Association Between Chronic Hepatitis C Virus Infection and Myocardial Infarction Among People Living With HIV in the United States.

Hepatitis C virus (HCV) infection is common among people living with human immunodeficiency virus (PLWH). Extrahepatic manifestations of HCV, including myocardial infarction (MI), are a topic of active research. MI is classified into types, predominantly atheroembolic type 1 MI (T1MI) and supply-demand mismatch type 2 MI (T2MI). We examined the association between HCV and MI among patients in the Centers for AIDS Research (CFAR) Network of Integrated Clinical Systems, a US multicenter clinical cohort of PLWH. MIs were centrally adjudicated and categorized by type using the Third Universal Definition of Myocardial Infarction. We estimated the association between chronic HCV (RNA+) and time to MI while adjusting for demographic characteristics, cardiovascular risk factors, clinical characteristics, and history of injecting drug use. Among 23,407 PLWH aged ≥18 years, there were 336 T1MIs and 330 T2MIs during a median of 4.7 years of follow-up between 1998 and 2016. HCV was associated with a 46% greater risk of T2MI (adjusted hazard ratio (aHR) = 1.46, 95% confidence interval (CI): 1.09, 1.97) but not T1MI (aHR = 0.87, 95% CI: 0.58, 1.29). In an exploratory cause-specific analysis of T2MI, HCV was associated with a 2-fold greater risk of T2MI attributed to sepsis (aHR = 2.01, 95% CI: 1.25, 3.24). Extrahepatic manifestations of HCV in this high-risk population are an important area for continued research

Life-Expectancy Disparities Among Adults With HIV in the United States and Canada: The Impact of a Reduction in Drug- and Alcohol-Related Deaths Using the Lives Saved Simulation Model.

Improvements in life expectancy among people living with human immunodeficiency virus (PLWH) receiving antiretroviral treatment in the United States and Canada might differ among key populations. Given the difference in substance use among key populations and the current opioid epidemic, drug- and alcohol-related deaths might be contributing to the disparities in life expectancy. We sought to estimate life expectancy at age 20 years in key populations (and their comparison groups) in 3 time periods (2004-2007, 2008-2011, and 2012-2015) and the potential increase in expected life expectancy with a simulated 20% reduction in drug- and alcohol-related deaths using the novel Lives Saved Simulation model. Among 92,289 PLWH, life expectancy increased in all key populations and comparison groups from 2004-2007 to 2012-2015. Disparities in survival of approximately a decade persisted among black versus white men who have sex with men and people with (vs. without) a history of injection drug use. A 20% reduction in drug- and alcohol-related mortality would have the greatest life-expectancy benefit for black men who have sex with men, white women, and people with a history of injection drug use. Our findings suggest that preventing drug- and alcohol-related deaths among PLWH could narrow disparities in life expectancy among some key populations, but other causes of death must be addressed to further narrow the disparities

Effect of Neutrino Heating on Primordial Nucleosynthesis

We have modified the standard code for primordial nucleosynthesis to include the effect of the slight heating of neutrinos by $e^\pm$ annihilations. There is a small, systematic change in the $^4$He yield, $\Delta Y \simeq +1.5\times 10^{-4}$, which is insensitive to the value of the baryon-to-photon ratio $\eta$ for 10^{-10}\la \eta \la 10^{-9}. We also find that the baryon-to-photon ratio decreases by about 0.5\% less than the canonical factor of 4/11 because some of the entropy in $e^\pm$ pairs is transferred to neutrinos. These results are in accord with recent analytical estimates.Comment: 14 pages/4 Figs (upon request

NOD-like receptors and inflammation

The nucleotide-binding and oligomerization domain, leucine-rich repeat (also known as NOD-like receptors, both abbreviated to NLR) family of intracellular pathogen recognition receptors are increasingly being recognized to play a pivotal role in the pathogenesis of a number of rare monogenic diseases, as well as some more common polygenic conditions. Bacterial wall constituents and other cellular stressor molecules are recognized by a range of NLRs, which leads to activation of the innate immune response and upregulation of key proinflammatory pathways, such as IL-1β production and translocation of nuclear factor-κB to the nucleus. These signalling pathways are increasingly being targeted as potential sites for new therapies. This review discusses the role played by NLRs in a variety of inflammatory diseases and describes the remarkable success to date of these therapeutic agents in treating some of the disorders associated with aberrant NLR function

The evolution and consequences of snaR family transposition in primates

The small NF90 associated RNA (snaR) family of small noncoding RNAs (ncRNA) appears to have evolved from retrotransposon ancestors at or soon after pivotal stages in primate evolution. snaRs are thought to be derived from a FLAM C-like (free left Alu monomer) element through multiple short insertion/deletion (indel) and nucleotide (nt) substitution events. Tracing snaR’s complex evolutionary history through primate genomes led to the recent discovery of two novel retrotransposons: the Alu/snaR related (ASR) and catarrhine ancestor of snaR (CAS) elements. ASR elements are present in the genomes of Simiiformes, CAS elements are present in Old World Monkeys and apes, and snaRs are restricted to the African Great Apes (Homininae, including human, gorilla, chimpanzee and bonobo). Unlike their ancestors, snaRs have disseminated by multiple rounds of segmental duplication of a larger encompassing element. This process has produced large tandem gene arrays in humans and possibly precipitated the accelerated evolution of snaR. Furthermore, snaR segmental duplication created a new form of chorionic gonadotropin β subunit (CGβ) gene, recently classified as Type II CGβ, which has altered mRNA tissue expression and can generate a novel short peptide

Pion-nucleus elastic scattering on 12C, 40Ca, 90Zr, and 208Pb at 400 and 500 MeV

Pion-nucleus elastic scattering at energies above the Delta(1232) resonance is studied using both pi+ and pi- beams on 12C, 40Ca, 90Zr, and 208Pb. The present data provide an opportunity to study the interaction of pions with nuclei at energies where second-order corrections to impulse approximation calculations should be small. The results are compared with other data sets at similar energies, and with four different first-order impulse approximation calculations. Significant disagreement exists between the calculations and the data from this experiment

Free Energy of an Inhomogeneous Superconductor: a Wave Function Approach

A new method for calculating the free energy of an inhomogeneous superconductor is presented. This method is based on the quasiclassical limit (or Andreev approximation) of the Bogoliubov-de Gennes (or wave function) formulation of the theory of weakly coupled superconductors. The method is applicable to any pure bulk superconductor described by a pair potential with arbitrary spatial dependence, in the presence of supercurrents and external magnetic field. We find that both the local density of states and the free energy density of an inhomogeneous superconductor can be expressed in terms of the diagonal resolvent of the corresponding Andreev Hamiltonian, resolvent which obeys the so-called Gelfand-Dikii equation. Also, the connection between the well known Eilenberger equation for the quasiclassical Green's function and the less known Gelfand-Dikii equation for the diagonal resolvent of the Andreev Hamiltonian is established. These results are used to construct a general algorithm for calculating the (gauge invariant) gradient expansion of the free energy density of an inhomogeneous superconductor at arbitrary temperatures.Comment: REVTeX, 28 page

Cellular mRNA Activates Transcription Elongation by Displacing 7SK RNA

The positive transcription elongation factor P-TEFb is a pivotal regulator of gene expression in higher cells. Originally identified in Drosophila, attention was drawn to human P-TEFb by the discovery of its role as an essential cofactor for HIV-1 transcription. It is recruited to HIV transcription complexes by the viral transactivator Tat, and to cellular transcription complexes by a plethora of transcription factors. P-TEFb activity is negatively regulated by sequestration in a complex with the HEXIM proteins and 7SK RNA. The mechanism of P-TEFb release from the inhibitory complex is not known. We report that P-TEFb-dependent transcription from the HIV promoter can be stimulated by the mRNA encoding HIC, the human I-mfa domain-containing protein. The 3′-untranslated region of HIC mRNA is necessary and sufficient for this action. It forms complexes with P-TEFb and displaces 7SK RNA from the inhibitory complex in cells and cell extracts. A 314-nucleotide sequence near the 3′ end of HIC mRNA has full activity and contains a predicted structure resembling the 3′-terminal hairpin of 7SK that is critical for P-TEFb binding. This represents the first example of a cellular mRNA that can regulate transcription via P-TEFb. Our findings offer a rationale for 7SK being an RNA transcriptional regulator and suggest a practical means for enhancing gene expression

Rare Copy Number Variants in \u3cem\u3eNRXN1\u3c/em\u3e and \u3cem\u3eCNTN6\u3c/em\u3e Increase Risk for Tourette Syndrome

Tourette syndrome (TS) is a model neuropsychiatric disorder thought to arise from abnormal development and/or maintenance of cortico-striato-thalamo-cortical circuits. TS is highly heritable, but its underlying genetic causes are still elusive, and no genome-wide significant loci have been discovered to date. We analyzed a European ancestry sample of 2,434 TS cases and 4,093 ancestry-matched controls for rare (\u3c 1% frequency) copy-number variants (CNVs) using SNP microarray data. We observed an enrichment of global CNV burden that was prominent for large (\u3e 1 Mb), singleton events (OR = 2.28, 95% CI [1.39–3.79], p = 1.2 × 10−3) and known, pathogenic CNVs (OR = 3.03 [1.85–5.07], p = 1.5 × 10−5). We also identified two individual, genome-wide significant loci, each conferring a substantial increase in TS risk (NRXN1 deletions, OR = 20.3, 95% CI [2.6–156.2]; CNTN6 duplications, OR = 10.1, 95% CI [2.3–45.4]). Approximately 1% of TS cases carry one of these CNVs, indicating that rare structural variation contributes significantly to the genetic architecture of TS

Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults.

New neurons continue to be generated in the subgranular zone of the dentate gyrus of the adult mammalian hippocampus. This process has been linked to learning and memory, stress and exercise, and is thought to be altered in neurological disease. In humans, some studies have suggested that hundreds of new neurons are added to the adult dentate gyrus every day, whereas other studies find many fewer putative new neurons. Despite these discrepancies, it is generally believed that the adult human hippocampus continues to generate new neurons. Here we show that a defined population of progenitor cells does not coalesce in the subgranular zone during human fetal or postnatal development. We also find that the number of proliferating progenitors and young neurons in the dentate gyrus declines sharply during the first year of life and only a few isolated young neurons are observed by 7 and 13 years of age. In adult patients with epilepsy and healthy adults (18-77 years; n = 17 post-mortem samples from controls; n = 12 surgical resection samples from patients with epilepsy), young neurons were not detected in the dentate gyrus. In the monkey (Macaca mulatta) hippocampus, proliferation of neurons in the subgranular zone was found in early postnatal life, but this diminished during juvenile development as neurogenesis decreased. We conclude that recruitment of young neurons to the primate hippocampus decreases rapidly during the first years of life, and that neurogenesis in the dentate gyrus does not continue, or is extremely rare, in adult humans. The early decline in hippocampal neurogenesis raises questions about how the function of the dentate gyrus differs between humans and other species in which adult hippocampal neurogenesis is preserved