The rockefeller university

SARS-CoV-2, the causative agent of COVID-19, has been responsible for over 42 million infections and 1 million deaths since its emergence in December 2019. There are few therapeutic options and no approved vaccines. Here, we examine the properties of highly potent human monoclonal antibodies (hu-mAbs) in a Syrian hamster model of SARS-CoV-2 and in a mouse-adapted model of SARS-CoV-2 infection (SARS-CoV-2 MA). Antibody combinations were effective for prevention and in therapy when administered early. However, in vitro antibody neutralization potency did not uniformly correlate with in vivo protection, and some hu-mAbs were more protective in combination in vivo. Analysis of antibody Fc regions revealed that binding to activating Fc receptors contributes to optimal protection against SARS-CoV-2 MA. The data indicate that intact effector function can affect hu-mAb protective activity and that in vivo testing is required to establish optimal hu-mAb combinations for COVID-19 prevention.

Sex hormones alter the organization of the brain during early development and coordinate various behaviors throughout life. In zebra finches, song learning is limited to males, with the associated song learning brain pathways only maturing in males and atrophying in females. While this atrophy can be prevented by treating females with exogenous estrogen during early post-hatch development, the requirement of estrogen during normal male song system development is uncertain. For the first time in songbirds, we administered exemestane, a potent third generation estrogen synthesis inhibitor, from the day of hatching until adulthood in order to reassess the role of estrogen in song circuit development. We examined the behavior, brain anatomy, and transcriptomes of individual song nuclei in these pharmacologically manipulated animals. We found that males with long-term exemestane treatment had diminished male-specific plumage and impaired song learning, but minimal effect on song nuclei sizes and their specialized transcriptome. Consistent with prior findings, females with long-term estrogen treatment retained a functional song system with song nuclei that had specialized gene expression similar, but not identical to males. We also observed that different song nuclei responded to estrogen manipulation differently, with Area X in the striatum being the most altered by estrogen modulation. These findings support the hypothesis that song learning is an ancestral trait in both sexes that was subsequently suppressed in females of some species and that estrogen has come to play a critical role in modulating this suppression as well as refinement of song learning.

BACKGROUND: Dupilumab has demonstrated efficacy with acceptable safety in clinical trials in patients with moderate to severe atopic dermatitis (AD). OBJECTIVE: To assess dupilumab's impact on asthma and sinonasal conditions in adult patients with moderate to severe AD in four randomized, double-blinded, placebo-controlled trials. METHODS: In LIBERTY AD SOLO 1 (NCT02277743), SOLO 2 (NCT02755649), CHRONOS (NCT02260986), and CAFE (NCT02755649), patients received placebo, dupilumab 300 mg every 2 weeks (q2w), or dupilumab 300 mg weekly (qw). In CHRONOS and CAFE, patients received concomitant topical corticosteroids. This post hoc analysis assessed Asthma Control Questionnaire-5 (ACQ-5) scores in patients with asthma, Sino-Nasal Outcome Test-22 (SNOT-22) scores in patients with sinonasal conditions, and AD signs and symptoms in all patients. RESULTS: Of the 2444 patients, 463 had asthma with baseline ACQ-5 >= 0.5 (19%); 1171 had sinonasal conditions (48%); and 311 had both (13%). At week 16, ACQ-5 scores (least squares mean change from baseline [standard error]) improved by 0.27 (0.07), 0.59 (0.08), and 0.56 (0.07) in placebo-, q2w-, and qw-treated patients with asthma, respectively, whereas SNOT-22 scores improved by 5.1 (0.8), 9.9 (0.9), and 10.8 (0.8) in patients with sinonasal conditions (P <.01 for all dupilumab vs placebo). Improvements in ACQ-5 and SNOT-22 were also seen in patients with both conditions. Dupilumab also significantly improved AD signs and symptoms among all subgroups. CONCLUSIONS: In this first analysis of patients with comorbid moderate to severe AD, asthma, and/or chronic sinonasal conditions, dupilumab improved all three diseases in a clinically meaningful and statistically significant manner (vs placebo), based on validated outcome measures. (C) 2021 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology.

Objectives: Methicillin-resistantStaphylococcus aureus (MRSA) remains a major human pathogen. MRSA decolonisation strategies frequently combine chlorhexidine baths and mupirocin nasal ointment. Although MRSA remains widespread in Portuguese hospitals, information regarding resistance to biocides and mupirocin is scarce. We evaluated the prevalence of biocide resistance genes and chlorhexidine and mupirocin non-susceptibility in a representative and well-characterised collection of MRSA isolated in Portuguese hospitals during a 31-year period (1985-2016). Methods: Prevalence of five biocide resistance genes (lmrS, mepA, sepA, qacand smr) was determined by PCR. Antibiotic susceptibility was assessed by disk diffusion and by MIC determination using broth microdilution (chlorhexidine) and Etest (mupirocin). Results: Chromosomal genessepA and mepA were detected in all isolates, while lmrS was found in 87.1%. The prevalence of plasmid-borne genes was significant for qac(22.4%), associated with the Iberian (ST247-I/IA) clone (P < 0.0001), and low for smr (1.0%) detected among isolates belonging to the ST239-III/ IIIvariant clone. Chlorhexidine non-susceptibility (MIC > 4 mg/L) was observed in two isolates belonging to the EMRSA-15 clone (ST22-IV). Non-susceptibility to mupirocin (MIC > 1 mg/L) was significant (15.4%; n = 31) and mainly found among isolates of the EMRSA-15 clone (P < 0.0001; n = 29). One isolate presented low-level mupirocin resistance (MIC = 32 mg/L), and two missense mutations N213D (A637G) and V588F (G1762T) were identified in the ileS gene. Conclusion: Concerningly, we detected a high prevalence of biocide resistance genes and an association of mupirocin and chlorhexidine non-susceptibility with the dominant EMRSA-15 clone in Portuguese hospitals. (c) 2021 The Authors. Published by Elsevier Ltd on behalf of International Society for Antimicrobial Chemotherapy. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/).

We study the noncommutativity of different orders of zero energy-momentum limit pertaining to the axial chemical potential in the chiral magnetic effect. While this noncommutativity issue originates from the pinching singularity at one-loop order, it cannot be removed by introducing a damping term to the fermion propagators. The physical reason is that modifying the propagator alone would violate the axial-vector Ward identity and as a result a modification of the longitudinal component of the axial-vector vertex is required, which contributes to chiral magnetic effect (CME). The pinching singularity with free fermion propagators was then taken over by the singularity stemming from the dressed axial-vector vertex. We show this mechanism by a concrete example. Moreover, we proved, in general, the vanishing CME in the limit order that the static limit was taken prior to the homogeneous limit in the light of Coleman-Hill theorem for a static external magnetic field. For the opposite limit that the homogeneous limit is taken first, we show that the nonvanishing CME was a consequence of the nonrenormalization of chiral anomaly for an arbitrary external magnetic field.

Analysis of single-cell measurements of bacterial growth and division often relied on testing preconceived models of cell size control mechanisms. Such an approach could limit the scope of data analysis and prevent us from uncovering new information. Here, we take an "agnostic'' approach by applying regression methods to multiple simultaneously measured cellular variables, which allow us to infer dependencies among those variables from their apparent correlations. Besides previously observed correlations attributed to particular cell size control mechanisms, we identify dependencies that point to potentially new mechanisms. In particular, cells born smaller than their sisters tend to grow faster and make up for the size difference acquired during division. We also find that sister cells are correlated beyond what single-cell, size-control models predict. These trends are consistently found in repeat experiments, although the dependencies vary quantitatively. Such variation highlights the sensitivity of cell growth to environmental variations and the limitation of currently used experimental setups.

Cryo-EM structures of the enzyme complexes catalyzing the rate-limiting step in sphingolipid synthesis reveal mechanisms of substrate recognition and modulation by regulatory subunits. Sphingolipids are essential lipids in eukaryotic membranes. In humans, the first and rate-limiting step of sphingolipid synthesis is catalyzed by the serine palmitoyltransferase holocomplex, which consists of catalytic components (SPTLC1 and SPTLC2) and regulatory components (ssSPTa and ORMDL3). However, the assembly, substrate processing and regulation of the complex are unclear. Here, we present 8 cryo-electron microscopy structures of the human serine palmitoyltransferase holocomplex in various functional states at resolutions of 2.6-3.4 angstrom. The structures reveal not only how catalytic components recognize the substrate, but also how regulatory components modulate the substrate-binding tunnel to control enzyme activity: ssSPTa engages SPTLC2 and shapes the tunnel to determine substrate specificity. ORMDL3 blocks the tunnel and competes with substrate binding through its amino terminus. These findings provide mechanistic insights into sphingolipid biogenesis governed by the serine palmitoyltransferase complex.

Olivieri, Walker, Karamafrooz et al. show that the fusion of the dynamic J-domain to PKA-C (PKA-CDNAJB1) disrupts the internal allosteric network, attenuating the nucleotide/PKI binding cooperativity. This study suggests that the reduced allosteric cooperativity may contribute to the pathology that PKA-CDNAJB1 drives. An aberrant fusion of the DNAJB1 and PRKACA genes generates a chimeric protein kinase (PKA-C-DNAJB1) in which the J-domain of the heat shock protein 40 is fused to the catalytic alpha subunit of cAMP-dependent protein kinase A (PKA-C). Deceivingly, this chimeric construct appears to be fully functional, as it phosphorylates canonical substrates, forms holoenzymes, responds to cAMP activation, and recognizes the endogenous inhibitor PKI. Nonetheless, PKA-C-DNAJB1 has been recognized as the primary driver of fibrolamellar hepatocellular carcinoma and is implicated in other neoplasms for which the molecular mechanisms remain elusive. Here we determined the chimera's allosteric response to nucleotide and pseudo-substrate binding. We found that the fusion of the dynamic J-domain to PKA-C disrupts the internal allosteric network, causing dramatic attenuation of the nucleotide/PKI binding cooperativity. Our findings suggest that the reduced allosteric cooperativity exhibited by PKA-C-DNAJB1 alters specific recognitions and interactions between substrates and regulatory partners contributing to dysregulation.

Groucho-related genes (GRGs) are transcriptional co-repressors that are crucial for many developmental processes. Several essential pancreatic transcription factors are capable of interacting with GRGs; however, the in vivo role of GRG-mediated transcriptional repression in pancreas development is still not well understood. In this study, we used complex mouse genetics and transcriptomic analyses to determine that GRG3 is essential for beta cell development, and in the absence of Grg3 there is compensatory upregulation of Grg4. Grg3/4 doublemutant mice have severe dysregulation of the pancreas gene program with ectopic expression of canonical liver genes and Foxa1, a master regulator of the liver program. Neurod1, an essential beta cell transcription factor and predicted target of Foxa1, becomes downregulated in Grg3/4 mutants, resulting in reduced beta cell proliferation, hyperglycemia, and early lethality. These findings uncover novel functions of GRG-mediated repression during pancreas development.

The intestine is a site of direct encounter with the external environment and must consequently balance barrier defense with nutrient uptake. To investigate how nutrient uptake is regulated in the small intestine, we tested the effect of diets with different macronutrient compositions on epithelial gene expression. We found that enzymes and transporters required for carbohydrate digestion and absorption were regulated by carbohydrate availability. The "on-demand" induction of this machinery required gamma delta T cells, which regulated this program through the suppression of interleukin-22 production by type 3 innate lymphoid cells. Nutrient availability altered the tissue localization and transcriptome of gamma delta T cells. Additionally, transcriptional responses to diet involved cellular remodeling of the epithelial compartment. Thus, this work identifies a role for gamma delta T cells in nutrient sensing.