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A pyrrolidine-based small-molecule inhibitor competes with H3K27me3 for binding to EED leading to inactivation of PRC2 and global reduction in H3K27me3 levels. Polycomb repressive complex 2 (PRC2) is a regulator of epigenetic states required for development and homeostasis. PRC2 trimethylates histone H3 at lysine 27 (H3K27me3), which leads to gene silencing, and is dysregulated in many cancers. The embryonic ectoderm development (EED) protein is an essential subunit of PRC2 that has both a scaffolding function and an H3K27me3-binding function. Here we report the identification of A-395, a potent antagonist of the H3K27me3 binding functions of EED. Structural studies demonstrate that A-395 binds to EED in the H3K27me3-binding pocket, thereby preventing allosteric activation of the catalytic activity of PRC2. Phenotypic effects observed in vitro and in vivo are similar to those of known PRC2 enzymatic inhibitors; however, A-395 retains potent activity against cell lines resistant to the catalytic inhibitors. A-395 represents a first-in-class antagonist of PRC2 protein–protein interactions (PPI) for use as a chemical probe to investigate the roles of EED-containing protein complexes.

Nat. Chem. Biol. 13, 389–395 (2017); published online 30 January 2017; corrected after print 14 June 2017 In the version of this article initially published, the keys for the graphs in Figure 5b–e incorrectly stated GDK126 instead of GSK126. The error has been corrected in the HTML and PDF versions of the article.

The mechanisms explaining excess morbidity and mortality in respiratory infections among males are poorly understood. Innate immune responses are critical in protection against respiratory virus infections. We hypothesised that innate immune responses to respiratory viruses may be deficient in males. We stimulated peripheral blood mononuclear cells from 345 participants at age 16 years in a population-based birth cohort with three live respiratory viruses (rhinoviruses A16 and A1, and respiratory syncytial virus) and two viral mimics (R848 and CpG-A, to mimic responses to SARS-CoV-2) and investigated sex differences in interferon (IFN) responses. IFN-α responses to all viruses and stimuli were 1.34–2.06-fold lower in males than females ( P  = 0.018 −  < 0.001). IFN-β, IFN-γ and IFN-induced chemokines were also deficient in males across all stimuli/viruses. Healthcare records revealed 12.1% of males and 6.6% of females were hospitalized with respiratory infections in infancy ( P  = 0.017). In conclusion, impaired innate anti-viral immunity in males likely results in high male morbidity and mortality from respiratory virus infections.

Patterns of human immune responses to viruses and bacteria and how this impacts risk of infections or onset/exacerbation of chronic respiratory diseases are poorly understood. In a population-based birth cohort, we measured peripheral blood mononuclear cell responses (28 cytokines) to respiratory viruses and bacteria, Toll-like receptor ligands and phytohemagglutinin, in 307 children. Cytokine responses were highly variable with > 1000-fold differences between children. Machine learning revealed clear distinction between virus-associated and bacteria-associated stimuli. Cytokines clustered into three functional groups (anti-viral, pro-inflammatory and T-cell derived). To investigate mechanisms potentially explaining such variable responses, we investigated cytokine Quantitative Trait Loci (cQTLs) of IL-6 responses to bacteria and identified nine (eight novel) loci. Our integrative approach describing stimuli, cytokines and children as variables revealed robust immunologically and microbiologically plausible clustering, providing a framework for a greater understanding of host-responses to infection, including novel genetic associations with respiratory disease.

As compared with placebo, carvedilol reduced the risk of death by 35 percent and the combined risk of death or hospitalization by 24 percent. Beta-blocking agents have been shown to reduce the risk of hospitalization and death in patients with mild-to-moderate heart failure, 1 – 4 but little is known about the efficacy or safety of these agents in severe heart failure. Earlier large-scale studies with bisoprolol, carvedilol, and metoprolol enrolled primarily patients with New York Heart Association class II or III symptoms, and thus they did not provide meaningful information about the effects of these drugs in patients who have symptoms at rest or on minimal exertion. Only one large-scale study of beta-blockade (with bucindolol) focused on patients with severe heart failure; it did not . . .

The leakage of quantum information out of the two computational states of a qubit into other energy states represents a major challenge for quantum error correction. During the operation of an error-corrected algorithm, leakage builds over time and spreads through multi-qubit interactions. This leads to correlated errors that degrade the exponential suppression of the logical error with scale, thus challenging the feasibility of quantum error correction as a path towards fault-tolerant quantum computation. Here, we demonstrate a distance-3 surface code and distance-21 bit-flip code on a quantum processor for which leakage is removed from all qubits in each cycle. This shortens the lifetime of leakage and curtails its ability to spread and induce correlated errors. We report a tenfold reduction in the steady-state leakage population of the data qubits encoding the logical state and an average leakage population of less than 1 × 10−3 throughout the entire device. Our leakage removal process efficiently returns the system back to the computational basis. Adding it to a code circuit would prevent leakage from inducing correlated error across cycles. With this demonstration that leakage can be contained, we have resolved a key challenge for practical quantum error correction at scale.Physical realizations of qubits are often vulnerable to leakage errors, where the system ends up outside the basis used to store quantum information. A leakage removal protocol can suppress the impact of leakage on quantum error-correcting codes.

Immunophenotypes of antiviral responses, and their relationship with asthma, allergy, and lower respiratory tract infections, are poorly understood. We characterized multiple cytokine responses of peripheral blood mononuclear cells to rhinovirus stimulation, and their relationship with clinical outcomes. In a population-based birth cohort, we measured 28 cytokines after stimulation with rhinovirus-16 in 307 children aged 11 years. We used machine learning to identify patterns of cytokine responses, and related these patterns to clinical outcomes, using longitudinal models. We also ascertained phytohemagglutinin-induced T-helper cell type 2 (Th2)-cytokine responses (PHA-Th2). We identified six clusters of children based on their rhinovirus-16 responses, which were differentiated by the expression of four cytokine/chemokine groups: interferon-related (IFN), proinflammatory (Inflam), Th2-chemokine (Th2-chem), and regulatory (Reg). Clusters differed in their clinical characteristics. Children with an IFN Inflam Th2-chem Reg rhinovirus-16-induced pattern had a PHA-Th2 response, and a very low asthma risk (odds ratio [OR], 0.08; 95% confidence interval [CI], 0.01-0.81; P = 0.03). Two clusters had a high risk of asthma and allergic sensitization, but with different trajectories from infancy to adolescence. The IFN Inflam Th2-chem Reg cluster exhibited a PHA-Th2 response and was associated with early-onset asthma and sensitization, and the highest risk of asthma exacerbations (OR, 1.37; 95% CI, 1.07-1.76; P = 0.014) and lower respiratory tract infection hospitalizations (OR, 2.40; 95% CI, 1.26-4.58; P = 0.008) throughout childhood. In contrast, the IFN Inflam Th2-chem Reg cluster with a rhinovirus-16-cytokine pattern was characterized by a PHA-Th2 response, and a low prevalence of asthma/sensitization in infancy that increased sharply to become the highest among all clusters by adolescence (but with a low risk of asthma exacerbations). Early-onset troublesome asthma with early-life sensitization, later-onset milder allergic asthma, and disease protection are each associated with different patterns of rhinovirus-induced immune responses.

To identify the molecular cause in five unrelated families with a distinct autosomal dominant ocular systemic disorder we called ROSAH syndrome due to clinical features of retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache. Independent discovery exome and genome sequencing in families 1, 2, and 3, and confirmation in families 4 and 5. Expression of wild-type messenger RNA and protein in human and mouse tissues and cell lines. Ciliary assays in fibroblasts from affected and unaffected family members. We found the heterozygous missense variant in the ɑ-kinase gene, ALPK1, (c.710C>T, [p.Thr237Met]), segregated with disease in all five families. All patients shared the ROSAH phenotype with additional low-grade ocular inflammation, pancytopenia, recurrent infections, and mild renal impairment in some. ALPK1 was notably expressed in retina, retinal pigment epithelium, and optic nerve, with immunofluorescence indicating localization to the basal body of the connecting cilium of the photoreceptors, and presence in the sweat glands. Immunocytofluorescence revealed expression at the centrioles and spindle poles during metaphase, and at the base of the primary cilium. Affected family member fibroblasts demonstrated defective ciliogenesis. Heterozygosity for ALPK1, p.Thr237Met leads to ROSAH syndrome, an autosomal dominant ocular systemic disorder.

Although lower-extremity disease (LED), which includes lower-extremity peripheral arterial disease (PAD) and peripheral neuropathy (PN), is disabling and costly, no nationally representative estimates of its prevalence exist. The aim of this study was to examine the prevalence of lower-extremity PAD, PN, and overall LED in the overall U.S. population and among those with and without diagnosed diabetes. The analysis consisted of data for 2873 men and women aged >or=40 years, including 419 with diagnosed diabetes, from the 1999-2000 National Health and Nutrition Examination Survey. The main outcome measures consisted of the prevalence of lower-extremity PAD (defined as ankle-brachial index <0.9), PN (defined as >or=1 insensate area based on monofilament testing), and of any LED (defined as either PAD, PN, or history of foot ulcer or lower-extremity amputations). Of the U.S. population aged >or=40 years, 4.5% (95% CI 3.4-5.6) have lower-extremity PAD, 14.8% (12.8-16.8) have PN, and 18.7% (15.9-21.4) have any LED. Prevalence of PAD, PN, and overall LED increases steeply with age and is higher (P < 0.05) in non-Hispanic blacks and Mexican Americans than non-Hispanic whites. The prevalence of LEDs is approximately twice as high for individuals with diagnosed diabetes (PAD 9.5% [5.5-13.4]; PN 28.5% [22.0-35.1]; any LED 30.2% [22.1-38.3]) as the overall population. LED is common in the U.S. and twice as high among individuals with diagnosed diabetes. These conditions disproportionately affect the elderly, non-Hispanic blacks, and Mexican Americans.

Vaccine protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection wanes over time, requiring updated boosters. In a phase 2, open-label, randomized clinical trial with sequentially enrolled stages at 22 US sites, we assessed safety and immunogenicity of a second boost with monovalent or bivalent variant vaccines from mRNA and protein-based platforms targeting wild-type, Beta, Delta and Omicron BA.1 spike antigens. The primary outcome was pseudovirus neutralization titers at 50% inhibitory dilution (ID 50 titers) with 95% confidence intervals against different SARS-CoV-2 strains. The secondary outcome assessed safety by solicited local and systemic adverse events (AEs), unsolicited AEs, serious AEs and AEs of special interest. Boosting with prototype/wild-type vaccines produced numerically lower ID 50 titers than any variant-containing vaccine against all variants. Conversely, boosting with a variant vaccine excluding prototype was not associated with decreased neutralization against D614G. Omicron BA.1 or Beta monovalent vaccines were nearly equivalent to Omicron BA.1 + prototype or Beta + prototype bivalent vaccines for neutralization of Beta, Omicron BA.1 and Omicron BA.4/5, although they were lower for contemporaneous Omicron subvariants. Safety was similar across arms and stages and comparable to previous reports. Our study shows that updated vaccines targeting Beta or Omicron BA.1 provide broadly crossprotective neutralizing antibody responses against diverse SARS-CoV-2 variants without sacrificing immunity to the ancestral strain. ClinicalTrials.gov registration: NCT05289037 . Analysis of antibody responses to COVID-19 vaccines encoding variant-specific spike, with or without ancestral spike, suggests no loss of neutralization of the ancestral virus with variant-only vaccines, which may simplify future vaccine updates.