Mechanistic insights into the regulation of cell wall hydrolysis by FtsEX and EnvC at the bacterial division site.

The peptidoglycan (PG) cell wall produced by the bacterial division machinery is initially shared between the daughters and must be split to promote cell separation and complete division. In gram-negative bacteria, enzymes that cleave PG called amidases play major roles in the separation process. To prevent spurious cell wall cleavage that can lead to cell lysis, amidases like AmiB are autoinhibited by a regulatory helix. Autoinhibition is relieved at the division site by the activator EnvC, which is in turn regulated by the ATP-binding cassette (ABC) transporter-like complex called FtsEX. EnvC is also known to be autoinhibited by a regulatory helix (RH), but how its activity is modulated by FtsEX and the mechanism by which it activates the amidases have remained unclear. Here, we investigated this regulation by determining the structure of Pseudomonas aeruginosa FtsEX alone with or without bound ATP, in complex with EnvC, and in a FtsEX-EnvC-AmiB supercomplex. In combination with biochemical studies, the structures reveal that ATP binding is likely to activate FtsEX-EnvC and promote its association with AmiB. Furthermore, the AmiB activation mechanism is shown to involve a RH rearrangement. In the activated state of the complex, the inhibitory helix of EnvC is released, freeing it to associate with the RH of AmiB, which liberates its active site for PG cleavage. These regulatory helices are found in many EnvC proteins and amidases throughout gram-negative bacteria, suggesting that the activation mechanism is broadly conserved and a potential target for lysis-inducing antibiotics that misregulate the complex.

Defining the single base importance of human mRNAs and lncRNAs.

As the fundamental unit of a gene and its transcripts, nucleotides have enormous impacts on the gene function and evolution, and thus on phenotypes and diseases. In order to identify the key nucleotides of one specific gene, it is quite crucial to quantitatively measure the importance of each base on the gene. However, there are still no sequence-based methods of doing that. Here, we proposed Base Importance Calculator (BIC), an algorithm to calculate the importance score of each single base based on sequence information of human mRNAs and long noncoding RNAs (lncRNAs). We then confirmed its power by applying BIC to three different tasks. Firstly, we revealed that BIC can effectively evaluate the pathogenicity of both genes and single bases through single nucleotide variations. Moreover, the BIC score in The Cancer Genome Atlas somatic mutations is able to predict the prognosis of some cancers. Finally, we show that BIC can also precisely predict the transmissibility of SARS-CoV-2. The above results indicate that BIC is a useful tool for evaluating the single base importance of human mRNAs and lncRNAs.

Hepatic GDP-fucose transporter SLC35C1 attenuates cholestatic liver injury and inflammation by inducing CEACAM1 N153 fucosylation.

BACKGROUND AND AIMS: Inflammatory response is crucial for bile acid (BA)-induced cholestatic liver injury, but molecular mechanisms remain to be elucidated. Solute Carrier Family 35 Member C1 (SLC35C1) can transport GDP-fucose into the Golgi to facilitate protein glycosylation. Its mutation leads to the deficiency of leukocyte adhesion and enhances inflammation in humans. However, little is known about its role in liver diseases. APPROACH AND RESULTS: Hepatic SLC35C1 mRNA transcripts and protein expression were significantly increased in patients with obstructive cholestasis (OC) and mouse models of cholestasis. Immunofluorescence revealed that the upregulated SLC35C1 expression mainly occurred in hepatocytes. Liver-specific ablation of Slc35c1 (Slc35c1 cKO) significantly aggravated liver injury in mouse models of cholestasis induced by bile duct ligation and 1% cholic acid-feeding, evidenced by increased liver necrosis, inflammation, fibrosis, and bile ductular proliferation. The Slc35c1 cKO increased hepatic chemokine Ccl2 and Cxcl2 expression and T-cell, neutrophil and F4/80 macrophage infiltration, but did not affect the levels of serum and liver BA in mouse models of cholestasis. LC-MS/MS analysis revealed that hepatic Slc35c1 deficiency substantially reduced the fucosylation of cell-cell adhesion protein CEACAM1 at N153. Mechanistically, cholestatic levels of conjugated BAs stimulated SLC35C1 expression by activating the STAT3 signaling to facilitate CEACAM1 fucosylation at N153, and deficiency in the fucosylation of CEACAM1 at N135 enhanced the BA-stimulated CCL2 and CXCL2 mRNA expression in primary mouse hepatocytes and PLC/PRF/5-ASBT cells. CONCLUSIONS: Elevated hepatic SLC35C1 expression attenuates cholestatic liver injury by enhancing CEACAM1 fucosylation to suppress CCL2 and CXCL2 expression and liver inflammation.

Vascular smooth muscle cell-specific miRNA-214 deficiency alleviates simulated microgravity-induced vascular remodeling.

The human cardiovascular system has evolved to accommodate the gravity of Earth. Microgravity during spaceflight has been shown to induce vascular remodeling, leading to a decline in vascular function. The underlying mechanisms are not yet fully understood. Our previous study demonstrated that miR-214 plays a critical role in angiotensin II-induced vascular remodeling by reducing the levels of Smad7 and increasing the phosphorylation of Smad3. However, its role in vascular remodeling evoked by microgravity is not yet known. This study aimed to determine the contribution of miR-214 to the regulation of microgravity-induced vascular remodeling. The results of our study revealed that miR-214 expression was increased in the forebody arteries of both mice and monkeys after simulated microgravity treatment. In vitro, rotation-simulated microgravity-induced VSMC migration, hypertrophy, fibrosis, and inflammation were repressed by miR-214 knockout (KO) in VSMCs. Additionally, miR-214 KO increased the level of Smad7 and decreased the phosphorylation of Smad3, leading to a decrease in downstream gene expression. Furthermore, miR-214 cKO protected against simulated microgravity induced the decline in aorta function and the increase in stiffness. Histological analysis showed that miR-214 cKO inhibited the increases in vascular medial thickness that occurred after simulated microgravity treatment. Altogether, these results demonstrate that miR-214 has potential as a therapeutic target for the treatment of vascular remodeling caused by simulated microgravity.

Garnet secondary ion mass spectrometry oxygen isotopes reveal crucial roles of pulsed magmatic fluid and its mixing with meteoric water in lode gold genesis.

SignificanceThere is a common consensus that lode gold deposits mostly precipitated from metamorphic fluids via fluid boiling and/or fluid-rock interaction, but whether magmatic hydrothermal fluids and the mixing of such fluids with an external component have played a vital role in the formation of lode gold deposits remains elusive. We use garnet secondary ion mass spectrometry oxygen isotope analysis to demonstrate that the world-class Dongping lode gold deposit has been formed by multiple pulses of magmatic hydrothermal fluids and their mixing with large volumes of meteoric water. This study opens an opportunity to tightly constrain the origin of lode gold deposits worldwide and other hydrothermal systems that may have generated giant ore deposits in the Earth's crust.

DNI-MDCAP: improvement of causal MiRNA-disease association prediction based on deep network imputation.

BACKGROUND: MiRNAs are involved in the occurrence and development of many diseases. Extensive literature studies have demonstrated that miRNA-disease associations are stratified and encompass ~ 20% causal associations. Computational models that predict causal miRNA-disease associations provide effective guidance in identifying novel interpretations of disease mechanisms and potential therapeutic targets. Although several predictive models for miRNA-disease associations exist, it is still challenging to discriminate causal miRNA-disease associations from non-causal ones. Hence, there is a pressing need to develop an efficient prediction model for causal miRNA-disease association prediction. RESULTS: We developed DNI-MDCAP, an improved computational model that incorporated additional miRNA similarity metrics, deep graph embedding learning-based network imputation and semi-supervised learning framework. Through extensive predictive performance evaluation, including tenfold cross-validation and independent test, DNI-MDCAP showed excellent performance in identifying causal miRNA-disease associations, achieving an area under the receiver operating characteristic curve (AUROC) of 0.896 and 0.889, respectively. Regarding the challenge of discriminating causal miRNA-disease associations from non-causal ones, DNI-MDCAP exhibited superior predictive performance compared to existing models MDCAP and LE-MDCAP, reaching an AUROC of 0.870. Wilcoxon test also indicated significantly higher prediction scores for causal associations than for non-causal ones. Finally, the potential causal miRNA-disease associations predicted by DNI-MDCAP, exemplified by diabetic nephropathies and hsa-miR-193a, have been validated by recently published literature, further supporting the reliability of the prediction model. CONCLUSIONS: DNI-MDCAP is a dedicated tool to specifically distinguish causal miRNA-disease associations with substantially improved accuracy. DNI-MDCAP is freely accessible at http://www.rnanut.net/DNIMDCAP/ .

Runt-related transcription factor-1 ameliorates bile acid-induced hepatic inflammation in cholestasis through JAK/STAT3 signaling.

BACKGROUND AND AIMS: Bile acids trigger a hepatic inflammatory response, causing cholestatic liver injury. Runt-related transcription factor-1 (RUNX1), primarily known as a master modulator in hematopoiesis, plays a pivotal role in mediating inflammatory responses. However, RUNX1 in hepatocytes is poorly characterized, and its role in cholestasis is unclear. Herein, we aimed to investigate the role of hepatic RUNX1 and its underlying mechanisms in cholestasis. APPROACH AND RESULTS: Hepatic expression of RUNX1 was examined in cholestatic patients and mouse models. Mice with liver-specific ablation of Runx1 were generated. Bile duct ligation and 1% cholic acid diet were used to induce cholestasis in mice. Primary mouse hepatocytes and the human hepatoma PLC/RPF/5- ASBT cell line were used for mechanistic studies. Hepatic RUNX1 mRNA and protein levels were markedly increased in cholestatic patients and mice. Liver-specific deletion of Runx1 aggravated inflammation and liver injury in cholestatic mice induced by bile duct ligation or 1% cholic acid feeding. Mechanistic studies indicated that elevated bile acids stimulated RUNX1 expression by activating the RUNX1 -P2 promoter through JAK/STAT3 signaling. Increased RUNX1 is directly bound to the promotor region of inflammatory chemokines, including CCL2 and CXCL2 , and transcriptionally repressed their expression in hepatocytes, leading to attenuation of liver inflammatory response. Blocking the JAK signaling or STAT3 phosphorylation completely abolished RUNX1 repression of bile acid-induced CCL2 and CXCL2 in hepatocytes. CONCLUSIONS: This study has gained initial evidence establishing the functional role of hepatocyte RUNX1 in alleviating liver inflammation during cholestasis through JAK/STAT3 signaling. Modulating hepatic RUNX1 activity could be a new therapeutic target for cholestasis.

Total Laparoscopic Radical Resection of S1 + S4 for Bismuth-Corlette Type IV Hilar Cholangiocarcinoma (With Video).

BACKGROUND: The management of Bismuth-Corlette type IV hilar cholangiocarcinoma typically necessitates extensive hepatectomy, resection of the extrahepatic bile ducts, regional lymph node dissection, and reconstruction of the biliary tract; however, there is a high incidence of postoperative liver dysfunction and failure. METHODS: A 64-year-old male patient was admitted to our department after 1 month of escalating jaundice and abdominal discomfort. Upon admission, his total bilirubin was 334 µmol/L and his direct bilirubin was 221 µmol/L. His carbohydrate antigen 19-9 was > 1200.00 U/mL, his carcinoembryonic antigen was 98.90 U/mL, and his α-fetoprotein was normal. Enhanced computed tomography (CT) and magnetic resonance imaging scans revealed a thickened and enlarged biliary tree extending from the common hepatic duct to the orifices of the left and right hepatic ducts. RESULTS: The patient underwent total laparoscopic radical resection of S1 + S4, accompanied by radical lymphadenectomy with skeletonization and biliary reconstruction. The surgery was successfully conducted within 450 min, with a minimal blood loss of 200 mL. The histological grading was T2bN1M0 (stage III). CT on postoperative day 5 showed satisfactory postoperative recovery. The patient was discharged from the hospital on postoperative day 10 without complications, following which the patient underwent a regimen of single-agent capecitabine chemotherapy. Over a 20-month follow-up period, no recurrence was observed. CONCLUSIONS: Resection of hepatic segments S1 + S4 is a viable surgical option for hilar carcinoma in cases with poor liver function or when the carcinoma is confined to both hepatic ducts without invasion of the hepatic artery and portal vein.

Indocyanine Green Fluorescence-Guided Laparoscopic Anatomical Segmentectomy of Liver Segment 6: Surgical Strategy and Technical Details.

BACKGROUND: Because of the complex anatomy of the right posterior hepatic pedicle, there have been few reports on standardized laparoscopic portal territory staining-guided anatomical resection of liver segment 6 (LPTAR-S6). This study aimed to elucidate the indocyanine green (ICG) fluorescence staining methods for LPTAR-S6. PATIENTS AND METHODS: LPTAR-S6 can be performed using positive and negative fluorescence staining approaches. We implemented these two approaches for patients with hepatocellular carcinoma. Descriptions of the surgical strategy and technical details are presented. RESULTS: Two patients safely underwent LPTAR-S6 using a preoperative three-dimensional reconstruction plan. The intraoperative ICG fluorescence staining effect was satisfactory, and the anatomical landmarks were fully exposed. CONCLUSIONS: A detailed preoperative three-dimensional reconstruction plan, complete intraoperative application of real-time laparoscopic ultrasound guidance, and ICG fluorescence staining can result in accurate transection of the liver parenchyma during LPTAR-S6.

Laparoscopic Tracer Technique for Liver Lymphatic Drainage by Injecting Indocyanine Green into the Glisson Pedicle.

BACKGROUND: Currently, an effective tracer technique for lymphatic drainage during laparoscopic surgery has not been established. This study aimed to elucidate a new fluorescence, imaging technique targeting the hepatic lymphatic drainage area, using indocyanine green (ICG). METHODS: A patient diagnosed with intrahepatic cholangiocarcinoma (ICC) located in segment 8 of the liver was injected with ICG into the connective tissue of the Glisson pedicle supplied by the lesion's liver segment, avoiding the bile duct, portal vein, and hepatic artery. This was performed under the guidance of laparoscopic ultrasonographic localization to trace the lymph nodes. RESULTS: The lymphatic drainage area traced intraoperatively by ICG was consistent with the definition of the right regional lymph nodes for ICC. The lymph nodes were dissected, followed by addition of a fluorescence tracer. CONCLUSIONS: Mastering intraoperative ultrasonic puncture technology can enable effective and accurate tracing of the lymph nodes of the liver segment where the lesion is located. However, the technical standards for this methodology need to be established through further studies.

Laparoscopic liver resection versus radiofrequency ablation for small hepatocellular carcinoma: randomized clinical trial.

BACKGROUND: The aim of this study was to compare the efficacy of laparoscopic liver resection versus radiofrequency ablation for treatment of small hepatocellular carcinoma. METHODS: This single-centre RCT was conducted at a tertiary referral centre in China. Patients with small hepatocellular carcinoma who had a single nodule no larger than 5 cm, or up to three nodules of 3 cm or smaller, were eligible. Patients were assigned randomly in a 1 : 1 ratio to either laparoscopic liver resection or radiofrequency ablation. Blinding was not attempted. Sample size calculations led to 75 patients per group. The primary outcome was overall survival, and the secondary outcome was recurrence-free survival. RESULTS: Seventy-five patients were included in each group. Overall survival (HR 1.26, 95% c.i. 0.69 to 2.30; P = 0.451) and recurrence-free survival (HR 1.34, 0.86 to 2.08; P = 0.189) did not differ between the resection and ablation groups. The 1-, 3- and 5-year overall survival rates were 94.7, 80.0, and 74.7% respectively after laparoscopic liver resection versus 93.3, 78.7, and 67.9% after radiofrequency ablation. Corresponding recurrence-free survival rates were 78.7, 61.3, and 51.6%, and 69.3, 53.3, and 41.0%, respectively. CONCLUSION: For small hepatocellular carcinoma, percutaneous radiofrequency ablation provides therapeutic effects similar to those of laparoscopic liver resection. REGISTRATION NUMBER: NCT02243384 (http://www.clinicaltrials.gov).

Percutaneous radiofrequency ablation may provide similar therapeutic effects to laparoscopic liver resection for patients with small hepatocellular carcinoma. This study compared the two treatments. Survival was similar after the two treatments. The choice of treatment may depend on the patient's preference and local availability.

Interaction between Wnt/ß-catenin signaling pathway and EMT pathway mediates the mechanism of sunitinib resistance in renal cell carcinoma.

BACKGROUND: Targeted drugs are the main methods of RCC treatment. However, drug resistance is common in RCC patients, in-depth study of the drug-resistant mechanism is essential. METHODS: We constructed sunitinib resistant and Twist overexpressed A498 cells, and studied its mechanisms in vitro and in vivo. RESULTS: In cell research, we found that either sunitinib resistance or Twist overexpression can activate Wnt/ß-catenin and EMT signaling pathway, and the sunitinib resistance may work through ß-catenin/TWIST/TCF4 trimer. In zebrafish research, we confirmed the similarity of Twist overexpression and sunitinib resistance, and the promoting effect of Twist overexpression on drug resistance. CONCLUSIONS: Sunitinib resistance and Twist overexpression can activate Wnt/ß-catenin signaling pathway and EMT to promote the growth and metastasis of RCC cells.

Lipids Extracted from Mycobacterial Membrane and Enveloped PLGA Nanoparticles for Encapsulating Antibacterial Drugs Elicit Synergistic Antimicrobial Response against Mycobacteria.

Tuberculosis (TB) is a chronic disease caused byMycobacterium tuberculosis (Mtb), which shows a long treatment cycle often leads to drug resistance, making treatment more difficult. Immunogens present in the pathogen's cell membrane can stimulate endogenous immune responses. Therefore, an effective lipid-based vaccine or drug delivery vehicle formulated from the pathogen's cell membrane can improve treatment outcomes. Herein, we extracted and characterized lipids fromMycobacterium smegmatis, and the extracts contained lipids belonging to numerous lipid classes and compounds typically found associated with mycobacteria. The extracted lipids were used to formulate biomimetic lipid reconstituted nanoparticles (LrNs) and LrNs-coated poly(lactic-co-glycolic acid) nanoparticles (PLGA-LrNs). Physiochemical characterization and results of morphology suggested that PLGA-LrNs exhibited enhanced stability compared with LrNs. And both of these two types of nanoparticles inhibited the growth of M. smegmatis. After loading different drugs, PLGA-LrNs containing berberine or coptisine strongly and synergistically prevented the growth of M. smegmatis. Altogether, the bacterial membrane lipids we extracted with antibacterial activity can be used as nanocarrier coating for synergistic antibacterial treatment of M. smegmatis─an alternative model of Mtb, which is expected as a novel therapeutic system for TB treatment.

Effects of an Early Intensive Blood Pressure-lowering Strategy Using Remifentanil and Dexmedetomidine in Patients with Spontaneous Intracerebral Hemorrhage: A Multicenter, Prospective, Superiority, Randomized Controlled Trial.

BACKGROUND: Although it has been established that elevated blood pressure and its variability worsen outcomes in spontaneous intracerebral hemorrhage, antihypertensives use during the acute phase still lacks robust evidence. A blood pressure-lowering regimen using remifentanil and dexmedetomidine might be a reasonable therapeutic option given their analgesic and antisympathetic effects. The objective of this superiority trial was to validate the efficacy and safety of this blood pressure-lowering strategy that uses remifentanil and dexmedetomidine in patients with acute intracerebral hemorrhage. METHODS: In this multicenter, prospective, single-blinded, superiority randomized controlled trial, patients with intracerebral hemorrhage and systolic blood pressure (SBP) 150 mmHg or greater were randomly allocated to the intervention group (a preset protocol with a standard guideline management using remifentanil and dexmedetomidine) or the control group (standard guideline-based management) to receive blood pressure-lowering treatment. The primary outcome was the SBP control rate (less than 140 mmHg) at 1 h posttreatment initiation. Secondary outcomes included blood pressure variability, neurologic function, and clinical outcomes. RESULTS: A total of 338 patients were allocated to the intervention (n = 167) or control group (n = 171). The SBP control rate at 1 h posttreatment initiation in the intervention group was higher than that in controls (101 of 161, 62.7% vs. 66 of 166, 39.8%; difference, 23.2%; 95% CI, 12.4 to 34.1%; P < 0.001). Analysis of secondary outcomes indicated that patients in the intervention group could effectively reduce agitation while achieving lighter sedation, but no improvement in clinical outcomes was observed. Regarding safety, the incidence of bradycardia and respiratory depression was higher in the intervention group. CONCLUSIONS: Among intracerebral hemorrhage patients with a SBP 150 mmHg or greater, a preset protocol using a remifentanil and dexmedetomidine-based standard guideline management significantly increased the SBP control rate at 1 h posttreatment compared with the standard guideline-based management.

Dynamical modelling of viral infection and cooperative immune protection in COVID-19 patients.

Once challenged by the SARS-CoV-2 virus, the human host immune system triggers a dynamic process against infection. We constructed a mathematical model to describe host innate and adaptive immune response to viral challenge. Based on the dynamic properties of viral load and immune response, we classified the resulting dynamics into four modes, reflecting increasing severity of COVID-19 disease. We found the numerical product of immune system's ability to clear the virus and to kill the infected cells, namely immune efficacy, to be predictive of disease severity. We also investigated vaccine-induced protection against SARS-CoV-2 infection. Results suggested that immune efficacy based on memory T cells and neutralizing antibody titers could be used to predict population vaccine protection rates. Finally, we analyzed infection dynamics of SARS-CoV-2 variants within the construct of our mathematical model. Overall, our results provide a systematic framework for understanding the dynamics of host response upon challenge by SARS-CoV-2 infection, and this framework can be used to predict vaccine protection and perform clinical diagnosis.

Ultrasound-guided percutaneous radiofrequency ablation versus surgery for solitary T1N0M0 papillary thyroid carcinoma in the danger triangle.

OBJECTIVES: To compare the safety and efficiency of ultrasound-guided percutaneous radiofrequency ablation (RFA) and surgical resection (SR) for thyroid papillary carcinoma (PTC) in the danger triangle area. METHODS: The clinical data of 298 patients who underwent either percutaneous RFA or SR for PTC in the thyroid danger triangle at our hospital between January 2018 and April 2020 were retrospectively analyzed. Propensity score matching is employed to regulate for confounding factors. All patients undergoing ablation were treated using a strategy that combined sufficient paratracheal fluid isolation with a low-power, short electrode. Disease progression was analyzed in patients with T1N0M0 PTC (T1a and T1b) employed in Kaplan‒Meier curves. Treatment parameters and the rates of local recurrence, distant metastasis, and complications are recorded and compared. RESULTS: Of 182 eligible patients who were included, 91 were in the RFA (age 44.84 ± 13.19; 71 females; 77 T1a) and 91 were in the SR (age 47.36 ± 11.05; 68 females; 69 T1a). The average treatment time, length of hospital stays, blood loss volume, and scar length are substantially less in the RFA than in the SR. Major complications as well as postoperative permanent recurrent laryngeal nerve injury and postoperative transient parathyroid dysfunction occurred only in the SR, with a substantial distinction between the two groups (p < 0.05). There is no substantial distinction in the disease progression between RFA and SR treatment of T1N0M0 PTC. CONCLUSION: RFA is as effective as surgery for PTC in the danger triangle area in the short term, with faster recovery and fewer complications. CLINICAL RELEVANCE STATEMENT: Radiofrequency ablation has a clinical efficacy comparable to surgery in the treatment of papillary thyroid carcinoma in the danger triangle area in the short term with the advantages of faster recovery and fewer complications when compared with surgery. KEY POINTS: Use of radiofrequency ablation (RFA) in the thyroid danger triangle is still controversial. RFA and surgery groups showed no difference in disease progressions, and no major complications occurred with RFA. Radiofrequency ablation offers a new option for papillary thyroid carcinoma patients in the danger triangle.

Prediction of Cognitive Impairment Risk among Older Adults: A Machine Learning-Based Comparative Study and Model Development.

INTRODUCTION: The prevalence of cognitive impairment and dementia in the older population is increasing, and thereby, early detection of cognitive decline is essential for effective intervention. METHODS: This study included 2,288 participants with normal cognitive function from the Ma'anshan Healthy Aging Cohort Study. Forty-two potential predictors, including demographic characteristics, chronic diseases, lifestyle factors, anthropometric indices, physical function, and baseline cognitive function, were selected based on clinical importance and previous research. The dataset was partitioned into training, validation, and test sets in a proportion of 60% for training, 20% for validation, and 20% for testing, respectively. Recursive feature elimination was used for feature selection, followed by six machine learning algorithms that were employed for model development. The performance of the models was evaluated using area under the curve (AUC), specificity, sensitivity, and accuracy. Moreover, SHapley Additive exPlanations (SHAP) was conducted to access the interpretability of the final selected model and to gain insights into the impact of features on the prediction outcomes. SHAP force plots were established to vividly show the application of the prediction model at the individual level. RESULTS: The final predictive model based on the Naive Bayes algorithm achieved an AUC of 0.820 (95% CI, 0.773-0.887) on the test set, outperforming other algorithms. The top ten influential features in the model included baseline Mini-Mental State Examination (MMSE), education, self-reported economic status, collective or social activities, Pittsburgh sleep quality index (PSQI), body mass index, systolic blood pressure, diastolic blood pressure, instrumental activities of daily living, and age. The model demonstrated the potential to identify individuals at a higher risk of cognitive impairment within 3 years from older adults. CONCLUSION: The predictive model developed in this study contributes to the early detection of cognitive impairment in older adults by primary healthcare staff in community settings.

The prevalence and factors of willingness to accept circumcision among MSM in Maanshan City, China.

To investigate the prevalence of male circumcision and the willingness to undergo male circumcision and influencing factors among MSM in Maanshan City, we conducted a cross-sectional study from June 2016 to December 2019. Respondent-driven sampling (RDS) was used to recruit participants. Influential factors of willingness to accept circumcision were identified by a multivariable logistic regression model. The multivariable logistic regression model revealed that five variables were independent influential factors for willingness to participate. The factors include that used condoms during last anal intercourse (OR = 1.87, 95% CI:1.03-3.41, P = 0.04), sex with female sex partners (OR = 0.499, 95% CI:0.298-0.860, P = 0.012, level of education (junior college: OR = 0.413, 95% CI:0.200-0.854, P = 0.017; bachelor's degree or higher: OR = 0.442, 95% CI:0.208-0.938, P = 0.033), condom use during oral sex in the last six months (OR = 4.20, 95% CI:1.47-12.0, P = 0.007) and level of knowledge of PrEP (OR = 5.09, 95% CI:1.39-18.7, P = 0.014). Given the willingness of MSM to accept circumcision was low in China, establishing a proper understanding of circumcision is essential if it is to be used as a strategy to prevent HIV infection among MSM. Therefore, publicity and education on the operation should be strengthened to increase the willingness to undergo male circumcision.

A molecular container providing supramolecular protection against acetylcholine hydrolysis.

Alzheimer's disease (AD) is characterized by cognitive decline, often attributed to the deficiency of acetylcholine, which can undergo hydrolysis by acetylcholinesterase (AChE) within the biological milieu. Here, we report a supramolecular strategy that takes advantage of confinement effects to inhibit such a hydrolysis process, shedding some light on AD therapy. A water-soluble and bowl-shaped molecule, hexacarboxylated tribenzotriquinacene (TBTQ-C6), was employed to shield acetylcholine (G1) from enzymatic degradation through host-guest binding interactions. Our study revealed highly efficient host-guest interactions with a binding ratio of 1 : 3, resulting in a significant reduction in acetylcholine hydrolysis from 91.1% to 7.4% in the presence of AChE under otherwise identical conditions. Furthermore, TBTQ-C6 showed potential for attenuating the degradation of butyrylcholine (G2) by butyrylcholinesterase (BChE). The broader implications of this study extend to the potential use of molecular containers in various biochemical and pharmacological applications, opening new avenues for research in the field of neurodegenerative diseases.

Arsenite S-Adenosylmethionine Methyltransferase Is Responsible for Antimony Biomethylation in Nostoc sp. PCC7120.

Antimony (Sb) biomethylation is an important but uninformed process in Sb biogeochemical cycling. Methylated Sb species have been widely detected in the environment, but the gene and enzyme for Sb methylation remain unknown. Here, we found that arsenite S-adenosylmethionine methyltransferase (ArsM) is able to catalyze Sb(III) methylation. The stepwise methylation by ArsM forms mono-, di-, and trimethylated Sb species. Sb(III) is readily coordinated with glutathione, forming the preferred ArsM substrate which is anchored on three conserved cysteines. Overexpressing arsM in Escherichia coli AW3110 conferred resistance to Sb(III) by converting intracellular Sb(III) into gaseous methylated species, serving as a detoxification process. Methylated Sb species were detected in paddy soil cultures, and phylogenetic analysis of ArsM showed its great diversity in ecosystems, suggesting a high metabolic potential for Sb(III) methylation in the environment. This study shows an undiscovered microbial process methylating aqueous Sb(III) into the gaseous phase, mobilizing Sb on a regional and even global scale as a re-emerging contaminant.