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Yu-Jun Shi,1,* Li-Feng Wang,1,* Jun Ma,1 Yi Chen,1 Wei-Jun Wang,2 Cui-Ying Xie1 1Department of Emergency, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 2Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Cui-Ying Xie, Department of Emergency, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China, Tel +86 13817204797, Email xiecuiying25@126.comObjective: The clinical manifestations and treatment of three patients with hemodynamically unstable lupus myocarditis (LM) were analyzed.Methods: The clinical data of three patients with LM with hemodynamic instability, who were admitted to the emergency ICU of the south hospital of the Renji Hospital, School of Medicine, Shanghai Jiao Tong University of Medicine from January 2018 to December 2021, were collected and analyzed, and relevant literatures were reviewed.Results: Two of the three patients had the first onset of systemic lupus erythematosus. The other patient had mixed connective tissue disease in the past, and lupus was the main manifestation of this disease. At the onset of the disease, all patients had chest tightness and shortness of breath; two patients had a fever, and the markers of myocardial injury increased. Cardiac color Doppler ultrasound indicated that left ventricular ejection fraction decreased significantly. Cardiac insufficiency with cardiogenic shock rapidly appeared as the main manifestation. Two patients immediately started veno-arterial extracorporeal membrane oxygenation (VA-ECMO), and ECMO was also started in one patient after a pacemaker placement was ineffective. For all three patients, high-dose hormones were given to control the primary disease, and then the ECMO machines were removed successfully.Conclusion: VA-ECMO treatment should be implemented in patients with hemodynamically unstable LM as soon as possible to maintain the patient’s hemodynamics and help them overcome the crisis of cardiac dysfunction, allowing more time for primary disease treatment.Keywords: VA-ECMO, lupus myocarditis, hemodynamic instability

COVID-19 survivors concerning about the rehabilitation and sustained sequelae of Coronavirus Disease 2019 (COVID-19) infection. We aimed to investigate the sequelae of patients' psychological and physical condition and its related factors in the early and late stages. This longitudinal study tracked 281 COVID-19 patients discharged from hospitals in Guangdong, China, for one year. Assessments occurred at 2,4,12,24 and 48 weeks post-discharge. We define 2 weeks, 4 weeks, and 12 weeks as early stage, and 24 weeks and 48 weeks as late stage. Psychological health was measured using the Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5), and Pittsburgh Sleep Quality Index (PSQI) scales. Physical health was assessed through laboratory tests, chest computed tomography (CT) scans, and pulmonary function tests. Data were analyzed using multivariate regression models to evaluate the influence of demographic and clinical variables on health outcomes. COVID-19 survivors exhibited psychological and physical sequelae in both the early and late stages. Compared to the early stage, the proportions of patients with depression (early stage 14.6%, late stage 4.6%), anxiety (early stage 8.9%, late stage 5.3%), PTSD(early stage 3.6%, late stage 0.7%), abnormal liver function (early stage 24.6%, late stage 11.0%), abnormal cardiac function (early stage 10.0%, late stage 7.8%), abnormal renal function (early stage 20.6%, late stage 11.0%) and abnormal pulmonary function (early stage 40.9%, late stage 13.5%) were significantly reduced in the late stage. Factors such as gender, age, severity of COVID-19, hospitalization duration, and various comorbidities were significantly associated with these sequelae. We noticed that psychological and physical sequelae occurred to COVID-19 survivors in short and long stages, and these would gradually decrease as time went on. Male gender, age > 50 years old, severe clinical condition, longer hospitalization time and comorbidity history were related factors that significantly affected the rehabilitation of COVID-19 patients., (© 2024. The Author(s).)

Heterochromatin, a key component of the eukaryotic nucleus, is fundamental to the regulation of genome stability, gene expression and cellular functions. However, the factors and mechanisms involved in heterochromatin formation and maintenance still remain largely unknown. Here, we show that insulin receptor tyrosine kinase substrate (IRTKS), an I-BAR domain protein, is indispensable for constitutive heterochromatin formation via liquid‒liquid phase separation (LLPS). In particular, IRTKS droplets can infiltrate heterochromatin condensates composed of HP1α and diverse DNA-bound nucleosomes. IRTKS can stabilize HP1α by recruiting the E2 ligase Ubc9 to SUMOylate HP1α, which enables it to form larger phase-separated droplets than unmodified HP1α. Furthermore, IRTKS deficiency leads to loss of heterochromatin, resulting in genome-wide changes in chromatin accessibility and aberrant transcription of repetitive DNA elements. This leads to activation of cGAS-STING pathway and type-I interferon (IFN-I) signaling, as well as to the induction of cellular senescence and senescence-associated secretory phenotype (SASP) responses. Collectively, our findings establish a mechanism by which IRTKS condensates consolidate constitutive heterochromatin, revealing an unexpected role of IRTKS as an epigenetic mediator of cellular senescence., (© 2024. The Author(s).)

Objectives: To observe effects of electroacupuncture (EA) on the activation of astrocytes and high mobility group protein B1(HMGB1)/Toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88) signaling pathway, as well as related cytokines in rats with cervical spondylosis radiculopathy(CSR), so as to explore the analgesic mechanism of EA in treating CSR., Methods: Twenty-four male SD rats were randomly divided into blank, sham surgery, model, and EA groups, with 6 rats in each group. CSR rat model was established by using cervical spinal cord canal puncture method. On the 7 th day after successful modeling, EA was applied to rats in the EA group at bilateral "Hegu"(LI4) and "Taichong"(LR3) for 20 minutes(1.5 Hz, 1 mA), once daily for 7 consecutive days. Before and after intervention, gait impairment scores and mechanical pain thresholds were assessed. HE staining was used to observe pathological changes in spinal cord tissue. Western blot was used to detect the expression of HMGB1, TLR4, MyD88, and glial fibrillary acidic protein (GFAP) in the spinal cord. ELISA was used to measure the contents of CXC chemokine ligand 1 (CXCL1), chemokine ligand 2 (CCL2), tumor necrosis factor (TNF)-α, and interleukin (IL)-1β in spinal cord. Immunofluorescence staining was used to observe GFAP protein positive expression in spinal cord tissue., Results: There was no significant difference of all indexes between the blank group and the sham surgery group. Compared with the sham surgery group, mechanical pain threshold of rats in the model group was decreased( P <0.01), while gait impairment score, the contents of CXCL1, CCL2, TNF-α, IL-1β, protein expressions of HMGB1, TLR4, MyD88 and GFAP, and positive expression of GFAP in spinal cord tissue were increased ( P <0.01)；HE staining indicated severe overall morphological damage in the spinal cord of rats in the model group, with significant shrinkage of gray matter neurons, reduced number of Nissl bodies, and increased inflammatory cell infiltration. Compared with the model group, mechanical pain threshold in the EA group was increased ( P <0.01), while gait impairment score, the contents of CXCL1, CCL2, TNF-α, IL-1β, protein expressions of HMGB1, TLR4, MyD88 and GFAP, and positive expression of GFAP in spinal cord were reduced ( P <0.01)；HE staining showed more intact neuronal cell bodies, increased number of Nissl bodies, and reduced shrinkage of gray matter neurons, inflammatory cell infiltration, and microvascular dilation in the spinal cord of rats in the EA group., Conclusions: EA can effectively alleviate pain in CSR rats, which is possibly by inhibiting astrocyte activation, HMGB1/TLR4/MyD88 signaling pathway, and reducing the release of related inflammatory cytokines, thus alleviating central sensitization in spinal segments.

Protein structure prediction is important for understanding their function and behavior. This review study presents a comprehensive review of the computational models used in predicting protein structure. It covers the progression from established protein modeling to state-of-the-art artificial intelligence (AI) frameworks. The paper will start with a brief introduction to protein structures, protein modeling, and AI. The section on established protein modeling will discuss homology modeling, ab initio modeling, and threading. The next section is deep learning-based models. It introduces some state-of-the-art AI models, such as AlphaFold (AlphaFold, AlphaFold2, AlphaFold3), RoseTTAFold, ProteinBERT, etc. This section also discusses how AI techniques have been integrated into established frameworks like Swiss-Model, Rosetta, and I-TASSER. The model performance is compared using the rankings of CASP14 (Critical Assessment of Structure Prediction) and CASP15. CASP16 is ongoing, and its results are not included in this review. Continuous Automated Model EvaluatiOn (CAMEO) complements the biennial CASP experiment. Template modeling score (TM-score), global distance test total score (GDT&#95;TS), and Local Distance Difference Test (lDDT) score are discussed too. This paper then acknowledges the ongoing difficulties in predicting protein structure and emphasizes the necessity of additional searches like dynamic protein behavior, conformational changes, and protein-protein interactions. In the application section, this paper introduces some applications in various fields like drug design, industry, education, and novel protein development. In summary, this paper provides a comprehensive overview of the latest advancements in established protein modeling and deep learning-based models for protein structure predictions. It emphasizes the significant advancements achieved by AI and identifies potential areas for further investigation.

Thermophilic semi-continuous composting (TSC) is effective for kitchen waste (KW) treatment, but large amounts of NH 3 -rich odorous gas are generated. This study proposes a TSC-biofiltration (BF) two-stage process. Compost from the front-end TSC was used as the packing material in the BF to remove NH 3 from the exhaust gas. The BF process was effective in removing up to 83.7 % of NH 3 , and the NH 3 content was reduced to < 8 ppm. Seven days of BF improved the quality of the product from TSC by enhancing the germination index to 134.6 %, 36.5 % higher than that in the aerated-only group. Microbial community analysis revealed rapid proliferation and eventual dominance in the BF of members related to compost maturation and the nitrogen cycle from Actinobacteria, Proteobacteria, Chloroflexi, and Bacteroidetes. The results suggest that the TSC-BF two-stage process is effective in reducing NH 3 emissions from TSC and improving compost quality., 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 © 2024 Elsevier Ltd. All rights reserved.)

Iron plays a key role in maternal health during pregnancy and fetal growth. Enteromorpha polysaccharide-iron (EP-Fe) as an organic iron chelate may improve the iron transmission of mother and offspring, ameliorate the poor pregnancy outcomes of sows, and alleviate the growth restriction of piglets caused by iron deficiency. This study aimed to evaluate the effects of maternal dietary supplementation with EP-Fe on reproductive performance and placental iron transmission of sows, as well as growth performance of piglets. Sixty pregnant sows at the 95th day of gestation were randomly divided into control group and EP-Fe group (EP-Fe, 139 mg kg -1 ). Blood samples of sows and neonatal piglets, colostrum, and tissue samples were collected on the day of delivery. The animal experiment ended at the 21st day of post-delivery. Results showed that maternal dietary EP-Fe increased colostrum iron (P < 0.05) of sows, as well as final litter weight (P < 0.05) and average daily weight of piglets (P < 0.05) during days 1-21 of lactation, as well as iron and manganese content in umbilical cord blood (P < 0.05) and hepatic iron of neonatal piglets (P < 0.01), and decreased fecal iron (P < 0.001), serum calcium (P < 0.05), phosphorus (P < 0.05), and zinc (P < 0.01) in the parturient sow. RT-qPCR results showed that Fpn1 and Zip14 in placenta, as well as TfR1 and Zip14 in duodenum of neonatal piglets, were activated by maternal EP-Fe supplement. These findings suggest that maternal dietary EP-Fe could increase iron storage of neonatal piglets via improving placental iron transport and iron secretion in colostrum, thus enhancing the growth performance of sucking piglets., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The production of succinic acid (SA) from biomass has attracted worldwide interest. Saccharomyces cerevisiae is preferred for SA production due to its strong tolerance to low pH conditions, ease of genetic manipulation, and extensive application in industrial processes. However, when compared with bacterial producers, the SA titers and productivities achieved by engineered S. cerevisiae strains were relatively low. To develop efficient SA-producing strains, it's necessary to clearly understand how S. cerevisiae cells respond to SA., Results: In this study, we cultivated five S. cerevisiae strains with different genetic backgrounds under different concentrations of SA. Among them, KF7 and NBRC1958 demonstrated high tolerance to SA, whereas NBRC2018 displayed the least tolerance. Therefore, these three strains were chosen to study how S. cerevisiae responds to SA. Under a concentration of 20 g/L SA, only a few differentially expressed genes were observed in three strains. At the higher concentration of 60 g/L SA, the response mechanisms of the three strains diverged notably. For KF7, genes involved in the glyoxylate cycle were significantly downregulated, whereas genes involved in gluconeogenesis, the pentose phosphate pathway, protein folding, and meiosis were significantly upregulated. For NBRC1958, genes related to the biosynthesis of vitamin B6, thiamin, and purine were significantly downregulated, whereas genes related to protein folding, toxin efflux, and cell wall remodeling were significantly upregulated. For NBRC2018, there was a significant upregulation of genes connected to the pentose phosphate pathway, gluconeogenesis, fatty acid utilization, and protein folding, except for the small heat shock protein gene HSP26. Overexpression of HSP26 and HSP42 notably enhanced the cell growth of NBRC1958 both in the presence and absence of SA., Conclusions: The inherent activities of small heat shock proteins, the levels of acetyl-CoA and the strains' potential capacity to consume SA all seem to affect the responses and tolerances of S. cerevisiae strains to SA. These factors should be taken into consideration when choosing host strains for SA production. This study provides a theoretical basis and identifies potential host strains for the development of robust and efficient SA-producing strains., (© 2024. The Author(s).)

Precipitation in the plum rain period accounts for 40%-50% of annual precipitation in the monsoon region. To clarify the temporal variability of the isotopic composition of precipitation during the plum rain period from event to interannual time scale and identify the influencing factors, we analyzed the isotopic composition of precipitation and its influencing factors in Nanjing from 2015 to 2022. By using the Hybrid Single-particle Lagran-gian Integrated Trajectory (HYSPLIT) model with specific humidity analysis, we investigated the water vapor source and influencing factors. The results showed that 1) the isotopic abundance of atmospheric precipitation was depleted in the summer and enriched in winter. d x was lower in summer and higher in winter. The isotopic abundance of precipitation from the plum rain was depleted compared to mean value of the whole-year. 2) There was no significant correlation between δ 2 H and δ 1 8 O of the plum rain (precipitation) with local meteorological factors. However, d x was lower in light rain, reflecting the effect of sub-cloud evaporation. The average d x was higher during plum rain period in years with more total plum rain precipitation. 3) The low-latitude South China Sea and the western Pacific Ocean source area provided water vapor for the plum rain. The shift of moisture source region led to abrupt changes in precipitation isotopes. Our results could provide data support for studies on precipitation isotopes in the monsoon region, as well as a reference point for further understanding the precipitation mechanism of the plum rain and stu-dying the seasonal variability of atmospheric circulation in the East Asian monsoon region.

HER3 (human epidermal growth factor receptor 3) acts through heterodimerization with EGFR (epidermal growth factor receptor) or HER2 to play an essential role in activating phosphoinositide 3-kinase (PI3K) and AKT signaling-a crucial pathway that promotes tumor cell survival. HER3 is a promising target for cancer therapy, and several HER3-directed antibodies have already entered into clinical trials. In this study we characterized a novel anti-HER3 monoclonal antibody, SIBP-03. SIBP-03 (0.01-10 μg/mL) specifically and concentration-dependently blocked both neuregulin (NRG)-dependent and -independent HER3 activation, attenuated HER3-mediated downstream signaling and inhibited cell proliferation. This antitumor activity was dependent, at least in part, on SIBP-03-induced, cell-mediated cytotoxicity and cellular phagocytosis. Importantly, SIBP-03 enhanced the antitumor activity of EGFR- or HER2-targeted drugs (cetuximab or trastuzumab) in vitro and in vivo. The mechanisms underlying this synergy involve increased inhibition of HER3-mediated downstream signaling. Collectively, these results demonstrated that SIBP-03, which is currently undergoing a Phase I clinical trial in China, may offer a new treatment option for patients with cancers harboring activated HER3, particularly as part of a combinational therapeutic strategy., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Background: Acute kidney injury (AKI) has high morbidity and mortality, which is manifested by inflammation and apoptosis. Effective treatment methods for AKI are currently lacking., Objective: This study demonstrated the protecting effects of Madecassoside (MA) in the cisplatin- and hypoxia-reoxygenation-induced renal tubular epithelial cells in vitro and AKI mice in vivo., Methods: In vivo AKI mouse models were established by inducing them with cisplatin and renal ischemia-reperfusion. In vitro injury models of mouse renal tubular epithelial cells were established by inducing them with cisplatin and hypoxia and reoxygenation, respectively. The mechanism of MA effects was further explored using molecular docking and RNA-sequencing., Results: MA could significantly reduce kidney injury in the cisplatin-and renal ischemia-reperfusion (IRI)-induced AKI. Further validation in the two cellular models also showed that MA had protect effects. MA can alleviate AKI in vitro and in vivo by inhibiting inflammation, cell apoptosis, and oxidative stress. MA exhibited high permeability across the Caco-2 cell, can enter cells directly. Through RNA-seq and molecular docking analysis, this study further demonstrated that MA inhibits its activity by directly binding to JNK kinase, thereby inhibiting c-JUN mediated cell apoptosis and improving AKI. In addition, MA has better renal protective effects compared to curcumin and JNK inhibitor SP600125., Conclusion: The results demonstrate that MA might be a potential drug for the treatment of AKI and act through the JNK/c-JUN signaling pathway., Competing Interests: Declaration of Competing Interest We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted., (Copyright © 2023. Published by Elsevier GmbH.)

Rationale: Immune dysregulation is a common feature of pulmonary arterial hypertension (PAH). Histone deacetylase (HDAC)-dependent transcriptional reprogramming epigenetically modulates immune homeostasis and is a novel disease-oriented approach in modern times. Objectives: To identify a novel functional link between HDAC and regulatory T cells (Tregs) in PAH, aiming to establish disease-modified biomarkers and therapeutic targets. Methods: Peripheral blood mononuclear cells were isolated from patients with idiopathic PAH (IPAH) and rodent models of pulmonary hypertension (PH): monocrotaline rats, Sugen5416-hypoxia rats, and Treg-depleted mice. HDAC inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) was used to examine the immune modulatory effects in vivo , ex vivo , and in vitro . Measurements and Main Results: Increased HDAC expression was associated with reduced Foxp3 + Tregs and increased PD-1 (programmed cell death-1) signaling in peripheral blood mononuclear cells from patients with IPAH. SAHA differentially modified a cluster of epigenetic-sensitive genes and induced Foxp3 + Treg conversion in IPAH T cells. Rodent models recapitulated these epigenetic aberrations and T-cell dysfunction. SAHA attenuated PH phenotypes and restored FOXP3 transcription and Tregs in PH rats; interestingly, the effects were more profound in female rats. Selective depletion of CD25 + Tregs in Sugen5416-hypoxia mice neutralized the effects of SAHA. Furthermore, SAHA inhibited endothelial cytokine/chemokine release upon stimulation and subsequent immune chemotaxis. Conclusions: Our results indicated HDAC aberration was associated with Foxp3 + Treg deficiency and demonstrated an epigenetic-mediated mechanism underlying immune dysfunction in PAH. Restoration of Foxp3 + Tregs by HDAC inhibitors is a promising approach to resolve pulmonary vascular pathology, highlighting the potential benefit of developing epigenetic therapies for PAH.

The detection of nucleic acid sequences in parallel with the discrimination of single nucleotide variations (SNVs) is critical for research and clinical applications. A few limitations make the detection technically challenging, such as too small variation in probe-hybridization energy caused by SNVs, the non-specific amplification of false nucleic acid fragments and the few options of dyes limited by spectral overlaps. To circumvent these limitations, we developed a single-molecule nucleic acid detection assay without amplification or fluorescence termed THREF (hybridization-induced tandem DNA hairpin refolding failure) based on multiplexed magnetic tweezers. THREF can detect DNA and RNA sequences at femtomolar concentrations within 30 min, monitor multiple probes in parallel, quantify the expression level of miR-122 in patient tissues, discriminate SNVs including the hard-to-detect G-U or T-G wobble mutations and reuse the probes to save the cost. In our demonstrative detections using mock clinic samples, we profiled the let-7 family microRNAs in serum and genotyped SARS-CoV-2 strains in saliva. Overall, the THREF assay can discriminate SNVs with the advantages of high sensitivity, ultra-specificity, multiplexing, reusability, sample hands-free and robustness., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Global transcription machinery engineering (gTME) is an effective approach employed in strain engineering to rewire gene expression and reshape cellular metabolic fluxes at the transcriptional level., Results: In this study, we utilized gTME to engineer the positive transcription factor, DegU, in the regulation network of major alkaline protease, AprE, in Bacillus pumilus. To validate its functionality when incorporated into the chromosome, we performed several experiments. First, three negative transcription factors, SinR, Hpr, and AbrB, were deleted to promote AprE synthesis. Second, several hyper-active DegU mutants, designated as DegU(hy), were selected using the fluorescence colorimetric method with the host of the Bacillus subtilis ΔdegSU mutant. Third, we integrated a screened degU(L113F) sequence into the chromosome of the Δhpr mutant of B. pumilus SCU11 to replace the original degU gene using a CRISPR/Cas9 system. Finally, based on transcriptomic and molecular dynamic analysis, we interpreted the possible mechanism of high-yielding and found that the strain produced alkaline proteases 2.7 times higher than that of the control strain (B. pumilus SCU11) in LB medium., Conclusion: Our findings serve as a proof-of-concept that tuning the global regulator is feasible and crucial for improving the production performance of B. pumilus. Additionally, our study established a paradigm for gene function research in strains that are difficult to handle., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Introduction: The COVID-19 pandemic affected the lives of military members and their families, with over 400,000 cases among U.S. military members since the start of the pandemic. The objective of this study is to examine and compare COVID-19 vaccination coverage of military members (active duty and Reserve/National Guard) and their family members (spouses, children, and adolescents) to that of their civilian counterparts using a large, nationally representative study., Methods: Data from March 2 to May 9, 2022, of the Household Pulse Survey were analyzed for this study (n = 207,758). COVID-19 vaccination status (≥1 dose) was assessed for military members and their spouses, civilians, and children (aged 5 to 11 and 12 to 17 years) from both military and civilian families. Differences between military members, spouses, and their children compared to civilian adults and children were assessed using chi-squared and t-tests. Multivariable logistic regression was used to examine the association between military status and COVID-19 vaccination after controlling for sociodemographic characteristics. Reasons for not getting vaccinated for adults and children from military and civilian families were assessed., Results: Compared to civilian adults and adjusted for sociodemographic characteristics, military members were more likely to be vaccinated (adjusted prevalence ratio = 1.07, 95% CI: 1.01-1.13). Vaccination coverage between active duty and civilian adults differed by subgroups. For example, among military members, COVID-19 vaccination coverage decreased with increasing age, from 87.5% among those aged 18 to 39 years to 56.0% among those aged ≥55 years. In contrast, among civilian adults, vaccination coverage increased with increasing age, from 78.5% among those aged 18 to 39 years to 91.2% among those aged ≥55 years. Military members were also less likely to be vaccinated than their civilian counterparts if they were Hispanic (68.5% vs. 85.2%), had a Bachelor's degree or higher (87.5% vs. 93.8%), or had $100,000 or more in annual household income (76.7% vs. 92.6%). Military members who had anxiety or depression (70.1%) were less likely to be vaccinated compared to civilian adults (84.4%). Military spouses (74.4%) were less likely to be vaccinated than civilian adults (84.7%). Children and adolescents who were homeschooled (35.1%) or had no preventive checkups in the past year (32.4%) were less likely to be vaccinated than their respective counterparts (52.5% and 54.0%, respectively). Military adults compared to civilian adults were more likely to report lack of trust in the government (47.5% vs. 35.2%) and, for children/adolescents, the belief that the vaccine is not needed (42.1% vs. 28.1%) as reasons for non-vaccination., Conclusions: Despite vaccine mandates and the high vaccination coverage found among the majority of military members, disparities exist in some subgroups. Educational interventions and increased communication from trusted leaders, such as medical providers and commanders, could increase confidence in vaccines among military families. Ensuring access to vaccines, empowering healthcare providers to recommend vaccines, and reminding parents of missed vaccinations or preventive checkups can help improve vaccination coverage. Achieving high vaccination among military members and their families is essential in protecting those in the forefront of the pandemic response and promoting the safety and security of the nation., (© The Association of Military Surgeons of the United States 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Contezolid acefosamil is a novel O-acyl phosphoramidate prodrug of contezolid. In the current study, we aimed to systemically evaluate the efficacy of contezolid acefosamil against infections caused by multiple Gram-positive pathogens, and compare the efficacy of the prodrug by oral and intravenous administrations., Methods: The in vivo pharmacodynamic efficacy of contezolid acefosamil was evaluated in mouse models of systemic (with five S. aureus, three S. pneumoniae and two S. pyogenes bacterial isolates) and thigh (with two S. aureus isolates) infections using linezolid as the reference agent., Results: In both models, contezolid acefosamil administrated either orally or intravenously, demonstrated high antibacterial efficacy similar to linezolid, and the antibacterial efficacy of oral and intravenous contezolid acefosamil were comparable., Conclusions: The high aqueous solubility and great efficacy of contezolid acefosamil support its clinical development as an injectable and oral antibiotic suitable for serious Gram-positive infections., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The KRAS G12C mutant has emerged as an important therapeutic target in recent years. Covalent inhibitors have shown promising antitumor activity against KRAS G12C -mutant cancers in the clinic. In this study, a structure-based and focused chemical library analysis was performed, which led to the identification of 143D as a novel, highly potent and selective KRAS G12C inhibitor. The antitumor efficacy of 143D in vitro and in vivo was comparable with that of AMG510 and of MRTX849, two well-characterized KRAS G12C inhibitors. At low nanomolar concentrations, 143D showed biochemical and cellular potency for inhibiting the effects of the KRAS G12C mutation. 143D selectively inhibited cell proliferation and induced G 1 -phase cell cycle arrest and apoptosis by downregulating KRAS G12C -dependent signal transduction. Compared with MRTX849, 143D exhibited a longer half-life and higher maximum concentration (C max ) and area under the curve (AUC) values in mouse models, as determined by tissue distribution assays. Additionally, 143D crossed the blood‒brain barrier. Treatment with 143D led to the sustained inhibition of KRAS signaling and tumor regression in KRAS G12C -mutant tumors. Moreover, 143D combined with EGFR/MEK/ERK signaling inhibitors showed enhanced antitumor activity both in vitro and in vivo. Taken together, our findings indicate that 143D may be a promising drug candidate with favorable pharmaceutical properties for the treatment of cancers harboring the KRAS G12C mutation., (© 2023. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

The O-carbamoyltransferase VtdB catalyzes the carbamoylation of venturicidin B, which is essential for the biosynthesis of the antibiotic venturicidin A. Here, the crystal structures of VtdB and VtdB in complex with the intermediate carbamoyladenylate (VtdB CAO ) were determined at resolutions of 2.99 Å and 2.90 Å, respectively. The structures resemble the conserved YrdC-like and specific Kae1-like domains. A magnesium ion and the intermediate carbamoyladenylate were also observed in the Kae1-like domain of VtdB. The structure of VtdB CAO in complex with the substrate venturicidin B was modeled by a molecular docking method to better understand the substrate binding mode, revealing a novel venturicidin B binding pocket., 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 © 2023 Elsevier Inc. All rights reserved.)

To explore an effective decentralized kitchen waste (KW) treatment system, the performance and bacterial community succession of thermophilic semi-continuous composting (TSC) of KW followed by static stacking (SS) was studied. A daily feeding ratio of 10% ensured stable performance of TSC using an integrated automatic reactor; the efficiencies of organic matter degradation and seed germination index (GI) reached 80.88% and 78.51%, respectively. SS for seven days further promoted the quality of the compost by improving the GI to 91.58%. Alpha- and beta-diversity analyses revealed significant differences between the bacterial communities of TSC and SS. Firmicutes, Actinobacteria, Chloroflexi, Gemmatimonadetes, and Myxococcota were dominant during the TSC of KW, whereas the members of Proteobacteria and Bacteroidetes responsible for product maturity rapidly proliferated during the subsequent SS and ultimately dominated the compost with Firmicutes and Actinobacteria. These results provide new perspectives for decentralized KW treatment using TSC for practical applications., 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 © 2023 Elsevier Ltd. All rights reserved.)

The increasing and intensifying ultraviolet B (UVB) radiation in sunlight is an environmental threat to aquatic ecosystems, potentially affecting the entire life cycle of wild or aquacultural Pacific oyster Crassostrea gigas with photoreception. Due to its complex composition, plasma is an important biological specimen for investigating the degree of disturbance from its steady state caused by the external environment in the open-pipe-type hemolymph of mollusks. We performed a multi-omic analysis of C. gigas plasma exposed to daylight UVB radiation. Hub differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) were identified using the functional classification of Clusters of Orthologous Groups of proteins (COGs) through the protein-protein interaction (PPI)-based maximal clique centrality (MCC) algorithm. Our results summarize three types of UVB influences (disruption of the cell membrane, promotion of nucleotide metabolism, and inhibition of energy metabolism) on C. gigas based on transcriptomic, proteomic, and metabolomic analyses. The associated hub DEGs, DEPs (e.g., nucleoside diphosphate kinase, malate dehydrogenase, and hydroxyacyl-coenzyme A dehydrogenase), and metabolites (e.g., uridine, adenine, deoxyguanosine, guanosine, and xylitol) in the plasma were identified as biomarkers of mollusk response to UVB radiation, and could be used to evaluate the influence of environmental UVB on mollusks in future studies., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2022 Elsevier B.V. All rights reserved.)

This study evaluated the compostability of rice straw as the main feedstock (75 % in dry weight), supplemented with three different nitrogen-rich wastes, namely food waste (FW), dairy manure (DM), and sewage sludge (SS). Organic matter (OM) degradation, maturity and fertility of the end-product, and bacterial community structure during the composting processes were compared. All composting processes generated mature end-product within 51 days. Notably, FW addition was more effective to accelerate rice straw OM degradation and significantly improved end-product fertility with a high yield of Chinese cabbage. The succession of the bacterial community was accelerated with FW supplementation. Genera Geobacillus, Chryseolinea, and Blastocatella were significantly enriched during the composting of rice straw with FW supplementation. Finally, temperature, total nitrogen, moisture, pH, and total carbon were the key factors affecting microorganisms. This study provides a promising alternative method to enhance the disposal of larger amounts of rice straw in a shorter time., 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 © 2022 Elsevier Ltd. All rights reserved.)

This study evaluated the feasibility, system stability, and microbial community succession of thermophilic semi-continuous composting of kitchen waste (KW). The results revealed that treatment performance was stable at a 10 % feeding ratio, with an organic matter (OM) degradation efficiency of 81.5 % and seed germination index (GI) of 50.0 %. Moreover, the OM degradation efficiency and GI were improved to 83.4 % and 70.0 %, respectively, by maintaining an optimal compost moisture content (50-60 %). However, feeding ratios of ≥ 20 % caused deterioration of the composter system owing to OM overloading. Microbial community analysis revealed that Firmicutes, Actinobacteria, Chloroflexi, Proteobacteria, and Gemmatimonadetes were dominant. Additionally, moisture regulation significantly increased the Proteobacteria abundance by 57.1 % and reduced the Actinobacteria abundance by 57.8 %. Moreover, network analysis indicated that the bacterial community stability and positive interactions between genera were enhanced by moisture regulation. This information provides a useful reference for practical KW composting treatment in the semi-continuous mode., 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 © 2022 Elsevier Ltd. All rights reserved.)

Sishen pill (SSP) is an old Chinese medicine used to treat colitis with spleen-kidney-yang deficiency (SKYD) syndromes. However, its exact mechanism of action has not yet been fully elucidated. The aim of this study was to evaluate the effects and potential mechanisms of SSP on colitis with SKYD syndromes in mice. Colitis with SKYD syndromes was induced by rhubarb, hydrocortisone, and dextran sulfate sodium (DSS), and treatment was provided with SSP. Flow cytometry was performed to examine the inflammatory dendritic cell (infDC) regulations of SSP. The changes in the gut microbiota (GM) and fecal metabolites post-SSP treatment were investigated using the combination of 16S rRNA sequencing and untargeted metabolomics. Additionally, we also examined whether SSPs could regulate the infDCs by modifying TLR4/NF- κ B signaling pathways. Compared with the DSS group, the disease activity index, colonic weight, index of colonic weight, and colonic injury scores, as well as the levels of tumor necrosis factor (TNF)- α , interleukin (IL)-1 β , IL-6, and IL-12p70 decreased significantly in the DSS + SSP group, while free triiodothyronine (FT3), free tetraiodothyronine (FT4), testosterone (TESTO), body weight change, colonic length, and the levels of IL-10 increased. Also, SSP decreased the amounts of CD103 + CD11c + iNOS + , CD103 + CD11c + TNF- α + , CD11c + CD103 + CD324 + , CD103 + CD11c + MHC-II + , and CD103 + CD11c + CD115 + . Interestingly, 16S rRNA sequencing and untargeted metabolomics showed that SSP treatment restored the dysbiosis of GM and improved the dysfunction in fecal metabolism in colitis mice with SKYD syndromes. Correlation analysis indicated that the modulatory effects of SSP on FT3, FT4, IL-10, colonic weight index, CD103 + CD11c + TNF- α + , CD103 + CD11c + MHC-II + , and 13 common differential metabolites were related to alterations in the abundance of Parvibacter, Aerococcus, norank&#95;f&#95;Lachnospiraceae, Lachnospiraceae&#95;UCG-006, Akkermansia, and Rhodococcus in the GM. In addition, SSP markedly inhibited the activation of the TLR4, MyD88, TRAF6, TAB2, and NF- κ Bp65 proteins and activated I κ B. These results indicate that SSP can effectively alleviate colitis mice with SKYD syndrome by regulating infDCs, GM, fecal metabolites, and TLR4/NF- κ B signaling pathways., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Wei Ge et al.)

Inhibitors targeting the antiapoptotic molecule BCL-2 have therapeutic potential for the treatment of acute myeloid leukaemia (AML); however, BCL-2 inhibitors such as venetoclax exhibit limited monotherapy efficacy in relapsed or refractory human AML. PI3Kδ/AKT signalling has been shown to be constitutively active in AML patients. Here, we demonstrate that the combination of BCL-2 and PI3Kδ inhibitors exerts synergistic antitumour effects both in vitro and in vivo in AML. Cotreatment with venetoclax and the specific PI3Kδ inhibitor idelalisib significantly enhanced antiproliferative effects and induced caspase-dependent apoptosis in a panel of AML cell lines. The synergistic effects were mechanistically based on the inactivation of AKT/4E-BP-1 signalling and the reduction of MCL-1 expression, which diminished the binding of Bim to MCL-1. Notably, compared with the parental FLT3-ITD-positive MV-4-11, the acquired FLT3 inhibitor quizartinib-resistant xenograft model carrying the F691L mutation, exhibited a markedly higher sensitivity to venetoclax. Furthermore, venetoclax combined with idelalisib led to tumour regression in all animals in this quizartinib-resistant AML model. Thus, these data indicate that combined inhibition of BCL-2 and PI3Kδ may be a promising strategy in AML, especially for patients with FLT3-ITD and/or FLT3-TKD mutations., Competing Interests: None., (AJCR Copyright © 2022.)

Objective: The aim of this study was to assess the current status of disease-related knowledge and to analyze the relationship among the general condition, illness perception, and psychological status of patients with coronavirus disease 2019 (COVID-19)., Methods: A hospital-based cross-sectional study was conducted on 118 patients using convenience sampling. The general questionnaire, disease-related knowledge questionnaire of COVID-19, Illness Perception Questionnaire (IPQ), and Profile of Mood States (POMS) were used to measure the current status of participants., Results: The overall average score of the disease-related knowledge of patients with COVID-19 was (79.19 ± 14.25), the self-care situation was positively correlated with knowledge of prevention and control ( r = 0.265; P = 0.004) and total score of disease-related knowledge ( r = 0.206; P = 0.025); the degree of anxiety was negatively correlated with the knowledge of diagnosis and treatment ( r = -0.182; P = 0.049). The score of disease-related knowledge was negatively correlated with negative cognition (volatility, consequences, emotional statements) and negative emotions (tension, fatigue, depression) ( P < 0.05); positively correlated with positive cognition (disease coherence) and positive emotion (self-esteem) ( P < 0.05)., Conclusions: It was recommended that we should pay more attention to the elderly and low-income groups, and increase the knowledge about diagnosis and treatment of COVID-19 and self-care in the future health education for patients.

Background: Various inhibitors coexist in the hydrolysate derived from lignocellulosic biomass. They inhibit the performance of Saccharomyces cerevisiae and further restrict the development of industrial bioethanol production. Transcription factors are regarded as targets for constructing robust S. cerevisiae by genetic engineering. The tolerance-related transcription factors have been successively reported, while their regulatory mechanisms are not clear. In this study, we revealed the regulation mechanisms of Haa1p and Tye7p that had outstanding contributions to the improvement of the fermentation performance and multiple inhibitor tolerance of S. cerevisiae., Results: Comparative transcriptomic analyses were applied to reveal the regulatory mechanisms of Haa1p and Tye7p under mixed sugar fermentation conditions with mixed inhibitors [acetic acid and furfural (AFur)] or without inhibitor (C) using the original strain s6 (S), the HAA1-overexpressing strain s6H3 (H), and the TYE7-overexpressing strain s6T3 (T). The expression of the pathways related to carbohydrate, amino acid, transcription, translation, cofactors, and vitamins metabolism was enhanced in the strains s6H3 and s6T3. Compared to C&#95;H vs. C&#95;S group, the unique DEGs in AFur&#95;H vs. AFur&#95;S group were further involved in oxidative phosphorylation, purine metabolism, vitamin B6 metabolism, and spliceosome under the regulation of Haa1p. A similar pattern appeared under the regulation of Tye7p, and the unique DEGs in AFur&#95;T vs. AFur&#95;S group were also involved in riboflavin metabolism and spliceosome. The most significant difference between the regulations of Haa1p and Tye7p was the intracellular energy supply. Haa1p preferred to enhance oxidative phosphorylation, while Tye7p tended to upregulate glycolysis/gluconeogenesis., Conclusions: Global gene expressions could be rewired with the overexpression of HAA1 or TYE7. The positive perturbations of energy and amino acid metabolism were beneficial to the improvement of the fermentation performance of the strain. Furthermore, strengthening of key cofactor metabolism, and transcriptional and translational regulation were helpful in improving the strain tolerance. This work provides a novel and comprehensive understanding of the regulation mechanisms of Haa1p and Tye7p in S. cerevisiae., (© 2022. The Author(s).)

Organic fertilizer application can replace a part of chemical fertilizer (CF) to improve the quality and efficiency of litchi production. To further explore the soil microbiological mechanism, with 19-year-old 'Feizixiao' litchi trees as the research objects, we examined the effects of two consecutive years of reduced CF applications (average 21.5% of total nutrients) combined with sheep manure (OF) and bio-organic fertilizers (BIO) on soil microbial diversity, community composition and differential microorganisms. The results showed that reducing the application of chemical fertilizers and combining it with the application of sheep manure and bio-organic fertilizer for two consecutive years could significantly improve yield and quality. The average increase of yield in the two years was 23.1% and 39.0%, respectively. Soil organic matter content and pH increased significantly in response to the combination treatments. Compared to that in the chemical fertilizer treatment, the contents of soil available phosphorus, potassium, calcium, magnesium, iron, manganese, copper, and zinc displayed an increasing trend in the combination treatments. The application of organic fertilizer increased the diversity of bacteria and fungi in rhizosphere soil, but not in non-rhizosphere soil. Both treatments significantly changed soil microbial community structure, increased eutrophic bacterial groups such as Bacteroides, Proteobacteria, and Bacillus phylum, and reduced anatrophic bacterial groups such as Acidobacteria and Chloroflexus. Compared with CF, the relative abundances of MND 1 under OF and TK 10, Gemmatimonas , Pseudolabrys , Trichoderma and Botryotrichum under BIO were significantly increased, which was positively correlated with yield. In conclusion, reducing CF and applying organic ferti-lizer for two consecutive years could effectively improve soil pH and nutrient availability, increase rhizosphere microbial richness and diversity, change soil microbial community structure, and shape microbial communities being more conducive to yield and quality improvement.

Background: Asymptomatic transmission is a major concern for SARS-CoV-2 community spread; however, little information is available on demographic, virological characteristics and prognosis of asymptomatic cases., Methods: All COVID-19 patients hospitalized in Guangdong Province from September 1, 2020 to February 28, 2021, were included and were divided into asymptomatic and symptomaticgroup. The source country of all patients, clinical laboratory test results, the genotype of virus and the time of SARS-CoV-2 RNA turning negative or hospitalization were confirmed., Results: Total 233 patients from 57 different countries or regions were included, with 83 (35.6%) asymptomatic and 150 (64.4%) symptomatic patients. Asymptomatic cases were younger ( P = 0.019), lower rate in comorbidities ( P = 0.021) such as hypertension ( P = 0.083) and chronic liver disease ( P = 0.045), lower PCT ( P = 0.021), DDI ( P < 0.001) and ALT ( P = 0.029), but higher WBC count ( P = 0.002) and lymphocyte ( P = 0.011) than symptomatic patients. As for SARS-CoV-2 subtypes, patients infected with B.1.1 (53.8%), B.1.351 (81.8%) and B.1.524 (60%) are mainly asymptomatic, while infected with B, B.1, B.1.1.63, B.1.1.7, B.1.36, B.1.36.1, B.1.36.16, B.1.5 and B.6 were inclined to be symptomatic. Patients infected with variant B.1.351 and B.1.524 spent longer time in SARS-CoV-2 RNA turn negative (26 days, P = 0.085; 41 days, P = 0.007) and hospitalization (28 days, P = 0.085; 43 days, P = 0.004)., Conclusions: The asymptomatic cases are prone to develop in patients with younger age, less comorbidities andinfected with B.1.1 and B.1.524 variants. More attention should be paid for lineage B.1.524 because it can significantly prolong the SARS-CoV-2 RNA negative conversion time and hospitalization in infected cases., Competing Interests: The 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 Xu, Xie, Li, Ji, Sun, Hu, Li and Fang.)

Background: Strong multiple stress-tolerance is a desirable characteristic for Saccharomyces cerevisiae when different feedstocks are used for economical industrial ethanol production. Random mutagenesis or genome shuffling has been applied for improving multiple stress-tolerance, however, these techniques are generally time-consuming and labor cost-intensive and their molecular mechanisms are unclear. Genetic engineering, as an efficient technology, is poorly applied to construct multiple stress-tolerant industrial S. cerevisiae due to lack of clear genetic targets. Therefore, constructing multiple stress-tolerant industrial S. cerevisiae is challenging. In this study, some target genes were mined by comparative transcriptomics analysis and applied for the construction of multiple stress-tolerant industrial S. cerevisiae strains with prominent bioethanol production., Results: Twenty-eight shared differentially expressed genes (DEGs) were identified by comparative analysis of the transcriptomes of a multiple stress-tolerant strain E-158 and its original strain KF-7 under five stress conditions (high ethanol, high temperature, high glucose, high salt, etc.). Six of the shared DEGs which may have strong relationship with multiple stresses, including functional genes (ASP3, ENA5), genes of unknown function (YOL162W, YOR012W), and transcription factors (Crz1p, Tos8p), were selected by a comprehensive strategy from multiple aspects. Through genetic editing based on the CRISPR/Case9 technology, it was demonstrated that expression regulation of each of these six DEGs improved the multiple stress-tolerance and ethanol production of strain KF-7. In particular, the overexpression of ENA5 significantly enhanced the multiple stress-tolerance of not only KF-7 but also E-158. The resulting engineered strain, E-158-ENA5, achieved higher accumulation of ethanol. The ethanol concentrations were 101.67% and 27.31% higher than those of the E-158 when YPD media and industrial feedstocks (straw, molasses, cassava) were fermented, respectively, under stress conditions., Conclusion: Six genes that could be used as the gene targets to improve multiple stress-tolerance and ethanol production capacities of S. cerevisiae were identified for the first time. Compared to the other five DEGs, ENA5 has a more vital function in regulating the multiple stress-tolerance of S. cerevisiae. These findings provide novel insights into the efficient construction of multiple stress-tolerant industrial S. cerevisiae suitable for the fermentation of different raw materials., (© 2022. The Author(s).)

Objectives: This study aimed to evaluate the immediate accuracy of the digital osteotomy template in the digital stackable template., Methods: From November 2018 to January 2020, 4 patients with dentition loss were selected from the Prosthodontics Department, West China Stomatological Hospital. All patients met the conditions for immediate planting and immediate restoration. Owing to the lack of vertical target-restoration space, the implantation plan included intraoperative osteotomy. According to the preoperative cone beam CT (CBCT) data, combined with aesthetic digital smile design (DSD) analysis, virtual wax design, and so on, the ideal bone plane design was performed. According to the virtual osteotomy plane, the virtual implantation plan was designed, and then the digital stackable template assuming osteotomy template, implantation guide, and temporary restoration were made and 3D printed. Osteotomy was performed under the guidance of digital osteotomy template during the operation. The preoperative CBCT and postoperative CBCT of all patients overlapped, the deviation between the actual osteotomy and the ideal osteotomy was calculated, and the angle deviation between the postoperative bone plane and the ideal bone plane was measured., Results: The ave-rage volume deviation between the postoperative design and the ideal one was 492.94 mm³, accounting for 21.21% of the preset osteotomy volume. The average deviation between the postoperative osteotomy and the ideal osteotomy in four patients was 0.024 8 mm. The average angle between the postoperative bone plane and the ideal bone plane was 6.03°., Conclusions: The displacement deviation of virtual osteotomy design and the actual osteotomy one under the guidance of digital osteotomy template in the digital stackable template are highly consistent with the original design. Thus, this clinical technique is worth popularizing, accurate, and quantifiable.

The chemical constituents from the roots of Aconitum kongboense were studied. Twenty-five diterpenoid alkaloids were isolated from the 95% methanol extract of the roots of A. kongboense by silica gel, reverse-phase silica gel and basic alumina column chromatography. They included a new aconitine-type diterpenoid alkaloid, named as kongboensenine(1), and twenty-four known ones(2-25), i.e., acotarine F(2), acotarine G(3), 14-acetyltalatisamine(4), talatisamine(5), indaconitine(6), yunaconitine(7), chasmanine(8), 6-epi-foresticine(9), homochasmanine(10), 8-deacetyl-yunaconitine(11), chasmaconitine(12), ajaconine(13), franchetine(14), ezochasmanine(15), crassicautine(16), 14-O-deacylcrassicausine(17), genicunine A(18), falconeridine(19), sachaconitine(20), liljestrandisine(21), 8-methyl-14-acetyltalatisamine(22), kongboendine(23), 14-benzoylchasmanine(24) and pseudaconine(25). Their structures were elucidated by common spectroscopic methods including high-resolution electrospray ionization mass spectrometry(HR-ESI-MS) and nuclear magnetic resonance(NMR) techniques. Compounds 2-4, 10, 13, 15-19 and 21-22 were isolated from this plant for the first time. Experimental results showed that all compounds did not have a significant inhibitory activity against acetylcholinesterase(AChE).

Objective: To analyze the epidemiological characteristics and diagnosis of imported malaria before and after malaria elimination in Nanjing City of Jiangsu Province, so as to provide the scientific evidence for formulating the malaria control strategy after malaria elimination., Methods: Data pertaining to the epidemic situation and individual investigation of malaria in Nanjing City before (from 2012 to 2016) and after malaria elimination (from 2017 to 2020) were captured from the National Notifiable Communicable Disease Reporting System and the Information System for Parasitic Diseases Control and Prevention and were analyzed statistically., Results: A total of 178 malaria cases were reported in Nanjing City from 2012 to 2020, and all were imported cases. There were 99 malaria cases reported before malaria elimination in Nanjing City, including 78 cases with Plasmodium falciparum malaria (78.79%), 5 cases with P. vivax malaria (5.05%), 10 cases with P. ovale malaria (10.10%), 3 cases with P. malariae malaria (3.03%) and 3 cases with mixed infections (3.03%), and 79 malaria cases reported after elimination, including 63 cases with P. falciparum malaria (79.75%), 5 cases with P. vivax malaria (6.33%), 9 cases with P. ovale malaria (11.39%), 2 cases with P. malariae malaria (2.53%). There was no significant difference in the proportion of each type of malaria cases in Nanjing City before and after malaria elimination ( χ 2 =2.400, P > 0.05). Malaria cases mainly acquired Plasmodium infections in African regions, and no significant difference was seen in the proportion of malaria cases returning to Nanjing City from African countries before and after malaria elimination ( χ 2 = 0.093, P > 0.05). The number of malaria cases peaked in Nanjing City in January and during the period from May to July before elimination, and there was no apparent seasonal variation in the distribution of malaria cases after elimination. The proportion of malaria cases living in Nanjing City was significantly greater after malaria elimination than before elimination (72.15% vs. 55.56%; χ 2 = 5.187, P = 0.023). The proportions of businessmen and international students were both 5.05% before malaria elimination, and increased to 15.19% and 13.92% after elimination, respectively ( χ 2 = 5.229 and 4.229, both P values < 0.05). The percentage of definitive diagnosis of malaria at initial diagnosis was 18.75% in county-level hospitals before malaria elimination and increased to 61.11% after elimination ( χ 2 = 6.275, P = 0.012), while the proportion of malaria cases with definitive diagnoses in county-level hospitals was 4.04% before malaria elimination and increased to 13.92% after elimination ( χ 2 = 5.562, P = 0.018). During the period from 2012 to 2020, the proportion of malaria cases with definitive diagnoses within 1 to 3 days post-admission increased from 27.27% in Nanjing City before malaria elimination to 45.57% after elimination ( χ 2 = 6.433, P = 0.011)., Conclusions: The epidemic situation of imported malaria remains serious in Nanjing City during the post-elimination stage, and malaria parasite infections predominantly occur in African regions. In addition, there are changes in regional and occupational distributions of malaria cases and the diagnostic capability of malaria increases in county-level hospitals in Nanjing City after malaria elimination. Further improvements in the malaria surveillance system and the diagnostic and treatment capability of malaria in medical institutions at each level are required to consolidate malaria elimination achievements in Nanjing City.

Objective To explore the factors related to tympanic membrane perforation in children with acute suppurative otitis media,and to provide reference for clinical practice. Methods We reviewed the clinical data of 1274 children with acute suppurative otitis media from February 2017 to May 2020,and analyzed the factors related to tympanic membrane perforation. Results Tympanic membrane perforation occurred in 67 out of the 1274 children with acute suppurative otitis media,with the incidence of 5.27%.The univariate analysis showed that 11 factors including the duration of onset( t =2.381, P =0.017),upper respiratory tract infection( χ 2 =12.228, P =0.000),pulmonary infection( χ 2 =5.242, P =0.022),chronic sinusitis( χ 2 =12.715, P =0.000),adenoid hypertrophy( χ 2 =4.783, P =0.029),tympanic empyema( χ 2 =16.020, P =0.000),the duration of using antibiotics( t =-2.277, P =0.025),combined use of antibiotics( χ 2 =5.587, P =0.018),the time from onset to selection of antibiotics according to drug sensitivity( t =3.716, P =0.000),procalcitonin( t =2.599, P =0.009),and white blood cell count in peripheral blood( t =2.196, P =0.031)were related to tympanic membrane perforation in children with acute suppurative otitis media.The multivariate logistic analysis showed that the duration of onset( OR =4.854,95% CI =2.675-8.806, P =0.000),upper respiratory tract infection( OR =6.506,95% CI =3.213-13.171, P =0.000),chronic sinusitis( OR =7.866,95% CI =3.780-16.370, P =0.000),tympanic empyema( OR =2.625,95% CI =1.442-4.777, P =0.002),and time from onset to selection of antibiotics according to drug sensitivity( OR =5.107,95% CI =2.129-12.248, P =0.000)were independent risk factors for tympanic membrane perforation in children with acute suppurative otitis media. Conclusion The incidence of tympanic membrane perforation in children with acute suppurative otitis media can be reduced by early treatment,keeping the Eustachian tube unobstructed,draining the tympanic cavity,preventing chronic sinusitis and upper respiratory tract infection,early drug sensitivity test,and selection of antibiotics based on the test results.

Chronic heart failure (CHF) and diabetes mellitus are associated with morbidity and mortality. CHF and diabetes generally simultaneously occur, resulting in adverse outcomes. Diabetes complicates cardiomyopathy and exacerbates heart failure conditions. An increase in natriuretic peptides, including atrial natriuretic peptide (ANP), and another endsogenously generated peptide, brain natriuretic peptide (BNP), serves an essential role in CHF. The aim of this study was to explore the molecular regulation between bone morphogenetic protein-2 (BMP-2) and ANP or BNP in diabetes-associated cardiomyopathy. In total, 25 serum samples were collected from patients with CHF with or without type 2 diabetes mellitus to compare with 25 controls. Cardiomyopathy and hyperglycemia were induced in rats by doxorubicin and streptozotocin, respectively. AC16 cells were used to study molecular mechanisms. BMP, ANP and BNP concentration in patients and rats were measured by ELISA. Flow cytometry was performed to analyze cell pyroptosis and ROS production. Reverse transcription-quantitative PCR and western blotting were used to examine mRNA and protein expression of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), pro-caspase-1, caspase-1 (p20) and gasdermin D. BMP-2 was negatively correlated with ANP and BNP in CHF patients with type 2 diabetes mellitus. Similar results were obtained in rats and AC16 cells. BMP-2 decreased the NLRP3 inflammasome activation and cell pyroptosis. The present study found evidence that the cardioprotective effects of BMP-2 act through ANP and BNP both in vivo and in vitro . BMP-2 inhibits inflammasome formation. The results suggested that BMP-2 may serve as a novel therapeutic target for the treatment of diabetic heart conditions., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2020, Spandidos Publications.)

Objective: To estimate the prevalence and distribution of tooth wear among groups of adolescents and adults in Shanghai, China through an epidemiological survey, and explore the associated factors., Methods: Multistage, stratified, constant volume and cluster sampling methods were used in an epidemiological survey conducted in Shanghai in 2014. The basic erosive wear examination (BEWE) index was used to screen for tooth wear in different age groups: 12 years, 15 years, 18 to 35 years, 36 to 49 years and 50 to 74 years. A previously published questionnaire collected information including dietary habits, oral hygiene habits and general conditions., Results: This survey reports the results for 1806 participants in Shanghai. The prevalence of tooth wear was 59.7% in adolescents (BEWE ≥ 1) and 93.1% in adults (BEWE ≥ 2). The prevalence and severity of disease increased with age (P < 0.01). The teeth most susceptible to wear were the central incisors and first molars. Multivariate analysis of covariance (ANCOVA) results showed that soft drinks, alcoholic drinks, pickled vegetables and hard food, gastroesophageal reflux disease (GERD), xerostomia and poor tooth brushing habits were statistically correlated with tooth wear in different age groups., Conclusion: The prevalence of tooth wear appears to be high in adolescents and adults in Shanghai. Frequent consumption of soft or alcoholic drinks, GERD, xerostomia and poor tooth brushing habits were positively associated with tooth wear in different age groups.

The objective of this study was to compare the effects of nanoselenium (NS) and selenium yeast (SY) on the performance, egg selenium (Se) concentration, and anti-oxidative capacity of hens. A total of 216 Brown Hy-line hens (29-week old) were randomly allocated into three treatments (6 replicate/treatment, 12 hens/replicate). The pre-trial period lasted 7 days, and the experimental period lasted 35 days. Dietary treatments included corn-soybean meal basal diet (containing 0.16 μg Se/g, as control group), and basal diet supplemented with 0.3 mg Se/kg diet (Se was from NS or SY), called as SY group or NS group, respectively. At the end of the experiment, one hen per replicate from each treatment was slaughtered. Liver, spleen, and kidney tissues were sampled for the determination of Se concentrations. The results showed that NS or SY supplement significantly improved feed conversion ratio (P < 0.05), soft broken egg rate (P < 0.05), and the serum T-AOC value (P < 0.05) when compared with control group. Remarkably, the deposition of Se increased significantly (P < 0.05) and equivalently in egg, liver, and kidney of hens supplemented with both NS and SY. Interestingly, SY supplement also enhanced the serum CAT and SOD activities (P < 0.05), NS but not SY significantly reduced serum MDA (P < 0.05), whereas RT-PCR results did not show significant differences in the mRNA levels of antioxidant genes among three groups (P > 0.05). Taken together, dietary supplemented with SY or NS improved the Se deposition in eggs, liver and kidney of laying hens, increased antioxidant activity, and NS supplement had greater Se deposition in the kidney tissue than SY supplement. SY or NS supplement could be considered to be applied for Se-enriched egg production.

Esophageal cancer (EC) is of public health significance as one of the leading causes of cancer death worldwide. Accurate staging, treatment planning and prognostication in EC patients are of vital importance. Recent advances in machine learning (ML) techniques demonstrate their potential to provide novel quantitative imaging markers in medical imaging. Radiomics approaches that could quantify medical images into high-dimensional data have been shown to improve the imaging-based classification system in characterizing the heterogeneity of primary tumors and lymph nodes in EC patients. In this review, we aim to provide a comprehensive summary of the evidence of the most recent developments in ML application in imaging pertinent to EC patient care. According to the published results, ML models evaluating treatment response and lymph node metastasis achieve reliable predictions, ranging from acceptable to outstanding in their validation groups. Patients stratified by ML models in different risk groups have a significant or borderline significant difference in survival outcomes. Prospective large multi-center studies are suggested to improve the generalizability of ML techniques with standardized imaging protocols and harmonization between different centers.

Purpose: To evaluate the prognostic value of baseline and restaging CT-based radiomics with features associated with gene expression in esophageal squamous cell carcinoma (ESCC) patients receiving neoadjuvant chemoradiation (nCRT) plus surgery., Methods: We enrolled 106 ESCC patients receiving nCRT from two institutions. Gene expression profiles of 28 patients in the training set were used to detect differentially expressed (DE) genes between patients with and without relapse. Radiomic features that were correlated to DE genes were selected, followed by additional machine learning selection. A radiomic nomogram for disease-free survival (DFS) prediction incorporating the radiomic signature and prognostic clinical characteristics was established for DFS estimation and validated., Results: The radiomic signature with DE genes feature selection achieved better performance for DFS prediction than without. The nomogram incorporating the radiomic signature and lymph nodal status significantly stratified patients into high and low-risk groups for DFS ( p < 0.001). The areas under the curve (AUCs) for predicting 5-year DFS were 0.912 in the training set, 0.852 in the internal test set, 0.769 in the external test set., Conclusions: Genomics association was useful for radiomic feature selection. The established radiomic signature was prognostic for DFS. The radiomic nomogram could provide a valuable prediction for individualized long-term survival.

Objectives: To compare the prevalence of chronic periodontitis between men who had semen abnormalities and those who had normozoospermia through a case-control study., Materials and Methods: Male patients who visited the assisted reproduction clinic of a large general hospital and were diagnosed with semen abnormalities were included in the case group. The control group was composed of patients of the same clinic with normozoospermia. The semen analysis included sperm concentration, count and progressive and total motility, which were measured in the laboratory. A questionnaire and clinical periodontal examination were conducted for all participants. Logistic regression was performed to explore the relationship between chronic periodontitis and male infertility., Results: A total of 192 participants were included: 63 participants (32.8%) had some type of semen abnormality (case group), while 129 participants (67.2%) had normozoospermia (control group). The case group had a significantly higher prevalence of moderate/severe periodontitis than the control group (33.3% vs. 17.8%, p = .012). The logistic regression showed that participants who had moderate/severe periodontitis had a greater chance of having semen abnormalities after adjusting for other confounding factors (OR = 3.377, p = .005)., Conclusions: Periodontitis is associated with semen abnormalities and sperm motility in men., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. All rights reserved.)

Purpose: To evaluate the effect of auricular acupressure (AA) on cancer-related fatigue (CRF), sleep disturbance and anxiety in lung cancer patients undergoing chemotherapy., Materials and Methods: Patients were recruited from the respiratory department of a general hospital and were randomised into three groups. A 9-week course of AA using Semen Vaccariae (SV) (Group A)/AA using magnetic beads (Group B)/routine care (Group C) was implemented. CRF scores were used as the primary outcome while the sleep and anxiety scores were the secondary outcomes. Analysis of variance and least significant difference t-test were used to determine the intergroup differences and paired-sample t-test was used for the intragroup comparison., Results: 100 lung cancer patients undergoing chemotherapy were included. Compared with Group C, AA could significantly alleviate CRF (F:24.63, p<0.01), especially for physical and affective fatigue and Group A was more effective for managing physical fatigue than Group B in per-protocol (PP) (-1.75 (-2.69 to -0.82), p<0.01)/Intention to Treat analysis (ITT) (-1.41 (-2.39 to -0.41), p=0.01) analysis. However, AA had no effect on cognitive fatigue. Compared with Group C, only Group A produced significant improvements in sleep quality in PP analysis (-1.17 (-2.23 to -0.10), p=0.03) while it yielded negative results in ITT analysis (-0.82 (-1.74 to 0.10), p=0.08). Compared with Group C, AA could significantly reduce anxiety in PP analysis (F:9.35, p<0.01) while there was no statistical difference between Group B and Group C (-0.95 (-2.81 to 0.90), p=0.31), Group A and Group B (-1.26 (-3.12 to 0.59), p=0.18) in ITT analysis., Conclusion: AA can alleviate CRF of lung cancer patients undergoing chemotherapy, especially for physical and affective fatigue. AA using SV is more effective for physical fatigue while AA using magnetic beads works better for anxiety. However, AA cannot improve the sleep quality., Trial Registration Number: ISRCTNregistry (ISRCTN16408424)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Renewable chemicals have attracted attention due to increasing interest in environmental concerns and resource utilization. Biobased production of industrial compounds from nonfood biomass has become increasingly important as a sustainable replacement for traditional petroleum-based production processes depending on fossil resources. Therefore, we engineered an Enterobacter cloacae budC and ldhA double-deletion strain (namely, EC∆budC∆ldhA) to redirect carbon fluxes and optimized the culture conditions to co-produce succinic acid and acetoin., Results: In this work, E. cloacae was metabolically engineered to enhance its combined succinic acid and acetoin production during fermentation. Strain EC∆budC∆ldhA was constructed by deleting 2,3-butanediol dehydrogenase (budC), which is involved in 2,3-butanediol production, and lactate dehydrogenase (ldhA), which is involved in lactic acid production, from the E. cloacae genome. After redirecting and fine-tuning the E. cloacae metabolic flux, succinic acid and acetoin production was enhanced, and the combined production titers of acetoin and succinic acid from glucose were 17.75 and 2.75 g L -1 , respectively. Moreover, to further improve acetoin and succinic acid production, glucose and NaHCO 3 modes and times of feeding were optimized during fermentation of the EC∆budC∆ldhA strain. The maximum titers of acetoin and succinic acid were 39.5 and 20.3 g L -1 at 72 h, respectively., Conclusions: The engineered strain EC∆budC∆ldhA is useful for the co-production of acetoin and succinic acid and for reducing microbial fermentation costs by combining processes into a single step.

Background: We previously showed, using the Traditional Chinese Medicine System Pharmacology Database, that Gegen Qinlian decoction (GQD) had a direct antitumor effect, and was combined with programmed cell death protein (PD)-1 inhibitors to treat microsatellite stable (MSS) tumor-bearing mice. However, the effect of GQD on patients with colorectal cancer (CRC) is not clear., Aim: To determine the therapeutic mechanism of GQD in improving immune function, reducing inflammation and protecting intestinal barrier function., Methods: Seventy patients with CRC were included in this study: 37 in the control group and 33 in the treatment group. The proportions of CD4 + T, CD8 + T, natural killer (NK), NKT and T regulatory cells were measured by flow cytometry. Levels of the cytokines tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-2, IL-6, IL-10 and serotonin (5-hydroxytryptamine; 5-HT) in serum were assessed by enzyme-linked immunosorbent assay (ELISA). The expression of zonula occludens (ZO)-1, occludin, nuclear factor (NF)-κB and TNF-α in tumor and normal tissues was measured by immunohistochemistry. The composition of gut microbiota from patients in the treatment group was assessed using 16S rDNA analysis., Results: There were no adverse events in the treatment group. The proportion of CD4 + T cells and NKT cells in the post-treatment group was significantly higher than that in the pre-treatment and control groups ( P < 0.05). The level of TNF-α in the post-treatment group was significantly lower than that in the pre-treatment and control groups ( P < 0.05). The concentration of 5-HT in the post-treatment group was significantly lower than that in the pre-treatment group ( P < 0.05). The expression of ZO-1 and occludin in tumor tissues in the treatment group was significantly higher than that in the control group ( P < 0.05). The expression of ZO-1 in normal tissues of the treatment group was significantly higher than that in the control group ( P = 0.010). Compared with the control group, expression of NF-κB and TNF-α in tumor tissues of the treatment group was significantly decreased ( P < 0.05). Compared with the pre-treatment group, GQD decreased the relative abundance of Megamonas and Veillonella . In addition, GQD increased the relative abundance of Bacteroides , Akkermansia and Prevotella ., Conclusion: GQD enhances immunity and protects intestinal barrier function in patients with CRC by regulating the composition of gut microbiota., Competing Interests: Conflict-of-interest statement: The authors report no conflicts of interests., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Engineered Saccharomyces cerevisiae can reduce xylose to xylitol. However, in S.cerevisiae, there are several endogenous enzymes including xylitol dehydrogenase encoded by XYL2, sorbitol dehydrogenases encoded by SOR1/SOR2 and xylulokinase encoded by XKS1 may lead to the assimilation of xylitol. In this study, to increase xylitol accumulation, these genes were separately deleted through CRISPR/Cas9 system. Their effects on xylitol yield of an industrial S. cerevisiae CK17 overexpressing Candida tropicalis XYL1 (encoding xylose reductase) were investigated. Deletion of SOR1/SOR2 or XKS1 increased the xylitol yield in both batch and fed-batch fermentation with different concentrations of glucose and xylose. The analysis of the transcription level of key genes in the mutants during fed-batch fermentation suggests that SOR1/SOR2 are more crucially responsible for xylitol oxidation than XYL2 under the genetic background of S.cerevisiae CK17. The deletion of XKS1 gene could also weaken SOR1/SOR2 expression, thereby increasing the xylitol accumulation. The XKS1-deleted strain CK17ΔXKS1 produced 46.17 g/L of xylitol and reached a xylitol yield of 0.92 g/g during simultaneous saccharification and fermentation (SSF) of pretreated corn stover slurry. Therefore, the deletion of XKS1 gene provides a promising strategy to meet the industrial demands for xylitol production from lignocellulosic biomass., (© The Author(s) 2020. Published by Oxford University Press on behalf of FEMS.)

Objective: To observe and compare the clinical efficacy of CO₂ fractional laser in the early control of scar post-secondary repair in patients with a cleft lip., Methods: In the treatment group, 43 patients with secondary repair of cleft lip were treated via CO₂ fractional laser. The control group covered 70 patients post-cheiloplasty. The effect in the two groups after six months was compared. The duration from the beginning of the laser treatment to surgery and patient gender were analyzed to determine if they affected the efficacy of the laser treatment for scars., Results: 1) The curative effect in the treatment group was better than that in the control group (P<0.000 1), the total effectiveness rate was 90.7% in the treatment group. 2) No significant statistical difference in efficacy was observed between men and women (P=0.487). Moreover, no significant statistical difference in efficacy (P=0.055) was observed among patients one year after surgery, within the duration of <3 months, and within the duration of ≥3 months., Conclusions: CO₂ fractional laser had a definite effect on the treatment of scar post-secondary repair in patients with a cleft lip. No significant correlation was observed between treatment effect and patient gender, and no difference was noted among patients one year after surgery. In the beginning of the laser treatment, no difference was observed between the durations of <3 months and ≥3 months after the reconstruction, Therefore, early intervention of scars a year after secondary repair of a cleft lip can achieve good results.