Proteomic Profiling of Muscular Adaptations to Short-Term Concentric Versus Eccentric Exercise Training in Humans.

The molecular mechanisms underlying muscular adaptations to concentric (CON) and eccentric (ECC) exercise training have been extensively explored. However, most previous studies have focused on specifically selected proteins, thus, unable to provide a comprehensive protein profile and potentially missing the crucial mechanisms underlying muscular adaptation to exercise training. We herein aimed to investigate proteomic profiles of human skeletal muscle in response to short-term resistance training. Twenty young males were randomly and evenly assigned to two groups to complete a 4-week either ECC or CON training program. Measurements of body composition and physiological function of the quadriceps femoris were conducted both before and after the training. Muscle biopsies from the vastus lateralis of randomly selected participants (five in ECC and four in CON) of both before and after the training were analyzed using the liquid-chromatography tandem mass spectrometry in combination with bioinformatics analysis. Neither group presented a significant difference in body composition or leg muscle mass; however, muscle peak torque, total work, and maximal voluntary contraction were significantly increased after the training in both groups. Proteomics analysis revealed 122 differentially abundant proteins (DAPs; p value < 0.05 & fold change >1.5 or <0.67) in ECC, of which the increased DAPs were mainly related to skeletal muscle contraction and cytoskeleton and enriched specifically in the pentose phosphate pathway, extracellular matrix-receptor interaction, and PI3K-Akt signaling pathway, whereas the decreased DAPs were associated with the mitochondrial respiratory chain. One hundred one DAPs were identified in CON, of which the increased DAPs were primarily involved in translation/protein synthesis and the mitochondria respiratory, whereas the decreased DAPs were related to metabolic processes, cytoskeleton, and de-ubiquitination. In conclusion, the 4-week CON and ECC training resulted in distinctly different proteomic profiles, especially in proteins related to muscular structure and metabolism.

N6-methyladenosine triggers renal fibrosis via enhancing translation and stability of ZEB2 mRNA.

In recent years, a surge in studies investigating N6-methyladenosine (m6A) modification in human diseases has occurred. However, the specific roles and mechanisms of m6A in kidney disease remain incompletely understood. This study revealed that m6A plays a positive role in regulating renal fibrosis (RF) by inducing epithelial-to-mesenchymal phenotypic transition (EMT) in renal tubular cells. Through comprehensive analyses, including m6A sequencing, RNA sequencing, and functional studies, we confirmed the pivotal involvement of zinc finger E-box binding homeobox 2 (ZEB2) in m6A-mediated RF and EMT. Notably, the m6A-modified coding sequence (CDS) of ZEB2 mRNA significantly enhances its translational elongation and mRNA stability by interacting with the YTHDF1/eEF-2 complex and IGF2BP3, respectively. Moreover, targeted demethylation of ZEB2 mRNA using the dm6ACRISPR system substantially decreases ZEB2 expression and disrupts the EMT process in renal tubular epithelial cells. In vivo and clinical data further support the positive influence of m6A/ZEB2 on RF progression. Our findings highlight the m6A-mediated regulation of RF through ZEB2, revealing a novel therapeutic target for RF treatment and enhancing our understanding of the impact of mRNA methylation on kidney disease.

Cord Blood Transplantation for Very Early-Onset Inflammatory Bowel Disease Caused by Interleukin-10 Receptor Deficiency.

PURPOSE: Interleukin-10 receptor (IL-10R) deficiency can result in life-threatening very early-onset inflammatory bowel disease (VEO-IBD). Umbilical cord blood transplantation (UCBT) is a curative therapy for patients with IL-10R deficiency. This study aimed to investigate the efficacy of UCBT in treating IL-10R deficiency and develop a predictive model based on pre-transplant factors. METHODS: Eighty patients with IL-10R deficiency who underwent UCBT between July 2015 and April 2023 were retrospectively analyzed. Cox proportional hazards regression and random survival forest were used to develop a predictive model. RESULTS: Median age at transplant was 13.0 months (interquartile range [IQR], 8.8-25.3 months). With a median follow-up time of 29.4 months (IQR, 3.2-57.1 months), the overall survival (OS) rate was 65.0% (95% confidence interval [CI], 55.3%-76.3%). The engraftment rate was 85% (95% CI, 77%-93%). The cumulative incidences of acute and chronic graft-versus-host disease were 48.2% (95% CI, 37.1%-59.4%) and 12.2% (95% CI, 4.7%-19.8%), respectively. VEO-IBD-associated clinical symptoms were resolved in all survivors. The multivariate analysis showed that IL-6 and stool occult blood were independent prognostic risk factors. The multivariate Cox proportional hazards regression model with stool occult blood, length- or height-for-age Z-score, medical history of sepsis, and cord blood total nucleated cells showed good discrimination ability, with a bootstrap concordance index of 0.767-0.775 in predicting OS. CONCLUSION: Better inflammation control before transplantation and higher cord blood total nucleated cell levels can improve patient prognosis. The nomogram can successfully predict OS in patients with IL-10R deficiency undergoing UCBT.

Immunophenotype of lymphocytes and real-world outcome of COVID-19 infection in children with hematology and oncology.

BACKGROUND: Patients with immunocompromise were suspected to encounter a high risk for severe coronavirus disease 2019 (COVID-19) infection on early period; however, data is lacking nowadays and immune response remain unclear. METHODS: In this retrospective study, internet questionnaire survey and medical records were acquired in pediatric hematology oncology patients. Clinical severity, immunological characteristics, and outcomes were analyzed from December 1, 2022 to January 31, 2023 at the 3rd year of pandemic in China. RESULTS: A total of 306 patients were included, with 21 patients (6.9%) asymptomatic, 262 (85.6%) mild severity, 17 (5.6%) moderate severity, 5 (1.6%) severe severity, and 1 (0.3%) critical severity. Seventy-eight (25.5%) patients were on intensive chemotherapy, and 32.0% children were on maintenance chemotherapy. Delays in cancer therapy occurred in 86.7% patients. Univariable analysis revealed active chemotherapy (P < 0.0001), long duration of symptom (P < 0.0001), low lymphocytes count (P = 0.095), low CD3 + and CD8 + T cell count (P = 0.013, P = 0.022), high percentage of CD4 + TCM (P = 0.016), and low percentage of transitional B cells (P = 0.045) were high risk factors for severe COVID-19 infection. Cox regression model showed that the absolute lymphocytes count (P = 0.027) and long duration of symptom (P = 0.002) were the independent factors for severity. Patients with CD8 + dominant and B cell depletion subtype wasn't related with severity, but had higher percentage of CD8 + effector memory T cells (TEM) and terminally differentiated effector memory T cells (TEMRA) (P < 0.001, P < 0.001), and a longer COVID-19 duration (P = 0.045). CONCLUSION: The severity was relatively mild in children with immunodeficiencies in the third year of COVID-19 pandemic. Low lymphocyte count and long duration of symptom were the independent risk factors with COVID-19 severity. Delays in cancer care remain a major concern and the long outcome is pending.

Clinical efficacy of early microsurgical clipping of tumor neck in the treatment of cerebral aneurysm rupture and bleeding and its impact on oxidative stress response and prognosis of patients.

Cerebral aneurysm can rupture a blood vessel and cause bleeding in the brain. Microsurgical clipping of the tumor neck has been reported to be effective in treating cerebral aneurysm rupture and bleeding. This research attempted to clarify the clinical efficacy of early microsurgical clipping of tumor neck for treating cerebral aneurysm rupture and bleeding, and its impact on the prognosis of patients. One hundred patients with cerebral aneurysm rupture and bleeding patients were treated. They were selected and divided into experimental group (n=25) and control group (n=25) according to surgical time. All patients underwent microsurgical clipping of tumor neck for therapy. The control group chose to undergo surgery 72 hours after the onset of cerebral aneurysm rupture and bleeding, while the experimental group chose to undergo complete surgery within 72 hours after the onset of cerebral aneurysm rupture and bleeding. Primary outcome measures were incidence of complications, cognitive function scores, prognosis, surgical indicators, oxidative stress response and quality of life. Results showed that compared to the control group, the incidence of complications in experimental group exhibited depletion (P<0.05), the prognosis in experimental group exhibited elevation (P<0.05), the hospitalization time in experimental group exhibited depletion (P<0.05), the nomination, abstraction, language, orientation, attention, delayed recall and visual and executive function scores and total scores in experimental group exhibited elevation (P<0.05), serum levels of oxidative stress-related indicators in experimental group exhibited depletion (P<0.05) and the quality of life in experimental group exhibited elevation (P<0.05). In conclusion, early microsurgical clipping of the tumor neck can reduce the risk of complications and cognitive impairment in patients with cerebral aneurysm rupture and bleeding.

Spatiotemporal pattern of leprosy in southwest China from 2010 to 2020: an ecological study.

BACKGROUND: Despite many efforts to control leprosy worldwide, it is still a significant public health problem in low- and middle-income regions. It has been endemic in China for thousands of years, and southwest China has the highest leprosy burden in the country. METHODS: This observational study was conducted with all newly detected leprosy cases in southwest China from 2010 to 2020. Data were extracted from the Leprosy Management Information System (LEPMIS) database in China. The Joinpoint model was used to determine the time trends in the study area. Spatial autocorrelation statistics was performed to understand spatial distribution of leprosy cases. Spatial scan statistics was applied to identify significant clusters with high rate. RESULTS: A total of 4801 newly detected leprosy cases were reported in southwest China over 11 years. The temporal trends declined stably. The new case detection rate (NCDR) dropped from 4.38/1,000,000 population in 2010 to 1.25/1,000,000 population in 2020, with an average decrease of 12.24% (95% CI: -14.0 to - 10.5; P < 0.001). Results of global spatial autocorrelation showed that leprosy cases presented clustering distribution in the study area. Most likely clusters were identified during the study period and were frequently located at Yunnan or the border areas between Yunnan and Guizhou Provinces. Secondary clusters were always located in the western counties, the border areas between Yunnan and Sichuan Provinces. CONCLUSIONS: Geographic regions characterized by clusters with high rates were considered as leprosy high-risk areas. The findings of this study could be used to design leprosy control measures and provide indications to strengthen the surveillance of high-risk areas. These areas should be prioritized in the allocation of resources.

Clinical Efficacy of Early Microsurgical Clipping of Tumor Neck in the Treatment of Cerebral Aneurysm Rupture and Bleeding and Its Impact on Oxidative Stress Response and Prognosis of Patients.

Background: Cerebral aneurysm can rupture a blood vessel and cause bleeding in the brain. Microsurgical clipping of the tumor neck has been reported to be effective in treating cerebral aneurysm rupture and bleeding. Objective: This research attempted to clarify the clinical efficacy of early microsurgical clipping of tumor neck for treating cerebral aneurysm rupture and bleeding, and its impact on prognosis of patients. Design: This was a retrospective study. Setting: This study was carried out in the Department of Neurosurgery, The Yancheng School of Clinical Medicine of Nanjing Medical University, Yancheng Third People's Hospital.One hundred patients with cerebral aneurysm rupture and bleeding patients aged from 23 to 70 years old, and diagnosed with CA rupture and bleeding through imaging examinations such as CT angiography (CTA) and digital subtraction angiography (DSA), and there was spontaneous subarachnoid hemorrhage treated in our hospital from November 2020 to November 2022 were selected and divided into an experimental group (n=25) and a control group (n=25) according to surgical time. Interventions: All patients underwent microsurgical clipping of the tumor neck for therapy. Under microscope monitoring, the temporal and frontal lobes of the patient were separated, and the tumor body was selected in the internal carotid artery and cerebral artery. After the tumor neck of the patient was exposed, the artery supplying blood was clipped and appropriate tumor clips were selected. The control group chose to undergo surgery 72 h after the onset of cerebral aneurysm rupture and bleeding, while the experimental group chose to undergo complete surgery within 72 h after the onset of cerebral aneurysm rupture and bleeding. After surgery, targeted treatment were given to patients in 2 groups based on their physical condition, such as dehydration to reduce intracranial pressure, anti-vasospasm, anti-infection, monitoring of neurological changes, and monitoring of vital signs. Cerebral angiography should also be performed for reexamination. Primary Outcome Measures: (1) incidence of complications (2) cognitive function scores assessed by Montreal Cognitive Assessment (MoCA) (3) prognosis assessed by Glasgow Outcome Scale (GOS) (4) surgical indicators (5) oxidative stress response and (6) quality of life assessed by short form 36 health survey questionnaire (SF-36). Results: Compared to the control group, the incidence of complications in the experimental group exhibited depletion (24.0% vs 8.0%) (P < .05), the prognosis in the experimental group exhibited elevation [(2.23±0.45) points vs (4.12±0.3) points] (P < .05), the hospitalization time in the experimental group exhibited depletion [(15.69±1.21) d vs (11.31±0.65) d] (P < .05), the nomination, abstraction, language, orientation, attention, delayed recall and visual and executive function scores and total scores in experimental group exhibited elevation [(2.69±0.52 points, 2.07±0.63 points, 3.02±0.44 points, 2.45±0.51 points, 3.12±0.36 points, 2.14±0.75 points, 3.15±0.64 points and 17.24±2.15 points) vs (4.25±0.65 points, 3.88±1.08 points, 5.03±0.73 points, 3.34±0.72 points, 4.05±0.66 points, 3.85±0.33 points, 5.02±1.04 points and 26.89±1.33 points)] (P < .05), serum levels of oxidative stress-related indicators in the experimental group exhibited depletion [(462.14±48.47 ng/mL, 281.14±36.44 ng/mL and 1.62±0.12 nmol/mL) vs (365.58±44.56 ng/mL, 201.51±34.47 ng/mL and 1.15±0.1 nmol/mL)](P < .05) and the quality of life in experimental group exhibited elevation [(73.65±7.43 points, 72.24±7.23 points, 73.25±7.36 points, 70.24±7.05 points and 72.16±7.25 points) vs (81.25±8.14 points, 80.87±8.09 points, 81.43±8.15 points, 80.57±8.07 points and 81.32±8.14 points)] (P < .05). Conclusion: Early microsurgical clipping of the tumor neck can downregulate risk of complications and cognitive impairment of cerebral aneurysm rupture and bleeding patients, which is worthy for clinical application.

Granulysin-mediated reduction of PDZRN3 induces Cx43 gap junctions activity exacerbating skin damage in trichloroethylene hypersensitivity syndrome.

Trichloroethylene (TCE)-induced hypersensitivity syndrome (THS) has been a concern for many researchers in the field of environmental and occupational health. Currently, there is no specific treatment for THS, leaving patients to contend with severe infections arising from extensive skin lesions, consequently leading to serious adverse effects. However, the pathogenesis of severe skin damage in THS remains unclear. This study aims to investigate the specific danger signals and mechanisms underlying skin damage in THS through in vivo and in vitro experiments. We identified that cell supernatant containing 15 kDa granulysin (GNLY), released from activated CD3-CD56+NK cells or CD3+CD56+NKT cells in PBMC induced by TCE or its metabolite, promoted apoptosis in HaCaT cells. The apoptosis level decreased upon neutralization of GNLY in the supernatant by a GNLY-neutralizing antibody in HaCaT cells. Subcutaneous injection of recombinant 15 kDa GNLY exacerbated skin damage in the THS mouse model and better mimicked patients' disease states. Recombinant 15 kDa GNLY could directly induce cellular communication disorders, inflammation, and apoptosis in HaCaT cells. In addition to its cytotoxic effects, GNLY released from TCE-activated NK cells and NKT cells or synthesized GNLY alone could induce aberrant expression of the E3 ubiquitin ligase PDZRN3, causing dysregulation of the ubiquitination of the cell itself. Consequently, this resulted in the persistent opening of gap junctions composed of connexin43, thereby intensifying cellular inflammation and apoptosis through the "bystander effect". This study provides experimental evidence elucidating the mechanisms of THS skin damage and offers a novel theoretical foundation for the development of effective therapies targeting severe dermatitis induced by chemicals or drugs.

Small Molecule-Inducible and Photoactivatable Cellular RNA N1-Methyladenosine Editing.

N1-methyladenosine (m1A) modification is one of the most prevalent epigenetic modifications on RNA. Given the vital role of m1A modification in RNA processing such as splicing, stability and translation, developing a precise and controllable m1A editing tool is pivotal for in-depth investigating the biological functions of m1A. In this study, we developed an abscisic acid (ABA)-inducible and reversible m1A demethylation tool (termed AI-dm1A), which targets specific transcripts by combining the chemical proximity-induction techniques with the CRISPR/dCas13b system and ALKBH3. We successfully employed AI-dm1A to selectively demethylate the m1A modifications at A8422 of MALAT1 RNA, and this demethylation process could be reversed by removing ABA. Furthermore, we validated its demethylation function on various types of cellular RNAs including mRNA, rRNA and lncRNA. Additionally, we used AI-dm1A to specifically demethylate m1A on ATP5D mRNA, which promoted ATP5D expression and enhanced the glycolysis activity of tumor cells. Conversely, by replacing the demethylase ALKBH3 with methyltransferase TRMT61A, we also developed a controllable m1A methylation tool, namely AI-m1A. Finally, we caged ABA by 4,5-dimethoxy-2-nitrobenzyl (DMNB) to achieve light-inducible m1A methylation or demethylation on specific transcripts. Collectively, our m1A editing tool enables us to flexibly study how m1A modifications on specific transcript influence biological functions and phenotypes.

Toxicity of low dose bisphenols in human iPSC-derived cardiomyocytes and human cardiac organoids - Impact on contractile function and hypertrophy.

Bisphenol A (BPA) and its analogs are common environmental chemicals with various adverse health impacts, including cardiac toxicity. In this study, we examined the long term effect of low dose BPA and three common BPA analogs, bisphenol S (BPS), bisphenol F (BPF), and bisphenol AF (BPAF), in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) based models. HiPSC-CMs and human cardiac organoids were exposed to these chemicals for 4-5 or 20 days. 1 nM BPA, BPS, and BPAF, but not BPF, resulted in suppressed myocyte contractility, retarded contraction kinetics, and aberrant Ca2+ transients in hiPSC-CMs. In cardiac organoids, BPAF and BPA, but not the other bisphenols, resulted in suppressed contraction and Ca2+ transients, and aberrant contraction kinetics. The order of toxicities was BPAF > BPA>∼BPS > BPF and the toxicities of BPAF and BPA were more pronounced under longer exposure. The impact of BPAF on myocyte contraction and Ca2+ handling was mediated by reduction of sarcoplasmic reticulum Ca2+ load and inhibition of L-type Ca2+ channel involving alternation of Ca2+ handling proteins. Impaired myocyte Ca2+ handling plays a key role in cardiac pathophysiology and is a characteristic of cardiac hypertrophy; therefore we examined the potential pro-hypertrophic cardiotoxicity of these bisphenols. Four to five day exposure to BPAF did not cause hypertrophy in normal hiPSC-CMs, but significantly exacerbated the hypertrophic phenotype in myocytes with existing hypertrophy induced by endothelin-1, characterized by increased cell size and elevated expression of the hypertrophic marker proBNP. This pro-hypertrophic cardiotoxicity was also occurred in cardiac organoids, with BPAF having the strongest toxicity, followed by BPA. Our findings demonstrate that long term exposures to BPA and some of its analogs cause contractile dysfunction and abnormal Ca2+ handling, and have potential pro-hypertrophic cardiotoxicity in human heart cells/tissues, and suggest that some bisphenol chemicals may be a risk factor for cardiac hypertrophy in human hearts.

The RNA m6A reader IGF2BP3 regulates NFAT1/IRF1 axis-mediated anti-tumor activity in gastric cancer.

N6-methyladenosine (m6A) and its associated reader protein insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3) are involved in tumor initiation and progression via regulating RNA metabolism. This study aims to investigate the biological function and clinical significance of IGF2BP3 in gastric cancer (GC). The clinical significance of IGF2BP3 was evaluated using tumor related databases and clinical tissues. The biological role and molecular mechanism of IGF2BP3 in GC progression were investigated by multi-omics analysis including Ribosome sequence (Ribo-seq), RNA sequence (RNA-seq) and m6A sequence (m6A-seq) combined with gain- and loss- of function experiments. IGF2BP3 expression is significantly elevated in GC tissues and associated with poor prognosis of GC patients. Knockdown of IGF2BP3 significantly weakens the migration and clonogenic ability, promotes the apoptosis, inhibits translation, and suppresses in vitro growth and progression of GC cells. Mechanistically, IGF2BP3 regulates the mRNA stability and translation of the nuclear factor of activated T cells 1(NFAT1) in a m6A dependent manner. Then NFAT1 induced by IGF2BP3 acts as a transcription factor (TF) to negatively regulates the promoter activities of interferon regulatory factor 1 (IRF1) to inhibit its expression. Inhibition of IGF2BP3-induced expression of IRF1 activates interferon (IFN) signaling pathway and then exerts its anti-tumor effect. Elevated IGF2BP3 promotes in vivo and in vitro GC progression via regulation of NFAT1/IRF1 pathways. Targeted inhibition of IGF2BP3 might be a potential therapeutic approach for GC treatment.

TeamSTEPPS improves patient safety.

BACKGROUND: Examine how Team Strategies and Tools to Enhance Performance and Patient Safety (TeamSTEPPS) can be used to manage patient safety and improve the standard of care for patients. METHODS: In order to improve key medical training in areas like surgical safety management, blood transfusion closed-loop management, drug safety management and identity recognition, we apply the TeamSTEPPS teaching methodology. We then examine the effects of this implementation on changes in pertinent indicators. RESULTS: Our hospital's perioperative death rate dropped to 0.019%, unscheduled reoperations dropped to 0.11%, and defined daily doses fell to 24.85. Antibiotic usage among hospitalised patients declined to 40.59%, while the percentage of antibacterial medicine prescriptions for outpatient patients decreased to 13.26%. Identity recognition requirements were implemented at a rate of 94.5%, and the low-risk group's death rate dropped to 0.01%. Critical transfusion episodes were less common, with an incidence of 0.01%. The physician's TeamSTEPPS Teamwork Perceptions Questionnaire and Teamwork Attitudes Questionnaire scores dramatically improved following the TeamSTEPPS team instruction course. CONCLUSION: An evidence-based team collaboration training programme called TeamSTEPPS combines clinical practice with team collaboration skills to enhance team performance in the healthcare industry and raise standards for medical quality, safety, and effectiveness.

Parents' Experiences of Communicating With Children About Their Diagnosis of Nonterminal Cancer and Its Related Issues: A Systematic Review of Qualitative Studies.

BACKGROUND: Many children experience serious symptoms when they are diagnosed with and treated for cancer. Through appropriate parent-child communication, parents were able to identify children's physical and psychological problems, adjust their behavior, and help them cope with the disease. OBJECTIVE: This study aimed to systematically search for and integrate evidence from qualitative studies on communication between parents and children with nonterminal cancer from parents' perspectives. METHODS: A thorough systematic review and metasynthesis of qualitative studies were conducted. Articles were searched from PubMed/MEDLINE, EMBASE, Web of Science, CINAHL, PsycINFO, and PsycArticles from the database inception to November 6, 2022. After screening and quality appraisal, 14 articles were finally included in the metasynthesis. RESULTS: Three themes and 11 subthemes were identified: (1) communication content, including diagnosis, treatment, health management, health risk, and emotion; (2) factors influencing communication, including ages of children, parents' experience of communication, parents' awareness of protection, and culture; and (3) children's responses, including acceptance and resistance. CONCLUSIONS: This systematic review found that parents were influenced by various factors during the decision-making process of parent-child communication about childhood cancer and its related issues. Parents tended to adjust their communication content and style to protect their children. IMPLICATIONS FOR PRACTICE: Future research should be conducted to explore children's experiences of communicating with their parents and analyze the similarities and differences between the communication needs of parents and children. Healthcare professionals should provide professional communication guidance to facilitate the parent-child relationship and improve the mental health of both children and their parents.

Association of same-day urinary phenol levels and cardiac electrical alterations: analysis of the Fernald Community Cohort.

Background: Exposure to phenols has been linked in animal models and human populations to cardiac function alterations and cardiovascular diseases, although their effects on cardiac electrical properties in humans remains to be established. This study aimed to identify changes in electrocardiographic (ECG) parameters associated with environmental phenol exposure in adults of a midwestern large cohort known as the Fernald Community Cohort (FCC). Methods: During the day of the first comprehensive medical examination, urine samples were obtained, and electrocardiograms were recorded. Cross-sectional linear regression analyses were performed. Results: Bisphenol A (BPA) and bisphenol F (BPF) were both associated with a longer PR interval, an indication of delayed atrial-to-ventricle conduction, in females (p < 0.05) but not males. BPA combined with BPF was associated with an increase QRS duration, an indication of delayed ventricular activation, in females (P < 0.05) but not males. Higher triclocarban (TCC) level was associated with longer QTc interval, an indication of delayed ventricular repolarization, in males (P < 0.01) but not females. Body mass index (BMI) was associated with a significant increase in PR and QTc intervals and ventricular rate in females and in ventricular rate in males. In females, the combined effect of being in the top tertile for both BPA urinary concentration and BMI was an estimate of a 10% increase in PR interval. No associations were found with the other phenols. Conclusion: Higher exposure to some phenols was associated with alterations of cardiac electrical properties in a sex specific manner in the Fernald cohort. Our population-based findings correlate directly with clinically relevant parameters that are associated with known pathophysiologic cardiac conditions in humans.

The development of RT-RPA and CRISPR-Cas12a based assay for sensitive detection of infectious hematopoietic necrosis virus (IHNV).

Infectious hematopoietic necrosis virus (IHNV) is an economically important virus causing significant mortalities among wild and cultured salmonid fish worldwide. Rapid and sensitive diagnostic methods of IHNV are crucial for timely controlling infections. For better detection of IHNV, we have established a detection technology based on the reverse transcription and recombinase polymerase amplification (RT-RPA) and CRISPR/Cas12a to detect the N gene of IHNV in two steps. Following the screening of primer pairs, the reaction temperature and time for RPA were optimized to be 41 °C and 35 min, respectively, and the CRISPR/Cas12a reaction was performed at 37 °C for 15 min. The whole detection procedure including can be accomplished within one hour, with a detection sensitivity of about 9.5 copies/µL. The detection method exhibited high specificity with no cross-reaction to the other Novirhabdoviruses HIRRV and VHSV, allowing naked-eye interpretation of the results through lateral flow or fluorescence under ultraviolet light. Overall, our results demonstrated that the developed RT-RPA-Cas12a-mediated assay is a rapid, specific and sensitive detection method for routine and on-site detection of IHNV, which shows a great application promise for the prevention of IHNV infections.

Prevalence and Molecular Characteristics of Enterococci Isolated from Clinical Bovine Mastitis Cases in Ningxia.

Purpose: This study aimed to investigate the prevalence and genetic characterization of enterococcal isolates (Enterococcus faecalis, Enterococcus faecium and Enterococcus hirae) isolated from clinical bovine mastitis cases in Ningxia, China. Patients and Methods: The enterococci were identified by 16S rRNA amplification and sequencing. Antimicrobial resistance was determined by disc diffusion method. Virulence and antimicrobial resistance genes were detected by PCR assays. Results: Overall, 198 enterococcal isolates were identified from 2897 mastitis samples, including 137 (4.7%) E. faecalis, 50 (1.7%) E. faecium and 11 (0.4%) E. hirae. E. faecalis, E. faecium and E. hirae isolates showed high resistance to tetracycline (92.7%, 68.0%, 90.9%), followed by erythromycin (86.9%, 76.0%, 72.7%). The multidrug-resistant strains of E. faecalis and E. faecium were 29 (21.2%) and 13 (26.0%), respectively. The resistance of E. faecalis, E. faecium and E. hirae isolates to tetracycline is mainly attributed to the presence of tetL (alone or combined with tetM and/or tetK), the erythromycin resistance to ermB (alone or combined with ermC and/or ermA). Moreover, cpd (94.2%), gelE (77.4%), efaAfs (93.4%), and esp (79.6%) were the most common virulence genes in E. faecalis. In E. faecium, except for the gene efaAfs (82.0%), other virulence genes are rarely found. Only two strains of E. hirae carrying asa1 gene were detected. Conclusion: The results of this study can provide a reference for the prevention and treatment of bovine mastitis caused by enterococci.

IGF2BP3/NCBP1 complex inhibits renal tubular senescence through regulation of CDK6 mRNA stability.

Renal aging and the subsequent rise in kidney-related diseases are attributed to senescence in renal tubular epithelial cells (RTECs). Our study revealed that the abnormal expression of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), a reader of RNA N6-methyladenosine, is critically involved in cisplatin-induced renal tubular senescence. In cisplatin-induced senescence of RTECs, the promoter activity and transcription of IGF2BP3 is markedly suppressed. It was due to the down regulation of MYC proto-oncogene (MYC), which regulates IGF2BP3 transcription by binding to the putative site at 1852-1863 of the IGF2BP3 promoter. Overexpression of IGF2BP3 ameliorated cisplatin-induced renal tubular senescence in vitro. Mechanistic studies revealed that IGF2BP3 inhibits cellular senescence in RTECs by enhancing cyclin-dependent kinase 6 (CDK6) mRNA stability and increasing its expression. The inhibition effect of IGF2BP3 on tubular senescence is partially reversed by the knockdown of CDK6. Further, IGF2BP3 recruits nuclear cap binding protein subunit 1 (NCBP1) and inhibits CDK6 mRNA decay, by recognizing m6A modification. Specifically, IGF2BP3 recognizes m6A motif "GGACU" at nucleotides 110-114 in the 5' untranslated region (UTR) field of CDK6 mRNA. The involvement of IGF2BP3/CDK6 in alleviating tubular senescence was confirmed in a cisplatin-induced acute kidney injury (AKI)-to-chronic kidney disease (CKD) model. Clinical data also suggests an age-related decrease in IGF2BP3 and CDK6 levels in renal tissue or serum samples from patients. These findings suggest that IGF2BP3/CDK6 may be a promising target in cisplatin-induced tubular senescence and renal failure.

Disasters pile up on the rubbing heel: Sporothrix globosa as secondary infection to Mycobacterium chelonae infection.

Mycobacterium chelonae and Sporothrix globosa, both of which are opportunistic pathogens, have been proved to be possible multidrug resistant. However, are all recurring symptoms in chronic infections related to decreasing susceptibility? Here we report a case of sporotrichosis secondary to M. chelonae infection. In addition, we find that the blackish-red spots under the dermoscopic view can be employed as a signal for the early identification and regression of subcutaneous fungal infection.

Purification and analysis of kidney-infiltrating leukocytes in a mouse model of lupus nephritis.

Renal injury often occurs as a complication in autoimmune diseases such as systemic lupus erythematosus (SLE). It is estimated that a minimum of 20% SLE patients develop lupus nephritis, a condition that can be fatal when the pathology progresses to end-stage renal disease. Studies in animal models showed that incidence of immune cell infiltrates in the kidney was linked to pathological injury and correlated with severe lupus nephritis. Thus, preventing immune cell infiltration into the kidney is a potential approach to impede the progression to an end-stage disease. A requirement to investigate the role of kidney-infiltrating leukocytes is the development of reproducible and efficient protocols for purification and characterization of immune cells in kidney samples. This chapter describes a detailed methodology that discriminates tissue-resident leukocytes from blood-circulating cells that are found in kidney. Our protocol was designed to maximize cell viability and to reduce variability among samples, with a combination of intravascular staining and magnetic bead separation for leukocyte enrichment. Experiments included as example were performed with FcγRIIb[KO] mice, a well-characterized murine model of SLE. We identified T cells and macrophages as the primary leukocyte subsets infiltrating into the kidney during severe nephritis, and we extensively characterized them phenotypically by flow cytometry.

Human Adipose-Derived Mesenchymal Stem Cells Colonize and Promote Healing of Leprosy Ulcer by Inducing Neuro-Vascularization.

Leprosy ulcer is a chronic and recurrent disease resulting from nerve injury. While existing treatments partially facilitate ulcer healing, they exhibit limited ability to address localized nerve repair, leading to a risk of recurrence. Moreover, there is a dearth of animal models to evaluate the preclinical efficacy and safety of novel therapeutic approaches. Over the years, adipose-derived mesenchymal stem cells have been extensively employed in regenerative medicine as an optimal cell therapy source for fostering skin ulcer healing. They have also demonstrated the capacity to enhance nerve regeneration in in vitro experiments and clinical trials. In this study, we established a NU/NU mouse foot pad leprosy ulcer model, transplanted human adipose-derived stem cells (hADSCs) into leprosy ulcers via local injection, and conducted subsequent follow-up. Our findings revealed that hADSCs persisted in the leprosy ulcer and facilitated the healing process. In this respect, gross observation and histological analysis revealed increased granular formation, collagen synthesis, and re-epithelialization in the local ulcer area. RNA-Seq data revealed that the upregulated differential genes resulting from the transplantation intervention were not only enriched in pathways related to re-epithelialization and collagen synthesis but also contributed to local nerve regeneration. Furthermore, immunofluorescence assays revealed the increased expression of angiogenesis markers-CD31 and VEGFa, cell proliferation markers-Ki67 and TGF-ß, and nerve regeneration markers-ß3-tubulin, SOX10, NGF, and NT-3. These results underscore the potential of hADSCs in promoting the healing of leprosy ulcers and offer valuable preclinical data for their prospective clinical application.