In vivo and in vitro study on the regulatory mechanism of XiaoChaiHu decoction on PANoptosis in sepsis-induced cardiomyopathy.

ETHNOPHARMACOLOGICAL RELEVANCE: In accordance with the tenets of traditional Chinese medicine, sepsis is categorized into three distinct syndromes: heat syndrome, blood stasis syndrome, and deficiency syndrome. Xiaochaihu decoction (XCHD) has many functions, including the capacity to protect the liver, cholagogue, antipyretic, anti-inflammatory, and anti-pathogenic microorganisms. XCHD exerts the effect of clearing heat and reconciling Shaoyang. The XCHD contains many efficacious active ingredients, yet the mechanism of sepsis-induced cardiomyopathy (SIC) remains elusive. AIM OF THE STUDY: To investigate the molecular mechanisms underlying the protective effects of XCHD against SIC using an integrated approach combining network pharmacology and molecular biology techniques. MATERIALS AND METHODS: Network pharmacology methods identified the active ingredients, target proteins, and pathways affected by XCHD in the context of SIC. We conducted in vivo experiments using mice with lipopolysaccharide-induced SIC, evaluating cardiac function through echocardiography and histology. XCHD-containing serum was analyzed to determine its principal active components using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The effects of XCHD-containing serum on SIC were further tested in vitro in LPS-treated H9c2 cardiac cells. Protein expression levels were quantified via Western blotting and enzyme-linked immunosorbent assay (ELISA). Additionally, molecular docking was performed between the active components and ZBP1, a potential target protein. Overexpression of ZBP1 in H9c2 cells allowed for a deeper exploration of its role in modulating SIC-associated gene expression. RESULTS: UPLC-MS/MS identified 31 shared XCHD and XCHD-containing serum components. These included organic acids, terpenoids, and flavonoids, which have been identified as the active components of XCHD. Our findings revealed that XCHD alleviated LPS-induced myocardial injury, improved cardiac function, and preserved cardiomyocyte morphology in mice. In vitro studies, we demonstrated that XCHD-containing serum significantly suppressed the expression of inflammatory cytokines (IL-6, IL-1ß, and TNF-α) in LPS-induced H9c2 cells. Mechanistic investigations showed that XCHD downregulated genes associated with PANoptosis, a novel cell death pathway, suggesting its protective role in sepsis-damaged hearts. Conversely, overexpression of ZBP1 abolished the protective effects of XCHD and amplified PANoptosis-related gene expression. CONCLUSIONS: Our study provides the first evidence supporting the protective effects of XCHD against SIC, both in vitro and in vivo. The underlying mechanism involves the inhibition of ZBP1-initiated PANoptosis, offering new insights into treating SIC using XCHD.

Metabolic evolution and bottleneck insights into simultaneous autotroph-heterotroph anammox system for real municipal wastewater nitrogen removal.

When biological nitrogen removal (BNR) systems shifted from treating simulated wastewater to real wastewater, a microbial succession occurred, often resulting in a decline in efficacy. Notably, despite their high nitrogen removal efficiency for real wastewater, anammox coupled systems operating without or with minimal carbon sources also exhibited a certain degree of performance reduction. The underlying reasons and metabolic shifts within these systems remained elusive. In this study, the simultaneous autotrophic/heterotrophic anammox system demonstrated remarkable metabolic resilience upon exposure to real municipal wastewater, achieving a nitrogen removal efficiency (NRE) of 82.83 ± 2.29 %. This resilience was attributed to the successful microbial succession and the complementary metabolic functions of heterotrophic microorganisms, which fostered a resilient microbial community. The system's ability to harness multiple electron sources, including NADH oxidation, the TCA cycle, and organics metabolism, allowed it to establish a stable and efficient electron transfer chain, ensuring effective nitrogen removal. Despite the denitrification channel's nitrite supply capability, the analysis of the interspecies correlation network revealed that the synergistic metabolism between AOB and AnAOB was not fully restored, resulting in selective functional bacterial and genetic interactions and the system's PN/A performance declined. Additionally, the enhanced electron affinity of PD increased interconversion of NO3--N and NO2--N, limiting the efficient utilization of electrons and thereby constraining nitrogen removal performance. This study elucidated the metabolic mechanism of nitrogen removal limitations in anammox-based systems treating real municipal wastewater, enhancing our understanding of the metabolic functions and electron transfer within the symbiotic bacterial community.

Non-linear relationship between TyG index and the risk of prediabetes in young people: a 5-year retrospective cohort study in Chinese young adults.

Objective: Given the limited evidence on the relationship between the triglyceride-glucose (TyG) index and the risk of prediabetes among young adults, our study aimed to investigate the potential impact of the TyG index on the future development of prediabetes in young individuals. Methods: This retrospective cohort study included 125,327 healthy adults aged 20 to 45 years. We utilized Cox proportional hazards regression models, combined with cubic spline functions and smooth curve fitting, to assess the relationship between baseline TyG index and the risk of prediabetes among young adults, exploring its non-linear association. A series of sensitivity analyses and subgroup analyses were conducted to ensure the robustness of our findings. Results: After adjusting for covariates, the study found a positive correlation between the TyG index and the risk of prediabetes (HR=1.81, 95%CI: 1.54-2.13, p<0.0001). The risk of prediabetes increased progressively across quartiles of the TyG index (Q1 to Q4), with Q4 showing a significantly higher risk compared to Q1 (adjusted HR=2.33, 95% CI=1.72-3.16). Moreover, a non-linear relationship was identified between the TyG index and the risk of prediabetes, with an inflection point at 9.39. To the left of the inflection point, the HR was 2.04 (95% CI: 1.69 to 2.46), while to the right, the HR was 0.89 (95% CI: 0.48 to 1.65). Conclusion: Our study reveals a non-linear relationship and a saturation effect between the TyG index and the development of prediabetes among young individuals in China, with an inflection point at 9.39. Understanding this non-linear relationship can assist clinicians in identifying young individuals at high risk and implementing targeted interventions to reduce their risk of progressing to diabetes.

Arginine on immune function and post-operative obstructions in colorectal cancer patients: a meta-analysis.

BACKGROUND: The aim of this study is to investigate the impact of arginine on immune function and postoperative complications in colorectal cancer (CRC) patients. METHODS: We conducted a comprehensive search to identify eligible RCTs in various databases, such as PubMed, Cochrane Library, EMBASE, Web of Science, MEDLINE, China National Knowledge Infrastructure (CNKI), Wanfang, VIP Medicine Information System (VIP), and Chinese Biomedical Database (CBM). This study aimed to examine IgA, IgG, and IgM levels as well as CD4+ and CD8+ counts as well as the CD4+/CD8+ ratio. Anastomotic leaking, length of stay (LOS), and surgical site infection (SSI) were included as secondary outcomes. Stata (StataCorp, version 14.0) was utilized for data analysis. To ensure the results were reliable, we used meta-regression, sensitivity analysis, and publication bias analysis. RESULTS: A total of 24 publications (including 1883 patients) out of 681 that were retrieved fulfilled the inclusion criteria. The arginine group showed notable improvements in humoral immunity, with gains in IgA (SMD=0.45, 95% CI: 0.30-0.60), IgG (SMD=0.80, 95% CI: 0.64-0.96), and IgM (SMD=0.66, 95% CI: 0.39-0.93). With regards to cellular immunity, the arginine group exhibited a substantial increase in the CD4+ T cell count (SMD = 1.03, 95% CI: 0.67-1.38) compared to the control group. However, the CD4+/CD8+ ratio decreased significantly (SMD=1.37, 95% CI: 0.88-1.86) in the same arginine group, indicating a change in the balance between these two cell types. Additionally, the CD8+ T cell count showed a notable decrease (SMD=-0.70, 95% CI: -1.09 to -0.32) in the arginine group when compared to the control group. Anastomotic leakage was also considerably lower in the arginine group (SMD=-0.05, 95% CI: -0.08 to -0.02), the rate of SSIs was lower (RR = -0.02, 95% CI: -0.05-0), and the length of time patients spent in the hospital was shorter (SMD=-0.15, 95% CI: -0.38 to -0.08). CONCLUSIONS: After radiation treatment for CRC, arginine improves immune function and decreases the risk of infection problems. TRIAL REGISTRATION: Registration with PROSPERO for this meta-analysis is number CRD42024520509.

Urolithin a Improves Motor Dysfunction Induced by Copper Exposure in SOD1G93A Transgenic Mice Via Activation of Mitophagy.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease pathologically characterized by selective degeneration of motor neurons resulting in a catastrophic loss of motor function. The present study aimed to investigate the effect of copper (Cu) exposure on progression of ALS and explore the therapeutic effect and mechanism of Urolithin A (UA) on ALS. 0.13 PPM copper chloride drinking water was administrated in SOD1G93A transgenic mice at 6 weeks, UA at a dosage of 50 mg/kg/day was given for 6 weeks after a 7-week Cu exposure. Motor ability was assessed before terminal anesthesia. Muscle atrophy and fibrosis, motor neurons, astrocytes and microglia in the spinal cord were evaluated by H&E, Masson, Sirius Red, Nissl and Immunohistochemistry Staining. Proteomics analysis, Western blotting and ELISA were conducted to detect protein expression. Mitochondrial adenosine triphosphate (ATP) and malondialdehyde (MDA) levels were measured using an assay kit. Cu-exposure worsened motor function, promoted muscle fibrosis, loss of motor neurons, and astrocyte and microglial activation. It also induced abnormal changes in mitochondria-related biological processes, leading to a significant reduction in ATP levels and an increase in MDA levels. Upregulation of P62 and downregulation of Parkin, PINK1, and LAMP1 were revealed in SOD1G93A mice with Cu exposure. Administration of UA activated mitophagy, modulated mitochondria dysfunction, reduced neuroinflammation, and improved gastrocnemius muscle atrophy and motor dysfunction in SOD1G93A mice with Cu exposure. Mitophagy plays critical role in ALS exacerbated by Cu exposure. UA administration may be a promising treatment strategy for ALS.

Gastrointestinal tract organoids as novel tools in drug discovery.

Organoids, characterized by their high physiological attributes, effectively preserve the genetic characteristics, physiological structure, and function of the simulated organs. Since the inception of small intestine organoids, other organoids for organs including the liver, lungs, stomach, and pancreas have subsequently been developed. However, a comprehensive summary and discussion of research findings on gastrointestinal tract (GIT) organoids as disease models and drug screening platforms is currently lacking. Herein, in this review, we address diseases related to GIT organoid simulation and highlight the notable advancements that have been made in drug screening and pharmacokinetics, as well as in disease research and treatment using GIT organoids. Organoids of GIT diseases, including inflammatory bowel disease, irritable bowel syndrome, necrotizing enterocolitis, and Helicobacter pylori infection, have been successfully constructed. These models have facilitated the study of the mechanisms and effects of various drugs, such as metformin, Schisandrin C, and prednisolone, in these diseases. Furthermore, GIT organoids have been used to investigate viruses that elicit GIT reactions, including Norovirus, SARS-CoV-2, and rotavirus. Previous studies by using GIT organoids have shown that dasabuvir, gemcitabine, and imatinib possess the capability to inhibit viral replication. Notably, GIT organoids can mimic GIT responses to therapeutic drugs at the onset of disease. The GIT toxicities of compounds like gefitinib, doxorubicin, and sunset yellow have also been evaluated. Additionally, these organoids are instrumental for the study of immune regulation, post-radiation intestinal epithelial repair, treatment for cystic fibrosis and diabetes, the development of novel drug delivery systems, and research into the GIT microbiome. The recent use of conditioned media as a culture method for replacing recombinant hepatocyte growth factor has significantly reduced the cost associated with human GIT organoid culture. This advancement paves the way for large-scale culture and compound screening of GIT organoids. Despite the ongoing challenges in GIT organoid development (e.g., their inability to exist in pairs, limited cell types, and singular drug exposure mode), these organoids hold considerable potential for drug screening. The use of GIT organoids in this context holds great promises to enhance the precision of medical treatments for patients living with GIT diseases.

A Clinically Immersive Medical Innovation Program for US MD Students: Curricular Description and Program Outcomes.

Background: There is growing need for physician-innovators to address the mounting challenges within the US healthcare system. Despite this, there remains a significant gap in understanding of the efficacy of innovation programs for US MD candidates. We present initial program outcomes of a novel, clinically immersive medical innovation program offered to MD candidates at the David Geffen School of Medicine (DGSOM) at UCLA. Methods: A novel clinically immersive medical innovation curriculum was developed based on existing and reputable medical innovation frameworks and tailored for medical students. Curricular topics broadly included clinical ethnography, interviewing techniques, mind mapping, needs formulation and prioritization, quality improvement, intellectual property, reimbursement pathways, solution landscaping and prioritization, regulatory processes. The program was trialed during an unscheduled summer with voluntary enrollees from DGSOM Class of 2024. The traditional four-level Kirkpatrick model was employed to assess program outcomes. Results: Program outcomes were positive on all four Kirkpatrick levels. Students rated enjoyment at 9.5/10 for lectures and 9.1/10 for clinical immersion. Student-perceived confidence in key skills increased by 43%, and 75% of faculty directly perceived improvement in ethnographic skills. Students were highly engaged in both didactics and clinical immersion, discovering on average 2.6 faculty-verified needs per week. Faculty largely felt their students discovered important unmet clinical needs and added value to their clinical practice. Conclusion: We developed and trialed a novel clinically immersive medical innovation curriculum tailored for medical students. This program achieved positive outcomes on all four levels of the Kirkpatrick model. Our findings have driven the local adoption of this program into our institution's medical school curriculum. We hope that the program efficacy demonstrated herein catalyzes more institutions to trial similar medical innovation programs.

We conducted this investigation after recent literature identified a significant gap in our understanding of the role of innovation and entrepreneurship (I&E) programs in the United States (US) medical education. I&E programs are meant to teach the skills necessary to identify and assess ongoing challenges in health care and subsequently formulate a solution for such challenges. The rate of adoption of I&E programs into US medical education has been unexplainably slow, despite a strong reported interest among medical students in learning the associated topics. We sought to answer the question: how effectively can an I&E curriculum be integrated into the traditional US medical doctorate (M.D). curriculum? We designed a novel medical innovation program tailored for medical students and offered this six-week program to 16 M.D. candidates at UCLA during an unscheduled summer. By describing the curriculum in detail and presenting our holistic assessment of program outcomes including learners' feeling, learnings, transference of knowledge, and the program's real-world impact, we demonstrate methods by which medical innovation can effectively be taught to medical students and the impact this may have on our future physician workforce. Our implementation of a quality improvement conceptual framework examining multiple process measures enabled iterative and real-time improvement of the program throughout its offering. Our surveys were administered at regular intervals through the course, thereby allowing iterative feedback from enrolled students to drive course improvement, similar to how quality improvement frameworks incrementally improve outcomes through closed-loop feedback in health care settings. We posit that analogous medical innovation curricula should be increasingly integrated into MD curricula more broadly.

Sexual and Gender-Diverse Individuals Face More Health Challenges during COVID-19: A Large-Scale Social Media Analysis with Natural Language Processing.

Background: The COVID-19 pandemic has caused a disproportionate impact on the sexual and gender-diverse (SGD) community. Compared with non-SGD populations, their social relations and health status are more vulnerable, whereas public health data regarding SGD are scarce. Methods: To analyze the concerns and health status of SGD individuals, this cohort study leveraged 471,371,477 tweets from 251,455 SGD and 22,644,411 non-SGD users, spanning from 2020 February 1 to 2022 April 30. The outcome measures comprised the distribution and dynamics of COVID-related topics, attitudes toward vaccines, and the prevalence of symptoms. Results: Topic analysis revealed that SGD users engaged more frequently in discussions related to "friends and family" (20.5% vs. 13.1%, P < 0.001) and "wear masks" (10.1% vs. 8.3%, P < 0.001) compared to non-SGD users. Additionally, SGD users exhibited a marked higher proportion of positive sentiment in tweets about vaccines, including Moderna, Pfizer, AstraZeneca, and Johnson & Johnson. Among 102,464 users who self-reported COVID-19 diagnoses, SGD users disclosed significantly higher frequencies of mentioning 61 out of 69 COVID-related symptoms than non-SGD users, encompassing both physical and mental health challenges. Conclusion: The results provide insights into an understanding of the unique needs and experiences of the SGD community during the pandemic, emphasizing the value of social media data in epidemiological and public health research.

Bioactive Nb2C MXene-Functionalized Hydrogel with Microenvironment Remodeling and Enhanced Neurogenesis to Promote Skeletal Muscle Regeneration and Functional Restoration.

The complete structure-functional repair of volumetric muscle loss (VML) remains a giant challenge and biomedical hydrogels to remodel microenvironment and enhance neurogenesis have appeared to be a promising direction. However, the current hydrogels for VML repair hardly achieve these two goals simultaneously due to their insufficient functionality and the challenge in high-cost of bioactive factors. In this study, a facile strategy using Nb2C MXene-functionalized hydrogel (OPTN) as a bioactive scaffold is proposed to promote VML repair with skeletal muscle regeneration and functional restoration. In vitro experiments show that OPTN scaffold can effectively scavenge reactive oxygen species (ROS), guide macrophages polarization toward M2 phenotype, and resist bacterial infection, providing a favorable microenvironment for myoblasts proliferation as well as the endothelial cells proliferation, migration, and tube formation. More importantly, OPTN scaffold with electroactive feature remarkably boosts myoblasts differentiation and mesenchymal stem cells neural differentiation. Animal experiments further confirm that OPTN scaffold can achieve a prominent structure-functional VML repair by attenuating ROS levels, alleviating inflammation, reducing fibrosis, and facilitating angiogenesis, newborn myotube formation, and neurogenesis. Collectively, this study provides a highly promising and effective strategy for the structure-functional VML repair through designing bioactive multifunctional hydrogel with microenvironment remodeling and enhanced neurogenesis.

Generative Large Language Models in Electronic Health Records for Patient Care Since 2023: A Systematic Review.

BACKGROUND: Generative Large language models (LLMs) represent a significant advancement in natural language processing, achieving state-of-the-art performance across various tasks. However, their application in clinical settings using real electronic health records (EHRs) is still rare and presents numerous challenges. OBJECTIVE: This study aims to systematically review the use of generative LLMs, and the effectiveness of relevant techniques in patient care-related topics involving EHRs, summarize the challenges faced, and suggest future directions. METHODS: A Boolean search for peer-reviewed articles was conducted on May 19th, 2024 using PubMed and Web of Science to include research articles published since 2023, which was one month after the release of ChatGPT. The search results were deduplicated. Multiple reviewers, including biomedical informaticians, computer scientists, and a physician, screened the publications for eligibility and conducted data extraction. Only studies utilizing generative LLMs to analyze real EHR data were included. We summarized the use of prompt engineering, fine-tuning, multimodal EHR data, and evaluation matrices. Additionally, we identified current challenges in applying LLMs in clinical settings as reported by the included studies and proposed future directions. RESULTS: The initial search identified 6,328 unique studies, with 76 studies included after eligibility screening. Of these, 67 studies (88.2%) employed zero-shot prompting, five of them reported 100% accuracy on five specific clinical tasks. Nine studies used advanced prompting strategies; four tested these strategies experimentally, finding that prompt engineering improved performance, with one study noting a non-linear relationship between the number of examples in a prompt and performance improvement. Eight studies explored fine-tuning generative LLMs, all reported performance improvements on specific tasks, but three of them noted potential performance degradation after fine-tuning on certain tasks. Only two studies utilized multimodal data, which improved LLM-based decision-making and enabled accurate rare disease diagnosis and prognosis. The studies employed 55 different evaluation metrics for 22 purposes, such as correctness, completeness, and conciseness. Two studies investigated LLM bias, with one detecting no bias and the other finding that male patients received more appropriate clinical decision-making suggestions. Six studies identified hallucinations, such as fabricating patient names in structured thyroid ultrasound reports. Additional challenges included but were not limited to the impersonal tone of LLM consultations, which made patients uncomfortable, and the difficulty patients had in understanding LLM responses. CONCLUSION: Our review indicates that few studies have employed advanced computational techniques to enhance LLM performance. The diverse evaluation metrics used highlight the need for standardization. LLMs currently cannot replace physicians due to challenges such as bias, hallucinations, and impersonal responses.

CircSMAD3 represses VSMC phenotype switching and neointima formation via promoting hnRNPA1 ubiquitination degradation.

Circular RNAs (circRNAs) are novel regulatory RNAs with high evolutionary conservation and stability, which makes them effective therapeutic agents for various vascular diseases. The SMAD family is a downstream mediator of the canonical transforming growth factor beta (TGF-ß) signalling pathway and has been considered as a critical regulator in vascular injury. However, the role of circRNAs derived from the SMAD family members in vascular physiology remains unclear. In this study, we initially identified potential functional circRNAs originating from the SMAD family using integrated transcriptome screening. circSMAD3, derived from the SMAD3 gene, was identified to be significantly downregulated in vascular injury and atherosclerosis. Transcriptome analysis was conducted to comprehensively illustrate the pathways modulated by circRNAs. Functionally, circSMAD3 repressed vascular smooth muscle cell (VSMC) proliferation and phenotype switching in vitro evidenced by morphological assays, and ameliorated arterial injury-induced neointima formation in vivo. Mechanistically, circSMAD3 interacted with heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) within the nucleus, enhanced its interaction with E3 ligase WD repeat domain 76 to promote hnRNPA1 ubiquitination degradation, facilitated p53 pre-RNA splicing, activated the p53γ signalling pathway, and finally suppressed VSMC proliferation and phenotype switching. Our study identifies circSMAD3 as a novel epigenetic regulator that suppresses VSMC proliferation and phenotype switching, thereby attenuating vascular remodelling and providing a new circRNA-based therapeutic strategy for cardiovascular diseases.

Mitigating the Kinetic Hysteresis of Co-free Ni-rich Cathodes via Gradient Penetration of Nonmagnetic Silicon.

Co-free Ni-rich layered oxides are considered a promising cathode material for next-generation Li-ion batteries due to their cost-effectiveness and high capacity. However, they still suffer from the practical challenges of low discharge capacity and poor rate capability due to the hysteresis of Li-ion diffusion kinetics. Herein, based on the regulation of the lattice magnetic frustration, the Li/Ni intermixing defects as the primary origin of kinetic hysteresis are radically addressed via the doping of the nonmagnetic Si element. Meanwhile, by adopting gradient penetration doping, a robust Si-O surface structure with reversible lattice oxygen evolution and low lattice strain is constructed on Co-free Ni-rich cathodes to suppress the formation of surface dense  barrier layer. With the remarkably enhanced Li-ion diffusion kinetics in atomic and electrode particle scales, the as-obtained cathodes (LiNixMn1-xSi0.01O2, 0.6 ≤ x ≤ 0.9) achieve superior performance in discharge capacity, rate capability, and durability. This work highlights the coupling effect of magnetic structure and interfacial chemicals on Li-ion transport properties, and the concept will inspire more researchers to conduct an intensive study.

Effect of irisin on ovarian phosphatidylinositol-3-kinase/protein kinase B signaling pathway and mitogen-activated protein kinase/extracellular signal-regulated kinase pathways of rats with polycystic ovary syndrome.

OBJECTIVE: To investigate the independent effects of irisin on insulin resistance (IR) in ovary of polycystic ovary syndrome (PCOS) and explore possible pathways. METHODS: We established PCOS medel using Poretsky L's method, then PCOS rats were randomly divided into model group (M) and irisin group (I), and normal rats (N) were used as the control. Then rats in the group I were injected with recombinant irisin. Then the levels of circulating fasting blood glucose (FBG), fasting insulin (FINS), homeostasis model assessment of IR (HOMA-IR) and PI3K/AKT and MAPK/ERK pathways in each group were observed, as well as the effects of irisin on the levels of circulating HOMA-IR and PI3K/AKT and MAPK/ERK pathways in ovary of PCOS rats were evaluated. RESULTS: Compared with normal group, levels of FBG, FINS, and HOMA-IR of model group were significantly increased (p < 0.001, p < 0.001, and p < 0.001, respectively), levels of average optical density by IHC of p-PI3K, PI3K, p-AKT, and AKT (p = 0.015, p = 0.010, p = 0.005, and p = 0.009, respectively) and levels of mRNA concentration of PI3K and AKT (p = 0.001, and p = 0.005, respectively) were decreased, while the levels of average optical density of p-ERK, ERK (p = 0.011, and p = 0.013, respectively) and level of mRNA concentration of ERK (p < 0.001) were increased in ovary. After irisin intervention, compared with model group, levels of FBG, FINS, and HOMA-IR of rats in irisin group were significantly decreased (p = 0.001, p < 0.001, and p < 0.001, respectively), levels of average optical density by IHC of p-PI3K, PI3K, p-AKT, and AKT (p = 0.030, p = 0.024, p = 0.012, and p = 0.025, respectively) and levels of mRNA concentration of PI3K and AKT (p = 0.002, and p = 0.003, respectively) were significantly increased, while the levels of average optical density of p-ERK, ERK (p = 0.004, and p = 0.026, respectively) and level of mRNA concentration of ERK (p = 0.001) were significantly decreased. CONCLUSION: Our study demonstrated that irisin could not only improve circulating insulin resistance, but may also improve ovarian IR through an increase in the activity of PI3K/AKT signaling and a decrease of MAPK/ERK signaling.

The application value of Rs-fMRI-based machine learning models for differentiating mild cognitive impairment from Alzheimer's disease: a systematic review and meta-analysis.

BACKGROUND: Various machine learning (ML) models based on resting-state functional MRI (Rs-fMRI) have been developed to facilitate differential diagnosis of mild cognitive impairment (MCI) and Alzheimer's disease (AD). However, the diagnostic accuracy of such models remains understudied. Therefore, we conducted this systematic review and meta-analysis to explore the diagnostic accuracy of Rs-fMRI-based radiomics in differentiating MCI from AD. METHODS: PubMed, Embase, Cochrane, and Web of Science were searched from inception up to February 8, 2024, to identify relevant studies. Meta-analysis was conducted using a bivariate mixed-effects model, and sub-group analyses were carried out by the types of ML tasks (binary classification and multi-class classification tasks). FINDINGS: In total, 23 studies, comprising 5,554 participants were enrolled in the study. In the binary classification tasks (twenty studies), the diagnostic accuracy of the ML model for AD was 0.99 (95%CI: 0.34 ~ 1.00), with a sensitivity of 0.94 (95%CI: 0.89 ~ 0.97) and a specificity of 0.98 (95%CI: 0.95 ~ 1.00). In the multi-class classification tasks (six studies), the diagnostic accuracy of the ML model was 0.98 (95%CI: 0.98 ~ 0.99) for NC, 0.96 (95%CI: 0.96 ~ 0.96) for early mild cognitive impairment (EMCI), 0.97 (95%CI: 0.96 ~ 0.97) for late mild cognitive impairment (LMCI), and 0.95 (95%CI: 0.95 ~ 0.95) for AD. CONCLUSIONS: The Rs-fMRI-based ML model can be adapted to multi-class classification tasks. Therefore, multi-center studies with large samples are needed to develop intelligent application tools to promote the development of intelligent ML models for disease diagnosis.

The siEGFR nanoplexes for the enhanced brain glioma treatment: Endoplasmic reticulum biomimetic strategy to induce homing effect and non-degradable intracellular transport.

The epidermal growth factor receptor (EGFR) plays a pivotal role in tumor progression and is an essential therapeutic target for treating malignant gliomas. Small interfering RNA (siRNA) has the potential to selectively degrade EGFR mRNA, yet its clinical utilization is impeded by various challenges, such as inefficient targeting and limited escape from lysosomes. Our research introduces polyethylene glycol (PEG) and endoplasmic reticulum membrane-coated siEGFR nanoplexes (PEhCv/siEGFR NPs) as an innovative approach to brain glioma therapy by overcoming several obstacles: 1) Tumor-derived endoplasmic reticulum membrane modifications provide a homing effect, facilitating targeted accumulation and cellular uptake; 2) Endoplasmic reticulum membrane proteins mediate a non-degradable "endosome-Golgi-endoplasmic reticulum" transport pathway, circumventing lysosomal degradation. These nanoplexes demonstrated significantly enhanced siEGFR gene silencing in both in vitro and in vivo U87 glioma models. The findings of this study pave the way for the advanced design and effective application of nucleic acid-based therapeutic nanocarriers.

Tislelizumab for treatment of a pediatric patient with primary mediastinal choriocarcinoma: a case report.

Background: Primary mediastinal choriocarcinoma (PCC) is a rare, highly vascular invasive, and prognostically unfavorable malignant tumor. When occurring outside the gonads, primary choriocarcinoma is commonly found in midline locations such as the mediastinum or retroperitoneum. Currently, there is no standardized treatment strategy for PCC. In the case reported herein, we employed tislelizumab and chemotherapy in the treatment of a patient with PCC, and as in March 2024, the patient remained survive. Case Description: A 15-year-old boy who presented with symptoms of fever and cough for a year. Chest computed tomography (CT) scan showed a relatively large soft tissue shadow in the right upper anterior mediastinum, measuring approximately 5.4 cm × 3.8 cm. The patient's soft tissue exhibited unclear demarcation from surrounding mediastinal structures and was accompanied by lung metastasis. The patient underwent a fine needle aspiration biopsy for a mediastinal mass, and the pathology results indicated a germ cell tumor with solid malignant components in the mediastinum, along with pulmonary metastasis of the solid malignancy. The patient's serum levels of beta-human chorionic gonadotropin (ß-HCG) were elevated at 125,554 mIU/mL (normal range: <5 mIU/mL), and alpha-fetoprotein (AFP) was 75.8 ng/mL (normal range, 0.605-7 ng/mL). The patient's cranial magnetic resonance imaging (MRI) plain scan indicated multiple scattered abnormal signals in both cerebral hemispheres. Subsequently, the patient was transferred to Children's Hospital of Nanjing Medical University for his further treatment. During the treatment period, we employed various therapeutic approaches, including chemotherapy, radiotherapy and tislelizumab therapy. After five cycles of tislelizumab treatment, the patient's symptoms of cerebral edema significantly improved, ß-HCG levels decreased. Brain MRI of the patient revealed multiple abnormal signals within the skull, with some lesions showing reduction in size and significant improvement in the surrounding edema zones. The clinical symptoms of the patient improved and he achieved partial remission (PR). At the moment, the patient is living with the disease. Conclusions: The effectiveness of chemotherapy for PCC is limited. Tislelizumab may potentially serve as salvage treatment options for PCC.

Niches, interspecific associations, and community stability of main understory regeneration species after understory removal in temperate forests.

Introduction: Understory removal is frequently used to relieve the renewal pressure on trees and promote the growth capability of trees for maintaining community stability, while the lack of previous study on temperate forests limits our assessment of the effectiveness of this essential management measurement. Methods: In this study, we calculated the niche characteristics and interspecific association of main understory species and community stability in temperate forests [original broad-leaved Korean pine forest (BKF), Betula platyphylla secondary forest (BF), and Larix gmelinii plantation (LF)] after understory removal for characterizing the resource utilization capacity of the regeneration trees. Results: During the restoration stage, the niche breadth of understory plants with similar habits varied across stands and layers; regeneration tree species with heliophile and semishade occupied a larger niche in BKF and LF, while it was the opposite in LF. Niche overlap among heliophile regeneration trees increased in both BKF and BF, but not in LF. The interspecific association among main species revealed that the distribution of each species was independent and the interspecific association was loose and it varied in different forests and different light-demanding species with regeneration trees. The stability of shrub communities in BF and LF improved whereas that of BKF declined, while that of the herb communities of corresponding forests showed the opposite state. Discussion: Our study demonstrated that the effectiveness of understory removal depends on species' ecological habits, which enhances the renewal and resource utilization capacity of regeneration tree species in temperate forests and shrub community stability in BF and LF.

Methylparaben changes the community composition, structure, and assembly processes of free-living bacteria, phytoplankton, and zooplankton.

Parabens are common contaminants in river and lake environments. However, few studies have been conducted to determine the effects of parabens on bacteria, phytoplankton, and zooplankton communities in aquatic environments. In this study, the effect of methylparaben (MP) on the diversity and community structure of the aquatic plankton microbiome was investigated by incubating a microcosm with MP at 0.1, 1, 10, and 100 µg/L for 7 days. The results of the Simpson index showed that MP treatment altered the α-diversity of free-living bacteria (FL), phytoplankton, and zooplankton but had no significant effect on the α-diversity of particle-attached bacteria (PA). Further, the relative abundances of the sensitive bacteria Chitinophaga and Vibrionimonas declined after MP addition. Moreover, the relative abundances of Desmodesmus sp. HSJ717 and Scenedesmus armatus, of the phylum Chlorophyta, were significantly lower in the MP treatment group than in the control group. In addition, the relative abundance of Stoeckeria sp. SSMS0806, of the Dinophyta phylum, was higher than that in the control group. MP addition also increased the relative abundance of Arthropoda but decreased the relative abundance of Rotifera and Ciliophora. The ß-diversity analysis showed that FL and phytoplankton communities were clustered separately after treatment with different MP concentrations. MP addition changed community assembly mechanisms in the microcosm, including increasing the stochastic processes for FL and the deterministic processes for PA and phytoplankton. Structural equation modeling analysis showed a significant negative relationship between bacteria richness and phytoplankton richness, and a significant positive relationship between phytoplankton (richness and community composition) and zooplankton. Overall, this study emphasizes that MP, at environmental concentrations, can change the diversity and structure of plankton microbial communities, which might have a negative effect on ecological systems.