Integrative analysis with microbial modelling and machine learning uncovers potential alleviators for ulcerative colitis.

Ulcerative colitis (UC) is a challenging form of inflammatory bowel disease, and its etiology is intricately linked to disturbances in the gut microbiome. To identify the potential alleviators of UC, we employed an integrative analysis combining microbial community modeling with advanced machine learning techniques. Using metagenomics data sourced from the Integrated Human Microbiome Project, we constructed individualized microbiome community models for each participant. Our analysis highlighted a significant decline in both α and ß-diversity of strain-level microbial populations in UC subjects compared to controls. Distinct differences were also observed in the predicted fecal metabolite profiles and strain-to-metabolite contributions between the two groups. Using tree-based machine learning models, we successfully identified specific microbial strains and their associated metabolites as potential alleviators of UC. Notably, our experimental validation using a dextran sulfate sodium-induced UC mouse model demonstrated that the administration of Parabacteroides merdae ATCC 43,184 and N-acetyl-D-mannosamine provided notable relief from colitis symptoms. In summary, our study underscores the potential of an integrative approach to identify novel therapeutic avenues for UC, paving the way for future targeted interventions.

Mannan-oligosaccharides promote gut microecological recovery after antibiotic disturbance.

Antibiotic treatment often causes collateral damage to the gut microbiota, including changes in its diversity and composition. Dietary fiber helps maintain intestinal health, regulate short-chain fatty acids, and promote the recovery of the intestinal microbiome. However, it is currently unknown which specific plant-based dietary fiber is optimal as a dietary supplement for restoring the intestinal microbiota after antibiotic disturbance. Previously, we proposed predictive recovery-associated bacterial species (p-RABs) and identified the most important interventions. This study aimed to identify an optimal form of dietary fiber to recover the gut microbiome after antibiotic treatment. Therefore, we examined the types of dietary fibers associated with p-RABs through a p-RAB-metabolite bilayer network constructed from prior knowledge; we searched for dietary fiber that could provide nutritional support for Akkermansia muciniphila and Bacteroides uniformis. C57BL/6J mice were fed with 500 mg kg-1 of different types of dietary fibers daily for one week after being treated with ampicillin. The results showed that mannan-oligosaccharides could better promote the diversity of intestinal microbial growth, enhance the recovery of most genera, including Akkermansia and Bacteroides, and inhibit certain pathogenic bacteria, such as Proteus, compared to the other fiber types. Furthermore, mannan-oligosaccharides could regulate the levels of short-chain fatty acids, especially butyric acid. Functional predictions showed that starch metabolism, galactose metabolism, and the metabolism of other carbohydrates played key roles in the early recovery process. In conclusion, mannan-oligosaccharides could enhance the recovery of the intestinal microbiome after antibiotic treatment, offering valuable insights for targeted dietary strategies.

Gastrodin ameliorates postoperative cognitive dysfunction in aged mice by promoting nuclear translocation of Nrf2 through activation of AMPK.

BACKGROUND: Perioperative neurocognitive disorder (PND) remains a prevalent complication following anesthesia and surgery. Recent studies have revealed the therapeutic potential of gastrodin (GAS) in treating cognitive disturbances. This study delves deeper into the mechanisms through which GAS impacts PND. METHODS: Male C57BL/6 mice (18 months old) underwent laparotomies and were administered GAS orally daily for three weeks preceding surgery and one week post-surgery. Thirty minutes before GAS administration, an intraperitoneal injection of Compound C was given. In vitro, H2O2-incubated SH-SY-5Y cells, with or without Nrf2-siRNA transfection, were set up and subjected to GAS or Compound C treatments. Cell viability was assessed via MTT assays, and apoptosis levels were assessed through flow cytometry. Cognitive function was evaluated using the Morris water maze, novel object recognition, and Y-maze tests. Oxidative stress markers, including MDA, SOD, GSH, GSH-px, and intracellular ROS (determined through immunofluorescence), were quantified. The expression of the genes Caspase3, Bax, Bcl-2, GST, and NQO1 was gauged using real-time RT-PCR. Brain, cortex and hippocampal pathologies were examined with hematoxylin-eosin (HE) and NeuN/TUNEL costaining. Finally, Nrf2 and p-AMPK were analyzed using Western blotting (WB) and immunofluorescence assays. RESULTS: GAS improved cognitive dysfunction in PND mice and reduced oxidative stress, neuro-apoptosis, and ROS levels both in vivo and in vitro experiment. In vivo, Immunofluorescence and Western blot outcomes indicated that postoperative p-AMPK and Nrf2 levels in the hippocampus were mitigated but were augmented by GAS. In vitro studies revealed GAS's protective effect against H2O2-induced oxidative stress and apoptosis and its upregulation of p-AMPK and Nrf2 in SH-SY-5Y cells. Notably, this protective effect was negated when Nrf2 siRNA was introduced. ELISA and PCR results highlighted the role of GAS in enhancing GST and NQO1 activity in both the mice hippocampus and SH-SY-5Y cells. Compound C, an AMPK inhibitor, both in vitro and in vivo, reversed the beneficial effects of GAS on Nuc-Nrf2/Cyt-Nrf2 expression and counteracted the positive influence of GAS on cognitive functions in PND mice. CONCLUSION: GAS facilitates the nuclear translocation of Nrf2 via AMPK activation, offering a therapeutic avenue for alleviating postoperative cognitive impairments in mice, with a significant reduction in oxidative stress.

Dynamic Observations on Formation of Coffee-Ring Structures from the Degradation of Cesium Lead Halide Perovskite Nanocrystals.

Nanomaterials of halide perovskites have attracted increasing attention for their remarkable potential in optoelectronic devices, but their instability to environmental factors is the core issue impeding their applications. In this context, the microscopic understanding of their structural degradation mechanisms upon external stimuli remains incomplete. Herein, we took an emerging member of this material family, Cs4PbBr6 nanocrystals (NCs), as an example and investigated the degradation pathways as well as underlying mechanisms under an electron beam by using in situ transmission electron microscopy. Our atomic-scale study identified the distinct degradation stages for the NCs toward interesting coffee-ring PbBr2 structures, which are caused by the organic surface capping agents as well as surface energy of NCs. Our findings present a fundamental insight for the degradation of halide perovskite NCs and may provide indispensable guidance for their structural design and stability improvement.

Site-specific nanoswitch circumventing immune resistance via activating TLR and inhibiting PD-L1/PD-1 axis.

Immunotherapy has fundamentally altered cancer treatment; however, its effectiveness is clinically hampered by insufficient intratumoral T lymphocyte infiltration and failed T lymphocyte priming. Additionally, inducing cancer-specific immune responses while sparing normal cells remains challenging. Herein, we developed a redox-activatable polymeric nanoswitch (c-N@IM/JQ) that remained 'off' status in circulation but rapidly switched 'on' after entering the tumor. Toll-like receptor (TLR) 7/8 agonist (imidazoquinoline, IMQ) and bromodomain and extraterminal inhibitor (JQ1) are locked in c-N@IM/JQ with a redox-cleavable linker (switch off). Upon systemic administration, c-N@IM/JQ with c-RGD peptide modification preferentially accumulated at tumor sites and responded to the high glutathione levels to release native IMQ for fully mobilizing T lymphocyte army, and JQ1 for removing the programmed death ligand (PD-L)-1 protection on tumor cells (switch on). These strengthened T lymphocyte armies are easily accessible to these de-protected tumor cells, revitalizing the immune response against tumors.

Statistical modeling of gut microbiota for personalized health status monitoring.

BACKGROUND: The gut microbiome is closely associated with health status, and any microbiota dysbiosis could considerably impact the host's health. In addition, many active consortium projects have generated many reference datasets available for large-scale retrospective research. However, a comprehensive monitoring framework that analyzes health status and quantitatively present bacteria-to-health contribution has not been thoroughly investigated. METHODS: We systematically developed a statistical monitoring diagram for personalized health status prediction and analysis. Our framework comprises three elements: (1) a statistical monitoring model was established, the health index was constructed, and the health boundary was defined; (2) healthy patterns were identified among healthy people and analyzed using contrast learning; (3) the contribution of each bacterium to the health index of the diseased population was analyzed. Furthermore, we investigated disease proximity using the contribution spectrum and discovered multiple multi-disease-related targets. RESULTS: We demonstrated and evaluated the effectiveness of the proposed monitoring framework for tracking personalized health status through comprehensive real-data analysis using the multi-study cohort and another validation cohort. A statistical monitoring model was developed based on 92 microbial taxa. In both the discovery and validation sets, our approach achieved balanced accuracies of 0.7132 and 0.7026, and AUC of 0.80 and 0.76, respectively. Four health patterns were identified in healthy populations, highlighting variations in species composition and metabolic function across these patterns. Furthermore, a reasonable correlation was found between the proposed health index and host physiological indicators, diversity, and functional redundancy. The health index significantly correlated with Shannon diversity ([Formula: see text]) and species richness ([Formula: see text]) in the healthy samples. However, in samples from individuals with diseases, the health index significantly correlated with age ([Formula: see text]), species richness ([Formula: see text]), and functional redundancy ([Formula: see text]). Personalized diagnosis is achieved by analyzing the contribution of each bacterium to the health index. We identified high-contribution species shared across multiple diseases by analyzing the contribution spectrum of these diseases. CONCLUSIONS: Our research revealed that the proposed monitoring framework could promote a deep understanding of healthy microbiomes and unhealthy variations and served as a bridge toward individualized therapy target discovery and precise modulation. Video Abstract.

Application of vagus nerve stimulation on the rehabilitation of upper limb dysfunction after stroke: a systematic review and meta-analysis.

Objective: This study aimed to elucidate the efficacy, safety, and long-term implications of vagus nerve stimulation (VNS) as a viable therapeutic option for patients with upper limb dysfunction following a stroke. Methods: Data from the following libraries were searched from inception to December 2022: PubMed, Wanfang, Scopus, China Science and Technology Journal Database, Embase, Web of Science, China Biology Medicine Disc, Cochrane Library, and China National Knowledge Infrastructure. Outcomes included indicators of upper limb motor function, indicators of prognosis, and indicators of safety (incidence of adverse events [AEs] and serious AEs [SAEs]). Two of the authors extracted the data independently. A third researcher arbitrated when disputes occurred. The quality of each eligible study was evaluated using the Cochrane Risk of Bias tool. Meta-analysis and bias analysis were performed using Stata (version 16.0) and RevMan (version 5.3). Results: Ten trials (VNS combined with rehabilitation group vs. no or sham VNS combined with rehabilitation group) with 335 patients were included in the meta-analysis. Regarding upper extremity motor function, based on Fugl-Meyer assessment scores, VNS combined with other treatment options had immediate (mean difference [MD] = 2.82, 95% confidence interval [CI] = 1.78-3.91, I2 = 62%, p < 0.00001) and long-term (day-30 MD = 4.20, 95% CI = 2.90-5.50, p < 0.00001; day-90 MD = 3.27, 95% CI = 1.67-4.87, p < 0.00001) beneficial effects compared with that of the control treatment. Subgroup analyses showed that transcutaneous VNS (MD = 2.87, 95% CI = 1.78-3.91, I2 = 62%, p < 0.00001) may be superior to invasive VNS (MD = 3.56, 95% CI = 1.99-5.13, I2 = 77%, p < 0.0001) and that VNS combined with integrated treatment (MD = 2.87, 95% CI = 1.78-3.91, I2 = 62%, p < 0.00001) is superior to VNS combined with upper extremity training alone (MD = 2.24, 95% CI = 0.55-3.93, I2 = 48%, p = 0.009). Moreover, lower frequency VNS (20 Hz) (MD = 3.39, 95% CI = 2.06-4.73, I2 = 65%, p < 0.00001) may be superior to higher frequency VNS (25 Hz or 30 Hz) (MD = 2.29, 95% CI = 0.27-4.32, I2 = 58%, p = 0,03). Regarding prognosis, the VNS group outperformed the control group in the activities of daily living (standardized MD = 1.50, 95% CI = 1.10-1.90, I2 = 0%, p < 0.00001) and depression reduction. In contrast, quality of life did not improve (p = 0.51). Safety was not significantly different between the experimental and control groups (AE p = 0.25; SAE p = 0.26). Conclusion: VNS is an effective and safe treatment for upper extremity motor dysfunction after a stroke. For the functional restoration of the upper extremities, noninvasive integrated therapy and lower-frequency VNS may be more effective. In the future, further high-quality studies with larger study populations, more comprehensive indicators, and thorough data are required to advance the clinical application of VNS. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42023399820.

New Suggested Enhancing Safe Apneic Time in Edentulous Elderly: A Comparison of Transnasal Humidified Rapid-Insufflation Ventilatory Exchange and Facemask.

BACKGROUND Edentulous elderly patients often face challenges in airway management and are susceptible to hypoxemia. Transnasal humidified rapid-insufflation ventilatory exchange (THRIVE) provides high-flow nasal oxygenation, potentially extending safe apneic time (SAT). This study compared the efficacy of THRIVE versus facemask ventilation in improving oxygenation and extending SAT in edentulous elderly patients. MATERIAL AND METHODS Patients with more than 10 missing teeth and who were over 65 years old were randomly assigned to the facemask group (Group M, n=25) or the THRIVE group (Group T, n=25). Patients in Group M were pre-oxygenated with a facemask (6 L/min, FiO2 100%), while patients in Group T were pre-oxygenated with their mouths closed via THRIVE (30 L/min, FiO2 100%). After anesthesia induction, patients in Group M were ventilated with pressure-controlled ventilation. In Group T, the patient's mouth was kept closed, and the flow rate was adjusted to 70 L/min. Four min after cisatracurium administration, ventilation was stopped in Group M while Group T continued to receive oxygen (70 L/min, FiO2 100%).The primary outcome was SAT, which was attained at 4 min after injection of cisatracurium and ended when SpO2 decreased to 95% or when apneic time reached 480 s. A secondary outcome was the reoxygenation time, defined as the time from the beginning of mechanical ventilation to the time when SpO2 98% was reached. RESULTS An SAT of 480 s was reached by all patients in Group T, but by only 6 patients in Group M (P<0.05). Compared with Group M, the reoxygenation time in Group T was significantly shorter (P<0.05). CONCLUSIONS As compared to facemask, THRIVE can extend the SAT, improve oxygenation, and reduce reoxygenation time.

Krill Oil Turns Off TGF-ß1 Profibrotic Signaling in the Prevention of Diabetic Nephropathy.

Diabetic nephropathy (DN), a severe microvascular complication of diabetes mellitus (DM), results in high mortality due to the lack of effective interventions. The current study investigated the preventive effect of krill oil (KO) on DN using a type 2 DM mouse model induced by streptozotocin and high-fat diet for 24 weeks. The diabetic mice developed albuminuria, mesangial matrix accumulation, glomerular hypertrophy, and fibrosis formation, with an increase in renal proinflammatory, oxidative and profibrotic gene expression. KO significantly prevented these effects but did not improve hyperglycemia and glucose intolerance. In high-glucose-treated mesangial cells (MCs), KO preferably modulated TGF-ß1 signaling as revealed by RNA-sequencing. In TGF-ß1-treated MCs, KO abolished SMAD2/3 phosphorylation and nuclear translocation and activated Smad7 gene expression. The action of KO on the SMADs was confirmed in the diabetic kidneys. Therefore, KO may prevent DN predominantly by suppressing the TGF-ß1 signaling pathway.

The effect of high-frequency oscillatory ventilator combined with pulmonary surfactant in the treatment of neonatal respiratory distress syndrome.

OBJECTIVE: To investigate the efficacy of high-frequency oscillatory ventilation (HFOV) combined with pulmonary surfactant (PS) in the treatment of neonatal respiratory distress syndrome (NRDS). METHODS: This study is a retrospective clinical study. Seventy-two NRDS neonates were selected as the subjects from November 2019 to November 2020, and divided into observation group (40 cases, HFOV treatment) and control group (32 cases, conventional mechanical ventilation treatment). All cases were treated with PS and comprehensive treatment. The therapeutic effect, arterial partial pressure of oxygen (PaO2), arterial partial pressure of carbon dioxide (PaCO2), Percentage of inhaled oxygen concentration (FiO2), mean arterialpressure, oxygenation index (OI), and complications were compared in the 2 groups. RESULTS: The total effective rate of the observation group was 90.0%, significantly higher than that of the control group. After treatment, the observation group has higher PaO2 levels and lower levels of PaCO2, mean arterial pressure, FiO2, and OI than the control group. There was no significant difference in the incidence of complications between the 2 groups. CONCLUSION: HFOV combined with PS has a significant effect on NRDS, which can improve the arterial blood gas index without increasing the incidence of complications.

Knockdown of long non-coding RNA SOX2OT downregulates SOX2 to improve hippocampal neurogenesis and cognitive function in a mouse model of sepsis-associated encephalopathy.

BACKGROUND: Aberrant hippocampal neurogenesis is an important pathological feature of sepsis-associated encephalopathy. In the current study, we examined the potential role of the long noncoding RNA (lncRNA) sex-determining region Y-box 2 (SOX2) overlapping transcript (SOX2OT), a known regulator of adult neurogenesis in sepsis-induced deficits in hippocampal neurogenesis and cognitive function. METHODS: Sepsis was induced in adult C57BL/6 J male mice by cecal ligation and perforation (CLP) surgery. Randomly selected CLP mice were transfected with short interfering RNAs (siRNAs) against SOX2OT or SOX2, or with scrambled control siRNA. Cognitive behavior was tested 8-12 days post-surgery using a Morris water maze. Western blotting and RT-qPCR were used to determine expression of SOX2, Ki67, doublecortin (DCX), nestin, brain lipid-binding protein, and glial fibrillary acidic protein (GFAP) in the hippocampus. The number of bromodeoxyuridine (BrdU)+/DCX+ cells, BrdU+/neuronal nuclei (NeuN)+ neurons, and BrdU+/GFAP+ glial cells in the dentate gyrus were assessed by immunofluorescence. RESULTS: CLP mice showed progressive increases in SOX2OT and SOX2 mRNA levels on days 3, 7, and 14 after CLP surgery, accompanied by impaired cognitive function. Sepsis led to decrease in all neuronal markers in the hippocampus, except GFAP. Immunofluorescence confirmed the decreased numbers of BrdU+/DCX+ cells and BrdU+/NeuN+ neurons, and increased numbers of BrdU+/GFAP+ cells. SOX2OT knockdown partially inhibited the effects of CLP on levels of SOX2 and neuronal markers, neuronal populations in the hippocampus, and cognitive function. SOX2 deficiency recapitulated the effects of SOX2OT knockdown. CONCLUSION: SOX2OT knockdown improves sepsis-induced deficits in hippocampal neurogenesis and cognitive function by downregulating SOX2 in mice. Inhibiting SOX2OT/SOX2 signaling may be effective for treating or preventing neurodegeneration in sepsis-associated encephalopathy.

Anthocyanins attenuate neuroinflammation through the suppression of MLK3 activation in a mouse model of perioperative neurocognitive disorders.

Perioperative neurocognitive disorder (PND) is a common complication that lacks effective prevention and treatment measures. Neuroinflammation is considered to be one of the important mechanisms of PND. In this study, we investigated the effect and mechanism of anthocyanins (ANT), a natural plant ingredient, on postoperative cognition and neuroinflammation. Mice were subjected to laparotomy and treated with ANT (50-100 mg/kg, orally) 4 weeks before surgery and then once per day for 7 days after surgery. Morris water maze and fear conditioning tests were used to evaluate learning and memory function. Western blotting, RT-PCR and immunofluorescence were used to test the neuroprotective effects and mechanism of ANT. The results showed that ANT improved learning and memory in mice after surgery. ANT also inhibited MLK3 activation and its downstream JNK and p38 MAPK signaling cascades. Moreover, the inhibitor of MLK3 could mimic the effects of ANT. In addition, treatment with ANT significantly reduced neuroinflammation and microglia activation. In conclusion, MLK3 represents a novel target in surgery-induced neuroinflammation and cognitive dysfunction. ANT could inhibit the activation of MLK3 and be a promising agent for the prevention and treatment of PND.

Tunable Three-Dimensional Nanostructured Conductive Polymer Hydrogels for Energy-Storage Applications.

Three-dimensional (3D) nanostructured conducting polymer hydrogels represent a group of high-performance electrochemical energy-storage materials. Here, we demonstrate a molecular self-assembly approach toward controlled synthesis of nanostructured polypyrrole (PPy) conducting hydrogels, which was "cross-linked" by a conjugated dopant molecule trypan blue (TB) to form a 3D network with controlled morphology. The protonated TB by ion bonding aligns the free sulfonic acid groups into a certain spatial structure. The sulfonic acid group and the PPy chain are arranged by a self-sorting mechanism to form a PPy nanofiber structure by electrostatic interaction and hydrogen bonding. It is found that PPy hydrogels doped with varying dopant concentrations and changing dopant molecules exhibited controllable morphology and tunable electrochemical properties. In addition, the conjugated TB dopants promoted interchain charge transport, resulting in higher electrical conductivity (3.3 S/cm) and pseudocapacitance for the TB-doped PPy, compared with PPy synthesized without TB. When used as supercapacitor electrodes, the TB-doped PPy hydrogel reaches maximal specific capacitance of 649 F/g at the current density 1 A/g. The result shows that PPy nanostructured hydrogels can be tuned for potential applications in next-generation energy-storage materials.