Blueberry extract attenuates DSS-induced inflammatory bowel disease in mice through inhibiting ER stress-mediated colonic apoptosis in mice.

Inflammatory bowel disease (IBD) is a chronic, debilitating condition with limited therapeutic options. Dietary components like blueberries have emerged as potential modulators of inflammation and tissue repair in gastrointestinal diseases. This study investigated endoplasmic reticulum (ER) stress-mediated apoptosis mediated protective effects of blueberries in ameliorating dextran sulfate sodium (DSS)-induced IBD. Firstly, a total of 86 anthocyanin compounds were identified in blueberry extract by LC-MS spectroscopy, including 35 cyanidin, 9 delphinidin, 14 malvidin, 10 peonidin, and 9 petunidin. Then, the animal study showed that blueberry supplementation notably ameliorated DSS-induced IBD symptoms, as evidenced by improved histopathological scores and a reduced disease activity index (DAI) score. Additionally, blueberries attenuated ER stress by inhibiting the colonic PERK/eIF2α/ATF4/CHOP signaling pathway. Furthermore, blueberries inhibited the expression of the pro-apoptotic protein, caspase-3, and decreased colonic apoptosis, as evidenced by TUNEL assay results. However, it did not affect the expression of anti-apoptotic proteins, bcl-2 and bcl-xl. Finally, blueberries enhanced the intestinal barrier by upregulating ZO-1, claudin-1, occludin, and E-cadherin. In conclusion, blueberries demonstrate therapeutic potential against DSS-induced IBD-like symptoms in mice, possibly by regulating ER stress-mediated apoptosis pathways. These findings suggest that blueberries might be an effective dietary intervention for IBD management.

Anthocyanins-rich cranberry extract attenuates DSS-induced IBD in an intestinal flora independent manner.

Cranberry is abundantly rich in anthocyanins, a type of flavonoid with potent antioxidant properties and the resistance against certain diseases. In this study, anthocyanin-rich cranberry extract was extracted, purified, and its components were analyzed. 92.18 % of anthocyanins was obtained and the total content of anthocyanins was 302.62 mg/g after AB-8 resin purification. Quantification analysis showed that the extract mainly contained cyanidin-3-galactoside, procyanidin B2 and procyanidin B4. Then we explored its effects on dextran sulfate sodium (DSS)-induced inflammatory bowel disease (IBD) in mice. The supplementation of cranberry extract resulted in an alleviation of IBD symptoms, evidenced by improvements in the disease activity index (DAI), restoration of colon length and colonic morphology. Cranberry extract reversed the elevated iron and malondialdehyde (MDA) levels and restored glutathione (GSH) levels in IBD mice. Further analysis revealed that cranberry modulated ferroptosis-associated genes and reduced expression of pro-inflammatory cytokines. Although cranberry influenced the intestinal flora balance by reducing Proteobacteria and Escherichia-Shigella, and increasing Lactobacillus, as well as enhancing SCFAs content, these effects were not entirely dependent on intestinal flora modulation, as indicated by antibiotic intervention and fecal microbiota transplantation (FMT) experiments. In conclusion, our findings suggest that the beneficial impact of cranberry extract on IBD may primarily involve the regulation of colonic ferroptosis, independent of significant alterations in intestinal flora.

Bioelectrical Impedance Analysis to Assess Energy Expenditure in Critically Ill Patients: A Cross-Sectional Study.

BACKGROUND: Evaluating energy expenditure is important for establishing optimal goals for nutrition treatment. However, indirect calorimetry, the reference standard for measuring energy expenditure, is difficult to apply widely in clinical practice. OBJECTIVE: To test the consistency of bioelectrical impedance analysis (BIA) relative to indirect calorimetry for evaluating energy expenditure in critically ill patients. METHODS: A cross-sectional study of 140 critically ill adult patients was conducted. Within 24 hours of a patient being transferred to the intensive care unit, trained researchers assessed the patient's energy expenditure by use of BIA and indirect calorimetry simultaneously. Consistency of the 2 measurements was detected by intraclass correlation coefficients with a 2-way random-effects model. Factors affecting consistency were analyzed. RESULTS: Median energy expenditure measured by indirect calorimetry was 1430.0 kcal/d (IQR, 1190.5-1650.8 kcal/d). Median energy expenditure measured by BIA was 1407.0 kcal/d (IQR, 1248.5-1563.5 kcal/d). The correlation coefficient between indirect calorimetry and BIA was 0.813 (95% CI, 0.748-0.862; P < .001). The consistency of the 2 measurements was lower in patients with comorbidities than in those without (P = .004). CONCLUSIONS: Results of BIA were highly consistent with indirect calorimetry assessments of energy expenditure in critically ill patients. Few factors except comorbidity affect the accuracy of BIA when assessing energy expenditure. Therefore, as a low-cost, easy-to-use, and noninvasive method, BIA is a valuable clinical tool for assessing energy expenditure in critically ill patients.

Clinical outcomes after endoscopic resection and the risk of lymph node metastasis in rectal neuroendocrine tumors: a single-center retrospective study.

BACKGROUND AND AIM: The incidence of rectal neuroendocrine tumors (R-NETs) has increased in recent years. However, the predictors of lymph node (LN) metastasis and clinical outcomes, particularly following endoscopic treatment, remain unclear. Our study aims to elucidate the potential risk factors for LN metastasis and the clinical outcomes of patients undergoing endoscopic resection in R-NETs. METHODS: A total of 128 patients with R-NETs were retrospectively identified from a single center between June 2012 and December 2021. Risk factors for LN metastasis in R-NETs were analyzed using multivariate analysis. Additionally, the clinical outcomes of endoscopic resections in patients with R-NETs were assessed. RESULTS: In our study, 128 patients with R-NETs were retrospectively analyzed. The risk factors for LN metastasis determined by multivariate analysis were tumor size and patient age at diagnosis. Among the 111 patients treated with endoscopic resection and with tumor margin records available, 92 underwent endoscopic submucosal dissection (ESD) and 19 underwent conventional endoscopic mucosal resection (EMR). There was no significant difference between the two groups regarding the positive rates of basal tumor margin and lateral tumor margin. Furthermore, 64 patients who underwent endoscopic resection for R-NETs were successfully followed up (range, 1.64-76.71 months), during which only one patient developed local recurrence. CONCLUSION: Tumor size and age at diagnosis were predictors for LN metastasis of R-NETs. Both ESD and EMR are alternative techniques with a favorable prognosis for R-NETs, even in cases with positive resection margins. However, due to the relatively small number of patients undergoing EMR and missing data in follow-up protocols, definitive conclusions require further large-scale studies.

IQGAP1 domesticates macrophages to favor mycobacteria survival via modulating NF-κB signal and augmenting VEGF secretion.

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), still ranks among the leading causes of annual human death by infectious disease. Mtb has developed several strategies to survive for years at a time within the host despite the presence of a robust immune response, including manipulating the progression of the inflammatory response and forming granulomatous lesions. Here we demonstrate that IQGAP1, a highly conserved scaffolding protein, compartmentalizes and coordinates multiple signaling pathways in macrophages infected with Mycobacterium marinum (Mm or M.marinum), the closest relative of Mtb. Upregulated IQGAP1 ultimately suppresses TNF-α production by repressing the MKK3 signal and reducing NF-κBp65 translocation, deactivating the p38MAPK pathway. Accordingly, IQGAP1 silencing and overexpression significantly alter p38MAPK activity by modulating the production of phosphorylated MKK3 during mycobacterial infection. Pharmacological inhibition of IQGAP1-associated microtubule assembly not only alleviates tissue damage caused by M.marinum infection but also significantly decreases the production of VEGF-a critical player for granuloma-associated angiogenesis during pathogenic mycobacterial infection. Similarly, IQGAP1 silencing in Mm-infected macrophages diminishes VEGF production, while IQGAP1 overexpression upregulates VEGF. Our data indicate that mycobacteria induce IQGAP1 to hijack NF-κBp65 activation, preventing the expression of proinflammatory cytokines as well as promoting VEGF production during infection and granuloma formation. Thus, therapies targeting host IQGAP1 may be a promising strategy for treating tuberculosis, particularly in drug-resistant diseases.

Structure-Based Virtual Screening for Methyltransferase Inhibitors of SARS-CoV-2 nsp14 and nsp16.

The ongoing COVID-19 pandemic still threatens human health around the world. The methyltransferases (MTases) of SARS-CoV-2, specifically nsp14 and nsp16, play crucial roles in the methylation of the N7 and 2'-O positions of viral RNA, making them promising targets for the development of antiviral drugs. In this work, we performed structure-based virtual screening for nsp14 and nsp16 using the screening workflow (HTVS, SP, XP) of Schrödinger 2019 software, and we carried out biochemical assays and molecular dynamics simulation for the identification of potential MTase inhibitors. For nsp14, we screened 239,000 molecules, leading to the identification of three hits A1-A3 showing N7-MTase inhibition rates greater than 60% under a concentration of 50 µM. For the SAM binding and nsp10-16 interface sites of nsp16, the screening of 210,000 and 237,000 molecules, respectively, from ZINC15 led to the discovery of three hit compounds B1-B3 exhibiting more than 45% of 2'-O-MTase inhibition under 50 µM. These six compounds with moderate MTase inhibitory activities could be used as novel candidates for the further development of anti-SARS-CoV-2 drugs.

Efficacy and Safety of Endoscopic Resection for Gastric Gastrointestinal Stromal Tumors Originating from the Muscularis Propria.

BACKGROUND: The role of endoscopic resection (ER) in gastric gastrointestinal stromal tumors (GISTs) has not been fully elucidated. AIMS: The purpose of this work was to evaluate the clinical effectiveness and safety of ER in patients with GISTs originating from the muscularis propria (MP). METHODS: A total of 233 consecutive patients with gastric GISTs originating from the MP layer, who underwent ER between February 2012 and May 2023, were included in this study. Clinical characteristics, tumor features, and outcomes were recorded and compared between patients who underwent en bloc resection and piecemeal resection. RESULTS: Among the 233 patients, the median size of GISTs was 12 mm (range 5-60 mm). Risk assessment categorized 190 patients as very low risk, 26 as low risk, 10 as moderate risk, and 7 as high risk. The procedures performed included endoscopic submucosal excavation (127 cases), endoscopic full-thickness resection (103 cases), and submucosal tunneling endoscopic resection (3 cases). The complete and R0 resection rate was 93.1%. Complications occurred in 4.7% of cases (perioperative perforations 1.7%, perioperative bleeding 1.3%, both 0.9%), resulting in conversion to surgery in 1.3% of cases. Risk factors associated with piecemeal resection were tumor size [odds ratio (OR) 0.402, 95% confidence interval (CI) 0.207-0.783; P = 0.007] and shape (OR 0.045, 95% CI 0.009-0.235; P < 0.001). CONCLUSIONS: ER is proven to be an effective and reasonably safe approach for gastric GISTs originating from the MP. Notably, larger tumor size and irregular shape are identified as risk factors for piecemeal resection during ER procedures.

Threshold of hyperglycaemia associated with mortality in critically ill patients: a multicentre, prospective, observational study using continuous glucose monitoring.

AIMS/HYPOTHESIS: Continuous glucose monitoring (CGM) provides comprehensive information on the exposure to dysglycaemia. This study aimed to investigate the threshold of hyperglycaemia related to mortality risk in critically ill patients using CGM technology. METHODS: A total of 293 adult critically ill patients admitted to intensive care units of five medical centres were prospectively included between May 2020 and November 2021. Participants wore intermittently scanned CGM for a median of 12.0 days. The relationships between different predefined time above ranges (TARs), with the thresholds of hyperglycaemia ranging from 7.8 to 13.9 mmol/l (140-250 mg/dl), and in-hospital mortality risk were assessed by multivariate Cox proportional regression analysis. Time in ranges (TIRs) of 3.9 mmol/l (70 mg/dl) to the predefined hyperglycaemic thresholds were also assessed. RESULTS: Overall, 66 (22.5%) in-hospital deaths were identified. Only TARs with a threshold of 10.5 mmol/l (190 mg/dl) or above were significantly associated with the risk of in-hospital mortality, after adjustment for covariates. Furthermore, as the thresholds for TAR increased from 10.5 mmol/l to 13.9 mmol/l (190 mg/dl to 250 mg/dl), the hazards of in-hospital mortality increased incrementally with every 10% increase in TARs. Similar results were observed concerning the associations between TIRs with various upper thresholds and in-hospital mortality risk. For per absolute 10% decrease in TIR 3.9-10.5 mmol/l (70-190 mg/dl), the risk of in-hospital mortality was increased by 12.1% (HR 1.121 [95% CI 1.003, 1.253]). CONCLUSIONS/INTERPRETATION: A glucose level exceeding 10.5 mmol/l (190 mg/dl) was significantly associated with higher risk of in-hospital mortality in critically ill patients.

Discovery of the small molecular inhibitors against sclerostin loop3 as potential anti-osteoporosis agents by structural based virtual screening and molecular design.

Sclerostin is a secreted glycoprotein that expresses predominantly in osteocytes and inhibits bone formation by antagonizing the Wnt/ß-catenin signaling pathway, and the loop3 region of sclerostin has recently discovered as a novel therapeutic target for bone anabolic treatment without increasing cardiovascular risk. Herein, we used a structural based virtual screening to search for small molecular inhibitors selectively targeting sclerostin loop3. A novel natural product hit ZINC4228235 (THFA) was identified as the sclerostin loop3-selective inhibitor with a Kd value of 42.43 nM against sclerostin loop3. The simplification and derivation of THFA using molecular modeling-guided modification allowed the discovery of an effective and loop3-selective small molecular inhibitor, compound (4-(3-acetamidoprop-1-yn-1-yl)benzoyl)glycine (AACA), with improved binding affinity (Kd = 15.4 nM) compared to the hit THFA. Further in-vitro experiment revealed that compound AACA could attenuate the suppressive effect of transfected sclerostin on Wnt signaling and bone formation. These results make AACA as a potential candidate for development of anti-osteoporosis agents without increasing cardiovascular risk.

Characteristics of Clinical Isolates of Listeria monocytogenes in Sichuan, China, in 2022 Based on Whole Genome Sequencing Analysis.

Listeria monocytogenes is a foodborne pathogen. In 2022, we collected 15 strains of L. monocytogenes isolated from patients in some foodborne disease sentinel monitoring hospitals in Sichuan Province. Through whole genome sequencing (WGS), we obtained the virulence genes carried by the strains, multi-locus sequence typing (MLST), core genome MLST (cgMLST), clonal complex (CC), and serum groups and constructed a phylogenetic tree and minimum spanning tree with nonhuman strains. An analysis shows that all 15 strains of L. monocytogenes carry virulence genes LIPI-1 and LIPI-2, whereas the carrying rates of LIPI-3 and LIPI-4 virulence genes are relatively low. The MLST typing results showed a total of 10 sequence types (ST), including 10 CCs, with ST7 being the dominant type. The cgMLST clearly distinguishes strains of different lineages and CC types. The serum group is divided into three types: IIa, IIb, and IVb, with IIa being the dominant serum group. An analysis of antibiotic genes showed that all 15 strains carried FosX, lin, mprF, and norB with high carrying rates. The minimum inhibitory concentration results indicated that all were susceptible to eight antibiotics (ampicillin, penicillin, tetracycline, meropenem, erythromycin, vancomycin, ciprofloxacin, and trimethoprim-sulfamethoxazole). The analysis of strains isolated from different sources of Listeria revealed varying degrees of diversity, and the contamination of meat and environment within the province is closely related to clinical cases. L. monocytogenes isolated from clinical cases in Sichuan Province carry multiple virulence and antibiotic genes, with high potential pathogenicity. It is necessary to further strengthen the monitoring and control of food and environment by L. monocytogenes within Sichuan Province.

A temperature-adjustable in situ infrared diffuse reflectance spectroscopy system for catalysts.

We introduce an innovative in situ infrared diffuse reflection rapid detection system, endowed with a temperature regulation function. This system is adept at conducting rapid infrared spectra scanning as well as simulating the catalytic environment of diverse reaction systems. The infrared absorption spectra of four kinds of Pt-based catalysts under vacuum conditions across a wide temperature spectrum ranging from -180 to 300 °C are obtained and analysed through IR correlation spectroscopy. A key finding is the notable variance in peak intensity within Pt/CeO2/CNT catalysts, highlighting a robust adsorption capacity for oxygen-containing groups at lower temperatures and a marked desorption at higher temperatures. By enabling rapid and accurate assessments of catalyst behavior under varying temperatures, it not only accelerates the evaluation process but also provides valuable insights that can guide the synthesis of more efficient catalysts.

DynamicBind: predicting ligand-specific protein-ligand complex structure with a deep equivariant generative model.

While significant advances have been made in predicting static protein structures, the inherent dynamics of proteins, modulated by ligands, are crucial for understanding protein function and facilitating drug discovery. Traditional docking methods, frequently used in studying protein-ligand interactions, typically treat proteins as rigid. While molecular dynamics simulations can propose appropriate protein conformations, they're computationally demanding due to rare transitions between biologically relevant equilibrium states. In this study, we present DynamicBind, a deep learning method that employs equivariant geometric diffusion networks to construct a smooth energy landscape, promoting efficient transitions between different equilibrium states. DynamicBind accurately recovers ligand-specific conformations from unbound protein structures without the need for holo-structures or extensive sampling. Remarkably, it demonstrates state-of-the-art performance in docking and virtual screening benchmarks. Our experiments reveal that DynamicBind can accommodate a wide range of large protein conformational changes and identify cryptic pockets in unseen protein targets. As a result, DynamicBind shows potential in accelerating the development of small molecules for previously undruggable targets and expanding the horizons of computational drug discovery.

Pathogenic mycobacterium upregulates cholesterol 25-hydroxylase to promote granuloma development via foam cell formation.

Pathogenic mycobacteria orchestrate the complex cell populations known as granuloma that is the hallmark of tuberculosis. Foam cells, a lipid-rich cell-type, are considered critical for granuloma formation; however, the causative factor in foam cell formation remains unclear. Atherosclerosis is a chronic inflammatory disease characterized by the abundant accumulation of lipid-laden-macrophage-derived foam cells during which cholesterol 25-hydroxylase (CH25H) is crucial in foam cell formation. Here, we show that M. marinum (Mm), a relative of M. tuberculosis, induces foam cell formation, leading to granuloma development following CH25H upregulation. Moreover, the Mm-driven increase in CH25H expression is associated with the presence of phthiocerol dimycocerosate, a determinant for Mm virulence and integrity. CH25H-null mice showed decreased foam cell formation and attenuated pathology. Atorvastatin, a recommended first-line lipid-lowering drug, promoted the elimination of M. marinum and concomitantly reduced CH25H production. These results define a previously unknown role for CH25H in controlling macrophage-derived foam cell formation and Tuberculosis pathology.

Temperature-Tunable Operando Nondestructive Detection of Electronic and Geometrical Structures in Battery Electrodes.

Real-time monitoring of the structural evolution of battery materials is crucial for understanding their underlying reaction mechanisms, which cannot be satisfied by the typically used post-mortem analysis. While more and more operando techniques were constructed and employed, they are all based on ambient working conditions that are not generally the case for real-world applications. Indeed, batteries work in an environment where self-heat dissipation increases the surrounding temperature, and extreme temperature applications (<-20 °C or >60 °C) are also frequently proposed. Operando characterization techniques under variable temperatures are therefore highly desired for tracking battery reactions under real-working conditions. Here, we develop a methodology to operando monitor the electronic and geometrical structures of battery materials over a wide range of temperatures based on X-ray spectroscopies. It is substantiated with data collected on a model LiNi0.90Co0.05Mn0.05O2/Si@C pouch cell under operando quick X-ray absorption fine structure spectroscopy, by which we found a temperature-dependent structure evolution behavior that is highly correlated with the electrochemical performance. Our work establishes an exemplary protocol for analyzing battery materials under temperature-variable environments that can be widely used in other related fields.

Development and clinical application of loop-mediated isothermal amplification combined with lateral flow assay for rapid diagnosis of SARS-CoV-2.

BACKGROUND: The diagnostic assay leveraging multiple reverse transcription loop-mediated isothermal amplification (RT-LAMP) could meet the requirements for rapid nucleic acid detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: The devised assay merged the lateral flow assay with the RT-LAMP technology and designed specific primers for the simultaneous detection of the target and human-derived internal reference genes within a single reaction. An inquiry into the assay's limit of detection (LOD), sensitivity, and specificity was carried out. The effectiveness of this assay was validated using 498 clinical specimens. RESULTS: This LOD of the assay was determined to be 500 copies/mL, and there was no observed cross-reaction with other respiratory pathogens. The detection results derived from clinical specimens showed substantial concordance with those from real-time reverse transcription-polymerase chain reaction (RT-qPCR) (Cohen's kappa, 0.876; 95% CI: 0.833-0.919; p<0.005). The diagnostic sensitivity and specificity were 87.1% and 100%, respectively. CONCLUSION: The RT-LAMP assay, paired with a straightforward and disposable lateral immunochromatographic strip, achieves visual detection of dual targets for SARS-CoV-2 immediatly. Moreover, the entire procedure abstains from nucleic acids extraction. The samples are lysed at room temperature and subsequently proceed directly to the RT-LAMP reaction, which can be executed within 30 minutes at a constant temperature of 60-65°C. Then, the RT-LAMP amplification products are visualized using colloidal gold test strips. TRIAL REGISTRATION: This study was registered at the Chinese Clinical Trial Registry (Registration number: ChiCTR2200060495, Date of registration 2022-06-03).