AA-amyloidosis in cats (Felis catus) housed in shelters.

Systemic AA-amyloidosis is a protein-misfolding disease characterized by fibril deposition of serum amyloid-A protein (SAA) in several organs in humans and many animal species. Fibril deposits originate from abnormally high serum levels of SAA during chronic inflammation. A high prevalence of AA-amyloidosis has been reported in captive cheetahs and a horizontal transmission has been proposed. In domestic cats, AA-amyloidosis has been mainly described in predisposed breeds but only rarely reported in domestic short-hair cats. Aims of the study were to determine AA-amyloidosis prevalence in dead shelter cats. Liver, kidney, spleen and bile were collected at death in cats from 3 shelters. AA-amyloidosis was scored. Shedding of amyloid fibrils was investigated with western blot in bile and scored. Descriptive statistics were calculated. In the three shelters investigated, prevalence of AA-amyloidosis was 57.1% (16/28 cats), 73.0% (19/26) and 52.0% (13/25), respectively. In 72.9% of cats (35 in total) three organs were affected concurrently. Histopathology and immunofluorescence of post-mortem extracted deposits identified SAA as the major protein source. The duration of stay in the shelters was positively associated with a histological score of AA-amyloidosis (B = 0.026, CI95% = 0.007-0.046; p = 0.010). AA-amyloidosis was very frequent in shelter cats. Presence of SAA fragments in bile secretions raises the possibility of fecal-oral transmission of the disease. In conclusion, AA-amyloidosis was very frequent in shelter cats and those staying longer had more deposits. The cat may represent a natural model of AA-amyloidosis

Foundations for Open Scholarship Strategy Development, Version 2.1 [Pre-print]

This document aims to agree on a broad, international strategy for the implementation of open scholarship that meets the needs of different national and regional communities but works globally. Scholarly research can be idealised as an inspirational process for advancing our collective knowledge to the benefit of all humankind. However, current research practices often struggle with a range of tensions, in part due to the fact that this collective (or “commons”) ideal conflicts with the competitive system in which most scholars work, and in part because much of the infrastructure of the scholarly world is becoming largely digital. What is broadly termed as Open Scholarship is an attempt to realign modern research practices with this ideal. We do not propose a definition of Open Scholarship, but recognise that it is a holistic term that encompasses many disciplines, practices, and principles, sometimes also referred to as Open Science or Open Research. We choose the term Open Scholarship to be more inclusive of these other terms. When we refer to science in this document, we do so historically and use it as shorthand for more general scholarship. The purpose of this document is to provide a concise analysis of where the global Open Scholarship movement currently stands: what the common threads and strengths are, where the greatest opportunities and challenges lie, and how we can more effectively work together as a global community to recognise and address the top strategic priorities. This document was inspired by the Foundations for OER Strategy Development and work in the FORCE11 Scholarly Commons Working Group, and developed by an open contribution working group. Our hope is that this document will serve as a foundational resource for continuing discussions and initiatives about implementing effective strategies to help streamline the integration of Open Scholarship practices into a modern, digital research culture. Through this, we hope to extend the reach and impact of Open Scholarship into a global context, making sure that it is truly open for all. We also hope that this document will evolve as the conversations around Open Scholarship progress, and help to provide useful insight for both global co-ordination and local action. We believe this is a step forward in making Open Scholarship the norm. Ultimately, we expect the impact of widespread adoption of Open Scholarship to be diverse. We expect novel research practices to accelerate the pace of innovation, and therefore stimulate critical industries around the world. We could also expect to see an increase in public trust of science and scholarship, as transparency becomes more normative. As such, we expect interest in Open Scholarship to increase at multiple levels, due to its inherent influence on society and global economics

Foundations for Open Scholarship Strategy Development

This document aims to agree on a broad, international strategy for the implementation of open scholarship that meets the needs of different national and regional communities but works globally.Scholarly research can be idealised as an inspirational process for advancing our collective knowledge to the benefit of all humankind. However, current research practices often struggle with a range of tensions, in part due to the fact that this collective (or “commons”) ideal conflicts with the competitive system in which most scholars work, and in part because much of the infrastructure of the scholarly world is becoming largely digital. What is broadly termed as Open Scholarship is an attempt to realign modern research practices with this ideal. We do not propose a definition of Open Scholarship, but recognise that it is a holistic term that encompasses many disciplines, practices, and principles, sometimes also referred to as Open Science or Open Research. We choose the term Open Scholarship to be more inclusive of these other terms. When we refer to science in this document, we do so historically and use it as shorthand for more general scholarship.The purpose of this document is to provide a concise analysis of where the global Open Scholarship movement currently stands: what the common threads and strengths are, where the greatest opportunities and challenges lie, and how we can more effectively work together as a global community to recognise and address the top strategic priorities. This document was inspired by the Foundations for OER Strategy Development and work in the FORCE11 Scholarly Commons Working Group, and developed by an open contribution working group.Our hope is that this document will serve as a foundational resource for continuing discussions and initiatives about implementing effective strategies to help streamline the integration of Open Scholarship practices into a modern, digital research culture. Through this, we hope to extend the reach and impact of Open Scholarship into a global context, making sure that it is truly open for all. We also hope that this document will evolve as the conversations around Open Scholarship progress, and help to provide useful insight for both global co-ordination and local action. We believe this is a step forward in making Open Scholarship the norm.Ultimately, we expect the impact of widespread adoption of Open Scholarship to be diverse. We expect novel research practices to accelerate the pace of innovation, and therefore stimulate critical industries around the world. We could also expect to see an increase in public trust of science and scholarship, as transparency becomes more normative. As such, we expect interest in Open Scholarship to increase at multiple levels, due to its inherent influence on society and global economics

Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance.

Esophageal adenocarcinoma (EAC) has a poor outcome, and targeted therapy trials have thus far been disappointing owing to a lack of robust stratification methods. Whole-genome sequencing (WGS) analysis of 129 cases demonstrated that this is a heterogeneous cancer dominated by copy number alterations with frequent large-scale rearrangements. Co-amplification of receptor tyrosine kinases (RTKs) and/or downstream mitogenic activation is almost ubiquitous; thus tailored combination RTK inhibitor (RTKi) therapy might be required, as we demonstrate in vitro. However, mutational signatures showed three distinct molecular subtypes with potential therapeutic relevance, which we verified in an independent cohort (n = 87): (i) enrichment for BRCA signature with prevalent defects in the homologous recombination pathway; (ii) dominant T>G mutational pattern associated with a high mutational load and neoantigen burden; and (iii) C>A/T mutational pattern with evidence of an aging imprint. These subtypes could be ascertained using a clinically applicable sequencing strategy (low coverage) as a basis for therapy selection.Whole-genome sequencing of esophageal adenocarcinoma samples was performed as part of the International Cancer Genome Consortium (ICGC) through the oEsophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium and was funded by Cancer Research UK. We thank the ICGC members for their input on verification standards as part of the benchmarking exercise. We thank the Human Research Tissue Bank, which is supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, from Addenbrooke’s Hospital and UCL. Also the University Hospital of Southampton Trust and the Southampton, Birmingham, Edinburgh and UCL Experimental Cancer Medicine Centres and the QEHB charities. This study was partly funded by a project grant from Cancer Research UK. R.C.F. is funded by an NIHR Professorship and receives core funding from the Medical Research Council and infrastructure support from the Biomedical Research Centre and the Experimental Cancer Medicine Centre. We acknowledge the support of The University of Cambridge, Cancer Research UK (C14303/A17197) and Hutchison Whampoa Limited. We would like to thank Dr. Peter Van Loo for providing the NGS version of ASCAT for copy number calling. We are grateful to all the patients who provided written consent for participation in this study and the staff at all participating centres. Some of the work was undertaken at UCLH/UCL who received a proportion of funding from the Department of Health’s NIHR Biomedical Research Centres funding scheme. The work at UCLH/UCL was also supported by the CRUK UCL Early Cancer Medicine Centre.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.365

Characterisation of age and polarity at onset in bipolar disorder

Background Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools. Aims To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics. Method Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts. Results Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO. Conclusions AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses

Genome-wide interaction study of a proxy for stress-sensitivity and its prediction of major depressive disorder

Individual response to stress is correlated with neuroticism and is an important predictor of both neuroticism and the onset of major depressive disorder (MDD). Identification of the genetics underpinning individual differences in response to negative events (stress-sensitivity) may improve our understanding of the molecular pathways involved, and its association with stress-related illnesses. We sought to generate a proxy for stress-sensitivity through modelling the interaction between SNP allele and MDD status on neuroticism score in order to identify genetic variants that contribute to the higher neuroticism seen in individuals with a lifetime diagnosis of depression compared to unaffected individuals. Meta-analysis of genome-wide interaction studies (GWIS) in UK Biobank (N = 23,092) and Generation Scotland: Scottish Family Health Study (N = 7,155) identified no genome-wide significance SNP interactions. However, gene-based tests identified a genome-wide significant gene, ZNF366, a negative regulator of glucocorticoid receptor function implicated in alcohol dependence (p = 1.48x10-7; Bonferroni-corrected significance threshold p < 2.79x10-6). Using summary statistics from the stress-sensitivity term of the GWIS, SNP heritability for stress-sensitivity was estimated at 5.0%. In models fitting polygenic risk scores of both MDD and neuroticism derived from independent GWAS, we show that polygenic risk scores derived from the UK Biobank stress-sensitivity GWIS significantly improved the prediction of MDD in Generation Scotland. This study may improve interpretation of larger genome-wide association studies of MDD and other stress-related illnesses, and the understanding of the etiological mechanisms underpinning stress-sensitivity

The Human Phenotype Ontology in 2024: phenotypes around the world.

The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English. Since our last report, a total of 2239 new HPO terms and 49235 new HPO annotations were developed, many in collaboration with external groups in the fields of psychiatry, arthrogryposis, immunology and cardiology. The Medical Action Ontology (MAxO) is a new effort to model treatments and other measures taken for clinical management. Finally, the HPO consortium is contributing to efforts to integrate the HPO and the GA4GH Phenopacket Schema into electronic health records (EHRs) with the goal of more standardized and computable integration of rare disease data in EHRs

Towards a muon collider

A muon collider would enable the big jump ahead in energy reach that is needed for a fruitful exploration of fundamental interactions. The challenges of producing muon collisions at high luminosity and 10 TeV centre of mass energy are being investigated by the recently-formed International Muon Collider Collaboration. This Review summarises the status and the recent advances on muon colliders design, physics and detector studies. The aim is to provide a global perspective of the field and to outline directions for future work