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Kim-Seng Law,1– 3 Tien-Yung Wei1 1Department of Obstetrics and Gynecology, Tung’s Taichung Metro Harbor Hospital, Taichung, Taiwan; 2Department of Nursing, Jenteh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan; 3Department of Life Science, National Chung Hsing University, Taichung, TaiwanCorrespondence: Kim-Seng LawTung’s Taichung Metro Harbor Hospital, 699 Taiwan Boulevard, Section 8, Wuchi, Taichung City, 435, TaiwanTel +886 916120758Fax +886 26582000Email kimsenglaw@gmail.comPurpose: To evaluate the effect of low-dose aspirin on preventing early-onset preeclampsia during first-trimester screening using maternal factors and biochemistry.Patients and Methods: This study was a retrospective cohort study of pregnant women with singleton pregnancies at a gestational age of 11– 13+6 weeks from May 2017 to August 2019. Serum pregnancy-associated plasma protein A (PAPP-A)/placental growth factor (PLGF) and maternal demographic and clinical characteristics were collected and analyzed using a logistic regression model with a preset detection rate of 74% and a 10% false-positive rate. Low-dose aspirin was initiated for those screened positive for the prevention of early-onset preeclampsia.Results: Of the 805 women who underwent preeclampsia screening, 78 were screened positive for early-onset preeclampsia. With a preset detection rate of 74% and a 10% false-positive rate, there were a total of 28 women with preeclampsia, of which 11 developed preterm preeclampsia (< 37 GA) and three had early-onset preeclampsia with 72% and 75% sensitivity and specificity of 93% and 91%, respectively, resulting in an estimated 95% risk reduction for early-onset preeclampsia. Early-onset preeclampsia had lower serum PLGF (0.29 multiple of the median [MoM], range 0.1– 0.67) compared with preterm preeclampsia (0.74 MoM, range 0.1– 2.26). PLGF remains the only predictor of early-onset preeclampsia, while mean arterial pressure and chronic hypertension are predictors of preterm preeclampsia using multivariate regression. No variables accurately predicted the development of early-onset preeclampsia with the initiation of low-dose aspirin before the gestational age of 16 weeks.Conclusion: A remarkable reduction in early-onset preeclampsia was observed with early initiation of low-dose aspirin in those screened positive for maternal characteristics and serum PAPP-A/PLGF.Keywords: low-dose aspirin, placental growth factor, preeclampsia, pregnancy-associated plasma, protein

Study Objectives: To report the efficacy and findings of a large-scale preventive screening program for severe acute respiratory syndrome-associated coronavirus (SARS-CoV) using amplification of the virus from a nasopharyngeal swab (NPS) obtained from the health-care workers (HCWs).Design: A prospective observational study.Setting: A medical center in Taiwan.Participants: Two hundred thirty HCWs.Intervention: NPS examination for the presence of SARS-CoV by two nested reverse transcription-polymerase chain reaction (RT-PCR) assays.Measurements and Results: During the outbreak of severe acute respiratory syndrome (SARS), NPS polymerase chain reaction screening of HCWs for SARS-CoV was performed. SARS-CoV was examined by two nested RT-PCRs and a quantitative RT-PCR. Serum-specific antibodies were assessed by enzyme immunoassay and indirect immunofluorescence. We monitored 230 HCWs, including 217 first-line HCWs and 13 non-first-line HCWs. One hundred ninety first-line HCWs and 13 non-first-line HCWs had negative results in both nested RT-PCR assays. Two first-line HCWs who were positive on both nested RT-PCR assays had SARS. They had 16,900 +/- 7,920 copies (mean +/- SD) of RNA per milliliter in the NPS and had detectable anti-SARS antibodies. The remaining 25 first-line HCWs were negative for the first nested RT-PCR but positive for the second nested RT-PCR. Their corresponding titers were 338 +/- 227 copies of RNA per milliliter; antibodies developed in none of these 25 HCWs. The expression and function of angiotensin-converting enzyme-2 were not different among these HCWs. This study shows that colonization of SARS-CoV occurred in 25 of 217 well-protected first-line HCWs on a SARS-associated service, but they remained seronegative.Conclusion: With the second RT-PCR assay more sensitive than the first RT-PCR assay, we are able to show that approximately 11.5% of well-protected HCWs exposed to SARS patients or specimens may have colonization without seroconversion. Only those with significant clinical symptoms or disease would have active immunity. Thus, regular NPS screening for nested RT-PCR assays in conjunction with a daily recording of body temperature in all first-line HCWs may provide an effective way of early detection. [ABSTRACT FROM AUTHOR]

Mass spectrometry-based sample multiplexing with isobaric tags permits the development of high-throughput and precise quantitative biological assays with proteome-wide coverage and minimal missing values. Here, we nearly doubled the multiplexing capability of the TMTpro reagent set to a 35-plex through the incorporation of one deuterium isotope into the reporter group. Substituting deuterium frequently results in suboptimal peak coelution, which can compromise the accuracy of reporter ion-based quantification. To counteract the deuterium effect on quantitation, we implemented a strategy that necessitated the segregation of nondeuterium and deuterium-containing channels into distinct subplexes during normalization procedures, with reassembly through a common bridge channel. This multiplexing strategy of "design independent sub-plexes but acquire together" (DISAT) was used to compare protein expression differences between human cell lines and in a cysteine-profiling (i.e., chemoproteomics) experiment to identify compounds binding to cysteine-113 of Pin1.

Aims: The aim of this study was to investigate whether the H 2 FPEF score, which was developed to improve the diagnosis of heart failure (HF) with preserved ejection fraction, is associated with HF outcomes in patients with hypertrophic cardiomyopathy (HCM)., Methods and Results: Patients with HCM and preserved left ventricular ejection fraction (LVEF ≥50%) were included from a multicentre registry and the H 2 FPEF score was calculated. Patients were divided into three groups: low (0-1), intermediate (2-5) and high (6-9) H 2 FPEF score. The primary combined endpoint was a composite of all-cause death and HF admissions, while the secondary endpoints were all-cause death and HF admissions separately. A total of 955 patients were included (age 51 ± 17 years, 310 [32.5%] female). Patients with a high H 2 FPEF score (n = 105) were more often female, and presented with more symptoms and comorbidities. On echocardiography, patients with a high H 2 FPEF score had lower LVEF, more impaired diastolic function and more frequently left ventricular outflow tract obstruction. During follow-up (median 90 months [interquartile range 49-176]), 103 (11%) patients died and 57 (6%) patients had a first HF hospitalization. Event-free survival rate for the primary combined and secondary endpoints was lower for patients with an intermediate and high H 2 FPEF score. On multivariate Cox regression analysis, female sex (hazard ratio [HR] 1.670, 95% confidence interval [CI] 1.157-2.410; p = 0.006), Asian ethnicity (HR 6.711, 95% CI 4.076-11.048; p < 0.001), ischaemic heart disease (HR 1.732, 95% CI 1.133-2.650; p =  0.011), left atrial diameter (HR 1.028, 95% CI 1.005-1.051; p = 0.016) and intermediate (HR 2.757, 95% CI 1.612-4.713; p < 0.001) or high H 2 FPEF score (HR 3.689, 95% CI 1.908-7.134; p < 0.001) were independently associated with the primary combined endpoint., Conclusion: The H 2 FPEF score is independently associated with HF outcome in patients with HCM and may be considered for risk stratification., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

In response to an ever-increasing demand of new small molecules therapeutics, numerous chemical and genetic tools have been developed to interrogate compound mechanism of action. Owing to its ability to approximate compound-dependent changes in thermal stability, the proteome-wide thermal shift assay has emerged as a powerful tool in this arsenal. The most recent iterations have drastically improved the overall efficiency of these assays, providing an opportunity to screen compounds at a previously unprecedented rate. Taking advantage of this advance, we quantified more than one million thermal stability measurements in response to multiple classes of therapeutic and tool compounds (96 compounds in living cells and 70 compounds in lysates). When interrogating the dataset as a whole, approximately 80% of compounds (with quantifiable targets) caused a significant change in the thermal stability of an annotated target. There was also a wealth of evidence portending off-target engagement despite the extensive use of the compounds in the laboratory and/or clinic. Finally, the combined application of cell- and lysate-based assays, aided in the classification of primary (direct ligand binding) and secondary (indirect) changes in thermal stability. Overall, this study highlights the value of these assays in the drug development process by affording an unbiased and reliable assessment of compound mechanism of action.

Purpose: Oocyte maturation defect (OOMD) is a rare cause of in vitro fertilization failure characterized by the production of immature oocytes. Compound heterozygous or homozygous PATL2 mutations have been associated with oocyte arrest at the germinal vesicle (GV), metaphase I (MI), and metaphase II (MII) stages, as well as morphological changes., Methods: In this study, we recruited three OOMD cases and conducted a comprehensive multiplatform laboratory investigation., Results: Whole exome sequence (WES) revealed four diagnostic variants in PATL2, nonsense mutation c.709C > T (p.R237*) and frameshift mutation c.1486&#95;1487delinsT (p.A496Sfs*4) were novel mutations that have not been reported previously. Furthermore, the pathogenicity of these variants was predicted using in silico analysis, which indicated detrimental effects. Molecular dynamic analysis suggested that the A496S variant disrupted the hydrophobic segment, leading to structural changes that affected the overall protein folding and stability. Additionally, biochemical and molecular experiments were conducted on cells transfected with wild-type (WT) or mutant PATL2 (p.R237* and p.A496Sfs*4) plasmid vectors., Conclusions: The results demonstrated that PATL2 A496Sfs*4 and PATL2 R237* had impacts on protein size and expression level. Interestingly, expression levels of specific genes involved in oocyte maturation and early embryonic development were found to be simultaneously deregulated. The findings in our study expand the variation spectrum of the PATL2 gene, provide solid evidence for counseling on future pregnancies in affected families, strongly support the application of in the diagnosis of OOMD, and contribute to the understanding of PATL2 function., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Yeo's Index, product of the mitral leaflet separation index and dimensionless index, is a novel measure of the severity of rheumatic mitral stenosis (MS). We assess Yeo's index in patients with rheumatic MS with or without mixed valve disease., Methods: In a retrospective cohort study, Yeo's index was measured in 237 cases of rheumatic MS - 124 in a transthoracic echocardiography validation cohort using mitral valve area (MVA) by pressure half-time and planimetry as comparator and 113 in a transesophageal echocardiography (TEE) validation cohort using TEE three-dimensional MVA as comparator. Patients were considered to have mixed valve disease if they had MS and concomitant mitral regurgitation or aortic valve disease., Results: There were 113 patients with isolated MS and 124 patients with mixed valve disease. Overall, Yeo's index ≤ 0.26 cm showed 93.0 % sensitivity and 87.5 % specificity for identifying severe MS (MVA ≤ 1.5 cm 2 ). In isolated MS, Yeo's index ≤ 0.26 cm showed sensitivity of 94.6 % and specificity of 90.0 % for identifying severe MS, while in mixed valve disease sensitivity was 90.6 % and specificity 86.7 %. Overall, Yeo's index ≤ 0.15 cm showed 83.6 % sensitivity and 94.3 % specificity for very severe MS (MVA ≤ 1.0 cm 2 ). In isolated MS, the threshold of ≤0.15 cm showed sensitivity of 84.4 % and specificity of 92.6 % for very severe MS, while in mixed valve disease sensitivity was 81.3 % and specificity 95.3 %. The presence of atrial fibrillation did not influence the performance of Yeo's index., Conclusion: Yeo's Index accurately differentiates severity of rheumatic MS with or without mixed valve disease., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Cofilin, a key actin-binding protein, orchestrates the dynamics of the actomyosin network through its actin-severing activity and by promoting the recycling of actin monomers. Recent experiments suggest that cofilin forms functionally distinct oligomers via thiol post-translational modifications (PTMs) that promote actin nucleation and assembly. Despite these advances, the structural conformations of cofilin oligomers that modulate actin activity remain elusive because there are combinatorial ways to oxidize thiols in cysteines to form disulfide bonds rapidly. This study employs molecular dynamics simulations to investigate human cofilin 1 as a case study for exploring cofilin dimers via disulfide bond formation. Utilizing a biasing scheme in simulations, we focus on analyzing dimer conformations conducive to disulfide bond formation. Additionally, we explore potential PTMs arising from the examined conformational ensemble. Using the free energy profiling, our simulations unveil a range of probable cofilin dimer structures not represented in current Protein Data Bank entries. These candidate dimers are characterized by their distinct population distributions and relative free energies. Of particular note is a dimer featuring an interface between cysteines 139 and 147 residues, which demonstrates stable free energy characteristics and intriguingly symmetrical geometry. In contrast, the experimentally proposed dimer structure exhibits a less stable free energy profile. We also evaluate frustration quantification based on the energy landscape theory in the protein-protein interactions at the dimer interfaces. Notably, the 39-39 dimer configuration emerges as a promising candidate for forming cofilin tetramers, as substantiated by frustration analysis. Additionally, docking simulations with actin filaments further evaluate the stability of these cofilin dimer-actin complexes. Our findings thus offer a computational framework for understanding the role of thiol PTM of cofilin proteins in regulating oligomerization, and the subsequent cofilin-mediated actin dynamics in the actomyosin network.

Introduction Gonorrhea has become an emerging sexually transmitted infection worldwide. The multi-antibiotic resistance facilitates the transmission; thus, new antibiotics or alternatives are needed. Antimicrobial peptides (AMP) are antimicrobials naturally secreted by the host as a defense material. Teleost-derived AMP have gained attention over the past two decades due to their potent efficacy toward microorganisms. This study examines teleost-derived AMP against  Neisseria gonorrhoeae (GC), the responsible bacteria for gonorrhea, to evaluate the antibiotic potential as a future alternative for preventing gonorrhea. Methods Minimal inhibitory concentration (MIC) and time-killed assay were conducted to evaluate the inhibition concentration of each AMP. Transmission electron microscopy was used to confirm the potential mode of action. The inhibition of microcolony formation and adherence to epithelial cells were examined to assess the infection inhibition. Results Pardaxin-based (flatfish pardaxin {PB2}) and piscidin-based (striped bass piscidin 1 {PIS} and tilapia piscidin {TP} 4) AMP were effective toward GC under or equal to 7.5 μg/mL as of minimal inhibitory concentration. Transmission electron microscopy images revealed that these AMP attack bacterial membranes as membrane blebbing and breakage were observed. These AMP also effectively reduced the GC biofilm formation, as well as their adherence to human endocervical epithelial cells. Conclusion Pardaxin-based (PB2) and piscidin-based (PIS and TP4) teleost-derived AMP can inhibit GC and potentially serve as the new antibiotic alternative for preventing GC colonization and infection. This study will shed some light on the future development of teleost-derived AMP in treating gonorrhea and maintaining reproductive health., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Huang et al.)

Background: Patients with migraines, particularly those with auras, may present with stroke. Atrial fibrillation is a known risk factor for stroke. With common pathophysiological factors between migraines and atrial fibrillation, we aimed to clarify the association between migraine and atrial fibrillation in this systematic review and meta-analysis., Methods: A literature search was conducted in EMBASE, PubMed, Scopus and Cochrane electronic bibliographic databases from inception to 5 September 2022 with the following inclusion criteria: (a) cohort or cross-sectional studies; (b) studies that included only patients aged ≥18 years; and (c) studies that examined the association between atrial fibrillation and migraines. Exclusion criteria were case-control studies and the studies that included patients with previous diagnosis of atrial fibrillation or nonmigrainous headache. The Newcastle-Ottawa Scale was used to assess the quality of studies., Results: Six studies were included, demonstrating a pooled prevalence of atrial fibrillation of 1.61% (95% confidence interval [CI] 0.51, 3.29) in migraine with aura and 1.32% (95% CI 0.17, 3.41) in migraine without aura. The overall prevalence of atrial fibrillation in migraine was 1.39% (95% CI 0.24, 3.46)., Conclusion: In this systematic review and meta-analysis, the overall prevalence of atrial fibrillation in patients with migraine was low. Further studies are needed to clarify this relationship., (Copyright © 2024 Copyright: © 2024 Singapore Medical Journal.)

Background: A mitral leaflet separation index (MLSI), measuring the anatomical separation of the mitral valve (MV) leaflet tips in diastole, was previously described as an accurate method of assessing mitral stenosis (MS). We propose a novel modification of the MLSI by including a hemodynamic assessment which we term Yeo's index that may improve its diagnostic performance., Methods and Results: We retrospectively studied 174 patients with varying severity of MS without significant mitral regurgitation, aortic valve disease or ventricular septal defect. MLSI was measured in 2 orthogonal views on transthoracic echocardiography as previously described. MV dimensionless index (DI) was calculated by dividing the left ventricular outflow tract pulsed-wave Doppler time velocity integral (TVI) by the MV continuous-wave Doppler TVI. We defined Yeo's index as the product of MLSI and DI. With linear correlation, Yeo's index demonstrated good correlation against MVA by planimetry (r = 0.728), pressure half-time (r = 0.677), and continuity equation (r = 0.829), with improved performance over the MLSI. Using ROC analysis, Yeo's index demonstrated good ability to correctly classify MS as severe (MVA ≤1.5cm 2 ) (AUC 0.874, 95% CI 0.816-0.920). Yeo's index ≤0.260 cm correctly classified severe MS with sensitivity of 82% and specificity of 80%. Presence of AF did not affect the performance of Yeo's index. Yeo's index ≤0.147 cm also identified very severe MS (MVA ≤ 1.0 cm 2 ) with specificity of 94% and sensitivity of 78%., Conclusion: Yeo's index performed well in identifying severe MS and may be a useful adjunct to existing measures of MS severity., Competing Interests: Declaration of Competing Interest The authors report no conflict of interest for this study., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Multiple anticancer drugs have been proposed to cause cell death, in part, by increasing the steady-state levels of cellular reactive oxygen species (ROS). However, for most of these drugs, exactly how the resultant ROS function and are sensed is poorly understood. It remains unclear which proteins the ROS modify and their roles in drug sensitivity/resistance. To answer these questions, we examined 11 anticancer drugs with an integrated proteogenomic approach identifying not only many unique targets but also shared ones-including ribosomal components, suggesting common mechanisms by which drugs regulate translation. We focus on CHK1 that we find is a nuclear H 2 O 2 sensor that launches a cellular program to dampen ROS. CHK1 phosphorylates the mitochondrial DNA-binding protein SSBP1 to prevent its mitochondrial localization, which in turn decreases nuclear H 2 O 2 . Our results reveal a druggable nucleus-to-mitochondria ROS-sensing pathway-required to resolve nuclear H 2 O 2 accumulation and mediate resistance to platinum-based agents in ovarian cancers., Competing Interests: Declaration of interests A.P.P., C.M.S., M.P.S., and S.A.B. are employees of Cell Signaling Technology, Inc. L.B.-P. is a founder, consultant, and holds privately held equity in Scorpion Therapeutics., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Studies have shown that elevated plasma levels of platelet-derived soluble TREM-like transcript-1 (sTLT-1) are associated with an unfavorable outcome in patients with septic shock. However, the underlying molecular mechanisms are not well defined. This research aimed to study the role of sTLT-1 in mediating immune dysfunction during the development of sepsis. Our study demonstrated that patients with septic shock have significantly higher plasma concentrations of sTLT-1, whereas sTLT-1 is not detectable in healthy subjects. Plasma concentrations of sTLT-1 were correlated with the degree of immunosuppressive parameters in monocytes from patients with septic shock. sTLT-1 can first activate monocytes by binding to the TLR4/MD2 complex but subsequently induce immunosuppressive phenotypes in monocytes. Blocking Abs against TLR4 and MD2 led to a significant decrease in sTLT-1-induced activation. Treatment with an anti-TLT-1 Ab also significantly reduces sTLT-1 binding to monocytes and proinflammatory cytokine secretion in a mouse model of endotoxemia. sTLT-1 acts as an endogenous damage-associated molecular pattern molecule, triggering the activation of monocytes through the TLR4/MD2 complex followed by sustained immune suppression. This process plays a crucial role in the development of sepsis-associated pathophysiology. Our findings outline, to our knowledge, a novel pathway whereby platelets counteract immune dynamics against infection through sTLT-1., (Copyright © 2023 by The American Association of Immunologists, Inc.)

Background: Cardiac arrest is a leading cause of mortality prior to discharge for children admitted to the pediatric intensive care unit. To address this problem, we used machine learning to predict cardiac arrest up to three hours in advance., Methods: Our data consists of 240 Hz ECG waveform data, 0.5 Hz physiological time series data, medications, and demographics from 1,145 patients in the pediatric intensive care unit at the Johns Hopkins Hospital, 15 of whom experienced a cardiac arrest. The data were divided into training, validating, and testing sets, and features were generated every five minutes. 23 heart rate variability (HRV) metrics were determined from ECG waveforms. 96 summary statistics were calculated for 12 vital signs, such as respiratory rate and blood pressure. Medications were classified into 42 therapeutic drug classes. Binary features were generated to indicate the administration of these different drugs. Next, six machine learning models were evaluated: logistic regression, support vector machine, random forest, XGBoost, LightGBM, and a soft voting ensemble., Results: XGBoost performed the best, with 0.971 auROC, 0.797 auPRC, 99.5% sensitivity, and 69.6% specificity on an independent test set., Conclusion: We have created high-performing models that identify signatures of in-hospital cardiac arrest (IHCA) that may not be evident to clinicians. These signatures include a combination of heart rate variability metrics, vital signs data, and therapeutic drug classes. These machine learning models can predict IHCA up to three hours prior to onset with high performance, allowing clinicians to intervene earlier, improving patient outcomes., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Adult liver malignancies, including intrahepatic cholangiocarcinoma and hepatocellular carcinoma, are the second leading cause of cancer-related deaths worldwide. Most individuals are treated with either combination chemotherapy or immunotherapy, respectively, without specific biomarkers for selection. Here using high-throughput screens, proteomics and in vitro resistance models, we identify the small molecule YC-1 as selectively active against a defined subset of cell lines derived from both liver cancer types. We demonstrate that selectivity is determined by expression of the liver-resident cytosolic sulfotransferase enzyme SULT1A1, which sulfonates YC-1. Sulfonation stimulates covalent binding of YC-1 to lysine residues in protein targets, enriching for RNA-binding factors. Computational analysis defined a wider group of structurally related SULT1A1-activated small molecules with distinct target profiles, which together constitute an untapped small-molecule class. These studies provide a foundation for preclinical development of these agents and point to the broader potential of exploiting SULT1A1 activity for selective targeting strategies., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

There have been over 621 million cases of COVID-19 worldwide with over 6.5 million deaths. Despite the high secondary attack rate of COVID-19 in shared households, some exposed individuals do not contract the virus. In addition, little is known about whether the occurrence of COVID-19 resistance differs among people by health characteristics as stored in the electronic health records (EHR). In this retrospective analysis, we develop a statistical model to predict COVID-19 resistance in 8,536 individuals with prior COVID-19 exposure using demographics, diagnostic codes, outpatient medication orders, and count of Elixhauser comorbidities in EHR data from the COVID-19 Precision Medicine Platform Registry. Cluster analyses identified 5 patterns of diagnostic codes that distinguished resistant from non-resistant patients in our study population. In addition, our models showed modest performance in predicting COVID-19 resistance (best performing model AUROC = 0.61). Monte Carlo simulations conducted indicated that the AUROC results are statistically significant (p < 0.001) for the testing set. We hope to validate the features found to be associated with resistance/non-resistance through more advanced association studies., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Yang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: The objective of the study is to develop deep learning models using synthetic fundus images to assess the direction (intorsion versus extorsion) and amount (physiologic versus pathologic) of static ocular torsion. Static ocular torsion assessment is an important clinical tool for classifying vertical ocular misalignment; however, current methods are time-intensive with steep learning curves for frontline providers., Methods: We used a dataset (n = 276) of right eye fundus images. The disc-foveal angle was calculated using ImageJ to generate synthetic images via image rotation. Using synthetic datasets (n = 12,740 images per model) and transfer learning (the reuse of a pretrained deep learning model on a new task), we developed a binary classifier (intorsion versus extorsion) and a multiclass classifier (physiologic versus pathologic intorsion and extorsion). Model performance was evaluated on unseen synthetic and nonsynthetic data., Results: On the synthetic dataset, the binary classifier had an accuracy and area under the receiver operating characteristic curve (AUROC) of 0.92 and 0.98, respectively, whereas the multiclass classifier had an accuracy and AUROC of 0.77 and 0.94, respectively. The binary classifier generalized well on the nonsynthetic data (accuracy = 0.94; AUROC = 1.00)., Conclusions: The direction of static ocular torsion can be detected from synthetic fundus images using deep learning methods, which is key to differentiate between vestibular misalignment (skew deviation) and ocular muscle misalignment (superior oblique palsies)., Translational Relevance: Given the robust performance of our models on real fundus images, similar strategies can be adopted for deep learning research in rare neuro-ophthalmologic diseases with limited datasets.

Paris spp. are important medicinal plant and main raw material for many Chinese patent medicines, but viral diseases have became serious problems in cultivation of this group of important medicinal plants in China. In this study, eight viruses were identified in the diseased plants of Paris yunnanensis by high-throughput sequencing (HTS) and RT-PCR. These viruses include three novel viruses (two potyviruses and one nepovirus), Hippeastrum chlorotic ringspot virus (HCRV), Lychnis mottle virus (LycMoV), Paris mosaic necrosis virus (PMNV), Paris virus 1 and pepper mild mottle virus. The three new viruses were tentatively named Paris potyvirus 3 (ParPV-3), Paris potyvirus 4 (ParPV-4), Paris nepovirus 1 (ParNV-1) and their complete genome sequences were determined. Sequence analyses showed ParPV-3 and ParPV-4 shared the highest amino acid (aa) sequence identities of 54.3% to each other and 53.0-57.8% to other known potyviruses. ParNV-1 had aa sequence identities of 28.8-63.7% at protease-polymerase (Pro-Pol) with other nepoviruses. Phylogenetic analyses further support that the three viruses are new members of their corresponding genera. Analyses of the partial sequences of HCRV and LycMoV infecting P. yunnanensis revealed they diverged from existing isolates by aa sequence identities of 97.1% at glycoprotein precursor of HCRV and 93.3% at polyprotein of LycMoV. These two viruses are reported for the first time in Paris spp. A total of 123 field samples collected from P. yunnanensis in four counties of Yunnan, Southwest China were tested by RT-PCR for detecting each of the eight viruses. Results showed that nearly half of the samples were positive for at least one of the eight viruses. Two potyviruses, ParPV-3 (26.8%) and PMNV (24.4%), were predominant and widely distributed in the fields, while other viruses occurred in low rates and/or had limited distribution. This study insights into the virome infecting P. yunnanensis and provides valuable information for diagnosis and control of viral diseases in P. yunnanensis., Competing Interests: G-hZ was employed by Chinese Medicine Resources Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lan, He, Yang, Zhou, Chen, Wei, Li, Gu, Li and Li.)

Purpose: Degenerative mitral stenosis (DMS) is associated with a poor prognosis. Although mean transmitral gradient (TMG) has shown a good correlation with outcome, little is known about the association between other echocardiographic parameters and prognosis in patients with DMS. The current study aimed to evaluate the prognostic value of left atrial volume index (LAVI) in patients with DMS., Methods: A total of 155 patients with DMS (72[63-80] years, 67% female) were included. The population was divided according to LAVI: normal-sized LAVI (LAVI ≤ 34 ml/m2); and enlarged LAVI (> 34 ml/m2)., Results: Patients with enlarged LAVI had a higher left ventricular mass index (120[96-146] vs. 91[70-112] g/m2 p < 0.001), as well as a higher prevalence of significant mitral regurgitation and severe aortic stenosis (23% vs. 10% p = 0.046 and 38% vs. 15% p=0.001, respectively) compared to patients with normal-sized LAVI. During a median follow-up of 25 months, 56 (36%) patients died. Patients with enlarged LAVI had worse prognosis compared to patients with normal-sized LAVI (p = 0.026). In multivariable Cox regression model, an enlarged LAVI was independently associated with all-cause mortality (HR 2.009, 95% CI 1.040 to 3.880, P = 0.038)., Conclusion: An enlarged LAVI (> 34 ml/m2) is significantly associated with excess mortality in patients with DMS. After adjusting for potential confounders, an enlarged LAVI was the only parameter that remained independently associated with prognosis., (© 2022. The Author(s).)

A novel virus named Aconitum amalgavirus 1 (AcoAV-1) was identified in Chinese aconite (Aconitum carmichaelii) plants. The complete genome of AcoAV-1 is 3,370 nucleotides long, containing two partially overlapping open reading frames encoding a putative coat protein and a RNA-dependent RNA polymerase, respectively. Its fusion protein shares 34.9%-50.7% amino acid sequence identity with other amalgaviruses. Phylogenetic analysis showed that this virus formed a clade with blueberry latent virus and four other related viruses, suggesting that it belongs to the genus Amalgavirus in the family Amalgaviridae., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Patients with preexisting kidney disease or acute kidney injury had poorer outcomes in coronavirus disease 2019 (COVID-19) illness. Lymphopenia was associated with more severe illness. Risk stratification with simple laboratory tests may help appropriate site patients in a cost-effective manner and ease the burden on healthcare systems. We examined a ratio of serum creatinine level to absolute lymphocyte count at presentation (creatinine-lymphocyte ratio, CLR) in predicting outcomes in hospitalized patients with COVID-19. We analyzed 553 consecutive polymerase chain reaction-positive SARS-COV-2 hospitalized patients. Patients with end-stage kidney disease were excluded. Serum creatinine and full blood count (FBC) examination were obtained within the first day of admission. We examined the utility of CLR in predicting adverse clinical outcomes (requiring intensive care, mechanical ventilation, acute kidney injury requiring renal replacement therapy or death). An optimized cutoff of CLR > 77 was derived for predicting adverse outcomes (72.2% sensitivity, and 83.9% specificity). Ninety-seven patients (17.5%) fell within this cut off. These patients were older and more likely to have chronic medical conditions. A higher proportion of these patients had adverse outcomes (13.4% vs 1.1%, P < .001). On receiver operating curve analyses, CLR predicted patients who had adverse outcomes well (area under curve [AUC] = 0.82, 95%CI 0.72-0.92), which was comparable to other laboratory tests like serum ferritin, C-reactive protein and lactate dehydrogenase. Elevated CLR on admission, which may be determined by relatively simple laboratory tests, was able to reasonably discriminate patients who had experienced adverse outcomes during their hospital stay. This may be a simple and cost-effective means of risk stratification and triage., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

The compound FR901379, a sulfated echinocandin produced by the filamentous fungus Coleophoma empetri F-11899, is an important intermediate for the synthesis of the antifungal drug micafungin. In this study, we established an efficient clustered regularly interspaced short palindromic repeats/Cas9-based gene editing tool for the industrial production strain C. empetri SIPI1284. With this method, the efficiency of gene mutagenesis in the target locus is up to 84%, which enables the rapid gene disruption for the analysis of FR901379 biosynthetic genes. Next, we verified the putative functional genes of the FR901379 biosynthetic gene cluster via gene disruption and gene complementation in vivo. These core functional genes included the nonribosomal peptide synthetase gene ( CEnrps ), the fatty-acyl-AMP ligase gene ( CEligase ) responsible for the formation of the activated form of palmitic acid and its transfer to CEnrps , four nonheme mononuclear iron oxygenase genes ( CEoxy1 , CEoxy2 , CEoxy3 , and CEoxy4 ) responsible for the synthesis of nonproteinogenic amino acids, l-homotyrosine biosynthesis genes ( CEhtyA-D ), two cytochrome P450 enzyme genes ( CEp450-1 and CEp450-2 ), and a transcription regulator gene ( CEhyp ). In addition, by screening the whole genome, we identified two unknown genes ( CEp450-3 and CEsul ) responsible for the sulfonyloxy group of FR901379, which were separated from the core FR901379 biosynthetic cluster. Furthermore, during gene disruptions in the research, we obtained a series of FR901379 analogues and elucidated the relationship between the groups and antifungal activities.

Background: Concealed left ventricular hypertrophy (LVH) is a prevalent condition that is correlated with a substantial risk of cardiovascular events and mortality, especially in young to middle-aged adults. Early identification of LVH is warranted. In this work, we aimed to develop an artificial intelligence (AI)-enabled model for early detection and risk stratification of LVH using 12-lead ECGs., Methods: By deep learning techniques on the ECG recordings from 28 745 patients (20-60 years old), the AI model was developed to detect verified LVH from transthoracic echocardiography and evaluated on an independent cohort. Two hundred twenty-five patients from Japan were externally validated. Cardiologists' diagnosis of LVH was based on conventional ECG criteria. The area under the curve (AUC), sensitivity, and specificity were applied to evaluate the model performance. A Cox regression model estimated the independent effects of AI-predicted LVH on cardiovascular or all-cause death., Results: The AUC of the AI model in diagnosing LVH was 0.89 (sensitivity: 90.3%, specificity: 69.3%), which was significantly better than that of the cardiologists' diagnosis (AUC, 0.64). In the second independent cohort, the diagnostic performance of the AI model was consistent (AUC, 0.86; sensitivity: 85.4%, specificity: 67.0%). After a follow-up of 6 years, AI-predicted LVH was independently associated with higher cardiovascular or all-cause mortality (hazard ratio, 1.91 [1.04-3.49] and 1.54 [1.20-1.97], respectively). The predictive power of the AI model for mortality was consistently valid among patients of different ages, sexes, and comorbidities, including hypertension, diabetes, stroke, heart failure, and myocardial infarction. Last, we also validated the model in the international independent cohort from Japan (AUC, 0.83)., Conclusions: The AI model improved the detection of LVH and mortality prediction in the young to middle-aged population and represented an attractive tool for risk stratification. Early identification by the AI model gives every chance for timely treatment to reverse adverse outcomes.

Introduction: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of anti-hyperglycemic drugs that has been steadily increasing in popularity due to its cardiovascular and renal benefits. Dual SGLT1/SGLT2 (SGLT1/2) inhibitors have potentially augmented anti-hyperglycemic action due to additional SGLT1 inhibition. This network meta-analysis aimed to compare the treatment effect across various outcomes between pure SGLT2 inhibitors and combined SGLT1/2 inhibitors in patients with diabetes., Methodology: Four electronic databases (PubMed, Embase, Cochrane, and Scopus) were searched for randomized controlled trials published from inception to 15th January 2022. Frequentist network meta-analysis was conducted to summarize the treatment effects reported in individual trials, stratified by type 1 (T1DM) and type 2 diabetes mellitus (T2DM). This meta-analysis was registered on PROSPERO (CRD42020222031)., Results: Our meta-analysis included 111 articles, comprising a combined cohort of 103,922 patients. SGLT2 inhibitors (dapagliflozin, empagliflozin, canagliflozin, ipragliflozin, ertugliflozin, and luseogliflozin) and SGLT1/2 inhibitors (licogliflozin and sotagliflozin) were compared. Frequentist network meta-analysis demonstrated that in T2DM patients, SGLT1/2 inhibitors led to a decreased hazard rate of myocardial infarction (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.56-0.98) and stroke (HR 0.65, 95% CI 0.47-0.92) compared with SGLT2 inhibitors. SGLT2 inhibitors achieved a greater hemoglobin A1c (HbA1c) reduction than SGLT1/2 inhibitors (0.16%, 95% CI 0.06-0.26). In patients with T2DM, the risk of diarrhea (risk ratio [RR] 1.42, 95% CI 1.07-1.88) and severe hypoglycemia (RR 5.89, 95% CI 1.41-24.57) were found to be higher with SGLT1/2 inhibitor use compared with SGLT2 inhibitor use. No differences were observed for cardiovascular, metabolic, and safety outcomes between SGLT1/2 inhibitors and SGLT2 inhibitors in patients with T1DM., Conclusions: In patients with T2DM, compared with pure SGLT2 inhibitors, combined SGLT1/2 inhibitors demonstrated a lower risk of myocardial infarction and of stroke, but were associated with a higher risk of diarrhea and severe hypoglycemia., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Many haptic feedback methods have been proposed to enhance realism in virtual reality (VR). However, friction on the feet in VR, which renders feedback as if walking on different terrains or ground textures or stepping on objects is still less explored. Herein, we propose a wearable device, FrictShoes a pair of foot accessories, to provide multilevel nonuniform friction feedback to feet. This is achieved by the independent functioning of six brakes on six wheels underneath each FrictShoe, which allows the friction levels of the wheels from each to be either matched or to vary. We conducted a magnitude estimation study to understand users' distinguishability of friction force magnitudes (or levels). Based on the results, we performed an exploratory study to realize how users adjust and map the multilevel nonuniform friction patterns to common VR terrains or ground textures. Finally, a VR experience study was conducted to evaluate the performance of the proposed multilevel nonuniform friction feedback to the feet in VR experiences.

Isocitrate dehydrogenase 1 mutations (mIDH1) are common in cholangiocarcinoma. (R)-2-hydroxyglutarate generated by the mIDH1 enzyme inhibits multiple α-ketoglutarate-dependent enzymes, altering epigenetics and metabolism. Here, by developing mIDH1-driven genetically engineered mouse models, we show that mIDH1 supports cholangiocarcinoma tumor maintenance through an immunoevasion program centered on dual (R)-2-hydroxyglutarate-mediated mechanisms: suppression of CD8+ T-cell activity and tumor cell-autonomous inactivation of TET2 DNA demethylase. Pharmacologic mIDH1 inhibition stimulates CD8+ T-cell recruitment and interferon γ (IFNγ) expression and promotes TET2-dependent induction of IFNγ response genes in tumor cells. CD8+ T-cell depletion or tumor cell-specific ablation of TET2 or IFNγ receptor 1 causes treatment resistance. Whereas immune-checkpoint activation limits mIDH1 inhibitor efficacy, CTLA4 blockade overcomes immunosuppression, providing therapeutic synergy. The findings in this mouse model of cholangiocarcinoma demonstrate that immune function and the IFNγ-TET2 axis are essential for response to mIDH1 inhibition and suggest a novel strategy for potentiating efficacy., Significance: Mutant IDH1 inhibition stimulates cytotoxic T-cell function and derepression of the DNA demethylating enzyme TET2, which is required for tumor cells to respond to IFNγ. The discovery of mechanisms of treatment efficacy and the identification of synergy by combined CTLA4 blockade provide the foundation for new therapeutic strategies. See related commentary by Zhu and Kwong, p. 604. This article is highlighted in the In This Issue feature, p. 587., (©2021 American Association for Cancer Research.)

Background: Infective endocarditis (IE) confers significant mortality and morbidity in patients with underlying mitral stenosis (MS), with both diseased native valves and after valvular procedures., Purpose: We examined the clinical and echocardiographic parameters in association with the development of IE on patients with significant MS., Methods: A total of 478 consecutive patients with index echocardiographic diagnosis of significant mitral stenosis (mitral valve area <1.5 cm 2 ) were included. Patients were grouped into those with or without IE on at least 5 years of follow-up. Baseline clinical, echocardiographic profile and clinical outcomes were compared., Results: IE was observed in 4.4% (n = 21) of the cohort. These patients were younger (45.3 ± 14.6 vs. 53.2 ± 15.5 years, p = 0.022) at the time of MS diagnosis. NT-proBNP was higher in patients who developed IE (13529 ± 12230 vs. 4381 ± 5875 pg/ml, p < 0.001), with larger left atrial diameter (54.4 ± 10.1 vs. 49.9 ± 9.5 mm, p = 0.040) and elevated pulmonary artery systolic pressure (PASP, 62.3 ± 17.2 vs. 47.2 ± 16.5 mmHg, p = 0.026). There was no significant difference in terms of MS severity, other concomitant valvulopathies, or etiology (rheumatic or degenerative) of MS. Patients who smoked had higher incidence of IE (33.3% vs. 14.2%, log-rank 7.27, p = 0.007). After adjusting for age, valve procedure and PASP, patients who smoked remained at elevated risk of IE (adjusted hazards ratio 2.99, 95% confidence interval 1.18-7.56, p = 0.021)., Conclusion: IE occurs in a proportion of patients with MS. Smoking, younger age of diagnosis of MS as well as dilated left atria with elevated PASP may be associated with an elevated risk of this complication., (© 2021 Wiley Periodicals LLC.)

Background: Traditional teaching methods via faculty lectures and text-based materials lack interactivity. Hence, this research aimed to compare the effectiveness of story-based audiovisual mnemonics and the conventional text-reading method on medical students' memory consolidation., Methods: A single-center, systematically randomly sampled, single-blinded, controlled study was conducted among 80 first-year medical students. The students were randomly assigned to the text-reading (control) or story-based audiovisual mnemonics (intervention) group. After completing the learning session, the participants immediately took a test that consisted of ten multiple-choice questions, each of which had one correct single-response answer, and an oral recall test that consisted of ten keywords based on the given topics. The test was repeated at 1 week, 2 weeks, and 4 weeks post intervention. Descriptive and inferential statistics were utilized to assess the participants' responses. The mean score difference between the audiovisual mnemonics and control groups was determined by using a two-tailed unpaired t-test., Results: The participants in the intervention group had statistically significant higher marks in the multiple-choice test as compared to the participants in the control group. The intervention group also spent a statistically significant shorter time to recall keywords in the oral recall test in comparison to the control group., Conclusion: The story-based audiovisual mnemonics method is more effective than the conventional text-reading method in promoting memory retention among medical students., Competing Interests: Declaration of Competing Interests The authors declare that they have no competing interests., (Copyright © 2021 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Abstract: Liver dysfunction in patients with COVID-19 (coronavirus disease 2019) has been described. However, it is not clear if the presence of abnormal liver function tests at presentation was related to underlying undiagnosed liver disease, or a result of the viral infection.We retrospectively examined the first 554 consecutive polymerase chain reaction positive SARS-CoV-2 patients admitted from February 2020 to April 2020 to our academic medical centre. We reviewed their clinical data, chest radiography and laboratory studies obtained within 24 hour of admission.Despite similar hemodynamic parameters, we found significant aspartate transaminase elevation (64 ± 141 vs 35 ± 23 U/L, P < .001) in those with pneumonia compared to those without. Elevated liver enzymes were seen in 102 patients (18.4%). They presented with higher temperatures (38.5 ± 0.9 vs 37.5 ± 0.8 degC, P = .011), higher total white cell counts (6.95 ± 2.29 vs 6.39 ± 2.19 x109/L, P = .021), serum ferritin (240 ± 274 vs 165 ± 198 ng/ml, P = .002) and lactate dehydrogenase (632 ± 912 vs 389 ± 107 U/L, P < .001). These patients were more likely to require intensive care (6.9% vs 2.7% P = .036) and mechanical ventilation (5.9% vs 2.2%, P = .046). Migrant workers from dormitories had a higher rate of baseline liver function test abnormalities (88/425 vs 14/129, P = .01), which were more likely to persist at the time of discharge.Despite relatively mild COVID-19 disease, there was a significant prevalence of liver dysfunction, particularly amongst migrant workers. Elevated liver enzymes were associated with more severe disease, despite similar haemodynamic characteristics. Future studies should explore whether pre-existing liver disease may predispose to more severe COVID-19 disease., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

The incidence of childhood atopic dermatitis (AD) and allergic rhinitis (AR) is increasing. This warrants development of measures to predict and prevent these conditions. We aimed to investigate the predictive ability of a spectrum of data mining methods to predict childhood AD and AR using longitudinal birth cohort data. We conducted a 14-year follow-up of infants born to pregnant women who had undergone maternal examinations at nine selected maternity hospitals across Taiwan during 2000-2005. The subjects were interviewed using structured questionnaires to record data on basic demographics, socioeconomic status, lifestyle, medical history, and 24-h dietary recall. Hourly concentrations of air pollutants within 1 year before childbirth were obtained from 76 national air quality monitoring stations in Taiwan. We utilized weighted K-nearest neighbour method (k = 3) to infer the personalized air pollution exposure. Machine learning methods were performed on the heterogeneous attributes set to predict allergic diseases in children. A total of 1439 mother-infant pairs were recruited in machine learning analysis. The prevalence of AD and AR in children up to 14 years of age were 6.8% and 15.9%, respectively. Overall, tree-based models achieved higher sensitivity and specificity than other methods, with areas under receiver operating characteristic curve of 83% for AD and 84% for AR, respectively. Our findings confirmed that prenatal air quality is an important factor affecting the predictive ability. Moreover, different air quality indices were better predicted, in combination than separately. Combining heterogeneous attributes including environmental exposures, demographic information, and allergens is the key to a better prediction of children allergies in the general population. Prenatal exposure to nitrogen dioxide (NO 2 ) and its concatenation changes with time were significant predictors for AD and AR till adolescent., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Sperm motility is vital to human reproduction, and malformed sperm flagella can cause male infertility. Individuals with multiple morphological abnormalities of the flagella mostly have absent, short, coiled, bent, and/or irregular-caliber flagella. In this study, a patient with male infertility underwent a physical examination along with his wife. Genetic testing was performed by whole-exome sequencing of the couple, and Sanger sequencing was performed for validation. Novel biallelic variations in the DNAH1 : (NM&#95;015512.4) gene consisting of c.1336G>C (p.E446Q) and c.2912G>A (p.R971H) were identified. In silico structural analysis revealed that the amino acid residues affected by the variation were evolutionarily conserved, and the variant p.R971H influenced the stability of the DNAH1 protein. Morphological studies of the patient's sperm showed defects in its flagella. Results of Papanicolaou staining and scanning electron microscopy demonstrated coiled and short flagella with multiple anomalies. Transmission electron microscopy of the sperm flagella showed that the inner dynein arm and radial spoke were absent, and the dense fiber and microtubule doublets were displaced. Quantitative PCR of the mRNA of the patient's sperm showed that the expression of DNALI1 was dramatically reduced. Collectively, these findings elucidated the genetic cause of the family's infertility and provided insight into the functioning of the DNAH1 gene.

Polycystic kidney disease (PKD) is known to occur in three main forms, namely autosomal dominant PKD (ADPKD), autosomal recessive PKD (ARPKD) and syndromic PKD (SPKD), based on the clinical manifestations and genetic causes, which are diagnosable from the embryo stage to the later stages of life. Selection of the genetic test for the individuals with diagnostic imaging reports of cystic kidneys without a family history of the disease continues to be a challenge in clinical practice. With the objective of maintaining a limit on the time and medical cost of the procedure, a practical strategy for genotyping and targeted validation to resolve cystogene variations was developed in our clinical laboratory, which combined the techniques of whole-exome sequencing (WES), Long-range PCR (LR-PCR), Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) to work in a stepwise approach. In this context, twenty-six families with renal polycystic disorders were enrolled in the present study. Thirty-two variants involving four ciliary genes (PKD1, PKHD1, TMEM67 and TMEM107) were identified and verified in 23 families (88.5%, 23/26), which expanded the variant spectrum by 16 novel variants. Pathogenic variations in five foetuses of six families diagnosed with PKD were identified using prenatal ultrasound imaging. Constitutional biallelic and digenic variations constituted the pathogenic patterns in these foetuses. The preliminary clinical data highlighted that the WES + LR PCR-based workflow followed in the present study is efficient in detecting divergent variations in PKD. The biallelic and digenic mutations were revealed as the main pathogenic patterns in the foetuses with PKD., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Depression afflicts more than 300 million people worldwide, but there is currently no universally effective drug in clinical practice. In this study, chronic restraint stress (CRS)-induced mice depression model was used to study the antidepressant effects of resveratrol and its mechanism. Our results showed that resveratrol significantly attenuated depression-like behavior in mice. Consistent with behavioral changes, resveratrol significantly attenuated CRS-induced reduction in the density of dendrites and dendritic spines in both hippocampus and medial prefrontal cortex (mPFC). Meanwhile, in hippocampus and mPFC, resveratrol consistently alleviated CRS-induced cofilin1 activation by increasing its ser3 phosphorylation. In addition, cofilin1 immunofluorescence distribution in neuronal inner peri-membrane in controls, and cofilin1 diffusely distribution in the cytoplasm in CRS group were common in hippocampus. However, the distribution of cofilin1 in mPFC was reversed. Pearson's correlation analysis revealed that there was a significant positive correlation found between the sucrose consumption in sucrose preference test and the dendrite density in multiple sub-regions of hippocampus and mPFC, and a significant negative correlation between the immobility time in tail suspension test and the dendrite/dendritic spine density in several different areas of hippocampus and mPFC. P-cofilin1 was significantly positively correlated with the overall dendritic spine density in mPFC as well as with the overall dendrite density or BDNF in the hippocampus. Our results suggest that the BDNF/cofilin1 pathway, in which cofilin1 may be activated in a brain-specific manner, was involved in resveratrol's attenuating the dendrite and dendritic spine loss and behavioral abnormality.

An evolving understanding of disease pathogenesis has compelled the development of new drug delivery approaches. Recently, bioinspired microrobots have gained traction as drug delivery systems. By leveraging the microscale phenomena found in physiological systems, these microrobots can be designed with greater maneuverability, which enables more precise, controlled drug release. Their function could be further improved by testing their efficacy in physiologically relevant model systems as part of their development. In parallel with the emergence of microscale robots, organ-on-a-chip technologies have become important in drug discovery and physiological modeling. These systems reproduce organ-level functions in microfluidic devices, and can also incorporate specific biological, chemical, and physical aspects of a disease. This review highlights recent developments in both microrobotics and organ-on-a-chip technologies and envisions their combined use for developing future drug delivery systems.

d-Glycero-d-manno-heptose-1β,7-bisphosphate (HBP) and d-glycero-d-manno-heptose-1β-phosphate (H1P) are bacterial metabolites that were recently shown to stimulate inflammatory responses in host cells through the activation of the TIFA-dependent NF-κB pathway. To better understand structure-based activity in relation to this process, a family of nonhydrolyzable phosphonate analogues of HBP and H1P was synthesized. The inflammation modulation by which these molecules induce the TIFA-NF-κB signal axis was evaluated in vivo at a low-nanomolar concentration (6 nM) and compared to that of the natural metabolites. Our data showed that three phosphonate analogues had similar stimulatory activity to HBP, whereas two phosphonates antagonized HBP-induced TIFA-NF-κB signaling. These results open new horizons for the design of pro-inflammatory and innate immune modulators that could be used as vaccine adjuvant., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The integration of molecular robots and synthetic biology allows for the creation of sophisticated behaviors at the molecular level. Similar to the synergy between bioelectronics and soft robotics, synthetic biology provides control circuitry for molecular robots. By encoding perception-action modules within synthetic circuits, molecular machines can advance beyond repeating tasks to the incorporation of complex behaviors. In particular, cell-free synthetic biology provides biomolecular circuitry independent of living cells. This research update reviews the current progress in using synthetic biology as perception-action control modules in robots from molecular robots to macroscale robots. Additionally, it highlights recent developments in molecular robotics and cell-free synthetic biology and suggests their combined use as a necessity for future molecular robot development., (© 2020 Author(s).)

Glarea lozoyensis is an important industrial fungus that produces the pneumocandin B 0 , which is used for the synthesis of antifungal drug caspofungin. However, because of the limitations and complications of traditional genetic tools, G. lozoyensis strain engineering has been hindered. In this study, we established an efficient CRISPR/Cas9-based gene editing tool in G. lozoyensis SIPI1208. With this method, gene mutagenesis efficiency in the target locus can be up to 80%, which enables the rapid gene knockout. According to the reports, GloF and Ap-HtyE, proline hydroxylases involved in pneumocandin and Echinocandin B biosynthesis, respectively, can catalyze the proline to generate different ratios of trans -3-hydroxy-l-proline to trans -4-hydroxy-l-proline. Heterologous expression of Ap-HtyE in G. lozoyensis decreased the ratio of pneumocandin C 0 to (pneumocandin B 0 + pneumocandin C 0 ) from 33.5% to 11% without the addition of proline to the fermentation medium. Furthermore, the gloF was replaced by ap-htyE to study the production of pneumocandin C 0 . However, the gene replacement has been hampered by traditional gene tools since gloF and gloG , two contiguous genes indispensable in the biosynthesis of pneumocandins, are cotranscribed into one mRNA. With the CRISPR/Cas9 strategy, ap-htyE was knocked in and successfully replaced gloF , and results showed that the knock-in strain retained the ability to produce pneumocandin B 0 , but the production of pneumocandin C 0 was abolished. Thus, this strain displayed a competitive advantage in the industrial production of pneumocandin B 0 . In summary, this study showed that the CRISPR/Cas9-based gene editing tool is efficient for manipulating genes in G. lozoyensis .

Two novel lead-based coordination polymers, namely [Pb(cbdcp)]·0.5H 2 O·0.5CH 3 OH (1) and [Pb(cbdcp)] (2), have been solvothermally constructed by using a zwitterionic ligand 4-carboxy-1-(3,4-dicarboxy-benzyl)-pyridinium chloride (abbreviated as H 3 cbdcpCl). Compound 1 has a three-dimensional framework displaying a valence-bonded SrAl 2 topology with the 4 2 ·6 3 ·8 symbol, while compound 2 has a two-dimensional sheet structure that can be simplified into a three-dimensional ππ interaction-connected topology with the {4 4 ·6 2 } 2 {4 8 ·6 15 ·8 5 } symbol. Notably, compound 1 proved to be a promising potential luminescent sensor capable of selectively detecting anions, cations and small organic molecules, especially Cr 2 O 7 2- , CrO 4 2- , Fe 3+ and nitrobenzene.

Voriconazole (VCZ) is a widely used triazole drug for the treatment of serious incidence of invasive fungal infections (IFIs), and its most commonly reported clinical side effect is hepatotoxicity. The mechanism of VCZ-induced hepatotoxicity is unclear, and no specific marker can be used for prediction and diagnosis. This study aims to apply the targeted metabolomics approach to identify specific VCZ-induced metabolites related to hepatotoxicity via liquid chromatography-triple quadrupole mass spectrometry (LC-QqQ-MS) in a C57BL/6 mouse model. Mice treated with three repeated doses of 40 mg/kg VCZ by tail vein injection to induce hepatotoxicity (VCZ-induced hepatotoxicity group, n = 8) were compared with mice without treatment (control group, n = 10). Both liver tissue and plasma were collected and analyzed to propose underlying mechanisms associated with VCZ-induced hepatotoxicity. The results indicated that the metabolites associated with oxidative stress were altered, and alterations in the metabolites involved in glutathione biosynthesis were noticed. The ratio of glutamine to glutamate showed a significant reduction in the VCZ-induced hepatotoxicity group compared to the control group, suggesting that glutamine might be transformed into glutamate for glutathione biosynthesis. Accordingly, we proposed that VCZ-induced hepatotoxicity is associated with oxidative stress to cause cell dysfunction, leading to alterations in energy metabolism, the urea cycle, and nucleoside metabolism. To the best of our knowledge, this is the first study to apply metabolomics for investigating the mechanism of VCZ-induced hepatotoxicity.

Background: Sleep problem or disturbance often exists in pain or neurological/psychiatric diseases. However, sleep scoring is a time-consuming tedious labor. Very few studies discuss the 5-stage (wake/NREM1/NREM2/transition sleep/REM) automatic fine analysis of wake-sleep stages in rodent models. The present study aimed to develop and validate an automatic rule-based classification of 5-stage wake-sleep pattern in acid-induced widespread hyperalgesia model of the rat., Results: The overall agreement between two experts' consensus and automatic scoring in the 5-stage and 3-stage analyses were 92.32% (κ = 0.88) and 94.97% (κ = 0.91), respectively. Standard deviation of the accuracy among all rats was only 2.93%. Both frontal-occipital EEG and parietal EEG data showed comparable accuracies. The results demonstrated the performance of the proposed method with high accuracy and reliability. Subtle changes exhibited in the 5-stage wake-sleep analysis but not in the 3-stage analysis during hyperalgesia development of the acid-induced pain model. Compared with existing methods, our method can automatically classify vigilance states into 5-stage or 3-stage wake-sleep pattern with a promising high agreement with sleep experts., Conclusions: In this study, we have performed and validated a reliable automated sleep scoring system in rats. The classification algorithm is less computation power, a high robustness, and consistency of results. The algorithm can be implanted into a versatile wireless portable monitoring system for real-time analysis in the future.

Background & Problems: An investigation found that 66.7% of the neonatal hypothermia (body temperature < 36.5°C) cases diagnosed within one hour of transfer from the delivery room in our hospital were affected by a significantly increased risk of physiological abnormalities, which subsequently increased their risk for mortality. Therefore, monitoring and maintaining the normal body temperature of newborn infants are vital in infant care., Purpose: This project aimed to improve the current situation of neonatal hypothermia., Resolution: This project was implemented from Oct. 1, 2016 to Oct. 31, 2017 and used several approaches to improve neonatal hypothermia. A neonatal hypothermia caring protocol was developed and the infant admission materials were standardized; the infant hypothermia alert card and posters were displayed in easy-to-notice locations; an in-service training course on neonatal hypothermia was provided; and an infant hypothermia care checklist was tabulated for examination and recognition., Results: After the implementation of this project, the average time required to raise the body temperature of infants to normal (36.5°C) was 1.5 hours, which was 2 hours faster than the pre-project time of 3.5 hours. Moreover, the time needed to raise the body temperature to normal was one hour for newborn infants with birthweights ≥ 2,500 grams, which was one hour faster than the pre-project time of two hours, and 1.5 hours for newborn infants with birthweights < 2,500 grams, which was three hours faster than the pre-project time of 4.5 hours. The goals of this project were effectively achieved in both groups., Conclusions: Neonatal hypothermia is an important issue affecting the health status of newborn infants. This project strengthened the awareness of nurses regarding neonatal hypothermia and is worthwhile to be implemented in clinical neonatal care.

Objective: The incidence of gastroesophageal reflux disease (GERD) is increasing, and the disease has a close association with dietary habits. This study aims to investigate the role of tea and coffee drinking in the development of GERD., Materials and Methods: This study prospectively enrolled individuals who underwent an upper gastrointestinal endoscopy during a health checkup. Each participant completed the reflux disease questionnaire (RDQ). Coffee or tea drinking was defined as drinking the beverage at least 4 days/week for 3 months. Heavy coffee or tea consumption was defined as drinking at least two cups every day., Results: A total of 1837 participants (970 men; age 51.57 ± 10.21 years), who had data on clinical characteristics and consumption of coffee and tea with or without additives such as milk or sugar were included for final analysis. Among them, 467 (25.4%) were diagnosed as having symptomatic GERD based on the RDQ score, and 427 (23.2%) had erosive esophagitis (EE) on endoscopy. Drinking coffee or tea was not associated with reflux symptoms or EE in univariate and multivariate analyses. In contrast, drinking coffee with milk was associated with reflux symptoms and drinking "tea and coffee" was associated with EE in univariate analysis. However, these associations became insignificant after multivariate analysis., Conclusion: Drinking coffee or tea and adding milk or sugar was not associated with reflux symptoms or EE., Competing Interests: There are no conflicts of interest.