IRX3 promotes adipose tissue browning and inhibits fibrosis in obesity-resistant mice.

Obesity is one of the threats to human health and survival. High fat diet (HFD)-induced obesity leads to adipose tissue fibrosis and a series of metabolic diseases. There are some people still thin under HFD, a phenomenon known as the "obesity resistance (OR) phenotype". It was found that Iroquois homeobox 3 (IRX3) is considered as a regulator in obesity, but the regulatory mechanism between OR and IRX3 is still unclear. In this study, we investigated obesity resistance (OR) on a high-fat diet (HFD) and the role of the Iroquois homeobox 3 (IRX3) gene. Using mice, we observed that OR mice had lower body weights, reduced liver lipid synthesis, and increased white adipose tissue (WAT) lipolysis compared to obesity-prone (OP) mice. Additionally, OR mice exhibited spontaneous WAT browning and less fibrosis, correlating with higher Irx3 expression. Utilizing 3T3-L1 differentiated adipocytes, our study demonstrated that overexpression of Irx3 promoted thermogenesis-related gene expression and reduced adipocyte fibrosis. Therefore, Irx3 promotes WAT browning and inhibits fibrosis in OR mice. These results provide insight into the differences between obesity and OR, new perspectives on obesity treatment, and guidance for lessening adipose tissue fibrosis.

Harnessing Deep Learning for Accurate Pathological Assessment of Brain Tumor Cell Types.

Primary diffuse central nervous system large B-cell lymphoma (CNS-pDLBCL) and high-grade glioma (HGG) often present similarly, clinically and on imaging, making differentiation challenging. This similarity can complicate pathologists' diagnostic efforts, yet accurately distinguishing between these conditions is crucial for guiding treatment decisions. This study leverages a deep learning model to classify brain tumor pathology images, addressing the common issue of limited medical imaging data. Instead of training a convolutional neural network (CNN) from scratch, we employ a pre-trained network for extracting deep features, which are then used by a support vector machine (SVM) for classification. Our evaluation shows that the Resnet50 (TL + SVM) model achieves a 97.4% accuracy, based on tenfold cross-validation on the test set. These results highlight the synergy between deep learning and traditional diagnostics, potentially setting a new standard for accuracy and efficiency in the pathological diagnosis of brain tumors.

Nanotechnology for tau pathology in Alzheimer's disease.

Tau protein aggregation is a defining characteristic of Alzheimer's disease (AD), leading to the formation of neurofibrillary tangles that disrupt neural communication and ultimately result in cognitive decline. Nanotechnology presents novel strategies for both diagnosing and treating Alzheimer's disease. Nanotechnology. It has become a revolutionary tool in the fight against Alzheimer's disease, particularly in addressing the pathological accumulation of tau protein. This review explores the relationship between tau-related neurophysiology and the utilization of nanotechnology for AD treatment, focusing on the application of nanomaterials to regulate tau phosphorylation, hinder tau aggregation and propagation, stabilize microtubules, eliminate pathological tau and emphasize the potential of nanotechnology in developing personalized therapies and monitoring treatment responses in AD patients. This review combines tau-related neurophysiology with nanotechnology to provide new insights for further understanding and treating Alzheimer's disease.

Functionally Designed Nanovaccines against SARS-CoV-2 and Its Variants.

COVID-19, generated by SARS-CoV-2, has significantly affected healthcare systems worldwide. The epidemic has highlighted the urgent need for vaccine development. Besides the conventional vaccination models, which include live-attenuated, recombinant protein, and inactivated vaccines, nanovaccines present a distinct opportunity to progress vaccine research and offer convenient alternatives. This review highlights the many widely used nanoparticle vaccine vectors, outlines their benefits and drawbacks, and examines recent developments in nanoparticle vaccines to prevent SARS-CoV-2. It also offers a thorough overview of the many advantages of nanoparticle vaccines, including an enhanced host immune response, multivalent antigen delivery, and efficient drug delivery. The main objective is to provide a reference for the development of innovative antiviral vaccines.

C-reactive protein-albumin-lymphocyte index as a feasible nutrition-immunity-inflammation marker of the outcome of all-cause and cardiovascular mortality in elderly.

BACKGROUND & AIMS: The imbalance of nutrition-immunity-inflammation status might be associated with the mortality risk in the elderly. This study aimed to assess the relationship between the C-reactive protein (CRP)-albumin-lymphocyte (CALLY) index and all-cause and cardiovascular disease (CVD) mortality in the elderly. METHODS: The data from records of older adults (≥ 60 years) were derived from 1999 to 2010 and 2015-2018 National Health and Nutrition Examination Survey. Weighted Cox proportional hazard regression was used to analyze the relationship between CALLY and all-cause mortality and CVD mortality in three different models, and the linear trend was analyzed. A restricted cubic spline model was used to evaluate the nonlinear dose-response relationship and determine the critical threshold of CALLY to divide the population into two groups. Kaplan-Meier analysis and log-rank test were used to evaluate the cumulative survival rates of different groups. Subgroup analyses and sensitivity analyses were performed to ensure robustness. RESULTS: Compared to the first quartile of natural log-transformation (ln) CALLY, the highest quartile of ln CALLY was negatively correlated with the risk of all-cause mortality (HR = 0.67, 95% CI: 0.56-0.79. P < 0.05) and CVD mortality (HR = 0.65, 95% CI: 0.47-0.89. P < 0.05) in model 3. Ln CALLY was linear dose-response correlated with mortality. We determined that the critical threshold for ln CALLY in elderly was 1.00. Elderly with higher ln CALLY (≥ 1.00) had significantly increased survival rates (P < 0.05). CONCLUSION: CALLY showed a significant negative linear association with the risk of all-cause mortality and CVD mortality, and higher CALLY was beneficial to the survival outcomes of the elderly.

Epidermolysis Bullosa Pruriginosa treated with baricitinib: A case report.

INTRODUCTION: Epidermolysis Bullosa Pruriginosa (EBP) is a persistent, recurring disease that seriously affects quality of life. Fewer than 100 cases of EBP have been reported to date. Numerous inflammatory dermatoses are driven by soluble inflammatory mediators, which rely on Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling, and inhibition of this pathway using Janus kinase (JAK) inhibitors might be a useful therapeutic strategy for these diseases. PATIENT CONCERNS: A male patient, 28 years of age, was admitted to our hospital because of recurrent papules, nodules, and intense itching on the trunk and extremities for 12 years. Repeated large and intense itching has seriously affected the patient normal life. DIAGNOSIS: The patient was diagnosed with EBP based on examination results. INTERVENTIONS: Oral baricitinib tablets (2 mg, once a day) + Oral desloratadine citrate disodium tablets (8.8 mg, once a day) combined with topical compound flumethasone ointment and Fucidin cream. OUTCOMES: The patient skin rashes had subsided and flattened remarkable, and his itching was markedly relieved. The visual analogue scale (VAS) itching score of the patient gradually declined from 8 to 9 points to 2 to 3 points. CONCLUSION: This study confirms that baricitinib is effective and feasible in treating EBP, especially in remarkable relieving itching, which rendered new ideas for therapeutic approaches for EBP in the future.

Altered leptin level in autism spectrum disorder and meta-analysis of adipokines.

BACKGROUND: Increasing evidence suggests that leptin is involved in the pathology of autism spectrum disorder (ASD). In this study, our objective was to investigate the levels of leptin in the blood of children with ASD and to examine the overall profile of adipokine markers in ASD through meta-analysis. METHODS: Leptin concentrations were measured using an enzyme-linked immunosorbent assay (ELISA) kit, while adipokine profiling, including leptin, was performed via meta-analysis. Original reports that included measurements of peripheral adipokines in ASD patients and healthy controls (HCs) were collected from databases such as Web of Science, PubMed, and Cochrane Library. These studies were collected from September 2022 to September 2023 and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Standardized mean differences were calculated using a random effects model for the meta-analysis. Additionally, we performed meta-regression and explored heterogeneity among studies. RESULTS: Our findings revealed a significant increase in leptin levels in children with ASD compared to HCs (p = 0.0319). This result was consistent with the findings obtained from the meta-analysis (p < 0.001). Furthermore, progranulin concentrations were significantly reduced in children with ASD. However, for the other five adipokines analyzed, there were no significant differences observed between the children with ASD and HCs children. Heterogeneity was found among the studies, and the meta-regression analysis indicated that publication year and latitude might influence the results of the meta-analysis. CONCLUSIONS: These findings provide compelling evidence that leptin levels are increased in children with ASD compared to healthy controls, suggesting a potential mechanism involving adipokines, particularly leptin, in the pathogenesis of ASD. These results contribute to a better understanding of the pathology of ASD and provide new insights for future investigations.

Adipocyte-specific FAK deletion promotes pancreatic ß-cell apoptosis via adipose inflammatory response to exacerbate diabetes mellitus.

BACKGROUND: White adipose tissue (WAT) has a key role in maintaining energy balance throughout the body, and their dysfunction take part in the regulation of diabetes mellitus. However, the internal regulatory mechanisms underlying are still unknown. METHODS AND RESULTS: We generated adipocyte-specific FAK KO (FAK-AKO) mice and investigated their phenotype. The cascade of adipocyte, macrophage in adipocyte tissues, and pancreatic ß-cells were proposed in FAK-AKO mice and validated by cell line studies using 3T3-L1, Raw264.7 and Min6. The FAK-AKO mice exhibited glucose intolerance, reduced adipose tissue mass and increased apoptosis, lipolysis and inflammatory response in adipose tissue. We further demonstrate that adipocyte FAK deletion increases ß cell apoptosis and inflammatory infiltrates into islets, which is potentiated if mice were treated with STZ. In the STZ-induced diabetes model, FAK AKO mice exhibit less serum insulin content and pancreatic ß cell area. Moreover, serum pro-inflammatory factors increased and insulin levels decreased after glucose stimulation in FAK AKO mice. In a parallel vitro experiment, knockdown or inhibition of FAK during differentiation also increased apoptosis, lipolysis and inflammatory in 3T3-L1 adipocytes, whereas the opposite was observed upon overexpression of FAK. Moreover, coculturing LPS-treated RAW264.7 macrophages with knockdown FAK of 3T3-L1 adipocytes increased macrophage pro-inflammatory response. Furthermore, conditioned medium from above stimulated Min6 cells apoptosis (with or without STZ), whereas the opposite was observed upon overexpression of FAK. Mechanistically, FAK protein interact with TRAF6 in adipocytes and knockdown or inhibition of FAK activated TRAF6/TAK1/NF-κB signaling, which exacerbates inflammation of adipocytes themselves. CONCLUSION: Adipocyte FAK deletion promotes both adipocyte apoptosis and adipose tissue inflammation. Pro-inflammatory factors released by the FAK-null adipose tissue further trigger apoptosis in pancreatic islets induced by the administration of STZ, thereby exacerbating the diabetes mellitus. This study reveals a link between FAK-mediated adipose inflammation and diabetes mellitus, a mechanism that has not been previously recognized.

Effects of Silybum marianum, Pueraria lobate, combined with Salvia miltiorrhiza tablets on non-alcoholic fatty liver disease in adults: A triple-blind, randomized, placebo-controlled clinical trial.

BACKGROUND & AIMS: Several medicinal plant extracts have demonstrated hepatoprotective effects. However, data are scarce regarding their combined effects on non-alcoholic fatty liver disease (NAFLD). This study aimed to investigate the effects of tablets containing Silybum marianum, Pueraria lobata, and Salvia miltiorrhiza (SPS) on NAFLD progression in Chinese adults. METHODS: In this randomized, triple-blind, placebo-controlled clinical trial, 121 NAFLD patients (60 female and 61 male), diagnosed via magnetic resonance imaging (MRI) and aged 18-65 years, were enrolled. Participants were randomly allocated to receive SPS tablets (n = 60; three tablets per dose, twice daily) or placebo (n = 61) for 24 weeks. Each SPS tablet contained approximately 23.0 mg of silybin, 11.4 mg of puerarin, and 10.9 mg of salvianolic acid. There were no differences in appearance, taste and odour between the SPS tablets and placebo manufactured by BYHEALTH Co., LTD (Guangzhou, China). The primary endpoints were changes in the liver fat content (LFC) and steatosis grade from baseline to 24 weeks. Secondary outcomes included changes in biomarkers/scores of liver fibrosis and steatosis, oxidative stress, inflammatory cytokines, alcohol metabolism, and glucose metabolism. RESULTS: A total of 112 participants completed the research. The intention-to-treat results showed a trend toward reduction in both absolute LFC (-0.52%) and percentage of LFC (-4.57%) in the SPS group compared to the placebo group after 24 weeks, but these changes didn't reach statistical significance (p > 0.05). The SPS intervention (vs. placebo) significantly decreased hypersensitive C-reactive protein level (-6.76%) and increased aldehyde dehydrogenase activity (+18.1%) at 24 weeks post-intervention (all p < 0.05). Per-protocol analysis further supported these effects. This trial is registered at Clinical Trials.gov (NCT05076058). CONCLUSION: SPS supplementation may have potential benefits in improving NAFLD, but further larger-scale trials are necessary to confirm these findings.

The effects of vitamin D supplementation on serum lipid profiles in people with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials.

Introduction: People with type 2 diabetes (T2D) are highly susceptible to the development of cardiovascular diseases. Previous studies have suggested that the application of vitamin D may offer potential benefits in improving lipid profiles, but these effects remain controversial. Methods: This systematic review and meta-analysis focused on the effects of vitamin D supplementation on serum lipid profiles in people with T2D. Randomized controlled trials (RCTs) assessing the effects of vitamin D supplementation on lipid profiles and published before September 19th, 2023, were identified in PubMed, Embase, and Cochrane Library. This review protocol was registered in the PROSPERO (CRD42023461136). The random-effects model was employed to estimate unstandardized mean differences (MD) and 95% confidence intervals (CIs). The quality of studies was assessed by the Cochrane Risk of Bias tool 2. Results: Overall, 20 RCTs involving 1711 participants were included. Results indicated that vitamin D supplementation significantly improves serum high-density lipoprotein (HDL) (MD: 1.63 mg/dL, 95% CI: 0.19 to 3.08, P = 0.03), and triglyceride (TG) levels (MD: -8.56 mg/dL, 95% CI: -15.23 to -1.89, P = 0.01). However, vitamin D supplementation failed to improve low-density lipoprotein (LDL) levels and total cholesterol (TC) levels. Subgroup analyses and meta-regressions suggested that higher doses of vitamin D supplementation and shorter duration of intervention were more likely to have favorable effects on lipid profiles. Moreover, participants with lower baseline BMI and higher serum 25-hydroxy vitamin D levels exhibited greater improvements in lipid profiles following vitamin D supplementation. Conclusions: This meta-analysis highlighted the effects of vitamin D supplementation on improving serum HDL and TG levels while not exhibiting significant improvements in LDL and TC levels. Further long-term and high-quality studies are still needed to draw more precise conclusions. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=461136.

A 5:2 Intermittent Fasting Meal Replacement Diet and Glycemic Control for Adults With Diabetes: The EARLY Randomized Clinical Trial.

Importance: An intermittent fasting plan consisting of 2 nonconsecutive fasting days and 5 days of habitual intake per week and meal replacement diet (5:2 MR) could provide additional benefits to patients with type 2 diabetes. Objective: To evaluate the effect of the 5:2 MR on glycemic control among patients with early type 2 diabetes compared with metformin and empagliflozin. Design, Setting, and Participants: The EARLY (Exploration of Treatment of Newly Diagnosed Overweight/Obese Type 2 Diabetes Mellitus) study is a randomized, open-label, active parallel-controlled clinical trial conducted between November 13, 2020, and December 29, 2022, in 9 centers across China. A total of 509 eligible patients underwent screening, out of which 405 were randomly assigned to 3 groups and included in the intention-to-treat analysis. Interventions: Patients were randomly allocated in a 1:1:1 ratio to receive either metformin, empagliflozin, or 5:2 MR. The treatment was 16 weeks, with an 8-week follow-up. Main Outcomes and Measures: The primary end point was the change in hemoglobin A1c (HbA1c) level from baseline to 16 weeks. Secondary end points included changes in body weight, anthropometric measurements, and biochemical parameters. Results: Of the 405 randomized participants (265 men [65.4%]; mean [SD] age, 45.5 [11.0] years; mean [SD] body mass index, 29.5 [4.1]; and mean [SD] HbA1c level, 7.9% [0.6%]), 332 completed the 16-week treatment. From baseline to week 16, participants in the 5:2 MR group showed the greatest reduction in HbA1c (least-squares mean [LSM], -1.9% [SE, 0.2%]), significantly greater than patients receiving metformin (LSM, -1.6% [SE, 0.2%]; adjusted LSM difference, -0.3% [95% CI, -0.4% to -0.1%]) and empagliflozin (LSM, -1.5% [SE, 0.2%]; adjusted LSM difference, -0.4% [95% CI, -0.6% to -0.2%]). At week 16, the mean weight loss in the 5:2 MR group (LSM, -9.7 kg [SE, 2.2 kg]) was greater than that in the metformin group (LSM, -5.5 kg [SE, 2.3 kg]) and empagliflozin group (LSM, -5.8 kg [SE, 2.3 kg]). Conclusions and Relevance: This randomized clinical trial of Chinese adults with overweight or obesity and with early type 2 diabetes found that 5:2 MR could improve glycemic outcomes and weight loss in the short term compared with metformin or empagliflozin, making it a promising initial intervention and early management for type 2 diabetes. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2000040656.

Themis: advancing precision oncology through comprehensive molecular subtyping and optimization.

Recent advances in tumor molecular subtyping have revolutionized precision oncology, offering novel avenues for patient-specific treatment strategies. However, a comprehensive and independent comparison of these subtyping methodologies remains unexplored. This study introduces 'Themis' (Tumor HEterogeneity analysis on Molecular subtypIng System), an evaluation platform that encapsulates a few representative tumor molecular subtyping methods, including Stemness, Anoikis, Metabolism, and pathway-based classifications, utilizing 38 test datasets curated from The Cancer Genome Atlas (TCGA) and significant studies. Our self-designed quantitative analysis uncovers the relative strengths, limitations, and applicability of each method in different clinical contexts. Crucially, Themis serves as a vital tool in identifying the most appropriate subtyping methods for specific clinical scenarios. It also guides fine-tuning existing subtyping methods to achieve more accurate phenotype-associated results. To demonstrate the practical utility, we apply Themis to a breast cancer dataset, showcasing its efficacy in selecting the most suitable subtyping methods for personalized medicine in various clinical scenarios. This study bridges a crucial gap in cancer research and lays a foundation for future advancements in individualized cancer therapy and patient management.

A visual circuit related to the parabrachial nucleus for the antipruritic effects of bright light treatment.

In addition to its role in vision, light also serves non-image-forming visual functions. Despite clinical evidence suggesting the antipruritic effects of bright light treatment, the circuit mechanisms underlying the effects of light on itch-related behaviors remain poorly understood. In this study, we demonstrate that bright light treatment reduces itch-related behaviors in mice through a visual circuit related to the lateral parabrachial nucleus (LPBN). Specifically, a subset of retinal ganglion cells (RGCs) innervates GABAergic neurons in the ventral lateral geniculate nucleus and intergeniculate leaflet (vLGN/IGL), which subsequently inhibit CaMKIIα+ neurons in the LPBN. Activation of both the vLGN/IGL-projecting RGCs and the vLGN/IGL-to-LPBN projections is sufficient to reduce itch-related behaviors induced by various pruritogens. Importantly, we demonstrate that the antipruritic effects of bright light treatment rely on the activation of the retina-vLGN/IGL-LPBN pathway. Collectively, our findings elucidate a visual circuit related to the LPBN that underlies the antipruritic effects of bright light treatment.

Novel insights on room temperature-induced cellulose dissolution mechanism via ZnCl2 aqueous solution: Migration, penetration, interaction, and dispersion.

The unique molecular structure of cellulose makes it challenging to dissolve at room temperature (R.T.), and the dissolution mechanism remains unclear. In this study, we employed ZnCl2 aqueous solution for cellulose dissolution at R.T., proposing a novel four-stage dissolution mechanism. The efficient dissolution of cellulose in ZnCl2 aqueous solution at R.T. involves four indispensable stages: rapid migration of hydrated Zn2+ ions towards cellulose, sufficient penetration between cellulose sheets, strong interaction with cellulose hydroxyl groups, and effective dispersion of separated cellulose chains. The proposed four-stage dissolution mechanism was validated through theoretical calculations and experimental evidence. The hydrated Zn2+ ions in ZnCl2 + 3.5H2O solvent exhibited ideal migration, penetration, interaction, and dispersion abilities, resulting in efficient cellulose dissolution at R.T. Moreover, only slight degradation of cellulose occurred in ZnCl2 + 3.5H2O at R.T. Consequently, the regenerated cellulose materials obtained from ZnCl2 + 3.5H2O (R.T.) exhibited better mechanical properties. Notably, the solvent recovery rate reached about 95 % based on previous usage during five cycles. The solvent is outstanding for its green, low-cost, efficiency, simplicity, R.T. conditions and recyclability. This work contributes to a better understanding of the cellulose dissolution mechanisms within inorganic salt solvents at R.T., thereby guiding future development efforts towards greener and more efficient cellulosic solvents.

Transcriptome Analysis Reveals Potential Regulators of DMI Fungicide Resistance in the Citrus Postharvest Pathogen Penicillium digitatum.

Green mold, caused by Penicillium digitatum, is the major cause of citrus postharvest decay. Currently, the application of sterol demethylation inhibitor (DMI) fungicide is one of the main control measures to prevent green mold. However, the fungicide-resistance problem in the pathogen P. digitatum is growing. The regulatory mechanism of DMI fungicide resistance in P. digitatum is poorly understood. Here, we first performed transcriptomic analysis of the P. digitatum strain Pdw03 treated with imazalil (IMZ) for 2 and 12 h. A total of 1338 genes were up-regulated and 1635 were down-regulated under IMZ treatment for 2 h compared to control while 1700 were up-regulated and 1661 down-regulated under IMZ treatment for 12 h. The expression of about half of the genes in the ergosterol biosynthesis pathway was affected during IMZ stress. Further analysis identified that 84 of 320 transcription factors (TFs) were differentially expressed at both conditions, making them potential regulators in DMI resistance. To confirm their roles, three differentially expressed TFs were selected to generate disruption mutants using the CRISPR/Cas9 technology. The results showed that two of them had no response to IMZ stress while ∆PdflbC was more sensitive compared with the wild type. However, disruption of PdflbC did not affect the ergosterol content. The defect in IMZ sensitivity of ∆PdflbC was restored by genetic complementation of the mutant with a functional copy of PdflbC. Taken together, our results offer a rich source of information to identify novel regulators in DMI resistance.

The Impact of Caregiver Pressure to Eat on Food Neophobia in Children with Autism Spectrum Disorder: A Cross-Sectional Study.

(1) Background: With autistic children's high pervasiveness of eating problems and inappropriate feeding behaviors by their caregivers, this study wanted to inspect the connection between caregivers' pressure to eat and food neophobia in these children. (2) Methods: Cross-sectional overview of 160 guardians of kids aged 2 to 7 years. After one-on-one questioning by the researcher, the collected information on the socio-demographic characteristics of the children with autism, caregiver feeding behavior, and new food neophobia (FN) scores was entered into the Questionnaire Star system. (3) Results: The mean FN score was 25.56 ± 6.46. The caregiver's pressure to eat positively related to children's FN (ß = 0.164 95% CI, 0.078, 2.163). In these children, we found a negative correlation between FN score and the frequency of vegetable intake (p ≤ 0.001), fruit intake (p ≤ 0.05), aquatic product intake (p ≤ 0.05), and dietary diversity score (p ≤ 0.01), and positively correlated with the frequency of snack intake (p ≤ 0.05). (4) Conclusions: Caregiver pressure to eat was positively associated with high levels of FN in Chinese kids with ASD, which in turn negatively impacted dietary quality. To improve eating habits, caregivers should reconsider their feeding strategies and avoid using forceful methods to ease food neophobia in these children.

Ventricular Netrin-1 deficiency leads to defective pyramidal decussation and mirror movement in mice.

The corticospinal tract (CST) is the principal neural pathway responsible for conducting voluntary movement in the vertebrate nervous system. Netrin-1 is a well-known guidance molecule for midline crossing of commissural axons during embryonic development. Families with inherited Netrin-1 mutations display congenital mirror movements (CMM), which are associated with malformations of pyramidal decussation in most cases. Here, we investigated the role of Netrin-1 in CST formation by generating conditional knockout (CKO) mice using a Gfap-driven Cre line. A large proportion of CST axons spread laterally in the ventral medulla oblongata, failed to decussate and descended in the ipsilateral spinal white matter of Ntn1Gfap CKO mice. Netrin-1 mRNA was expressed in the ventral ventricular zone (VZ) and midline, while Netrin-1 protein was transported by radial glial cells to the ventral medulla, through which CST axons pass. The level of transported Netrin-1 protein was significantly reduced in Ntn1Gfap CKO mice. In addition, Ntn1Gfap CKO mice displayed increased symmetric movements. Our findings indicate that VZ-derived Netrin-1 deletion leads to an abnormal trajectory of the CST in the spinal cord due to the failure of CST midline crossing and provides novel evidence supporting the idea that the Netrin-1 signalling pathway is involved in the pathogenesis of CMM.

Resistance exercise upregulates Irisin expression and suppresses myocardial fibrosis following myocardial infarction via activating AMPK-Sirt1 and inactivating TGFß1-Smad2/3.

AIM: To reveal the contribution of Irisin in the beneficial effects of resistance exercise on myocardial fibrosis (MF) and cardiac function in the mice with myocardial infarction (MI). METHODS: The MI model was built by ligating the left anterior descending coronary artery in Fndc5 knockout mice (Fndc5-/-). Resistance exercise was started one week after surgery and continued for four weeks. In addition, H2O2, AICAR, recombinant human Irisin protein (rhIRISIN), and Sirt1 shRNA lentivirus (LV-Sirt1 shRNA) were used to intervene primary isolated cardiac fibroblasts (CFs). MF was observed through Masson staining, and apoptosis was assessed using TUNEL staining. MDA and T-SOD contents were detected by biochemical kits. The expression of proteins and genes was detected by Western blotting and RT-qPCR. RESULTS: Resistance exercise increased Fndc5 mRNA level, inhibited the activation of TGFß1-TGFßR2-Smad2/3 pathway, activated AMPK-Sirt1 pathway, reduced the levels of oxidative stress, apoptosis, and MF in the infarcted heart, and promoted cardiac function. However, Fndc5 knockout attenuated the protective effects of resistance exercise on the MI heart. Results of the in vitro experiments showed that AICAR and rhIRISIN intervention activated the AMPK-Sirt1 pathway and inactivated the TGFß1-Smad2/3 pathway, and promoted apoptosis in H2O2-treated CFs. Notably, these effects of rhIRISIN intervention, except for the TGFßR2 expression, were attenuated by LV-Sirt1 shRNA. CONCLUSION: Resistance exercise upregulates Fndc5 expression, activates AMPK-Sirt1 pathway, inhibits the activation of TGFß1-Smad2/3 pathway, attenuates MF, and promotes cardiac function after MI.

Transcriptome analysis of Gossypium hirsutum cultivar Zhongzhimian No.2 uncovers the gene regulatory networks involved in defense against Verticillium dahliae.

BACKGROUND: Cotton is globally important crop. Verticillium wilt (VW), caused by Verticillium dahliae, is the most destructive disease in cotton, reducing yield and fiber quality by over 50% of cotton acreage. Breeding resistant cotton cultivars has proven to be an efficient strategy for improving the resistance of cotton to V. dahliae. However, the lack of understanding of the genetic basis of VW resistance may hinder the progress in deploying elite cultivars with proven resistance. RESULTS: We planted the VW-resistant Gossypium hirsutum cultivar Zhongzhimian No.2 (ZZM2) in an artificial greenhouse and disease nursery. ZZM2 cotton was subsequently subjected to transcriptome sequencing after Vd991 inoculation (6, 12, 24, 48, and 72 h post-inoculation). Several differentially expressed genes (DEGs) were identified in response to V. dahliae infection, mainly involved in resistance processes, such as flavonoid and terpenoid quinone biosynthesis, plant hormone signaling, MAPK signaling, phenylpropanoid biosynthesis, and pyruvate metabolism. Compared to the susceptible cultivar Junmian No.1 (J1), oxidoreductase activity and reactive oxygen species (ROS) production were significantly increased in ZZM2. Furthermore, gene silencing of cytochrome c oxidase subunit 1 (COX1), which is involved in the oxidation-reduction process in ZZM2, compromised its resistance to V. dahliae, suggesting that COX1 contributes to VW resistance in ZZM2. CONCLUSIONS: Our data demonstrate that the G. hirsutum cultivar ZZM2 responds to V. dahliae inoculation through resistance-related processes, especially the oxidation-reduction process. This enhances our understanding of the mechanisms regulating the ZZM2 defense against VW.