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Viral infection is commonly associated with virus-driven hijacking of host proteins. Here we describe a novel mechanism by which influenza virus affects host cells through the interaction of influenza non-structural protein 1 (NS1) with the infected cell epigenome. We show that the NS1 protein of influenza A H3N2 subtype possesses a histone-like sequence (histone mimic) that is used by the virus to target the human PAF1 transcription elongation complex (hPAF1C). We demonstrate that binding of NS1 to hPAF1C depends on the NS1 histone mimic and results in suppression of hPAF1C-mediated transcriptional elongation. Furthermore, human PAF1 has a crucial role in the antiviral response. Loss of hPAF1C binding by NS1 attenuates influenza infection, whereas hPAF1C deficiency reduces antiviral gene expression and renders cells more susceptible to viruses. We propose that the histone mimic in NS1 enables the influenza virus to affect inducible gene expression selectively, thus contributing to suppression of the antiviral response. The H3N2 influenza virus immunomodulatory protein NS1 carries a sequence that mimics the histone H3 tail; this sequence interferes with the host antiviral response via binding to the cellular regulator of RNA elongation, hPAF1C. Flu-virus mimicry Histone proteins are essential regulators of gene function. The amino-terminal domain of the histone H2, or the histone 'tail', can be post-translationally modified, and it acts as a scaffold for the assembly of protein complexes that control gene function. Ivan Marazzi and colleagues now show that the immunosuppressive NS1 protein of the influenza virus carries a histone-like sequence that mimics key features of histone H3, including binding to key transcriptional regulators, so that the virus can hijack the host transcriptional machinery. Interaction between NS1 and transcriptional elongation complex PAF1C is shown to be crucial to the host antiviral response, validating PAF1 protein as a candidate for anti-inflammatory therapy using synthetic PAF1 antagonists.

Amyotrophic lateral sclerosis (ALS) is a heterogenous neurodegenerative disorder that affects motor neurons and voluntary muscle control 1 . ALS heterogeneity includes the age of manifestation, the rate of progression and the anatomical sites of symptom onset. Disease-causing mutations in specific genes have been identified and define different subtypes of ALS 1 . Although several ALS-associated genes have been shown to affect immune functions 2 , whether specific immune features account for ALS heterogeneity is poorly understood. Amyotrophic lateral sclerosis-4 (ALS4) is characterized by juvenile onset and slow progression 3 . Patients with ALS4 show motor difficulties by the time that they are in their thirties, and most of them require devices to assist with walking by their fifties. ALS4 is caused by mutations in the senataxin gene ( SETX ). Here, using Setx knock-in mice that carry the ALS4-causative L389S mutation, we describe an immunological signature that consists of clonally expanded, terminally differentiated effector memory (T EMRA ) CD8 T cells in the central nervous system and the blood of knock-in mice. Increased frequencies of antigen-specific CD8 T cells in knock-in mice mirror the progression of motor neuron disease and correlate with anti-glioma immunity. Furthermore, bone marrow transplantation experiments indicate that the immune system has a key role in ALS4 neurodegeneration. In patients with ALS4, clonally expanded T EMRA CD8 T cells circulate in the peripheral blood. Our results provide evidence of an antigen-specific CD8 T cell response in ALS4, which could be used to unravel disease mechanisms and as a potential biomarker of disease state. An immune signature characterized by activated antigen-specific CD8 T cells is identified in the brain and blood of mice with amyotrophic lateral sclerosis-4 (ALS4), suggesting that the immune system is involved in ALS4 neurodegeneration.

High spliceosome activity is a dependency for cancer cells, making them more vulnerable to perturbation of the splicing machinery compared to normal cells. To identify splicing factors important for prostate cancer (PCa) fitness, we performed pooled shRNA screens in vitro and in vivo. Our screens identified heterogeneous nuclear ribonucleoprotein M (HNRNPM) as a regulator of PCa cell growth. RNA- and eCLIP-sequencing identified HNRNPM binding to transcripts of key homeostatic genes. HNRNPM binding to its targets prevents aberrant exon inclusion and backsplicing events. In both linear and circular mis-spliced transcripts, HNRNPM preferentially binds to GU-rich elements in long flanking proximal introns. Mimicry of HNRNPM-dependent linear-splicing events using splice-switching-antisense-oligonucleotides was sufficient to inhibit PCa cell growth. This suggests that PCa dependence on HNRNPM is likely a result of mis-splicing of key homeostatic coding and non-coding genes. Our results have further been confirmed in other solid tumors. Taken together, our data reveal a role for HNRNPM in supporting cancer cell fitness. Inhibition of HNRNPM activity is therefore a potential therapeutic strategy in suppressing growth of PCa and other solid tumors.

Fast, high-throughput methods for measuring the level and duration of protective immune responses to SARS-CoV-2 are needed to anticipate the risk of breakthrough infections. Here we report the development of two quantitative PCR assays for SARS-CoV-2-specific T cell activation. The assays are rapid, internally normalized and probe-based: qTACT requires RNA extraction and dqTACT avoids sample preparation steps. Both assays rely on the quantification of CXCL10 messenger RNA, a chemokine whose expression is strongly correlated with activation of antigen-specific T cells. On restimulation of whole-blood cells with SARS-CoV-2 viral antigens, viral-specific T cells secrete IFN-γ, which stimulates monocytes to produce CXCL10 . CXCL10 mRNA can thus serve as a proxy to quantify cellular immunity. Our assays may allow large-scale monitoring of the magnitude and duration of functional T cell immunity to SARS-CoV-2, thus helping to prioritize revaccination strategies in vulnerable populations. The T cell response to SARS-CoV-2 is detected by a PCR assay on whole blood.

Cancer cells are differentially dependent on the splicing machinery compared to normal untransformed cells. The splicing machinery thus represents a potential therapeutic target in cancer. To identify splicing factors important for prostate cancer cell (PCa) cell growth, we performed a parallel pooled shRNA screen on in vitro passaged cells and in vivo xenografted PCa tumor lines. Our screen revealed HNRNPM as a potential regulator of PCa cell growth. RNA- and eCLIP-sequencing data suggest that HNRNPM is bound to transcripts of key homeostatic genes and that loss of HNRNPM binding in a subset of these genes results in aberrant exon inclusion and exon back-splicing events in target transcripts. In both linear and circular mis-spliced transcripts, HNRNPM appears to preferentially bind to GU-rich elements in long flanking proximal introns. Mimicry of HNRNPM dependent linear splicing events using splice-switching antisense oligonucleotides (SSOs) was sufficient to inhibit cell growth in HNRNPM expressing cells. This suggests that prostate cancer cell dependence on HNRNPM is likely a result of mis-splicing of key homeostatic coding and non-coding genes. Taken together, our data reveal a role for HNRNPM in supporting prostate cancer cell fitness, and also as a potential therapeutic target in PCa.

AbstractObjectivesTo assess whether declines in life expectancy occurred across high income countries during 2014-16, to identify the causes of death contributing to these declines, and to examine the extent to which these declines were driven by shared or differing factors across countries.DesignDemographic analysis using aggregated data.SettingVital statistics systems of 18 member countries of the Organisation for Economic Co-operation and Development.Participants18 countries with high quality all cause and cause specific mortality data available in 2014-16.Main outcome measuresLife expectancy at birth, 0-65 years, and 65 or more years and cause of death contributions to changes in life expectancy at birth.ResultsThe majority of high income countries in the study experienced declines in life expectancy during 2014-15; of the 18 countries, 12 experienced declines in life expectancy among women and 11 experienced declines in life expectancy among men. The average decline was 0.21 years for women and 0.18 years for men. In most countries experiencing declines in life expectancy, these declines were predominantly driven by trends in older age (≥65 years) mortality and in deaths related to respiratory disease, cardiovascular disease, nervous system disease, and mental disorders. In the United States, declines in life expectancy were more concentrated at younger ages (0-65 years), and drug overdose and other external causes of death played important roles in driving these declines.ConclusionsMost of the countries that experienced declines in life expectancy during 2014-15 experienced robust gains in life expectancy during 2015-16 that more than compensated for the declines. However, the United Kingdom and the United States appear to be experiencing stagnating or continued declines in life expectancy, raising questions about future trends in these countries.

Since the mid-1990s, the United States has witnessed a dramatic rise in drug overdose mortality. Educational gradients in life expectancy widened over the same period, and drug overdose likely plays a role in this widening, particularly for non-Hispanic whites. The contemporary drug epidemic is distinctive in terms of its scope, the nature of the substances involved, and its geographic patterning, which influence how it impacts different education groups. I use vital statistics and National Health Interview Survey data to examine the contribution of drug overdose to educational gradients in life expectancy from 1992–2011. I find that over this period, years of life lost due to drug overdose increased for all education groups and for both males and females. The contribution of drug overdose to educational gradients in life expectancy has increased over time and is greater for non-Hispanic whites than for the population as a whole. Drug overdose accounts for a sizable proportion of the increases in educational gradients in life expectancy, particularly at the prime adult ages (ages 30–60), where it accounts for 25 % to 100 % of the widening in educational gradients between 1992 and 2011. Drug overdose mortality has increased more rapidly for females than for males, leading to a gender convergence. These findings shed light on the processes driving recent changes in educational gradients in life expectancy and suggest that effective measures to address the drug overdose epidemic should take into account its differential burden across education groups.

Drug overdose mortality has reached unprecedented levels in the United States, more than tripling over the past two decades. This study situates the contemporary American drug overdose epidemic in broader perspective by comparing the US to 17 other high-income countries. Vital statistics data covering 1994-2015 are drawn from various sources including the Human Mortality Database and the WHO Mortality Database. The US now has the highest drug overdose death rates—3.5 times higher on average— among high-income countries. This is a fairly recent phenomenon; in the late 1990s and early 2000s, Nordic countries had the highest drug overdose death rates. Drug overdose is increasingly important for the US life expectancy shortfall. In 2013, drug overdose accounted for 12 percent and 8 percent of the average life expectancy gap for men and women, respectively, between the US and comparator countries. The increase in this gap between 2003 and 2013 would have been one-fifth (men) and one-third (women) smaller on average in the absence of drug overdose. Potential drivers of the US's strikingly elevated drug overdose mortality levels include a variety of factors such as health care provision and financing, institutional structures, and cultural attitudes toward pain and the medical establishment.

Prescription drug use has reached historic highs in the United States—a trend linked to increases in medicalization, institutional factors relating to the health care and pharmaceutical industries, and population aging and growing burdens of chronic disease. Despite the high and rising prevalence of use, no estimates exist of the total number of years Americans can expect to spend taking prescription drugs over their lifetimes. This study provides the first estimates of life course patterns of prescription drug use using data from the 1996–2019 Medical Expenditure Panel Surveys, the Human Mortality Database, and the National Center for Health Statistics. Newborns in 2019 could be expected to take prescription drugs for roughly half their lives: 47.54 years for women and 36.84 years for men. The number of years individuals can expect to take five or more drugs increased substantially. Americans also experienced particularly dramatic increases in years spent taking statins, antihypertensives, and antidepressants. There are also important differences in prescription drug use by race and ethnicity: non-Hispanic Whites take the most, Hispanics take the least, and non-Hispanic Blacks fall in between these extremes. Americans are taking drugs over a wide and expanding swathe of the life course, a testament to the centrality of prescription drugs in Americans' lives today.