An oral non-covalent non-peptidic inhibitor of SARS-CoV-2 Mpro ameliorates viral replication and pathogenesis in vivo.

Safe, effective, and low-cost oral antiviral therapies are needed to treat those at high risk for developing severe COVID-19. To that end, we performed a high-throughput screen to identify non-peptidic, non-covalent inhibitors of the SARS-CoV-2 main protease (Mpro), an essential enzyme in viral replication. NZ-804 was developed from a screening hit through iterative rounds of structure-guided medicinal chemistry.

Overloading And unpacKing (OAK) - droplet-based combinatorial indexing for ultra-high throughput single-cell multiomic profiling.

Multiomic profiling of single cells by sequencing is a powerful technique for investigating cellular diversity. Existing droplet-based microfluidic methods produce many cell-free droplets, underutilizing bead barcodes and reagents. Combinatorial indexing on microplates is more efficient for barcoding but labor-intensive.

KLF15-Cyp3a11 Axis Regulates Rifampicin-Induced Liver Injury.

Rifampicin (RFP) has demonstrated potent antibacterial effects in the treatment of pulmonary tuberculosis. However, the serious adverse effects on the liver intensively limit the clinical usage of the drug. Deacetylation greatly reduces the toxicity of RFP but also retains its curative activity.

Antithrombotic Treatment for Stroke Prevention in Cervical Artery Dissection: The STOP-CAD Study.

Background: Small, randomized trials of patients with cervical artery dissection showed conflicting results regarding optimal stroke prevention strategies. We aimed to compare outcomes in patients with cervical artery dissection treated with antiplatelets versus anticoagulation.

Methods: This is a multicenter observational retrospective international study (16 countries, 63 sites) that included patients with cervical artery dissection without major trauma.

A 39-Year-Old Man With Refractory Chronic Cough Accompanied by Regurgitation and Belching.

A 39-year-old man who did not smoke was admitted to the hospital with recurrent cough for 1 year, accompanied by sputum expectoration (with a small amount of white phlegm), acid regurgitation, and belching. Nasal symptoms or other cough-related contributing factors were denied. The patient reported that his cough mainly occurred at nighttime and was aggravated in the supine position.

Broadly neutralizing and protective nanobodies against SARS-CoV-2 Omicron subvariants BA.1, BA.2, and BA.4/5 and diverse sarbecoviruses.

As SARS-CoV-2 Omicron and other variants of concern (VOCs) continue spreading worldwide, development of antibodies and vaccines to confer broad and protective activity is a global priority. Here, we report on the identification of a special group of nanobodies from immunized alpaca with potency against diverse VOCs including Omicron subvariants BA.1, BA.

Lineage-mosaic and mutation-patched spike proteins for broad-spectrum COVID-19 vaccine.

SARS-CoV-2 spread in humans results in continuous emergence of new variants, highlighting the need for vaccines with broad-spectrum antigenic coverage. Using inter-lineage chimera and mutation-patch strategies, we engineered a recombinant monomeric spike variant (STFK1628x) that contains key regions and residues across multiple SAR-CoV-2 variants. STFK1628x demonstrated high immunogenicity and mutually complementary antigenicity to its prototypic form (STFK).

Endovascular Treatment Versus Best Medical Management in Acute Basilar Artery Occlusion Strokes: Results From the ATTENTION Multicenter Registry.

Background: The authors compare the effectiveness and safety of endovascular treatment (EVT) versus best medical management (BMM) in strokes attributable to acute basilar artery occlusion (BAO).

Methods: The present analysis was based on the ongoing, prospective, multicenter ATTENTION (Endovascular Treatment for Acute Basilar Artery Occlusion) trial registry in China. Our analytic sample comprised 2134 patients recruited at 48 sites between 2017 and 2021 and included 462 patients who received BMM and 1672 patients who received EVT.

LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-neutralizing monoclonal antibodies (mAbs) can reduce the risk of hospitalization from coronavirus disease 2019 (COVID-19) when administered early. However, SARS-CoV-2 variants of concern (VOCs) have negatively affected therapeutic use of some authorized mAbs. Using a high-throughput B cell screening pipeline, we isolated LY-CoV1404 (bebtelovimab), a highly potent SARS-CoV-2 spike glycoprotein receptor binding domain (RBD)-specific antibody.

Combined Approach to Eptifibatide and Thrombectomy in Acute Ischemic Stroke Because of Large Vessel Occlusion: A Matched-Control Analysis.

Background: In patients undergoing mechanical thrombectomy (MT), adjunctive antithrombotic might improve angiographic reperfusion, reduce the risk of distal emboli and reocclusion but possibly expose patients to a higher intracranial hemorrhage risk. This study evaluated the safety and efficacy of combined MT plus eptifibatide for acute ischemic stroke.

Methods: This was a propensity-matched analysis of data from 2 prospective trials in Chinese populations: the ANGEL-ACT trial (Endovascular Treatment Key Technique and Emergency Workflow Improvement of Acute Ischemic Stroke) in 111 hospitals between November 2017 and March 2019, and the EPOCH trial (Eptifibatide in Endovascular Treatment of Acute Ischemic Stroke) in 15 hospitals between April 2019 and March 2020.

Influence of Cr, Mn, Co and Ni Addition on Crystallization Behavior of AlFe Phase in Al-5Fe Alloys Based on ThermoDynamic Calculations.

Alloying is an effective method to refine coarse grains of an AlFe phase and strengthen Al-Fe alloys. However, the grain refinement mechanism remains unclear in terms of the thermodynamics. Herein, the influence of -element, i.

Joint prediction and time estimation of COVID-19 developing severe symptoms using chest CT scan.

With the rapidly worldwide spread of Coronavirus disease (COVID-19), it is of great importance to conduct early diagnosis of COVID-19 and predict the conversion time that patients possibly convert to the severe stage, for designing effective treatment plans and reducing the clinicians' workloads. In this study, we propose a joint classification and regression method to determine whether the patient would develop severe symptoms in the later time formulated as a classification task, and if yes, the conversion time will be predicted formulated as a classification task. To do this, the proposed method takes into account 1) the weight for each sample to reduce the outliers' influence and explore the problem of imbalance classification, and 2) the weight for each feature via a sparsity regularization term to remove the redundant features of the high-dimensional data and learn the shared information across two tasks, i.

Integrated genomic analysis reveals mutated ELF3 as a potential gallbladder cancer vaccine candidate.

Gallbladder cancer (GBC) is an aggressive gastrointestinal malignancy with no approved targeted therapy. Here, we analyze exomes (n = 160), transcriptomes (n = 115), and low pass whole genomes (n = 146) from 167 gallbladder cancers (GBCs) from patients in Korea, India and Chile. In addition, we also sequence samples from 39 GBC high-risk patients and detect evidence of early cancer-related genomic lesions.

Non-invasive early detection of cancer four years before conventional diagnosis using a blood test.

Early detection has the potential to reduce cancer mortality, but an effective screening test must demonstrate asymptomatic cancer detection years before conventional diagnosis in a longitudinal study. In the Taizhou Longitudinal Study (TZL), 123,115 healthy subjects provided plasma samples for long-term storage and were then monitored for cancer occurrence. Here we report the preliminary results of PanSeer, a noninvasive blood test based on circulating tumor DNA methylation, on TZL plasma samples from 605 asymptomatic individuals, 191 of whom were later diagnosed with stomach, esophageal, colorectal, lung or liver cancer within four years of blood draw.

Quantitative Histogram Analysis on Intracranial Atherosclerotic Plaques: A High-Resolution Magnetic Resonance Imaging Study.

Background And Purpose: Intracranial atherosclerosis is one of the main causes of stroke, and high-resolution magnetic resonance imaging provides useful imaging biomarkers related to the risk of ischemic events. This study aims to evaluate differences in histogram features between culprit and nonculprit intracranial atherosclerosis using high-resolution magnetic resonance imaging.

Methods: Two hundred forty-seven patients with intracranial atherosclerosis who underwent high-resolution magnetic resonance imaging sequentially between January 2015 and December 2016 were recruited.

Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia.

Background: The initial cases of novel coronavirus (2019-nCoV)-infected pneumonia (NCIP) occurred in Wuhan, Hubei Province, China, in December 2019 and January 2020. We analyzed data on the first 425 confirmed cases in Wuhan to determine the epidemiologic characteristics of NCIP.

Methods: We collected information on demographic characteristics, exposure history, and illness timelines of laboratory-confirmed cases of NCIP that had been reported by January 22, 2020.

Disrupting LILRB4/APOE Interaction by an Efficacious Humanized Antibody Reverses T-cell Suppression and Blocks AML Development.

Therapeutic strategies are urgently needed for patients with acute myeloid leukemia (AML). Leukocyte immunoglobulin-like receptor B4 (LILRB4), which suppresses T-cell activation and supports tissue infiltration of AML cells, represents an attractive drug target for anti-AML therapeutics. Here, we report the identification and development of an LILRB4-specific humanized mAb that blocks LILRB4 activation.

MicroRNAome Profile of in Response to Methyl Jasmonate.

miRNAs play vital regulatory roles in different plant developmental stages and in plant response to biotic and abiotic stresses. However, information is limited on the miRNA regulatory mechanism to methyl jasmonate (MeJA). In this study, we used the microRNAome profile to illustrate the relevant regulatory mechanisms of in response to methyl jasmonate (MeJA) through Illumina RNA-Seq.

Targeted Delivery of Sildenafil for Inhibiting Pulmonary Vascular Remodeling.

Pulmonary arterial hypertension is a fatal lung disease caused by the progressive remodeling of small pulmonary arteries (PAs). Sildenafil can prevent the remodeling of PAs, but conventional sildenafil formulations have shown limited treatment efficacy for their poor accumulation in PAs. Here, glucuronic acid (GlcA)-modified liposomes (GlcA-Lips) were developed to improve the delivery of sildenafil to aberrant over-proliferative PA smooth muscle cells via targeting the GLUT-1 (glucose transport-1), and, therefore, inhibiting the remodeling of PAs in a monocrotaline-induced PA hypertension model.

Targeted Genotyping Identifies Susceptibility Locus in Brain-derived Neurotrophic Factor Gene for Chronic Postsurgical Pain.

Background: The purpose of this study was to evaluate the association between single-nucleotide polymorphisms and chronic postsurgical pain.

Methods: Using GoldenGate genotyping assays, we genotyped 638 polymorphisms within 54 pain-related genes in 1,152 surgical patients who were enrolled in our Persistent Pain after Surgery Study. Patients were contacted by phone to determine whether they had chronic postsurgical pain at 12 months.

Thirty-Day Outcome of a Multicenter Registry Study of Stenting for Symptomatic Intracranial Artery Stenosis in China.

Background And Purpose: Although recent trials have suggested that stenting is worse than medical therapy for patients with severe symptomatic intracranial atherosclerotic stenosis, it is not clear whether this conclusion applies to a subset of patients with hypoperfusion symptoms. To justify for a new trial in China, we performed a multicenter prospective registry study to evaluate the safety and efficacy of endovascular stenting within 30 days for patients with severe symptomatic intracranial atherosclerotic stenosis.

Methods: Patients with symptomatic intracranial atherosclerotic stenosis caused by 70% to 99% stenosis combined with poor collaterals were enrolled.

An inactivated enterovirus 71 vaccine in healthy children.

Background: Enterovirus 71 (EV71) is a major cause of hand, foot, and mouth disease in children and may be fatal. A vaccine against EV71 is needed.

Methods: We conducted a randomized, double-blind, placebo-controlled phase 3 trial involving healthy children 6 to 71 months of age in Guangxi Zhuang Autonomous Region, China.