrenia, anorexia and obesity, and educational attainment and several diseases. These results highlight the power of genome-wide analyses, as there currently are no significantly associated SNPs for anorexia nervosa and only three for educational attainment. [ABSTRACT FROM AUTHOR]

Recent work has demonstrated that some functional categories of the genome contribute disproportionately to the heritability of complex diseases. Here we analyze a broad set of functional elements, including cell type-specific elements, to estimate their polygenic contributions to heritability in genome-wide association studies (GWAS) of 17 complex diseases and traits with an average sample size of 73,599. To enable this analysis, we introduce a new method, stratified LD score regression, for partitioning heritability from GWAS summary statistics while accounting for linked markers. This new method is computationally tractable at very large sample sizes and leverages genome-wide information. Our findings include a large enrichment of heritability in conserved regions across many traits, a very large immunological disease-specific enrichment of heritability in FANTOM5 enhancers and many cell type-specific enrichments, including significant enrichment of central nervous system cell types in the heritability of body mass index, age at menarche, educational attainment and smoking behavior. [ABSTRACT FROM AUTHOR]

We propose a method (GREML-LDMS) to estimate heritability for human complex traits in unrelated individuals using whole-genome sequencing data. We demonstrate using simulations based on whole-genome sequencing data that ∼97% and ∼68% of variation at common and rare variants, respectively, can be captured by imputation. Using the GREML-LDMS method, we estimate from 44,126 unrelated individuals that all ∼17 million imputed variants explain 56% (standard error (s.e.) = 2.3%) of variance for height and 27% (s.e. = 2.5%) of variance for body mass index (BMI), and we find evidence that height- and BMI-associated variants have been under natural selection. Considering the imperfect tagging of imputation and potential overestimation of heritability from previous family-based studies, heritability is likely to be 60-70% for height and 30-40% for BMI. Therefore, the missing heritability is small for both traits. For further discovery of genes associated with complex traits, a study design with SNP arrays followed by imputation is more cost-effective than whole-genome sequencing at current prices. [ABSTRACT FROM AUTHOR]

Multiple bone marrow stromal cell types have been identified as hematopoietic stem cell (HSC)-regulating niche cells. However, whether HSC progeny can serve directly as HSC niche cells has not previously been shown. Here we report a dichotomous role of megakaryocytes (MKs) in both maintaining HSC quiescence during homeostasis and promoting HSC regeneration after chemotherapeutic stress. We show that MKs are physically associated with HSCs in the bone marrow of mice and that MK ablation led to activation of quiescent HSCs and increased HSC proliferation. RNA sequencing (RNA-seq) analysis revealed that transforming growth factor β1 (encoded by Tgfb1) is expressed at higher levels in MKs as compared to other stromal niche cells. MK ablation led to reduced levels of biologically active TGF-β1 protein in the bone marrow and nuclear-localized phosphorylated SMAD2/3 (pSMAD2/3) in HSCs, suggesting that MKs maintain HSC quiescence through TGF-β-SMAD signaling. Indeed, TGF-β1 injection into mice in which MKs had been ablated restored HSC quiescence, and conditional deletion of Tgfb1 in MKs increased HSC activation and proliferation. These data demonstrate that TGF-β1 is a dominant signal emanating from MKs that maintains HSC quiescence. However, under conditions of chemotherapeutic challenge, MK ablation resulted in a severe defect in HSC expansion. In response to stress, fibroblast growth factor 1 (FGF1) signaling from MKs transiently dominates over TGF-β inhibitory signaling to stimulate HSC expansion. Overall, these observations demonstrate that MKs serve as HSC-derived niche cells to dynamically regulate HSC function. [ABSTRACT FROM AUTHOR]

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10−8) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition. [ABSTRACT FROM AUTHOR]

The goal of the Dynamic Buchberger Algorithm is to compute a Gröbner basis quickly by adjusting the term ordering as the computation proceeds. A known problem concerns the size and number of linear progams to be solved when refining the ordering. This paper describes two methods for reducing both their size and number. [ABSTRACT FROM AUTHOR]

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-21276-3 [ABSTRACT FROM AUTHOR]

The epigenetic regulation of imprinted genes by monoallelic DNA methylation of either maternal or paternal alleles is critical for embryonic growth and development. Imprinted genes were recently shown to be expressed in mammalian adult stem cells to support self-renewal of neural and lung stem cells; however, a role for imprinting per se in adult stem cells remains elusive. Here we show upregulation of growth-restricting imprinted genes, including in the H19-Igf2 locus, in long-term haematopoietic stem cells and their downregulation upon haematopoietic stem cell activation and proliferation. A differentially methylated region upstream of H19 (H19-DMR), serving as the imprinting control region, determines the reciprocal expression of H19 from the maternal allele and Igf2 from the paternal allele. In addition, H19 serves as a source of miR-675, which restricts Igf1r expression. We demonstrate that conditional deletion of the maternal but not the paternal H19-DMR reduces adult haematopoietic stem cell quiescence, a state required for long-term maintenance of haematopoietic stem cells, and compromises haematopoietic stem cell function. Maternal-specific H19-DMR deletion results in activation of the Igf2-Igfr1 pathway, as shown by the translocation of phosphorylated FoxO3 (an inactive form) from nucleus to cytoplasm and the release of FoxO3-mediated cell cycle arrest, thus leading to increased activation, proliferation and eventual exhaustion of haematopoietic stem cells. Mechanistically, maternal-specific H19-DMR deletion leads to Igf2 upregulation and increased translation of Igf1r, which is normally suppressed by H19-derived miR-675. Similarly, genetic inactivation of Igf1r partly rescues the H19-DMR deletion phenotype. Our work establishes a new role for this unique form of epigenetic control at the H19-Igf2 locus in maintaining adult stem cells. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the polymicrobial communities in an adult Cystic Fibrosis population stratified by gender and the most common CFTR mutation, F508del. In this pilot study, DNA was extracted from sputum samples of 29 adult patients (16 male: 13 female) with an F508del mutation in a stable clinical state. Universal primers were used to amplify DNA from bacterial and fungal communities and the resulting fragments were analysed by denaturing gradient gel electrophoresis. Bacterial profiles showed a significant effect of gender ( P = 0.046) and P. aeruginosa carriage ( P = 0.034) on community structure. Bacterial communities were found to be randomly assembled. Fungal community analysis found that F508del homozygous patients had a greater diversity than heterozygous patients ( P = 0.007). This study indicates that the bacterial lung communities of adult CF patients are randomly assembled but have distinct gender based differences. Furthermore, the fungal communities colonising the CF lung are more diverse in F508 homozygotes. This is the first paper to identify a reduced bacterial diversity in female patients with CF and to implicate more severe CFTR genotypes with increased risk of infection with multiple fungal species. [ABSTRACT FROM AUTHOR]

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10?8). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-?B signaling and mitochondrial dysfunction as biological processes related to timing of menopause. [ABSTRACT FROM AUTHOR]

Data sharing is increasingly recognized as critical to cross-disciplinary research and to assuring scientific validity. Despite National Institutes of Health and National Science Foundation policies encouraging data sharing by grantees, little data sharing of clinical data has in fact occurred. A principal reason often given is the potential of inadvertent violation of the Health Insurance Portability and Accountability Act privacy regulations. While regulations specify the components of private health information that should be protected, there are no commonly accepted methods to de-identify clinical data objects such as images. This leads institutions to take conservative risk-averse positions on data sharing. In imaging trials, where images are coded according to the Digital Imaging and Communications in Medicine (DICOM) standard, the complexity of the data objects and the flexibility of the DICOM standard have made it especially difficult to meet privacy protection objectives. The recent release of DICOM Supplement 142 on image de-identification has removed much of this impediment. This article describes the development of an open-source software suite that implements DICOM Supplement 142 as part of the National Biomedical Imaging Archive (NBIA). It also describes the lessons learned by the authors as NBIA has acquired more than 20 image collections encompassing over 30 million images. [ABSTRACT FROM AUTHOR]

To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10−60) and 9q31.2 (P = 2.2 × 10−33), we identified 30 new menarche loci (all P < 5 × 10−8) and found suggestive evidence for a further 10 loci (P < 1.9 × 10−6). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing. [ABSTRACT FROM AUTHOR]

The article presents a discussion on the treatment of the issue of identity, by the philosophers David Hume and Gottlob Frege in their respective works. The author comments on the element of uncertainty, that both the authors associate with identity. While Hume considers that identity can be difficult to be ascertained even by using multiple concepts, Frege reportedly considers that identity gives rise to challenging problems.

Classical Gricean pragmatics is usually conceived as dealing with far-side pragmatics, aimed at computing implicatures. It involves reasoning about why what was said, was said. Near-side pragmatics, on the other hand, is pragmatics in the service of determining, together with the semantical properties of the words used, what was said. But this raises the specter of ‘the pragmatic circle.’ If Gricean pragmatics seeks explanations for why someone said what they did, how can there be Gricean pragmatics on the near-side? Gricean reasoning seems to require what is said to get started. But then if Gricean reasoning is needed to get to what is said, we have a circle. [ABSTRACT FROM AUTHOR]

Adult height is a model polygenic trait, but there has been limited success in identifying the genes underlying its normal variation. To identify genetic variants influencing adult human height, we used genome-wide association data from 13,665 individuals and genotyped 39 variants in an additional 16,482 samples. We identified 20 variants associated with adult height (P < 5 × 10−7, with 10 reaching P < 1 × 10−10). Combined, the 20 SNPs explain ∼3% of height variation, with a ∼5 cm difference between the 6.2% of people with 17 or fewer 'tall' alleles compared to the 5.5% with 27 or more 'tall' alleles. The loci we identified implicate genes in Hedgehog signaling (IHH, HHIP, PTCH1), extracellular matrix (EFEMP1, ADAMTSL3, ACAN) and cancer (CDK6, HMGA2, DLEU7) pathways, and provide new insights into human growth and developmental processes. Finally, our results provide insights into the genetic architecture of a classic quantitative trait. [ABSTRACT FROM AUTHOR]

My aim in this study is not to praise Fischer's fine theory of moral responsibility, but to (try to) bury the “semi” in “semicompatibilism”. I think Fischer gives the Consequence Argument (CA) too much credit, and gives himself too little credit. In his book, The Metaphysics of Free Will, Fischer gave the CA as good a statement as it will ever get, and put his finger on what is wrong with it. Then he declared stalemate rather than victory. In my view, Fischer’s view amounts to sophisticated compatibilism. It would be nice to be able to call it by its right name. In The Metaphysics of Free Will, Fischer develops his own version of Consequence Argument, which turns on two principles, one of which is the fixity of the past. FP: For any action Y, agent S and time t, if it is true that is S were to do Y at t, some fact about that past relative to t would not have been a fact, then S cannot at t do Y at t. I argue that the equipment needed to reject FP (and thereby defend the most plausible version of compatibilism) is needed to deal with the problem of fatalism. In addition, I argue that the rejection of FP is compatible with Fischer’s approach to Frankfurt cases and with his account of transfer principles. [ABSTRACT FROM AUTHOR]

Recent work has identified a growing body of evidence that subtle changes in noncoding sequences can result in significant pathology. These mutations, which would have been called silent polymorphisms in the past, affect gene transcription and mRNA splicing and lead to drastic changes in gene expression. Previous work from our lab has characterized the murine flexed-tail ( f) mutation, which encodes Smad5, a transcription factor that functions downstream of the receptors for bone morphogenetic proteins (BMPs). f/f mice are unable to rapidly respond to acute anemia. Our analysis of these mice led to the development of a new model for stress erythropoiesis, where BMP4 expression in the spleen leads to the Smad5-dependent expansion of a specialized population of stress erythroid progenitors during the recovery from acute anemia. f/f mutant mice exhibit a defect in Smad5 mRNA splicing in the spleen such that the majority of Smad5 transcripts are two misspliced mRNAs. One of these mRNAs encodes a truncated form of Smad5 that inhibits BMP4 signaling when overexpressed. Here we show that a mutation in a poly(T) element in intron 4 causes the splicing defect in f/f mutant mice. This subtle mutation (loss of 1 or 2 Ts in a 16-T element) results in defects in splicing throughout the Smad5 gene. Furthermore, we show that this mutation results in tissue-specific splicing defects, which may explain why f/f mice are viable when Smad5-/- mice are embryonic lethal. [ABSTRACT FROM AUTHOR]

Human height is a classic, highly heritable quantitative trait. To begin to identify genetic variants influencing height, we examined genome-wide association data from 4,921 individuals. Common variants in the HMGA2 oncogene, exemplified by rs1042725, were associated with height (P = 4 × 10−8). HMGA2 is also a strong biological candidate for height, as rare, severe mutations in this gene alter body size in mice and humans, so we tested rs1042725 in additional samples. We confirmed the association in 19,064 adults from four further studies (P = 3 × 10−11, overall P = 4 × 10−16, including the genome-wide association data). We also observed the association in children (P = 1 × 10−6, N = 6,827) and a tall/short case-control study (P = 4 × 10−6, N = 3,207). We estimate that rs1042725 explains ∼0.3% of population variation in height (∼0.4 cm increased adult height per C allele). There are few examples of common genetic variants reproducibly associated with human quantitativetraits; these results represent, to our knowledge, the first consistently replicated association with adult and childhood height. [ABSTRACT FROM AUTHOR]

An essential function of both the Association for Applied Psychophysiology and Biofeedback (AAPB) and the Society for Neuronal Regulation (SNR) is the systematic evaluation of psychophysiological interventions that have been developed for the treatment of medical and psychiatric disorders. In order to address scientific concerns regarding the efficacy of specific clinical applications of biofeedback, these two societies formed and Efficacy Task Force. The process to be used in the assessment of treatment efficacy, specificity and clinical utility is presented in the form of a template that will serve as the foundation for a series of scientific reviews and practice guidlines to be published by both societies. [ABSTRACT FROM AUTHOR]

The organ culture of the mammary gland of lactating mice was used to examine the response of the differentiated gland to lactogenic stimuli, insulin, cortisol, and prolactin. Time course studies showed that casein synthesis in cultured tissue decreased rapidly during the first 2 d despite the presence of the three hormones, but on the 3rd d tissue cultured with either insulin and prolactin or all three hormones regained the ability to synthesize milk proteins, casein, and α-lactalbumin: a greater increase occurred in the three hormone system. The delayed addition of prolactin on Day 2 to the culture system containing insulin and cortisol also stimulated casein synthesis. The addition of cytarabine, which inhibited insulin-dependent cell proliferation in cultured explants, did not block the rebound of milk protein synthesis. The results indicate that in the presence of insulin, cortisol, and prolactin mammary epithelial cells in culture first lose and then regain the ability of synthesizing milk protein without requiring the formation of new daughter cells. [ABSTRACT FROM AUTHOR]

Cortisol was previously shown to elicit a concentration-dependent inhibition of α-lactalbumin accumulation in midpregnant mouse mammary gland cultured in medium containing optimal concentrations of 5 μg/ml prolactin and insulin. In contrast, casein accumulation under these conditions was progressively stimulated by addition of increasing amounts of cortisol (Ono, M.; Oka, T. Cell 19: 473-480; 1980). In the present study we found that in the presence of a suboptimal concentration of 0.5 μg/ml prolactin, 2.8×10 M to 2.8×10 M cortisol stimulated α-lactalbumin accumulation. Furthermore, higher concentrations of cortisol produced a smaller inhibition of α-lactalbumin accumulation as compared to that obtained in cultures containing 5 μg/ml prolactin. The maximal increase in α-lactalbumin accumulation attained in the presence of 1.4×10 M cortisol, 0.5 μg/ml prolactin, and insulin was comparable to that observed in culture containing 5 μg/ml prolactin and insulin. Similar results were obtained in a cortisol concentration-response study of α-lactalbumin accumulation in cultures containing a suboptimal concentration of 0.5 μg/ml human placental lactogen. Measurement of the rate of α-lactalbumin synthesis in cultured tissue indicated that the opposing effects of low and high concentrations of cortisol on α-lactalbumin accumulation involved an alteration in the rate of synthesis of the milk protein. In contrast to α-lactalbumin, the synthesis of casein was stimulated in a concentration-dependent manner by addition of cortisol that acted synergistically with either 0.5 μg/ml or 5 μg/ml prolactin. The maximal increases were obtained in the presence of 2.8×10 M cortisol. These results indicated that the action of cortisol on α-lactalbumin accumulation can be modulated by the concentration, of prolactin and suggest that the interplay between cortisol and prolactin in regulation of α-lactalbumin synthesis may be different from that involved in casein synthesis. [ABSTRACT FROM AUTHOR]

Describes how the Office of Fair Trading in Great Britain set out to produce and distribute information and advice to consumers using a variety of media. Lessons learnt about the consumer's reaction to and absorption of consumer advice material; Reasons for consumers'ignorance of their rights; Formation of Consumers' Association in 1957; Trends in the demand for consumer information material.