Phosphofructokinase 1 Glycosylation Regulates Cell Growth and Metabolism

Cancer cells must satisfy the metabolic demands of rapid cell growth within a continually changing microenvironment. We demonstrated that the dynamic posttranslational modification of proteins by O-linked β-N-acetylglucosamine (O-GlcNAcylation) is a key metabolic regulator of glucose metabolism. O-GlcNAcylation was induced at serine 529 of phosphofructokinase 1 (PFK1) in response to hypoxia. Glycosylation inhibited PFK1 activity and redirected glucose flux through the pentose phosphate pathway, thereby conferring a selective growth advantage on cancer cells. Blocking glycosylation of PFK1 at serine 529 reduced cancer cell proliferation in vitro and impaired tumor formation in vivo. These studies reveal a previously uncharacterized mechanism for the regulation of metabolic pathways in cancer and a possible target for therapeutic intervention

Inhibiting Inducible Nitric Oxide Synthase in Enteric Glia Restores Electrogenic Ion Transport in Mice With Colitis

BACKGROUND & AIMS: Disturbances in the control of ion transport lead to epithelial barrier dysfunction in patients with colitis. Enteric glia regulate intestinal barrier function and colonic ion transport. However, it is not clear whether enteric glia are involved in the epithelial hypo-responsiveness. We investigated enteric glial regulation of ion transport in mice with trinitrobenzene sulphonic acid- or dextran sodium sulfate-induced colitis and in Il10(−/−) mice. METHODS: Electrically-evoked ion transport was measured in full-thickness segments of colon from CD1 and Il10(−/−) mice with or without colitis in Ussing chambers. Nitric oxide (NO) production was assessed using amperometry. Bacterial translocation was investigated in the liver, spleen and blood of mice. RESULTS: Electrical stimulation of the colon evoked a tetrodotoxin-sensitive chloride secretion. In mice with colitis, ion transport almost completely disappeared. Inhibiting inducible NO synthase (NOS2), but not neuronal NOS (NOS1), partially restored the evoked secretory response. Blocking glial function with fluoroacetate, which is not a NOS2 inhibitor, also partially restored ion transport. Combined NOS2 inhibition and fluoroacetate administration fully restored secretion. Epithelial responsiveness to vasoactive intestinal peptide was increased after enteric glial function was blocked in mice with colitis. In colons of mice without colitis, NO was produced in the myenteric plexus almost completely via NOS1. NO production was increased in mice with colitis, compared to mice without colitis; a substantial proportion of NOS2 was blocked by fluoroacetate administration. Inhibition of enteric glial function in vivo reduced the severity of trinitrobenzene sulphonic acid -induced colitis and associated bacterial translocation. CONCLUSIONS: Increased production of NOS2 in enteric glia contributes to the dysregulation of intestinal ion transport in mice with colitis. Blocking enteric glial function in these mice restores epithelial barrier function and reduces bacterial translocation

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

The Sloan Digital Sky Survey Reverberation Mapping project : key results

Funding: Y.S. acknowledges support from NSF grants AST-1715579 and AST-2009947. C.J.G. acknowledges support from NSF grants AST-2009949 and AST-2108667. J.I.L. is supported by the Eric and Wendy Schmidt AI in Science Postdoctoral Fellowship, a Schmidt Futures program. Y.H. was supported as an Eberly Research Fellow by the Eberly College of Science at the Pennsylvania State University. J.R.T. acknowledges support from NSF grants CAREER-1945546, AST-2009539, and AST-2108668. W.N.B. acknowledges support from NSF grant AST-2106990 and the Eberly Endowment at Penn State. L.C.H. was supported by the National Science Foundation of China (11721303, 11991052, 12011540375, 12233001) and the China Manned Space Project (CMS-CSST-2021-A04, CMS-CSST-2021-A06). C.T. acknowledges Tsinghua University for the support to her work.We present the final data from the Sloan Digital Sky Survey (SDSS) Reverberation Mapping (RM) project, a precursor to the SDSS-V Black Hole Mapper RM program. This data set includes 11 yr photometric and 7 yr spectroscopic light curves for 849 broad-line quasars over a redshift range of 0.1 < z < 4.5 and a luminosity range of Lbol = 1044−47.5 erg s−1, along with spectral and variability measurements. We report 23, 81, 125, and 110 RM lags (relative to optical continuum variability) for broad Hα, Hβ, Mg ii, and C iv using the SDSS-RM sample, spanning much of the luminosity and redshift ranges of the sample. Using 30 low-redshift RM active galactic nuclei with dynamical-modeling black hole masses, we derive a new estimate of the average virial factor of ⟨logf⟩ = 0.62±0.07 for the line dispersion measured from the rms spectrum. The intrinsic scatter of individual virial factors is 0.31 ± 0.07 dex, indicating a factor of 2 systematic uncertainty in RM black hole masses. Our lag measurements reveal significant R–L relations for Hβ and Mg ii at high redshift, consistent with the latest measurements based on heterogeneous samples. While we are unable to robustly constrain the slope of the R–L relation for C iv given the limited dynamic range in luminosity, we found substantially larger scatter in C iv lags at fixed L1350. Using the SDSS-RM lag sample, we derive improved single-epoch (SE) mass recipes for Hβ, Mg ii, and C iv, which are consistent with their respective RM masses as well as between the SE recipes from two different lines, over the luminosity range probed by our sample. The new Hβ and Mg ii recipes are approximately unbiased estimators at given RM masses, but there are systematic biases in the C iv recipe. The intrinsic scatter of SE masses around RM masses is ∼0.45 dex for Hβ and Mg ii, increasing to ∼0.58 dex for C iv.Peer reviewe

The Sloan Digital Sky Survey Reverberation Mapping Project: Key Results

We present the final data from the Sloan Digital Sky Survey Reverberation Mapping (SDSS-RM) project, a precursor to the SDSS-V Black Hole Mapper Reverberation Mapping program. This data set includes 11-year photometric and 7-year spectroscopic light curves for 849 broad-line quasars over a redshift range of 0.1<z<4.5 and a luminosity range of Lbol=1E44-47.5 erg/s, along with spectral and variability measurements. We report 23, 81, 125, and 110 reverberation mapping lags (relative to optical continuum variability) for broad Halpha, Hbeta, MgII and CIV using the SDSS-RM sample, spanning much of the luminosity and redshift ranges of the sample. Using 30 low-redshift RM AGNs with dynamical-modeling black hole masses, we derive a new estimate of the average virial factor of =0.62+-0.07 for the line dispersion measured from the RMS spectrum. The intrinsic scatter of individual virial factors is 0.31+-0.07 dex, indicating a factor of two systematic uncertainty in RM black hole masses. Our lag measurements reveal significant R-L relations for Hbeta and MgII at high redshift, consistent with the latest measurements based on heterogeneous samples. While we are unable to robustly constrain the slope of the R-L relation for CIV given the limited dynamical range in luminosity, we found substantially larger scatter in CIV lags at fixed L1350. Using the SDSS-RM lag sample, we derive improved single-epoch (SE) mass recipes for Hbeta, MgII and CIV, which are consistent with their respective RM masses as well as between the SE recipes from two different lines, over the luminosity range probed by our sample. The new Hbeta and MgII recipes are approximately unbiased estimators at given RM masses, but there are systematic biases in the CIV recipe. The intrinsic scatter of SE masses around RM masses is ~0.45 dex for Hbeta and MgII, increasing to ~0.58 dex for CIV.Comment: 33 pages. Data products available at ftp://quasar.astro.illinois.edu/public/sdssrm/final_result

Intellectual enrichment and genetic modifiers of cognition and brain volume in Huntington's disease

An important step towards the development of treatments for cognitive impairment in ageing and neurodegenerative diseases is to identify genetic and environmental modifiers of cognitive function and understand the mechanism by which they exert an effect. In Huntington’s disease, the most common autosomal dominant dementia, a small number of studies have identified intellectual enrichment, i.e. a cognitively stimulating lifestyle and genetic polymorphisms as potential modifiers of cognitive function. The aim of our study was to further investigate the relationship and interaction between genetic factors and intellectual enrichment on cognitive function and brain atrophy in Huntington’s disease. For this purpose, we analysed data from Track-HD, a multi-centre longitudinal study in Huntington’s disease gene carriers and focused on the role of intellectual enrichment (estimated at baseline) and the genes FAN1, MSH3, BDNF, COMT and MAPT in predicting cognitive decline and brain atrophy. We found that carrying the 3a allele in the MSH3 gene had a positive effect on global cognitive function and brain atrophy in multiple cortical regions, such that 3a allele carriers had a slower rate of cognitive decline and atrophy compared with non-carriers, in agreement with its role in somatic instability. No other genetic predictor had a significant effect on cognitive function and the effect of MSH3 was independent of intellectual enrichment. Intellectual enrichment also had a positive effect on cognitive function; participants with higher intellectual enrichment, i.e. those who were better educated, had higher verbal intelligence and performed an occupation that was intellectually engaging, had better cognitive function overall, in agreement with previous studies in Huntington’s disease and other dementias. We also found that intellectual enrichment interacted with the BDNF gene, such that the positive effect of intellectual enrichment was greater in Met66 allele carriers than non-carriers. A similar relationship was also identified for changes in whole brain and caudate volume; the positive effect of intellectual enrichment was greater for Met66 allele carriers, rather than for non-carriers. In summary, our study provides additional evidence for the beneficial role of intellectual enrichment and carrying the 3a allele in MSH3 in cognitive function in Huntington’s disease and their effect on brain structure

Evidence-Based Guidelines for Cardiovascular Disease Prevention in Women

Significant advances in our knowledge about interventions to prevent cardiovascular disease (CVD) have occurred since publication of the first female-specific recommendations for preventive cardiology in 1999.1 Despite research-based gains in the treatment of CVD, it remains the leading killer of women in the United States and in most developed areas of the world.2–3 In the United States alone, more than one half million women die of CVD each year, exceeding the number of deaths in men and the next 7 causes of death in women combined. This translates into approximately 1 death every minute.2 Coronary heart disease (CHD) accounts for the majority of CVD deaths in women, disproportionately afflicts racial and ethnic minorities, and is a prime target for prevention.1–2 Because CHD is often fatal, and because nearly two thirds of women who die suddenly have no previously recognized symptoms, it is essential to prevent CHD.2 Other forms of atherosclerotic/thrombotic CVD, such as cerebrovascular disease and peripheral arterial disease, are critically important in women. Strategies known to reduce the burden of CHD may have substantial benefits for the prevention of noncoronary atherosclerosis, although they have been studied less extensively in some of these settings

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)