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Many variants that we inherit from our parents or acquire de novo or somatically are rare, limiting the precision with which we can associate them with disease. We performed exhaustive saturation genome editing (SGE) of BAP1, the disruption of which is linked to tumorigenesis and altered neurodevelopment. We experimentally characterized 18,108 unique variants, of which 6,196 were found to have abnormal functions, and then used these data to evaluate phenotypic associations in the UK Biobank. We also characterized variants in a large population-ascertained tumor collection, in cancer pedigrees and ClinVar, and explored the behavior of cancer-associated variants compared to that of variants linked to neurodevelopmental phenotypes. Our analyses demonstrated that disruptive germline BAP1variants were significantly associated with higher circulating levels of the mitogen IGF-1, suggesting a possible pathological mechanism and therapeutic target. Furthermore, we built a variant classifier with >98% sensitivity and specificity and quantify evidence strengths to aid precision variant interpretation.

Obesity is a major risk factor for many common diseases and has a substantial heritable component. To identify new genetic determinants, we performed exome-sequence analyses for adult body mass index (BMI) in up to 587,027 individuals. We identified rare loss-of-function variants in two genes (BSNand APBA1) with effects substantially larger than those of well-established obesity genes such as MC4R. In contrast to most other obesity-related genes, rare variants in BSNand APBA1were not associated with normal variation in childhood adiposity. Furthermore, BSNprotein-truncating variants (PTVs) magnified the influence of common genetic variants associated with BMI, with a common variant polygenic score exhibiting an effect twice as large in BSNPTV carriers than in noncarriers. Finally, we explored the plasma proteomic signatures of BSNPTV carriers as well as the functional consequences of BSNdeletion in human induced pluripotent stem cell-derived hypothalamic neurons. Collectively, our findings implicate degenerative processes in synaptic function in the etiology of adult-onset obesity.

The article discusses the United Nations' "group of human rights experts on Nicaragua" (GHREN) and their reports on alleged human rights violations in Nicaragua since April 2018. The article argues that the GHREN's reports are biased and omit important information, focusing only on alleged violations by the government while ignoring violence by opposition groups. The Nicaragua Solidarity Coalition and other organizations have criticized the GHREN's work and called for the reports to be withdrawn. The article also raises concerns about the functioning of the UN Human Rights Council and calls for reform. [Extracted from the article]

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A critical campaign analysis of the French and Indian War's 1759 Quebec campaign demonstrates that Britain achieved victory because it reflected the principles of joint operations better than its French [...]

An individual’s nutritional status has a powerful effect on sexual maturation. Puberty onset is delayed in response to chronic energy insufficiency and is advanced under energy abundance. The consequences of altered pubertal timing for human health are profound. Late puberty increases the chances of cardiometabolic, musculoskeletal and neurocognitive disorders, whereas early puberty is associated with increased risks of adult obesity, type 2 diabetes mellitus, cardiovascular diseases and various cancers, such as breast, endometrial and prostate cancer. Kennedy and Mitra’s trailblazing studies, published in 1963 and using experimental models, were the first to demonstrate that nutrition is a key factor in puberty onset. Building on this work, the field has advanced substantially in the past decade, which is largely due to the impressive development of molecular tools for experimentation and population genetics. In this Review, we discuss the latest advances in basic and translational sciences underlying the nutritional and metabolic control of pubertal development, with a focus on perspectives and future directions.

Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.

Mosaic loss of the X chromosome (mLOX) is the most common clonal somatic alteration in leukocytes of female individuals1,2, but little is known about its genetic determinants or phenotypic consequences. Here, to address this, we used data from 883,574 female participants across 8 biobanks; 12% of participants exhibited detectable mLOX in approximately 2% of leukocytes. Female participants with mLOX had an increased risk of myeloid and lymphoid leukaemias. Genetic analyses identified 56 common variants associated with mLOX, implicating genes with roles in chromosomal missegregation, cancer predisposition and autoimmune diseases. Exome-sequence analyses identified rare missense variants in FBXO10that confer a twofold increased risk of mLOX. Only a small fraction of associations was shared with mosaic Y chromosome loss, suggesting that distinct biological processes drive formation and clonal expansion of sex chromosome missegregation. Allelic shift analyses identified X chromosome alleles that are preferentially retained in mLOX, demonstrating variation at many loci under cellular selection. A polygenic score including 44 allelic shift loci correctly inferred the retained X chromosomes in 80.7% of mLOX cases in the top decile. Our results support a model in which germline variants predispose female individuals to acquiring mLOX, with the allelic content of the X chromosome possibly shaping the magnitude of clonal expansion.

Leukaemia stem cells (LSCs) in acute myeloid leukaemia present a considerable treatment challenge due to their resistance to chemotherapy and immunosurveillance. The connection between these properties in LSCs remains poorly understood. Here we demonstrate that inhibition of tyrosine phosphatase SHP-1 in LSCs increases their glycolysis and oxidative phosphorylation, enhancing their sensitivity to chemotherapy and vulnerability to immunosurveillance. Mechanistically, SHP-1 inhibition leads to the upregulation of phosphofructokinase platelet (PFKP) through the AKT–β-catenin pathway. The increase in PFKP elevates energy metabolic activities and, as a consequence, enhances the sensitivity of LSCs to chemotherapeutic agents. Moreover, the upregulation of PFKP promotes MYC degradation and, consequently, reduces the immune evasion abilities of LSCs. Overall, our study demonstrates that targeting SHP-1 disrupts the metabolic balance in LSCs, thereby increasing their vulnerability to chemotherapy and immunosurveillance. This approach offers a promising strategy to overcome LSC resistance in acute myeloid leukaemia.

Last Friday, armed Ecuadorian police attacked the Mexican embassy in Quito and kidnapped Ecuador's former vice-president, Jorge Glas, who had been granted political asylum by Mexico. The consul, Roberto Canseco, was also assaulted by the police. Glas, a key member of Rafael Correa's left-wing government, had been charged with corruption. Ecuador's violation of the Vienna Convention, which protects embassies and their staff, was condemned by almost all Latin American governments. The attack may have been influenced by the country's drug-related crime wave and the recent Israeli attack on the Iranian consulate in Damascus. [Extracted from the article]

With the US air force general Mike Minihan saying there will be war between the US and China within two years (Letter from Kinmen, 31 March), Graham Allison's warnings about [...]

Linkage and candidate gene studies have identified several breast cancer susceptibility genes, but the overall contribution of coding variation to breast cancer is unclear. To evaluate the role of rare coding variants more comprehensively, we performed a meta-analysis across three large whole-exome sequencing datasets, containing 26,368 female cases and 217,673 female controls. Burden tests were performed for protein-truncating and rare missense variants in 15,616 and 18,601 genes, respectively. Associations between protein-truncating variants and breast cancer were identified for the following six genes at exome-wide significance (P<2.5 × 10−6): the five known susceptibility genes ATM, BRCA1, BRCA2, CHEK2and PALB2, together with MAP3K1. Associations were also observed for LZTR1, ATRIPand BARD1with P< 1 × 10−4. Associations between predicted deleterious rare missense or protein-truncating variants and breast cancer were additionally identified for CDKN2Aat exome-wide significance. The overall contribution of coding variants in genes beyond the previously known genes is estimated to be small.

Identification of genetic causes of central precocious puberty have revealed epigenetic mechanisms as regulators of human pubertal timing. MECP2, an X-linked gene, encodes a chromatin-associated protein with a role in gene transcription. MECP2 loss-of-function mutations usually cause Rett syndrome, a severe neurodevelopmental disorder. Early pubertal development has been shown in several patients with Rett syndrome. The aim of this study was to explore whether MECP2 variants are associated with an idiopathic central precocious puberty phenotype.

It's right to draw attention to human rights abuses in countries such as China and Saudi Arabia that acquire British businesses, but why not express similar qualms about the US [...]

Necrotic ring spot can be a frustrating disease to deal with in turfgrass, especially when we are talking about areas of high traffic or high play. There are only a [...]

MAY 29, 2023 During the attempted coup in Nicaragua in 2018, Masaya was one of the cities most affected by the violence and by the widespread use of roadblocks to control the streets, many manned by armed youths. Randall is one of Masaya's "historic fighters", a veteran from Nicaragua's revolutionary war against the Somoza dictatorship in the 1970s. Randall explained that on the day this part of Masaya was liberated (July 17), the national police and volunteer police started to enter the barrio very early in the morning. [Extracted from the article]

Premature ovarian insufficiency (POI) affects 1% of women and is a leading cause of infertility. It is often considered to be a monogenic disorder, with pathogenic variants in ~100 genes described in the literature. We sought to systematically evaluate the penetrance of variants in these genes using exome sequence data in 104,733 women from the UK Biobank, 2,231 (1.14%) of whom reported at natural menopause under the age of 40 years. We found limited evidence to support any previously reported autosomal dominant effect. For nearly all heterozygous effects on previously reported POI genes, we ruled out even modest penetrance, with 99.9% (13,699 out of 13,708) of all protein-truncating variants found in reproductively healthy women. We found evidence of haploinsufficiency effects in several genes, including TWNK(1.54 years earlier menopause, P= 1.59 × 10−6) and SOHLH2(3.48 years earlier menopause, P= 1.03 × 10−4). Collectively, our results suggest that, for the vast majority of women, POI is not caused by autosomal dominant variants either in genes previously reported or currently evaluated in clinical diagnostic panels. Our findings, plus previous studies, suggest that most POI cases are likely oligogenic or polygenic in nature, which has important implications for future clinical genetic studies, and genetic counseling for families affected by POI.

T cell acute lymphoblastic leukaemia (T-ALL) is an aggressive malignancy with poor prognosis, but a decisive marker and effective treatment for leukaemia stem cells (LSCs) remain unclear. Here, using lineage tracing, limiting dilution assays and in vivo live imaging approaches, we identify rare inhibitory receptor programmed cell death 1 (PD-1)-expressing cells that reside at the apex of leukaemia hierarchy for initiation and relapse in T-ALL. Ablation of PD-1-expressing cells, deletion of PD-1 in T-ALL cells or blockade of PD-1 or PD-1 ligand 1 significantly eradicated LSCs and suppressed disease progression. Combination therapy using PD-1 blockade and chemotherapy substantially extended the survival of mice engrafted with mouse or human T-ALL cells. Mechanistically, PD-1+LSCs had high NOTCH1–MYC activity for disease initiation. Furthermore, PD-1 signalling maintained quiescence and protected LSCs against T cell receptor-signal-induced apoptosis. Overall, our data highlight the hierarchy of leukaemia by identifying PD-1+LSCs and provide a therapeutic approach for the elimination of LSCs through PD-1 blockade in T-ALL.

A frequent criticism of Richard Vallee’s “pluri-propositionalism” is that it multiplies propositions beyond necessity. I argue that this criticism, recently voiced by Robert Stanton and Arthur Sullivan, is based in misconceptions about propositions are and how they help us classify utterances and the mental states and events that lead to them, relying for the most part on extended discussions of examples.

Hematopoietic stem cells (HSCs) have reduced capacities to properly maintain and replenish the hematopoietic system during myelosuppressive injury or aging. Expanding and rejuvenating HSCs for therapeutic purposes has been a long-sought goal with limited progress. Here, we show that the enzyme Sphk2 (sphingosine kinase 2), which generates the lipid metabolite sphingosine-1-phosphate, is highly expressed in HSCs. The deletion of Sphk2 markedly promotes self-renewal and increases the regenerative potential of HSCs. More importantly, Sphk2 deletion globally preserves the young HSC gene expression pattern, improves the function, and sustains the multilineage potential of HSCs during aging. Mechanistically, Sphk2 interacts with prolyl hydroxylase 2 and the Von Hippel-Lindau protein to facilitate HIF1α ubiquitination in the nucleus independent of the Sphk2 catalytic activity. Deletion of Sphk2 increases hypoxic responses by stabilizing the HIF1α protein to upregulate PDK3, a glycolysis checkpoint protein for HSC quiescence, which subsequently enhances the function of HSCs by improving their metabolic fitness; specifically, it enhances anaerobic glycolysis but suppresses mitochondrial oxidative phosphorylation and generation of reactive oxygen species. Overall, targeting Sphk2 to enhance the metabolic fitness of HSCs is a promising strategy to expand and rejuvenate functional HSCs.

Using a nontargeted metabolomics approach of 447 fasting plasma metabolites, we searched for novel molecular markers that arise before and after hyperglycemia in a large population-based cohort of 2,204 females (115 type 2 diabetic [T2D] case subjects, 192 individuals with impaired fasting glucose [IFG], and 1,897 control subjects) from TwinsUK. Forty-two metabolites from three major fuel sources (carbohydrates, lipids, and proteins) were found to significantly correlate with T2D after adjusting for multiple testing; of these, 22 were previously reported as associated with T2D or insulin resistance. Fourteen metabolites were found to be associated with IFG. Among the metabolites identified, the branched-chain keto-acid metabolite 3-methyl-2-oxovalerate was the strongest predictive biomarker for IFG after glucose (odds ratio [OR] 1.65 [95% CI 139-1951, P = 8.46 x [10.sup.-9]) and was moderately heritable ([h.sup.2] = 0.20). The association was replicated in an independent population (n = 720, OR 1.68 [1.34-2.11], P = 6.52 x [10.sup.-6]) and validated in 189 twins with urine metabolomics taken at the same time as plasma (OR 1.87 [1.27-2.75], P = 1 x [10.sup.-3]). Results confirm an important role for catabolism of branched-chain amino acids in T2D and IFG. In conclusion, this T2D-IFG biomarker study has surveyed the broadest panel of nontargeted metabolites to date, revealing both novel and known associated metabolites and providing potential novel targets for clinical prediction and a deeper understanding of causal mechanisms., Currently, stratification of individuals at risk for type 2 diabetes (T2D) within the general population is based on well-established factors such as age, BMI, and fasting glucose (1). Although these [...]

The article presents the discussion on Malinda Maynor Lowery's efforts to enrich Southern history with Lumbee perspectives, challenging simplistic racial narratives. Topics include her academic contributions at Emory University, initiatives in Native American studies, and creative projects like filmmaking and foodways research bridging Indigenous and African American experiences.