Mastl is required for timely activation of APC/C in meiosis I and Cdk1 reactivation in meiosis II

In mitosis, the Greatwall kinase (called microtubule-associated serine/threonine kinase like [Mastl] in mammals) is essential for prometaphase entry or progression by suppressing protein phosphatase 2A (PP2A) activity. PP2A suppression in turn leads to high levels of Cdk1 substrate phosphorylation. We have used a mouse model with an oocyte-specific deletion of Mastl to show that Mastl-null oocytes resume meiosis I and reach metaphase I normally but that the onset and completion of anaphase I are delayed. Moreover, after the completion of meiosis I, Mastl-null oocytes failed to enter meiosis II (MII) because they reassembled a nuclear structure containing decondensed chromatin. Our results show that Mastl is required for the timely activation of anaphase-promoting complex/cyclosome to allow meiosis I exit and for the rapid rise of Cdk1 activity that is needed for the entry into MII in mouse oocytes

Implementation and resource needs for long-acting PrEP in low- and middle-income countries: a scoping review

INTRODUCTION: Several low- and middle-income countries (LMICs) are preparing to introduce long-acting pre-exposure prophylaxis (LAP). Amid multiple pre-exposure prophylaxis (PrEP) options and constrained funding, decision-makers could benefit from systematic implementation planning and aligned costs. We reviewed national costed implementation plans (CIPs) to describe relevant implementation inputs and activities (domains) for informing the costed rollout of LAP. We assessed how primary costing evidence aligned with those domains. METHODS: We conducted a rapid review of CIPs for oral PrEP and family planning (FP) to develop a consensus of implementation domains, and a scoping review across nine electronic databases for publications on PrEP costing in LMICs between January 2010 and June 2022. We extracted cost data and assessed alignment with the implementation domains and the Global Health Costing Consortium principles. RESULTS: We identified 15 implementation domains from four national PrEP plans and FP-CIP template; only six were in all sources. We included 66 full-text manuscripts, 10 reported LAP, 13 (20%) were primary cost studies-representing seven countries, and none of the 13 included LAP. The 13 primary cost studies included PrEP commodities (n = 12), human resources (n = 11), indirect costs (n = 11), other commodities (n = 10), demand creation (n = 9) and counselling (n = 9). Few studies costed integration into non-HIV services (n = 5), above site costs (n = 3), supply chains and logistics (n = 3) or policy and planning (n = 2), and none included the costs of target setting, health information system adaptations or implementation research. Cost units and outcomes were variable (e.g. average per person-year). DISCUSSION: LAP planning will require updating HIV prevention policies, technical assistance for logistical and clinical support, expanding beyond HIV platforms, setting PrEP achievement targets overall and disaggregated by method, extensive supply chain and logistics planning and support, as well as updating health information systems to monitor multiple PrEP methods with different visit schedules. The 15 implementation domains were variable in reviewed studies. PrEP primary cost and budget data are necessary for new product introduction and should match implementation plans with financing. CONCLUSIONS: As PrEP services expand to include LAP, decision-makers need a framework, tools and a process to support countries in planning the systematic rollout and costing for LAP

High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations.

The impact of somatic structural variants (SVs) on gene expression in cancer is largely unknown. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole-genome sequencing data and RNA sequencing from a common set of 1220 cancer cases, we report hundreds of genes for which the presence within 100 kb of an SV breakpoint associates with altered expression. For the majority of these genes, expression increases rather than decreases with corresponding breakpoint events. Up-regulated cancer-associated genes impacted by this phenomenon include TERT, MDM2, CDK4, ERBB2, CD274, PDCD1LG2, and IGF2. TERT-associated breakpoints involve ~3% of cases, most frequently in liver biliary, melanoma, sarcoma, stomach, and kidney cancers. SVs associated with up-regulation of PD1 and PDL1 genes involve ~1% of non-amplified cases. For many genes, SVs are significantly associated with increased numbers or greater proximity of enhancer regulatory elements near the gene. DNA methylation near the promoter is often increased with nearby SV breakpoint, which may involve inactivation of repressor elements

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

mHealth interventions targeting movement behaviors in Asia: A scoping review

10.1111/obr.13396OBESITY REVIEWS23

Atomate: A high-level interface to generate, execute, and analyze computational materials science workflows

We introduce atomate, an open-source Python framework for computational materials science simulation, analysis, and design with an emphasis on automation and extensibility. Built on top of open source Python packages already in use by the materials community such as pymatgen, FireWorks, and custodian, atomate provides well-tested workflow templates to compute various materials properties such as electronic bandstructure, elastic properties, and piezoelectric, dielectric, and ferroelectric properties. Atomate also enables the computational characterization of materials by providing workflows that calculate X-ray absorption (XAS), Electron energy loss (EELS) and Raman spectra. One of the major features of atomate is that it provides both fully functional workflows as well as reusable components that enable one to compose complex materials science workflows that use a diverse set of computational tools. Additionally, atomate creates output databases that organize the results from individual calculations and contains a builder framework that creates summary reports for each computed material based on multiple simulations