Keeping the Faith 2.0 Embedding a new normal for partnership working in post-pandemic Britain

This report reflects the views and experiences of senior representatives and practitioners of both local authorities and faith groups across England, expressed in 35 in-depth interviews. It is a follow up report to the original Keeping the Faith report, published in November 2020 and covers the 12 months of experience of working in partnership to tackle COVID-19 since the time of that publication. The key theme emerging from the research is that we are now entering a more reflexive stage of the pandemic as we move from ‘rescue and emergency’ mode to ‘building back better’. In other words, addressing the longer-term implications of partnership working if the ‘new normal’ - identified in the original report as being the useful learning and practices developed in the ‘eye of the storm’ of the first lockdown - is to be preserved and built upon. These longer-term implications are expressed in areas of policy and technical change, many of which are highlighted in the appendix to this report and include those associated with the ‘hotspots’ of policy partnership that have emerged in this second phase of the pandemic. As well as the ongoing need for emergency food relief and food distribution, faith groups and local authorities have also found themselves collaborating closely in areas of mental health, public health, domestic violence, the care and integration of refugees and migrants, mentoring highly vulnerable families and individuals, being the conduits for other clinical and public health interventions in their recovery, as well as providing emergency childcare services via fostering and adoption services. The growing use of worship and other faith-based centres in the delivery of statutory mental health and public health is likely to be a permanent feature of health and social care provision going forward. However, the bulk of the content of this report is concerned with highlighting the importance of values as the basis for more effective and sustainable partnership and policy development. The key message around the capability of faith/secular partnerships to build back better is that ‘shared values’ are much more likely to lead to ‘shared outcomes’. Shared values identified as being held in common across both local authorities and faith groups include: compassion, social justice (including an end to discrimination and poverty), friendship, an ethos of service, kindness, empathy, and hope

Keeping the Faith. Partnerships between faith groups and local authorities during and beyond the pandemic

We report here on research which has been undertaken across the UK to explore the changing contours of partnership between local authorities and faith groups and faith-based organisations in the context of responses to COVID-19. The research examines the types and amount of joint activity that has emerged since the pandemic began. It also identifies how new experiences of collaboration and partnership point towards changing relationships and mutual perceptions between local authorities and faith communities, and what the implications might be for future policy

The Eukaryotic Proteome Is Shaped by E3 Ubiquitin Ligases Targeting C-Terminal Degrons

Degrons are minimal elements that mediate the interaction of proteins with degradation machineries to promote proteolysis. Despite their central role in proteostasis, the number of known degrons remains small and a facile technology to characterize them is lacking. Using a strategy combining Global Protein Stability (GPS) profiling with a synthetic human peptidome, we identify thousands of peptides containing degron activity. Using CRISPR screening, we established that the stability of many proteins is regulated through degrons located at their C-terminus. We characterize eight Cullin-RING E3 ubiquitin ligase (CRL) complexes adaptors that regulate C-terminal degrons including six CRL2 and two CRL4 complexes and computationally implicate multiple non-CRLs in end recognition. Human proteome analysis revealed that the C-termini of eukaryotic proteins are depleted for C-terminal degrons, suggesting an E3 ligase-dependent modulation of proteome composition. Thus, we propose that a series of ‘C-end rules’ operate to govern protein stability and shape the eukaryotic proteome

Mitochondrial Protein Lipoylation and the 2-Oxoglutarate Dehydrogenase Complex Controls HIF1α Stability in Aerobic Conditions.

Hypoxia-inducible transcription factors (HIFs) control adaptation to low oxygen environments by activating genes involved in metabolism, angiogenesis, and redox homeostasis. The finding that HIFs are also regulated by small molecule metabolites highlights the need to understand the complexity of their cellular regulation. Here we use a forward genetic screen in near-haploid human cells to identify genes that stabilize HIFs under aerobic conditions. We identify two mitochondrial genes, oxoglutarate dehydrogenase (OGDH) and lipoic acid synthase (LIAS), which when mutated stabilize HIF1α in a non-hydroxylated form. Disruption of OGDH complex activity in OGDH or LIAS mutants promotes L-2-hydroxyglutarate formation, which inhibits the activity of the HIFα prolyl hydroxylases (PHDs) and TET 2-oxoglutarate dependent dioxygenases. We also find that PHD activity is decreased in patients with homozygous germline mutations in lipoic acid synthesis, leading to HIF1 activation. Thus, mutations affecting OGDHC activity may have broad implications for epigenetic regulation and tumorigenesis.This work was supported by a Wellcome Trust Senior Clinical Research Fellowship to J.A.N. (102770/Z/13/Z), Wellcome Trust Principal Research Fellowship to P.J.L. (084957/Z/08/Z), and the Medical Research Council (A.S.H.C. and C.F.). The Cambridge Institute for Medical Research is in receipt of a Wellcome Trust Strategic Award (100140).This is the final version of the article. It first appeared from Elsevier (Cell Press) via https://doi.org/10.1016/j.cmet.2016.09.01

PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution

Mosaicism is increasingly recognized as a cause of developmental disorders with the advent of next-generation sequencing (NGS). Mosaic mutations of PIK3CA have been associated with the widest spectrum of phenotypes associated with overgrowth and vascular malformations. We performed targeted NGS using 2 independent deep-coverage methods that utilize molecular inversion probes and amplicon sequencing in a cohort of 241 samples from 181 individuals with brain and/or body overgrowth. We identified PIK3CA mutations in 60 individuals. Several other individuals (n = 12) were identified separately to have mutations in PIK3CA by clinical targetedpanel testing (n = 6), whole-exome sequencing (n = 5), or Sanger sequencing (n = 1). Based on the clinical and molecular features, this cohort segregated into three distinct groups: (a) severe focal overgrowth due to low-level but highly activating (hotspot) mutations, (b) predominantly brain overgrowth and less severe somatic overgrowth due to less-activating mutations, and (c) intermediate phenotypes (capillary malformations with overgrowth) with intermediately activating mutations. Sixteen of 29 PIK3CA mutations were novel. We also identified constitutional PIK3CA mutations in 10 patients. Our molecular data, combined with review of the literature, show that PIK3CA-related overgrowth disorders comprise a discontinuous spectrum of disorders that correlate with the severity and distribution of mutations

Homologous recombination deficiency in newly diagnosed FIGO stage III/IV high-grade epithelial ovarian cancer: a multi-national observational study

OBJECTIVE: Olaparib plus bevacizumab maintenance therapy improves survival outcomes in women with newly diagnosed, advanced, high-grade ovarian cancer with a deficiency in homologous recombination. We report data from the first year of routine homologous recombination deficiency testing in the National Health Service (NHS) in England, Wales, and Northern Ireland between April 2021 and April 2022. METHODS: The Myriad myChoice companion diagnostic was used to test DNA extracted from formalin-fixed, paraffin-embedded tumor tissue in women with newly diagnosed International Federation of Gynecology and Obstetrics (FIGO) stage III/IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. Tumors with homologous recombination deficiency were those with a BRCA1/2 mutation and/or a Genomic Instability Score (GIS) ≥42. Testing was coordinated by the NHS Genomic Laboratory Hub network. RESULTS: The myChoice assay was performed on 2829 tumors. Of these, 2474 (87%) and 2178 (77%) successfully underwent BRCA1/2 and GIS testing, respectively. All complete and partial assay failures occurred due to low tumor cellularity and/or low tumor DNA yield. 385 tumors (16%) contained a BRCA1/2 mutation and 814 (37%) had a GIS ≥42. Tumors with a GIS ≥42 were more likely to be BRCA1/2 wild-type (n=510) than BRCA1/2 mutant (n=304). The distribution of GIS was bimodal, with BRCA1/2 mutant tumors having a higher mean score than BRCA1/2 wild-type tumors (61 vs 33, respectively, χ2 test p<0.0001). CONCLUSION: This is the largest real-world evaluation of homologous recombination deficiency testing in newly diagnosed FIGO stage III/IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. It is important to select tumor tissue with adequate tumor content and quality to reduce the risk of assay failure. The rapid uptake of testing across England, Wales, and Northern Ireland demonstrates the power of centralized NHS funding, center specialization, and the NHS Genomic Laboratory Hub network

Molecular epidemiology of coagulase-negative Staphylococcus species isolated at different lactation stages from dairy cattle in the United States

Background Coagulase negative Staphylococcus (CNS) species are currently the most prevalent intra-mammary pathogens causing subclinical mastitis and occasional clinical mastitis or persistent infection in lactating dairy cattle. More than 10 CNS species have been identified, but they are generally managed as one group on most dairies in the United States. However, improved management decisions and treatment outcomes may be achieved with better understanding of the prevalent species, pathogenicity and strain diversity within and across dairies. Methodology A total of 604 CNS isolates were cultured from milk samples collected during a dry-cow treatment clinical trial conducted on 6 dairy herds in 4 states in the US. All the study cows were randomized to receive 1 of the 3 different intra-mammary antimicrobial infusions (Quatermaster, Spectramast DC or ToMorrow Dry Cow) at dry-off. Milk samples were collected at dry-off, calving (0–6 days in milk, DIM), post-calving (7–13 DIM) and at mastitis events within the first 100 DIM. The CNS isolates were identified to species level by partial sequencing of the rpoβ gene, and genetic relatedness within species was investigated by phylogenetic analysis of the pulse-field gel electrophoresis profiles of the isolates. Results The major CNS species identified were S. chromogenes (48.3%), S. haemolyticus (17.9%), S. simulans and S. epidermidis (each at 6.5%). Other CNS species identified at lower frequencies included S. hominis, S. auricularis, S. sciuri, S. spp KS-SP, S. capitis, S. cohnii, S. warneri, S. pasteuri, S. xylosus, S. hyicus, S. equorum, S. microti, S. rostri, S. gallinarum, S. saprophyticus and S. succinus. Phylogenetic analyses of the major species types demonstrated an association between genetic relatedness and epidemiological distributions of S. chromogenes, S. simulans, S. haemolyticus and S. auricularis. Additionally, identical strains of S. chromogenes and S. simulans were isolated from the same udder quarter of several cows at consecutive sample stages. The rest of the minor species had no deducible genetic-epidemiological link. Discussion The observed association between genetic and epidemiological distributions indicated animal-adapted nature of four CNS species, suggesting possible host-adapted and environmental transmission of these species. Multi-stage isolation of the same udder quarter strain was evidence for chronic intra-mammary infection. Conclusion The different CNS species and strains circulating on US dairy herds were genetically diverse. Four species identified were likely udder-adapted pathogens, 2 of which caused persistent infection. Our findings are important in guiding the design of effective mastitis control strategies