β-Catenin is a pH sensor with decreased stability at higher intracellular pH.

β-Catenin functions as an adherens junction protein for cell-cell adhesion and as a signaling protein. β-catenin function is dependent on its stability, which is regulated by protein-protein interactions that stabilize β-catenin or target it for proteasome-mediated degradation. In this study, we show that β-catenin stability is regulated by intracellular pH (pHi) dynamics, with decreased stability at higher pHi in both mammalian cells and Drosophila melanogaster β-Catenin degradation requires phosphorylation of N-terminal residues for recognition by the E3 ligase β-TrCP. While β-catenin phosphorylation was pH independent, higher pHi induced increased β-TrCP binding and decreased β-catenin stability. An evolutionarily conserved histidine in β-catenin (found in the β-TrCP DSGIHS destruction motif) is required for pH-dependent binding to β-TrCP. Expressing a cancer-associated H36R-β-catenin mutant in the Drosophila eye was sufficient to induce Wnt signaling and produced pronounced tumors not seen with other oncogenic β-catenin alleles. We identify pHi dynamics as a previously unrecognized regulator of β-catenin stability, functioning in coincidence with phosphorylation

Development of an Acute and Highly Pathogenic Nonhuman Primate Model of Nipah Virus Infection

Nipah virus (NiV) is an enigmatic emerging pathogen that causes severe and often fatal neurologic and/or respiratory disease in both animals and humans. Amongst people, case fatality rates range between 40 and 75 percent and there are no vaccines or treatments approved for human use. Guinea pigs, hamsters, cats, ferrets, pigs and most recently squirrel monkeys (New World monkey) have been evaluated as animal models of human NiV infection, and with the exception of the ferret, no model recapitulates all aspects of NiV-mediated disease seen in humans. To identify a more viable nonhuman primate (NHP) model, we examined the pathogenesis of NiV in African green monkeys (AGM). Exposure of eight monkeys to NiV produced a severe systemic infection in all eight animals with seven of the animals succumbing to infection. Viral RNA was detected in the plasma of challenged animals and occurred in two of three subjects as a peak between days 7 and 21, providing the first clear demonstration of plasma-associated viremia in NiV experimentally infected animals and suggested a progressive infection that seeded multiple organs simultaneously from the initial site of virus replication. Unlike the cat, hamster and squirrel monkey models of NiV infection, severe respiratory pathology, neurological disease and generalized vasculitis all manifested in NiV-infected AGMs, providing an accurate reflection of what is observed in NiV-infected humans. Our findings demonstrate the first consistent and highly pathogenic NHP model of NiV infection, providing a new and critical platform in the evaluation and licensure of either passive and active immunization or therapeutic strategies for human use

Collagen I but not Matrigel matrices provide an MMP-dependent barrier to ovarian cancer cell penetration

Abstract Background The invasive potential of cancer cells is usually assessed in vitro using Matrigel as a surrogate basement membrane. Yet cancer cell interaction with collagen I matrices is critical, particularly for the peritoneal metastatic route undertaken by several cancer types including ovarian. Matrix metalloprotease (MMP) activity is important to enable cells to overcome the barrier constraints imposed by basement membranes and stromal matrices in vivo. Our objective was to compare matrices reconstituted from collagen I and Matrigel as representative barriers for ovarian cancer cell invasion. Methods The requirement of MMP activity for ovarian cancer cell penetration of Matrigel and collagen matrices was assessed in 2D transwell and 3D spheroid culture systems. Results The broad range MMP inhibitor GM6001 completely prevented cell perforation of polymerised collagen I-coated transwell membranes. In contrast, GM6001 decreased ES-2 cell penetration of Matrigel by only ~30% and had no effect on HEY cell Matrigel penetration. In 3D culture, ovarian cancer cells grown as spheroids also migrated into surrounding Matrigel matrices despite MMP blockade. In contrast, MMP activity was required for invasion into 3D matrices of collagen I reconstituted from acid-soluble rat-tail collagen I, but not from pepsin-extracted collagen I (Vitrogen/Purecol), which lacks telopeptide regions. Conclusion Matrigel does not form representative barriers to ovarian cancer cells in either 2D or 3D culture systems. Our findings support the use of collagen I rather than Matrigel as a matrix barrier for invasion studies to better approximate critical interactions and events associated with peritoneal metastasis

Cell–cell and cell–matrix dynamics in intraperitoneal cancer metastasis

The peritoneal metastatic route of cancer dissemination is shared by cancers of the ovary and gastrointestinal tract. Once initiated, peritoneal metastasis typically proceeds rapidly in a feed-forward manner. Several factors contribute to this efficient progression. In peritoneal metastasis, cancer cells exfoliate into the peritoneal fluid and spread locally, transported by peritoneal fluid. Inflammatory cytokines released by tumor and immune cells compromise the protective, anti-adhesive mesothelial cell layer that lines the peritoneal cavity, exposing the underlying extracellular matrix to which cancer cells readily attach. The peritoneum is further rendered receptive to metastatic implantation and growth by myofibroblastic cell behaviors also stimulated by inflammatory cytokines. Individual cancer cells suspended in peritoneal fluid can aggregate to form multicellular spheroids. This cellular arrangement imparts resistance to anoikis, apoptosis, and chemotherapeutics. Emerging evidence indicates that compact spheroid formation is preferentially accomplished by cancer cells with high invasive capacity and contractile behaviors. This review focuses on the pathological alterations to the peritoneum and the properties of cancer cells that in combination drive peritoneal metastasis

Genotype-stratified treatment for monogenic insulin resistance: a systematic review

This is the final version. Available from Nature Research via the DOI in this record. Data availability: All data used in this review is available from publicly available and herein referenced sources. A list of included studies is provided in Supplementary Data 1. All data generated or analyzed during this study are included in this published article and its supplementary information files. Source data for the figures are available as Supplementary Data 2.BACKGROUND: Monogenic insulin resistance (IR) includes lipodystrophy and disorders of insulin signalling. We sought to assess the effects of interventions in monogenic IR, stratified by genetic aetiology. METHODS: Systematic review using PubMed, MEDLINE and Embase (1 January 1987 to 23 June 2021). Studies reporting individual-level effects of pharmacologic and/or surgical interventions in monogenic IR were eligible. Individual data were extracted and duplicates were removed. Outcomes were analysed for each gene and intervention, and in aggregate for partial, generalised and all lipodystrophy. RESULTS: 10 non-randomised experimental studies, 8 case series, and 23 case reports meet inclusion criteria, all rated as having moderate or serious risk of bias. Metreleptin use is associated with the lowering of triglycerides and haemoglobin A1c (HbA1c) in all lipodystrophy (n = 111), partial (n = 71) and generalised lipodystrophy (n = 41), and in LMNA, PPARG, AGPAT2 or BSCL2 subgroups (n = 72,13,21 and 21 respectively). Body Mass Index (BMI) is lowered in partial and generalised lipodystrophy, and in LMNA or BSCL2, but not PPARG or AGPAT2 subgroups. Thiazolidinediones are associated with improved HbA1c and triglycerides in all lipodystrophy (n = 13), improved HbA1c in PPARG (n = 5), and improved triglycerides in LMNA (n = 7). In INSR-related IR, rhIGF-1, alone or with IGFBP3, is associated with improved HbA1c (n = 17). The small size or absence of other genotype-treatment combinations preclude firm conclusions. CONCLUSIONS: The evidence guiding genotype-specific treatment of monogenic IR is of low to very low quality. Metreleptin and Thiazolidinediones appear to improve metabolic markers in lipodystrophy, and rhIGF-1 appears to lower HbA1c in INSR-related IR. For other interventions, there is insufficient evidence to assess efficacy and risks in aggregated lipodystrophy or genetic subgroups.Wellcome TrustWellcome Trus

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017.

The Global Burden of Diseases, Injuries and Risk Factors 2017 includes a comprehensive assessment of incidence, prevalence, and years lived with disability (YLDs) for 354 causes in 195 countries and territories from 1990 to 2017. Previous GBD studies have shown how the decline of mortality rates from 1990 to 2016 has led to an increase in life expectancy, an ageing global population, and an expansion of the non-fatal burden of disease and injury. These studies have also shown how a substantial portion of the world's population experiences non-fatal health loss with considerable heterogeneity among different causes, locations, ages, and sexes. Ongoing objectives of the GBD study include increasing the level of estimation detail, improving analytical strategies, and increasing the amount of high-quality data. METHODS: We estimated incidence and prevalence for 354 diseases and injuries and 3484 sequelae. We used an updated and extensive body of literature studies, survey data, surveillance data, inpatient admission records, outpatient visit records, and health insurance claims, and additionally used results from cause of death models to inform estimates using a total of 68 781 data sources. Newly available clinical data from India, Iran, Japan, Jordan, Nepal, China, Brazil, Norway, and Italy were incorporated, as well as updated claims data from the USA and new claims data from Taiwan (province of China) and Singapore. We used DisMod-MR 2.1, a Bayesian meta-regression tool, as the main method of estimation, ensuring consistency between rates of incidence, prevalence, remission, and cause of death for each condition. YLDs were estimated as the product of a prevalence estimate and a disability weight for health states of each mutually exclusive sequela, adjusted for comorbidity. We updated the Socio-demographic Index (SDI), a summary development indicator of income per capita, years of schooling, and total fertility rate. Additionally, we calculated differences between male and female YLDs to identify divergent trends across sexes. GBD 2017 complies with the Guidelines for Accurate and Transparent Health Estimates Reporting

Global, regional, and national disability-adjusted life-years (DALYs) for 359 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017.

How long one lives, how many years of life are spent in good and poor health, and how the population's state of health and leading causes of disability change over time all have implications for policy, planning, and provision of services. We comparatively assessed the patterns and trends of healthy life expectancy (HALE), which quantifies the number of years of life expected to be lived in good health, and the complementary measure of disability-adjusted life-years (DALYs), a composite measure of disease burden capturing both premature mortality and prevalence and severity of ill health, for 359 diseases and injuries for 195 countries and territories over the past 28 years. Methods We used data for age-specific mortality rates, years of life lost (YLLs) due to premature mortality, and years lived with disability (YLDs) from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 to calculate HALE and DALYs from 1990 to 2017. We calculated HALE using age-specific mortality rates and YLDs per capita for each location, age, sex, and year. We calculated DALYs for 359 causes as the sum of YLLs and YLDs. We assessed how observed HALE and DALYs differed by country and sex from expected trends based on Socio-demographic Index (SDI). We also analysed HALE by decomposing years of life gained into years spent in good health and in poor health, between 1990 and 2017, and extra years lived by females compared with males. Findings Globally, from 1990 to 2017, life expectancy at birth increased by 7·4 years (95% uncertainty interval 7·1-7·8), from 65·6 years (65·3-65·8) in 1990 to 73·0 years (72·7-73·3) in 2017. The increase in years of life varied from 5·1 years (5·0-5·3) in high SDI countries to 12·0 years (11·3-12·8) in low SDI countries. Of the additional years of life expected at birth, 26·3% (20·1-33·1) were expected to be spent in poor health in high SDI countries compared with 11·7% (8·8-15·1) in low-middle SDI countries. HALE at birth increased by 6·3 years (5·9-6·7), from 57·0 years (54·6-59·1) in 1990 to 63·3 years (60·5-65·7) in 2017. The increase varied from 3·8 years (3·4-4·1) in high SDI countries to 10·5 years (9·8-11·2) in low SDI countries. Even larger variations in HALE than these were observed between countries, ranging from 1·0 year (0·4-1·7) in Saint Vincent and the Grenadines (62·4 years [59·9-64·7] in 1990 to 63·5 years [60·9-65·8] in 2017) to 23·7 years (21·9-25·6) in Eritrea (30·7 years [28·9-32·2] in 1990 to 54·4 years [51·5-57·1] in 2017). In most countries, the increase in HALE was smaller than the increase in overall life expectancy, indicating more years lived in poor health. In 180 of 195 countries and territories, females were expected to live longer than males in 2017, with extra years lived varying from 1·4 years (0·6-2·3) in Algeria to 11·9 years (10·9-12·9) in Ukraine. Of the extra years gained, the proportion spent in poor health varied largely across countries, with less than 20% of additional years spent in poor health in Bosnia and Herzegovina, Burundi, and Slovakia, whereas in Bahrain all the extra years were spent in poor health. In 2017, the highest estimate of HALE at birth was in Singapore for both females (75·8 years [72·4-78·7]) and males (72·6 years [69·8-75·0]) and the lowest estimates were in Central African Republic (47·0 years [43·7-50·2] for females and 42·8 years [40·1-45·6] for males). Globally, in 2017, the five leading causes of DALYs were neonatal disorders, ischaemic heart disease, stroke, lower respiratory infections, and chronic obstructive pulmonary disease. Between 1990 and 2017, age-standardised DALY rates decreased by 41·3% (38·8-43·5) for communicable diseases and by 49·8% (47·9-51·6) for neonatal disorders. For non-communicable diseases, global DALYs increased by 40·1% (36·8-43·0), although age-standardised DALY rates decreased by 18·1% (16·0-20·2)