Human neutralizing antibodies against SARS-CoV-2 require intact Fc effector functions for optimal therapeutic protection.

SARS-CoV-2 has caused the global COVID-19 pandemic. Although passively delivered neutralizing antibodies against SARS-CoV-2 show promise in clinical trials, their mechanism of action in vivo is incompletely understood. Here, we define correlates of protection of neutralizing human monoclonal antibodies (mAbs) in SARS-CoV-2-infected animals. Whereas Fc effector functions are dispensable when representative neutralizing mAbs are administered as prophylaxis, they are required for optimal protection as therapy. When given after infection, intact mAbs reduce SARS-CoV-2 burden and lung disease in mice and hamsters better than loss-of-function Fc variant mAbs. Fc engagement of neutralizing antibodies mitigates inflammation and improves respiratory mechanics, and transcriptional profiling suggests these phenotypes are associated with diminished innate immune signaling and preserved tissue repair. Immune cell depletions establish that neutralizing mAbs require monocytes and CD8+ T cells for optimal clinical and virological benefit. Thus, potently neutralizing mAbs utilize Fc effector functions during therapy to mitigate lung infection and disease.

SARS-CoV-2 infection of human ACE2-transgenic mice causes severe lung inflammation and impaired function.

Although animal models have been evaluated for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, none have fully recapitulated the lung disease phenotypes seen in humans who have been hospitalized. Here, we evaluate transgenic mice expressing the human angiotensin I-converting enzyme 2 (ACE2) receptor driven by the cytokeratin-18 (K18) gene promoter (K18-hACE2) as a model of SARS-CoV-2 infection. Intranasal inoculation of SARS-CoV-2 in K18-hACE2 mice results in high levels of viral infection in lungs, with spread to other organs. A decline in pulmonary function occurs 4 days after peak viral titer and correlates with infiltration of monocytes, neutrophils and activated T cells. SARS-CoV-2-infected lung tissues show a massively upregulated innate immune response with signatures of nuclear factor-κB-dependent, type I and II interferon signaling, and leukocyte activation pathways. Thus, the K18-hACE2 model of SARS-CoV-2 infection shares many features of severe COVID-19 infection and can be used to define the basis of lung disease and test immune and antiviral-based countermeasures.

Publisher Correction: SARS-CoV-2 infection of human ACE2-transgenic mice causes severe lung inflammation and impaired function.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

PARP9-DTX3L ubiquitin ligase targets host histone H2BJ and viral 3C protease to enhance interferon signaling and control viral infection.

Enhancing the response to interferon could offer an immunological advantage to the host. In support of this concept, we used a modified form of the transcription factor STAT1 to achieve hyper-responsiveness to interferon without toxicity and markedly improve antiviral function in transgenic mice and transduced human cells. We found that the improvement depended on expression of a PARP9-DTX3L complex with distinct domains for interaction with STAT1 and for activity as an E3 ubiquitin ligase that acted on host histone H2BJ to promote interferon-stimulated gene expression and on viral 3C proteases to degrade these proteases via the immunoproteasome. Thus, PARP9-DTX3L acted on host and pathogen to achieve a double layer of immunity within a safe reserve in the interferon signaling pathway.

Organocatalytic enantioselective construction of Si-stereocenters: recent advances and perspectives.

Silicon-stereogenic chiral organosilanes have found increasing applications in synthetic chemistry, medicinal chemistry, and materials science. In this context, various asymmetric catalytic methods have been established for the diverse synthesis of silicon-stereogenic silanes. In particular, asymmetric organocatalysis is emerging as an important and complementary synthetic tool for the enantioselective construction of silicon-stereocenters, along with the rapid development of chiral-metal catalyzed protocols. Its advent provides a powerful platform to achieve functionalized silicon-stereogenic organosilanes with structural diversity, and should lead to great development in chiral organosilicon chemistry. In this Tutorial Review, we highlight these latest achievements from two aspects: desymmetrizations of prochiral tetraorganosilanes and dynamic kinetic asymmetric transformations of racemic organosilanes by employing five organocatalytic activation modes. The advantages, limitations and synthetic value of each protocol, as well as the synthetic opportunities still open for further exploration, are also discussed.

25-hydroxycholesterol promotes brain cytokine production and leukocyte infiltration in a mouse model of lipopolysaccharide-induced neuroinflammation.

Neuroinflammation has been implicated in the pathogenesis of several neurologic and psychiatric disorders. Microglia are key drivers of neuroinflammation and, in response to different inflammatory stimuli, overexpress a proinflammatory signature of genes. Among these, Ch25h is a gene overexpressed in brain tissue from Alzheimer's disease as well as various mouse models of neuroinflammation. Ch25h encodes cholesterol 25-hydroxylase, an enzyme upregulated in activated microglia under conditions of neuroinflammation, that hydroxylates cholesterol to form 25-hydroxycholesterol (25HC). 25HC can be further metabolized to 7α,25-dihydroxycholesterol, which is a potent chemoattractant of leukocytes. We have previously shown that 25HC increases the production and secretion of the proinflammatory cytokine, IL-1ß, by primary mouse microglia treated with lipopolysaccharide (LPS). In the present study, wildtype (WT) and Ch25h-knockout (KO) mice were peripherally administered LPS to induce an inflammatory state in the brain. In LPS-treated WT mice, Ch25h expression and 25HC levels increased in the brain relative to vehicle-treated WT mice. Among LPS-treated WT mice, females produced significantly higher levels of 25HC and showed transcriptomic changes reflecting higher levels of cytokine production and leukocyte migration than WT male mice. However, females were similar to males among LPS-treated KO mice. Ch25h-deficiency coincided with decreased microglial activation in response to systemic LPS. Proinflammatory cytokine production and intra-parenchymal infiltration of leukocytes were significantly lower in KO compared to WT mice. Amounts of IL-1ß and IL-6 in the brain strongly correlated with 25HC levels. Our results suggest a proinflammatory role for 25HC in the brain following peripheral administration of LPS.

H-Bond Donor-Directed Switch of Diastereoselectivity in the Enantioselective Intramolecular Aza-Henry Reaction of Ketimines.

We report an H-bond donor controlled diastereoselective switchable intramolecular aza-Henry reaction of ketimines derived from α-ketoesters and 2-(2-nitroethyl)anilines, allowing facile access to chiral tetrahydroquinolines bearing an aza-quaternary carbon stereocenter, which are privileged scaffold for medicinal researches. While newly developed cinchona alkaloid derived phosphoramide-bearing quaternary ammonium salt C2 selectively give cis-adducts in up to 20 : 1 dr and 99 % ee, the corresponding urea-bearing analogue C8 preferentially give trans-adducts in up to 20 : 1 dr and 99 % ee.

Synthesis of carbon quantum dots/porous aromatic frameworks (CQDs/PAF-45) composites and their enhanced photocatalytic performance.

Modification and functionalization of porous aromatic framework (PAF) materials have emerged as crucial research directions in various fields. In this study, we employed a hydrothermal method to synthesize a carbon quantum dots (CQDs) solution. By loading different amounts of CQDs onto the surface of PAF-45 material through ultrasonic and hydrothermal treatments, we successfully formed CQDs/PAF-45 composite materials. The introduction of CQDs effectively transformed the hydrophobic nature of PAF-45 into a hydrophilic material, thereby overcoming the challenge of achieving efficient contact between PAF catalysts and reactants in aqueous solutions. In the photocatalytic degradation experiments of Rhodamine B (RhB), tetracycline, CQDs/PAF-45 composite materials surpassed that of the pristine PAF-45 material. Notably, the 1 wt% CQDs/PAF-45 composite material exhibited the highest photocatalytic activity, with degradation efficiencies for Rhodamine B, tetracycline, and phenol approximately 1.4 times, 1.5 times and 1.5 times higher than those of the PAF-45 material, respectively.

Impact of particulate-matter air pollution on 25-hydroxyvitamin D levels: a mendelian randomisation study.

OBJECTIVES: In observational studies, the 25-hydroxyvitamin D (25(OH)D) level in body has been found to be closely related to particulate matter (PM) air pollution. In this study, we used the two-sample mendelian randomisation (MR) method to investigate and discuss the potential causal relationship and mode of influence. STUDY DESIGN: MR study. METHODS: PM data (PM10, PM2.5-10, PM2.5, PM2.5 absorbance) came from the UK Biobank database, and 25(OH)D data came from European Bioinformatics Institute (EBI) database. The analysis was conducted utilising three prominent methods (inverse-variance-weighted [IVW], MR-Egger, weighted median, weighted mode, and simple mode). The primary emphasis was placed on IVW, accompanied by heterogeneity and horizontal pleiotropy tests. Furthermore, sensitivity analysis was undertaken. RESULTS: The MR analysis revealed a significant association between exposure to PM10 and a decrease in levels of 25(OH)D (odds ratio [OR]: 0.878, 95% confidence interval [CI]: 0.789-0.977). However, no significant relationship was observed between PM2.5 exposure and 25(OH)D (OR: 0.943, 95%CI: 0.858-1.037). Further analysis indicated that the main contributor to the decline in 25(OH)D levels is linked to PM2.5-10 exposure (OR: 0.840, 95%CI: 0.751-0.940) and PM2.5 absorbance (OR: 0.875, 95%CI: 0.824-0.929). No heterogeneity and horizontal pleiotropy existed. CONCLUSIONS: The MR results suggest that PM (PM10, PM2.5-10 and PM2.5 absorbance) exposure lowers vitamin D (VD) levels, but PM2.5 was not found to have a significant effect on VD in humans.

Highly Enantioselective Construction of Multifunctional Silicon-Stereogenic Silacycles by Asymmetric Enamine Catalysis.

We report the first highly enantioselective construction of silicon-stereocenters by asymmetric enamine catalysis. An unprecedented desymmetric intramolecular aldolization of prochiral siladials was thus developed for the facile access of multifunctional silicon-stereogenic silacycles in high to excellent enantioselectivity. With an enal moiety, these adducts could be readily elaborated for the diverse synthesis of silicon-stereogenic compounds, and for late-stage modification.

A complement-microglial axis drives synapse loss during virus-induced memory impairment.

Over 50% of patients who survive neuroinvasive infection with West Nile virus (WNV) exhibit chronic cognitive sequelae. Although thousands of cases of WNV-mediated memory dysfunction accrue annually, the mechanisms responsible for these impairments are unknown. The classical complement cascade, a key component of innate immune pathogen defence, mediates synaptic pruning by microglia during early postnatal development. Here we show that viral infection of adult hippocampal neurons induces complement-mediated elimination of presynaptic terminals in a murine WNV neuroinvasive disease model. Inoculation of WNV-NS5-E218A, a WNV with a mutant NS5(E218A) protein leads to survival rates and cognitive dysfunction that mirror human WNV neuroinvasive disease. WNV-NS5-E218A-recovered mice (recovery defined as survival after acute infection) display impaired spatial learning and persistence of phagocytic microglia without loss of hippocampal neurons or volume. Hippocampi from WNV-NS5-E218A-recovered mice with poor spatial learning show increased expression of genes that drive synaptic remodelling by microglia via complement. C1QA was upregulated and localized to microglia, infected neurons and presynaptic terminals during WNV neuroinvasive disease. Murine and human WNV neuroinvasive disease post-mortem samples exhibit loss of hippocampal CA3 presynaptic terminals, and murine studies revealed microglial engulfment of presynaptic terminals during acute infection and after recovery. Mice with fewer microglia (Il34(-/-) mice with a deficiency in IL-34 production) or deficiency in complement C3 or C3a receptor were protected from WNV-induced synaptic terminal loss. Our study provides a new murine model of WNV-induced spatial memory impairment, and identifies a potential mechanism underlying neurocognitive impairment in patients recovering from WNV neuroinvasive disease.

The Bifunctional Silyl Reagent Me2 (CH2 Cl)SiCF3 Enables Highly Enantioselective Ketone Trifluoromethylation and Related Tandem Processes.

We report the development of bifunctional trifluoromethylsilyl reagents for selective trifluoromethylation. The newly developed reagent, Me2 (CH2 Cl)SiCF3 , allows highly enantioselective trifluoromethylations of ketones with broad scope. Notably, by taking advantage of the chloromethyl group, a tandem synthesis of chiral trifluoromethylated oxasilacyclopentanes is developed, paving way to α-CF3 tertiary alcohols with vicinal tertiary or quaternary stereocenters. Theoretical studies revealed the important role of nonclassical C-H⋅⋅⋅F-C interactions in stabilizing the transition state, and that the presence of the chlorine atom enhances such interactions for better enantiofacial control.

Construction of gem-Difluoroenol Esters through Catalytic O-Selective Addition of Difluoroenoxysilanes to Ketenes.

The O-site reactivity of difluoroenoxysilanes is disclosed for the first time, which enabled the direct construction of versatile gem-difluoroalkenes through an unprecedented highly efficient addition reaction with ketenes. A series of valuable gem-difluoroenol esters were achieved in good to excellent yields. The synthetic versatility of this protocol is further demonstrated by the gram-scale synthesis and good functional group tolerance.

Catalyst-Free and Solvent-Controlled Divergent Synthesis of Difluoromethylene-Containing S-Heterocycles.

An unprecedented catalyst-free reaction of benzo[b]thiophene-2,3-diones with difluoroenoxysilanes has been developed using either MeOH or H2O as the solvent, which constitutes a facile and efficient protocol for the solvent-controlled divergent synthesis of five- and seven-membered S-heterocycles featuring a gem-difluoromethylene group. A gram-scale synthesis and the diversification of the product transformations to other difluorinated S-heterocycles further highlight its utility.

Host Gene Expression in Nose and Blood for the Diagnosis of Viral Respiratory Infection.

BACKGROUND: Recently there has been a growing interest in the potential for host transcriptomic analysis to augment the diagnosis of infectious diseases. METHODS: We compared nasal and blood samples for evaluation of the host transcriptomic response in children with acute respiratory syncytial virus (RSV) infection, symptomatic non-RSV respiratory virus infection, asymptomatic rhinovirus infection, and virus-negative asymptomatic controls. We used nested leave-one-pair-out cross-validation and supervised principal components analysis to define small sets of genes whose expression patterns accurately classified subjects. We validated gene classification scores using an external data set. RESULTS: Despite lower quality of nasal RNA, the number of genes detected by microarray in each sample type was equivalent. Nasal gene expression signal derived mainly from epithelial cells but also included a variable leukocyte contribution. The number of genes with increased expression in virus-infected children was comparable in nasal and blood samples, while nasal samples also had decreased expression of many genes associated with ciliary function and assembly. Nasal gene expression signatures were as good or better for discriminating between symptomatic, asymptomatic, and uninfected children. CONCLSUSIONS: Our results support the use of nasal samples to augment pathogen-based tests to diagnose viral respiratory infection.

Traceless Electrophilic Amination for the Synthesis of Unprotected Cyclic ß-Amino Acids.

Electrophilic aminations involve an umpolung of a nitrogen atom, providing an alternate, distinctive synthetic strategy. The recent advent of various designed O-substituted hydroxylamines has significantly advanced this research field. An underappreciated issue is atom economy of the transformations: The necessary activating group on the oxygen atom is left in coproduced waste. Herein, we describe Rh-catalyzed electrophilic amination of substituted isoxazolidin-5-ones for the synthesis of unprotected, cyclic ß-amino acids featuring either benzo-fused or spirocyclic scaffolds. Using the cyclic hydroxylamines allows for retaining both nitrogen and oxygen functionalities in the product. The traceless, redox neutral process proceeds on a gram scale with as little as 0.1 mol % catalyst loading. In contrast to related electrophilic aminations in the literature, a series of mechanistic experiments suggests a unique pathway involving spirocyclization, followed by the skeletal rearrangement. The insights provided herein shed light on a nuanced reactivity of the active species, Rh-nitrenoid generated from the activated hydroxylamine, and extend the knowledge on electrophilic aromatic substitutions.

Mobilization of allogeneic peripheral blood stem cell donors with intravenous plerixafor mobilizes a unique graft.

A single subcutaneous (SC) injection of plerixafor results in rapid mobilization of hematopoietic progenitors, but fails to mobilize 33% of normal allogeneic sibling donors in 1 apheresis. We hypothesized that changing the route of administration of plerixafor from SC to IV may overcome the low stem cell yields and allow collection in 1 day. A phase 1 trial followed by a phase 2 efficacy trial was conducted in allogeneic sibling donors. The optimal dose of IV plerixafor was determined to be 0.32 mg/kg. The primary outcome of reducing the failure to collect ≥2 × 106 CD34+/kg recipient weight in 1 apheresis collection to ≤10% was not reached. The failure rate was 34%. Studies evaluating the stem cell phenotype and gene expression revealed a novel plasmacytoid dendritic cell precursor preferentially mobilized by plerixafor with high interferon-α producing ability. The observed cytomegalovirus (CMV) viremia rate for patients at risk was low (15%), as were the rates of acute grade 2-4 graft-versus-host disease (GVHD) (21%). Day 100 treatment related mortality was low (3%). In conclusion, plerixafor results in rapid stem cell mobilization regardless of route of administration and resulted in novel cellular composition of the graft and favorable recipient outcomes. These trials were registered at clinicaltrials.gov as #NCT00241358 and #NCT00914849.

HClO4 catalysed aldol-type reaction of fluorinated silyl enol ethers with acetals or ketals toward fluoroalkyl ethers.

A highly efficient metal-free aldol-type reaction of various acetals or ketals with fluorinated silyl enol ethers catalysed by less than 1 mol% HClO4 (70 wt%, aq.) is developed. This provides expedient access to a wide array of valuable fluoroalkyl ethers featuring a ketone carbonyl functionality in good to excellent yields (40 examples). Furthermore, the thus obtained adducts are readily elaborated into other fluorine-containing alkyl ethers with a rich structure.

PMS1T, producing phased small-interfering RNAs, regulates photoperiod-sensitive male sterility in rice.

Phased small-interfering RNAs (phasiRNAs) are a special class of small RNAs, which are generated in 21- or 24-nt intervals from transcripts of precursor RNAs. Although phasiRNAs have been found in a range of organisms, their biological functions in plants have yet to be uncovered. Here we show that phasiRNAs generated by the photopheriod-sensetive genic male sterility 1 (Pms1) locus were associated with photoperiod-sensitive male sterility (PSMS) in rice, a germplasm that started the two-line hybrid rice breeding. The Pms1 locus encodes a long-noncoding RNA PMS1T that was preferentially expressed in young panicles. PMS1T was targeted by miR2118 to produce 21-nt phasiRNAs that preferentially accumulated in the PSMS line under long-day conditions. A single nucleotide polymorphism in PMS1T nearby the miR2118 recognition site was critical for fertility change, likely leading to differential accumulation of the phasiRNAs. This result suggested possible roles of phasiRNAs in reproductive development of rice, demonstrating the potential importance of this RNA class as regulators in biological processes.

Purification of starch and phosphorus wastewater using core-shell magnetic seeds prepared by sulfated roasting.

Core-shell magnetic seeds with certain adsorption capacity that were prepared by sulfated roasting, served as the core of a magnetic separation technology for purification of starch wastewater. XRD and SEM results indicate that magnetite's surface transformed to be porous α-Fe2O3 structure. Compared with magnetite particles, the specific surface area was significantly improved to be 8.361 from 2.591 m2/g, with little decrease in specific susceptibility. Zeta potential, FT-IR and XPS experiments indicate that both phosphate and starch adsorbed on the surface of the core-shell magnetic seeds by chemical adsorption, which fits well with the Langmuir adsorption model. The porous surface structure of magnetic seeds significantly contributes to the adsorption of phosphate and starch species, which can be efficiently removed to be 1.51 mg/L (phosphate) and 9.51 mg/L (starch) using magnetic separation.