Propionic acid ameliorates cognitive function through immunomodulatory effects on Th17 cells in perioperative neurocognitive disorders.

Background: Elderly patients undergoing surgery are prone to cognitive decline known as perioperative neurocognitive disorders (PND). Several studies have shown that the microglial activation and the decrease of short-chain fatty acids (SCFAs) in gut induced by surgery may be related to the pathogenesis of PND. The purpose of this study was to determine whether microglia and short-chain fatty acids were involved in cognitive dysfunction in aged rats. Methods: Male wild-type Wistar rats aged 11-12 months were randomly divided into control group (Ctrl: Veh group), propionic acid group (Ctrl: PA group), exploratory laparotomy group (LP: Veh group) and propionic acid + exploratory laparotomy group (LP: PA group) according to whether exploratory laparotomy (LP) or PA pretreatment for 21 days was performed. The motor ability of the rats was evaluated by open field test on postoperative day 3 (POD3), and then the cognitive function was evaluated by Y-maze test and fear conditioning test. The expression of IL-1ß, IL-6, RORγt and IL-17A mRNA in hippocampus was detected by RT-qPCR, the expression of IL-17A and IL-17RA in hippocampus was detected by Western blot, and the activation of microglia was detected by immunofluorescence. Results: The PND rat model was successfully established by laparotomy. Compared with Ctrl: Veh group, the body weight of LP: Veh group decreased, the percentage of spontaneous alternations in Y maze decreased (P < 0.001), and the percentage of freezing time in contextual fear test decreased (P < 0.001). Surgery triggers neuroinflammation, manifested as the elevated levels of the inflammatory cytokines IL-1ß (P < 0.001) and IL-6 (P < 0.001), the increased expression of the transcription factor RORγt (P = 0.0181, POD1; P = 0.0073, POD5)and major inflammatory cytokines IL-17A (P = 0.0215, POD1; P = 0.0071, POD5), and the increased average fluorescence intensity of Iba1 (P < 0.001, POD1; P < 0.001, POD5). After PA preconditioning, the recovery of rats in LP: PA group was faster than that in LP: Veh group as the body weight lost on POD1 (P = 0.0148) was close to the baseline level on POD5 (P = 0.1846), and they performed better in behavioral tests. The levels of IL-1ß (P < 0.001) and IL-6 (P = 0.0035) inflammatory factors in hippocampus decreased on POD1 and the average fluorescence intensity of Iba1 decreased (P = 0.0024, POD1; P < 0.001, POD5), representing the neuroinflammation was significantly improved. Besides, the levels of RORγt mRNA (P = 0.0231, POD1; P = 0.0251, POD5) and IL-17A mRNA (P = 0.0208, POD1; P = 0.0071, POD5) in hippocampus as well as the expression of IL-17A (P = 0.0057, POD1; P < 0.001, POD5) and IL-17RA (P = 0.0388) decreased. Conclusion: PA pretreatment results in reduced postoperative neuroinflammation and improved cognitive function, potentially attributed to the regulatory effects of PA on Th17-mediated immune responses.

GATA binding protein 2 mediated ankyrin repeat domain containing 26 high expression in myeloid-derived cell lines.

BACKGROUND: Thrombocytopenia 2, an autosomal dominant inherited disease characterized by moderate thrombocytopenia, predisposition to myeloid malignancies and normal platelet size and function, can be caused by 5'-untranslated region (UTR) point mutations in ankyrin repeat domain containing 26 (ANKRD26). Runt related transcription factor 1 (RUNX1) and friend leukemia integration 1 (FLI1) have been identified as negative regulators of ANKRD26. However, the positive regulators of ANKRD26 are still unknown. AIM: To prove the positive regulatory effect of GATA binding protein 2 (GATA2) on ANKRD26 transcription. METHODS: Human induced pluripotent stem cells derived from bone marrow (hiPSC-BM) and urothelium (hiPSC-U) were used to examine the ANKRD26 expression pattern in the early stage of differentiation. Then, transcriptome sequencing of these iPSCs and three public transcription factor (TF) databases (Cistrome DB, animal TFDB and ENCODE) were used to identify potential TF candidates for ANKRD26. Furthermore, overexpression and dual-luciferase reporter experiments were used to verify the regulatory effect of the candidate TFs on ANKRD26. Moreover, using the GENT2 platform, we analyzed the relationship between ANKRD26 expression and overall survival in cancer patients. RESULTS: In hiPSC-BMs and hiPSC-Us, we found that the transcription levels of ANKRD26 varied in the absence of RUNX1 and FLI1. We sequenced hiPSC-BM and hiPSC-U and identified 68 candidate TFs for ANKRD26. Together with three public TF databases, we found that GATA2 was the only candidate gene that could positively regulate ANKRD26. Using dual-luciferase reporter experiments, we showed that GATA2 directly binds to the 5'-UTR of ANKRD26 and promotes its transcription. There are two identified binding sites of GATA2 that are located 2 kb upstream of the TSS of ANKRD26. In addition, we discovered that high ANKRD26 expression is always related to a more favorable prognosis in breast and lung cancer patients. CONCLUSION: We first discovered that the transcription factor GATA2 plays a positive role in ANKRD26 transcription and identified its precise binding sites at the promoter region, and we revealed the importance of ANKRD26 in many tissue-derived cancers.

Effects of weight loss on QTc in people with obesity: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Overweight and obesity have been found to exhibit a statistically significant increase in corrected QT interval (QTc), a major contributing factor to sudden death. However, the influence of widely used weight loss strategies including diet, exercise, anti-obesity drugs, and bariatric surgery on QTc remains inconsistent. Therefore, the present systematic review and meta-analysis aim to quantitatively analyse and evaluate the effect of weight loss on QTc in obese patients after diet control with exercise intervention and anti-obesity drugs, as well as bariatric surgery. METHODS: Twenty randomised controlled trials (RCT) and observational studies were included in the meta-analysis on the effects of weight loss on QTc. The fixed-effects model was employed in the RCTs, and the random-effects model was employed due to the presence of statistical heterogeneity among observational studies. Subgroup analysis was conducted to understand the differences in distinct weight loss methods and follow-up time. RESULTS: Overall, the QTc of people with obesity after weight loss was shorter than that before (mean difference (MD) = 21.97 ms, 95% confidence interval (CI) = 12.42, 31.52, p < .0001). Subgroup analysis restricted to seven included studies whose intervention was diet control with exercise showed a decrease of QTc with statistical significance (MD = 9.35 ms, 95%CI = 2.56, 37.54, p = .007). In the remaining 11 studies, bariatric surgery was the weight loss method. The results also showed a shortening of QTc after surgery, and the difference was statistically significant (MD = 29.04 ms, 95%CI = -16.46, 41.62, p < .00001). A statistically significant difference in QTc shortening at 6 months compared to pre-operation values was further observed (MD = -31.01 ms, 95%CI = -2.89, -59.12, p = .03). The shortening of QTc at 12 months of follow-up was also significantly different from that before surgery (MD = 36.47 ms, 95%CI = 14.17, 58.78, p < .00001). Moreover, the differences became more pronounced as the follow-up time extended. CONCLUSIONS: We demonstrate that weight loss links to a shortened QTc, without considering the means of weight loss. Bariatric surgery has been found to result in a greater reduction in QTc.

Rejuvenation of peripheral immune cells attenuates Alzheimer's disease-like pathologies and behavioral deficits in a mouse model.

Immunosenescence contributes to systematic aging and plays a role in the pathogenesis of Alzheimer's disease (AD). Therefore, the objective of this study was to investigate the potential of immune rejuvenation as a therapeutic strategy for AD. To achieve this, the immune systems of aged APP/PS1 mice were rejuvenated through young bone marrow transplantation (BMT). Single-cell RNA sequencing revealed that young BMT restored the expression of aging- and AD-related genes in multiple cell types within blood immune cells. The level of circulating senescence-associated secretory phenotype proteins was decreased following young BMT. Notably, young BMT resulted in a significant reduction in cerebral Aß plaque burden, neuronal degeneration, neuroinflammation, and improvement of behavioral deficits in aged APP/PS1 mice. The ameliorated cerebral amyloidosis was associated with an enhanced Aß clearance of peripheral monocytes. In conclusion, our study provides evidence that immune system rejuvenation represents a promising therapeutic approach for AD.

Global status and trends of gastric cancer and gastric microbiota research: a bibliometric analysis.

Background: Numerous studies have cast light on the relationship between the gastric microbiota and gastric carcinogenesis. In this study, we conducted a bibliometric analysis of the relevant literature in the field of gastric cancer and the gastric microbiota and clarified its research status, hotspots, and development trends. Materials and methods: Publications were retrieved from the Web of Science Core Collection on 18 July 2023. CiteSpace 6.2.R4, VOSviewer 1.6.19.0, and Biblioshiny were used for the co-occurrence and cooperation analyses of countries, institutions, authors, references, and keywords. A keyword cluster analysis and an emergence analysis were performed, and relevant knowledge maps were drawn. Results: The number of published papers in this field totaled 215 and showed an increasing trend. The analysis of funding suggested that the input in this field is increasing steadily. China had the highest number of publications, while the United States had the highest betweenness centrality. Baylor College of Medicine published the most articles cumulatively. Both Ferreira RM and Cooker OO had the highest citation frequency. The journal Helicobacter showed the most interest in this field, while Gut provided a substantial research foundation. A total of 280 keywords were obtained using CiteSpace, which were primarily focused on the eradication and pathogenic mechanisms of Helicobacter pylori, as well as the application of the gastric microbiota in the evaluation and treatment of gastric cancer. The burst analysis suggested that in the future, research may focus on the application of gastric microorganisms, particularly Fusobacterium nucleatum, in the diagnosis and treatment of gastric cancer, along with their pathogenic mechanisms. Conclusion: Current studies have been tracking the eradication of Helicobacter pylori and its pathogenic mechanisms, as well as changes in the gastric microbiota during gastric carcinogenesis. Future research may focus on the clinical application and pathogenesis of stomach microorganisms through bacteria such as Fusobacterium nucleatum.

GENESIS CGDYN: large-scale coarse-grained MD simulation with dynamic load balancing for heterogeneous biomolecular systems.

Residue-level coarse-grained (CG) molecular dynamics (MD) simulation is widely used to investigate slow biological processes that involve multiple proteins, nucleic acids, and their complexes. Biomolecules in a large simulation system are distributed non-uniformly, limiting computational efficiency with conventional methods. Here, we develop a hierarchical domain decomposition scheme with dynamic load balancing for heterogeneous biomolecular systems to keep computational efficiency even after drastic changes in particle distribution. These schemes are applied to the dynamics of intrinsically disordered protein (IDP) droplets. During the fusion of two droplets, we find that the changes in droplet shape correlate with the mixing of IDP chains. Additionally, we simulate large systems with multiple IDP droplets, achieving simulation sizes comparable to those observed in microscopy. In our MD simulations, we directly observe Ostwald ripening, a phenomenon where small droplets dissolve and their molecules redeposit into larger droplets. These methods have been implemented in CGDYN of the GENESIS software, offering a tool for investigating mesoscopic biological processes using the residue-level CG models.

Construction and validation of key genes-related prognosis model in children with acute myeloid leukaemia.

INTRODUCTION: To identify the differentially expressed genes of acute myeloid leukaemia (AML) and construct and verify a survival prognosis model combined with patient survival information. METHODS: The TARGET database was searched to identify differentially expressed peripheral blood genes in children with AML and healthy children. A gene set functional analysis and pathway analysis were performed using gene ontology and the KEGG pathway. A prognostic model for children with AML was constructed using univariate Cox, LASSO Cox regression and multivariate Cox regression analyses. Time-dependent receiver operating characteristic (ROC) curves were adopted to assess the predictive capacity of the prognostic models. RESULTS: In total, 1640 differentially expressed genes were screened (1119 upregulated and 521 downregulated genes). The differentially expressed genes were mainly involved in nutrient metabolism and cytochrome P450 metabolism. Six key genes related to the prognosis of AML, FAM157A, GPR78, IRX5, RP4-800G7.1, RP11-179H18.5 and RP11-61N20.3, were identified. Kaplan-Meier curves indicated that 3-year and 5-year overall survival was significantly higher in the low-risk group than in the high-risk group. The area under the ROC curve was 0.722. At different stages of AML, FAM157A and RP4-800G7.1 exhibited significant differences in expression. The expression levels of FAM157A were significantly decreased in AML, whereas the expression levels of GPR78, IRX5, RP4-800G7.1, RP11-179H18.5 and RP11-61N20.3 were significantly increased in AML. CONCLUSION: A prognosis-related gene model of AML was successfully constructed, and the expression levels of the model genes varied with AML stage.

Common gastrointestinal symptoms and their impact on psychological state and quality of life in patients with inflammatory bowel disease: a cross-sectional multicenter study in China.

Objective: To explore the impact of common gastrointestinal (GI) symptoms on psychological symptoms, sleep quality, and quality of life in patients with inflammatory bowel disease (IBD). Methods: A unified questionnaire was developed to collect clinical data on the mental psychology and quality of life of IBD patients from 42 hospitals in 22 provinces in P. R. China from September 2021 to May 2022. The general clinical characteristics, psychological symptoms, sleep quality, and quality of life of IBD patients with different numbers of GI symptoms were analyzed by descriptive statistical analysis. Results: A total of 2,478 IBD patients were finally analysed in this study, including 365 without GI symptoms (14.7%), 752 with single symptoms (30.4%), 841 with double symptoms (33.9%), and 520 with three symptoms (21.0%). Compared with patients without GI symptoms, patients with only simple abdominalgia or diarrhea or hematochezia showed significantly higher levels of anxiety and depression and worse quality of life (all P < 0.05). Compared with asymptomatic patients, patients with double symptoms (e.g. abdominalgia plus hematochezia, diarrhea plus hematochezia, abdominalgia plus diarrhea) and patients with three symptoms (abdominalgia, diarrhea, and hematochezia) showed significantly higher levels of anxiety and depression and worse sleep quality and quality of life (all P < 0.05). Conclusion: Compared with IBD patients without gastrointestinal symptoms, patients with gastrointestinal symptoms were more likely to experience anxiety, depression, sleep disturbances, and poorer quality of life.

Seroevidence of SARS-CoV-2 spillback to rodents in Sarawak, Malaysian Borneo.

BACKGROUND: SARS-CoV-2 is believed to have originated from a spillover event, where the virus jumped from bats to humans, leading to an epidemic that quickly escalated into a pandemic by early 2020. Despite the implementation of various public health measures, such as lockdowns and widespread vaccination efforts, the virus continues to spread. This is primarily attributed to the rapid emergence of immune escape variants and the inadequacy of protection against reinfection. Spillback events were reported early in animals with frequent contact with humans, especially companion, captive, and farmed animals. Unfortunately, surveillance of spillback events is generally lacking in Malaysia. Therefore, this study aims to address this gap by investigating the presence of SARS-CoV-2 neutralising antibodies in wild rodents in Sarawak, Malaysia. RESULTS: We analysed 208 archived plasma from rodents collected between from 2018 to 2022 to detect neutralising antibodies against SARS-CoV-2 using a surrogate virus neutralisation test, and discovered two seropositive rodents (Sundamys muelleri and Rattus rattus), which were sampled in 2021 and 2022, respectively. CONCLUSION: Our findings suggest that Sundamys muelleri and Rattus rattus may be susceptible to natural SARS-CoV-2 infections. However, there is currently no evidence supporting sustainable rodent-to-rodent transmission.

Electrically Tunable, Rapid Spin-Orbit Torque Induced Modulation of Colossal Magnetoresistance in Mn3Si2Te6 Nanoflakes.

As a quasi-layered ferrimagnetic material, Mn3Si2Te6 nanoflakes exhibit magnetoresistance behavior that is fundamentally different from their bulk crystal counterparts. They offer three key properties crucial for spintronics. First, at least 106 times faster response compared to that exhibited by bulk crystals has been observed in current-controlled resistance and magnetoresistance. Second, ultralow current density is required for resistance modulation (∼5 A/cm2). Third, electrically gate-tunable magnetoresistance has been realized. Theoretical calculations reveal that the unique magnetoresistance behavior in the Mn3Si2Te6 nanoflakes arises from a magnetic field induced band gap shift across the Fermi level. The rapid current induced resistance variation is attributed to spin-orbit torque, an intrinsically ultrafast process (∼nanoseconds). This study suggests promising avenues for spintronic applications. In addition, it highlights Mn3Si2Te6 nanoflakes as a suitable platform for investigating the intriguing physics underlying chiral orbital moments, magnetic field induced band variation, and spin torque.

Modified Broadband Ruthroff-Type Transmission Line Transformer Balun for Isolation-Enhanced Passive Mixer Design.

Generalized broadband operation facilitates multifunction or multiband highly integrated applications, such as modern transceiver systems, where ultra-wideband bidirectional passive mixers are favored to avoid a complex up/down-conversion scheme. In this paper, a modified Ruthroff-type transmission line transformer (TLT) balun is presented to enhance the isolation of the mixer from the local oscillator (LO) to the radio frequency (RF). Compared to the conventional methods, the proposed Ruthroff-type architecture adopts a combination of shunt capacitors and parallel coupled lines to improve the return loss at the LO port, thus effectively avoiding the area consumption for the diode-to-balun impedance transformation while simultaneously providing a suitable point for IF extraction. In addition, a parallel compensation technique consisting of an inductor and resistor is applied to the RF balun to significantly improve the amplitude/phase balance performance over a wide bandwidth. Benefiting from the aforementioned operations, an isolation-enhanced 8-30 GHz passive double-balanced mixer is designed as a proof-of-principle demonstration via 0.15-micrometer GaAs p-HEMT technology. It exhibits ultra-broadband performance with 7 dB average conversion loss and 50 dB LO-to-RF isolation under 15 dBm LO power. The monolithic microwave integrated circuit area is 0.96 × 1.68 mm2 including all pads.

Volatile Organic Compound-Based Predictive Modeling of Smoke Taint in Wine.

Smoke taint in wine has become a critical issue in the wine industry due to its significant negative impact on wine quality. Data-driven approaches including univariate analysis and predictive modeling are applied to a data set containing concentrations of 20 VOCs in 48 grape samples and 56 corresponding wine samples with a taster-evaluated smoke taint index. The resulting models for predicting the smoke taint index of wines are highly predictive when using as inputs VOC concentrations after log conversion in both grapes and wines (Pearson Correlation Coefficient PCC = 0.82; R2 = 0.68) and less so when only grape VOCs are used (Pearson Correlation Coefficient PCC = 0.76; R2 = 0.56), and the classification models also show the capacity for detecting smoke-tainted wines using both wine and grape VOC concentrations (Recall = 0.76; Precision = 0.92; F1 = 0.82) or using only grape VOC concentrations (Recall = 0.74; Precision = 0.92; F1 = 0.80). The performance of the predictive model shows the possibility of predicting the smoke taint index of the wine and grape samples before fermentation. The corresponding code of data analysis and predictive modeling of smoke taint in wine is available in the Github repository (https://github.com/IBPA/smoke_taint_prediction).

Geographic differences in psychological symptoms, sleep quality, and quality of life in patients with inflammatory bowel disease: A multicenter study in China.

OBJECTIVE: We aimed to explore the geographic differences in psychological symptoms, sleep quality, and quality of life (QoL) among adult patients with inflammatory bowel disease (IBD). METHODS: A unified questionnaire was developed to collect data on psychological status and QoL of IBD patients from 42 hospitals across 22 provinces, municipalities, and autonomous regions in China's mainland from September 2021 to May 2022. RESULTS: A total of 2478 patients with IBD were surveyed. The proportions of patients with anxiety (28.5% vs 23.1%), depression (32.3% vs 27.8%), and poor QoL (44.8% vs 32.2%) were significantly higher in patients from the northern region compared to the southern region (all P < 0.05). In the western region, the proportions of patients with anxiety (31.9% vs 23.0%), depression (37.7% vs 26.7%), sleep disturbances (64.5% vs 58.5%), and poor QoL (44.9% vs 34.8%) were significantly higher than in the eastern and central regions (all P < 0.01). Patients from inland regions had significantly higher rates of anxiety (27.1% vs 23.3%), depression (32.5% vs 26.0%), sleep disturbance (62.0% vs 57.7%), and poor QoL (43.5% vs 29.9%) compared to those from coastal regions (all P < 0.05). In economically underdeveloped areas, the proportions of patients with depression (33.1% vs 28.5%) and poor QoL (52.0% vs 32.4%) were significantly higher than in economically (relatively) developed areas (both P < 0.05). CONCLUSION: There are significant geographic differences in psychological symptoms, sleep quality, and QoL among Chinese patients with IBD, which might provide valuable insights for global IBD research and clinical practice.

Evaluating disease status in idiopathic inflammatory myopathies with quantitative muscle ultrasound.

INTRODUCTION/AIMS: Muscle strength, functional status, and muscle enzymes are conventionally used to evaluate disease status in idiopathic inflammatory myopathies (IIM). This study aims to investigate the role of quantitative muscle ultrasound in evaluating disease status in IIM patients. METHODS: Patients with IIM, excluding inclusion body myositis, were recruited along with age- and sex-matched healthy controls (HC). All participants underwent muscle ultrasound and clinical assessments. Six limb muscles were unilaterally scanned using a standardized protocol, measuring muscle thickness (MT) and echo intensity (EI). Results were compared with HC, and correlations were made with outcome measures. RESULTS: Twenty IIM patients and 24 HC were recruited. The subtypes of IIM were dermatomyositis (6), necrotizing myositis (6), polymyositis (3), antisynthetase syndrome (3), and nonspecific myositis (2). Mean disease duration was 8.7 ± 6.9 years. There were no significant differences in demographics and anthropometrics between patients and controls. MT of rectus femoris in IIM patients was significantly lower than HC. Muscle EI of biceps brachii and vastus medialis in IIM patients were higher than HC. There were moderate correlations between MT of rectus femoris and modified Rankin Scale, Physician Global Activity Assessment, and Health Assessment Questionnaire, as well as between EI of biceps brachii and Manual Muscle Testing-8. DISCUSSION: Muscle ultrasound can detect proximal muscle atrophy and hyperechogenicity in patients with IIM. The findings correlate with clinical outcome measures, making it a potential tool for evaluating disease activity of patients with IIM in the late phase of the disease.

Search for Snail Repellents: Antimollusc Activities from Stemona parviflora and Six Other Chinese Stemona Species.

Snails are important agricultural pests difficult to control, but data regarding molluscicidal assays are scant. Stemona alkaloids are typical secondary metabolites for the taxa and have been broadly investigated for their pharmacological and toxicological effects. This makes it possible for us to further develop the toxicities of these compounds to snails. In this work, we tested the antifeedant properties of leaves from seven Chinese Stemona species against the land snail species Bradybaena ravida in choice and non-choice feeding assays. The tested leaves Stemona parviflora exhibited the most deterrent effects, and a further phytochemical investigation of aerial parts led to the identification of 16 alkaloids. Among them, three novel alkaloids could be identified. The alkaloidal fraction and single alkaloids were further assayed against this snail species, and the results suggest a cocktail effect because the impact of the alkaloidal fraction was higher than the effects caused by single alkaloids. The study can promote the search process of natural antimollusc products from plants to control snails.

Observer-based event-triggered H∞ control for Hamiltonian systems.

This paper investigates the problem of designing an observer-based event-triggered H∞ controller for a Hamiltonian system with delays incorporated in the underlying network. As our contributions, we first propose an event-triggered scheme which uses the Hamiltonian to decide whether to trigger the event generator at the sampling time. Additionally, when states are not exactly known globally asymptotically stable, we proceed to design an observer-based controller with which the resulting closed-loop system can be transformed into a time-delay Hamiltonian system. Based on the structural characteristic of the Hamiltonian systems, sufficient conditions are given to guarantee the closed-loop system to achieve the H∞ performance index with external disturbances in available and unavailable states, respectively. Finally, multi-machine power systems as simulation examples are illustrated to validate our proposed results.

Deciphering Endothelial and Mesenchymal Organ Specification in Vascularized Lung and Intestinal Organoids.

To investigate the co-development of vasculature, mesenchyme, and epithelium crucial for organogenesis and the acquisition of organ-specific characteristics, we constructed a human pluripotent stem cell-derived organoid system comprising lung or intestinal epithelium surrounded by organotypic mesenchyme and vasculature. We demonstrated the pivotal role of co-differentiating mesoderm and endoderm via precise BMP regulation in generating multilineage organoids and gut tube patterning. Single-cell RNA-seq analysis revealed organ specificity in endothelium and mesenchyme, and uncovered key ligands driving endothelial specification in the lung (e.g., WNT2B and Semaphorins) or intestine (e.g., GDF15). Upon transplantation under the kidney capsule in mice, these organoids further matured and developed perfusable human-specific sub-epithelial capillaries. Additionally, our model recapitulated the abnormal endothelial-epithelial crosstalk in patients with FOXF1 deletion or mutations. Multilineage organoids provide a unique platform to study developmental cues guiding endothelial and mesenchymal cell fate determination, and investigate intricate cell-cell communications in human organogenesis and disease. Highlights: BMP signaling fine-tunes the co-differentiation of mesoderm and endoderm.The cellular composition in multilineage organoids resembles that of human fetal organs.Mesenchyme and endothelium co-developed within the organoids adopt organ-specific characteristics.Multilineage organoids recapitulate abnormal endothelial-epithelial crosstalk in FOXF1-associated disorders.

The effects of transcranial magnetic stimulation for freezing of gait in Parkinson's disease: a systematic review and meta-analysis of randomized controlled trials.

Background: Freezing of gait (FOG) is one of the most disabling gait disturbances in Parkinson's disease (PD), affecting mobility and balance severely, thereby leading to an increased risk of falls. Objectives: The purpose of this systematic review and meta-analysis was to investigate the effects of transcranial magnetic stimulation on FOG in PD. Methods: Based on PRISMA guidelines, we searched the databases of MEDLINE (PubMed), Cochrane Library, PEDro, Embase, and Web of Science. Studies of the English language published up to July 2023 were searched. We retrieved for studies of randomized controlled trials (RCTs) of transcranial magnetic stimulation to treat FOG after PD and screened by inclusion and exclusion criteria. Risk of bias was assessed using the Cochrane Collaboration's tool (Revman5.30). Characteristics of RCTs were extracted. The heterogeneity of the trials was measured by I2 statistic. The effect size was expressed by a standardized mean difference (SMD) with a 95% confidence interval (CI). Results: A total of 488 articles were screened, after screening sixteen RCTs involved in 408 patients were included in the qualitative analysis, and 15 RCTs were included in meta-analysis. The outcome measures included FOG-Q, walking time, TUG, and UPDRS. Six studies used FOG-Q as outcome measure, six studies used walking time, four studies used TUG, and six studies used UPDRS. Compared with placebo treatment, transcranial magnetic stimulation has positive significant effects in improving gait status with increased walking speed (SMD = -0.41, 95% CI = -0.75 to -0.06, I2 = 7% p = 0.02), FOG-Q scores (SMD = -0.55, 95% CI = -0.89 to -0.21, I2 = 29%, p = 0.002), UPDRS scores (SMD = -1.08, 95% CI = -1.39 to -0.78, I2 = 49%, P < 0.001) and the time of TUG (SMD = -0.56, 95% CI = -0.88 to -0.23, I2 = 25%, p = 0.02) decreased. Conclusion: Transcranial magnetic stimulation could significantly improving gait conditions in PD patients with FOG. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/#recordDetails, CRD42023434286.

Discovery of ent-labdane derivatives from Andrographis paniculata and their anti-inflammatory activity.

The plant Andrographis paniculata has a long history of cultivation in Southeast Asia, especially its extensive anti-inflammatory activity, and the famous natural antibiotic andrographolide comes from this plant. In China, A. paniculata, as the main crop, has become a major source of traditional Chinese medicine (TCM) for the clinical treatment of inflammation. To further explore the diverse diterpene lactones with better anti-inflammatory activity from A. paniculata, twenty-one ent-labdanes, including six undescribed compounds (andropanilides D-I), were isolated. Their structures with absolute configurations were thoroughly determined by comprehensive NMR spectroscopic data, HRESIMS analysis and quantum chemical calculations. All isolated compounds were evaluated for anti-inflammatory activities based on the Griess method. Meanwhile, after structure-activity relationships analysis, the anti-inflammatory activity of andropanilide D (1) (IC50 = 2.31 µM) was found to be better than that of the positive control drug (dexamethasone, IC50 = 6.52 µM) and andrographolide (IC50 = 5.89 µM). Further mechanisms of activity indicated that andropanilide D significantly reduced the secretion of TNF-α, IL-6 and IL-1ß and downregulated the protein expression of COX-2 and iNOS in LPS-induced RAW264.7 macrophages in a concentration-dependent manner based on Western blot and ELISA experiments. In conclusion, andropanilide D possesses potential medicinal value for the treatment of inflammation and further expands the material basis of the anti-inflammatory effect of A. paniculata.