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STUDY OBJECTIVES: To evaluate the impact of the coronavirus disease 2019 (COVID-19) pandemic on insomnia and other sleep disturbances in health care professionals. METHODS: A survey was distributed using social media and organizational emails to Brazilian active health care professionals during the COVID-19 outbreak. We explored potential associated factors including age, sex, occupation, workplace, work hours, income, previous infection with COVID-19, recent/current contact with COVID-19 patients, regional number of incident deaths, anxiety, and burnout. We evaluated new-onset/previous insomnia worsening episodes (primary outcome), new pharmacological treatments, sleep quality, duration, nightmares, and snoring (secondary outcomes). RESULTS: A total of 4,384 health professionals from all regions of the country were included in the analysis (44 ± 12 years, 76% females, 53.8% physicians). Overall, 55.7% were assisting patients with COVID-19, and 9.2% had a previous COVID-19 infection. The primary outcome occurred in 32.9% of respondents in parallel to 13% new pharmacological treatments for insomnia. The sleep quality worsened for 61.4%, while 43.5% and 22.8% reported ≥ 1-hour sleep duration reduction and worsening or new-onset nightmares, respectively. Multivariate analyses showed that age (odds ratio [OR]: 1.008; 95% confidence interval [CI] 1.001–1.015), females (OR: 1.590; 95% CI 1.335–1.900), weight change (decrease: OR: 1.772; 95% CI 1.453–2.161; increase: OR: 1.468; 95% CI 1.249–1.728), prevalent anxiety (OR: 3.414; 95% CI 2.954–3.948), new-onset burnout (OR: 1.761; 95% CI 1.489–2.083), family income reduction > 30% (OR: 1.288; 95% CI 1.069–1.553), and assisting patients with COVID-19 (OR: 1.275; 95% CI 1.081–1.506) were independently associated with new-onset or worsening of previous insomnia episodes. CONCLUSIONS: We observed a huge burden of insomnia episodes and other sleep disturbances in health care professionals during the COVID-19 pandemic. CITATION: Drager LF, Pachito DV, Moreno CRC, et al. Insomnia episodes, new-onset pharmacological treatments, and other sleep disturbances during the COVID-19 pandemic: a nationwide cross-sectional study in Brazilian health care professionals. J Clin Sleep Med. 2022;18(2):373–382.

Heart disease seriously threatens human life due to high morbidity and mortality. Accurate prediction and diagnosis become more critical for early prevention, detection and treatment. The Internet of Medical Things (IoMT) and Artificial Intelligence (AI) support healthcare services in heart disease monitoring, prediction and diagnosis. However, most prediction models only predict whether people are sick, and rarely further determine the severity of the disease. In this paper, we propose a machine learning based prediction model to achieve binary and multiple classification heart disease prediction simultaneously. We first design a Fuzzy-GBDT algorithm combining fuzzy logic and Gradient Boosting Decision Tree (GBDT) to reduce data complexity and increase the generalization of binary classification prediction. Then, we integrate Fuzzy-GBDT with Bagging to avoid over-fitting. The Bagging-Fuzzy-GBDT for multi-classification prediction further classify the severity of heart disease. Evaluation results demonstrate the Bagging-Fuzzy-GBDT has excellent accuracy and stability in both binary and multiple classification predictions.

Monoacylglycerol lipase (MAGL) is a pivotal enzyme in the endocannabinoid system, which metabolizes 2-arachidonoylglycerol (2-AG) into the proinflammatory eicosanoid precursor arachidonic acid (AA). MAGL and other endogenous cannabinoid (EC) degrading enzymes are involved in the fibrogenic signaling pathways that induce hepatic stellate cell (HSC) activation and ECM accumulation during chronic liver disease. Our group recently developed an 18F-labeled MAGL inhibitor ([18F]MAGL-4-11) for PET imaging and demonstrated highly specific binding in vitro and in vivo. In this study, we determined [18F]MAGL-4-11 PET enabled imaging MAGL levels in the bile duct ligation (BDL) and carbon tetrachloride (CCl4) models of liver cirrhosis; we also assessed the hepatic gene expression of the enzymes involved with EC system including MAGL, NAPE-PLD, FAAH and DAGL that as a function of disease severity in these models; [18F]MAGL-4-11 autoradiography was performed to assess tracer binding in frozen liver sections both in animal and human. [18F]MAGL-4-11 demonstrated reduced PET signals in early stages of fibrosis and further significantly decreased with disease progression compared with control mice. We confirmed MAGL and FAAH expression decreases with fibrosis severity, while its levels in normal liver tissue are high; in contrast, the EC synthetic enzymes NAPE-PLD and DAGL are enhanced in these different fibrosis models. In vitro autoradiography further supported that [18F]MAGL-4-11 bound specifically to MAGL in both animal and human fibrotic liver tissues. Our PET ligand [18F]MAGL-4-11 shows excellent sensitivity and specificity for MAGL visualization in vivo and accurately reflects the histological stages of liver fibrosis in preclinical models and human liver tissues., Graphical abstract This study comprehensively evaluated [18F]MAGL-4-11, a 18F-labeled monoacylglycerol lipase (MAGL) radioligand, in preclinical liver fibrosis models and human specimens, which would facilitate drug development in MAGL-related liver fibrosis disease.Image 1

The main protease (M(pro)) plays a crucial role in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication and is highly conserved, rendering it one of the most attractive therapeutic targets for SARS-CoV-2 inhibition. Currently, although two drug candidates targeting SARS-CoV-2 M(pro) designed by Pfizer are under clinical trials, no SARS-CoV-2 medication is approved due to the long period of drug development. Here, we collect a comprehensive list of 817 available SARS-CoV-2 and SARS-CoV M(pro) inhibitors from the literature or databases and analyze their molecular mechanisms of action. The structure–activity relationships (SARs) among each series of inhibitors are discussed. Additionally, we broadly examine available antiviral activity, ADMET (absorption, distribution, metabolism, excretion, and toxicity), and animal tests of these inhibitors. We comment on their druggability or drawbacks that prevent them from becoming drugs. This Perspective sheds light on the future development of M(pro) inhibitors for SARS-CoV-2 and future coronavirus diseases.

Autotaxin (ATX) is a secreted phosphodiesterase that has been implicated in a remarkably wide array of pathologies, especially in fibrosis and cancer. While ATX inhibitors have entered the clinical arena, a validated probe for positron emission tomography (PET) is currently lacking. With the aim to develop a suitable ATX-targeted PET radioligand, we have synthesized a focused library of fluorinated imidazo[1,2-a]pyridine derivatives, determined their inhibition constants, and confirmed their binding mode by crystallographic analysis. Based on their promising in vitro properties, compounds 9c, 9f, 9h, and 9j were radiofluorinated. Also, a deuterated analog of [18F]9j, designated as [18F]ATX-1905 ([18F]20), was designed and proved to be highly stable against in vivo radiodefluorination compared with [18F]9c, [18F]9f, [18F]9h, and [18F]9j. These results along with in vitro and in vivo studies toward ATX in a mouse model of LPS-induced liver injury suggest that [18F]ATX-1905 is a suitable PET probe for the non-invasive quantification of ATX.

Clinical evidence has established that concomitant traumatic brain injury (TBI) accelerates bone healing, but the underlying mechanism is unclear. This study shows that after TBI, injured neurons, mainly those in the hippocampus, release osteogenic microRNA (miRNA)-enriched small extracellular vesicles (sEVs), which targeted osteoprogenitors in bone to stimulate bone formation. We show that miR-328a-3p and miR-150-5p, enriched in the sEVs after TBI, promote osteogenesis by directly targeting the 3′UTR of FOXO4 or CBL, respectively, and hydrogel carrying miR-328a-3p-containing sEVs efficiently repaires bone defects in rats. Importantly, increased fibronectin expression on sEVs surface contributes to targeting of osteoprogenitors in bone by TBI sEVs, thereby implying that modification of the sEVs surface fibronectin could be used in bone-targeted drug delivery. Together, our work unveils a role of central regulation in bone formation and a clear link between injured neurons and osteogenitors, both in animals and clinical settings., Concomitant traumatic brain injury accelerates bone healing, but the mechanism is unclear. Here, the authors show that injured neurons, mainly those in the hippocampus, release osteogenic miRNA-enriched small extracellular vesicles, which targete osteoprogenitors to stimulate bone formation.

Mutations of fibrillin-1 (FBN1) have been associated with Marfan syndrome and pleiotropic connective tissue disorders, collectively termed as "type I fibrillinopathy". However, few genotype-phenotype correlations are known in the ocular system. Patients with congenital ectopia lentis (EL) received panel-based next-generation sequencing, complemented with multiplex ligation-dependent probe amplification. In a total of 125 probands, the ocular phenotypes were compared for different types of FBN1 mutations. Premature termination codons were associated with less severe EL and a thinner central corneal thickness (CCT) than the inframe mutations. The eyes of patients with mutations in the C-terminal region had a higher incidence of posterior staphyloma than those in the middle and N-terminal regions. Mutations in the TGF-β-regulating sequence had larger horizontal corneal diameters (white-to-white [WTW]), higher incidence of posterior staphyloma, but less severe EL than those with mutations in other regions. Mutations in the neonatal region were associated with thinner CCT. Longer axial length (AL) was associated with mutations in the C-terminal region or TGF-β regulating sequence after adjusting for age, EL severity, and corneal curvature radius. FBN1 genotype-phenotype correlations were established for some ocular features, including EL severity, AL, WTW, CCT, and so forth, providing novel perspectives and directions for further mechanistic studies.

Apatinib in combination with chemotherapy (CT) has been used in the treatment of ovarian cancer (OC), however, the safety and efficacy are unclear. The study aims at systematic evaluation of the safety and efficacy of the apatinib targeted therapy in combination with CT for the treatment of patients with advanced OC.Literature about randomized controlled clinical trials was searched using search engines such as PubMed, EMBASE, Web of Science, CNKI, the Cochrane Library, CBM, VIP and the Wanfang. We collected the related clinical studies of apatinib in combination with CT in the treatment of OC. The duration of the data retrieval related to clinical studies was from the database establishment to September 2020. Adverse reactions (ADRs) due to treatment, disease control rate (DCR), and that of objective response rate (ORR), were collected as indicators to show treatment outcomes. The literature was independently screened by two researchers. They extracted the data and evaluated the risk of biases of the included studies. Then, Revman 5.4 software was employed for performing the meta-analysis.Twelve randomized controlled clinical trials with 698 patients having an advanced stage of OC were included. The results revealed that in comparison with the treatment with only CT, apatinib targeted therapy combination with CT showed significant improvement in the patients' ORR [OR =3.19, 95% CI: (2.06, 4.94), P0.00001] and DCR [OR =4.97, 95% CI: (2.90, 8.52), P0.00001]. The group that was treated with a combined therapy had shown proteinuria in higher amount (OR =3.08, 95% CI: 51.13-8.42, P0.00001), while the analyses of other ADRs, such nausea and vomiting (OR =1.10, 95% CI: 0.67-1.79, P=0.71), hand-foot syndrome (OR =1.73, 95% CI: 0.97-3.10, P=0.06), hypertension (OR =1.18, 95% CI: 0.73-1.91, P=0.0.51), diarrhea (OR =1.05, 95% CI: 0.56-1.97, P=0.87), leucopenia (OR =1.22, 95% CI: 0.70-2.12, P=0.48), and myelosuppression (OR =1.00, 95% CI: 0.28-3.62, P=1.00), did not show any significant difference (P0.05).The effects of apatinib combination with CT for the treatment of OC are significantly better than the CT used alone in ORR and DCR, despite with a relative low incidence of adverse effects. However, due to the very low number of studies available, the results need to be further verified using a high-quality, large sample and long-term studies.

Background Transmembrane proteins are vital for intercellular signalling and play important roles in the control of cell fate. However, their physiological functions and mechanisms of action in myogenesis and muscle disorders remain largely unexplored. It has been found that transmembrane protein 182 (TMEM182) is dramatically up‐regulated during myogenesis, but its detailed functions remain unclear. This study aimed to analyse the function of TMEM182 during myogenesis and muscle regeneration. Methods RNA sequencing, quantitative real‐time polymerase chain reaction, and immunofluorescence approaches were used to analyse TMEM182 expression during myoblast differentiation. A dual‐luciferase reporter assay was used to identify the promoter region of the TMEM182 gene, and a chromatin immunoprecipitation assay was used to investigate the regulation TMEM182 transcription by MyoD. We used chickens and TMEM182‐knockout mice as in vivo models to examine the function of TMEM182 in muscle growth and muscle regeneration. Chickens and mouse primary myoblasts were used to extend the findings to in vitro effects on myoblast differentiation and fusion. Co‐immunoprecipitation and mass spectrometry were used to identify the interaction between TMEM182 and integrin beta 1 (ITGB1). The molecular mechanism by which TMEM182 regulates myogenesis and muscle regeneration was examined by Transwell migration, cell wound healing, adhesion, glutathione‐S‐transferse pull down, protein purification, and RNA immunoprecipitation assays. Results TMEM182 was specifically expressed in skeletal muscle and adipose tissue and was regulated at the transcriptional level by the myogenic regulatory factor MyoD1. Functionally, TMEM182 inhibited myoblast differentiation and fusion. The in vivo studies indicated that TMEM182 induced muscle fibre atrophy and delayed muscle regeneration. TMEM182 knockout in mice led to significant increases in body weight, muscle mass, muscle fibre number, and muscle fibre diameter. Skeletal muscle regeneration was accelerated in TMEM182‐knockout mice. Furthermore, we revealed that the inhibitory roles of TMEM182 in skeletal muscle depend on ITGB1, an essential membrane receptor involved in cell adhesion and muscle formation. TMEM182 directly interacted with ITGB1, and this interaction required an extracellular hybrid domain of ITGB1 (aa 387–470) and a conserved region (aa 52–62) within the large extracellular loop of TMEM182. Mechanistically, TMEM182 modulated ITGB1 activation by coordinating the association between ITGB1 and laminin and regulating the intracellular signalling of ITGB1. Myogenic deletion of TMEM182 increased the binding activity of ITGB1 to laminin and induced the activation of the FAK‐ERK and FAK‐Akt signalling axes during myogenesis. Conclusions Our data reveal that TMEM182 is a novel negative regulator of myogenic differentiation and muscle regeneration.

To evaluate the efficacy and safety of laser alone therapy and laser combination therapy (mainly combined with other kinds of laser or steroids) for keloid. PubMed, Embase and Web of Science were searched for relevant articles from inception to June 2020. Comprehensive Meta-Analysis software 2.0 (CMA) was used to perform the meta-analysis. A total of 29 articles were included in this meta-analysis. During the mean follow-up of 14 (1–84) months, the overall improvement rates of baseline Vancouver scar scale (VSS) score and itch were 0.454 (95%CI 0.351–0.561, I2 = 0) and 0.786 (95%CI 0.613–0.895, I2 = 0) in the laser combination therapy group. The improvement rates of scar height and flexibility in the laser combination therapy group were 0.629 (95%CI 0.519–0.727, I2 = 52.089) and 0.784 (95%CI 0.251–0.975, I2 = 89.420). The average improvement rate of the scar score in laser combination therapy was 0.338 (0.201–0.510); however, there were insufficient data for laser alone therapy comparison. The laser combination therapy had a greater pain improvement rate, 0.580 (0.389–0.750) versus 0.420 (0.224–0.645), compared to laser alone therapy, and a greater degree of good or excellent (> 50%) improvement in the overall scar, 0.636 (95%CI 0.347–0.852) versus 0.149 (95%CI 0.032–0.482), with laser alone therapy. Moreover, a lower regrowth rate of 0.187 (0.129–0.263) versus 0.249 (0.060–0.631), a lower post-treatment pigmentation rate of 0.125 (0.091–0.169) versus 0.135 (0.058–0.282), and a lower infection rate of 0.047 (0.009–0.209) versus 0.076 (0.012–0.351) were observed in the laser combination therapy compared with those rates in the laser alone therapy. The overall effect of laser combination therapy was better than that of laser alone therapy, and the incidence of adverse reactions was lower in laser combination therapy than in laser alone therapy.

AimsTo identify the mutation spectrum and genotype–phenotype correlations offibrillin-1(FBN1) mutations in a Chinese cohort with congenital ectopia lentis (EL).MethodsPatients clinically suspected of congenital zonulopathy were screened using panel-based next-generation sequencing followed by multiplex ligation-dependent probe amplification. All the probands were subjected to thorough ocular examinations. Molecular and clinical data were integrated in pursuit of genotype–phenotype correlation.ResultsA total of 131 probands ofFBN1mutations from unrelated families were recruited. Around 65% of the probands were children younger than 9 years old. Overall, 110 distinctFBN1mutations were identified, including 39 novel ones. The most at-risk regions were exons 13, 2, 6, 15, 24 and 33 in descending order of mutation frequency. The most prevalent mutation was c.184C>T (seven, 5.34%) in the coding sequence and c.5788+5G>A (three, 2.29%) in introns. Missense mutations were the most frequent type (103, 78.63%); half of which were distributed in the N-terminal regions (53, 51.46%). The majority of missense mutations were detected in one of the calcium-binding epidermal growth factor-like domains (62, 60.19%), and 39 (62.90%) of them were substitutions of conserved cysteine residues. Microspherophakia (MSP) was found in 15 patients (11.45%). Mutations in the middle region (exons 22–42), especially exon 26, had higher risks of combined MSP (OR, 5.51 (95% CI 1.364 to 22.274), p=0.017).ConclusionsThis study extended the knowledge of theFBN1mutation spectrum and provided novel insights into its clinical correlation regarding EL and MSP in the Chinese population.

Recently, the SARS-CoV-2 variants from the United Kingdom (UK), South Africa, and Brazil have received much attention for their increased infectivity, potentially high virulence, and possible threats to existing vaccines and antibody therapies. The question remains if there are other more infectious variants transmitted around the world. We carry out a large-scale study of 506,768 SARS-CoV-2 genome isolates from patients to identify many other rapidly growing mutations on the spike (S) protein receptor-binding domain (RBD). We reveal that essentially all 100 most observed mutations strengthen the binding between the RBD and the host angiotensin-converting enzyme 2 (ACE2), indicating the virus evolves toward more infectious variants. In particular, we discover new fast-growing RBD mutations N439K, S477N, S477R, and N501T that also enhance the RBD and ACE2 binding. We further unveil that mutation N501Y involved in United Kingdom (UK), South Africa, and Brazil variants may moderately weaken the binding between the RBD and many known antibodies, while mutations E484K and K417N found in South Africa and Brazilian variants, L452R and E484Q found in India variants, can potentially disrupt the binding between the RBD and many known antibodies. Among these RBD mutations, L452R is also now known as part of the California variant B.1.427. Finally, we hypothesize that RBD mutations that can simultaneously make SARS-CoV-2 more infectious and disrupt the existing antibodies, called vaccine escape mutations, will pose an imminent threat to the current crop of vaccines. A list of most likely vaccine escape mutations is given, including S494P, Q493L, K417N, F490S, F486L, R403K, E484K, L452R, K417T, F490L, E484Q, and A475S. Mutation T478K appears to make the Mexico variant B.1.1.222 the most infectious one. Our comprehensive genetic analysis and protein-protein binding study show that the genetic evolution of SARS-CoV-2 on the RBD, which may be regulated by host gene editing, viral proofreading, random genetic drift, and natural selection, gives rise to more infectious variants that will potentially compromise existing vaccines and antibody therapies.

As a serine hydrolase, monoacylglycerol lipase (MAGL) is principally responsible for the metabolism of 2-arachidonoylglycerol (2-AG) in the central nervous system (CNS), leading to the formation of arachidonic acid (AA). Dysfunction of MAGL has been associated with multiple CNS disorders and symptoms, including neuroinflammation, cognitive impairment, epileptogenesis, nociception and neurodegenerative diseases. Inhibition of MAGL provides a promising therapeutic direction for the treatment of these conditions, and a MAGL positron emission tomography (PET) probe would greatly facilitate preclinical and clinical development of MAGL inhibitors. Herein, we design and synthesize a small library of fluoropyridyl-containing MAGL inhibitor candidates. Pharmacological evaluation of these candidates by activity-based protein profiling identified 14 as a lead compound, which was then radiolabeled with fluorine-18 via a facile SNAr reaction to form 2-[18F]fluoropyridine scaffold. Good blood–brain barrier permeability and high in vivo specific binding was demonstrated for radioligand [18F]14 (also named as [18F]MAGL-1902). This work may serve as a roadmap for clinical translation and further design of potent 18F-labeled MAGL PET tracers.

Treatment resistance of the tumors to photodynamic therapy (PDT) owing to O2 deficiency largely compromised the therapeutic efficacy, which could be addressed via modulating oxygen levels by using O2 self-enriched nanosystems. Here, we report on augmenting the O2-evolving strategy based on a biomimetic, catalytic nanovehicle (named as N/P@MCC), constructed by the catalase-immobilized hollow mesoporous nanospheres by enveloping a cancer cell membrane (CCM), which acts as an efficient nanocontainer to accommodate nitrogen-doped graphene quantum dots (N-GQDs) and protoporphyrin IX (PpIX). Inheriting the virtues of biomimetic CCM cloaking, the CCM-derived shell conferred N/P@MCC nanovehicles with highly specific self-recognition and homotypic targeting toward cancerous cells, ensuring tumor-specific accumulation and superior circulation durations. N-GQDs, for the first time, have been evidenced as a new dual-functional nanoagents with PTT and PDT capacities, enabling the generation of 1O2 for PDT and inducing local low-temperature hyperthermia for thermally ablating cancer cells and infrared thermal imaging (IRT). Leveraging the intrinsic catalytic features of catalase, such N/P@MCC nanovehicles effectively scavenged the excessive H2O2 to sustainably evolve oxygen for a synchronous O2 self-supply and hypoxia alleviation, with an additional benefit because the resulting O2 bubbles could function as an echo amplifier, leading to the sufficient echogenic reflectivity for ultrasound imaging. Concurrently, the elevated O2 reacted with N-GQDs and PpIX to elicit a maximally increased 1O2 output for augmented PDT. Significantly, the ultrasound imaging coupled with fluorescence imaging, IRT, performs a tumor-modulated trimodal bioimaging effect. Overall, this offers a paradigm to rationally explore O2 self-supply strategies focused on versatile nanotheranostics for hypoxic tumor elimination.

Objective: To evaluate surgical outcomes of modified capsular tension ring (MCTR) and intraocular lens (IOL) implantation in eyes of Marfan syndrome (MFS). Methods: This retrospective case series included MFS patients receiving MCTR transscleral fixation and IOL in-the-bag implantation. The MCTR was sutured to the sclera through a sulcus by 9–0 polypropylene with the modified knotless Z-suture technique. Main outcomes were visual acuity and postoperative complications. Results: A total of 109 MFS patients (187 eyes) had the surgery. Patients were 15.47 ± 14.36 years old and followed up for 10.07 ± 8.99 months. MCTR and IOL implantations were performed in 174 eyes (93.05%). The postoperative BCVA (LogMAR) was 0.24 ± 0.24 (1 month), 0.26 ± 0.20 (3 months), 0.22 ± 0.20 (6 months), 0.20 ± 0.19 (12 months) and 0.25 ± 0.32 (over 12 months), which was significantly better than preoperatively (0.63 ± 0.35) ( p Conclusions: The visual improvement is significant in eyes of MFS undergoing MCTR transscleral fixation and IOL in-the-bag implantation. The long-term monitoring of complications is warranted, especially in the first-two years.

Prior cross-sectional and unidirectional longitudinal research has investigated the associations among academic achievement, depressive symptoms, and suicidal ideation without distinguishing between-person effects from within-person effects. Our study aimed to examine the longitudinal relations among academic achievement, depressive symptoms, and suicidal ideation in a sample of elementary school children at the within-person level using cross-lagged panel models (CLPMs) and random intercept cross-lagged panel models (RI-CLPMs). Also, multiple models replicated these findings by using three measures of academic achievement (i.e., objective academic achievement, subjective academic achievement, and teacher-assigned academic achievement). A sample of 715 Chinese elementary schoolchildren completed self-report measures of subjective academic achievement, depressive symptoms, and suicidal ideation on five occasions, using 6-month intervals. Objective academic achievement data were obtained from school records and teacher-assigned academic achievement data were reported by teachers. The results showed that: (a) In CLPMs, objective academic achievement negatively predicted suicidal ideation. However, RI-CLPMs supported the negative effect of suicidal ideation on objective academic achievement. (b) The CLPMs revealed reciprocal associations between subjective and teacher-assigned academic achievement and depressive symptoms, respectively. However, RI-CLPMs only provided support for the negative effect of depressive symptoms on subjective academic achievement. (c) Both the CLPMs and the RI-CLPMs showed bidirectional relations between depressive symptoms and suicidal ideation. These findings highlight that mental health problems (e.g., depressive symptoms and suicidal ideation) serve as antecedents of academic performance and that it is beneficial to distinguish between between-person and within-person effects in research informing the development of prevention and intervention programs.

SARS-CoV-2 has been mutating since it was first sequenced in early January 2020. Here, we analyze 45,494 complete SARS-CoV-2 geneome sequences in the world to understand their mutations. Among them, 12,754 sequences are from the United States. Our analysis suggests the presence of four substrains and eleven top mutations in the United States. These eleven top mutations belong to 3 disconnected groups. The first and second groups consisting of 5 and 8 concurrent mutations are prevailing, while the other group with three concurrent mutations gradually fades out. Moreover, we reveal that female immune systems are more active than those of males in responding to SARS-CoV-2 infections. One of the top mutations, 27964C > T-(S24L) on ORF8, has an unusually strong gender dependence. Based on the analysis of all mutations on the spike protein, we uncover that two of four SARS-CoV-2 substrains in the United States become potentially more infectious. Rui Wang et al. report a comprehensive analysis of nearly 13,000 SARS-CoV-2 genome sequences isolated from patients in the United States, comprising more than 7000 single mutations. They show that SARS-CoV-2 genomes cluster into four distinct groups and that two of these groups are potentially more infectious, underlining the urgent need for viral control strategies in the US.

PurposeGastric cancer (GC) has substantial biological differences between Asian and non-Asian populations, which makes it difficult to have a unified predictive measure for all people. We aimed to identify novel prognostic biomarkers to help predict the prognosis of Asian GC patients.Materials and MethodsWe investigated the differential gene expression between GC and normal tissues of GSE66229. Univariate, multivariate and Lasso Cox regression analyses were conducted to establish a four-gene-related prognostic model based on the risk score. The risk score was based on a linear combination of the expression levels of individual genes multiplied by their multivariate Cox regression coefficients. Validation of the prognostic model was conducted using The Cancer Genome Atlas (TCGA) database. A nomogram containing clinical characteristics and the prognostic model was established to predict the prognosis of Asian GC patients. ResultsFour genes (RBPMS2, RGN, PLEKHS1, and CT83) were selected to establish the prognostic model, and it was validated in the TCGA Asian cohort. Receiver operating characteristic analysis confirmed the sensitivity and specificity of the prognostic model. Based on the prognostic model, a nomogram containing clinical characteristics and the prognostic model was established, and Harrell’s concordance index of the nomogram for evaluating the overall survival significantly higher than the model only focuses on the pathologic stage (0.74 vs. 0.64, p < 0.001).ConclusionThe four-gene-related prognostic model and the nomogram based on it are reliable tools for predicting the overall survival of Asian GC patients.

Studies reported that women in a low‐risk cohort with stage 1 hypertension defined as 130–139 mmHg/80–89 mmHg, according to the American College of Cardiology/American Heart Association, are more likely to develop into preeclampsia than women with normotensive in the early gestation. In this study, the authors investigated whether preeclampsia was more likely to occur in stage 1 hypertensive women compared to the normotensive pregnant women in a high‐risk cohort, which was based on the randomized controlled trial of "Low‐dose Aspirin in the Prevention of Preeclampsia in China." Meanwhile, the authors further evaluated the preventive effect of aspirin for preeclampsia in stage 1 hypertension subset. In women enrolled at or before 16 weeks of gestation, in the control group, the preeclampsia occurrence was significantly higher in stage 1 hypertensive woman than in the normotensive women (20.4% vs. 6.2%, aOR 3.960, 95% CI 1.299–12.074, p = .016), while no difference was observed in the aspirin group (4.5% vs. 4.2%, aOR 0.921, 95% CI 0.140–6.070, p = .932). In stage 1 hypertension, the incidences of preeclampsia and preterm birth were significantly lower in the aspirin group as compared to the control group (4.5% vs. 20.4%, aOR 0.139, 95% CI 0.027–0.716, p = .018; 4.5% vs. 18.4%, aOR 0.141, 95% CI 0.025–0.782, p = .025). Compared with the control group, the aspirin group displayed significantly prolonged gestational age at delivery (38.6 ± 1.2 vs. 37.4 ± 3.4, p = .042). This study indicates that the newly classified stage 1 hypertension might be an additional risk factor for preeclampsia in Chinese high‐risk pregnant women, and aspirin intervention might be useful.

Surgery is the most important and effective method for the treatment of gastric cancer. Since the first gastrectomy in the early 19th century, surgical treatment of gastric cancer has undergone more than 100 years of development. With the increasing understanding of gastric cancer and the promotion of a series of clinical trials, the concept of gastric cancer surgery has evolved from the initial "bigger is better" to today's "standardized surgery" and is developing towards individualized surgery focusing on accurate resection and quality of life. This trend has had a tremendous impact on the development of surgical treatments, such as minimally invasive surgeries, function-preserving surgeries, and the optimal extent of lymph node dissection. Understanding the development and current status of gastric cancer surgery and exploring the remaining academic controversies are goals that every gastric surgeon should constantly pursue. However, how should gastric cancer surgery develop in the future? What opportunities and challenges will we encounter? In this review, we elaborate on the development and current status of gastric cancer surgery based on a series of clinical studies and discuss the controversy in the development of gastric cancer surgery.

Introduction: Marfan syndrome (MFS) is characterized by ectopia lentis (EL) and elongated axial length (AL). The characteristics of AL in young patients with MFS and bilateral EL before the lens surgery are not fully understood. Methods: This study reviewed MFS patients under 20 years old with bilateral EL from January 2015 to October 2020. The Z-scores were introduced in terms of the number of standard deviations from the mean of age-matched normative data. Using Z-scores, the distribution of AL and influence factors were evaluated. The correlations between AL and other biometrics were analyzed. Results: We reviewed 183 patients and enrolled both eyes. The mean age was 8.44 ± 4.69 years. About 36% of the patients were children under 6 years old. The median AL increased from 23.16 mm under 5 years old to 26.20 mm in the 16–20 age group, and when plotted, the trend presented a logarithmic curvature (R2 = 0.145, p < 0.001). The median Z-AL score was 1.24. One-third of eyes had Z-score p = 0.013). The eye complicated with megalocornea (10, 7.04%) had larger Z-AL scores (4.72 ± 3.51 vs. 1.10 ± 2.25, p = 0.002). A positive correlation was found between Z-AL and Z-corneal curvature radius (r = 0.265, p < 0.001). Conclusion: Young patients with bilateral EL but small AL should not be excluded from MFS without systematic examination. The age-adjusted Z-score will facilitate further study of the individual variations in AL across different ages.

One of the major challenges in controlling the coronavirus disease 2019 (COVID-19) outbreak is its asymptomatic transmission. The pathogenicity and virulence of asymptomatic COVID-19 remain mysterious. On the basis of the genotyping of 75775 SARS-CoV-2 genome isolates, we reveal that asymptomatic infection is linked to SARS-CoV-2 11083G>T mutation (i.e., L37F at nonstructure protein 6 (NSP6)). By analyzing the distribution of 11083G>T in various countries, we unveil that 11083G>T may correlate with the hypotoxicity of SARS-CoV-2. Moreover, we show a global decaying tendency of the 11083G>T mutation ratio indicating that 11083G>T hinders the SARS-CoV-2 transmission capacity. Artificial intelligence, sequence alignment, and network analysis are applied to show that NSP6 mutation L37F may have compromised the virus’s ability to undermine the innate cellular defense against viral infection via autophagy regulation. This assessment is in good agreement with our genotyping of the SARS-CoV-2 evolution and transmission across various countries and regions over the past few months.

WHAT IS KNOWN AND OBJECTIVE Cilostazol is a specific and strong inhibitor of phosphodiesterase (PDE) type III which can suppress the platelet aggregation by increasing cyclic adenosine monophosphate (cAMP) levels. The clinical benefit of cilostazol in ACS patients suggested that the drug may have non-platelet-directed properties. Some in vitro and animal studies also indicated that the 'pleiotropic' properties of cilostazol might be related to the interaction with adenosine metabolism. Adenosine is an important regulatory metabolite and an inhibitor of platelet activation. However, no human study has been conducted to determine whether cilostazol could increase the adenosine plasma concentration in vivo. As a result, this study aimed to investigate the impact of cilostazol on adenosine plasma concentration (APC) in acute coronary syndrome (ACS) patients. METHODS We prospectively analysed 149 ACS patients undergoing percutaneous coronary intervention (PCI) with drug-eluting stents. The included patients were divided into two groups according to the presence (cilostazol group, n = 64) or absence (aspirin group, n = 85) of aspirin intolerance. The inhibition of platelet aggregation (IPA), APC and cAMP concentration was measured. Patient characteristics, medications and 30-day clinical outcomes were examined. RESULTS Patients receiving cilostazol had a significantly higher adenosine and cAMP plasma concentration than patients receiving aspirin (3.00 ± 0.67 vs 2.56 ± 0.74 mol/L, P

Currently, there is neither effective antiviral drugs nor vaccine for coronavirus disease 2019 (COVID-19) caused by acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Due to its high conservativeness and low similarity with human genes, SARS-CoV-2 main protease (Mpro) is one of the most favorable drug targets. However, the current understanding of the molecular mechanism of Mpro inhibition is limited by the lack of reliable binding affinity ranking and prediction of existing structures of Mpro–inhibitor complexes. This work integrates mathematics (i.e., algebraic topology) and deep learning (MathDL) to provide a reliable ranking of the binding affinities of 137 SARS-CoV-2 Mpro inhibitor structures. We reveal that Gly143 residue in Mpro is the most attractive site to form hydrogen bonds, followed by Glu166, Cys145, and His163. We also identify 71 targeted covalent bonding inhibitors. MathDL was validated on the PDBbind v2016 core set benchmark and a carefully curated SARS-CoV-2 inhibitor dataset to ensure the reliability of the present binding affinity prediction. The present binding affinity ranking, interaction analysis, and fragment decomposition offer a foundation for future drug discovery efforts., By integrating algebraic topology and deep learning, we provide a reliable ranking of binding affinities, binding site analysis, and fragment decomposition for 137 SARS-CoV-2 main protease inhibitors.

A measure with satisfactory psychometric properties to address if stress is eustress or distress remains undeveloped in the cultural context of China. Thus, we revised and validated a Chinese version of the Eustress–Distress Psychological Response Scale (CEDPRS), examining the structure and indicators of eustress and distress with 1,079 undergraduate students in China. We found that the CEDPRS is best explained using a 2-factor second-order model comprising psychological responses to eustress and distress. Indicators of psychological responses to eustress included hope, meaningfulness, positive affect, and sense of control; responses to distress included anxiety, negative affect, meaninglessness, loss of control, and anger/hostility. We found that the CEDPRS is a valid and reliable measure in the Chinese context, thus providing empirical support for its use in assessing Chinese people's eustress and distress simultaneously from the individual's psychological response to the same stressor.

Cardiac fibrosis is a reparative process after myocardial infarction (MI), which leads to cardiac remodeling and finally heart failure. Endothelial-to-mesenchymal transition (EndMT) is induced after MI and contributes to cardiac fibrosis after MI. Orphan nuclear receptor Nur77 is a key regulator of inflammation, angiogenesis, proliferation, and apoptosis in vascular endothelial cells. Here, we investigated the role of orphan nuclear receptor Nur77 in EndMT and cardiac fibrosis after MI. Cardiac fibrosis was induced through MI by ligation of the left anterior descending coronary artery. We demonstrated that Nur77 knockout aggravated cardiac dysfunction and cardiac fibrosis 30 days after MI. Moreover, Nur77 deficiency resulted in enhanced EndMT as shown by increased expression of FSP-1, SM22α, Snail, and decreased expression of PECAM-1 and eNOS compared with wild-type mice after MI. Then, we found overexpression Nur77 in human coronary artery endothelial cells significantly inhibited interleukin 1β and transforming growth factor β2-induced EndMT, as shown by a reduced transition to a fibroblast-like phenotype and preserved angiogenesis potential. Mechanistically, we demonstrated that Nur77 downregulated EndMT by inhibiting the nuclear factor-κB-dependent pathway. In conclusion, Nur77 is involved in cardiac fibrosis by inhibiting EndMT and may be a promising target for therapy of cardiac fibrosis after MI.

Background Recent studies showed bioresorbable scaffold (BRS) increased risks of late target lesion failure (TLF) and thrombosis. XINSORB scaffold is a poly-L-lactic acid based BRS. Methods The study included randomization and registry parts. Eligible patients with one or two de novo lesions were randomly 1:1 assigned to XINSORB scaffold and sirolimus-eluting stent (SES) in randomization part. These patients were clinically and angiographically assessed. In registry part, patients were treated with XINSORB scaffold only and were clinically assessed. The primary endpoint was in-segment late luminal loss (LLL) at 12-month in randomization part. The secondary endpoint was 12-month TLF in all XINSORB-treated patients. Results Total 395 and 798 patients were enrolled in randomization and registry part, respectively. Device success was 98.0% (1069/1091) in all XINSORB-treated and 100% (221/221) in SES-treated lesions. The primary endpoint of in-segment LLL at 12-month was 0.19 ± 0.32 mm in XINSORB and 0.31 ± 0.41 mm in SES (P = 0.003), which met the noninferior margin of 0.195 mm (95% CI: −0.20, −0.04, P ≪ 0.0001). No difference was found in TLF between two devices. In all XINSORB-treated patients, 12-month TLF was 0.8% (8/998), which also met the noninferior margin of 9.0% (95% CI: 0.3%, 1.4%, P ≪ 0.0001). Only one device thrombosis was recorded in all XINSORB-treated patients while none in SES. Conclusions In the multicenter clinical trial, XINSORB BRS was noninferior to sirolimus-eluting stent for the primary endpoint of in-segment LLL at 12-month in patients with simple and moderate complex de novo coronary lesions. TLF at 12-month was low and comparable.

Purpose: To analyze the anterior, posterior, and total corneal spherical aberrations (ASA, PSA, and TSA) in patients with Chinese bilateral ectopia lentis (EL).Methods: A cross-sectional study was conducted to evaluate corneal spherical aberration (CSA) using a Pentacam system at the 6-mm optical zone. Axial length, keratometry, astigmatism, and corneal asphericity were also determined.Results: This study included 247 patients (420 eyes) with a mean age of 18.1 years. The values of ASA, PSA, and TSA were 0.136 ± 0.100 μm, −0.118 ± 0.030 μm, and 0.095 ± 0.095 μm, respectively. In the EL patients with Marfan syndrome (MFS), ASA and TSA were significantly lower than in the non-MFS patients (0.126 ± 0.094 μm vs. 0.155 ± 0.107 μm, P = 0.004 for ASA; 0.085 ± 0.091 μm vs. 0.114 ± 0.099 μm, P = 0.003 for TSA), whereas PSA was not significantly different (P = 0.061). The values of ASA and TSA were significantly higher in the patients with EL aged ≥ 40 years old than in younger patients, whereas ASA and PSA were lower in patients aged P < 0.05). In the multiple linear regression analysis, age, keratometry, astigmatism, anterior asphericity, higher-order aberration (HOA), and lower-order aberration (LOA) were positively or negatively correlated with TSA in the patients with EL (r = 0.681, P < 0.001).Conclusions: Corneal spherical aberration was low in the patients with EL especially for MFS and tended to increase with aging. Preoperatively, individual measurement of CSA was necessary for bilateral EL patients with MFS.

In this work, lipid profile migration from muscle to juice during the tilapia muscle steaming process was revealed by a transactional analysis of data from ultra-high-performance liquid chromatography coupled with Q Exactive (UHPLC-QE) Orbitrap mass spectrometry (MS) and lipidomics. Firstly, the lipids in tilapia muscles and juices at different steaming time points were extracted and examined by UHPLC-QE Orbitrap mass spectrometry. Secondly, a transactional analysis procedure was developed to analyze the data from UHPLC-QE Orbitrap MS and lipidomics. Finally, the corrected lipidomics data and the normalized MS data were used for lipid migration analysis. The results suggested that the transactional analysis procedure was efficient to significantly decrease UHPLC-QE Orbitrap MS workloads and delete the false-positive data (22.4–36.7%) in lipidomics data, which compensated the disadvantages of the current lipidomics method. The lipid changes could be disappearance, full migration into juice, appearance in juice, appearance in muscle, appearance in both muscle and juice, and retention in the muscle. Moreover, the results showed 9 (compared with 52), 5 (compared with 116), and 10 (compared with 178) of lipid class (compared with individual lipid) variables showed significant differences among the different steaming times (0, 10, 30, and 60 min) in all the muscles, juices, and muscle-juice systems, respectively. These results showed significant lipid profile migration from muscle to juice during the tilapia steaming process.

Background Ovarian cancer, a highly metastatic malignancy, has benefited tremendously from advances in modern human genomics. However, the genomic variations related to the metastasis remains unclear. Methods We filtered various significant genes (n = 6722) associated with metastasis within a large-scale functional genomic CRISPR/Cas9 knock-out library including 122,756 single guide RNAs, and identified ITK (IL2 Inducible T Cell Kinase) as a potential cancer suppressor gene for ovarian cancer metastasis. Downstream bioinformatic analysis was performed for ITK using public databases. Results We found that patients in low-ITK group had poor prognosis and more distant metastasis than those in high-ITK group in TCGA and GEO databases. We also demonstrated that ITK combined with the clinical factors could accurately predict prognosis through multiple Cox regression analysis and ROC analysis. Moreover, alterations correlated with distant metastasis emereged with significantly increased expression in SAMRCD1 in low-ITK group, but CD244 and SOCS1 in high-ITK group. Integrated analysis revealed dysregulated molecular processes including predominantly oncogenic signaling pathways in low-ITK group but immune related pathways in high-ITK group, which suggested ITK might inhibit distant metastasis in ovarian cancer. Furtherly, deconvolution of the cellular composition of all samples validated the close correlation between ITK and immune related function especially for cytotoxic lymphocytes. Conclusions Together, these data provide insights into the potential role of ITK, with implications for the future development of tansformative ovarian cancer therapeutics.

Objectives To enable non-invasive real-time quantification of vasopressin 1A (V1A) receptors in peripheral organs, we sought to develop a suitable PET probe that would allow specific and selective V1A receptor imaging in vitro and in vivo. Methods We synthesized a high-affinity and -selectivity ligand, designated compound 17. The target structure was labeled with carbon-11 and tested for its utility as a V1A-targeted PET tracer by cell uptake studies, autoradiography, in vivo PET imaging and ex vivo biodistribution experiments. Results Compound 17 (PF-184563) and the respective precursor for radiolabeling were synthesized in an overall yield of 49% (over 7 steps) and 40% (over 8 steps), respectively. An inhibitory constant of 0.9 nM towards the V1A receptors was measured, while excellent selectivity over the related V1B, V2 and OT receptor (IC50 >10,000 nM) were obtained. Cell uptake studies revealed considerable V1A binding, which was significantly reduced in the presence of V1A antagonists. Conversely, there was no significant blockade in the presence of V1B and V2 antagonists. In vitro autoradiography and PET imaging studies in rodents indicated specific tracer binding mainly in the liver. Further, the pancreas, spleen and the heart exhibited specific binding of [11C]17 ([11C]PF-184563) by ex vivo biodistribution experiments. Conclusion We have developed the first V1A-targeted PET ligand that is suitable for subtype-selective receptor imaging in peripheral organs including the liver, heart, pancreas and spleen. Our findings suggest that [11C]PF-184563 can be a valuable tool to study the role of V1A receptors in liver diseases, as well as in cardiovascular pathologies.

Purpose To evaluate the diagnostic yield of congenital ectopia lentis (EL) in a Chinese cohort by combining panel-based next-generation sequencing with clinical findings Design A cohort study. Methods In total, 175 patients with congenital EL and their available family members (n = 338) were enrolled. All congenital EL patients underwent genetic testing. Genotype-phenotype analyses were conducted to assess the biometric and structural ocular manifestations of congenital EL. Results In total, 175 patients with congenital EL and 338 of their relatives were included in this study. In these patients, 92.57% (162/175) of disease-related variants were detected in FBN1 (83.43%), CPAMD8 (1.71%), COL4A5 (0.57%), ADAMTSL4 (3.43%), LTBP2 (1.71%), and CBS (2.29%). Based on genetic and clinical findings, the primary diagnostic rate was increased to 40.57% from 19.43% with the exception of the 91 diagnoses of potential MFS, with a new diagnostic strategy for congenital ectopia lentis thus having been developed. Within this group of patients harboring FBN1 mutations, 16.44% (19/141) probands were diagnosed with ectopia lentis syndrome (ELS) and 2.13% (3/141) were diagnosed with Marfan syndrome (MFS). Conclusions The results of this cohort study expand the genomic landscape associated with congenital EL in Chinese cohorts. FBN1 mutations represent the most common cause of congenital EL in this population, and we have developed a new diagnostic strategy for congenital EL subtypes via the use of a well-designed panel-based next-Generation Sequencing (NGS) which can be used to efficiently and precisely diagnose patients with congenital EL in a cost-effective manner.

Background Foot-and-mouth disease (FMD) is a highly contagious disease of livestock worldwide. Russia is a big agricultural country with a wide geographical area where FMD outbreaks have become an obstacle for the development of the animal and animal products trade. In this study, we aimed to assess the export risk of FMD from Russia. Results After simulation by Monte Carlo, the results showed that the probability of cattle infected with FMD in the surveillance zone (Surrounding the areas where no epidemic disease has occurred within the prescribed time limit, the construction of buffer areas is called surveillance zone.) of Russia was 1.29 × 10− 6. The probability that at least one FMD positive case was exported from Russia per year in the surveillance zone was 6 %. The predicted number of positive cattle of the 39,530 - 50,576 exported from Russia per year was 0.06. A key node in the impact model was the probability of occurrence of FMD outbreaks in the Russian surveillance zone. By semi-quantitative model calculation, the risk probability of FMD defense system defects was 1.84 × 10− 5, indicating that there was a potential risk in the prevention and control measures of FMD in Russia. The spatial time scan model found that the most likely FMD cluster (P Conclusions There was a risk of FMDV among cattle exported from Russia, and the infection rate of cattle in the monitored area was the key factor. Understanding the export risk of FMD in Russia and relevant epidemic prevention measures will help policymakers to develop targeted surveillance plans.

Gypsum (calcium sulfate dihydrate, CaSO4 ·2H₂O) is commonly applied to improve soil quality and nutrient supply. Previous studies also suggested it is a cost-effective soil amendment in alleviating cadmium (Cd) toxicity and accumulation in plants. The aim of this study was to investigate how this is achieved. We used pak choi as our research material because it is a popular vegetable in Asia, and as a leafy vegetable, it accumulates higher Cd level than other types of vegetable. Under Cd stress, application of CaSO4 promoted pak choi seedling growth, decreased the oxidative stress in roots, reduced Cd accumulation, and enhanced the photosynthesis in shoots. We revealed the inhibition of Cd2+ absorption by CaSO4 is largely due to the competition between Ca2+ and Cd2+ for ion channels or transporter. Moreover, under Cd stress, CaSO4 facilitated the sulphate assimilation, increased the biosynthesis of phytochelatins, and activated the expression of transporters for vacuolar sequestration. Together, CaSO4 could benefit plant growth and enhance Cd tolerance by suppressing Cd root uptake and lowering the Cd content in cytoplasm.

Objective To collect computed tomography data of the laryngeal anatomy of Chinese men and to determine the feasibility of using the size 4 Ambu AuraOnce laryngeal mask (Ambu A/S, Copenhagen, Denmark) in Chinese men weighing >70 kg. Methods This prospective study involved men who underwent surgery from May 2018 to January 2019 at Jinshan Hospital. Pharyngeal and laryngeal parameters were measured by computed tomography. The laryngeal mask insertion success rate, requirement for tracheal tube insertion, laryngeal mask insertion time, fiberoptic bronchoscopy grading, air leakage pressure, and pharyngeal complications were analyzed. Results In a comparison of the size 4 and 5 Ambu AuraOnce devices, the first insertion success rate was 100% and 87% and the three-times insertion success rate was 100% and 93%, respectively, with no significant differences. However, the insertion time was significantly different at 19.6 ± 5.9 versus 31.1 ± 11.2 s, respectively, and the proportions of fiberoptic grading levels were also significantly different. There were no significant differences in the air leakage pressure or pharyngeal complications. Conclusion The size 4 Ambu AuraOnce is more adequate than the size 5 for Chinese men weighing >70 kg, with a shorter insertion time and higher fiberoptic bronchoscopic grading.

The ongoing massive vaccination and the development of effective intervention offer the long-awaited hope to end the global rage of the COVID-19 pandemic. However, the rapidly growing SARS-CoV-2 variants might compromise existing vaccines and monoclonal antibody (mAb) therapies. Although there are valuable experimental studies about the potential threats from emerging variants, the results are limited to a handful of mutations and Eli Lilly and Regeneron mAbs. The potential threats from frequently occurring mutations on the SARS-CoV-2 spike (S) protein receptor-binding domain (RBD) to many mAbs in clinical trials are largely unknown. We fill the gap by developing a topology-based deep learning strategy that is validated with tens of thousands of experimental data points. We analyze 261,348 genome isolates from patients to identify 514 non-degenerate RBD mutations and investigate their impacts on 16 mAbs in clinical trials. Our findings, which are highly consistent with existing experimental results about variants from the UK, South Africa, Brazil, US-California, and Mexico shed light on potential threats of 95 high-frequency mutations to mAbs not only from Eli Lilly and Regeneron but also from Celltrion and Rockefeller University that are in clinical trials. We unveil, for the first time, that high-frequency mutations R346K/S, N439K, G446V, L455F, V483F/A, E484Q/V/A/G/D, F486L, F490L/V/S, Q493L, and S494P/L might compromise some of mAbs in clinical trials. Our study gives rise to a general perspective about how mutations will affect current vaccines.

GABA has beneficial effects on salinity stress tolerance in Arabidopsis linked to increased activity of H+-ATPase, reduced ROS-induced K+ efflux from root epidermis, and increased SOS1 and NHX1 transcript levels in plant roots., The non-protein amino acid γ-aminobutyric acid (GABA) rapidly accumulates in plant tissues in response to salinity. However, the physiological rationale for this elevation remains elusive. This study compared electrophysiological and whole-plant responses of salt-treated Arabidopsis mutants pop2-5 and gad1,2, which have different abilities to accumulate GABA. The pop2-5 mutant, which was able to overaccumulate GABA in its roots, showed a salt-tolerant phenotype. On the contrary, the gad1,2 mutant, lacking the ability to convert glutamate to GABA, showed oversensitivity to salinity. The greater salinity tolerance of the pop2-5 line was explained by: (i) the role of GABA in stress-induced activation of H+-ATPase, thus leading to better membrane potential maintenance and reduced stress-induced K+ leak from roots; (ii) reduced rates of net Na+ uptake; (iii) higher expression of SOS1 and NHX1 genes in the leaves, which contributed to reducing Na+ concentration in the cytoplasm by excluding Na+ to apoplast and sequestering Na+ in the vacuoles; (iv) a lower rate of H2O2 production and reduced reactive oxygen species-inducible K+ efflux from root epidermis; and (v) better K+ retention in the shoot associated with the lower expression level of GORK channels in plant leaves.

Ultraviolet (UV) photochromism is observed from natural light in amorphous TiO2 nanotube arrays (NTAs) for the first time. Surface color of the NTAs film would change from light yellow to dark brown eventually, either under ultraviolet bulb irradiation or basking under natural sunlight. This photochromism is attributed to the appearance of Ti3 + ions in the TiO2 NTAs after UV illumination. Furthermore, a UV radiation cumulative dosimeter is designed and fabricated, consisting of a photochromic film and a colorimetric card, which convert invisible ultraviolet rays into visible color changes. This device helps people to understand intuitively how much UV radiation has been received in total from surrounding environments, which is of great importance for skin safety and public health.

Introduction: Incomplete pubertal development is a common phenomenon found in patients with Klinefelter syndrome (KFS). KFS combined with central precocious puberty (CPP) rarely occurs. We herein report a rare case of KFS with CPP and review several studies to determine the possible mechanism underlying this condition. Case presentation: An 8-year, 5-month-old male patient was admitted to our hospital because of enlargement of the penis and small testes. Laboratory evaluation revealed high luteinizing hormone and follicle-stimulating hormone levels, a high testosterone level, and the 48,XXYY karyotype. He was treated with triptorelin. One year later, the patient’s testosterone level decreased and pubertal arrest occurred. Conclusion: The literature review in this study showed that the occurrence of hypogonadism combined with CPP is not unique to patients with KFS; it has also been reported in individuals with Turner syndrome, adrenal hypoplasia congenita, and other diseases. Such individuals share common features including partial hypogonadism and a normal hypothalamic-pituitary-gonadal axis. CPP is considered a prelude to hypogonadism, and treatment with a gonadotropin-releasing hormone agonist may prevent gonadal failure. Key words: Central precocious puberty; 48,XXYY; Klinefelter syndrome; Hypogonadism; Turner syndrome

Two-dimensional (2D) graphitic carbon nitride (g-C3N4) nanosheets, as the promising photocatalyst with fascinating properties, have become a “rising star” in the field of photocatalysis. Although g-C3N4 nanosheets exfoliated from the bulk g-C3N4 powders are extensively emerged, developing a simple synthetic approach is still full of challenge. To this end, here we report a direct polymerization strategy to fabricate the ultrathin g-C3N4 nanosheets, that is only heating treatment of thiourea in air without addition of any template. The photocatalytic activities of as-prepared samples were evaluated by photoreduction of water to hydrogen (H2) using triethanolamine as sacrificial agent and Pt as co-catalyst under visible-light irradiation (λ > 420 nm). As a result, our few-layered g-C3N4 nanosheets with an average thickness of 3.5 nm exhibit a superior visible-light photocatalytic H2 evolution rate (HER) of 1391 μmol g−1 h−1 and a remarkable apparent quantum efficiency of 6.6% at 420 nm. Eventually, the HER of as-fabricated ultrathin g-C3N4 nanosheets is not only much higher than the dicyandiamide-derived g-C3N4 or melamine-derived g-C3N4, but also greater than the thermal-oxidation etched g-C3N4 nanosheets under the same condition.

Avian influenza is a serious zoonotic infectious disease with huge negative impacts on local poultry farming, human health and social stability. Therefore, the design of new compounds against avian influenza has been the focus in this field. In this study, computational methods were applied to investigate the compounds with neuraminidase inhibitory activity. First, 2D-SAR model was built to recognize neuraminidase inhibitors (NAIs). As a result, the accuracy of 10 cross-validation and independent tests is 96.84% and 98.97%, respectively. Then, the Topomer CoMFA model was constructed to predict the inhibitory activity and analyses molecular fields. Two models were obtained by changing the cutting methods. The second model is employed to predict the activity (q2 = 0.784 and r2 = 0.982). Molecular docking was also used to further analyze the binding sites between NAIs and neuraminidase from human and avian virus. As a result, it is found that same binding Total Score has some differences, but the binding sites are basically the same. At last, some potential NAIs were screened and some optimal opinions were taken. It is expected that our study can assist to study and develop new types of NAIs., Graphical Abstract Unlabelled Image

Purpose To evaluate the differences in corneal higher-order aberrations (HOAs) between cataract patients with high axial myopia and normal cataract patients, and to identify the associated factors. Setting Department of Ophthalmology and Vision Science of the Eye and ENT Hospital of Fudan University, Shanghai, China. Design Retrospective case series. Methods Corneal aberrations and axial lengths (ALs) were measured using a rotating Scheimpflug camera (Pentacam) and partial coherence interferometry (IOLMaster) in the high myopia group and the control group. Results The study comprised 287 patients (520 eyes). There were 194 eyes in the high myopia group and 326 eyes in the control group. The 5 anterior corneal aberrations—vertical coma, vertical trefoil, horizontal coma, oblique trefoil, and primary spherical aberration—in the high myopia group were 0.07 μm ± 0.38 (SD), −0.11 ± 0.23 μm, 0.07 ± 0.28 μm, −0.02 ± 0.18 μm, and 0.39 ± 0.19 μm, respectively. No negative primary spherical aberrations of the total or anterior corneal surface were found in the high myopia group. Differences between the 2 groups were found in terms of central corneal thickness, astigmatism, primary spherical aberration, vertical coma, and oblique trefoil; however, these differences were not consistent between different age subgroups. Higher-order aberrations were correlated with age. Posterior corneal vertical coma was correlated with AL (Pearson correlation = −0.188, P = .047). Conclusions Negative primary spherical aberrations of the anterior or total corneal surface were not found in the high myopia group. Age showed a strong relationship with HOAs. For cataract patients with high myopia, aspheric intraocular lens implantation is recommended.