The rockefeller university

Histoplasma capsulatum is an endemic, dimorphic fungus commonly found in areas such as midwestern USA, Mexico, and South America [1]. In Mexico, the estimated incidence of histoplasmosis has ranged from 0.1 to 0.29 cases per 100,000, and it is most frequent in the central and southeastern parts of the country [1]. Humans may be infected with H. capsulatum via inhaling microconidia and mycelial fragments of the organism [2]. Clinical presentation depends on the host immune status and the extent of exposed inoculum [3]. The majority of individuals exposed to H. capsulatum (> 99%) are typically asymptomatic or have self-limiting infections [3]. Disseminated histoplasmosis is rare occurring mostly in acute rather than chronic forms of histoplasma infections [2]. After acute exposure, the rate of dissemination in infected population is low, in about one in 2000 patients, and have been more frequent in immunosuppressed patients with a tenfold higher risk [2]. The most frequent immunocompromise associated with disseminated histoplasmosis in adults is secondary to the human immunodeficiency virus (HIV) infection [1, 3]. On the other side, there are sporadic cases of primary immunodeficiencies (PID) or inborn errors of immunity associated with disseminated histoplasmosis [4] that characteristically have a beginning in childhood, such as chronic granulomatous disease [5] or Mendelian susceptibility to mycobacterial disease (MSMD) [4], and patients with chronic mucocutaneous disease associated with heterozygous STAT1 mutation, gain-of-function mutation (GOF) [6]. We report a case of an adult otherwise healthy with disseminated histoplasmosis and autosomal recessive (AR) complete IL-12Rβ1 deficiency.

Many of the genes disrupted in autism are identified as histone-modifying enzymes and chromatin remodelers, most prominently those that mediate histone methylation/demethylation. However, the role of histone methylation enzymes in the pathophysiology and treatment of autism remains unknown. To address this, we used mouse models of haploinsufficiency of theShank3gene (a highly penetrant monogenic autism risk factor), which exhibits prominent autism-like social deficits. We found that histone methyltransferases EHMT1 and EHMT2, as well as histone lysine 9 dimethylation (specifically catalyzed by EHMT1/2), were selectively increased in the prefrontal cortex (PFC) ofShank3-deficient mice and autistic human postmortem brains. Treatment with the EHMT1/2 inhibitor UNC0642 or knockdown of EHMT1/2 in PFC induced a robust rescue of autism-like social deficits inShank3-deficient mice, and restored NMDAR-mediated synaptic function. Activity-regulated cytoskeleton-associated protein (Arc) was identified as one of the causal factors underlying the rescuing effects of UNC0642 on NMDAR function and social behaviors inShank3-deficient mice. UNC0642 treatment also restored a large set of genes involved in neural signaling in PFC ofShank3-deficient mice. These results suggest that targeting histone methylation enzymes to adjust gene expression and ameliorate synaptic defects could be a potential therapeutic strategy for autism.

In 2001 it was announced that the 3.1 billion base (gigabase, Gb) human genome had been sequenced, but after 13 years of work and US$2.7 billion in cost, it was still considered to be only a draft. The initial assembly was missing over 30% of the genome and was made up of over 100,000 sequence fragments (scaffolds) with an average size of just 81,500 base pairs (bp) (International Human Genome Sequencing Consortium, 2004; Stein, 2004). As technologies improved, the draft human genome assembly has been repeatedly refined and corrected. By the time the genome assembly was published in 2004, the average length of scaffolds had increased to over 38 million bp (megabases, Mb) with only a few hundred gaps in the chromosome‐length scaffolds. However, the duplicated and highly repetitive regions of the human genome remained unresolved due to limitations of short‐read sequencing technology that requires piecing the genome together from billions of shorter sequences. Over the last decade, as highly parallel, much less expensive, short‐ and long‐read sequencing technologies have revolutionized genomic sequencing, thousands of individual human genomes have been sequenced, further refining the human genome assembly and characterizing its diversity. Together these genome sequences have produced a “reference‐quality” human genome assembly that covers 95% of the genome with far fewer and smaller gaps compared to the initial version. Despite this vast improvement, the human genome continues to be updated and refined (v. 39, RefSeq accession GCF_000001405.39).

HIV-1 evolution in the cerebrospinal fluid (CSF) and plasma may result in discordant drug resistance mutations (DRMs) in the compartments. Single-genome amplification (SGA) was used to generate partial HIV-1 polymerase genomes in paired CSF and plasma samples from 12 HIV-1-positive participants in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study who were classified as neurocognitively unimpaired or with various degrees of HIV-associated neurocognitive disorders (HAND). Subjects were viremic on combination antiretroviral therapy (cART). HIV-1 DRMs and phylogenetic characteristics were determined using the Stanford HIVdb program and phylogenetic analyses. Individual DRMs were identified more frequently in plasma than in paired CSF (P = 0.0078). Significant differences in the ratios of DRMs in CSF and plasma were found in 3 individuals with HAND (3/7 = 43%). Two HAND subjects (2/7 = 29%) demonstrated one DRM in CSF not identified in paired plasma. Longitudinal analyses (n = 4) revealed significant temporal differences in the ratios of DRMs in the compartments. Statistically significant differences in the frequency of DRMs in the CSF and plasma are readily found in those on nonsuppressive cART. While compartment-based DRM discordance was largely consistent with increased drug-selective pressures in the plasma, overrepresentation of DRMs in the central nervous system (CNS) can occur. Underlying mechanisms of HAND are complex and multifactorial. The clinical impact of DRM discordance on viral persistence and HAND pathogenesis remains unclear and warrants further investigation in larger, longitudinal cohorts. IMPORTANCE Several antiretroviral agents do not efficiently enter the CNS, and independent evolution of HIV-1 viral variants in the CNS and plasma can occur. We used single-genome amplification (SGA) in cross-sectional and longitudinal analyses to uniquely define both the identity and relative proportions of drug resistance mutations (DRMs) on individual HIV-1 polymerase genomes in the cerebrospinal fluid (CSF) and plasma in individuals with incomplete viral suppression and known neurocognitive status. Statistically significant differences in the ratio of DRMs in the CSF and plasma were readily found in those on nonsuppressive cART, and overrepresentation of DRMs in the CNS can occur. Although questions about the clinical significance of DRM discordance remain, in the quest for viral eradication, it is important to recognize that a significant, dynamic, compartment-based DRM ratio imbalance can exist, as it has the potential to go unnoticed in the setting of standard clinical drug resistance testing.

A 5',7-methylguanosine cap is a quintessential feature of RNA polymerase II-transcribed RNAs, and a textbook aspect of co-transcriptional RNA processing. The cap is bound by the cap-binding complex (CBC), canonically consisting of nuclear cap-binding proteins 1 and 2 (NCBP1/2). Interest in the CBC has recently renewed due to its participation in RNA-fate decisions via interactions with RNA productive factors as well as with adapters of the degradative RNA exosome. A novel cap-binding protein, NCBP3, was recently proposed to form an alternative CBC together with NCBP1, and to interact with the canonical CBC along with the protein SRRT. The theme of post-transcriptional RNA fate, and how it relates to co-transcriptional ribonucleoprotein assembly, is abundant with complicated, ambiguous, and likely incomplete models. In an effort to clarify the compositions of NCBP1-, 2- and 3-related macromolecular assemblies, we have applied an affinity capture-based interactome screen where the experimental design and data processing have been modified to quantitatively identify interactome differences between targets under a range of experimental conditions. This study generated a comprehensive view of NCBP-protein interactions in the ribonucleoprotein context and demonstrates the potential of our approach to benefit the interpretation of complex biological pathways.

Receptor-interacting protein kinase 1 (RIPK1), a regulator of inflammation and cell death, is a potential therapeutic target in immune-mediated inflammatory diseases (IMIDs). The objective of this phase IIa multicenter, randomized, double-blind, placebo-controlled study was to evaluate safety, tolerability pharmacokinetics, pharmacodynamics, and preliminary efficacy of GSK2982772, a RIPK1 inhibitor, in plaque-type psoriasis. Psoriasis patients (N = 65) were randomized to 60 mg twice daily (b.i.d.) or three times daily (t.i.d.), or placebo for 84 days. Most adverse events (AEs) were mild with no severe drug-related AEs reported. Plaque Lesion Severity Sum improved with b.i.d. treatment compared with placebo; interpretation of t.i.d. treatment results was complicated by a high placebo response. Reductions in epidermal thickness and infiltration by CD3+ T cells in the epidermis and dermis were observed compared with placebo. Results support the rationale for additional studies on RIPK1 inhibition in IMIDs.

Cardiac disease remains the leading cause of morbidity and mortality worldwide. The beta(1)-adrenergic receptor (beta(1)-AR) is a major regulator of cardiac functions and is downregulated in the majority of heart failure cases. A key physiological process is the activation of heterotrimeric G-protein Gs by beta(1)-ARs, leading to increased heart rate and contractility. Here, we use cryo-electron microscopy and functional studies to investigate the molecular mechanism by which beta(1)-AR activates Gs. We find that the tilting of alpha 5-helix breaks a hydrogen bond between the sidechain of His373 in the C-terminal alpha 5-helix and the backbone carbonyl of Arg38 in the N-terminal alpha N-helix of Ga-s. Together with the disruption of another interacting network involving Gln59 in the alpha 1-helix, Ala352 in the beta 6-alpha 5 loop, and Thr355 in the alpha 5-helix, these conformational changes might lead to the deformation of the GDP-binding pocket. Our data provide molecular insights into the activation of G-proteins by G-protein-coupled receptors.

A small fraction of HIV-1- infected humans develop broadly neutralizing antibodies (bNAbs) against HIV-1 that protect macaques from simian immunodeficiency HIV chimeric virus (SHIV). Similarly, a small number of macaques infected with SHIVs develop broadly neutralizing serologic activity, but less is known about the nature of simian antibodies. Here, we report on a monoclonal antibody, Ab1485, isolated from a macaque infected with SHIVAD8 that developed broadly neutralizing serologic activity targeting the V3-glycan region of HIV-1 Env. Ab1485 neutralizes 38.1% of HIV-1 isolates in a 42-pseudovirus panel with a geometric mean IC50 of 0.055 mu g/mLI and SHIVAD8 with an IC50 of 0.028 mu g/mLI. Ab1485 binds the V3-glycan epitope in a glycan-dependent manner. A 3.5 angstrom cryo-electron microscopy structure of Ab1485 in complex with a native-like SOSIP Env trimer showed conserved contacts with the N332gp120 glycan and gp120 GDIR peptide motif, but in a distinct Env-binding orientation relative to human V3/N332gp120 glycan-targeting bNAbs. Intravenous infusion of Ab1485 protected macaques from a high dose challenge with SHIVAD8. We conclude that macaques can develop bNAbs against the V3-glycan patch that resemble human V3-glycan bNAbs.