Clathrin-associated carriers enable recycling through a kiss-and-run mechanism.

Endocytosis and recycling control the uptake and retrieval of various materials, including membrane proteins and lipids, in all eukaryotic cells. These processes are crucial for cell growth, organization, function and environmental communication. However, the mechanisms underlying efficient, fast endocytic recycling remain poorly understood. Here, by utilizing a biosensor and imaging-based screening, we uncover a recycling mechanism that couples endocytosis and fast recycling, which we name the clathrin-associated fast endosomal recycling pathway (CARP). Clathrin-associated tubulovesicular carriers containing clathrin, AP1, Arf1, Rab1 and Rab11, while lacking the multimeric retrieval complexes, are generated at subdomains of early endosomes and then transported along actin to cell surfaces. Unexpectedly, the clathrin-associated recycling carriers undergo partial fusion with the plasma membrane. Subsequently, they are released from the membrane by dynamin and re-enter cells. Multiple receptors utilize and modulate CARP for fast recycling following endocytosis. Thus, CARP represents a previously unrecognized endocytic recycling mechanism with kiss-and-run membrane fusion.

Diagnosis of Major Depressive Disorder Based on Individualized Brain Functional and Structural Connectivity.

BACKGROUND: Traditional neuroimaging studies have primarily emphasized analysis at the group level, often neglecting the specificity at the individual level. Recently, there has been a growing interest in individual differences in brain connectivity. Investigating individual-specific connectivity is important for understanding the mechanisms of major depressive disorder (MDD) and the variations among individuals. PURPOSE: To integrate individualized functional connectivity and structural connectivity with machine learning techniques to distinguish people with MDD and healthy controls (HCs). STUDY TYPE: Prospective. SUBJECTS: A total of 182 patients with MDD and 157 HCs and a verification cohort including 54 patients and 46 HCs. FIELD STRENGTH/SEQUENCE: 3.0 T/T1-weighted imaging, resting-state functional MRI with echo-planar sequence, and diffusion tensor imaging with single-shot spin echo. ASSESSMENT: Functional and structural brain networks from rs-fMRI and DTI data were constructed, respectively. Based on these networks, individualized functional connectivity (IFC) and individualized structural connectivity (ISC) were extracted using common orthogonal basis extraction (COBE). Subsequently, multimodal canonical correlation analysis combined with joint independent component analysis (mCCA + jICA) was conducted to fusion analysis to identify the joint and unique independent components (ICs) across multiple modes. These ICs were utilized to generate features, and a support vector machine (SVM) model was implemented for the classification of MDD. STATISTICAL TESTS: The differences in individualized connectivity between patients and controls were compared using two-sample t test, with a significance threshold set at P < 0.05. The established model was tested and evaluated using the receiver operating characteristic (ROC) curve. RESULTS: The classification performance of the constructed individualized connectivity feature model after multisequence fusion increased from 72.2% to 90.3%. Furthermore, the prediction model showed significant predictive power for assessing the severity of depression in patients with MDD (r = 0.544). DATA CONCLUSION: The integration of IFC and ISC through multisequence fusion enhances our capacity to identify MDD, highlighting the advantages of the individualized approach and underscoring its significance in MDD research. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 2.

Distribution of virulence genes and antimicrobial resistance of Escherichia coli isolated from hospitalized neonates: A multi-center study across China.

Background: Escherichia coli is the most common gram-negative pathogen to cause neonatal infections. Contemporary virulence characterization and antimicrobial resistance (AMR) data of neonatal E. coli isolates in China are limited. Methods: A total of 159 E. coli strains isolated from neonates were collected and classified into invasive and non-invasive infection groups, according to their site of origin. The presence of virulence genes was determined using polymerase chain reaction (PCR). All the strains were subjected to antimicrobial susceptibility testing using the broth dilution method. Results: The top three virulence genes with the highest detection rates were fimH (90.6 %), iutA (88.7 %), and kspMT II (88.1 %). The prevalences of fyuA (p = 0.023), kpsMT K1 (p = 0.019), ibeA (p < 0.001), and iroN (p = 0.027) were significantly higher in the invasive infection group than in the non-invasive infection group. Resistance to ceftazixime, sulfamethoxazole/trimethoprim, and ciprofloxacin was 75.5 %, 65.4 %, and 48.4 %, respectively. Lower rates of resistance to ceftazidime (p = 0.022), cefepime (p = 0.005), ticarcillin/clavulanic acid (p = 0.020) and aztreonam (p = 0.001) were observed in the invasive infection group compared to the non-invasive infection group. The number of virulence genes carried by E. coli was positively correlated with the number of antibiotics to which the isolates were resistant (r = 0.71, p = 0.016), and a specific virulence gene was associated with resistance to various species of antibiotics. Conclusions: Neonatal E. coli isolates carried multiple virulence genes and were highly resistant to antibiotics. Further studies are needed to understand the molecular mechanisms underlying the association between virulence and AMR.

Regional structural-functional connectivity coupling in major depressive disorder is associated with neurotransmitter and genetic profiles.

BACKGROUND: Abnormalities in structural-functional connectivity (SC-FC) coupling have been identified globally in patients with major depressive disorder (MDD). However, investigations have neglected the variability and hierarchical distribution of these abnormalities across different brain regions. Furthermore, the biological mechanisms underlying regional SC-FC coupling patterns are not well understood. METHODS: We enrolled 182 patients with MDD and 157 healthy control (HC) subjects, quantifying the intergroup differences in regional SC-FC coupling. The extreme gradient boosting (XGBoost), support vector machines (SVM) and random forest (RF) models were constructed to assess the potential of SC-FC coupling as biomarkers for MDD diagnosis and symptom prediction. Then, we examined the link between changes in regional SC-FC coupling in patients with MDD, neurotransmitter distributions, and gene expression. RESULTS: We observed increased regional SC-FC coupling in default mode network (T = 3.233) and decreased coupling in frontoparietal network (T = -3.471) in MDD relative to HC. XGBoost (AUC = 0.853), SVM (AUC = 0.832) and RF (p < 0.05) models exhibited good prediction performance. The alterations in regional SC-FC coupling in patients with MDD were correlated with the distributions of four neurotransmitters (p < 0.05) and expression maps of specific genes. These genes were strongly enriched in genes implicated in excitatory neurons, inhibitory neurons, cellular metabolism, synapse function, and immune signaling. These findings were replicated on two brain atlases. CONCLUSIONS: This work enhances our understanding of MDD and pave the way for the development of additional targeted therapeutic interventions.

Research progress and application strategies of sugar transport mechanisms in rice.

In plants, carbohydrates are central products of photosynthesis. Rice is a staple that contributes to the daily calorie intake for over half of the world's population. Hence, the primary objective of rice cultivation is to maximize carbohydrate production. The "source-sink" theory is proposed as a valuable principle for guiding crop breeding. However, the "flow" research lag, especially in sugar transport, has hindered high-yield rice breeding progress. This review concentrates on the genetic and molecular foundations of sugar transport and its regulation, enhancing the fundamental understanding of sugar transport processes in plants. We illustrate that the apoplastic pathway is predominant over the symplastic pathway during phloem loading in rice. Sugar transport proteins, such as SUTs and SWEETs, are essential carriers for sugar transportation in the apoplastic pathway. Additionally, we have summarized a regulatory pathway for sugar transport genes in rice, highlighting the roles of transcription factors (OsDOF11, OsNF-YB1, OsNF-YC12, OsbZIP72, Nhd1), OsRRM (RNA Recognition Motif containing protein), and GFD1 (Grain Filling Duration 1). Recognizing that the research shortfall in this area stems from a lack of advanced research methods, we discuss cutting-edge analytical techniques such as Mass Spectrometry Imaging and single-cell RNA sequencing, which could provide profound insights into the dynamics of sugar distribution and the associated regulatory mechanisms. In summary, this comprehensive review serves as a valuable guide, directing researchers toward a deep understanding and future study of the intricate mechanisms governing sugar transport.

Evaluating large language models for health-related text classification tasks with public social media data.

OBJECTIVES: Large language models (LLMs) have demonstrated remarkable success in natural language processing (NLP) tasks. This study aimed to evaluate their performances on social media-based health-related text classification tasks. MATERIALS AND METHODS: We benchmarked 1 Support Vector Machine (SVM), 3 supervised pretrained language models (PLMs), and 2 LLMs-based classifiers across 6 text classification tasks. We developed 3 approaches for leveraging LLMs: employing LLMs as zero-shot classifiers, using LLMs as data annotators, and utilizing LLMs with few-shot examples for data augmentation. RESULTS: Across all tasks, the mean (SD) F1 score differences for RoBERTa, BERTweet, and SocBERT trained on human-annotated data were 0.24 (±0.10), 0.25 (±0.11), and 0.23 (±0.11), respectively, compared to those trained on the data annotated using GPT3.5, and were 0.16 (±0.07), 0.16 (±0.08), and 0.14 (±0.08) using GPT4, respectively. The GPT3.5 and GPT4 zero-shot classifiers outperformed SVMs in a single task and in 5 out of 6 tasks, respectively. When leveraging LLMs for data augmentation, the RoBERTa models trained on GPT4-augmented data demonstrated superior or comparable performance compared to those trained on human-annotated data alone. DISCUSSION: The results revealed that using LLM-annotated data only for training supervised classification models was ineffective. However, employing the LLM as a zero-shot classifier exhibited the potential to outperform traditional SVM models and achieved a higher recall than the advanced transformer-based model RoBERTa. Additionally, our results indicated that utilizing GPT3.5 for data augmentation could potentially harm model performance. In contrast, data augmentation with GPT4 demonstrated improved model performances, showcasing the potential of LLMs in reducing the need for extensive training data. CONCLUSIONS: By leveraging the data augmentation strategy, we can harness the power of LLMs to develop smaller, more effective domain-specific NLP models. Using LLM-annotated data without human guidance for training lightweight supervised classification models is an ineffective strategy. However, LLM, as a zero-shot classifier, shows promise in excluding false negatives and potentially reducing the human effort required for data annotation.

Disease trend analysis platform accurately predicts the occurrence of cervical cancer under mixed diseases.

Cervical cancer (CC) is one of the most common gynecological malignancies. Cytological screening, while being the most common and accurate method for detecting cervical cancer, is both time-consuming and costly. Predicting CC based on bioinformatics can assist in the rapid early screening of CC in clinical practice. Most recent CC prediction methods require a large amount of detection data or sequencing data and are not ideal for CC detection in complex disease samples. We developed the Disease trend analysis platform (Dtap), which can quickly predict the occurrence of diseases using only blood routine data. Blood routine data was collected from 1,292 cervical cancer patients, 4,860 patients with complex diseases, and 4,980 healthy individuals from various sources. The results show that the Dtap-based trend model maintained good and stable performance in the prediction task of multiple datasets as well as complex disease samples. Finally, we built DTAPCC (http://bioinfor.imu.edu.cn/dtapcc), a Dtap-based CC disease prediction platform, to help users quickly predict CC and visualize trend features.

A pharmacovigilance study of chronic kidney disease in diabetes mellitus patients with statin treatment by using the US Food and Drug Administration adverse event reporting system.

Background: Statins were regarded as a main medication for managing hypercholesterolemia. Administration of statin therapy could reduce the incidence of cardiovascular disease in individuals diagnosed with type 2 diabetes mellitus (DM), which was recognized by multipal clinical guidelines. But previous studies had conflicting results on whether the long-term use of statins could benefit the renal function in diabetic patients. Aim: To evaluate the association between statin treatment and Chronic Kidney Disease in DM patients. Methods: This is a retrospective disproportionality analysis and cohort study based on real-world data. All DM cases reported in US Food and Drug Administration adverse event reporting system (FAERS) between the first quarter of 2004 and the fourth quarter of 2022 were included. Disproportionality analyses were conducted by estimating the reporting odds ratio (ROR) and the information component (IC). We further compared the CKD odds ratio (OR) between the statins group and the other primary suspected drug group among the included diabetes mellitus cases. Results: We finally included 593647 DM cases from FAERS, 5113 (5.31%) CKD cases in the statins group and 8810 (1.77%) CKD cases in the control group. Data analysis showed that the statins group showed a significant CKD signal (ROR: 3.11, 95% CI: 3.00-3.22; IC: 1.18, 95% CI: 1.07-1.29). In case group with two or more statins treatment history, the CKD signal was even stronger (ROR: 19.56, 95% CI: 18.10-21.13; IC: 3.70, 95% CI:3.44-3.93) compared with cases with one statin treatment history. Conclusion: The impact of statin therapy on the progression of renal disease in individuals diagnosed with type 2 diabetes mellitus (DM) remains inconclusive. After data mining on the current FAERS dataset, we discovered significant signals between statin treatment and CKD in diabetic patients. Furthermore, the incidence rate of CKD was higher among DM patients who used statins compared to those who did not.

Managing faba bean wilt disease through intercropping with wheat and reasonable nitrogen application: enhancing nutrient absorption and biochemical resistance in faba beans.

Faba bean wilt disease is a key factor limiting its production. Intercropping of faba bean with wheat has been adopted as a prevalent strategy to mitigate this disease. Nitrogen fertilizer improves faba bean yield, yet wilt disease imposes limitations. However, faba bean-wheat intercropping is effective in controlling wilt disease. To investigate the effect of intercropping under varying nitrogen levels on the incidence of faba bean wilt disease, nutrient uptake, and biochemical resistance in faba bean. Field and pot experiments were conducted in two cropping systems: faba bean monocropping (M) and faba bean-wheat intercropping (I). At four nitrogen levels, we assessed the incidence rate of wilt disease, quantified nutrient uptake, and evaluated biochemical resistance indices of plants. The application of N decreased the incidence rate of wilt disease, with the lowest reduction observed in intercropping at the N2 level. N application at levels N1, N2, and N3 enhanced the content of N, P, K, Fe, and Mn as well as superoxide dismutase (SOD), phenylalanine ammonia lyase (PAL), and polyphenol oxidase (PPO) activities and defense gene expression in monocultured plants. Additionally, these levels increased the contents of total phenols, flavonoids, soluble sugars, and soluble proteins, and all reached their maximum in intercropping at the N2 level. The application of intercropping and N effectively controlled the occurrence of faba bean wilt disease by promoting nutrient absorption, alleviating peroxidation stress, and enhancing resistance in plants. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-024-01466-1.

A horizontal and perpendicular interlaminar approach for intrathecal nusinersen injection in patients with spinal muscular atrophy and scoliosis: an observational study.

BACKGROUND: Lumbar puncture is challenging for patients with scoliosis. Previous ultrasound-assisted techniques for lumbar puncture used the angle of the probe as the needle trajectory; however, reproducing the angle is difficult and increases the number of needle manipulations. In response, we developed a technique that eliminated both the craniocaudal and lateromedial angulation of the needle trajectory to overall improve this technique. We assessed the feasibility and safety of this method in patients with scoliosis and identify factors related to difficult lumbar puncture. METHODS: Patients with spinal muscular atrophy and scoliosis who were referred to the anesthesia department for intrathecal nusinersen administrations were included. With a novel approach that utilized patient position and geometry, lumbar puncture was performed under ultrasound guidance. Success rates, performance times and adverse events were recorded. Clinical-demographic and spinal radiographic data pertaining to difficult procedures were analyzed. RESULTS: Success was achieved in all 260 (100%) lumbar punctures for 44 patients, with first pass and first attempt success rates of 70% (183/260) and 87% (226/260), respectively. Adverse events were infrequent and benign. Higher BMI, greater skin dural sac depth and smaller interlaminar size might be associated with greater difficulty in lumbar puncture. CONCLUSIONS: The novel ultrasound-assisted horizontal and perpendicular interlaminar needle trajectory approach is an effective and safe method for lumbar puncture in patients with spinal deformities. This method can be reliably performed at the bedside and avoids other more typical and complex imaging such as computed tomography guided procedure.

Intrauterine exposure to long-chain perfluorocarboxylic acids (PFCAs) were associated with reduced primary bile acids in three-year-old children: Findings from a prospective birth cohort study.

Bile acids (BAs) play a crucial role in lipid metabolism of children. However, the association between per- and polyfluoroalkyl substance (PFAS) exposure and BAs in children is scarce. To address this need, we selected 252 children from the Maoming Birth Cohort and measured 32 PFAS, encompassing short- and long-chain perfluorocarboxylic acids (PFCAs) and perfluorosulfonic acids (PFSAs) in the cord blood. Additionally, we analyzed nine primary and eight secondary BAs in the serum of three-year-old children. Generalized linear models with FDR-adjusted and Bayesian kernel machine regression (BKMR) were used to explore the associations of individual and mixture effects of PFAS and BAs. We found negative associations between cord blood long-chain PFCAs exposure and serum primary BAs in three-year-old children. For example, one ln-unit (ng/mL) increase of perfluoro-n-tridecanoic acid (PFTrDA), perfluoro-n-undecanoic acid (PFUnDA) and perfluoro-n-decanoic acid (PFDA) were associated with decreased taurochenodeoxycholic acid, with estimated percentage change of -24.28% [95% confidence interval (CI): -36.75%, -9.35%], -25.84% (95% CI: -39.67%, -8.83%), and -22.97% (95% CI: -34.45%, -9.47%) respectively. Notably, the observed associations were more pronounced in children with lower vegetable intake. Additionally, the BKMR model also demonstrated a monotonical decline in primary BAs as the PFAS mixture increased. We provided the first evidence of the association between intrauterine exposure to PFAS and its mixture with BAs in children. Further large-sample-size studies are needed to verify this finding.

Fourteen-Day Tegoprazan-Amoxicillin Dual Therapy as the First-Line Treatment of Helicobacter pylori Infection (SHARE2301): A Multicenter, Noninferiority, Randomized Clinical Trial.

BACKGROUND: Potassium-competitive acid blockers have demonstrated enormous potential in the eradication treatment of Helicobacter pylori infection, with tegoprazan being one of the representatives. The available data on the safety and efficacy of tegoprazan in dual therapy are limited. MATERIALS AND METHODS: The multicenter, noninferiority, randomized-controlled trial was conducted from May 2023 to March 2024. Treatment-naive subjects were randomly assigned (1:1) to enter either the tegoprazan-amoxicillin (TA) group (tegoprazan 50 mg twice daily and amoxicillin 750 mg four times daily) or the esomeprazole-amoxicillin (EA) group (esomeprazole 20 mg and amoxicillin 750 mg all four times daily), with a duration for 14 days. The primary outcome was eradication rate as determined by 13C-urea breath test, including per-protocol (PP) analysis and intention-to-treat (ITT) analysis. Secondary outcomes were adverse events and compliance. RESULTS: A total of 368 individuals were included in the randomization. The eradication rates in the EA group and the TA group were 84.2% and 85.8%, respectively, according to an ITT analysis (p = 0.77), and 88.5% and 88.2%, respectively, according to PP analysis (p = 1.00). The eradication rates for the TA group were not inferior to those of the EA group in both PP (p = 0.0023) and ITT analyses (p = 0.0009). There were no significant statistical differences in the incidence of adverse events and compliance between the two groups. The multivariate logistic regression analysis revealed that poor compliance increased the risk of eradication failure (p < 0.001). CONCLUSIONS: Dual therapy containing tegoprazan is safe and effective to be considered as a clinical first-line treatment option, but further optimization involving antimicrobial susceptibility testing and adjustments in dosage and frequency is warranted. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT05870683.

Causal relationships between gut microbiota, gut metabolites, and diabetic neuropathy: A mendelian randomization study.

BACKGROUND: Previous studies have shown a strong correlation between gut microbiota and diabetes and its associated complications. We aimed to evaluate the causal relationships between the gut microbiota, gut metabolites, and diabetic neuropathy. METHODS: Summary statistics of 211 gut microbiota and 12 gut-related metabolites (ß-hydroxybutyric acid, betaine, trimethylamine-N-oxide, carnitine, choline, glutamate, kynurenine, phenylalanine, propionic acid, serotonin, tryptophan, and tyrosine) were obtained from previous genome-wide association studies (GWAS). A two-sample Mendelian randomization (MR) design was used to estimate the effects of gut microbiota and gut metabolites on the risk of diabetic neuropathy based on FinnGen GWAS. RESULTS: Higher levels of Acidaminococcaceae (OR = 0.62; 95%CI = 0.46 to 0.84; P = 0.002), Peptococcaceae (OR = 0.70; 95%CI = 0.54 to 0.90; P = 0.006), and Eubacterium coprostanoligenes group (OR = 0.68; 95%CI = 0.50 to 0.93; P = 0.016) are genetically determined to provide protection against diabetic neuropathy. Conversely, the presence of Alistipes (OR = 1.65; 95%CI = 1.18 to 2.31; P = 0.003), ChristensenellaceaeR7 group (OR = 1.52; 95%CI = 1.03 to 2.23; P = 0.033), Eggerthella (OR = 1.28; 95%CI = 1.05 to 1.55; P = 0.014), RuminococcaceaeUCG013 (OR = 1.35; 95%CI = 1.01 to 1.82; P = 0.046), and Firmicutes (OR = 1.42; 95%CI = 1.05 to 1.93; P = 0.023) increases the risk of diabetic neuropathy. Moreover, a correlation has been identified between diabetic neuropathy and two gut metabolites: betaine (OR = 0.95; 95%CI = 0.90 to 1.00; P = 0.033) and tyrosine (OR = 1.03; 95%CI = 1.01 to 1.06; P = 0.019). Sensitivity analysis indicated robust results with no sign of heterogeneity or pleiotropy. CONCLUSION: The present study elucidated the impact of specific gut microbiota and gut metabolites on the susceptibility to diabetic neuropathy. Interventions targeting the improvement of the gut microbiota diversity and composition hold considerable promise as a potential strategy.

Liver injury associated with endothelin receptor antagonists: a pharmacovigilance study based on FDA adverse event reporting system data.

BACKGROUND: Endothelin receptor antagonists are commonly used in clinical practice, with concerns about their hepatotoxicity. AIM: This study aimed to conduct a comprehensive pharmacovigilance study based on FDA adverse event reporting system data to evaluate the possible association between endothelin receptor antagonists and drug-induced liver injury. METHOD: Adverse event reports from FDA adverse event reporting system between January 2004 and December 2022 were analyzed. Disproportionality algorithms, including reporting odds ratio and information component, were used to evaluate the association between endothelin receptor antagonists and liver injury. Sex- and age-stratified analyses of drug-induced liver injury events were also conducted in relation to endothelin receptor antagonists. RESULTS: Significant associations between bosentan, macitentan, and liver injury were identified. Bosentan showed a strong link with liver injury, with reporting odds ratios for cholestatic injury at 7.59 (95% confidence interval: 6.90-8.35), hepatocellular injury at 5.63 (5.29-6.00), and serious drug-related hepatic disorders events at 1.33 (1.24-1.43). Drug-induced liver injury signals associated with bosentan were detected in all age groups. Macitentan was associated with liver injury, with reporting odds ratios for hepatic failure at 1.64 (1.39-1.94), cholestatic injury at 1.62 (1.43-1.83), and serious drug-related hepatic disorders events at 1.40 (1.29-1.51). No drug-induced liver injury signal was detected for ambrisentan, and no significant sex differences were observed in drug-induced liver injury events. CONCLUSION: Both bosentan and macitentan are associated with liver injury. Routine monitoring of serum aminotransferase levels is recommended, especially in patients at higher risk of liver injury. Further research into drug-drug interactions involving endothelin receptor antagonists is warranted.

A Zn(II) Coordination Polymer for Fluorescent Turn-Off Selective Sensing of Heavy Metal Cation and Toxic Inorganic Anions.

A novel coordination polymer [Zn(atyha)2]n (1) (Hatyha = 2-(2-aminothiazole-4-yl)-2- hydroxyiminoacetic acid) was constructed by hydrothermal reaction of Zn2+ with Hatyha ligand. CP 1 exhibits a 2D (4,4)-connected topological framework with Schläfli symbol of {44·62}, where atyha- anions serve as tridentate ligands, bridging with Zn2+ through carboxylate, thiazole and oxime groups. CP 1 displays a strong ligand-based photoluminescence at 390 nm in the solid state, and remains significantly structurally stable in water. Interestingly, it can be utilized as a fluorescent probe for selective and sensitive sensing of Fe3+, Cr2O72- and MnO4- through the fluorescent turn-off effect with limit of detection (LOD) of 3.66 × 10-6, 2.38 × 10-5 and 2.94 × 10-6 M, respectively. Moreover, the efficient recyclability for detection of Fe3+ and Cr2O72- is better than that for MnO4-. The mechanisms of fluorescent quenching involve reversible overlap of UV-Vis absorption bands of the analytes (Fe3+, Cr2O72- and MnO4-) with fluorescence excitation and emission bands for CP 1, respectively.

Localized, highly efficient secretion of signaling proteins by migrasomes.

Migrasomes, enriched with signaling molecules such as chemokines, cytokines and angiogenic factors, play a pivotal role in the spatially defined delivery of these molecules, influencing critical physiological processes including organ morphogenesis and angiogenesis. The mechanism governing the accumulation of signaling molecules in migrasomes has been elusive. In this study, we show that secretory proteins, including signaling proteins, are transported into migrasomes by secretory carriers via both the constitutive and regulated secretion pathways. During cell migration, a substantial portion of these carriers is redirected to the rear of the cell and actively transported into migrasomes, driven by the actin-dependent motor protein Myosin-5a. Once at the migrasomes, these carriers fuse with the migrasome membrane through SNARE-mediated mechanisms. Inhibiting migrasome formation significantly reduces secretion, suggesting migrasomes as a principal secretion route in migrating cells. Our findings reveal a specialized, highly localized secretion paradigm in migrating cells, conceptually paralleling the targeted neurotransmitter release observed in neuronal systems.

Altered intersubject functional variability of brain white-matter in major depressive disorder and its association with gene expression profiles.

Major depressive disorder (MDD) is a clinically heterogeneous disorder. Its mechanism is still unknown. Although the altered intersubject variability in functional connectivity (IVFC) within gray-matter has been reported in MDD, the alterations to IVFC within white-matter (WM-IVFC) remain unknown. Based on the resting-state functional MRI data of discovery (145 MDD patients and 119 healthy controls [HCs]) and validation cohorts (54 MDD patients, and 78 HCs), we compared the WM-IVFC between the two groups. We further assessed the meta-analytic cognitive functions related to the alterations. The discriminant WM-IVFC values were used to classify MDD patients and predict clinical symptoms in patients. In combination with the Allen Human Brain Atlas, transcriptome-neuroimaging association analyses were further conducted to investigate gene expression profiles associated with WM-IVFC alterations in MDD, followed by a set of gene functional characteristic analyses. We found extensive WM-IVFC alterations in MDD compared to HCs, which were associated with multiple behavioral domains, including sensorimotor processes and higher-order functions. The discriminant WM-IVFC could not only effectively distinguish MDD patients from HCs with an area under curve ranging from 0.889 to 0.901 across three classifiers, but significantly predict depression severity (r = 0.575, p = 0.002) and suicide risk (r = 0.384, p = 0.040) in patients. Furthermore, the variability-related genes were enriched for synapse, neuronal system, and ion channel, and predominantly expressed in excitatory and inhibitory neurons. Our results obtained good reproducibility in the validation cohort. These findings revealed intersubject functional variability changes of brain WM in MDD and its linkage with gene expression profiles, providing potential implications for understanding the high clinical heterogeneity of MDD.

Exercise training modalities in prediabetes: a systematic review and network meta-analysis.

Background: Lifestyle modification based on exercise intervention is still the primary way to delay or reverse the development of diabetes in patients with prediabetes. However, there are still challenges in setting up a detailed exercise prescription for people with prediabetes. This study mainly ranks exercise prescriptions by comparing the improvement of glucose and lipid metabolism and the level of weight loss in patients. Method: All studies on exercise intervention in prediabetes were identified by searching five electronic databases. Risk assessment and meta-analysis were performed on eligible studies. Results: Twenty-four studies involving 1946 patients with prediabetes and seven exercise intervention models were included in the final analysis. The meta-analysis showed that exercise of any type was more effective for glycemic control in prediabetes than no exercise. However, the changes in blood glucose were moderate. In prediabetes, combining moderate-intensity aerobic exercise with low-to moderate-load resistance training showed the most significant improvements in glycosylated hemoglobin (HbA1c), body mass index (BMI), body weight (BW), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL) (P-score=0.82; 0.70; 0.87; 1; 0.99), low-to moderate-load resistance training showed the most significant improvements in fasting blood glucose (FBG) (P-score=0.98), the vigorous-intensity aerobic exercise showed the most significant improvements in 2-hour post-meal blood glucose (2hPG) and systolic blood pressure (SBP) (P-score=0.79; 0.78), and moderate-intensity aerobic exercise showed the most significant improvements in diastolic blood pressure (DBP) (P-score=0.78). Conclusion: In summary, moderate-intensity aerobic exercise, low-to moderate-load resistance training and the combination of both have beneficial effects on glycemic control, weight loss, and cardiovascular health in patients with prediabetes. These findings provide valuable guidance for rehabilitation clinicians and patients alike to follow. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD 42021284922.

Transcription factor KLF9 inhibits the proliferation, invasion, and migration of pancreatic cancer cells by repressing KIAA1522.

AIM: Pancreatic cancer (PC) has a poor prognosis and high mortality. Kruppel-like factor 9 (KLF9), a transcription factor, is aberrantly expressed in various neoplasms. The current study sought to analyze the functional role of KLF9 in the proliferation, invasion, and migration of PC cells. METHODS: The expression patterns of KLF9 and KIAA1522 in normal pancreatic cells (HPDE-C7) and PC cells (Panc 03.27, BxPc3, SW1990) were determined by real-time quantitative polymerase chain reaction and Western blot assay. After treatment of KLF9 overexpression, proliferation, invasion, and migration were evaluated by cell counting kit-8, 5-ethynyl-2'-deoxyuridine staining, and Transwell assays. The binding of KLF9 to the KIAA1522 promoter was analyzed by dual-luciferase assay and chromatin immunoprecipitation. The rescue experiment was conducted to analyze the role of KIAA1522. RESULTS: KLF9 was downregulated, while KIAA1522 was upregulated in PC cells. KLF9 overexpression mitigated the proliferation, invasion, and migration of PC cells. Enrichment of KLF9 led to inhibition of the KIAA1522 promoter and repressed KIAA1522 expression. KIAA1522 overexpression neutralized the inhibitory role of KLF9 in PC cell functions. CONCLUSION: KLF9 is enriched in the KIAA1522 promoter and negatively regulates KIAA1522 expression, thereby mitigating the proliferation, invasion, and migration of PC cells.

Progress of plant polyphenol extracts in treating depression by anti-neuroinflammatory mechanism: A review.

There is a growing body of evidence supporting the involvement of central nervous system inflammation in the pathophysiology of depression. Polyphenols are a diverse group of compounds known for their antioxidative and anti-inflammatory properties. They offer a promising and effective supplementary approach to alleviating neuropsychiatric symptoms associated with inflammation-induced depression. This paper provides a summary of the potential anti-neuroinflammatory mechanisms of plant polyphenol extracts against depression. This includes direct interference with inflammatory regulators and inhibition of the expression of pro-inflammatory cytokines. Additionally, it covers downregulating the expression of pro-inflammatory cytokines by altering protein kinases or affecting the activity of the signaling pathways that they activate. These pathways interfere with the conduction of signaling molecules, resulting in the destruction and reduced synthesis of all inflammatory mediators and cytokines. This reduces the apoptosis of neurons and plays a neuroprotective role. This paper provides a theoretical basis for the clinical application of plant polyphenols.