Dapagliflozin ameliorates myocardial infarction injury through AMPKα-dependent regulation of oxidative stress and apoptosis.

Dapagliflozin (DAPA) has been demonstrated to reduce cardiovascular mortality and heart failure hospitalization rates in diabetic patients. However, the mechanism underlying its cardio-protective effect in non-diabetic patients remains unclear. Our study aimed to explore the cardio-protective impact of DAPA on myocardial infarction in non-diabetic mice. We induced myocardial infarction in C57BL/6 mice by ligating the descending branch of the left coronary artery. After surgery, the animals were randomly treated with either saline or DAPA. We employed echocardiography, Western blot analysis, and tissue staining to assess post-infarction myocardial injury. Additionally, we investigated the mechanism of action through cell experiments. Compared to the myocardial infarction group, DAPA treatment significantly attenuated ventricular remodeling and improved cardiac function. By mitigating myocardial oxidative stress and apoptosis, DAPA may activate the AMPKα signaling pathway, thereby exerting a protective effect. These findings suggest that DAPA could serve as a novel therapeutic approach for patients with cardiac infarction.

Racial/Ethnic Differences in Long-COVID-Associated Symptoms among Pediatrics Population: Findings from Difference-in-differences Analyses in RECOVER Program.

Racial/ethnic differences are associated with the potential symptoms and conditions of post-acute sequelae SARS-CoV-2 infection (PASC) in adults. These differences may exist among children and warrant further exploration. We conducted a retrospective cohort study for children and adolescents under the age of 21 from the thirteen institutions in the RECOVER Initiative. The cohort is 225,723 patients with SARS-CoV-2 infection or COVID-19 diagnosis and 677,448 patients without SARS-CoV-2 infection or COVID-19 diagnosis between March 2020 and October 2022. The study compared minor racial/ethnic groups to Non-Hispanic White (NHW) individuals, stratified by severity during the acute phase of COVID-19. Within the severe group, Asian American/Pacific Islanders (AAPI) had a higher prevalence of fever/chills and respiratory symptoms, Hispanic patients showed greater hair loss prevalence in severe COVID-19 cases, while Non-Hispanic Black (NHB) patients had fewer skin symptoms in comparison to NHW patients. Within the non-severe group, AAPI patients had increased POTS/dysautonomia and respiratory symptoms, and NHB patients showed more cognitive symptoms than NHW patients. In conclusion, racial/ethnic differences related to COVID-19 exist among specific PASC symptoms and conditions in pediatrics, and these differences are associated with the severity of illness during acute COVID-19.

Influence of interactions between bubbles on physico-chemical effects of acoustic cavitation.

Ultrasound technology has been extensively used as one of the efficient and economic methodology to achieve the desired outcomes in many applications by harnessing the physico-chemical effects of acoustic cavitation. However, the cavitation-associated effects, primarily determined by the oscillatory dynamics of cavitation bubbles, are considerably complex and still remain poorly understood. The main objective of this study was to perform a numerical analysis of the acoustic cavitation (i.e., the cavitation dynamics, the resultant temperature, pressure and chemical yields within collapsing bubbles), particularly focusing on the influence of the interactions between bubbles. A comprehensive model was developed to simulate the acoustic cavitation dynamics via combining the influences of mass transfer, heat conduction and chemical reactions as well as the interaction effects between bubbles. The results demonstrated that only the large bubble exerts a greater impact on the small one in a two-bubble system. Specifically, within parameter ranges covered this study, there are noticeable decreases in the expansion ratio of the small bubble, the resultant temperature, pressure and molar yields of free radicals, hence weakening the cavitation intensity and cavitation- associated physico-chemical effects. Moreover, the influences of the interactions between bubbles were further assessed quantitatively under various parameters, such as the ultrasound amplitude PA and frequency f, the distance between bubbles d0, the initial radius of the large bubble R20, as well as the liquid properties (e.g., surface tension σ and viscosity µ). It was found that the suppression effect can be amplified when subjected to ultrasound with an increased PA and/or a decreased f, probably due to a stronger cavitation intensity under this condition. Additionally, the suppression effect is also enhanced with a decrease in d0, σ and µ, but with R20 increasing. This study can contribute to deepening knowledge about acoustic cavitation and the resultant physical and/or chemical effects, potentially further facilitating the ultrasound-assisted various applications involving acoustic cavitation.

Real-World Effectiveness of BNT162b2 Against Infection and Severe Diseases in Children and Adolescents.

BACKGROUND: The efficacy of the BNT162b2 vaccine in pediatrics was assessed by randomized trials before the Omicron variant's emergence. The long-term durability of vaccine protection in this population during the Omicron period remains limited. OBJECTIVE: To assess the effectiveness of BNT162b2 in preventing infection and severe diseases with various strains of the SARS-CoV-2 virus in previously uninfected children and adolescents. DESIGN: Comparative effectiveness research accounting for underreported vaccination in 3 study cohorts: adolescents (12 to 20 years) during the Delta phase and children (5 to 11 years) and adolescents (12 to 20 years) during the Omicron phase. SETTING: A national collaboration of pediatric health systems (PEDSnet). PARTICIPANTS: 77 392 adolescents (45 007 vaccinated) during the Delta phase and 111 539 children (50 398 vaccinated) and 56 080 adolescents (21 180 vaccinated) during the Omicron phase. INTERVENTION: First dose of the BNT162b2 vaccine versus no receipt of COVID-19 vaccine. MEASUREMENTS: Outcomes of interest include documented infection, COVID-19 illness severity, admission to an intensive care unit (ICU), and cardiac complications. The effectiveness was reported as (1-relative risk)*100, with confounders balanced via propensity score stratification. RESULTS: During the Delta period, the estimated effectiveness of the BNT162b2 vaccine was 98.4% (95% CI, 98.1% to 98.7%) against documented infection among adolescents, with no statistically significant waning after receipt of the first dose. An analysis of cardiac complications did not suggest a statistically significant difference between vaccinated and unvaccinated groups. During the Omicron period, the effectiveness against documented infection among children was estimated to be 74.3% (CI, 72.2% to 76.2%). Higher levels of effectiveness were seen against moderate or severe COVID-19 (75.5% [CI, 69.0% to 81.0%]) and ICU admission with COVID-19 (84.9% [CI, 64.8% to 93.5%]). Among adolescents, the effectiveness against documented Omicron infection was 85.5% (CI, 83.8% to 87.1%), with 84.8% (CI, 77.3% to 89.9%) against moderate or severe COVID-19, and 91.5% (CI, 69.5% to 97.6%) against ICU admission with COVID-19. The effectiveness of the BNT162b2 vaccine against the Omicron variant declined 4 months after the first dose and then stabilized. The analysis showed a lower risk for cardiac complications in the vaccinated group during the Omicron variant period. LIMITATION: Observational study design and potentially undocumented infection. CONCLUSION: This study suggests that BNT162b2 was effective for various COVID-19-related outcomes in children and adolescents during the Delta and Omicron periods, and there is some evidence of waning effectiveness over time. PRIMARY FUNDING SOURCE: National Institutes of Health.

Salinomycin and IR780-loaded upconversion nanoparticles influence biological behavior of liver cancer stem cells by persistently activating the MAPK signaling pathway.

The combination of chemotherapy and phototherapy has emerged as a promising therapeutic approach for enhancing the efficacy of cancer treatment and mitigating drug resistance. Salinomycin (SAL), a polyether antibiotic, exhibits potent cytotoxicity against chemotherapy-resistant cancer cells. IR780 iodide, a novel photosensitive reagent with excellent near-infrared (NIR) light absorption and photothermal conversion abilities, is suitable for use in photothermal therapy for cancers. However, both SAL and IR780 exhibit hydrophobic properties that limit their clinical applicability. Upconversion nanoparticles (UCNPs) are an emerging class of fluorescent probe materials capable of emitting high-energy photons upon excitation by low-energy NIR light. The UCNPs not only function as nanocarriers for drug delivery but also serve as light transducers to activate photosensitizers for deep-tissue photodynamic therapy. Here, to enhance the targeting and bioavailability of hydrophobic drugs in liver cancer stem cells (LCSCs), we employ distearoyl phosphorethanolamine-polyethylene glycol (DSPE-PEG) to encapsulate SAL and IR780 on the surface of UCNPs. Cell viability was evaluated using the CCK-8 assay. Cell migration was assessed by the Transwell Boyden Chamber. The activation of the mitogen-activated protein kinase (MAPK) signaling pathway was measured via western blot. The results demonstrated successful loading of both IR780 and SAL onto the UCNPs, and the SAL and IR780-loaded UCNPs (UISP) exhibited a robust photothermal effect under NIR light irradiation. The UISP effectively inhibited the viability of HCCLM3 and LCSCs. Under NIR light irradiation, the UISP further suppressed HCCLM3 viability but had no impact on LCSC viability; however, it could further inhibit LCSC migration. Meanwhile, under NIR light irradiation, the UISP persistently activated the MAPK pathway more significantly in LCSCs. These findings suggest that exposure to NIR light results in persistent activation of the MAPK pathway by UISP, thereby influencing the biological behavior of LCSCs and enhancing their therapeutic efficacy against liver cancer.

Research protocol of the efficacy of probiotics for the treatment of alcohol use disorder among adult males: A comparison with placebo and acceptance and commitment therapy in a randomized controlled trial.

BACKGROUND AND AIM: Primarily, this study compares the efficacy of probiotic and acceptance and commitment therapy (ACT) in alleviating the severity of alcohol craving and alcohol use disorder (AUD) among patients who had undergo two weeks of in-patient detoxification. Secondarily, this study compares the efficacy of probiotic and ACT in mitigating the severity of comorbid depression and anxiety symptoms; decreasing serum level of pro-inflammatory cytokines, such as interleukin 1ß (IL-1ß), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α); changing the event-related potential in electroencephalogram (EEG) and restoring microbiota flora in the gut of AUD patients. METHODS AND ANALYSIS: Initially, during Phase I of the study, the serum level of IL-1ß, IL-6 and TNF-α; ERP changes in the EEG and fecal microbiota content will be compared between 120 AUD patients and 120 healthy controls. Subsequently in Phase II of the study, 120 AUD patients will be randomized by stratified permuted block randomization into the probiotic, ACT and placebo groups in a 1:1:1 ratio. Participants in the probiotic and placebo groups will be administered one sachet per day of Lactobacillus spp. probiotic and placebo, respectively for 12 weeks. While those in the ACT group will receive one session per week of ACT for 8 weeks. Outcome measures will be administered at four timepoints, such as t0 = baseline assessment prior to intervention, t1 = 8 weeks after intervention began, t2 = 12 weeks after intervention and t3 = 24 weeks after intervention. Primary outcomes are the degrees of alcohol craving, alcohol withdrawal during abstinence and AUD. Secondary outcomes to be assessed are the severity of co-morbid depression and anxiety symptoms; the serum levels of IL-1ß, IL-6 and TNF-α; changes in ERP and fecal microbiota content. TRIAL REGISTRATION NUMBER: NCT05830708 (ClinicalTrials.gov). Registered on April 25, 2023.

Real-world Effectiveness of BNT162b2 Against Infection and Severe Diseases in Children and Adolescents.

Background: The efficacy of the BNT162b2 vaccine in pediatrics was assessed by randomized trials before the Omicron variant's emergence. The long-term durability of vaccine protection in this population during the Omicron period remains limited. Objective: To assess the effectiveness of BNT162b2 in preventing infection and severe diseases with various strains of the SARS-CoV-2 virus in previously uninfected children and adolescents. Design: Comparative effectiveness research accounting for underreported vaccination in three study cohorts: adolescents (12 to 20 years) during the Delta phase, children (5 to 11 years) and adolescents (12 to 20 years) during the Omicron phase. Setting: A national collaboration of pediatric health systems (PEDSnet). Participants: 77,392 adolescents (45,007 vaccinated) in the Delta phase, 111,539 children (50,398 vaccinated) and 56,080 adolescents (21,180 vaccinated) in the Omicron period. Exposures: First dose of the BNT162b2 vaccine vs. no receipt of COVID-19 vaccine. Measurements: Outcomes of interest include documented infection, COVID-19 illness severity, admission to an intensive care unit (ICU), and cardiac complications. The effectiveness was reported as (1-relative risk)*100% with confounders balanced via propensity score stratification. Results: During the Delta period, the estimated effectiveness of BNT162b2 vaccine was 98.4% (95% CI, 98.1 to 98.7) against documented infection among adolescents, with no significant waning after receipt of the first dose. An analysis of cardiac complications did not find an increased risk after vaccination. During the Omicron period, the effectiveness against documented infection among children was estimated to be 74.3% (95% CI, 72.2 to 76.2). Higher levels of effectiveness were observed against moderate or severe COVID-19 (75.5%, 95% CI, 69.0 to 81.0) and ICU admission with COVID-19 (84.9%, 95% CI, 64.8 to 93.5). Among adolescents, the effectiveness against documented Omicron infection was 85.5% (95% CI, 83.8 to 87.1), with 84.8% (95% CI, 77.3 to 89.9) against moderate or severe COVID-19, and 91.5% (95% CI, 69.5 to 97.6)) against ICU admission with COVID-19. The effectiveness of the BNT162b2 vaccine against the Omicron variant declined after 4 months following the first dose and then stabilized. The analysis revealed a lower risk of cardiac complications in the vaccinated group during the Omicron variant period. Limitations: Observational study design and potentially undocumented infection. Conclusions: Our study suggests that BNT162b2 was effective for various COVID-19-related outcomes in children and adolescents during the Delta and Omicron periods, and there is some evidence of waning effectiveness over time. Primary Funding Source: National Institutes of Health.

The efficacy of virtual reality exposure therapy for the treatment of alcohol use disorder among adult males: a randomized controlled trial comparing with acceptance and commitment therapy and treatment as usual.

Background: This multicenter, three-armed, parallel, single-blind randomized controlled trial (RCT) primarily aims to compare the efficacy of virtual reality exposure therapy (VRET) with that of acceptance and commitment therapy (ACT) and treatment as usual (TAU) to depreciate the degree of alcohol craving among alcohol use disorder patients who have undergone in-patient detoxification across four timelines (t0 = baseline prior to intervention, t1 = 4 weeks after baseline, t2 = 12 weeks after baseline, and t3 = 24 weeks after baseline). The secondary aims of this RCT are to compare the efficacy of VRET with that of ACT and TAU to alleviate the severity of alcohol use disorder, dissipate comorbid depressive and anxiety symptoms, and normalize event-related potential (ERP) in electroencephalogram (EEG) monitoring across the four timelines. Methods: Initially, after 2 weeks of in-patient detoxification, 120 patients with alcohol use disorder will be randomized into three groups (VRET, ACT, and TAU control groups) via stratified permuted block randomization in a 1:1:1 ratio. Baseline assessment (t0) commences, whereby all the participants will be administered with sociodemographic, clinical, and alcohol use characteristics questionnaire, such as Alcohol Use Disorder Identification Test (AUDIT), Penn Alcohol Craving Scale (PACS), Hamilton Anxiety Rating Scale (HAM-A), and Hamilton Depression Rating Scale (HAM-D), while event-related potential (ERP) detection in electroencephalogram (EEG) will also be carried out. Then, 4 weeks of VRET, ACT, and non-therapeutic supportive activities will be conducted in the three respective groups. For the subsequent three assessment timelines (t1, t2, and t3), the alcohol use characteristic questionnaire, such as AUDIT, PACS, HAM-D, HAM-A, and ERP monitoring, will be re-administered to all participants. Discussion: As data on the effects of non-pharmacological interventions, such as VRET and ACT, on the treatment of alcohol craving and preventing relapse in alcohol use disorder are lacking, this RCT fills the research gap by providing these important data to treating clinicians. If proven efficacious, the efficacy of VRET and ACT for the treatment of other substance use disorders should also be investigated in future. Clinical trial registration: NCT05841823 (ClinicalTrials.gov).

The Importance of Using Realistic 3D Canopy Models to Calculate Light Interception in the Field.

Quantifying canopy light interception provides insight into the effects of plant spacing, canopy structure, and leaf orientation on radiation distribution. This is essential for increasing crop yield and improving product quality. Canopy light interception can be quantified using 3-dimensional (3D) plant models and optical simulations. However, virtual 3D canopy models (VCMs) have often been used to quantify canopy light interception because realistic 3D canopy models (RCMs) are difficult to obtain in the field. This study aims to compare the differences in light interception between VCMs and RCM. A realistic 3D maize canopy model (RCM) was reconstructed over a large area of the field using an advanced unmanned aerial vehicle cross-circling oblique (CCO) route and the structure from motion-multi-view stereo method. Three types of VCMs (VCM-1, VCM-4, and VCM-8) were then created by replicating 1, 4, and 8 individual realistic plants constructed by CCO in the center of the corresponding RCM. The daily light interception per unit area (DLI), as computed for the 3 VCMs, exhibited marked deviation from the RCM, as evinced by the relative root mean square error (rRMSE) values of 20.22%, 17.38%, and 15.48%, respectively. Although this difference decreased as the number of plants used to replicate the virtual canopy increased, rRMSE of DLI for VCM-8 and RCM still reached 15.48%. It was also found that the difference in light interception between RCMs and VCMs was substantially smaller in the early stage (48 days after sowing [DAS]) than in the late stage (70 DAS). This study highlights the importance of using RCM when calculating light interception in the field, especially in the later growth stages of plants.

Integrated transcriptome and microRNA sequencing analyses reveal gene responses in poplar leaves infected by the novel pathogen bean common mosaic virus (BCMV).

Recently, a novel poplar mosaic disease caused by bean common mosaic virus (BCMV) was investigated in Populus alba var. pyramidalis in China. Symptom characteristics, physiological performance of the host, histopathology, genome sequences and vectors, and gene regulation at the transcriptional and posttranscriptional levels were analyzed and RT-qPCR (quantitative reverse transcription PCR) validation of expression was performed in our experiments. In this work, the mechanisms by which the BCMV pathogen impacts physiological performance and the molecular mechanisms of the poplar response to viral infection were reported. The results showed that BCMV infection decreased the chlorophyll content, inhibited the net photosynthesis rate (Pn) and stomatal conductance (Gs), and significantly changed chlorophyll fluorescence parameters in diseased leaves. Transcriptome analysis revealed that the expression of the majority of DEGs (differentially expressed genes) involved in the flavonoid biosynthesis pathway was promoted, but the expression of all or almost all DEGs associated with photosynthesis-antenna proteins and the photosynthesis pathway was inhibited in poplar leaves, suggesting that BCMV infection increased the accumulation of flavonoids but decreased photosynthesis in hosts. Gene set enrichment analysis (GSEA) illustrated that viral infection promoted the expression of genes involved in the defense response or plant-pathogen interaction. MicroRNA-seq analysis illustrated that 10 miRNA families were upregulated while 6 families were downregulated in diseased poplar leaves; moreover, miR156, the largest family with the most miRNA members and target genes, was only differentially upregulated in long-period disease (LD) poplar leaves. Integrated transcriptome and miRNA-seq analyses revealed 29 and 145 candidate miRNA-target gene pairs; however, only 17 and 76 pairs, accounting for 2.2% and 3.2% of all DEGs, were authentically negatively regulated in short-period disease (SD) and LD leaves, respectively. Interestingly, 4 miR156/SPL (squamosa promoter-binding-like protein) miRNA-target gene pairs were identified in LD leaves: the miR156 molecules were upregulated, but SPL genes were downregulated. In conclusion, BCMV infection significantly changed transcriptional and posttranscriptional gene expression in poplar leaves, inhibited photosynthesis, increased the accumulation of flavonoids, induced systematic mosaic symptoms, and decreased physiological performance in diseased poplar leaves. This study elucidated the fine-tuned regulation of poplar gene expression by BCMV; moreover, the results also suggested that miR156/SPL modules played important roles in the virus response and development of viral systematic symptoms in plant virus disease.

Bubble pulsation characteristics in multi-bubble systems affected by bubble size polydispersity and spatial structure.

This study seeks to explore the bubble pulsation characteristics in multi-bubble environment with a special focus on the influences of the size polydispersity and the two-dimensional structure of bubbles. Three representative configurations of three interacting bubbles are formed by setting the initial radii of cavitation bubbles and inter-bubble distances appropriately, then the pulsation characteristics of a small bubble are investigated and compared by the bifurcation analysis. The results illustrate that the bubble size polydispersity and two-dimensional structure would greatly affect the bubble pulsations (i.e., the amplitude and nonlinearity of pulsations). Furthermore, the effects of two-dimensional structure are strong at a small inter-bubble distance of the large and small bubbles while the bubble size polydispersity always significantly affects the bubble pulsations for all cases. Moreover, the influences of both bubble size polydispersity and two-dimensional structure can be enhanced as the acoustic pressure increases, which can also become stronger when the large bubble is located at the same side as the small bubble and the initial radius of large bubble increases. Additionally, the effects would also be increased when the tissue viscoelasticity varies within a certain range. The present findings shed new light on the dynamics of multiple polydisperse microbubbles in viscoelastic tissues, potentially contributing to an optimization of their applications with ultrasound excitation.

Diazepam promotes active avoidance extinction associating with increased dorsal CA3 and amygdala activity.

Active avoidance (AA) is an adaptive response to potentially harmful situations while maladapted avoidance that does not extinguish is one of the core symptoms of anxiety and post-traumatic stress disorder. However, the neural mechanisms of AA extinction and its relationship to anxiety remain unclear. We examined AA extinction during three extinction training sessions in two-way active avoidance paradigm and tested the effect of anxiolytic on AA extinction. Then we performed a meta-analysis of rodent studies, identified anxiolytic diazepam facilitates AA acquisition, and tested the same treatment in AA extinction. Diazepam-treated rats significantly reduced avoidance in the first two extinction training, compared with the saline-treated rats, and the reduction in avoidance remained in the third drug-free session. Then we explored extinction associated hippocampal and amygdala activity in saline-and diazepam-treated rats using c-Fos immunostaining following the last extinction session. The density of c-Fos positive cells was higher in dorsal CA3 of the diazepam group than in that of saline-treated animals, and was also higher in the central and basolateral amygdala regions of diazepam-treated rats than in that of saline-treated animals. Combined, these results suggest anxiolytics promotes AA extinction associated with dorsal CA3 and amygdala activity changes.

Research advances in identification procedures of endocrine disrupting chemicals.

Endocrine disrupting chemicals (EDCs) are increasingly concerned substance endangering human health and environment. However, there is no unified standard for identifying chemicals as EDCs, which is also controversial internationally. In this review, the procedures for EDC identification in different organizations/countries were described. Importantly, three aspects to be considered in identifying chemical substances as EDCs were summarized, which were mechanistic data, animal experiments, and epidemiological information. The relationships between them were also discussed. To elaborate more clearly on these three aspects of evidence, scientific data on some chemicals including bisphenol A, 1,2-dibromo-4-(1,2 dibromoethyl) cyclohexane and perchlorate were collected and evaluated. Altogether, the above three chemicals were assessed for interfering with hormones and elaborated their health hazards from macroscopic to microscopic. This review is helpful for standardizing the identification procedure of EDCs.

Effects of medium viscoelasticity on bubble collapse strength of interacting polydisperse bubbles.

Due to its physical and/or chemical effects, acoustic cavitation plays a crucial role in various emerging applications ranging from advanced materials to biomedicine. The cavitation bubbles usually undergo oscillatory dynamics and violent collapse within a viscoelastic medium, which are closely related to the cavitation-associated effects. However, the role of medium viscoelasticity on the cavitation dynamics has received little attention, especially for the bubble collapse strength during multi-bubble cavitation with the complex interactions between size polydisperse bubbles. In this study, modified Gilmore equations accounting for inter-bubble interactions were coupled with the Zener viscoelastic model to simulate the dynamics of multi-bubble cavitation in viscoelastic media. Results showed that the cavitation dynamics (e.g., acoustic resonant response, nonlinear oscillation behavior and bubble collapse strength) of differently-sized bubbles depend differently on the medium viscoelasticity and each bubble is affected by its neighboring bubbles to a different degree. More specifically, increasing medium viscosity drastically dampens the bubble dynamics and weakens the bubble collapse strength, while medium elasticity mainly affects the bubble resonance at which the bubble collapse strength is maximum. Differently-sized bubbles can achieve resonances and even subharmonic resonances at high driving acoustic pressures as the elasticity changes to certain values, and the resonance frequency of each bubble increases with the elasticity increasing. For the interactions between the size polydisperse bubbles, it indicated that the largest bubble generally has a dominant effect on the dynamics of smaller ones while in turn it is almost unaffected, exhibiting a pattern of destructive and constructive interactions. This study provides a valuable insight into the acoustic cavitation dynamics of multiple interacting polydisperse bubbles in viscoelastic media, which may offer a potential of controlling the medium viscoelasticity to appropriately manipulate the dynamics of multi-bubble cavitation for achieving proper cavitation effects according to the desired application.

Mechanical stretch promotes tenocyte migration via chromatin remodelling-mediated nuclear morphology changes.

Wound healing and function recovery of injured tendons are still a big challenge for orthopaedic surgery. Evidence in clinic shows that early controlled motion has significant favourable effects on tendon healing; however, the mechanisms involved in are not fully understood. In the present study, it was shown that an appropriate mechanical stretch (10% strain, 0.5 Hz for 1 h) evidently promotes rat tenocyte migration and nuclear morphology changes. The farther research discovered that mechanical stretch had no effect on Lamin A/C expression, but it could promote chromatin decondensation. Moreover, the histone modification plays an important role in mechanical stretch-mediated chromatin decondensation. Inhibition histone modification could inhibit mechanical stretch-promoted nuclear morphology changes and tenocyte migration. These results indicating that mechanical stretch may promote tenocyte migration via chromatin remodelling-mediated nuclear morphology changes, which contribute to a better understanding of the role of mechanical stretch on tenocyte migration and repair of injured tendon.

Association between bisphenol A exposure and thyroid dysfunction in adults: a systematic review and meta-analysis.

The occurrence of thyroid dysfunction is affected by environmental factors, and BPA is a ubiquitous environmental pollutant with the potential to cause thyroid dysfunction. However, the limited epidemiological evidence shows an inconsistent association between BPA exposure and thyroid dysfunction. Therefore, the literature on the impact of BPA on thyroid was sorted and analyzed to study the relationship between BPA and adult thyroid function. The studies published on or before 23rd May 2022 from PubMed, Web of Science, and Scopus were collected analyzing the association between BPA exposure and the levels of thyroid hormones. The methodological quality of each study was assessed, the sensitivity analysis and subgroup analysis based on study population and gender were also performed, and publication bias was evaluated. A total of 2969 literature studies were retrieved. Based on inclusion and exclusion criteria, eleven studies were included. Our results showed that BPA concentration was negatively correlated with FT4 and TSH in males. Pooled correlation coefficients between BPA and FT4/TSH were -0.027 (95%CI = -0.030∼-0.024) and -0.058 (95%CI = -0.111∼-0.004). BPA concentration was positively correlated with FT4 in females, and the pooled correlation coefficient was 0.006 (95%CI = 0.003-0.008). The effects of BPA on thyroid hormone levels were significantly different between males and females. BPA may significantly decrease the levels of FT4 and TSH in males but increase the levels of FT4 in females. Considering the high heterogeneity among studies and the limited investigations into subgroups, the relationship between BPA exposure and thyroid dysfunction needs to be further investigated.

microRNA-181a contributes to gastric hypersensitivity in rats with diabetes by regulating TLR4 expression.

Aim: The aim of this study is to investigate the mechanism and interaction of microRNA-181a (miR-181a), toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-κB) in gastric hypersensitivity in diabetic rats. Methods: Diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ; 65 mg/kg) in female SD rats. Gastric balloon distension technique was used to measure diabetic gastric hypersensitivity. Gastric-specific (T7-T10) dorsal root ganglion (DRG) neurons were acutely dissociated to measure excitability with patch-clamp techniques. Western blotting was employed to measure the expressions of TLR4, TRAF6 and NF-κB subunit p65 in T7-T10 DRGs. The expressions of microRNAs in T7-T10 DRGs were measured with quantitative real-time PCR and fluorescence in situ hybridization. Dual-luciferase reporter gene assay was used to detect the targeting regulation of microRNAs on TLR4. Results: (1) Diabetic rats were more sensitive to graded gastric balloon distention at 2 and 4 weeks. (2) The expression of TLR4 was significantly up-regulated in T7-T10 DRGs of diabetic rats. Intrathecal injection of CLI-095 (TLR4-selective inhibitor) attenuated diabetic gastric hypersensitivity, and markedly reversed the hyper-excitability of gastric-specific DRG neurons. (3) The expressions of miR-181a and miR-7a were significantly decreased in diabetic rats. MiR-181a could directly regulate the expression of TLR4, while miR-7a couldn't. (4) Intrathecal injection of miR-181a agomir down-regulated the expression of TLR4, reduced the hyper-excitability of gastric-specific neurons, and alleviated gastric hypersensitivity. (5) p65 and TLR4 were co-expressed in Dil-labeled DRG neurons. (6) Inhibition of p65 attenuated diabetic gastric hypersensitivity and hyper-excitability of gastric-specific DRG neurons. (7) The expression of TRAF6 was significantly up-regulated in diabetic rats. CLI-095 treatment also reduced the expression of TRAF6 and p65. Conclusion: The reduction of microRNA-181a in T7-T10 DRGs might up-regulate TLR4 expression. TLR4 activated NF-κB through MyD88-dependent signaling pathway, increased excitability of gastric-specific DRG neurons, and contributed to diabetic gastric hypersensitivity.

The gut microbiota: A new perspective for tertiary prevention of hepatobiliary and gallbladder diseases.

The gut microbiota is a complex ecosystem that has coevolved with the human body for hundreds of millions of years. In the past 30 years, with the progress of gene sequencing and omics technology, the research related to gut microbiota has developed rapidly especially in the field of digestive system diseases and systemic metabolic diseases. Mechanical, biological, immune, and other factors make the intestinal flora form a close bidirectional connection with the liver and gallbladder, which can be called the "gut-liver-biliary axis." Liver and gallbladder, as internal organs of the peritoneum, suffer from insidious onset, which are not easy to detect. The diagnosis is often made through laboratory chemical tests and imaging methods, and intervention measures are usually taken only when organic lesions have occurred. At this time, some people may have entered the irreversible stage of disease development. We reviewed the literature describing the role of intestinal flora in the pathogenesis and biotherapy of hepatobiliary diseases in the past 3-5 years, including the dynamic changes of intestinal flora at different stages of the disease, as well as the signaling pathways involved in intestinal flora and its metabolites, etc. After summarizing the above contents, we hope to highlight the potential of intestinal flora as a new clinical target for early prevention, early diagnosis, timely treatment and prognosis of hepatobiliary diseases. GRAPHICAL ABSTRACT.

Mechanical stretch facilitates tenomodulin expression to induce tenocyte migration via MAPK signaling pathway.

Tenomodulin (Tnmd) is a type II transmembrane glycoprotein that regulates tendon development and maturation. Our previous study indicated that mechanical stretch could induce Tnmd expression to promote tenocyte migration, associated with reinforcement of fibrous actin (F-actin) stress fibers and chromatin decondensation. However, the detailed molecular mechanisms of this processes are far from clear. Activation of mitogen-activated protein kinase (MAPK) signaling occurs in response to various extracellular stimuli and controls a large number of fundamental cellular processes. The present study we investigated the influence of MAPK signaling on mechanical stretch-induced Tnmd expression and its action way. Expression and activities of extracellular signal-related kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinases (JNK) and p38 MAPK (p38) were determined by Western blot. Cell migration was detected by Transwell assay. Immunofluorescence staining was used to detect F-actin stress fibers. Nuclear chromatin decondensation was detected by in situ DNaseI sensitivity assay. It was found that mechanical stretch promoted Tnmd expression by activating ERK1/2, JNK and p38 signaling. The inhibition of the ERK1/2, JNK or p38 repressed mechanical stretch-promoted tenocyte migration and mechanical stretch-induced reinforcement of F-actin stress fibers. However, only ERK1/2 and p38 inhibitor could repress mechanical stretch-induced chromatin decondensation, and the JNK inhibitor had no significant effect. Moreover, latrunculin (Lat A), the most widely used reagent to depolymerize actin filaments, could inhibit the stretch-induced chromatin decondensation. Taken together, our findings elucidated a molecular pathway by which a mechanical signal is transduced via activation of MAPK signaling to influence reinforcement of F-actin stress fibers and chromatin decondensation, which could further lead Tnmd expression to promote tenocyte migration.