CTL Group Research Articles

The potential role of gut microbiota in the occurrence and development of endometriosis

Endometriosis (EMT) has a significant impact on women’s physical and mental health. In this study, high-throughput sequencing technology was employed to detect differences in gut microbiota between EMT patients and healthy individuals (CTL). Additionally, Spearman correlation analysis was utilized to analyze the correlation between different bacterial genera and EMT biomarkers (CA125 and CA199). The results demonstrated that at the phylum level, the relative abundances of Proteobacteria and Desulfobacterota_G_459546 in the EMT group were significantly higher than those in the CTL group, while the relative abundances of Bacteroidota and Firmicutes_A in the EMT group were significantly lower than those in the CTL group. At the genus level, the relative abundances of Burkholderiales and Sphingomonadales in the EMT group were significantly higher than those in the CTL group, while the relative abundances of Bacteroidales and Roseburia in the EMT group were significantly lower than those in the CTL group. The correlation analysis results show that CA125 and CA199 are significantly positively correlated with Burkholderiales and Sphingomonadales, and significantly negatively correlated with Bacteroidales, Oscillospirales, and Roseburia. The PICRUSt2 results show that the relative abundance in the cell motility and xenobiotics biodegradation and metabolism pathways in the EMT group was higher than that in the CTL group, while the relative abundance in the translation, replication and repair, folding, sorting and degradation, metabolism of terpenoids and polyketides and metabolism of cofactors and vitamins pathways in the EMT group was lower than that in the CTL group. In brief, there is a close correlation between the imbalance of gut microbiota and the onset of EMT. The intestinal microbiota has great significance broad prospects for the prevention, diagnosis and treatment of EMT.

PSX-16 The effect of short-term heat stress on physiological, hematological, and immunological parameters of Florida Cracker Sheep

Abstract Florida Cracker sheep are a heritage sheep breed that was developed under natural selection in Florida, US. The objective of this study was to evaluate the effect of short-term heat stress on rectal temperature, respiration rate, hematological parameters, and IgA concentrations of Florida Cracker ewes (2 yr of age). A total of fourteen ewes were allocated to heat stress (HT, n = 7) or cooling (CTL, n = 7) conditions for 6 wk during the summer season. Treatment groups were grouped in covered concrete floor pens with similar dimensions and characteristics and had access to shelter, feed, and freshwater ad libitum. The HT pen was exposed to regular ambient temperatures, and for the cooling pen, an evaporative cooling fan was used. Data for ambient temperature and relative humidity of HT and CTL pens were recorded every week to estimate the temperature humidity index (THI). Blood samples were collected from each experimental ewe 1 wk before the start of the experiment (baseline) and at wk 1, wk 2, wk 3, wk 4, wk 5, and wk 6 post-treatment. Blood samples were analyzed using a hematology analyzer (Vetscan HM5, Zoetis). Plasma was extracted from the blood and was used to evaluate IgA concentrations with a commercial kit. For the statistical analysis of the physiological, hematological, and immunological parameters, a mixed model with repeated measures was used. Fixed effects included treatment (HT or CTL), wk (1 to 6), and the treatment by week interaction. Animal was fitted as a random effect and the baseline data was used as a covariate. The THI for the HT and CTL groups ranged from 81.3 to 89.5 and from 73.5 to 75.6, respectively. The HT group presented a significant (P < 0.05) increase in respiratory rate when compared with the CTL group. No significant changes were observed for rectal temperature and IgA concentrations in the experimental groups. However, for wk 3, a significant (P < 0.05) increase of neutrophils and a decrease in lymphocyte % was observed for the HT group. In conclusion, short-term heat stress increased respiratory rate and neutrophil % and decreased the lymphocyte % in Florida Cracker ewes. It is possible that heat stress could have a detrimental impact on immune mechanisms in Florida Cracker ewes. Further studies are required to investigate the effects of long-term heat stress.

Gemcitabine, carboplatin, and Epstein–Barr virus-specific autologous cytotoxic T lymphocytes for recurrent or metastatic nasopharyngeal carcinoma: VANCE, an international randomized phase III trial

Epstein-Barr virus-specific cytotoxic T lymphocyte (EBV-CTL) is an autologous adoptive T-cell immunotherapy generated from the blood of individuals and manufactured without genetic modification. In a previous phase II trial of locally recurrent or metastatic nasopharyngeal carcinoma (R/M NPC) patients, first-line gemcitabine and carboplatin (GC) and EBV-CTL combination demonstrated objective antitumor EBV-CTL activity and a favorable safety profile. The present study explored whether this combined first-line chemo-immunotherapy strategy would produce superior clinical efficacy and better quality of life compared with conventional chemotherapy treatment. This multicenter, randomized, phase III trial evaluated the efficacy and safety of GC followed by EBV-CTL versus GC alone as first-line treatment of R/M NPC patients. Thirty clinical sites in Singapore, Malaysia, Taiwan, Thailand, and the USA were included. Subjects were randomized to first-line GC (four cycles) and EBV-CTL (six cycles) or GC (six cycles) in a 1 : 1 ratio. The primary outcome was overall survival (OS) and secondary outcomes included progression-free survival, objective response rate, clinical benefit rate, quality of life, and safety. gov identifier: NCT02578641. A total of 330 subjects with NPC were enrolled. Most subjects in both treatment arms received four or more cycles of chemotherapy and most subjects in the GC+ EBV-CTL group received two or more infusions of EBV-CTL. The central Good Manufacturing Practices (GMP) facility produced sufficient EBV-CTL for 94% of GC+ EBV-CTL subjects. The median OS was 25.0 months in the GC+ EBV-CTL group and 24.9 months in the GC group (hazard ratio= 1.19; 95% confidence interval 0.91-1.56; P= 0.194). Only one subject experienced a grade 2 serious adverse event related to EBV-CTL. GC+ EBV-CTL in subjects with R/M NPC demonstrated a favorable safety profile but no overall improvement in OS versus chemotherapy. This is the largest adoptive T-cell therapy trial reported in solid tumors to date.

Low Thyroid Hormones Level Attenuates Mitochondrial Dysfunction and Right Ventricular Failure in Pulmonary Hypertensive Rats.

This study is to investigate the repercussions of hypothyroidism in the pathophysiological progression of pulmonary arterial hypertension (PAH). While the control (CTL, n = 5) male Wistar rats received vehicle, PAH was induced with monocrotaline (MCT group, n = 15). Hypothyroidism was induced in a subset of rats by methimazole 3weeks prior to the MCT injection (MMZ + MCT group, n = 15). Plasma thyroid hormones were measured by radioimmunoassay. Electrocardiographic, echocardiographic, and hemodynamic analyses were performed to evaluate the progression of PAH. Gene expression of antioxidant enzymes and cardiac hypertrophy markers were assessed by qPCR. Mitochondrial respiration, ATP levels, and ROS production were measured in right ventricular (RV) samples. Plasma T3 and T4 decreased in both MCT and MMZ + MCT groups (p < 0.05). Right ventricular systolic pressure (RVSP) increased, and RV - dP/dt, + dP/dt, and contractility index decreased in the MCT versus the CTL group and remained within control levels in the MMZ + MCT group (p < 0.05). Relative RV weight, RV wall thickness, RV diastolic area, and relative lung weight were augmented in the MCT versus the CTL group, whereas all parameters were improved to the CTL levels in the MMZ + MCT group (p < 0.05). Only the MCT group exhibited an increased duration of QTc interval compared to the baseline period (p < 0.05). ADP-induced mitochondrial respiration and ATP levels were decreased, and ROS production was increased in MCT versus the CTL group (p < 0.05), while the MMZ + MCT group exhibited increased mitochondrial respiration versus the MCT group (p < 0.05). Hypothyroidism attenuated the RV mitochondrial dysfunction and the pathophysiological progression of MCT-induced PAH.

Early-age heat exposure improved growth performance and heat tolerance in broilers

A total of 440 one-day-old healthy male Arbor Acres broilers were equally assigned to a control group (CTL) and an early-age high-temperature exposure (EHT) group (4 replicates per group, 55 chickens per replicate). At d 3, the broilers in CTL group were reared in the normal temperature 33 ± 1°C, while the broilers in EHT group were exposed to 36 ± 1°C for 24 h. At d 43, all broilers were treated with an acute high temperature 35 ± 1°C for 5 h. The results showed that average daily gain in EHT group was decreased at d 3, but average daily gain in EHT group was increased at d 36 to 42 (P < 0.05). Plasma GLU level in EHT group was lower in broilers at d 7 or facing subsequently high temperature for 5 h (P < 0.05). The relative expression of myogenic differentiation (MyoD) gene in pectoralis major and myogenic factor 5 (Myf5) gene in biceps femoris were significantly improved at d 42 after early-age heat exposure (P < 0.05). Broilers in EHT group have a higher temperature tolerance with a lower mortality than control broilers (P < 0.05). Broilers in EHT group have a lower rectal temperature and a higher comb and ear temperature when facing subsequently acute high temperature than control broilers (P < 0.05). In addition, our study demonstrated that early-age heat exposure significantly decreased the mortality and increased the heat tolerance of broilers when facing an acute short-term heat exposures. Early-age heat exposure increased the process of myogenesis via up-regulating the MyoD and Myf5 gene expression in skeletal muscle, which accelerated average daily gain.

The effects of Bacillus subtilis spores and yeast cell wall supplementation on growth and health in Holstein dairy calves

The study aimed to assess the impact of Bacillus subtilis spores and yeast cell wall (YCW) on the performance and health of dairy calves during the milk-feeding period. Thirty female Holstein calves (birth body weight [BW] of 36.7 ± 4.81 kg) were randomly assigned to three treatments: Control (CTL, no additives), T1 (Bacillus subtilis spores), and T2 (Bacillus subtilis + YCW). Animals were individually housed with free access to water and commercial pellet starter. Calves received 8 L/d of pasteurized waste milk and were weaned at 63 d of age. The treatments (T1 and T2) were mixed into milk and administered daily from 3 to 63 d of age. Dry matter (DM) intake (from liquid and starter feed), fecal score, and rectal temperature were recorded daily. Additionally, heart girth was measured at 0, 15, 30, 45, and 60 d of age, and BW was measured at 0 and 60 d of age. Blood was sampled from the jugular vein at 0, 20, and 60 d of age for analysis of serum immunoglobulin G (IgG). There was treatment × time interaction (P = 0.04) for fecal consistency scores. Calves supplemented with Bacillus subtilis tended (χ2 test, P = 0.07) to have lower cases of diarrhea than other groups. T1 or T2 supplementations did not affect milk DM intake, starter DM intake, or total DM intake. Growth performance (BW at weaning and average daily gain) was similar between treatments. Dairy calves fed Bacillus subtilis plus YCW tended to have (P = 0.09) higher rectal temperature and had higher frequency (χ2 test, P < 0.01) of rectal temperature >39.1°C compared to the CTL and Bacillus subtilis groups. However, treatments had similar levels of serum IgG (CTL = 18.3, T1 = 16.7, and T2 = 18.6 mg/mL; P = 0.58). Our results suggest that Bacillus subtills and YCW may interact in the digestive tract of young calves as evidenced by the increased rectal temperature in T2. While the cause of this interaction remains uncertain, there was no negative effect on the animal health or growth performance. The use of Bacillus subtilis spores shows promise in improving fecal consistency scoring in dairy calves fed pasteurized waste milk during the pre-weaning phase.

Evidence of the Existence of Site-Specific Female Contact Pheromones Involved in the Sexual Interaction Behavior of the Pacific Whiteleg Shrimp Penaeus vannamei.

Although the presence of female contact sex pheromones in P. vannamei has been hypothesized, to date its existence has not been proven. To gather more evidence of their existence, cuticular liposoluble extracts were obtained from the following samples of adult females to be used as the experimental treatments: (1) ventral exoskeleton of immature female (VI), (2) dorsolateral exoskeleton of immature female (DI), (3) ventral exoskeleton of mature female (VM), and (4) dorsolateral exoskeleton of mature female (DM). Polyvinyl chloride tubes (artificial females; AF) were coated with each extract and the behavior displayed by sexually mature males in contact with the AF was recorded and classified as follows: 0 = no response; 1 = contact; 2 = pushing; and 3 = prolonged contact (≥10 s). To test the hypothesis that the extracts collected from the ventral portion of the abdomen exoskeleton have a higher effect on the behavior of males than the extracts collected from the dorsolateral portion of the abdomen exoskeleton, the experiment was divided into two bioassays: Bioassay I (VI vs. DI) and Bioassay II (VM vs. DM). In each bioassay, all experimental treatments were significantly different (p > 0.05) from the CTL group (AF coated with hexane). Notably, the pushing behavior was significantly higher (p < 0.05) in the VI treatment compared to the CTL and DI treatment. These results provide evidence of the existence of contact female sex pheromones with sexual recognition function located primarily in the ventral portion of the abdomen exoskeleton of P. vannamei.

Postoperative Morbidity after Dental Treatment under General Anesthesia in Children with and without Disabilities.

Background and Objectives: General anesthesia induces reversible unconsciousness, eliminating sensation and enabling painless medical procedures. Vital for dental care, it addresses patients with medical conditions, those needing extensive procedures, and those unable to cooperate due to fear. Dental care for patients with disabilities is a significant unmet need, with studies showing increased oral disease prevalence. This research aims to analyze postoperative morbidity both in healthy and disabled children undergoing dental procedures under general anesthesia. Materials and Methods: This study involved 96 children aged 3 to 15 with dental caries. Two groups were formed: the control group (CTL) (52.94%) included healthy patients requiring general anesthesia due to unsatisfactory cooperation, and the other group included children with physical or intellectual disabilities (CD) (47.96%). Postoperative complications were monitored 1 h after the procedure and 1, 3, 7, and 14 days after the procedure by contacting parents/caregivers by phone. The intensity of postoperative pain was assessed using the Wong-Baker faces pain rating scale. General anesthesia was conducted following a standardized protocol for dental procedures. Results: CTL patients complained more often about postoperative pain 1 h after the procedure (p = 0.03). One day after the procedure, oral bleeding (p = 0.04), fever (p = 0.009), and diarrhea (p = 0.037) occurred more often in CD. In the same period, sore throat appeared more often in CTL (p = 0.036). Three days after the dental treatment, there were statistically significant increases in the occurrence of agitation (p = 0.043) and constipation (p = 0.043) in CD. Seven days later, CD demonstrated a higher occurrence of agitation (p = 0.037). According to the Wong-Baker faces pain rating scale, CTL experienced more frequent and intense pain. Conclusions: CD more frequently reported complications like oral bleeding, fever, and diarrhea. In contrast, the CTL group more often reported pain-related symptoms. The conclusion underscores the need for a pain control protocol for CD and emphasizes the importance of frequent monitoring to prevent unwanted consequences during tooth restoration under general anesthesia.

Comparative profiling of the skin and gut microbiota during metamorphosis in Chinese spiny frogs (Quasipaa spinosa) highlights microbial communities involved in disease pathogenesis

The symbiotic microbiota inhabiting the skin and gut of amphibians exerts roles in maintaining host health, especially during the critical stage of complete metamorphosis where failure to remodel the microbiota can result in various diseases. However, the composition and alterations in the amphibian microbiota in diverse diseased populations, as well as the exact mechanisms underlying disruptions in skin and gut microbial communities leading to diseases, are not yet well established. Herein, skin and gut microbiota were sampled from healthy Chinese spiny frogs (CTL group) as well as individuals with ascites disease (AD group), cataract disease (CD group), and rotten-skin disease (RD group) for Illumina high-throughput sequencing analysis to comprehensively explore potential associations between microbiota composition and the health status of the host. Venn diagrams and UpSet analysis revealed that the CTL group exhibited the highest number of unique amplicon sequence variants (ASVs) in their skin, while the CD group displayed the lowest abundance of ASVs in their gut. Compared to the CTL group, the alpha-diversity of skin microbiota was dramatically depressed in diseased groups, and notable variations in the beta-diversity of both skin and gut microbiota were observed. Further compositional analysis identified Firmicutes, Proteobacteria, and Bacteroidota as the dominant bacterial phyla in both skin and gut microbiota, although their relative abundances varied widely among groups. The linear discriminant analysis effect size (LEfSe) analysis identified various bacteria species with substantial differences between skin and gut microbiota groups including beneficial populations as well as opportunistic ones. Functional predictions indicated significant differences between CTL and diseased groups mainly enriched in metabolism-relevant pathways. Furthermore, in vitro culture experiments confirmed the presence of a total of 19 strains of bacteria from the skin microbiota of RD group, including opportunistic bacteria population Acinetobacter closely associated with spiny frog rotten-skin disease. Taken together, this work provides insights into the composition dynamics of skin and gut microbiota under different health conditions in spiny frogs, highlighting potential applications for symbiotic microbiota modification in promoting healthy amphibian culture practices as well as preventing diseases.

Pubertal glyphosate-based herbicide exposure aggravates high-fat diet-induced obesity in female mice.

Glyphosate-based herbicides (GBH) are the most widely used pesticides globally. Studies have indicated that they may increase the risk of various organic dysfunctions. Herein, we verified whether exposure to GBH during puberty increases the susceptibility of male and female mice to obesity when they are fed a high-fat diet (HFD) in adulthood. From the 4th-7th weeks of age, male and female C57Bl/6 mice received water (CTL group) or 50mg GBH /kg body weight (BW; GBH group). From the 8th-21st weeks of age, the mice were fed a standard diet or a HFD. It was found that pubertal GBH exposure exacerbated BW gains and hyperphagia induced by HFD, but only in female GBH-HFD mice. These female mice also exhibited high accumulation of perigonadal and subcutaneous fat, as well as reduced lean body mass. Both male and female GBH-HFD displayed hypertrophic white adipocytes. However, only in females, pubertal GBH exposure aggravated HFD-induced fat accumulation in brown adipocytes. Furthermore, GBH increased plasma cortisol levels by 80% in GBH-HFD males, and 180% in GBH-HFD females. In conclusion, pubertal GBH exposure aggravated HFD-induced obesity, particularly in adult female mice. This study provides novel evidence that GBH misprograms lipid metabolism, accelerating the development of obesity when individuals are challenged by a second metabolic stressor, such as an obesogenic diet.

Too close for comfort? Social distance and emotion perception in remitted bipolar I disorder

Introduction: Bipolar disorder (BD) is a chronic psychiatric disorder that is associated with heightened and persistent positive emotion (Gruber, 2011; Johnson, 2005). Yet, we know little about how troubled emotion responding may translate into dynamic face-to-face interactions involving others, especially in contexts where automatic social regulation of personal distance from others is key to maintaining social boundaries. Method: Using a novel social distance paradigm adapted from a prior work (Kennedy et al., 2009), participants with a clinical history of bipolar I disorder (n = 30) and healthy controls (CTL; n = 31) provided online measurements of social distance preferences in response to positive, negative, and neutral facial images, as well as subsequent social judgment and emotion perception ratings. Results: Results suggest no group differences on social distance, social perception, or general emotion perception ratings. However, exploratory analyses suggest that the BD group rated positive images higher in happiness, but lower in amusement, compared to the CTL group. Conclusion: These findings contribute to a growing literature on socioemotional processes in BD.

Pupil Dynamics, Salivary Alpha-Amylase, and Prefrontal Haemodynamics in Response to Very Light Exercise.

This study aimed to investigate the effects of exercise on pupil dynamics, prefrontal haemodynamic, and salivary alpha-amylase (sAA) responses in 45 healthy graduate students. These participants were divided into two groups: a resting control group (CTL) and a very-light-intensity exercise group (EX). Participants in the EX-group engaged in a 10-min exercise at 30% O2 peak on a cycle ergometer. Salivary samples and pupillometry assessments were collected before the exercise, at the end of the exercise, and 5 min after the completion to evaluate changes over time. Our analysis showed that exercise induced significant changes in the secretion of salivary alpha-amylase, with elevated levels suggesting increased neuroendocrine activity linked to the arousal state triggered by exercise. In addition, functional oxyHb signals indicated greater fluctuations in the mid-left prefrontal cortex among participants in the EX-group compared to those in the CTL group, pointing to altered prefrontal haemodynamic.

Therapeutic effects of the combination of moderate-intensity endurance training and MitoQ supplementation in rats with isoproterenol-induced myocardial injury: The role of mitochondrial fusion, fission, and mitophagy

IntroductionMitochondrial dysfunction causes myocardial disease. This study investigated the effects of MitoQ alone and in combination with moderate-intensity endurance training (EX) on cardiac function and content and mRNA expression of several proteins involved in mitochondrial quality control in isoproterenol (ISO)-induced heart injuries MethodsSeven groups of CTL, ISO, ISO-EX, ISO-MitoQ-125, ISO-MitoQ-250, ISO-EX+MitoQ-125, and ISO-EX+MitoQ-250 were assigned. Rats were trained on a treadmill, and the MitoQ groups received MitoQ in drinking water for 8 weeks, starting one week after the induction of heart injury. Arterial pressure and cardiac function indices, mRNA expression, protein content, oxidant and antioxidant markers, fibrosis, and histopathological changes were assessed by physiograph, Real-Time PCR, immunofluorescence, calorimetry, Masson’s trichrome, and H&E staining, respectively. ResultsThe impacts of MitoQ-125, EX+MitoQ-125, and EX+MitoQ-250 on arterial pressure and left ventricular systolic pressure were higher than MitoQ-250 or EX alone. ± dp/dt max were higher in ISO-EX+MitoQ-125 and ISO-EX+MitoQ-250 than ISO-MitoQ-125 and ISO-MitoQ-250 groups, respectively. Histopathological scores and fibrosis decreased in ISO-EX, ISO-MitoQ-125, ISO-EX+MitoQ-125, and ISO-EX+MitoQ-250 groups. The restoration of MFN2, PINK-1, and FIS-1 changes was higher in ISO-EX+MitoQ-125 and ISO-EX+MitoQ-250 than ISO-EX, ISO-MitoQ-125 and ISO-MitoQ-250 groups. The expression of MFN2 and PINK-1 was lower in ISO-MitoQ-125 and ISO-EX+MitoQ-125 than ISO and CTL groups. The expression of FIS-1 in ISO-EX and ISO-EX+MitoQ-250 increased compared to CTL and ISO groups. MDA decreased in ISO-MitoQ-125 and ISO-EX+MitoQ-125 groups. ConclusionExercise and MitoQ combination have additive effects on cardiac function by modulating cardiac mitochondria quality. This study provided a possible therapy to treat heart injuries.

Autologous mitochondrial transplantation in male mice as a strategy to prevent deleterious effects of peripheral ischemia-reperfusion.

Ischemia-reperfusion (IR) is known to induce severe tissue damage, notably through mitochondrial dysfunction. Mitochondrial transplantation has emerged as a promising therapeutic strategy in cardiac IR; however, few studies have previously assessed its efficacy in the context of peripheral IR. Therefore, the objective of this study was to assess the effect of mitochondrial transplantation in a hindlimb model of IR injury. Thirty-six SWISS mice were divided into three groups: control (CTL, n = 12), ischemia-reperfusion (IR, n = 12), and IR with mitochondrial transplantation (MT, n = 12). Ischemia (2 h) was induced using the tourniquet model around the right hind limb in the IR and MT groups. In MT group, mitochondria isolated from the right rectus muscle, a nonischemic region, were injected shortly before reperfusion. Mitochondrial respiration, calcium retention capacity, and Western blotting analysis were performed 2 h after reperfusion. Compared with the CTL group, IR led to a decrease in the mitochondrial respiratory capacity, particularly for the basal state (-30%; P = 0.015), oxidative phosphorylation (-36%; P = 0.024), and calcium retention capacity (-45%; P = 0.007). Interestingly, mitochondrial transplantation partially restored these functions since no differences between MT and CTL groups were found. In addition, the administration of healthy mitochondria resulted in a positive regulation of redox balance and mitochondrial dynamics within the skeletal muscle. Although further investigations are needed to better characterize underlying mechanisms, mitochondrial transplantation represents a promising strategy in the setting of IR-induced muscular damage.NEW & NOTEWORTHY Ischemia-reperfusion injury leads to severe muscular damage. Even if prompt revascularization is the treatment of choice, muscular alterations can lead to severe sequalae as mitochondrial dysfunction. Accordingly, adjunctive strategies are needed to overcome the muscular damage. Mitochondrial transplantation has shown beneficial effects in cardiac ischemia-reperfusion, but its role in peripheral muscle is not well established. In this study, we found that mitochondrial transplantation partially restored muscular function when submitted to ischemia reperfusion.

Ultrasound-Controlled Delivery of Growth Factor-Loaded Cerasomes Combined with Polycaprolactone Scaffolds Seeded with Bone Marrow Mesenchymal Stem Cells for Biomimetic Tendon-to-Bone Interface Engineering.

Rotator cuff tear (RCT) is a prevalent shoulder injury that poses challenges for achieving continuous and functional regeneration of the tendon-to-bone interface (TBI). In this study, we controlled the delivery of growth factors (GFs) from liposomal nanohybrid cerasomes by ultrasound and implanted three-dimensional printed polycaprolactone (PCL) scaffolds modified with polydopamine loaded with bone marrow mesenchymal stem cells (BMSCs) to repair tears of the infraspinatus tendon in a lapine model. Direct suturing (control, CTL) was used as a control. The PCL/BMSC/cerasome (PBC) devices are sutured with the enthesis of the infraspinatus tendon. The cerasomes and PCL scaffolds are highly stable with excellent biocompatibility. The roles of GFs BMP2, TGFβ1, and FGF2 in tissue-specific differentiation are validated. Compared with the CTL group, the PBC group had significantly greater proteoglycan deposition (P = 0.0218), collagen volume fraction (P = 0.0078), and proportions of collagen I (P = 0.0085) and collagen III (P = 0.0048). Biotin-labeled in situ hybridization revealed a high rate of survival for transplanted BMSCs. Collagen type co-staining at the TBI is consistent with multiple collagen regeneration. Our studies demonstrate the validity of biomimetic scaffolds of TBI with BMSC-seeded PCL scaffolds and GF-loaded cerasomes to enhance the treatment outcomes for RCTs.

ANTIDIABETIC THERAPIES METFORMIN AND TRODUSQUEMINE MODULATE MIRNAS INVOLVED WITH LIVER METABOLISM

Abstract Type II diabetes mellitus (T2DM) afflicts approximately 33% of individuals over the age of 65 increasing susceptibility to dyslipidemia, a hallmark of non-alcoholic fatty liver disease (NAFLD). Due to the idiopathic nature of NAFLD, there is no standard of care with only lifestyle intervention strategies available to improve hepatic function. Although dietary modifications and physical activity can prevent the pathogenesis of NAFLD, poor compliance has sparked an urgent need for pharmacological options to achieve glycemic control and prevent the onset of comorbidities. Metformin (MF) is commonly used medication to treat T2DM and has recently gained attention as an anti-aging intervention in non-diabetic individuals. Trodusquemine (MSI-1436) is a drug that induces fat loss by inhibiting the protein tyrosine phosphatase 1B (PTP1B), an enzyme that impairs leptin and insulin signaling. Using miRNA sequencing, we identified a cohort of miRNAs that are influenced by MF and MSI-1436 in the livers of UMHET3 mice. Our in-depth analysis and RT-PCR validation indicated groups of miRNAs regulating the processes of de novo lipogenesis, fatty acid oxidation, very-low-density-lipoprotein and cholesterol transport. Importantly, miR-379-5p, a known modulator of cholesterol metabolism, reported to be inhibited in the livers of patients with NAFLD and in mouse models of diabetes, was found to be upregulated by MSI-1436 in both sexes when comparing with both CTL and MF groups. In summary, our study showed that MSI-1436 more potently inhibits mechanisms involved with liver homeostasis relative to MF yielding insight on its therapeutic potential in concurrent liver diseases resulting from T2DM.

Auraptene Alleviates Paclitaxel-induced Neuropathy in Mice

Background Paclitaxel administration causes peripheral neuropathy. Auraptene is a natural bioactive monoterpene with anti-inflammatory and anti-neuropathic effects that is widely used. Objectives We aimed to study auraptene effects on paclitaxel-induced neuropathy. Materials and Methods This study was comprised of two steps of evaluation of the preventive and treatment effects of auraptene in mice. In the first step, mice were randomly allocated into three groups of six animals, including the negative control (NEG CTL): animals injected with paclitaxel (PTX) together with normal saline, PTX (paclitaxel 2 mg/kg given on days 1, 3, 5, and 7), and PREVENTION: PTX + auraptene 100 mg/kg on days 1, 3, 5, and 7. In the second step, animals were allocated into six groups of six: NEG CTL (normal saline), PTX (paclitaxel 10 mg/kg given on days 1, 3, 5, and 7), PTX AUR (PTX + auraptene 50, 75, and 100 mg/kg), and a positive control (PTX-treated animals receiving imipramine 10 mg/kg). Intraperitoneal injection of PTX 2 mg/kg on days 1, 3, 5, and 7 was used in order to induce neuropathy. In both steps of the study, a hot plate test was done on day 7 in order to determine the response to heat. After the scarification of animals, the interleukin-6 (IL-6) level in the sciatic nerve was assessed by western blotting. Results In the preventive group, auraptene could reduce hyperalgesia significantly. In the treatment step, the AUR 100 mg/kg compared to NEG CTL groups had significantly increased heat latency. The expression of IL-6 protein in the sciatic nerve was remarkably decreased in both the preventive and treatment groups compared to NEG CTL. Conclusion Taken together, our results confirmed that AUR could decrease paclitaxel-induced hyperalgesia in mice and IL-6 protein content in sciatic nerve samples.

Navigational Decision‐Making Among Older Drivers: An Analysis of Real‐World Driving Patterns

AbstractBackgroundDriving is an important aspect of independence for older adults. However, cognitive decline may impair driving abilities and safety. A deeper understanding of the impact of cognitive impairment on driving behaviours in older adults can inform public health strategies to support maintaining their ability to drive safely. This study investigates how older adults with and without cognitive impairment make navigational decisions (e.g., route choice) while driving in real‐world settings.MethodParticipants were enrolled in longitudinal driving studies at Washington University School of Medicine. GPS dataloggers tracked the daily driving patterns of 246 older drivers (aged 65+), including 230 cognitively normal older adults (CTL; Clinical Dementia Rating [CDR] = 0) and 16 older adults with cognitive impairment (DEM; CDR&gt;0). Spatial clustering and hashing algorithms were employed to analyze each participant’s destinations and route choices. Trips with hard‐braking, sudden‐acceleration, and over‐speeding were considered “adverse behavior.” The Mann‐Whitney U‐test was performed to identify significant differences between the two groups.ResultThe CTL group had an average age of 68.2 ± 5.7 years and was composed of 46% females, while the DEM group had an average age of 69.2 ± 6.8 years and had 36% females. Additionally, the CTL group had a mean of 16.5 ± 2.3 years of education, while the DEM group had a mean of 16.0 ± 2.3 years of education. The results indicated that drivers with cognitive impairment had fewer full‐cycle trips (i.e., trips with the same start point and destination; p = 0.0165), visited fewer new destinations (p = 0.0210), used fewer distinct routes to reach their most common destination (p = 0.0174), and took fewer distinct routes to reach their most common destination when normalized by the average monthly frequency of this trip (p = 0.0062). No significant differences were observed in the other driving measures.ConclusionThis study reveals significant differences in driving patterns between cognitively normal older adults and those with cognitive impairment. Older adults with cognitive impairment exhibited more conservative driving behaviors, such as taking fewer full‐cycle trips and having less variety in their daily driving routes. These findings have important implications for designing interventions to improve mobility for older adults.

Methylene blue as an adjuvant during cardiopulmonary resuscitation: an experimental study in rats

IntroductionMethylene Blue (MB) has been shown to attenuate oxidative, inflammatory, myocardial, and neurological lesions during ischemia-reperfusion and has great potential during cardiac arrest. This study aimed to determine the effects of MB combined with epinephrine during cardiac arrest on myocardial and cerebral lesions. MethodThirty-eight male Wistar rats were randomly assigned to four groups: the sham group (SH, n = 5), and three groups subjected to cardiac arrest (n = 11/group) and treated with EPI 20 µg.kg−1 (EPI), EPI 20 µg.kg−1 + MB 2 mg.kg−1 (EPI + MB), or saline 0.9% 0.2 ml (CTL). Ventricular fibrillation was induced by direct electrical stimulation in the right ventricle for 3 minutes, and anoxia was maintained for 5 minutes. Cardiopulmonary Resuscitation (CPR) consisted of medications, ventilation, chest compressions, and defibrillation. After returning to spontaneous circulation, animals were observed for four hours. Blood gas, troponin, oxidative stress, histology, and TUNEL staining measurements were analyzed. Groups were compared using generalized estimating equations. ResultsNo differences in the Returning of Spontaneous Circulation (ROSC) rate were observed among the groups (EPI: 63%, EPI + MB: 45%, CTL: 40%, p = 0.672). The mean arterial pressure immediately after ROSC was higher in the EPI+MB group than in the CTRL group (CTL: 30.5 [5.8], EPI: 63 [25.5], EPI+MB: 123 [31] mmHg, p = 0.007). Serum troponin levels were high in the CTL group (CTL: 130.1 [333.8], EPI: 3.70 [36.0], EPI + MB: 43.7 [116.31] ng/mL, p < 0.05). ConclusionThe coadministration of MB and epinephrine failed to yield enhancements in cardiac or brain lesions in a rodent model of cardiac arrest.

Study on the Specific Expression of Infrared Radiation Temperature on the Body Surface of Acupoint in Rats with Chronic Myocardial Ischemic Injury.

Infrared thermal imaging technology was used to observe the changes in infrared radiation temperature at acupoints in rats caused by chronic myocardial ischemia injury. This study aims to compare the difference of body surface infrared radiation temperature information of three groups of acupoints: bilateral Neiguan (PC6), bilateral Yanglingquan (GB33), and bilateral Sham Acupoints (SA) in the pathological state of myocardial ischemia injury, and to explore the relationship between acupoints and viscera state. SPF adult Wistar male rats (n = 20) were randomly divided into a control (CTL; n = 10) and an isoproterenol group (ISO; n = 10). Chronic myocardial injury was induced in rats by subcutaneous injection of isoproterenol hydrochloride for 14 d. On the second day after the establishment of the model, the serum levels of cardiac troponin (cTnI) and creatine kinase isoenzyme (CK-MB) were measured by enzyme-linked immunosorbent assay (ELISA). The morphological changes of the myocardial tissue in the two groups were observed by hematoxylin-eosin (HE) staining and their pathological scores were evaluated, which was then used to determine the myocardial ischemic injury. Two days before and after the establishment of the model, the electrocardiograms (ECG) of the two groups of rats were recorded by the (ECG) data acquisition system, and the infrared thermal imaging platform was used to detect the temperature of the six acupoints. 1. After subcutaneous injection of isoproterenol hydrochloride for 14 days, the ST segment of the ECG decreased in the ISO group compared with that of the CTL group; 2. Myocardial tissue injury was serious in the ISO group compared to the CTL group; 3. Serum cTn-I and CK-MB were significantly increased (P <0 01) in the ISO group, compared to that in the CTL group; 4. The infrared radiation temperature on the body surface of bilateral Neiguan (PC6) acupoints decreased significantly in the ISO group, compared to that of the CTL group. Infrared thermal imaging technology can be used to detect the changes in the energy state of acupoints. Chronic myocardial ischemic injury can cause a decrease in IR temperature on the body surface of bilateral Neiguan (PC6) acupoints, suggesting that visceral diseases can lead to changes in the energy metabolism of acupoints.