Giraffe: A tool for comprehensive processing and visualization of multiple long-read sequencing data.

Third-generation sequencing techniques have become increasingly popular due to their capacity to produce long, high-quality reads. Effective comparative analysis across various samples and sequencing platforms is essential for understanding biological mechanisms and establishing benchmark baselines. However, existing tools for long-read sequencing predominantly focus on quality control (QC) and processing for individual samples, complicating the comparison of multiple datasets. The lack of comprehensive tools for data comparison and visualization presents challenges for researchers with limited bioinformatics experience. To address this gap, we present Giraffe (https://github.com/lrslab/Giraffe_View), a Python3-based command-line tool designed for comparative analysis and visualization across diverse samples and platforms. Giraffe facilitates the assessment of read quality, sequencing bias, and genomic regional methylation proportions for both DNA and direct RNA sequencing reads. Its effectiveness has been demonstrated in various scenarios, including comparisons of sequencing methods (whole genome amplification vs. shotgun), sequencing platforms (Oxford Nanopore Technology, ONT vs. Pacific Biosciences, PacBio), tissues (kidney marrow with and without blood), and biological replicates (kidney marrows).

Design and Development of an Automatic Layout Algorithm for Laser GNSS RTK.

At the current stage, the automation level of GNSS RTK equipment is low, and manual operation leads to decreased accuracy and efficiency in setting out. To address these issues, this paper has designed an algorithm for automatic setting out that resolves the common problem of reduced accuracy in conventional RTK. First, the calculation of the laser rotation center is conducted using relevant parameters to calibrate the instrument's posture and angle. Then, by analyzing the posture information, the relative position and direction of the instrument to the point to be set out are determined, and the rotation angles in the horizontal and vertical directions are calculated. Following this, the data results are analyzed, and the obtained rotation angles are output to achieve automatic control of the instrument. Finally, a rotating laser composed of servo motors and laser modules is used to control the GNSS RTK equipment to locate the set-out point, thereby determining its position on the ground and displaying it in real-time. Compared to traditional GNSS RTK equipment, the proposed automatic setting out algorithm and the developed GNSS laser RTK equipment reduce the setting out error from 15 mm to 10.3 mm. This reduces the barrier to using GNSS RTK equipment, minimizes human influence, enhances the work efficiency of setting out measurements, and ensures high efficiency and stability under complex conditions.

Balloon Angioplasty vs Medical Management for Intracranial Artery Stenosis: The BASIS Randomized Clinical Trial.

Importance: Previous randomized clinical trials did not demonstrate the superiority of endovascular stenting over aggressive medical management for patients with symptomatic intracranial atherosclerotic stenosis (sICAS). However, balloon angioplasty has not been investigated in a randomized clinical trial. Objective: To determine whether balloon angioplasty plus aggressive medical management is superior to aggressive medical management alone for patients with sICAS. Design, Setting, and Participants: A randomized, open-label, blinded end point clinical trial at 31 centers across China. Eligible patients aged 35 to 80 years with sICAS defined as recent transient ischemic attack (<90 days) or ischemic stroke (14-90 days) before enrollment attributed to a 70% to 99% atherosclerotic stenosis of a major intracranial artery receiving treatment with at least 1 antithrombotic drug and/or standard risk factor management were recruited between November 8, 2018, and April 2, 2022 (final follow-up: April 3, 2023). Interventions: Submaximal balloon angioplasty plus aggressive medical management (n = 249) or aggressive medical management alone (n = 252). Aggressive medical management included dual antiplatelet therapy for the first 90 days and risk factor control. Main Outcomes and Measures: The primary outcome was a composite of any stroke or death within 30 days after enrollment or after balloon angioplasty of the qualifying lesion or any ischemic stroke in the qualifying artery territory or revascularization of the qualifying artery after 30 days through 12 months after enrollment. Results: Among 512 randomized patients, 501 were confirmed eligible (mean age, 58.0 years; 158 [31.5%] women) and completed the trial. The incidence of the primary outcome was lower in the balloon angioplasty group than the medical management group (4.4% vs 13.5%; hazard ratio, 0.32 [95% CI, 0.16-0.63]; P < .001). The respective rates of any stroke or all-cause death within 30 days were 3.2% and 1.6%. Beyond 30 days through 1 year after enrollment, the rates of any ischemic stroke in the qualifying artery territory were 0.4% and 7.5%, respectively, and revascularization of the qualifying artery occurred in 1.2% and 8.3%, respectively. The rate of symptomatic intracranial hemorrhage in the balloon angioplasty and medical management groups was 1.2% and 0.4%, respectively. In the balloon angioplasty group, procedural complications occurred in 17.4% of patients and arterial dissection occurred in 14.5% of patients. Conclusions and Relevance: In patients with sICAS, balloon angioplasty plus aggressive medical management, compared with aggressive medical management alone, statistically significantly lowered the risk of a composite outcome of any stroke or death within 30 days or an ischemic stroke or revascularization of the qualifying artery after 30 days through 12 months. The findings suggest that balloon angioplasty plus aggressive medical management may be an effective treatment for sICAS, although the risk of stroke or death within 30 days of balloon angioplasty should be considered in clinical practice. Trial Registration: ClinicalTrials.gov Identifier: NCT03703635.

LIM kinase 2 activates cardiac fibroblasts and exacerbates postinfarction left ventricular remodeling via crosstalk between the canonical and non-canonical Wnt pathways.

Ischemic heart failure rates rise despite decreased acute myocardial infarction (MI) mortality. Excessive myofibroblast activation post-MI leads to adverse remodeling. LIM kinases (LIMK1 and LIMK2) regulate cytoskeleton homeostasis and are pro-fibrotic markers in atrial fibrillation. However, their roles and mechanisms in postinfarction fibrosis and ventricular remodeling remain unclear. This study found that the expression of LIMKs elevated in the border zone (BZ) in mice MI models. LIMK1/2 double knockout (DKO) restrained pathological remodeling and reduced mortality by suppressing myofibroblast activation. By using adeno-associated virus (AAV) with a periostin promoter to overexpress LIMK1 or LIMK2, this study found that myofibroblast-specific LIMK2 overexpression diminished these effects in DKO mice, while LIMK1 did not. LIMK2 kinase activity was critical for myofibroblast proliferation by using AAV overexpressing mutant LIMK2 lack of kinase activity. According to phosphoproteome analysis, functional rescue experiments, co-immunoprecipitation, and protein-protein docking, LIMK2 led to the phosphorylation of ß-catenin at Ser 552. LIMK2 nuclear translocation also played a role in myofibroblast proliferation after MI with the help of AAV overexpressing mutant LIMK2 without nuclear location signal. Chromatin immunoprecipitation sequencing identified that LIMK2 bound to Lrp6 promoter region in TGF-ß treated cardiac fibroblasts, positively regulating Wnt signaling via Wnt receptor internalization. This study demonstrated that LIMK2 promoted myofibroblast proliferation and adverse cardiac remodeling after MI, by enhancing phospho-ß-catenin (Ser552) and Lrp6 signaling. This suggested that LIMK2 could be a target for the treatment of postinfarction injury.

Correlating local structure and migration dynamics in Na/Li dual ion conductor Na5YSi4O12.

Na5YSi4O12 (NYSO) is demonstrated as a promising electrolyte with high ionic conductivity and low activation energy for practical use in solid Na-ion batteries. Solid-state NMR was employed to identify the six types of coordination of Na+ ions and migration pathway, which is vital to master working mechanism and enhance performance. The assignment of each sodium site is clearly determined from high-quality 23Na NMR spectra by the aid of Density Functional Theory calculation. Well-resolved 23Na exchangespectroscopy and electrochemical tracer exchange spectra provide the first experimental evidence to show the existence of ionic exchange between sodium at Na5 and Na6 sites, revealing that Na transport route is possibly along three-dimensional chain of open channel-Na4-open channel. Variable-temperature NMR relaxometry is developed to evaluate Na jump rates and self-diffusion coefficient to probe the sodium-ion dynamics in NYSO. Furthermore, NYSO works well as a dual ion conductor in Na and Li metal batteries with Na3V2(PO4)3 and LiFePO4 as cathodes, respectively.

Multiplex Expression Cassette Assembly: A flexible and versatile method for building complex genetic circuits in conventional vectors.

The manipulation of multiple transcription units for simultaneous and coordinated expression is not only key to building complex genetic circuits to accomplish diverse functions in synthetic biology, but is also important in crop breeding for significantly improved productivity and overall performance. However, building constructs with multiple independent transcription units for fine-tuned and coordinated regulation is complicated and time-consuming. Here, we introduce the Multiplex Expression Cassette Assembly (MECA) method, which modifies canonical vectors compatible with Golden Gate Assembly, and then uses them to produce multi-cassette constructs. By embedding the junction syntax in primers that are used to amplify functional elements, MECA is able to make complex constructs using only one intermediate vector and one destination vector via two rounds of one-pot Golden Gate assembly reactions, without the need for dedicated vectors and a coherent library of standardized modules. As a proof-of-concept, we modified eukaryotic and prokaryotic expression vectors to generate constructs for transient expression of green fluorescent protein and ß-glucuronidase in Nicotiana benthamiana, genome editing to block monoterpene metabolism in tomato glandular trichomes, production of betanin in tobacco and synthesis of ß-carotene in Escherichia coli. Additionally, we engineered the stable production of thymol and carvacrol, bioactive compounds from Lamiaceae family plants, in glandular trichomes of tobacco. These results demonstrate that MECA is a flexible, efficient and versatile method for building complex genetic circuits, which will not only play a critical role in plant synthetic biology, but also facilitate improving agronomic traits and pyramiding traits for the development of next-generation elite crops.

M6A modification and T cells in adipose tissue inflammation.

Adipose tissue in the obese state can lead to low-grade chronic inflammation while inducing or exacerbating obesity-related metabolic diseases and impairing overall health.T cells, which are essential immune cells similar to macrophages, are widely distributed in adipose tissue and perform their immunomodulatory function; they also cross-talk with other cells in the vascular stromal fraction. Based on a large number of studies, it has been found that N6 methyl adenine (m6A) is one of the most representative of epigenetic modifications, which affects the crosstalk between T cells, as well as other immune cells, in several ways and plays an important role in the development of adipose tissue inflammation and related metabolic diseases. In this review, we first provide an overview of the widespread presence of T cells in adipose tissue and summarize the key role of T cells in adipose tissue inflammation. Next, we explored the effects of m6A modifications on T cells in adipose tissue from the perspective of adipose tissue inflammation. Finally, we discuss the impact of m6a-regulated crosstalk between T cells and immune cells on the prospects for improving adipose tissue inflammation research, providing additional new ideas for the treatment of obesity.

Neuromedin S regulates goat ovarian granulosa cell proliferation and steroidogenesis via endoplasmic reticulum Ca2+-YAP1-ATF4-c-Jun pathway.

Neuromedin S (NMS) plays key roles in reproductive regulation, while its function and mechanism in follicular development remain unclear. The current study aims to investigate the specific role and mechanisms of NMS and its receptors in regulating the proliferation and steroidogenesis of ovarian granulosa cells (GCs). Phenotypically, a certain concentration of NMS addition promoted the proliferation and estrogen production of goat GCs, accompanied by an increase in the G1/S cell population and upregulation of the expression levels of cyclin D1, cyclin dependent kinase 6, steroidogenic acute regulatory protein, cytochrome P450, family 11, subfamily A, polypeptide 1, 3beta-hydroxysteroid dehydrogenase, and cytochrome P450, family 11, subfamily A, polypeptide 1, while the effects of NMS treatment were effectively hindered by knockdown of neuromedin U receptor type 2 (NMUR2). Mechanistically, activation of NMUR2 with NMS maintained endoplasmic reticulum (ER) calcium (Ca2+) homeostasis by triggering the PLCG1-IP3R pathway, which helped preserve ER morphology, sustained an appropriate level of endoplasmic reticulum unfolded protein response (UPRer), and suppressed the nuclear translocation of activating transcription factor 4. Moreover, NMS maintained intracellular Ca2+ homeostasis to activate the calmodulin 1-large tumor suppressor kinase 1 pathway, ultimately orchestrating the regulation of goat GC proliferation and estrogen production through the Yes1 associated transcriptional regulator-ATF4-c-Jun pathway. Crucially, the effects of NMS were mitigated by concurrent knockdown of the NMUR2 gene. Collectively, these data suggest that activation of NMUR2 by NMS enhances cell proliferation and estrogen production in goat GCs through modulating the ER and intracellular Ca2+ homeostasis, leading to activation of the YAP1-ATF4-c-Jun pathway. These findings offer valuable insights into the regulatory mechanisms involved in follicular growth and development, providing a novel perspective for future research.

Comprehensive Assessment of Drug Kinetics, Neurotoxicity, and Safety of Sirolimus-Eluting Intracranial Stents in Canine Basilar Artery.

BACKGROUND AND OBJECTIVES: Sirolimus-eluting stents (SESs) have shown promise in treating intracranial atherosclerosis but concerns about potential neurotoxicity due to prolonged drug release exist. The aim of this study was to comprehensively assess the safety of SES, with a focus on neurotoxicity. METHODS: Stents (1.50 × 7 or 12 mm) were implanted into the basilar arteries of 154 Labrador Retrievers (weighing >25 kg and aged older than 1 year) divided into 4 groups: baer-metal stent, polymer-coated stent, standard-dose SES (sirolimus dose: 71 µg), and high-dose SES group (sirolimus dose: 284 µg). Pharmacokinetic analysis was conducted using liquid chromatography-mass spectrometry on blood and tissue samples, and analysis of brain tissue was performed with 5 different special stains and immunohistochemistry protocols to assess axonal degeneration, vacuolization, astrocyte proliferation, microglial activation, or widespread neurodegeneration. RESULTS: In the standard-dose SES group, the stent released 10.56% of the drug on day 1 and 95.41% on day 28 postimplantation. In the high-dose SES group, corresponding figures were 40.20% on day 1 and 98.08% on day 28. Systemic drug concentration consistently remained below 1.5 ng/mL throughout the study. Arterial tissue concentration reached its peak at day 28 days in the standard-dose group and at 7 days in the high-dose group. Importantly, the brain and related tissue concentrations remained below 0.4 µg/g in both standard-dose and high-dose SES groups, peaking on day 21 in the standard-dose group and day 1 in the high-dose group. The detailed 180-day safety assessment revealed no adverse effects on the brain, even at high sirolimus doses in the SES group. CONCLUSION: This study provides robust evidence supporting the long-term pharmacokinetic safety of SESs in the context of intracranial interventions for high-grade intracranial atherosclerosis. The results adequately alleviate concerns related to neurotoxicity and substantiate the feasibility of using these stents as a therapeutic choice in neurosurgery.

Excessive accumulation of epicardial adipose tissue promotes microvascular obstruction formation after myocardial ischemia/reperfusion through modulating macrophages polarization.

BACKGROUND: Owing to its unique location and multifaceted metabolic functions, epicardial adipose tissue (EAT) is gradually emerging as a new metabolic target for coronary artery disease risk stratification. Microvascular obstruction (MVO) has been recognized as an independent risk factor for unfavorable prognosis in acute myocardial infarction patients. However, the concrete role of EAT in the pathogenesis of MVO formation in individuals with ST-segment elevation myocardial infarction (STEMI) remains unclear. The objective of the study is to evaluate the correlation between EAT accumulation and MVO formation measured by cardiac magnetic resonance (CMR) in STEMI patients and clarify the underlying mechanisms involved in this relationship. METHODS: Firstly, we utilized CMR technique to explore the association of EAT distribution and quantity with MVO formation in patients with STEMI. Then we utilized a mouse model with EAT depletion to explore how EAT affected MVO formation under the circumstances of myocardial ischemia/reperfusion (I/R) injury. We further investigated the immunomodulatory effect of EAT on macrophages through co-culture experiments. Finally, we searched for new therapeutic strategies targeting EAT to prevent MVO formation. RESULTS: The increase of left atrioventricular EAT mass index was independently associated with MVO formation. We also found that increased circulating levels of DPP4 and high DPP4 activity seemed to be associated with EAT increase. EAT accumulation acted as a pro-inflammatory mediator boosting the transition of macrophages towards inflammatory phenotype in myocardial I/R injury through secreting inflammatory EVs. Furthermore, our study declared the potential therapeutic effects of GLP-1 receptor agonist and GLP-1/GLP-2 receptor dual agonist for MVO prevention were at least partially ascribed to its impact on EAT modulation. CONCLUSIONS: Our work for the first time demonstrated that excessive accumulation of EAT promoted MVO formation by promoting the polarization state of cardiac macrophages towards an inflammatory phenotype. Furthermore, this study identified a very promising therapeutic strategy, GLP-1/GLP-2 receptor dual agonist, targeting EAT for MVO prevention following myocardial I/R injury.

Elliptic-rogue waves and modulational instability in nonlinear soliton equations.

We present elliptic-rogue wave solutions for integrable nonlinear soliton equations in rational form by elliptic functions. Unlike solutions generated on the plane wave background, these solutions depict rogue waves emerging on elliptic function backgrounds. By refining the modified squared wave function method in tandem with the Darboux-Bäcklund transformation, we establish a quantitative correspondence between elliptic-rogue waves and the modulational instability. This connection reveals that the modulational instability of elliptic function solutions triggers rational-form solutions displaying elliptic-rogue waves, whereas the modulational stability of elliptic function solutions results in the rational-form solutions exhibiting the elliptic solitons or elliptic breathers. Moreover, this approach enables the derivation of higher-order elliptic-rogue waves, offering a versatile framework for constructing elliptic-rogue waves and exploring modulational stability in other integrable equations.

The activity of early-life gene regulatory elements is hijacked in aging through pervasive AP-1-linked chromatin opening.

A mechanistic connection between aging and development is largely unexplored. Through profiling age-related chromatin and transcriptional changes across 22 murine cell types, analyzed alongside previous mouse and human organismal maturation datasets, we uncovered a transcription factor binding site (TFBS) signature common to both processes. Early-life candidate cis-regulatory elements (cCREs), progressively losing accessibility during maturation and aging, are enriched for cell-type identity TFBSs. Conversely, cCREs gaining accessibility throughout life have a lower abundance of cell identity TFBSs but elevated activator protein 1 (AP-1) levels. We implicate TF redistribution toward these AP-1 TFBS-rich cCREs, in synergy with mild downregulation of cell identity TFs, as driving early-life cCRE accessibility loss and altering developmental and metabolic gene expression. Such remodeling can be triggered by elevating AP-1 or depleting repressive H3K27me3. We propose that AP-1-linked chromatin opening drives organismal maturation by disrupting cell identity TFBS-rich cCREs, thereby reprogramming transcriptome and cell function, a mechanism hijacked in aging through ongoing chromatin opening.

Metabolic determinants of germinal center B cell formation and responses.

Germinal center (GC) B cells are crucial for the generation of GCs and long-lived humoral immunity. Here we report that one-carbon metabolism determines the formation and responses of GC B cells. Upon CD40 stimulation, GC B cells selectively upregulate methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) expression to generate purines and the antioxidant glutathione. MTHFD2 depletion reduces GC B cell frequency and antigen-specific antibody production. Moreover, supplementation with nucleotides and antioxidants suffices to promote GC B cell formation and function in vitro and in vivo through activation of the mammalian target of rapamycin complex 1 signaling pathway. Moreover, we found that antigen stimulation enhances YY1 binding to the Mthfd2 promoter and promotes MTHFD2 transcription. Interestingly, these findings can be generalized to the pentose phosphate pathway, which is another major source of reducing power and nucleotides. Therefore, these results suggest that an increased capacity for nucleotide synthesis and redox balance is required for GC B cell formation and responses, revealing a key aspect of GC B cell fate determination.

A solid acid derived from fishbone catalyzes the hydrolysis of cellulose into nanocellulose.

The necessity to look into waste biomass resource regeneration has increased due to growing environmental and energy-related problems. This study successfully developed an innovative fishbone-derived carbon-based solid acid catalyst using the carbonation-sulfonation method, which was subsequently applied to catalyze the hydrolysis of cellulose to produce nanocellulose. The data analysis reveals that the sulfonation treatment affects the microstructure of the catalyst, resulting in a decline in its specific surface area (134.48 m2/g decreased to 9.66 m2/g). However, this treatment doesn't hinder the introduction of acidic functional groups. In particular, the solid acid catalyst derived from fishbone exhibited a total acid content of 3.76 mmol/g, with a concentration of -SO3H groups at 0.48 mmol/g. Furthermore, the solid acids originating from fishbones manifested remarkable thermal stability, exhibiting a mass loss of <15 % at temperatures up to 600 °C. Moreover, the catalyst displayed exceptional catalytic performance during the cellulose hydrolysis reaction, achieving an optimum nanocellulose yield of 45.7 % at an optimized reaction condition. An additional noteworthy feature is the solid acid catalyst's impressive recyclability, maintaining a nanocellulose yield of 44.87 % even after undergoing five consecutive usage cycles. This research outcome underscores an innovative approach to for the sustainable utilization of waste biomass resources.

Platelet Membrane-Coated Curcumin-PLGA Nanoparticles Promote Astrocyte-Neuron Transdifferentiation for Intracerebral Hemorrhage Treatment.

Intracerebral hemorrhage (ICH) is a hemorrhagic disease with high mortality and disability rates. Curcumin is a promising drug for ICH treatment due to its multiple biological activities, but its application is limited by its poor watersolubility and instability. Herein, platelet membrane-coated curcumin polylactic-co-glycolic acid (PLGA) nanoparticles (PCNPs) are prepared to achieve significantly improved solubility, stability, and sustained release of curcumin. Fourier transform infrared spectra and X-ray diffraction assays indicate good encapsulation of curcumin within nanoparticles. Moreover, it is revealed for the first time that curcumin-loaded nanoparticles can not only suppress hemin-induced astrocyte proliferation but also induce astrocytes into neuron-like cells in vitro. PCNPs are used to treat rat ICH by tail vein injection, using in situ administration as control. The results show that PCNPs are more effective than curcumin-PLGA nanoparticles in concentrating on hemorrhagic lesions, inhibiting inflammation, suppressing astrogliosis, promoting neurogenesis, and improving motor functions. The treatment efficacy of intravenously administered PCNPs is comparable to that of in situ administration, indicating a good targeting effect of PCNPs on the hemorrhage site. This study provides a potent treatment for hemorrhagic injuries and a promising solution for efficient delivery of water-insoluble drugs using composite materials of macromolecules and cell membranes.

The potential of organoids in renal cell carcinoma research.

Renal cell carcinoma, a leading cause of death in urological malignancies, arises from the nephron. Its characteristics include diversity in disease biology, varied clinical behaviors, different prognoses, and diverse responses to systemic therapies. The term 'organoids' is used to describe structures resembling tissues created through the three-dimensional cultivation of stem cells in vitro. These organoids, when derived from tumor tissues, can retain the diversity of the primary tumor, mirror its spatial tissue structure, and replicate similar organ-like functions. In contrast to conventional two-dimensional cell cultures and the transplantation of tumor tissues into other organisms, organoids derived from tumors maintain the complexity and microenvironment of the original tumor tissue. This fidelity makes them a more reliable model for the development of cancer drugs, potentially accelerating the translation of these drugs to clinical use and facilitating personalized treatment options for patients. This review aims to summarize the recent advancements in the use of organoids for studying renal cell carcinoma, focusing on their cultivation, potential applications, and inherent limitations.

Impact of metformin on melanoma: a meta-analysis and systematic review.

Background: There is evidence of a modest reduction in skin cancer risk among metformin users. However, no studies have further examined the effects of metformin on melanoma survival and safety outcomes. This study aimed to quantitatively summarize any influence of metformin on the overall survival (OS) and immune-related adverse effects (irAEs) in melanoma patients. Methods: Selection criteria: The inclusion criteria were designed based on the PICOS principles. Information sources: PubMed, EMBASE, Cochrane Library, and Web of Science were searched for relevant literature published from the inception of these databases until November 2023 using 'Melanoma' and 'Metformin' as keywords. Survival outcomes were OS, progression-free survival (PFS), recurrence-free survival (RFS), and mortality; the safety outcome was irAEs. Risk of bias and data Synthesis: The Cochrane tool for assessing the risk of bias in randomized trial 2 (RoB2) and methodological index for non-randomized studies (MINORS) were selected to assess the risk of bias. The Cochrane Q and I 2 statistics based on Stata 15.1 SE were used to test the heterogeneity among all studies. Funnel plot, Egger regression, and Begg tests were used to evaluate publication bias. The leave-one-out method was selected as the sensitivity analysis tool. Results: A total of 12 studies were included, involving 111,036 melanoma patients. The pooled HR for OS was 0.64 (95% CI [0.42, 1.00], p = 0.004, I2 = 73.7%), HR for PFS was 0.89 (95% CI [0.70, 1.12], p = 0.163, I2 = 41.4%), HR for RFS was 0.62 (95% CI [0.26, 1.48], p = 0.085, I2 = 66.3%), and HR for mortality was 0.53 (95% CI [0.46, 0.63], p = 0.775, I2 = 0.0%). There was no significant difference in irAEs incidence (OR = 1.01; 95% CI [0.42, 2.41]; p = 0.642) between metformin and no metformin groups. Discussion: The improvement in overall survival of melanoma patients with metformin may indirectly result from its diverse biological targets and beneficial effects on multiple systemic diseases. While we could not demonstrate a specific improvement in the survival of melanoma patients, the combined benefits and safety of metformin for patients taking the drug are worthy of recognition. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024518182.

Association between color value of tongue and T2DM based on dose-response analyses using restricted cubic splines in China: A cross-sectional study.

This study aimed to explore the relationship between international commission on illumination (CIE) L*a*b* color value of tongue and type 2 diabetes mellitus (T2DM). We used restricted cubic spline method and logistic regression method to assess the relationship between CIE L*a*b* color value of tongue and T2DM. A total of 2439 participants (991 T2DM and 1448 healthy) were included. A questionnaire survey and tongue images obtained with tongue diagnosis analysis-1 were analyzed. As required, chi-square and t tests were applied to compare the T2DM and healthy categories. Our findings suggest the 95% confidence interval and odds ratio for body mass index, hypertension, and age were 0.670 (0.531-0.845), 13.461 (10.663-16.993), and 2.595 (2.324-2.897), respectively, when compared to the healthy group. A linear dose-response relationship with an inverse U-shape was determined between CIE L* and CIE a* values and T2DM (P < .001 for overall and P < .001 for nonlinear). Furthermore, U-shaped and linear dose-response associations were identified between T2DM and CIE b* values (P = .0160 for nonlinear). Additionally, in adults, the CIE L*a*b* color value had a correlation with T2DM. This novel perspective provides a multidimensional understanding of traditional Chinese medicine tongue color, elucidating the potential of CIE L*a*b* color values of tongue in the diagnosis of T2DM.

Nasal mucosa-derived mesenchymal stem cells prolonged the survival of septic rats by protecting macrophages from pyroptosis.

Sepsis is characterized by an exacerbated inflammatory response, driven by the overproduction of cytokines, a phenomenon known as a cytokine storm. This condition is further compounded by the extensive infiltration of M1 macrophages and the pyroptosis of these cells, leading to immune paralysis. To counteract this, we sought to transition M1 macrophages into the M2 phenotype and safeguard them from pyroptosis. For this purpose, we employed ectodermal mesenchymal stem cells (EMSCs) sourced from the nasal mucosa to examine their impact on both macrophages and septic animal models. The co-culture protocol involving LPS-stimulated rat bone marrow macrophages and EMSCs was employed to examine the paracrine influence of EMSCs on macrophages. The intravenous administration of EMSCs was utilized to observe the enhancement in the survival rate of septic rat models and the protection of associated organs. The findings indicated that EMSCs facilitated M2 polarization of macrophages, which were stimulated by LPS, and significantly diminished levels of pro-inflammatory cytokines and NLRP3. Furthermore, EMSCs notably restored the mitochondrial membrane potential (MMP) of macrophages through paracrine action, eliminated excess reactive oxygen species (ROS), and inhibited macrophage pyroptosis. Additionally, the systemic integration of EMSCs substantially reduced injuries to multiple organs and preserved the fundamental functions of the heart, liver, and kidney in CLP rats, thereby extending their survival.

Zearalenone modulates the function of goat endometrial cells via the mitochondrial quality control system.

Zearalenone (ZEN) is a mycotoxin known for its estrogen-like effects, which can disrupt the normal physiological function of endometrial cells and potentially lead to abortion in female animals. However, the precise mechanism by which ZEN regulates endometrial function remains unclear. In this study, we found that the binding receptor estrogen receptors for ZEN is extensively expressed across various segments of the uterus and within endometrial cells, and a certain concentration of ZEN treatment reduced the proliferation capacity of goat endometrial epithelial cells (EECs) and endometrial stromal cells (ESCs). Meanwhile, cell cycle analysis revealed that ZEN treatment leaded to cell cycle arrest in goat EECs and ESCs. To explore the underlying mechanism, we investigated the mitochondrial quality control systems and observed that ZEN triggered excessive mitochondrial fission and disturbed the balance of mitochondrial fusion-fission dynamics, impaired mitochondrial biogenesis, increased mitochondrial unfolded protein response and mitophagy in goat EECs and ESCs. Additionally, ZEN treatment reduced the activities of mitochondrial respiratory chain complexes, heightened the production of hydrogen peroxide and reactive oxygen species, and caused cellular oxidative stress and mitochondrial dysfunction. These results suggest that ZEN has adverse effects on goat endometrium cells by disrupting the mitochondrial quality control system and affecting cell cycle and proliferation. Understanding the underlying molecular pathways involved in ZEN-induced mitochondrial dysfunction and its consequences on cell function will provide critical insights into the reproductive toxicity of ZEN and contribute to safeguarding the health and wellbeing of animals and humans exposed to this mycotoxin.