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Ionotropic γ-aminobutyric acid (GABA) receptor (GABAR) in an insect is the major inhibitory receptor and is one of the most important targets for insecticides. Due to the high spatiotemporal resolution of GABAR, the photopharmacological ligands acting on it in vertebrates but not insect have been developed.In this study, two types of photochromic ligands (PCLs) including DTFIPs (DTFIP1 and DTFIP2) and ABFIPs (p-, m-, and o-ABFIP) were synthesized by incorporating photoswitch azobenzene or dithienylethene into fipronil (FIP), which is the antagonist of insect GABAR. Their photomodulation was measured by mosquito larval behavior, and their potential action mechanism was explored by the two-electrode voltage clamp (TEVC) technique in vitro. DTFIP1 and m-ABFIP exhibited the most significant difference of insecticidal activity by about 90- and 5-fold to mosquito larvae between non-irradiated and irradiated formation, respectively, and allowed for optical control of mosquito swimming activity. TEVC assay results indicated that m-ABFIP and DTFIP1 enable optical control over the homomeric LsRDL-type GABAR, which is achieved by regulating the chloride channel of resistance to dieldrin (RDL)-type GABAR by photoisomerization.Our results suggested that PCLs synthesized from fipronil provide an alternative and precise tool for studying insect ionotropic GABARs and GABA-dependent behavior. © 2022 Society of Chemical Industry.

Natural products (NPs) and their structural analogs represent a major source of novel drug development for disease prevention and treatment. The development of new drugs from NPs includes two crucial aspects. One is the discovery of NPs from medicinal plants/microorganisms, and the other is the evaluation of the NPs in vivo at various physiological and pathological states. The heterogeneous spatial distribution of NPs in medicinal plants/microorganisms or in vivo can provide valuable information for drug development. However, few molecular imaging technologies can detect thousands of compounds simultaneously on a label-free basis. Over the last two decades, mass spectrometry imaging (MSI) methods have progressively improved and diversified, thereby allowing for the development of various applications of NPs in plants/microorganisms and in vivo NP research. Because MSI allows for the spatial mapping of the production and distribution of numerous molecules in situ without labeling, it provides a visualization tool for NP research. Therefore, we have focused this mini-review on summarizing the applications of MSI technology in discovering NPs from medicinal plants and evaluating NPs in preclinical studies from the perspective of new drug research and development (RD). Additionally, we briefly reviewed the factors that should be carefully considered to obtain the desired MSI results. Finally, the future development of MSI in new drug RD is proposed.

Zika virus (ZIKV) is primarily transmitted through mosquito bites and sexual contact, and vertical transmission of ZIKV has also been observed in humans. In addition, ZIKV infection via unknown transmission routes has been frequently reported in clinical settings. However, whether ZIKV can be transmitted via aerosol routes remains unknown. In this study, we demonstrated that aerosolized ZIKV is fully infectious in vitro and in vivo. Remarkably, intratracheal (i.t.) inoculation with aerosolized ZIKV led to rapid viremia and viral secretion in saliva, as well as robust humoral and innate immune responses in guinea pigs. Transcriptome analysis further revealed that the expression of genes related to viral processes, biological regulation and the immune response was significantly changed. Together, our results confirm that aerosolized ZIKV can result in systemic infection and induce both innate and adaptive immune responses in guinea pigs, highlighting the possibility of ZIKV transmission via aerosols.

Tax1 banding protein 1 (Tax1bp1) was originally identified as an NF-κB regulatory protein that participated in inflammatory, antiviral and innate immune processes. Tax1bp1 also functions as an autophagy receptor that plays a role in autophagy. Our previous study shows that Tax1bp1 protects against cardiomyopathy in STZ-induced diabetic mice. In this study we investigated the role of Tax1bp1 in heart failure. Pressure overload-induced heart failure model was established in mice by aortic banding (AB) surgery, and angiotensin II (Ang II)-induced heart failure model was established by infusion of Ang II through osmotic minipump for 4 weeks. We showed that the expression levels of Tax1bp1 in the heart were markedly increased 2 and 4 weeks after AB surgery. Knockdown of Tax1bp1 in mouse hearts significantly ameliorated both AB- and Ang II infusion-induced heart failure parameters. On the contrary, AB-induced heart failure was aggravated in cardiac-specific Tax1bp1 transgenic mice. Similar results were observed in neonatal rat cardiomyocytes (NRCMs) under Ang II insult. We demonstrated that the pro-heart failure effect of Tax1bp1 resulted from its interaction with the E3 ligase ITCH to promote the transcription factor P73 ubiquitination and degradation, causing enhanced BCL2 interacting protein 3 (BNIP3)-mediated cardiomyocyte apoptosis. Knockdown ITCH or BNIP3 in NRCMs significantly reduced Ang II-induced apoptosis in vitro. Similarly, BNIP3 knockdown attenuated heart failure in cardiac-specific Tax1bp1 transgenic mice. In the left ventricles of heart failure patients, Tax1bp1 expression level was significantly increased; Tax1bp1 gene expression was negatively correlated with left ventricular ejection fraction in heart failure patients. Collectively, the Tax1bp1 increase in heart failure enhances ITCH-P73-BNIP3-mediated cardiomyocyte apoptosis and induced cardiac injury. Tax1bp1 may serve as a potent therapeutic target for the treatment of heart failure.• Cardiac Tax1bp1 transgene mice were more vulnerable to cardiac dysfunction under stress.• Cardiac Tax1bp1 transgene mice were more vulnerable to cardiac dysfunction under stress.• Knockout of Tax1bp1 in mouse hearts ameliorated heart failure induced by pressure overload.• Tax1bp1 interacts with the E3 ligase Itch to promote P73 ubiquitination and degradation, causing enhanced BNIP3-mediated apoptosis.• Tax1bp1 may become a target of new therapeutic methods for treating heart failure.

To investigate the effect of Helicobacter pylori (HP) eradication therapy on salivary pepsin concentration in laryngopharyngeal reflux (LPR) patients with HP infection.A total of 477 patients with suspected LPR were enrolled from June 2020 to September 2021. Reflux symptom index, reflux finding score, the positive rates and disintegrations per minute values of HP infection detected byThe scores of nagging cough (0.88 vs. 0.50, P = 0.035), erythema or hyperemia (1.93 vs. 1.78, P = 0.035) and vocal fold edema (1.04 vs. 0.85, P = 0.025) were higher in the LPR (+) Hp (+) subgroup than in LPR (+) Hp (-) subgroup. The concentrations of salivary pepsin in the Hp (+) subgroup were higher than in the Hp (-) subgroup either in LPR patients (75.24 ng/ml vs. 61.39 ng/ml, P = 0.005) or the non-LPR patients (78.42 ng/ml vs. 48.96 ng/ml, P = 0.024). Compared to baseline (before treatment), scores of nagging cough (0.35 vs. 0.84, P = 0.019) and erythema or hyperemia (1.50 vs. 1.83, P = 0.039) and the concentrations of salivary pepsin (44.35 ng/ml vs. 74.15 ng/ml, P = 0.017) in LPR patients with HP infection decreased after HP treatment; yet, this was not observed for the LPR patients without HP infection treated with PPI only (P 0.05).HP infection may aggravate the symptoms and signs of LPR patients, partly by increasing their salivary pepsin concentration.

Colorectal cancer remains a considerable challenge in healthcare nowadays. Approximately 60%-80% of colorectal cancer is caused by intestinal polyps, and resection of intestinal polyps has been proved to reduce the incidence of colorectal cancer. The vast majority of intestinal polyps can be found during colonoscopy and removed endoscopically. Therefore, more attention has been paid to the development of endoscopic resection of intestinal polyps. In this study, we compared the efficacy and safety of cold snare polypectomy (CSP) and hot snare polypectomy (HSP).To investigate the efficacy and safety of CSP and HSP for colorectal polyps.Between January and December 2020, 301 patients with colorectal polyps 4-9 mm in diameter were treated with endoscopic therapy in our hospital, and were divided into the CSP group (We included 249 patients (301 polyps). No differences in gender, age, and polyp size, location, shape and type were observed between the CSP and HSP groups, and the resection rates in these two groups were 93.4% and 94.5%, respectively, with no significant difference. The use of titanium clips was 15.6% and 95.9%, the operating time was 3.2 ± 0.5 min and 5.6 ± 0.8 min, the delayed bleeding rate was 0% and 2.0%, and delayed perforation was 0% and 0.7%, in the CSP and HSP groups, respectively.For sessile colorectal polyps10 mm, CSP had the same resection rate of impaired tissue integrity as traditional HSP had. The rate of complications was lower in the CSP group. CSP is a safe and effective method for polypectomy.

Primary liver cancer (PLC) is a major contributor to cancer-related deaths. Data on global and country-specific levels and trends of PLC are essential for understanding the effects of this disease and helping policymakers to allocate resources.To investigate the association between the burden of PLC and socioeconomic development status.Cancer mortality and incidence rates were obtained from the Global Burden of Disease (GBD) 2019, and the data were stratified by country and territory, sex, and the Socio-demographic Index (SDI) level. The association between the attributable etiology of PLC and socioeconomic development status, represented using the SDI, was described. The attributable etiology of PLC included hepatitis B, hepatitis C, alcohol use, and nonalcoholic steatohepatitis. The association between the attributable etiology of PLC and SDI was further stratified by sex and geographical location. A confidence analysis was also performed based on bootstrap draw.The age-standardized incidence rate of PLC was 6.5 [95% confidence intervals (CI): 5.9-7.2] per 100000 person-years, which decreased by -27.5% (-37.0 to -16.6) from 1990 to 2019. Several countries located in East Asia, South Asia, West Africa, and North Africa shouldered the heaviest burden of PLC in 2019. In terms of incidence rates, the first leading underlying cause of PLC identified was hepatitis B, followed by hepatitis C, alcohol use, and nonalcoholic steatohepatitis. Regarding stratification using the SDI, the incidence rate of PLC was the highest for high and middle SDI locations. Further, the leading attributable etiologies of PLC were hepatitis B for the middle and high middle SDI locations while hepatitis C and nonalcoholic steatohepatitis for the high SDI locations.The pronounced association between socioeconomic development status and PLC burden indicates socioeconomic development status affects attributable etiologies for PLC. GBD 2019 data are valuable for policymakers implementing PLC cost-effective interventions.

Cold plasma pretreatment has the potential of anti-aging. However, its molecular mechanism is still not clear. Here, cold plasma pretreatment was firstly used to investigate the anti-aging effects of Caenorhabditis elegans using transcriptomic technique. It showed that the optimal parameters of discharge power, processing time, and working pressure for cold plasma pretreatment were separately 100 W, 15 s, and 135 Pa. The released 0.32 mJ/cm

Qing-Qing Tao,1 Rong-Rong Lin,1 Zhi-Ying Wu1,2 1Department of Neurology and Research Center of Neurology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, People’s Republic of China; 2MOE Frontier Science Center for Brain Science and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, People’s Republic of ChinaCorrespondence: Zhi-Ying Wu, Department of Neurology and Research Center of Neurology, Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, People’s Republic of China, Email zhiyingwu@zju.edu.cn

VV116 (JT001) is an oral drug candidate of nucleoside analog against SARS-CoV-2. The purpose of the three phase I studies was to evaluate the safety, tolerability, and pharmacokinetics of single and multiple ascending oral doses of VV116 in healthy subjects, as well as the effect of food on the pharmacokinetics and safety of VV116. Three studies were launched sequentially: Study 1 (single ascending-dose study, SAD), Study 2 (multiple ascending-dose study, MAD), and Study 3 (food-effect study, FE). A total of 86 healthy subjects were enrolled in the studies. VV116 tablets or placebo were administered per protocol requirements. Blood samples were collected at the scheduled time points for pharmacokinetic analysis. 116-N1, the metabolite of VV116, was detected in plasma and calculated for the PK parameters. In SAD, AUC and Cmax increased in an approximately dose-proportional manner in the dose range of 25–800 mg. T1/2 was within 4.80–6.95 h. In MAD, the accumulation ratio for Cmax and AUC indicated a slight accumulation upon repeated dosing of VV116. In FE, the standard meal had no effect on Cmax and AUC of VV116. No serious adverse event occurred in the studies, and no subject withdrew from the studies due to adverse events. Thus, VV116 exhibited satisfactory safety and tolerability in healthy subjects, which supports the continued investigation of VV116 in patients with COVID-19.

Background and Aims Regulation of macrophage polarization is a promising strategy for treating inflammatory bowel disease [IBD]. Tollip is an important negative regulator of Toll-like receptor [TLR]-mediated innate immunity with downregulated expression in the colon tissues of patients with IBD. This study aimed to regulate the expression of Tollip to affect macrophage polarization. Methods A molecular, targeted immunotherapy method was developed by linking mannose-modified trimethyl chitosan [MTC] with Tollip-expressing plasmids via ionic cross-linking, forming MTC-Tollip nanoparticles with a targeting function. MTC-Tollip selectively targeted mouse intestinal macrophages to regulate the polarization of macrophages for mucosal repair. Results Orally administered MTC-Tollip significantly elevated Tollip expression in intestinal tissue. Compared with MTC-negative control [NC]-treated mice in which colitis was induced with dextran sodium sulphate [DSS], the MTC-Tollip nanoparticle-treated mice exhibited decreased body weight loss and colon shortening, lower proinflammatory cytokine expression in colon tissues, and greater mucosal barrier integrity. MTC-Tollip treatment decreased TNF-α and iNOS expression but increased CD206 and Arg-1 expression in colon tissue. Tollip overexpression in mouse peritoneal macrophages inhibited lipopolysaccharide [LPS]-induced proinflammatory cytokine production and promoted IL-4-induced M2 expression. The progression of peritoneal macrophages extracted from Tollip−/− mice confirmed the effect of Tollip on macrophage polarization. Western blots showed that Tollip overexpression attenuated the upregulation of TLR pathway-associated targets in M1 macrophages. Conclusions MTC nanoparticles can be ‘intelligent’ carriers in immunotherapy. The modulation of Tollip expression in macrophages may be a novel treatment approach for IBD.

So far, it has been reached the academic consensus that the molecular subtypes are via genomic heterogeneity and immune infiltration patterns. Considering that oxidative stress (OS) is involved in tumorigenesis and prognosis prediction, we propose an innovative classification of colorectal cancer- (CRC-) OS subtypes. We obtain three datasets from The Cancer Genome Atlas Program (TCGA) and Gene Expression Omnibus (GEO) online databases. 1399 OS-related genes were selected from the GeneCards database. We remove the batch effect before conducting differentially expressed genes (DEGs) analyses between normal and tumor samples. Nonnegative matrix factorization (NMF) was used to perform an unsupervised cluster. Lasso regression and Cox regression were used to construct the signature model. DEGs, robust rank aggregation, and protein-protein interaction networks were used to select hub genes, and then use hub genes to predict OS subtypes by random forest algorithms. NMF identifies two OS-related subtypes of CRC patients. Eight OS-related gene signatures were built to predict the outcome of patients, based on the DEGs between two subtypes. A total of 61 DEGs overlap each dataset, and the RRA analysis shows that 17 genes are important in these three datasets, and 15 genes are shared genes between the two methods. PPI network suggests that five hub genes are confirmed, they are SPP1, SERPINE1, CAV1, PDGFRB, and PLAU. These five hub genes could predict the OS-related subtype of CRC accurately with AUC equal to 0.771. In our study, we identify two OS-related subtypes, which will provide an innovative insight into colorectal cancer.

BACKGROUND Androgen insensitivity syndrome is an X-linked recessive genetic disease caused by mutations in the androgen receptor gene (AR). However, the underlying molecular mechanisms for the majority of AR variants remain unclear. In this study, we identified a point variant in three patients with complete androgen insensitivity syndrome (CAIS), summarized the correlation analysis, and performed a literature review. CASE SUMMARY The proband was raised as a girl. In infancy, she was first referred to hospital with a right inguinal hernia. Ultrasonography revealed the absence of a uterus and ovaries, and a testis-like structure located at the inguinal canal. Further diagnostic workup detected a 46, XY karyotype, and fluorescence in situ hybridization analysis showed the presence of the SRY gene. Histological analysis revealed the excised tissue to be testicular. Twelve years later, she was admitted to our hospital with a lack of breast development. Her pubic hair and breasts were Tanner stage I. She had normal female external genitalia. Blood hormone tests showed normal testosterone levels, low estradiol levels, and high gonadotropin levels. Her two siblings underwent similar examinations, and all three had a rare hemizygous missense mutation in AR: c.2678C>T. In vitro functional analyses revealed decreased nuclear translocation in AR-c.2678C>T mutation cells. CONCLUSION This case of CAIS was caused by an AR variant (c.2678C>T). Functional studies showed impaired nuclear translocation ability of the mutant protein.

Cisplatin-induced acute kidney injury (CP-AKI) is a severe complication in patients receiving CP chemotherapy. However, effective therapies for CP-AKI are currently lacking. Curcumin (CUR), a natural polyphenol, is extracted from the rhizome of turmeric and has been reported to have nephroprotective activity. However, the role of CUR in CP-AKI remains unclear. This study aimed to explore the mechanism of CUR in CP-AKI by combining a network pharmacology approach with experimental validations. The analysis revealed 176 potential targets of CUR based on the HERB database and 1,286 related targets of CP-AKI from the GeneCards, DrugBank, and OMIM databases. Further, 106 common targets of CUR against CP-AKI were obtained, and these common targets constructed a protein-protein interaction (PPI) network. In addition, the core targets were screened from the PPI network using Cytoscape. Molecular docking revealed that CUR displayed the best binding to AKT1. Gene Ontology (GO) analysis indicated that the primary biological processes of CUR against CP-AKI included cellular response to chemical stress and apoptotic regulation. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis suggested that the PI3K-Akt signaling pathway was most significantly enriched in CUR against CP-AKI. Western blotting and flow cytometry showed that CUR inhibited apoptosis induced by CP by activating the Akt signaling pathway in human kidney tubular epithelial cells (HK-2). Altogether, our findings demonstrated that CUR alleviated apoptosis by activating the Akt signaling pathway in CP-AKI in vitro. These data provide a scientific basis for future investigations into the clinical application of CUR against CP-AKI.

BACKGROUND Cerebral hemorrhage secondary to cerebral embolism after mechanical thrombectomy is characterized by high morbidity, disability and mortality. If the patient also has severe pulmonary embolism (PE) at the same time, the treatment becomes more complex. This report describes the treatment strategy for a patient with PE and cerebral hemorrhage secondary to cerebral embolism after mechanical thrombectomy. CASE SUMMARY A 70-year-old woman presented to our emergency department with right-sided hemiplegia and mixed aphasia of 2.5 h duration. She was diagnosed with left cerebral embolism, left internal carotid artery occlusion, PE and left calf intramuscular vein thrombosis. Following mechanical thrombectomy, brain magnetic resonance imaging showed cerebral infarction with basal ganglia hemorrhage. We observed changes in cerebral hemorrhage on serial monitoring of brain computed tomography and adjusted the dose of anticoagulant drugs. After 3 wk of treatment, the patient’s neurological and respiratory symptoms significantly improved, and a favorable prognosis was obtained. CONCLUSION Anticoagulation could be a potential option for PE accompanied by hemorrhagic transformation of an ischemic infarct.

BACKGROUND Neonatal hepatic portal venous gas (HPVG) is associated with a high risk of necrotizing enterocolitis (NEC) and was previously believed to be associated with an increased risk of surgery. CASE SUMMARY A 3-day-old full-term male infant was admitted to the pediatrics department after presenting with “low blood glucose for 10 min”. Hypoglycemia was corrected by intravenous glucose administration and oral breast milk. On the 3rd d after admission, an ultrasound examination showed gas accumulation in the hepatic portal vein; this increased on the next day. Abdominal vertical radiograph showed intestinal pneumatosis. Routine blood examination showed that the total number of white blood cells was normal, but neutrophilia was related to age. There was a significant increase in C-reactive protein (CRP). The child was diagnosed with neonatal NEC (early-stage). With nil per os, rehydration, parenteral nutritional support, and anti-infection treatment with no sodium, his hepatic portal vein pneumatosis resolved. In addition, routine blood examination and CRP examination showed significant improvement and his symptoms resolved. The patient was given timely refeeding and gradually transitioned to full milk feeding and was subsequently discharged. Follow-up examination after discharge showed that the general condition of the patient was stable. CONCLUSION The presence of HPVG in neonates indicates early NEC. Early active anti-infective treatment is effective in treating NEC, minimizes the risk of severe NEC, and reduces the need for surgery. The findings of this study imply that early examination of the liver by ultrasound in a sick neonate can help with the early diagnosis of conditions such as NEC.

BACKGROUND Acute kidney injury (AKI) is one of the most common acute pancreatitis (AP)-associated complications that has a significant effect on AP, but the factors affecting the AP patients’ survival rate remains unclear. AIM To assess the influences of AKI on the survival rate in AP patients. METHODS A total of 139 AP patients were included in this retrospective study. Patients were divided into AKI group (n = 72) and non-AKI group (n = 67) according to the occurrence of AKI. Data were collected from medical records of hospitalized patients. Then, these data were compared between the two groups and further analysis was performed. RESULTS AKI is more likely to occur in male AP patients (P = 0.009). AP patients in AKI group exhibited a significantly higher acute physiologic assessment and chronic health evaluation II score, higher Sequential Organ Failure Assessment score, lower Glasgow Coma Scale score, and higher demand for mechanical ventilation, infusion of vasopressors, and renal replacement therapy than AP patients in non-AKI group (P < 0.01, P < 0.01, P = 0.01, P = 0.001, P < 0.01, P < 0.01, respectively). Significant differences were noted in dose of norepinephrine and adrenaline, duration of mechanical ventilation, maximum and mean values of intra-peritoneal pressure (IPP), maximum and mean values of procalcitonin, maximum and mean serum levels of creatinine, minimum platelet count, and length of hospitalization. Among AP patients with AKI, the survival rate of surgical intensive care unit and in-hospital were only 23% and 21% of the corresponding rates in AP patients without AKI, respectively. The factors that influenced the AP patients’ survival rate included body mass index (BMI), mean values of IPP, minimum platelet count, and hospital day, of which mean values of IPP showed the greatest impact. CONCLUSION AP patients with AKI had a lower survival rate and worse relevant clinical outcomes than AP patients without AKI, which necessitates further attention to AP patients with AKI in surgical intensive care unit.

Necrotizing enterocolitis, a devastating gastrointestinal disease with high mortality, poses great threats to global health. Therefore, we conducted this study to explore the role of ANGPT2, as well as the potential mechanism, in necrotizing enterocolitis. IEC-6 cells were stimulated with lipopolysaccharide (LPS) to induce necrotizing enterocolitis model in vitro. The expression of ANGPT2 was measured by RT-qPCR. The cell viability was detected using CCK-8. Besides, the expressions of endoplasmic reticulum (ER) stress-related proteins, Notch signaling pathway-related proteins and tight junction proteins were checked by western blot. The apoptosis and inflammatory response were detected by TUNEL and ELISA, respectively. Moreover, with the adoption of TEER, the cell monolayer permeability was detected. The results showed that ANGPT2 expression was greatly increased after LPS induction. In addition, ANGPT2 knockdown significantly decreased the apoptosis, inflammatory response, barrier dysfunction and endoplasmic reticulum stress of LPS-induced IEC-6 cells. What is more, ANGPT2 knockdown could block Notch signaling pathway. Additionally, with the treatment of Jagged-1, the protective effect of ANGPT2 knockdown on LPS-induced intestinal injury was partly abolished. To sum up, silencing ANGPT2 could improve LPS-induced inflammation, barrier dysfunction and ER stress of intestinal epithelial cells via blocking Notch signaling pathway.

A novel glycoside hydrolase (GH) family 46 chitosanase (SaCsn46A) from Streptomyces avermitilis was cloned and functionally expressed in Escherichia coli Rosetta (DE3) strains. SaCsn46A consists of 271 amino acids, which includes a 34-amino acids signal peptide. The protein sequence of SaCsn46A shows maximum identity (83.5%) to chitosanase from Streptomyces sp. SirexAA-E. Then the mature enzyme was purified to homogeneity through Ni-chelating affinity chromatography with a recovery yield of 78% and the molecular mass of purified enzyme was estimated to be 29 kDa by SDS-PAGE. The recombinant enzyme possessed a temperature optimum of 45 oC and a pH optimum of 6.2, and it was stable at pH ranging from 4.0 to 9.0 and below 30 oC. The Km and Vmax values of this enzyme were 1.32 mg∙mL− 1, 526.32 µM∙mg− 1∙min− 1, respectively (chitosan as substrate). The enzyme activity can be enhanced by Mg2+ and especially Mn2+, which could enhance the activity about 3.62-fold at a 3 mM concentration. The enzyme can hydrolyze a variety of polysaccharides which linked by β-1,4-glycosidic bonds such as chitin, xylan and cellulose, but it could not hydrolyze polysaccharides linked by α-1,4-glycosidic bonds. The results of thin layer chromatography and HPLC showed that the enzyme exhibited an endo-type cleavage pattern and could hydrolyze chitosan to glucosamine (GlcN) and (GlcN)2. This study demonstrated that SaCsn46A is a promising enzyme to produce glucosamine and chitooligosaccharides (COS) from chitosan.

BACKGROUND T-cell large granular lymphocytic leukemia (T-LGLL) is a rare type of aplastic anemia with diverse clinical manifestations. Concomitant diseases are often present at the first manifestation. We describe the treatment of a patient with CD57-negative γδT-LGLL with pure red cell aplasia (PRCA). CASE SUMMARY A 34-year-old woman with a 20-year history of anemia visited our hospital owing to severe dizziness and was admitted. Her condition was diagnosed as CD57-negative γδT-LGLL with PRCA through bone marrow cytology, bone marrow pathology, bone marrow flow cytometry, bone marrow multiplex polymerase chain reaction combined with fluorescent fragment analysis, and other tests. Treatment with prednisone, methotrexate, and subcutaneous erythropoietin did not significantly change her hemoglobin level. After treatment with oral cyclophosphamide for 3 mo, her hemoglobin level increased to approximately 100 g/L. After 5 mo of treatment, the patient could perform activities of daily living independently. CONCLUSION The treatment of CD57-negative γδT-LGLL with PRCA with cyclophosphamide helps to improve prognosis.

This meta-analysis aimed to assess the efficacy of omalizumab in the treatment of refractory-to-antihistamines chronic induced urticaria (CIndU) in comparison with that of refractory-to-antihistamines chronic spontaneous urticaria (CSU). We retrieved interventional studies and observational studies on omalizumab efficacy to CIndU patients and efficacy comparison between CSU and CIndU both refractory to H1-antihistamines in electronic databases (accessed till May 2022). The odd ratio (OR) and 95% confidence interval (CI) was calculated with a random-effect model in this meta-analysis. The majority of patients with different CIndU subtypes gained complete or partial response and good safety after omalizumab treatment. A total of five studies with 355 CSU patients and 103 CIndU patients were included for the meta-analysis. There was no significant difference in the efficacy of omalizumab in the treatment of CSU and CIndU (OR -0.83, 95% CI [0.84, 2.21], P 0.05). Based on the validity of omalizumab in the treatment of various CIndU subtypes and non-differential efficacy between CSU and CIndU, it is reasonable to list omalizumab as a third-line treatment of refractory CIndU.

[Background]Drought has been a considerable problem for many years in northern Bangladesh. However, the health impacts of drought in this region are not well understood. [Methods]This study analyzed the impact of drought duration and severity on select causes of mortality in northern Bangladesh. Rainfall data from three meteorological stations (Rangpur, Dinajpur and Nilphamari) in northern Bangladesh were used to assess drought and non-drought periods, and the Standardized Precipitation Index was used to categorize mild, moderate, severe, and extreme drought. Mortality data from 2007 to 2017 for the three areas were collected from the Sample Vital Registration System, which is a survey of 1 million people. The generalized linear model with Poisson regression link was used to identify associations between mortality and the drought severity and 1-month preceding SPI. [Results]Only severe and extreme drought in the short-term drought periods affected mortality. Long-term drought was not associated with natural cause mortality in Rangpur and Nilphamari. In Dinajpur, mild and moderate drought was associated with circulatory- and respiratory-related mortality. [Conclusion]The impact of drought on mortality varied by region. This study improves our understanding of how droughts affect specific causes of mortality and will help policy makers to take appropriate measures against drought impacts on selected cause of mortality. Future research will be critical to reduce drought-related risks of health.

BACKGROUND: The global pandemic coronavirus disease 2019 (COVID-19) has become a major public health problem and presents an unprecedented challenge. However, no specific drugs were currently proven. This study aimed to evaluate the comparative efficacy and safety of pharmacological interventions in patients with COVID-19. METHODS: Medline, Embase, the Cochrane Library, and clinicaltrials.gov were searched for randomized controlled trials (RCTs) in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)/SARS-CoV. Random-effects network meta-analysis within the Bayesian framework was performed, followed by the Grading of Recommendations Assessment, Development, and Evaluation system assessing the quality of evidence. The primary outcome of interest includes mortality, cure, viral negative conversion, and overall adverse events (OAEs). Odds ratio (OR) with 95% confidence interval (CI) was calculated as the measure of effect size. RESULTS: Sixty-six RCTs with 19,095 patients were included, involving standard of care (SOC), eight different antiviral agents, six different antibiotics, high and low dose chloroquine (CQ_HD, CQ_LD), traditional Chinese medicine (TCM), corticosteroids (COR), and other treatments. Compared with SOC, a significant reduction of mortality was observed for TCM (OR = 0.34, 95% CI: 0.20-0.56, moderate quality) and COR (OR = 0.84, 95% CI: 0.75-0.96, low quality) with improved cure rate (OR = 2.16, 95% CI: 1.60-2.91, low quality for TCM; OR = 1.17, 95% CI: 1.05-1.30, low quality for COR). However, an increased risk of mortality was found for CQ_HD vs. SOC (OR = 3.20, 95% CI: 1.18-8.73, low quality). TCM was associated with decreased risk of OAE (OR = 0.52, 95% CI: 0.38-0.70, very low quality) but CQ_HD (OR = 2.51, 95% CI: 1.20-5.24) and interferons (IFN) (OR = 2.69, 95% CI: 1.02-7.08) vs. SOC with very low quality were associated with an increased risk. CONCLUSIONS: COR and TCM may reduce mortality and increase cure rate with no increased risk of OAEs compared with standard care. CQ_HD might increase the risk of mortality. CQ, IFN, and other antiviral agents could increase the risk of OAEs. The current evidence is generally uncertain with low-quality and further high-quality trials are needed.

Objective: This study aimed to investigate the expression and clinical value of hsa-miR-504 in cervical cancer and its possible mechanism of regulating the progress of cervical cancer. Methods: The...

Background As a highly contagious disease, coronavirus disease 2019 (COVID-19) is wreaking havoc around the world due to continuous spread among close contacts mainly via droplets, aerosols, contaminated hands or surfaces. Therefore, centralized isolation of close contacts and suspected patients is an important measure to prevent the transmission of COVID-19. At present, the quarantine duration in most countries is 14 d due to the fact that the incubation period of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is usually identified as 1-14 d with median estimate of 4-7.5 d. Since COVID-19 patients in the incubation period are also contagious, cases with an incubation period of more than 14 d need to be evaluated. Case summary A 70-year-old male patient was admitted to the Department of Respiratory Medicine of The First Affiliated Hospital of Harbin Medical University on April 5 due to a cough with sputum and shortness of breath. On April 10, the patient was transferred to the Fever Clinic for further treatment due to close contact to one confirmed COVID-19 patient in the same room. During the period from April 10 to May 6, nucleic acid and antibodies to SARS-CoV-2 were tested 7 and 4 times, respectively, all of which were negative. On May 7, the patient developed fever with a maximum temperature of 39℃, and his respiratory difficulties had deteriorated. The results of nucleic acid and antibody detection of SARS-CoV-2 were positive. On May 8, the nucleic acid and antibody detection of SARS-CoV-2 by Heilongjiang Provincial Center for Disease Control were also positive, and the patient was diagnosed with COVID-19 and reported to the Chinese Center for Disease Control and Prevention. Conclusion This case highlights the importance of the SARS-CoV-2 incubation period. Further epidemiological investigations and clinical observations are urgently needed to identify the optimal incubation period of SARS-CoV-2 and formulate rational and evidence-based quarantine policies for COVID-19 accordingly.

BACKGROUND Breast cancer is the most common malignancy in women all around the world. According to the latest statistics in 2018, there were more than 2.08 million new breast cancer cases all around the world and more than 620000 deaths; the proportion of breast cancer deaths in women with cancer is 15%. By studying age, clinicopathological characteristics and molecular classification, age at menarche, age at birth, number of births, number of miscarriages, lactation time, surgical history of benign breast lesions, history of gynecological diseases, and other factors, we retrospectively summarized and compared the disease history of patients with primary breast cancer and patients with benign thyroid tumors admitted to our hospital in the past 10 years to explore the clinicopathological characteristics and risk factors for primary breast cancer. AIM To investigate the clinical and pathological features and risk factors for primary breast cancer treated at our center in order to provide a reference for the prevention and treatment of breast cancer in the Zhuhai-Macao region. METHODS Through a retrospective case-control study, 149 patients with primary breast cancer diagnosed and treated at Zhuhai Hospital of Guangdong Provincial Hospital of Traditional Chinese Medicine from January 2013 to March 2020 were included as a case group, and 165 patients with benign breast tumors diagnosed and treated from January 2019 to March 2020 were included as a control group. The data collected included age, age at menarche, age at first birth, number of births, number of miscarriages, lactation time, history of surgery for benign breast lesions, history of familial malignant tumors, history of gynecological diseases, history of thyroid diseases, and the tumor characteristics of the patients in the case group including pathological diagnosis, pathological type, tumor size, lymph node metastasis, distant metastasis, stage, and molecular classification, among others. In the case group, the chi-square test was used to analyze the clinical and pathological features of patients in three age groups (< 40, 40-59, and ≥ 60 years). A multifactor logistic regression analysis was used to analyze correlations between the two groups. RESULTS Among 149 patients with primary breast cancer, the average age was 48.20 ± 12.06 years, and the proportion of patients at 40-59 years old was the highest, accounting for 61.8% of cases. The molecular type was mainly luminal B type, accounting for 69.2% of cases, and at the time of diagnosis, the tumor stage was mainly stage I/II, accounting for 62.4% of cases. There were no statistically significant differences in the distributions of tumor location, pathological type, tumor size, lymph node metastasis, stage, or molecular classification among the three age groups (< 40, 40-59, and ≥ 60 years) (P ≥ 0.05). The differences in the distribution of distant metastasis among the three age groups (< 40, 40-59, and ≥ 60 years) were statistically significant (P < 0.01). The differences in lactation time, history of familial malignant tumors, history of gynecological diseases, and history of thyroid diseases between the two groups were not statistically significant (P ≥ 0.05). The differences in age at disease diagnosis, age at menarche, and history of surgery for benign breast lesions were statistically significant (P < 0.01). The difference in age at first birth was also statistically significant (P < 0.05). CONCLUSION The highest incidence of breast cancer in the Zhuhai-Macao region is present among women aged 40-59 years. There is a larger proportion of stage I/II patients, and the luminal B type is the most common molecular subtype. Distant metastasis occurs mainly in the ≥ 60-year-old group at the first diagnosis; increased age, late age at menarche, and late age at first birth may be risk factors for primary breast cancer, and a history of surgery for benign breast lesions may be a protective factor for primary breast cancer.

Background:. Prenatal evaluation of fetal lung maturity (FLM) is a challenge, and an effective non-invasive method for prenatal assessment of FLM is needed. The study aimed to establish a normal fetal lung gestational age (GA) grading model based on deep learning (DL) algorithms, validate the effectiveness of the model, and explore the potential value of DL algorithms in assessing FLM. Methods:. A total of 7013 ultrasound images obtained from 1023 normal pregnancies between 20 and 41 + 6 weeks were analyzed in this study. There were no pregnancy-related complications that affected fetal lung development, and all infants were born without neonatal respiratory diseases. The images were divided into three classes based on the gestational week: class I: 20 to 29 + 6 weeks, class II: 30 to 36 + 6 weeks, and class III: 37 to 41 + 6 weeks. There were 3323, 2142, and 1548 images in each class, respectively. First, we performed a pre-processing algorithm to remove irrelevant information from each image. Then, a convolutional neural network was designed to identify different categories of fetal lung ultrasound images. Finally, we used ten-fold cross-validation to validate the performance of our model. This new machine learning algorithm automatically extracted and classified lung ultrasound image information related to GA. This was used to establish a grading model. The performance of the grading model was assessed using accuracy, sensitivity, specificity, and receiver operating characteristic curves. Results:. A normal fetal lung GA grading model was established and validated. The sensitivity of each class in the independent test set was 91.7%, 69.8%, and 86.4%, respectively. The specificity of each class in the independent test set was 76.8%, 90.0%, and 83.1%, respectively. The total accuracy was 83.8%. The area under the curve (AUC) of each class was 0.982, 0.907, and 0.960, respectively. The micro-average AUC was 0.957, and the macro-average AUC was 0.949. Conclusions:. The normal fetal lung GA grading model could accurately identify ultrasound images of the fetal lung at different GAs, which can be used to identify cases of abnormal lung development due to gestational diseases and evaluate lung maturity after antenatal corticosteroid therapy. The results indicate that DL algorithms can be used as a non-invasive method to predict FLM.

Sustainable bioproduction usingcarbon neutral feedstocks, especially lignocellulosic biomass, has attracted increasing attention due to concern over climate change and carbon reduction. Consolidated bioprocessing (CBP) of lignocellulosic biomass using recombinantyeast of Saccharomyces cerevisiaeis a promising strategy forlignocellulosic biorefinery. However, the economic viability is restricted by low enzyme secretion levels.For more efficient CBP, MIG1

Plants respond to attackers by triggering phytohormones signaling associated metabolites, including herbivore-induced plant volatiles (HIPVs). HIPVs can indirectly act against herbivory by recruitment of natural enemies and priming of neighboring plants. Ostrinia furnacalis and Mythimna separata are important insect herbivores of maize plants that have a devastating influence on yield. However, little is known about how maize temporally reconfigures its defense systems against these herbivores and variation of neighboring plant resistance.This study investigated the effects of HIPVs on the behavior of the dominant predatory beetle Harmonia axyridis and priming in neighboring maize defense against O. furnacalis and M. separata over time. The results showed that maize damaged by either O. furnacalis or M. separata enhanced the release of volatiles including terpenes, aldehydes, alkanes and an ester, which elicited an increased attractive response to H. axyridis after 3 and 12 h, respectively. O. furnacalis damage resulted in accumulations of leaf jasmonic acid (JA) and salicylic acid in maize after 6 and 3 h, respectively, while M. separata damage only raised the JA level after 3 h. Furthermore, HIPVs were able to prime neighboring plants through the accumulation of JA after 24 h. Both larvae showed a significant decrease in weight accumulation after 48 h of feeding on the third leaves of the primed plant.Taken together, the findings provide a dynamic overview of how attacked maize reconfigures its volatiles and phytohormones to defend against herbivores, as well as priming of neighboring plants against oncoming attacks. © 2022 Society of Chemical Industry.

Microbial electrolysis cells (MECs) have rapidly developed into a promising technology to treat sulfate-rich wastewater that lacks electron donors. However, little is known regarding the effect of different carbon sources on the microbial community structure bioelectrochemical systems. This study sought to investigate the effect of different carbon sources (NaHCO3, ethanol, and acetate were employed as sole carbon source respectively) on the performance of sulfate-reducing biocathodes. The sulfate reduction efficiency enhanced by the bioelectrochemical systems was 8.09%−11.57% higher than that of open-circuit reference experiments. Furthermore, the optimum carbon source was ethanol with a maximum sulfate reduction rate of 170 mg L−1 d−1 in the bioelectrochemical systems. The different carbon sources induced significant differences in sulfate reduction efficiency as demonstrated by the application of a micro-electrical field. The dominant sulfate-reducing bacteria that use NaHCO3 and acetate as carbon sources were Desulfobacter and Desulfobulbus, whereas those that use ethanol as carbon source were Desulfomicrobium and Desulfovibrio. Our results suggest that ethanol is a more suitable carbon source for sulfate reduction in bioelectrochemical systems.

CHCHD2 mutations have been reported to cause Parkinson's disease (PD) by a loss of function in mitochondria. Most reported mutations, however, were missense, which was not the perfect model for a study of haploinsufficiency. Here, a truncated mutation, CHCHD2 p.Pro53Alafs*38, was identified in one familial early-onset PD patient. We generated a human-induced pluripotent stem cell (iPSC) line WCHSCUi001-A from this patient. The generated iPSCs resembled human embryonic stem cells, expressed pluripotency markers, exhibited a normal karyotype and could be differentiated into three germ layers in vitro. This line will be valuable for investigating the disease mechanisms and screening candidate drugs.

Background GnRHa treatment was established for improving final adult height (FAH) in children presenting with Idiopathic central precocious puberty (ICPP) up to age 8, while several controversies remained for older age groups. The primary objective was to evaluate whether boys diagnosed with ICPP over 9 years of chronological age (CA) could achieve a height benefit from GnRHa treatment. Methods We retrospectively evaluated the medical records of 23 boys treated for idiopathic central precocious puberty between January 2018 and January 2021 at Jiangsu Children’s Medical Center. All patients started treatment with intramuscular depot GnRHa at a dose of 80–100 μg/kg, followed by continuous intramuscular injection every 28 days at a dose of 60–80 μg/kg. The hormonal parameters, bone age/chronological age ratio, FAH, growth velocity (GV), tanner staging and body mass index (BMI) were assessed during the treatment period. Results After one course of treatment (3 months), the basal FSH and testosterone levels were reduced, while the basal LH value was not significantly changed compared with those before treatment. Furthermore, the mean BA/CA ratio reduction was statistically significant at month 12. The mean PAH following administration of GnRHa after 12 months was statistically improved compared with those at baseline. In addition, the clinical sign of puberty and GV were significantly improved and the BMI remained unchanged as desired at month 12. Conclusions This analysis highlighted the positive outcome on the decrease in the rate of bone maturation, with a favorable effect on progression of clinical signs of puberty. Furthermore, our study confirmed PAH was improved even in the older children at onset of treatment (ages 9–10), emphasizing the importance of personalized treatment in such population.

Background Tumor-related osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by severe hypophosphatemia and osteomalacia. The diagnosis of TIO can be very difficult because of its nonspecific nature of clinical manifestations. Here we reported a case of young TIO patient with “painful knee joint with difficulty in moving” to improve the clinical diagnosis and treatment levels. Case presentation The patient’s clinical features were consistent with TIO. A tumor was successfully located in left tibial by 68Ga-DOTATATE PET/CT, and then was surgically resected. Upon pathologic assessment, the tumor was diagnosed as phosphaturia stromal tumor (PMT) with positive Vim staining. After the surgery, serum phosphate level rapidly recovered and symptoms significantly improved. Conclusion TIO should be considered in patients with chronically hypophosphorus osteomalacia in the setting of no family history. Early removal of the responsible tumors is clinically essential for the treatment, and imaging examination is of great significance for tumor localization.

Serum and glucocorticoid-regulated kinase 1 (SGK1), as a serine threonine protein kinase of the AGC family, regulates different enzymes, transcription factors, ion channels, transporters, and cell proliferation and apoptosis. Inhibition of SGK1 is considered as a valuable approach for the treatment of various metabolic diseases. In this investigation, virtual screening methods, including pharmacophore models, Bayesian classifiers, and molecular docking, were combined to discover novel inhibitors of SGK1 from the database with 29,158 compounds. Then, the screened compounds were subjected to ADME/T, PAINS and drug-likeness analysis. Finally, 28 compounds with potential inhibition activity against SGK1 were selected for biological evaluation. The kinase inhibition activity test revealed that among these 28 hits, hit15 exhibited the highest inhibition activity against SGK1, which gave 44.79% inhibition rate at the concentration of 10 µM. In order to further investigate the interaction mechanism of hit15 and SGK1 at simulated physiological conditions, a molecular dynamics simulation was performed. The molecular dynamics simulation demonstrated that hit15 could bind to the active site of SGK1 and form stable interactions with key residues, such as Tyr178, ILE179, and VAL112. The binding free energy of the SGK1-hit15 was −48.90 kJ mol−1. Therefore, the identified hit15 with novel scaffold may be a promising lead compound for development of new SGK1 inhibitors for various diseases treatment.

Small-diameter artificial blood vessels have always faced the problem of thrombosis. In this research, three types of poly(-caprolactone)-cellulose acetate (PCL-CA) composite nanofiber membranes were prepared by various collectors to make into a tubular scaffold with a 4.5-mm diameter. The collector consisted of two sizes of stainless steel wire mesh large-mesh (LM) and small-mesh (SM), respectively. There is also a random flat (RF) that acts as the third type collector. The nanofiber membrane's surface structure mimicked the collectors' surface morphology, they named LM, SM and RF scaffolds. The water contact angles of RF and LM scaffolds are 126.5° and 105.5°, and the distinct square-groove construction greatly improves the contact angle of LM. The tubular scaffolds' radial mechanical property test demonstrated that the large-mesh (LM) tubular scaffold enhanced the strain and tensile strength; the tensile strength and strain are 30 % and 148 % higher than that of the random-flat (RF) tubular scaffold, respectively. The suture retention strength value of the LM tubular scaffold was 103 % higher than that of the RF tubular scaffold. The cytotoxicity and antithrombogenicity performance were also evaluated, the LM tubular scaffold has 88 % cell viability, and the 5-min blood coagulation index (BCI) value was 89 %, which is much higher than other tubular scaffolds. The findings indicate that changing the tubular scaffold's surface morphology cannot only enhance the mechanical and hydrophilic properties but also increase cell survival and antithrombogenicity performance. Thus, the development of a small-diameter artificial blood vessel will be a big step toward solving the problem on thrombosis. Furthermore, artificial blood vessel is expected to be a candidate material for biomedical applications.

Background The time of survival in patients with amyotrophic lateral sclerosis (ALS) varies greatly, and the genetic factors that contribute to the survival of ALS are not well studied. There is a lack of a comprehensive study to elucidate the role of genetic factors in the survival of ALS. Methods The published studies were systematically searched and obtained from PubMed, EMBASE, and the Cochrane Library without any language restrictions from inception to Oct 27, 2021. A network meta-analysis for ALS causative/risk genes and a systematic review and pairwise meta-analysis for other genetic modifiers were conducted. The PROSPERO registration number: CRD42022311646. Results A total of 29,764 potentially relevant references were identified, and 71 papers were eligible for analysis based on pre-decided criteria, including 35 articles in network meta-analysis for 9 ALS causative/risk genes, 17 articles in pairwise meta-analysis for four genetic modifiers, and 19 articles described in the systematic review. Variants in three genes, including ATXN2 (HR: 3.6), C9orf72 (HR: 1.6), and FUS (HR:1.8), were associated with short survival of ALS, but such association was not identified in SOD1, TARDBP, TBK1, NEK1, UBQLN2, and CCNF. In addition, UNC13A rs12608932 CC genotype and ZNF521B rs2275294 C allele also caused a shorter survival of ALS; however, APOE ε4 allele and KIFAP3 rs1541160 did not be found to have any effect on the survival of ALS. Conclusions Our study summarized and contrasted evidence for prognostic genetic factors in ALS and would help to understand ALS pathogenesis and guide clinical trials and drug development.