FGFR2-activating mutations disrupt cell polarity to potentiate migration and invasion in endometrial cancer cell models

Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases that control a diverse range of biological processes during development and in adult tissues. We recently reported that somatic FGFR2 mutations are associated with shorter survival in endometrial cancer. However, little is known about how these FGFR2 mutations contribute to endometrial cancer metastasis. Here, we report that expression of the activating mutations FGFR2N550K and FGFR2Y376C in an endometrial cancer cell model induce Golgi fragmentation, and loss of polarity and directional migration. In mutant FGFR2-expressing cells, this was associated with an inability to polarise intracellular pools of FGFR2 towards the front of migrating cells. Such polarization defects were exacerbated in three-dimensional culture, where FGFR2 mutant cells were unable to form well-organised acini, instead undergoing exogenous ligand-independent invasion. Our findings uncover collective cell polarity and invasion as common targets of disease-associated FGFR2 mutations that lead to poor outcome in endometrial cancer patients

Acinar Cell Apoptosis in Serpini2-Deficient Mice Models Pancreatic Insufficiency

Pancreatic insufficiency (PI) when left untreated results in a state of malnutrition due to an inability to absorb nutrients. Frequently, PI is diagnosed as part of a larger clinical presentation in cystic fibrosis or Shwachman–Diamond syndrome. In this study, a mouse model for isolated exocrine PI was identified in a mouse line generated by a transgene insertion. The trait is inherited in an autosomal recessive pattern, and homozygous animals are growth retarded, have abnormal immunity, and have reduced life span. Mice with the disease locus, named pequeño (pq), exhibit progressive apoptosis of pancreatic acinar cells with severe exocrine acinar cell loss by 8 wk of age, while the islets and ductal tissue persist. The mutation in pq/pq mice results from a random transgene insertion. Molecular characterization of the transgene insertion site by fluorescent in situ hybridization and genomic deletion mapping identified an approximately 210-kb deletion on Chromosome 3, deleting two genes. One of these genes, Serpini2, encodes a protein that is a member of the serpin family of protease inhibitors. Reintroduction of only the Serpini2 gene by bacterial artificial chromosome transgenic complementation corrected the acinar cell defect as well as body weight and immune phenotypes, showing that deletion of Serpini2 causes the pequeño phenotype. Dietary supplementation of pancreatic enzymes also corrected body size, body weight, and immunodeficiency, and increased the life span of Serpini2-deficient mice, despite continued acinar cell loss. To our knowledge, this study describes the first characterized genetic animal model for isolated PI. Genetic complementation of the transgene insertion mutant demonstrates that Serpini2 deficiency directly results in the acinar cell apoptosis, malabsorption, and malnutrition observed in pq/pq mice. The rescue of growth retardation, immunodeficiency, and mortality by either Serpini2 bacterial artificial chromosome transgenic expression or by pancreatic enzyme supplementation demonstrates that these phenotypes are secondary to malnutrition in pq/pq mice

Influence of Maternal Lifestyle and Diet on Perinatal DNA Methylation Signatures Associated With Childhood Arterial Stiffness at 8 to 9 Years

Increases in aortic pulse wave velocity, a measure of arterial stiffness, can lead to elevated systolic blood pressure and increased cardiac afterload in adulthood. These changes are detectable in childhood and potentially originate in utero, where an adverse early life environment can alter DNA methylation patterns detectable at birth. Here, analysis of epigenome-wide methylation patterns using umbilical cord blood DNA from 470 participants in the Southampton’s Women’s Survey identified differential methylation patterns associated with systolic blood pressure, pulse pressure, arterial distensibility, and descending aorta pulse wave velocity measured by magnetic resonance imaging at 8 to 9 years. Perinatal methylation levels at 16 CpG loci were associated with descending aorta pulse wave velocity, with identified CpG sites enriched in pathways involved in DNA repair (P=9.03×10−11). The most significant association was with cg20793626 methylation (within protein phosphatase, Mg2+/Mn2+ dependent 1D; β=−0.05 m/s/1% methylation change, [95% CI, −0.09 to −0.02]). Genetic variation was also examined but had a minor influence on these observations. Eight pulse wave velocity-linked dmCpGs were associated with prenatal modifiable risk factors, with cg08509237 methylation (within palmitoyl-protein thioesterase-2) associated with maternal oily fish consumption in early and late pregnancy. Lower oily fish consumption in early pregnancy modified the relationship between methylation and pulse wave velocity, with lower consumption strengthening the association between cg08509237 methylation and increased pulse wave velocity. In conclusion, measurement of perinatal DNA methylation signatures has utility in identifying infants who might benefit from preventive interventions to reduce risk of later cardiovascular disease, and modifiable maternal factors can reduce this risk in the child

Report of the 1st Workshop on Generative AI and Law

This report presents the takeaways of the inaugural Workshop on Generative AI and Law (GenLaw), held in July 2023. A cross-disciplinary group of practitioners and scholars from computer science and law convened to discuss the technical, doctrinal, and policy challenges presented by law for Generative AI, and by Generative AI for law, with an emphasis on U.S. law in particular. We begin the report with a high-level statement about why Generative AI is both immensely significant and immensely challenging for law. To meet these challenges, we conclude that there is an essential need for 1) a shared knowledge base that provides a common conceptual language for experts across disciplines; 2) clarification of the distinctive technical capabilities of generative-AI systems, as compared and contrasted to other computer and AI systems; 3) a logical taxonomy of the legal issues these systems raise; and, 4) a concrete research agenda to promote collaboration and knowledge-sharing on emerging issues at the intersection of Generative AI and law. In this report, we synthesize the key takeaways from the GenLaw workshop that begin to address these needs. All of the listed authors contributed to the workshop upon which this report is based, but they and their organizations do not necessarily endorse all of the specific claims in this report

The Genome of Mycobacterium Africanum West African 2 Reveals a Lineage-Specific Locus and Genome Erosion Common to the M. tuberculosis Complex

Mycobacterium africanum, a close relative of M. tuberculosis, is studied for the following reasons: M. africanum is commonly isolated from West African patients with tuberculosis yet has not spread beyond this region, it is more common in HIV infected patients, and it is less likely to lead to tuberculosis after one is exposed to an infectious case. Understanding this organism's unique biology gets a boost from the decoding of its genome, reported in this issue. For example, genome analysis reveals that M. africanum contains a region shared with “ancient” lineages in the M. tuberculosis complex and other mycobacterial species, which was lost independently from both M. tuberculosis and M. bovis. This region encodes a protein involved in transmembrane transport. Furthermore, M. africanum has lost genes, including a known virulence gene and genes for vitamin synthesis, in addition to an intact copy of a gene that may increase its susceptibility to antibiotics that are insufficiently active against M. tuberculosis. Finally, the genome sequence and analysis reported here will aid in the development of new diagnostics and vaccines against tuberculosis, which need to take into account the differences between M. africanum and other species in order to be effective worldwide

GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors

Objective: Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and crossvalidated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS metaanalysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures. Methods: This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses. Results: Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values &lt;5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors. Conclusions: This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.</p

GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors

OBJECTIVE: Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures. METHODS: This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses. RESULTS: Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values \u3c5×10 CONCLUSIONS: This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death

Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice.

Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems