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Li-Li Zhao,*,1 Ming-Xiang Huang,*,2 Tong-Yang Xiao,1 Hai-Can Liu,1 Ma-Chao Li,1 Xiu-Qin Zhao,1 Zhi-Guang Liu,1 Yi Jiang,1 Kang-Lin Wan11State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, People’s Republic of China; 2Clinical Laboratory, Fuzhou Pulmonary Hospital, Fuzhou, 350008, People’s Republic of China*These authors contributed equally to this workObjectives: To explore the prevalence, risk and genetic characteristics of drug-resistant tuberculosis (TB) from a tertiary care TB hospital in China.Patients and methods: We carried out a retrospective study including isolates from 189 patients with pulmonary TB at Fuzhou Pulmonary Hospital. All isolates from these patients were subjected to drug susceptibility testing and genotyping. For drug-resistant isolates, DNA sequencing was used to investigate mutations in 12 loci, including katG, inhA, oxyR–ahpC, rpoB, rpsL, rrs1 (nucleotides 388–1084 of rrs), embB, tlyA, eis, rrs2 (nucleotides 1158–1674 of rrs), gyrA and gyrB.Results: Among 189 isolates, 28.6% were resistant to at least one of the seven anti-TB drugs, including isoniazid (INH), rifampin (RIF), streptomycin (STR), ethambutol (EMB), capreomycin (CAP), kanzmycin (KAN) and ofloxacin (OFX). The proportion of multidrug-resistant TB and extensively drug-resistant TB isolates was 9.5% and 1.1%, respectively. Patients in rural areas as well as previously treated patients showed a significantly increased risk of developing drug resistance. In addition, among these isolates, 111 (58.7%) were Beijing genotype strains, 84 (75.7%) of which belonged to modern Beijing sublineage. There was no association between genotype and drug resistance. The most common mutations were katG315, rpoB531 rpsL43, embB306, rrs1401 and gyrA94. Conclusion: These findings provided additional information of drug-resistant TB in China. Previously treated patients and patients in rural areas should receive greater attention owing to their higher risk of developing drug resistance.Keywords: drug-resistant tuberculosis, genotype, risk, mutation

Developing ultrahigh-strength steels that are ductile, fracture resistant, and cost effective would be attractive for a variety of structural applications. We show that improved fracture resistance in a steel with an ultrahigh yield strength of nearly 2 gigapascals can be achieved by activating delamination toughening coupled with transformation-induced plasticity. Delamination toughening associated with intensive but controlled cracking at manganese-enriched prior-austenite grain boundaries normal to the primary fracture surface dramatically improves the overall fracture resistance. As a result, fracture under plane-strain conditions is automatically transformed into a series of fracture processes in "parallel" plane-stress conditions through the thickness. The present "high-strength induced multidelamination" strategy offers a different pathway to develop engineering materials with ultrahigh strength and superior toughness at economical materials cost.

This study explores the feasibility of identifying bound compounds in non-extractable residues (NERs) of pesticides in soil by 4-pool kinetic analysis. The 4-pools refer to parent compound, metabolites, NERs, and CO 2 in 14 C-labeled pesticide soil degradation studies. We discovered the following two characteristic 4-pool kinetic behaviors of formation of NERs: (1) if parent compound is bound as NERs, the metabolites (m(t) in % applied radioactivity (AR)) kinetically drive the evolution of CO 2 only; and (2) if a metabolite (x) in a sequential degradation pathway is bound as NERs, m(t) is split into m 1 (t) and m 2 (t) at the metabolite (x) that is bound as NERs, which kinetically drive the formation of NERs and evolution of CO 2 respectively. We developed two (i.e., Parent➔NER and metabolite➔NER) 4-pool models to capture the kinetic behaviors respectively. By fitting the models to a set of 4-pool data, we not only determine whether NERs form from parent compound or metabolites but also identify the bound metabolite (x) by resolving the metabolites into M 1 (t) and M 2 (t) (i.e., the variables used to simulate m 1 (t) and m 2 (t)) and then matching m 1 (t) (i.e., the sum of the bound metabolite (x) and its metabolite precursors) with M 1 (t). By applying the models to 14 C-labeled parent compound-dosed studies and then sequentially to metabolite-dosed studies for 7 pesticides with ≥70 % AR NERs, we identified the bound compounds, which have the moieties known to be responsible for NERs, are bound as NERs instantaneously when dosed into soil, and account for pH dependency of NER formation., 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 B.V. All rights reserved.)

Bacterial inactivation on antibacterial metal surfaces has been widely used in medicine and daily life to inhibit infection caused by surface contact. However, the underlying antibacterial mechanism of metal surfaces has remained elusive due to a lack of comprehensive theoretical perspectives and direct evidence. Here, we propose a universal understanding of the bacteria-inactivation mechanism of metal surfaces and reveal the changes in bacterial survival behavior with time and spatial location. In terms of bacterial survival over time, we established a quantitative ion influx model and predicted four bacterial survival behaviors based on osmotic pressure changes and ion release. To demonstrate the spatial distribution of bacterial survival, we consider variations in metal antibacterial properties and electrode potentials and design five corrosion galvanic couples to cover all possible metal combinations. The results on the bacterial survival behavior over time confirm our theoretical predictions, exhibiting a dependence of bacterial viability on environmental humidity and metal toxicity. In addition, on the surfaces of galvanic couples, bacteria will experience the most pronounced decrease in viability at anodes, irrespective of the location of the antibacterial metals. This abnormal distribution pattern can be fundamentally attributed to the highest toxic-ion concentration resulting from a low pH at anodes. The consistency between our predictions and observed bacterial survival rates supports the notion that the antibacterial mechanism follows surface ion release and subsequent free-ion influx into the cytoplasm, leading to lethal biochemical reactions in bacteria. STATEMENT OF SIGNIFICANCE: Numerous studies have been conducted on developing antibacterial metals, alloys, and their related applications. However, the underlying antibacterial mechanism of metal surfaces has remained elusive. This work is the first to propose a general understanding of the antibacterial mechanism of metal surfaces, including the temporal and spatial characteristics of bacterial survival behavior. By building a theoretical model, we predicted and confirmed the shapes of the four bacterial survival curves over time. In addition, we found that bacteria have the worst viability loss at the alloy anode, even if non-antibacterial metals occupy this position. The conclusions can provide theoretical support for the antibacterial behavior of metal surfaces, including but not limited to Ag, Cu, Zn, and their corresponding alloys., 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. Published by Elsevier Ltd.)

Background: While respiratory rate has proven to be a sensitive prognostic indicator in ICU settings, its relevance in the context of Acute Myocardial Infarction (AMI) patients complicated by Congestive Heart Failure (CHF) remains underexplored. Therefore, this study aims to investigate the relationship between respiratory rate and in-hospital mortality in this specific patient cohort. Methods: This retrospective cohort study utilized the Medical Information Mart for Intensive Care-IV database to analyze all AMI patients with concomitant CHF. The primary outcome, in-hospital mortality, was assessed through multivariate analysis. Logistic regression models, restricted cubic spline regression models, and subgroup analyses were employed to explore the association between respiratory rate and in-hospital mortality. Results: The study encompassed 5056 participants diagnosed with both CHF and AMI. After adjusting for confounding variables, each incremental unit rise in respiratory rate was associated with an 8% increase in the risk of patient mortality (OR = 1.08, 95% CI: 1.05∼1.11, P < 0.001). When comparing individuals with respiratory rates in the first tertile (≤17 breaths per minute) and the third tertile (>17-20 breaths per minute) to those in the second tertile (17-20 breaths per minute), the adjusted ORs for in-hospital mortality were 1.09 (95% CI: 0.82∼1.46, P = 0.546) and 1.62 (95% CI: 1.27∼2.06, P < 0.001), respectively. A dose-response relationship depicted a J-shaped curve between respiratory rate and the risk of in-hospital mortality, with an inflection point at approximately 19 breaths per minute. Stratified analyses confirmed the robustness of this correlation. Conclusions: This study reveals a J-shaped association between respiratory rate and in-hospital mortality in ICU patients suffering from both AMI and CHF., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Background: Escalating cases of multidrug-resistant tuberculosis (MDR-TB) pose a major challenge to global TB control efforts, necessitating innovative diagnostics to empower decentralized detection of gene mutations associated with resistance to rifampicin (RIF) and isoniazid (INH) in Mycobacterium tuberculosis (M. tuberculosis) in resource-constrained settings., Methods: Combining multiplex fluorescent PCR and Multiple Probes Melting Analysis, we identified mutations in the rpoB, katG, ahpC and inhA genes from sputum specimens. We first constructed a reference plasmid library comprising 40 prevalent mutations in the target genes' resistance determining regions and promoters, serving as positive controls. Our assay utilizes a four-tube asymmetric PCR method with specifically designed molecular beacon probes, enabling simultaneous detection of all 40 mutations. We evaluated the assay's effectiveness using DNA isolated from 50 clinically confirmed M. tuberculosis sputum specimens, comparing our results with those obtained from Sanger sequencing and retrospective validation involving bacteriological culture and phenotypic drug susceptibility testing (pDST). We also included the commercial Xpert MTB/RIF assay for accuracy comparison., Results: Our data demonstrated remarkable sensitivity in detecting resistance to RIF and INH, achieving values of 93.33% and 95.24%, respectively, with a specificity of 100%. The concordance between our assay and pDST was 98.00%. Furthermore, the accuracy of our assay was comparable to both Sanger sequencing and the Xpert assay. Importantly, our assay boasts a 4.2-h turnaround time and costs only $10 per test, making it an optimal choice for peripheral healthcare settings., Conclusion: These findings highlight our assay's potential as a promising tool for rapidly, accurately, and affordably detecting MDR-TB., Competing Interests: Declarations. Conflict of interest: All authors declare no competing interests as defined by Springer, or other interests that might be perceived to influence the results and/or discussion reported in this paper. Ethical approval, consent to participate and biosafety statement: This study received institutional approval from the Research Ethics Committee of Chaoshan Hospital (Approval number: CREA-CSH2021-003), affiliated with Jinan University First Affiliated Hospital, and the Medicine and Biological Engineering Technology Research Centre of the Ministry of Health, Guangzhou, China. This approval was in line with the Helsinki declaration as revised in 2013 and its later amendments. All participants provided written informed consent to the collection, the storage and the use of biological samples for scientific analysis before participating in the study. To ensure ethical compliance, data pertinent to disease control were collected and subsequently anonymized for analysis. All experimental protocols of this study were performed following national technical specification for TB prevention and control., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: To explore the application of neurofeedback (NFB) combined with learning style profile (LSP) intervention training in children with high-functioning autism (HFA)., Methods: A prospective study was conducted to select 86 children with HFA admitted to the hospital from February 2022 to February 2024. They were divided into two groups according to the random number table method, with 43 cases in each group. In this double-blind study, the control group was given LSP intervention training, and the observation group was given NFB intervention on the basis of the treatment used in the control group. Both groups were treated for 6 months. The scores of Autism Behavior Checklist (ABC), Autism Treatment Evaluation Checklist (ATEC), Social Responsiveness Scale (SRS), and Pediatric Quality of Life (PedsQL) were compared between the two groups before intervention and at 6 months after intervention. The relationship of PedsQL score with ABC, ATEC, and SRS scores was analyzed in children with HFA., Results: After 6 months of intervention, the scores of ABC, ATEC, and SRS in the observation group were significantly lower than those in the control group, while the PedsQL score in the observation group was significantly higher than that in the control group ( P <0.05). The PedsQL score was negatively correlated with the ABC, ATEC, and SRS scores in children with HFA ( r =-0.238, -0.381, -0.219 respectively; P <0.001)., Conclusions: NFB combined with LSP can effectively improve the clinical symptoms and social ability, control the development of the disease, and improve the quality of life in children with HFA.

Copper and boron seldom engage in reaction at ambient pressure. The few reports on copper-doped boron compounds that exist in the literature often lack definitive stoichiometry. Here, we report successful synthesis of Cu&#95;{2-δ}B&#95;{25} single crystals (δ∼0.03, indicating Cu understoichiometry) via a high-pressure melting method using copper and β-rhombohedral boron as precursors. Crystals thus synthesized are characterized by a tetragonal boron sublattice, within which Cu atoms are either partially or fully situated at different interstices between B&#95;{12} icosahedra. The crystals possess a high Vickers hardness of 26.5 GPa and an unusually high electrical conductivity of 1.19×10^{5}  S/m-the highest conductivity among the icosahedron-based borides. Hall measurements reveal a notable p-n conduction type transition around 30 GPa. This transition, alongside the remarkable conductivity, is potentially modulated by the copper content and its valence states within the structure. The synthesis of Cu&#95;{2-δ}B&#95;{25} not only broadens the spectrum of hard materials but also opens new avenues for innovative modulation of electronic properties in boron-rich compounds, with promising technological implications.

Although most cognitive impairments induced by prolonged alcohol consumption tend to improve within the initial months of abstinence, there is evidence suggesting certain cognitive deficits may persist. This study aimed to investigate the impact of aerobic exercise on learning and memory in alcohol use disorder (AUD) mice following a period of abstinence from alcohol. We also sought to assess the levels of monoamine neurotransmitters in the hippocampus. To this end, we established an AUD mouse model through a two-bottle choice (sucrose fading mode and normal mode) and chronic intermittent alcohol vapor (combined with intraperitoneal injection) and randomly allocated mice into exercise groups to undergo treadmill training. Learning and memory abilities were assessed through the Morris water maze test and spontaneous activity was evaluated using the open field test. The levels of dopamine, norepinephrine, serotonin, and brain-derived neurotrophic factor in the hippocampus were quantified using enzyme-linked immunoassay (ELISA) kits. The findings reveal that after cessation of alcohol consumption, learning and memory abilities in AUD mice did not completely return to normal levels. The observed enhancement of cognitive functions in AUD mice through aerobic exercise may be attributed to restoring levels of monoamine neurotransmitters in the hippocampus, boosting brain-derived neurotrophic factor (BDNF) concentrations, and facilitating an increase in hippocampal mass. These results offer empirical evidence to support aerobic exercise as a viable therapeutic strategy to alleviate cognitive deficits associated with AUD., (© 2024 The Author(s). FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

The inherent brittleness of ceramics, primarily due to restricted atomic motions from rigid ionic or covalent bonded structures, is a persistent challenge. This characteristic hinders dislocation nucleation in ceramics, thereby impeding the enhancement of plasticity through a dislocation-engineering strategy commonly used in metals. Finding a strategy that continuously generates dislocations within ceramics may enhance plasticity. Here, we propose a "borrowing-dislocations" strategy that uses a tailored interfacial structure with well-ordered bonds. Such an approach enables ceramics to have greatly improved tensile ductility by mobilizing a considerable number of dislocations in ceramic borrowed from metal through the interface, thereby overcoming the challenge associated with direct dislocation nucleation within ceramics. This strategy provides a way to enhance tensile ductility in ceramics.

Malignant peripheral nerve sheath tumor (MPNST) frequently metastasizes to the lungs, although pleural metastasis is rare. This article reported a case of pleural metastasis of MPNST. The patient was a young man who presented with 1 week of shortness of breath with dry cough. He had a history of malignant peripheral nerve sheath tumor. The patient was diagnosed with MPNST pleural metastasis after a thoracoscopic pleural biopsy, which revealed short spindle cell hyperplasia, immunohistochemical staining for S-100(+), SOX-10(+), Ki-67(+) with a positive index of 20%, and H3K27Me3(-) in the pleural pathology.

Background: Lifestyle factors play an important role in the development and management of childhood obesity and its related cardiometabolic complications., Objective/methods: We aimed to explore childhood obesity subtypes based on lifestyle factors and examine their association with cardiometabolic health. We included 1550 children with obesity from the National Health and Nutrition Examination Survey. Cluster analysis identified obesity subtypes based on four lifestyle factors (physical activity, diet quality, sedentary time and smoking). Multiple linear regression assessed their association with cardiometabolic factors., Results: Five subtypes of childhood obesity were identified: unhealthy subtype (n = 571; 36.8%), physically active subtype (n = 185; 21.1%), healthy diet subtype (n = 404; 26.1%), smoking subtype (n = 125; 8.1%) and non-sedentary subtype (n = 265; 17.1%). Compared with the unhealthy subtype, the physically active subtype had lower insulin and HOMA-IR levels, and smoking subtype was associated with lower HDL levels. When compared with children with normal weight, all obesity subtypes had worse cardiometabolic profile, except the physically active subtype who had similar DBP, HbA1c and TC levels; smoking subtype who had similar TC levels; and healthy diet and non-sedentary subtypes who had similar DBP levels., Conclusion: Children of different lifestyle-based obesity subtypes might have different cardiometabolic risks. Our new classification system might help personalize assessment of childhood obesity., (© 2024 World Obesity Federation.)

Aim: To figure out whether various atropine dosages may slow the progression of myopia in Chinese kids and teenagers and to determine the optimal atropine concentration for effectively slowing the progression of myopia., Methods: A systematic search was conducted across the Cochrane Library, PubMed, Web of Science, EMBASE, CNKI, CBM, VIP, and Wanfang database, encompassing literature on slowing progression of myopia with varying atropine concentrations from database inception to January 17, 2024. Data extraction and quality assessment were performed, and a network Meta-analysis was executed using Stata version 14.0 Software. Results were visually represented through graphs., Results: Fourteen papers comprising 2475 cases were included; five different concentrations of atropine solution were used. The network Meta-analysis, along with the surface under the cumulative ranking curve (SUCRA), showed that 1% atropine (100%)>0.05% atropine (74.9%) >0.025% atropine (51.6%)>0.02% atropine (47.9%)>0.01% atropine (25.6%)>control in refraction change and 1% atropine (98.7%)>0.05% atropine (70.4%)>0.02% atropine (61.4%)>0.025% atropine (42%)>0.01% atropine (27.4%)>control in axial length (AL) change., Conclusion: In Chinese children and teenagers, the five various concentrations of atropine can reduce the progression of myopia. Although the network Meta-analysis showed that 1% atropine is the best one for controlling refraction and AL change, there is a high incidence of adverse effects with the use of 1% atropine. Therefore, we suggest that 0.05% atropine is optimal for Chinese children to slow myopia progression., Competing Interests: Conflicts of Interest: Wang XY, None; Deng HW, None; Yang J, None; Zhu XM, None; Xiang FL, None; Tu J, None; Huang MX, None; Wang Y, None; Gan JH, None; Yang WH, None., (International Journal of Ophthalmology Press.)

As members of the protein tyrosine kinase family, the Epidermal Growth Factor Receptor (EGFR) and Human Epidermal Growth Factor Receptor 2 (HER2) play essential roles in cellular signal transduction pathways. Overexpression or abnormal activation of EGFR and HER2 can lead to the development of various solid tumors. Therefore, they have been confirmed as biological targets for the development of anticancer drugs. Due to the fact that many cancers are highly susceptible to developing resistance to single-target EGFR inhibitors in clinical practice, dual inhibitors that target both EGFR and HER2 have been developed to increase efficacy, reduce drug resistance and interactions, and improve patient compliance. Currently, a variety of EGFR/HER2 dual inhibitors have been developed, with several drugs already approved for marketing or in clinical trials. In this review, we summarize recent advancements in small-molecule EGFR/HER2 dual inhibitors by focusing on structure-activity relationships and share novel insights into developing anticancer agents., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective To assess the influences of self-and interviewer-administered methods on the scores of anxiety and depression questionnaires among the patients with sports injuries.Methods A total of 532 participants with sports injuries treated in the Sports Medicine Center of West China Hospital,Sichuan University from November 2022 to May 2023 were included.They were randomly assigned to either the interviewer-administered group ( n =270) or the self-administered group ( n =262) to complete the generalized anxiety disorder (GAD-7) and the patient health questionnaire (PHQ-9) scales.The total scores and prevalence rates of anxiety and depression were compared between the two groups.Results There was no statistically significant difference in gender,occupation,or surgical site between the two groups (all P >0.05).The self-administered group had higher scores of GAD-7 and PHQ-9 scales than the interviewer-administered group ( P <0.001, P <0.001).A greater proportion of participants in the self-administered group than in the interview-administered group met the criteria for mild to moderate anxiety and depression ( P <0.001, P =0.002).The prevalence rates of moderate to severe anxiety (GAD-7≥10) and depression (PHQ-9≥10) showed no statistically significant difference between the two groups ( P =0.761, P =0.086).Conclusion This study demonstrates that the participants in the self-administered group are more likely to report mild to moderate symptoms of anxiety and depression than those in the interviewer-administered group.

Liver fibrosis is a common pathological feature of most chronic liver diseases with no effective drugs available. Phosphodiesterase 1 (PDE1), a subfamily of the PDE super enzyme, might work as a potent target for liver fibrosis by regulating the concentration of cAMP and cGMP. However, there are few PDE1 selective inhibitors, and none has been investigated for liver fibrosis treatment yet. Herein, compound AG-205/1186117 with the dihydropyrimidine scaffold was selected as the hit by virtual screening. A hit-to-lead structural modification led to a series of dihydropyrimidine derivatives. Lead 13h exhibited the IC 50 of 10 nM against PDE1, high selectivity over other PDEs, as well as good safety properties. Administration of 13h exerted significant anti-liver fibrotic effects in bile duct ligation-induced fibrosis rats, which also prevented TGF-β-induced myofibroblast differentiation in vitro, confirming that PDE1 could work as a potential target for liver fibrosis.

Background: The coexistence of heart failure and diabetes is prevalent, particularly in Intensive Care Units (ICU). However, the relationship between the triglyceride-glucose (TyG) index, heart failure, diabetes, and the length of hospital stay (LHS) in patients with cerebrovascular disease in the ICU remains uncertain. This study aims to investigate the association between the TyG index and LHS in patients with heart failure and diabetes., Methods: This retrospective study utilized the Medical Information Mart for Intensive Care (MIMIC)-IV database to analyze patients with diabetes and heart failure. Participants were categorized into quartiles based on the TyG index, and the primary outcome was LHS. The association between the TyG index at ICU admission and LHS was examined through multivariable logistic regression models, restricted cubic spline regression, and subgroup analysis., Results: The study included 635 patients with concurrent diabetes and heart failure. The fully adjusted model demonstrated a positive association between the TyG index and LHS. As a tertile variable (Q2 and Q3 vs Q1), the beta (β) values were 0.88 and 2.04, with a 95% confidence interval (95%CI) of -0.68 to 2.44 and 0.33 to 3.74, respectively. As a continuous variable, per 1 unit increment, the β (95% CI) was 1.13 (0.18 to 2.08). The TyG index's relationship with LHS showed linearity (non-linear p = 0.751). Stratified analyses further confirmed the robustness of this correlation., Conclusion: The TyG index exhibited a linearly positive association with the LHS in patients with both heart failure and diabetes. Nevertheless, prospective, randomized, controlled studies are imperative to substantiate and validate the findings presented in this investigation., 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 © 2024 Zhang, Han, Gao, Gu, Cai, Gu, Yu, Min, Gao, Hu and Huang.)

Magnetoencephalography (MEG) is a non-invasive functional imaging technique for pre-surgical mapping. However, movement-related MEG functional mapping of primary motor cortex (M1) has been challenging in presurgical patients with brain lesions and sensorimotor dysfunction due to the large numbers of trials needed to obtain adequate signal to noise. Moreover, it is not fully understood how effective the brain communication is with the muscles at frequencies above the movement frequency and its harmonics. We developed a novel Electromyography (EMG)-projected MEG source imaging technique for localizing early-stage (-100 to 0 ms) M1 activity during ~l min recordings of left and right self-paced finger movements (~1 Hz). High-resolution MEG source images were obtained by projecting M1 activity towards the skin EMG signal without trial averaging. We studied delta (1-4 Hz), theta (4-7 Hz), alpha (8-12 Hz), beta (15-30 Hz), gamma (30-90 Hz), and upper-gamma (60-90 Hz) bands in 13 healthy participants (26 datasets) and three presurgical patients with sensorimotor dysfunction. In healthy participants, EMG-projected MEG accurately localized M1 with high accuracy in delta (100.0%), theta (100.0%), and beta (76.9%) bands, but not alpha (34.6%) or gamma/upper-gamma (0.0%) bands. Except for delta, all other frequency bands were above the movement frequency and its harmonics. In three presurgical patients, M1 activity in the affected hemisphere was also accurately localized, despite highly irregular EMG movement patterns in one patient. Altogether, our EMG-projected MEG imaging approach is highly accurate and feasible for M1 mapping in presurgical patients. The results also provide insight into movement-related brain-muscle coupling above the movement frequency and its harmonics., Competing Interests: All 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., (© 2023 Massachusetts Institute of Technology. Published under a Creative Commons Attribution 4.0 International (CC BY 4.0) license.)

Epstein‒Barr virus (EBV)-associated gastric cancer (GC) manifests an intriguing immunotherapy response. However, the cellular basis for EBV-imprinted tumour immunity and on-treatment response remains undefined. This study aimed to finely characterize the dynamic tumour immune contexture of human EBV (+) GC treated with immunochemotherapy by longitudinal scRNA-seq and paired scTCR/BCR-seq. EBV (+) GC exhibits an inflamed-immune phenotype with increased T-cell and B-cell infiltration. Immunochemotherapy triggers clonal revival and reinvigoration of effector T cells which step to determine treatment response. Typically, an antigen-specific ISG-15 + CD8 + T-cell population is highly enriched in EBV (+) GC patients, which represents a transitory exhaustion state. Importantly, baseline intratumoural ISG-15 + CD8 + T cells predict immunotherapy responsiveness among GC patients. Re-emerged clonotypes of pre-existing ISG-15 + CD8 + T cells could be found after treatment, which gives rise to a CXCL13-expressing effector population in responsive EBV (+) tumours. However, LAG-3 retention may render the ISG-15 + CD8 + T cells into a terminal exhaustion state in non-responsive EBV (+) tumours. In accordance, anti-LAG-3 therapy could effectively reduce tumour burden in refractory EBV (+) GC patients. Our results delineate a distinct implication of EBV-imprinted on-treatment T-cell immunity in GC, which could be leveraged to optimize the rational design of precision immunotherapy., (© 2023. West China Hospital, Sichuan University.)

The objectives of this machine-learning (ML) resting-state magnetoencephalography (rs-MEG) study involving children with mild traumatic brain injury (mTBI) and orthopedic injury (OI) controls were to define a neural injury signature of mTBI and to delineate the pattern(s) of neural injury that determine behavioral recovery. Children ages 8-15 years with mTBI ( n  = 59) and OI ( n  = 39) from consecutive admissions to an emergency department were studied prospectively for parent-rated post-concussion symptoms (PCS) at: 1) baseline (average of 3 weeks post-injury) to measure pre-injury symptoms and also concurrent symptoms; and 2) at 3-months post-injury. rs-MEG was conducted at the baseline assessment. The ML algorithm predicted cases of mTBI versus OI with sensitivity of 95.5 ± 1.6% and specificity of 90.2 ± 2.7% at 3-weeks post-injury for the combined delta-gamma frequencies. The sensitivity and specificity were significantly better ( p  < 0.0001) for the combined delta-gamma frequencies compared with the delta-only and gamma-only frequencies. There were also spatial differences in rs-MEG activity between mTBI and OI groups in both delta and gamma bands in frontal and temporal lobe, as well as more widespread differences in the brain. The ML algorithm accounted for 84.5% of the variance in predicting recovery measured by PCS changes between 3 weeks and 3 months post-injury in the mTBI group, and this was significantly lower ( p  < 10 -4 ) in the OI group (65.6%). Frontal lobe pole (higher) gamma activity was significantly ( p  < 0.001) associated with (worse) PCS recovery exclusively in the mTBI group. These findings demonstrate a neural injury signature of pediatric mTBI and patterns of mTBI-induced neural injury related to behavioral recovery.

Autoimmune regulator (Aire) and TGF-β signaling play important roles in central tolerance and peripheral tolerance, respectively, by eliminating or suppressing the activity of autoreactive T cells. We previously demonstrated that dnTGFβRII mice develop a defect in peripheral tolerance and a primary biliary cholangitis (PBC)-like disease. We hypothesized that by introducing the Aire gene to this model, we would observe a more severe PBC phenotype. Interestingly, however, we demonstrated that, while dnTGFβRII Aire -/- mice do manifest key histological and serological features of autoimmune cholangitis, they also develop mild to moderate interface hepatitis and show high levels of alanine transaminase (ALT) and antinuclear antibodies (ANA), characteristics of autoimmune hepatitis (AIH). To further understand this unique phenotype, we performed RNA sequencing (RNA-seq) and flow cytometry to explore the functional pathways and immune cell pathways in the liver of dnTGFβRII Aire -/- mice. Our data revealed enrichments of programmed cell death pathways and predominant CD8 + T cell infiltrates. Depleting CD8 + T cells using an anti-CD8α antibody significantly alleviated hepatic inflammation and prolonged the life span of these mice. Finally, RNA-seq data indicated the clonal expansion of hepatic CD8 + T cells. In conclusion, these mice developed an autoreactive CD8 + T-cell-mediated autoimmune cholangitis with concurrent hepatitis that exhibited key histological and serological features of the AIH-PBC overlap syndrome, representing a novel model for the study of tolerance and autoimmune liver disease. © 2023 The Pathological Society of Great Britain and Ireland., (© 2023 The Pathological Society of Great Britain and Ireland.)

Background Abnormal regulation of vascular smooth muscle cells is regarded as the iconic pathological change of aortic dissection (AD). Herein, we aim to identify circ&#95;0022920 as a crucial regulator in AD. Methods and Results Microarray analysis of circular RNAs, messenger RNAs, and micro RNAs in patients with AD was performed, and we identified that circ&#95;0022920 was significantly downregulated in these patients. The Pearson correlation analysis uncovered the negative correlation between miR-650 and circ&#95;0022920 or TGFβR1 (transforming growth factor beta receptor 1). Angiotensin II was used to treat human aortic vascular smooth muscle cells (HASMCs) and mice as models for AD. Hematoxylin and eosin and Masson's trichrome staining were used to analyze AD histopathology. Cell proliferation was analyzed with Cell Counting Kit-8 assay and EdU incorporation. Cell migration was assessed with transwell and wound healing assays. Enhanced circ&#95;0022920 expression dramatically inhibited HASMC proliferation and migration and maintained contractile marker expression induced by angiotensin II, whereas miR-650 exerted opposite effects. MiR-650 was a target of circ&#95;0022920 . MiR-650 targeted IRF1 (interferon regulatory factor 1) and thus negatively regulated TGFβR1 expression to promote HASMC proliferation and migration and inhibit contractile marker expression. Circ&#95;0022920 suppressed the progression of AD in vivo. Conclusions Circ&#95;0022920 modulates the contractile phenotype of HASMCs via regulating the miR-650 -IRF1-TGFβR1 axis in angiotensin II-induced models for AD, which provides potential therapeutic targets for AD.

Objective: To investigate the etiology, prevention and treatment status, and their corresponding regional differences of the patients with liver cirrhosis in China, in order to provide scientific basis for the development of diagnosis and control strategies in China. Methods: Clinical data of patients diagnosed with liver cirrhosis for the first time through January 1, 2018 to December 31, 2020 from 50 hospitals in seven different regions of China were collected and analyzed retrospectively, and the difference of etiology, treatment, and their differences in various regions were analyzed. Results: A total of 11 861 cases with liver cirrhosis were included in the study. Thereinto, 5 093 cases (42.94%) were diagnosed as compensated cirrhosis, and 6 768 cases (57.06%) had decompensated cirrhosis. Notably, 8 439 cases (71.15%) were determined as chronic hepatitis B-caused cirrhosis, 1 337 cases (11.27%) were alcoholic liver disease, 963 cases (8.12%) were chronic hepatitis C, 698 cases (5.88%) were autoimmune liver disease, 367 cases (3.09%) were schistosomiasis, 177 cases (1.49%) were nonalcoholic fatty liver, and 743 cases (6.26%) of other types of liver disease. There were significant differences in the incidence of chronic hepatitis B, chronic hepatitis C, alcoholic liver disease, fatty liver, schistosomiasis liver disease, and autoimmune liver disease among the seven regions ( P <0.001). Only 1 139 cases (9.60%) underwent endoscopic therapy, thereinto, 718 cases (6.05%) underwent surgical therapy, and 456 cases (3.84%) underwent interventional therapy treatment. In patients with compensated liver cirrhosis, 60 cases (0.51%) underwent non-selective β receptor blockers(NSBB), including 59 cases (0.50%) underwent propranolol and 1 case (0.01%) underwent carvedilol treatment. In patients with decompensated liver cirrhosis, 310 cases (2.61%) underwent NSBB treatment, including 303 cases (2.55%) underwent propranolol treatment and 7 cases (0.06%) underwent carvedilol treatment. Interestingly, there were significant differences in receiving endoscopic therapy, interventional therapy, NSBB therapy, splenectomy and other surgical treatments among the seven regions ( P <0.001). Conclusion: Currently, chronic hepatitis B is the main cause (71.15%) of liver cirrhosis in several regions of China, and alcoholic liver disease has become the second cause (11.27%) of liver cirrhosis in China. The three-level prevention and control of cirrhosis in China should be further strengthened.

Reverse transcriptase (RT) plays an indispensable role in the replication of human immunodeficiency virus (HIV) through its associated polymerase and ribonuclease H (RNase H) activities during the viral RNA genome transformation into proviral DNA. Due to the fact that HIV is a highly mutagenic virus and easily resistant to single-target RT inhibitors, dual inhibitors targeting HIV RT associated polymerase and RNase H have been developed. These dual inhibitors have the advantages of increasing efficacy, reducing drug resistance, drug-drug interactions, and cytotoxicity, as well as improving patient compliance. In this review, we summarize recent advances in polymerase/RNase H dual inhibitors focusing on drug design strategies, and structure-activity relationships and share new insights into developing anti-HIV drugs., 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 Masson SAS. All rights reserved.)

Background: Both N6-methyladenosine (m6A) ribonucleic acid (RNA) methylation and ferroptosis regulators are demonstrated to have significant effects on the malignant clinicopathological characteristics of pancreatic adenocarcinoma (PAAD) patients. However, the currently available clinical indexes are not sufficient to predict precise prognostic outcomes pf PAAD patients accurately. This study aims to examine the clinicopathologic features of m6A RNA methylation and ferroptosis regulators in predicting the outcomes of different types of cancer., Methods: As the foundation for this research, the differentially expressed genes (DEGs) between PAAD tissues and adjacent normal tissues were first identified. Next, dimensional reduction analysis (DCA) based on m6A RNA methylation regulators and ferroptosis regulators were performed and DEGs between good/poor prognosis PAAD patient clusters were identified. DEGs were then screened by Cox analysis, and finally a risk signature was established by least absolute shrinkage and selection operator (LASSO) analyses. The prediction model based on risk score was further evaluated by a validation set from Gene Expression Omnibus (GEO) database., Results: In total, 4 m6A RNA methylation regulator genes and 29 ferroptosis regulator genes were found to have close causal relationships with the prognosis of PAAD, and a risk score with 3 m6A methylation regulators (i.e., IGF2BP2, IGF2BP3 , and METTL16 ) and 4 ferroptosis regulators (i.e., ENPP2 , ATP6V1G2 , ITGB4 , and PROM2 ) was constructed and showed to be highly involved in PAAD progression and could serve as effective markers for prognosis with AUC value equaled 0.753 in training set and 0.803 in validation set., Conclusions: The combined prediction model, composed of seven regulators of m6A methylation and ferroptosis, in this study more effectively reflects the progression and prognosis of PAAD than previous single genome or epigenetic analysis. Our study provides a broader perspective for the subsequent establishment of prognostic models and the patients may benefit from more precision management., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-22-941/coif). The authors have no conflicts of interest to declare., (2022 Journal of Gastrointestinal Oncology. All rights reserved.)

Background: Tumor-derived lactate can modulate the function of infiltrating immune cells to establish an immunosuppressive microenvironment that favors tumor progression. However, possible effects of lactate-related genes (LRGs) on the tumor microenvironment (TME) of breast cancer (BRCA) are still unknown. Methods: LRGs were comprehensively screened from lactate metabolism-related pathways. We correlated the expression of these LRGs with immune cell infiltrating characteristics in the TME and clinicopathological features of patients. We also established a lactate score for quantifying lactate metabolism patterns of cancers and to predict of recurrence-free survival (RFS). Results: We successfully constructed a lactate score that was an independent prognostic factor in BRCA. A low lactate score, which was associated with immune activation with increased CD8 + T cells infiltration levels, indicated an inflamed TME. Consistently, higher expression levels of inhibitory immune checkpoints, including PD-L1, LAG3, CTLA4, and TIM3, as observed from high lactate score subgroup, suggested an immune-desert phenotype as well as poor prognosis. Moreover, a low lactate score predicted the increased chemotherapeutic drug sensitivity and enhanced anti-PD-1 immunotherapy responses. Conclusion: The present study analyzed the potential roles of LRGs in the TME diversity and prognosis. These results will help to improve our understanding of the characteristics of TME immune cell infiltration and guide the development of more effective immunotherapy strategies., 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 Yin, Huang, Wang, Jiang, Long, Li and Cao.)

This 33-color panel delineates immune phenotypes of the major lymphocyte subsets in murine tissues. The panel identifies surface markers for cell activation, differentiation, and exhaustion, and chemokine receptors, in CD4 T cells, CD8 T cells, γδ T cells, NK cells, NKT cells and B cells in spleen and liver. This panel was designed to include only surface markers to avoid the need for fixation and permeabilization steps. Cells were analyzed on a full spectrum flow cytometer, 5-Laser Aurora system (Cytek Biosciences). This panel enables in-depth immunophenotyping of murine lymphocytes in immune and non-immune tissues of mice. It could be a tool for systematic analysis of immune cell response to infectious diseases and immune disorders., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Our previous research demonstrated that phosphodiesterase-1 (PDE1) could work as a potential target against idiopathic pulmonary fibrosis. Nimodipine, a calcium antagonist commonly used to improve hypertension, was reported to have inhibition against PDE1. Herein, a series of nimodipine analogues were discovered as novel selective and potent PDE1 inhibitors after structural modifications. Compound 2g exhibited excellent inhibitory activity against PDE1C (IC 50 = 10 nM), high selectivity over other PDEs except for PDE4, and weak calcium channel antagonistic activity. Administration of compound 2g exhibited remarkable therapeutic effects in a rat model of pulmonary fibrosis induced by bleomycin and prevented myofibroblast differentiation induced by TGF-β1. The expressions of PDE1B and PDE1C were found to be increased and concentrated in the focus of fibrosis. Compound 2g increased the levels of 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP) in the lungs of rats with pulmonary fibrosis, supporting the fact that the anti-fibrosis effects of 2g were through the regulation of cAMP and cGMP.

Dipyridamole, apart from its well-known antiplatelet and phosphodiesterase inhibitory activities, is a promising old drug for the treatment of pulmonary fibrosis. However, dipyridamole shows poor pharmacokinetic properties with a half-life (T 1/2 ) of 7 min in rat liver microsomes (RLM). To improve the metabolic stability of dipyridamole, a series of pyrimidopyrimidine derivatives have been designed with the assistance of molecular docking. Among all the twenty-four synthesized compounds, compound ( S )-4h showed outstanding metabolic stability (T 1/2 = 67 min) in RLM, with an IC 50 of 332 nM against PDE5. Furthermore, some interesting structure-activity relationships (SAR) were explained with the assistance of molecular docking.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibits strong stability on conventional stainless steel (SS) surface, with infectious virus detected even after two days, posing a high risk of virus transmission via surface touching in public areas. In order to mitigate the surface toughing transmission, the present study develops the first SS with excellent anti-pathogen properties against SARS-COV-2. The stabilities of SARS-CoV-2, H1N1 influenza A virus (H1N1), and Escherichia coli (E.coli) on the surfaces of Cu-contained SS, pure Cu, Ag-contained SS, and pure Ag were investigated. It is discovered that pure Ag and Ag-contained SS surfaces do not display apparent inhibitory effects on SARS-CoV-2 and H1N1. In comparison, both pure Cu and Cu-contained SS with a high Cu content exhibit significant antiviral properties. Significantly, the developed anti-pathogen SS with 20 wt% Cu can distinctly reduce 99.75% and 99.99% of viable SARS-CoV-2 on its surface within 3 and 6 h, respectively. In addition, the present anti-pathogen SS also exhibits an excellent inactivation ability for H1N1 influenza A virus (H1N1), and Escherichia coli (E.coli) . Interestingly, the Cu ion concentration released from the anti-pathogen SS with 10 wt% and 20 wt% Cu was notably higher than the Ag ion concentration released from Ag and the Ag-contained SS. Lift buttons made of the present anti-pathogen SS are produced using mature powder metallurgy technique, demonstrating its potential applications in public areas and fighting the transmission of SARS-CoV-2 and other pathogens via surface touching., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 Elsevier B.V. All rights reserved.)

Aims: The study aims to explore the effects of the single-nucleotide polymorphism of miR-27a and its expression in Helicobacter pylori (H. pylori) -related diseases and the relationship between gastric pathology and traditional Chinese medicine (TCM)., Methods: Subjects were classified into six histopathological groups and five TCM syndrome groups. All specimens underwent H. pylori detection through rapid urease test and methylene blue staining. Histopathological characteristics were observed by hematoxylin-eosin. The expression of miR-27a and its genotype were, respectively, detected by Quantitative Real-Time PCR and direct sequencing., Results: H. pylori promoted the malignant evolution of gastric mucosa and were involved in the formation of TCM syndrome. In H. pylori -positive patients, the frequency of miR-27a CT genotype at the rs895819 locus and its expression in the gastric cancer group were higher than those in other pathological groups. TCM syndrome had a close relationship with histopathological changes, and patients with spleen-qi deficiency syndrome had a higher risk of gastric cancer than other syndromes, regardless of H. pylori infection., Conclusion: The C allele at miR-27a rs895819 locus may be an oncogene in gastric cancer. High levels of miR-27a could play an important role in gastric malignant evolution, especially cancerization. There is a certain connection between TCM syndrome and pathological changes of the gastric mucosa to some extent, where patients with SQD syndrome had a higher risk of GC., Competing Interests: All the authors declare that there are no conflicts of interest regarding the publication of this article., (Copyright © 2022 Ling Zhang et al.)

Objective: Microorganisms present a global public health problem and are the leading cause of hospital-acquired infections. Therefore, it is essential to study the prevalence of microorganisms in hospital environments. The conclusion from such a study can contribute to identify the areas most likely to be contaminated in a hospital and appropriate measures that can decrease the exposure risk., Materials and Methods: The prevalence of microorganisms in hospital air was examined in different departments by obtaining air samples with an impactor before and during the SARS-CoV-2 pandemic. A total of 2145 microorganisms were identified, and the corresponding data were jointly analyzed by area, sampling period, and concentration., Results: The most frequently detected microorganisms in hospital air were Staphylococcus, Micrococcus, Neisseria, and fungi, and the more polluted departments were the hemodialysis department, respiratory department, treatment room, and toilet. Significant differences were found between the concentration of bacteria and fungi before and during the pandemic, which could be related to multiple environmental conditions. Furthermore, SARS-CoV-2 was negative in all the air samples., Conclusions: Overall, this study confirmed the existence and dynamic characteristics of airborne microorganisms in a hospital. The results contribute to the adaptation of specific measures which can decrease the exposure risk of patients, visitors, and staff.

Objective: To explore the association between the levels of plasma D-dimer and the disease severity and prognosis of Mycoplasma pneumoniae pneumonia (MPP) in children., Methods: We retrospectively analyzed the clinical data of pediatric MPP patients who were admitted in our hospital between January 1, 2016 and December 31, 2018. According to the peak value of D-dimer, patients were divided into the normal group (D-dimer<0.55 mg/L) and the elevated group (D-dimer≥0.55 mg/L). Information regarding the demographics, clinical manifestations, auxiliary examinations and treatments of patients in the two groups was compared., Results: Of the 231 MPP patients included in the study, 70 were in the normal group and 161 were in the elevated group. The age of patients in the D-dimer elevated group was significantly higher than that of the normal group ( P <0.01). Compared with the normal group, the elevated group had longer lengths of fever, hospital stay and antibiotic therapy, and more severe radiographic manifestations (all P <0.01). In addition, the incidence of extrapulmonary complications, refractory MPP and severe MPP in the elevated group were significantly higher than those in the normal group ( P <0.01). As for the laboratory data, we found that neutrophils, C-reactive protein, lactate dehydrogenase, interleukin-6, interleukin-10 and interferon-γ were significantly higher in the elevated group than those in the normal group ( P <0.05). After treatments, all patients showed improvement and were discharged, but the proportions of patients requiring glucocorticoids, bronchoscopy, thoracentesis were significantly higher in the elevated group than those in the normal group ( P <0.05). Follow-up findings showed that the absorption rate of lung lesions 4 weeks after admission was significantly higher, the time needed for lung lesions absorption was significantly shorter, and the incidence of pulmonary sequelae was significantly lower in the normal group than those in the elevated group (all P <0.05). Correlation analysis showed that D-dimer level was positively correlated with the severity of pneumonia ( r =0.272, P =0.000) and the incidence of pulmonary sequelae ( r =0.235, P =0.000)., Conclusion: Pediatric patients of MPP who had elevated plasma D-dimer had clinical manifestations that were more severe, required longer duration of treatment and longer recovery time for lung lesions, and were more likely to have pulmonary sequelae., (Copyright© by Editorial Board of Journal of Sichuan University (Medical Sciences).)

Atherosclerosis (AS) is one a disease that seriously endangers human health. Previous studies have demonstrated that transient receptor potential channel-1 (TRPC1)/large conductance Ca 2+ activated K + channel (BK) signal complex is widely distributed in arteries. Therefore, it was hypothesized that TRPC1-BK signal complex may be a new target for the treatment of AS-related diseases. Apolipoprotein E -/- (ApoE -/- ) mice were used to establish an atherosclerotic animal model in the present study, and the association between AS and the TRPC1-BK signal complex was examined. The present study aimed to compare the differences in the expression levels of mRNAs and proteins of the TRPC1-BK signal complex expressed in the aortic vascular smooth muscle tissue, between mice with AS and control mice. There were 10 mice in each group. Reverse transcription PCR, western blotting and immunohistochemistry were used to detect the differences in the mRNA and protein expression levels of TRPC1, BKα (the α subunit of BK) and BKβ 1 (the β 1 subunit of BK). The mRNA expression level of TRPC1 in AS model mice was significantly higher compared with that in the control group (P<0.05). However, the mRNA expression levels of BKα and BKβ 1 were lower compared with those in the controls (both P<0.01). The mice in the ApoE -/- group successfully developed AS. In this group, the protein expression level of TRPC1 was significantly higher than that in the control group (P<0.01), while the protein expression levels of BKα and BKβ 1 were lower compared with those in the control group (P<0.01 and P<0.05, respectively). Collectively, it was identified that the protein and mRNA expression levels of the TRPC1/BK signal complex in the aortic vascular smooth muscle tissue could be influenced by the development of AS in mice. Hence, the TRPC1/BK signal complex may be a potential therapeutic target for the prevention and treatment of AS-related complications in the future., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Wang et al.)

Objective: The purpose of this study was to explore the effect of telehealth education and care guidance via WeChat (Tencent Ltd., Shenzhen, China; a popular smartphone-based social media application) on improving the quality of life of parents of children with type-1 diabetes mellitus., Methods: A prospective randomized controlled study was conducted in our hospital from March 2019 to September 2020 to compare the quality of life of parents of children with type-1 diabetes mellitus in the intervention group and the control group., Results: Six months after discharge, the Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS) scores of parents in the intervention group were significantly lower than those in the control group ( p  < 0.05). Compared with the SAS and SDS scores at discharge time, those scores of parents at 6 months after discharge time in intervention group were significantly lower ( p  < 0.05), while those scores of parents at 6 months after discharge time in control was similar ( p  > 0.05). Six months after discharge, the scores of the physiological field, psychological field, social relationship field, and environmental field in the intervention group were significantly higher than those of the control group according to the result of the World Health Organization Quality of Life Brief Scale (WHOQOL-BREF; p  < 0.05)., Conclusion: Using WeChat to provide telehealth education and home care guidance to the parents of children with type-1 diabetes mellitus can effectively relieve the anxiety and depression of the parents and improve their quality of life., Competing Interests: None declared., (Thieme. All rights reserved.)

The data demonstrated that a transgenic murine model of primary biliary cholangitis (PBC), expressing dominant negative TGF-β receptor Ⅱ (dnTGFβRⅡ) under the CD4 promoter, showed similarity to PBC patients that is female-dominant. Female dnTGFβRII mice developed more severe lymphocytic infiltration in the liver and had higher levels of inflammatory cytokines, including IFN-γ and TNF-α, than the male mice. Interestingly, elimination of testosterone through gonadectomy in male dnTGFβRII mice did not influence disease severity, supporting that testosterone is an unessential factor in sustaining liver immune homeostasis. Meanwhile, it was observed that treating dnTGFβRII mice with oral antibiotics markedly reduced the differences in the levels of lymphocytic infiltration and cytokines between males and females, suggesting that the commensal gut microbiome plays a role in determining the observed sexual differences in dnTGFβRII mice. Furthermore, the diversity of gut microbiota composition and their metabolic functions in the male and female groups through metagenomic sequencing analysis were identified. The results revealed a testosterone-independent and commensal gut microbiota-mediated female bias in PBC., (©2021 Society for Leukocyte Biology.)

Regulatory B cells (Breg) are considered as immunosuppressive cells. Different subsets of Breg cells have been identified both in human beings and in mice. However, there is a lack of unique markers to identify Breg cells, and the heterogeneity of Breg cells in different organs needs to be further illuminated. In this study, we performed high-throughput single-cell RNA sequencing (scRNA-seq) and single-cell B-cell receptor sequencing (scBCR-seq) of B cells from the murine spleen, liver, mesenteric lymph nodes, bone marrow, and peritoneal cavity to better define the phenotype of these cells. Breg cells were identified based on the expression of immunosuppressive genes and IL-10-producing B (B10) cell-related genes, to define B10 and non-B10 subsets in Breg cells based on the score of the B10 gene signatures. Moreover, we characterized 19 common genes significantly expressed in Breg cells, including Fcrl5 , Zbtb20 , Ccdc28b , Cd9 , and Ptpn22 , and further analyzed the transcription factor activity in defined Breg cells. Last, a BCR analysis was used to determine the clonally expanded clusters and the relationship of Breg cells across different organs. We demonstrated that Atf3 may potentially modulate the function of Breg cells as a transcription factor and that seven organ-specific subsets of Breg cells are found. Depending on gene expression and functional modules, non-B10 Breg cells exhibited activated the TGF-β pathway, thus suggesting that non-B10 Breg cells have specific immunosuppressive properties different from conventional B10 cells. In conclusion, our work provides new insights into Breg cells and illustrates their transcriptional profiles and BCR repertoire in different organs under physiological conditions., 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 © 2021 Yang, Long, Huang, Luo, Bian, Xu, Wang, Yang, Li, Selmi, Gershwin, Zhao and Lian.)

Phosphodiesterase-1 (PDE1) is a promising drug target closely related to central and peripheral diseases. With the assistance of molecular docking and dynamics simulations, we designed and synthesized a novel series of pyrazolopyrimidone derivatives as effective and metabolically stable inhibitors against PDE1. Most compounds have good inhibitory activities against PDE1 at the concentration of 20 nM. Compound 2j with the IC 50 of 21 nM against PDE1B, shows good metabolic stability in the rat liver microsomes (RLM) (t 1/2 of 28.5 min), indicating that compound 2j can be used as a tool to explore the molecular recognition mechanism between inhibitors and the target protein PDE1., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Behçet's disease (BD) is associated with an increased risk of cancer. Few reports have been published on the relationship between drug exposure and the risk of cancer in patients with BD. Herein, we explored the relationship between pharmacologic interventions for BD and the risk of cancer. Methods: we carried out a retrospective nested case-control study in a cohort of BD patients from attending our institution. Among 1,148 patients, 22 cancer patients were individually 1:2 matched to 44 cancer-free controls. The following biochemical indicators were evaluated: routine blood analysis, liver and kidney function tests, inflammatory indexes, blood gas analysis, blood electrolyte and previous pharmacologic interventions to manage BD including systemic glucocorticoids, methotrexate, cyclosporine-A, azathioprine, cyclophosphamide (CYC), and thalidomide, which are considered the primary medicines used for the management of BD. Results: Among the 22 BD patients with cancers, myelodysplastic syndrome (MDS) (22.72%) was the most common type. Furthermore, CYC administration was significantly higher in BD patients with cancer compared with the cancer-free matched control group. Further, we observed that complement 4 (C4) (odds ratio [OR] = 0.0001, 95% confidence interval [CI]: 0.001-0.065) and hemoglobin (Hb) (OR = 0.891, 95% CI: 0.795-0.998) levels were independent protective factors for predicting cancer risk in BD patients on multivariate analyses. Conclusion: Our study revealed that CYC was associated with a high risk of cancer in BD patients. Furthermore, C4 and Hb are independent protective factors for oncogenesis in BD patients. These findings may provide references and suggestions for clinicians to select appropriate treatments and for the early recognition of high-risk patients to reduce cancer incidence in BD patients., 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 © 2021 Huang, Wang, Guo, Li, Li, Zhang and Yu.)