Adult Control Research Articles

What do we talk about when we talk about leisure? Conceptualising leisure through the lived experiences of vocational pupils

ABSTRACT By adopting a unique approach that allowed participants to define leisure from their own perspective, this study employed semi-structured and photo-elicitation interviews to gain a deeper understanding of how young people from vocational education perceive and conceptualise leisure. The analysis revealed four crucial elements that are essential for experiencing leisure: (1) perceived freedom, where individuals have control over their time and activities; (2) enjoyment and pleasant experiences; (3) personal time for self-improvement or relaxation; and (4) social interactions with others. Notably, the notion of freedom emphasised young people’s perception of independence and lack of adult control over their leisure. The findings suggest a disparity between young people’s views on leisure and those of adults, who tend to have a future-oriented and instrumental perspective. This difference may be attributed to the lifeworlds in which young people find themselves, with limited opportunities for future-oriented leisure. Moreover, the study highlights the importance of considering young people’s living conditions and backgrounds when designing policies to promote equal opportunities for leisure. Future research should explore the interrelationships between the identified leisure components and further investigate the concept of freedom in different contexts.

Are Adult Mosquito Control Products (Adulticides) Harmful? A Review of the Potential Human Health Impacts from Exposure to Naled and Dichlorvos (DDVP)

We performed a thorough systematic review of published literature to determine potential links between human health impacts and naled, a registered adult mosquito control product (adulticide), and its major degradate, dichlorvos (DDVP). A search query was performed on 8 September 2023, capturing all articles published up to that date on the Scopus and PubMed databases. Inclusion criteria were the presence of either pesticide and a measured or modeled human health outcome or risk. The search string resulted in 382 articles; however, 354 articles were excluded, resulting in only 28 articles that met the inclusion criteria. The studies that directly relate to aerosolized ultra-low volume (ULV) mosquito control applications did not report any associated deleterious human health outcomes. Results from the reviewed papers displayed no negative health effects or led to inconclusive results. No studies showed adverse health effects from aerial ULV applications for mosquito management. Our findings are congruent with the United States Environmental Protection Agency and Centers for Disease Control and Prevention recommendations that aerial applications of naled, following label parameters, do not pose an adverse risk exposure to humans, wildlife, and the environment.

Neonatal Cystitis Makes Adult Female Rat Urinary Bladders More Sensitive to Low Concentration Microbial Antigens.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic pain disorder. Patients with IC/BPS often experience "flares" of symptom exacerbation throughout their lifetime, initiated by triggers, such as urinary tract infections. This study sought to determine whether neonatal bladder inflammation (NBI) alters the sensitivity of adult rat bladders to microbial antigens. Female NBI rats received intravesical zymosan treatments on postnatal days P14-P16 while anesthetized; Neonatal Control Treatment (NCT) rats were anesthetized. In adults, bladder and spinal cord Toll-like receptor type 2 and 4 (TLR2, TLR4) contents were determined using ELISAs. Other rats were injected intravesically with lipopolysaccharide (LPS; mimics an E. coli infection; 25, 50, 100, or 200 μg/mL) or Zymosan (mimics yeast infection; 0.01, 0.1, 1, and 10 mg/mL) solutions on the following day. Visceromotor responses (VMRs; abdominal contractions) to graded urinary bladder distention (UBD, 10-60 mm Hg, 20s) were quantified as abdominal electromyograms (EMGs). Bladder TLR2 and TLR4 protein levels increased in NBI rats. These rats displayed statistically significant, dose-dependent, robustly augmented VMRs following all but the lowest doses of LPS and Zymosan tested, when compared with their adult treatment control groups. The NCT groups showed minimal responses to LPS in adults and minimally increased EMG measurements following the highest dose of Zymosan. The microbial antigens LPS and Zymosan augmented nociceptive VMRs to UBD in rats that experienced NBI but had little effect on NCT rats at the doses tested. The greater content of bladder TLR2 and TLR4 proteins in the NBI group was consistent with increased responsiveness to their agonists, Zymosan and LPS, respectively. Given that patients with IC/BPS have a higher incidence of childhood urinary tract infections, this increased responsiveness to microbial antigens may explain the flares in symptoms following "subclinical" tract infections.

KLF2 Regulates NLRP3 Inflammasome Priming and Activation in Murine Myeloid Cells

Introduction: Krüppel-like factor-2 (KLF2) is a critical nodal transcription factor and a tonic repressor of myeloid cell activation. Loss of KLF2 is associated with a pro-inflammatory and pro-thrombotic state. Mice deficient in myeloid-KLF2 (MK2KO) experience significantly higher mortality from lipopolysaccharide (LPS), and have increased serum and tissue levels of pro-inflammatory cytokines such as IL-1β. IL-1β is a product of NLRP3 inflammasome priming and activation, which has been implicated in numerous inflammatory and immune-mediated diseases. Neutrophils are the first responders of the innate immune system and are responsible for bacterial antigen detection. We thus aimed to elucidate the role of KLF2 in the regulation of NLRP3 inflammasome activation and subsequent IL-1β release in the neutrophil compartment. Methods: 8-week old adult MK2KO ( Lyz2Cre/ Klf2fl/fl) and control ( Lyz2Cre) mice were used for obtaining neutrophils from the bone marrow. Neutrophils were plated in RPMI-1640 media and stimulated with 10 ng/mL of LPS for 1 hour (h) and 2 h, followed by nigericin for 30 minutes. LPS acts as a priming agent for NLRP3 inflammasome assembly, and nigericin is a potassium ionophore which enables the activation step and subsequent IL-1β release. Supernatant was used for IL-1β ELISA and cell lysate was used for protein extraction and Western blotting to quantify NLRP3 protein expression. GraphPad Prism was used for statistical analyses. Results: Neutrophils from both MK2KO and Cre mice have significantly increased production of IL-1β when stimulated with LPS followed by nigericin (Figure 1), and loss of KLF2 leads to significantly increased IL-1B release from neutrophils. MK2KO neutrophils also have significantly more NLRP3 protein expression as compared to Cre neutrophils at baseline, and in response to LPS and nigericin (Figure 2). This increase in NLRP3 protein expression was time dependent and dose-dependent (Figure 2). Conclusion: KLF2 negatively regulates the transcriptional expression of NLRP3 and loss of KLF2 leads to increased NLRP3 inflammasome priming, at baseline and in response to LPS. Loss of KLF2 also affects the second step of the NLRP3 inflammasome pathway - the activation step, leading to increased IL-1β release in neutrophils in adult mice. Ongoing studies are examining the mechanisms underlying KLF2 control of NLRP3 transcription and other aspects of inflammasome activation. Inflammasome activation has been implicated in sepsis-related mortality due to the pro-inflammatory cytokine storm, and thus modulating KLF2 might help in developing novel targets to reduce this burden of mortality.

Oxidative Stress Accompanies HIF1-Dependent Impairment of Glucose Metabolism in the Hippocampus of Adult Rats That Survived Prenatal Severe Hypoxia

Introduction: Many socially significant diseases are associated with prenatal developmental disorders. Previously, we showed the pathological role of hypoxia-inducible factor-1 (HIF1) in post-hypoxic reoxygenation. This study aimed to investigate the effect of prenatal severe hypoxia (PSH) on HIF1α protein expression as well as on HIF1-dependent activity of the pentose phosphate pathway (PPP) and anaerobic glycolysis in the hippocampus (HPC) of offspring that reached adulthood. Methods: PSH was induced during the critical period of fetal hippocampal formation on gestation days 14–16 in a hypobaric chamber (180 Torr, 5% oxygen, 3 h). Subsequent studies were conducted on both the HPC of adult control and PSH rats under normal conditions, as well as in response to severe hypoxia (SH) or psycho-emotional stress (“learned helplessness” [LH] model). We evaluated HIF1α protein levels using both immunohistochemistry and Western blotting techniques. The amount of glucose-6-phosphate dehydrogenase (G6PD) was also determined by Western blotting. Colorimetric enzymatic assays were employed to analyze enzymatic activity of lactate dehydrogenase (LDH), the concentration of lactate, NADPH, reduced glutathione (GSHred), and malonic dialdehyde (MDA). Results: We showed that PSH caused a stable increase in the content of HIF1α protein in the HPC, which was accompanied by an increase in the efficiency of anaerobic glycolysis. This was confirmed by increased LDH activity and lactate concentration. At the same time, the amounts of G6PD, NADPH, and GSHred decreased in the HPC of PSH rats, whereas the concentration of MDA, an oxidative stress marker, exceeded the control values. In a series of experiments using the LH or SH stress, it was shown that in the HPC of control rats, there was an increase in the amount of HIF1α in response to stress, which was also accompanied by more efficient anaerobic glycolysis and decrease of PPP-dependent NADPH production, similar to the intact PSH rats. In PSH rats, emotional stress resulted in higher HIF1α levels without affecting glycolysis or PPP. Conclusion: Therefore, the increased content and activity of the transcription factor HIF1α in the HPC of adult rats exposed to prenatal hypoxia leads to an imbalance between glycolysis and PPP, which is accompanied by oxidative stress.

Anopheles larval habitats seasonality and environmental factors affecting larval abundance and distribution in Arjo-Didessa sugar cane plantation, Ethiopia

BackgroundWater resource development projects are essential for increasing agricultural productivity and ensuring food security. However, these activities require the modification of pre-existing environmental settings, which may alter mosquito larval habitat availability and seasonality. The intensive utilization of current adult vector control tools results in insecticide resistance among the main vectors. When coupled with behavioural resistances, a shift in malaria vector feeding and resting behaviours could compromise the effectiveness of the current adult vector control strategies. Thus, it is important to look for new or alternative vector control interventions for immatures to complement adult control by focusing on different larval habitats and their seasonal availability. Thus, this study investigated larval habitat seasonality and seasonal larval abundance and distribution in irrigated sugar cane plantation settings in Ethiopia.MethodsAnopheles mosquito larval habitats were surveyed and visited twice a month for a period of 14 months. Anopheline larvae and pupae were collected, reared, and fed finely ground fish food. Adults were provided with sucrose solution and kept under standard conditions. Female Anopheles mosquitoes were identified morphologically and using a species-specific PCR assay. Environmental parameters, which include habitats’ physico-chemical characteristics, were assessed. Larval habitat diversity and larval abundance and distribution were determined across different seasons.ResultsThe study revealed that Anopheles gambiae sensu lato (s.l.) was the most predominant 4197(57%) vector species, followed by Anopheles coustani complex 2388 (32.8%). Molecular analysis of sub-samples of An. gambiae s.l. resulted in Anopheles arabiensis (77.9%) and Anopheles amharicus (21.5%), and the remaining 1.1% (n = 7) sub-samples were not amplified. Physico-chemical parameters such as temperature (t = 2.22, p = 0.028), conductivity (t = 3.21, p = 0.002), dissolved oxygen (t = 7.96, p = 0.001), nitrate ion (t = 2.51, p = 0.013), and ammonium ion (t = 2.26, p = 0.025) showed a significant and direct association with mosquito larval abundance. Furthermore, mosquito larval abundance was correlated with distance to the nearest houses (r = − 0.42, p = 0.001), exposure to sunlight (r = 0.34, p = 0.001), during long and short rainy season animal hoof prints, truck tires/road puddles and rain pools were negatively correlated (r = − 0.22, p = 0.01) and types of habitat (r = − 0.20, p = 0.01). Significant habitat type productivity were observed in man-made pools (t = 3.881, P = 0.01163), rain pools, animal hoof prints, (t = − 4.332, P = 0.00749 in both short and long rainy season, whereas, during dry seasons habitat type productivity almost similar and have no significance difference.ConclusionThe study found that different larval habitats had variable productivity in different seasons, and that physical and physicochemical features like ammonium and nitrate, as well as the distance between larval habitats and households, are related to larval production. As a result, vector control should take into account the seasonality of Anopheles larval habitat as well as the impact of pesticide application on larval source management.

Adolescent intermittent ethanol exposure alters adult exploratory and affective behaviors, and cerebellar Grin2b expression in C57BL/6J mice

Binge drinking is one of the most common patterns (more than 90%) of alcohol consumption by young people. During adolescence, the brain undergoes maturational changes that influence behavioral control and affective behaviors, such as cerebellar brain volume and function in adulthood. We investigated long-term impacts of adolescent binge ethanol exposure on affective and exploratory behaviors and cerebellar gene expression in adult male and female mice. Further, the cerebellum is increasingly recognized as a brain region integrating a multitude of behaviors that span from the traditional primary sensory-motor to affective functions, such as anxiety and stress reactivity. Therefore, we investigated the persistent effects of adolescent intermittent ethanol (AIE) on exploratory and affective behaviors and began to elucidate the role of the cerebellum in these behaviors through excitatory signaling gene expression. We exposed C57BL/6J mice to AIE or air (control) vapor inhalation from postnatal day 28–42. After prolonged abstinence (>34 days), in young adulthood (PND 77+) we assessed behavior in the open field, light/dark, tail suspension, and forced swim stress tests to determine changes in affective behaviors including anxiety-like, depressive-like, and stress reactivity behavior. Excitatory signaling gene mRNA levels of fragile X messenger ribonucleoprotein (FMR1), glutamate receptors (Grin2a, Grin2b and Grm5) and excitatory synaptic markers (PSD-95 and Eaat1) were measured in the cerebellum of adult control and AIE-exposed mice. AIE-exposed mice showed decreased exploratory behaviors in the open field test (OFT) where both sexes show reduced ambulation, however only females exhibited a reduction in rearing. Additionally, in the OFT, AIE-exposed females also exhibited increased anxiety-like behavior (entries to center zone). In the forced swim stress test, AIE-exposed male mice, but not females, spent less time immobile compared to their same-sex controls, indicative of sex-specific changes in stress reactivity. Male and female AIE-exposed mice showed increased Grin2b (Glutamate Ionotropic Receptor NMDA Type Subunit 2B) mRNA levels in the cerebellum compared to their same-sex controls. Together, these data show that adolescent binge-like ethanol exposure altered both exploratory and affective behaviors in a sex-specific manner and modified cerebellar Grin2b expression in adult mice. This indicates the cerebellum may serve as an important brain region that is susceptible to long-term molecular changes after AIE.

Altered brain serotonin 5-HT1A receptor expression and function in juvenile Fmr1 knockout mice

There are no approved pharmacotherapies for fragile X syndrome (FXS), a rare neurodevelopmental disorder caused by a mutation in the FMR1 promoter region that leads to various symptoms, including intellectual disability and auditory hypersensitivity. The gene that encodes inhibitory serotonin 1A receptors (5-HT1ARs) is differentially expressed in embryonic brain tissue from individuals with FXS, and 5-HT1ARs are highly expressed in neural systems that are disordered in FXS, providing a rationale to focus on 5-HT1ARs as targets to treat symptoms of FXS. We examined agonist-labeled 5-HT1AR densities in male and female Fmr1 knockout mice and found no differences in whole-brain 5-HT1AR expression in adult control compared to Fmr1 knockout mice. However, juvenile Fmr1 knockout mice had lower whole-brain 5-HT1AR expression than age-matched controls. Consistent with these results, juvenile Fmr1 knockout mice showed reduced behavioral responses elicited by the 5-HT1AR agonist (R)-8-OH-DPAT, effects blocked by the selective 5-HT1AR antagonist, WAY-100635. Also, treatment with the selective 5-HT1AR agonist, NLX-112, dose-dependently prevented audiogenic seizures (AGS) in juvenile Fmr1 knockout mice, an effect reversed by WAY-100635. Suggestive of a potential role for 5-HT1ARs in regulating AGS, compared to males, female Fmr1 knockout mice had a lower prevalence of AGS and higher expression of antagonist-labeled 5-HT1ARs in the inferior colliculus and auditory cortex. These results provide preclinical support that 5-HT1AR agonists may be therapeutic for young individuals with FXS hypersensitive to auditory stimuli.

Long-term effects of low prenatal alcohol exposure on GABAergic interneurons of the murine posterior parietal cortex.

Fetal alcohol spectrum disorders (FASDs) are characterized by a wide range of physical, cognitive, and behavioral impairments that occur throughout the lifespan. Prenatal alcohol exposure (PAE) can lead to adult impairments in cognitive control behaviors mediated by the posterior parietal cortex (PPC). The PPC plays a fundamental role in the performance of response tasks in both primates and rodents, specifically when choices between similar target and nontarget stimuli are required. Furthermore, the PPC is reciprocally connected with other cortical areas. Despite the extensive literature investigating the molecular mechanisms underlying PAE impairments in cognitive functions mediated by cortical areas, little is known regarding the long-term effects of PAE on PPC development and function. Here, we examined changes in the cellular organization of GABAergic interneurons and their function in PPC using behaviorally naïve control and PAE mice. We used a limited access model of PAE in which C57BL/6J females were exposed to a solution of 10% (w/v) ethanol and 0.066% (w/V) saccharin for 4 h/day throughout gestation. Using high-throughput fluorescent microscopy, we quantified the levels of GABAergic interneurons in the PPC of adult PAE and control offspring. In a separate cohort, we recorded spontaneous inhibitory postsynaptic currents (sIPSCs) using whole-cell patch clamp recordings from PPC layer 5 pyramidal neurons. PAE led to a significant overall reduction of parvalbumin-expressing GABAergic interneurons in PAE mice regardless of sex. Somatostatin- and calretinin-expressing GABAergic interneurons were not affected. Interestingly, PAE did not modulate sIPSC amplitude or frequency. These results suggest that impairments in cognitive control observed in FASD may be due to the significant reduction of parvalbumin-expressing GABAergic interneurons in the PPC. PAE animals may show compensatory changes in GABAergic function following developmental reduction of these interneurons.

Developmental estrogen exposure in mice disrupts uterine epithelial cell differentiation and causes adenocarcinoma via Wnt/β-catenin and PI3K/AKT signaling.

Tissue development entails genetically programmed differentiation of immature cell types to mature, fully differentiated cells. Exposure during development to non-mutagenic environmental factors can contribute to cancer risk, but the underlying mechanisms are not understood. We used a mouse model of endometrial adenocarcinoma that results from brief developmental exposure to an estrogenic chemical, diethylstilbestrol (DES), to determine causative factors. Single-cell RNA sequencing (scRNAseq) and spatial transcriptomics of adult control uteri revealed novel markers of uterine epithelial stem cells (EpSCs), identified distinct luminal and glandular progenitor cell (PC) populations, and defined glandular and luminal epithelium (LE) cell differentiation trajectories. Neonatal DES exposure disrupted uterine epithelial cell differentiation, resulting in a failure to generate an EpSC population or distinguishable glandular and luminal progenitors or mature cells. Instead, the DES-exposed epithelial cells were characterized by a single proliferating PC population and widespread activation of Wnt/β-catenin signaling. The underlying endometrial stromal cells had dramatic increases in inflammatory signaling pathways and oxidative stress. Together, these changes activated phosphoinositide 3-kinase/AKT serine-threonine kinase signaling and malignant transformation of cells that were marked by phospho-AKT and the cancer-associated protein olfactomedin 4. Here, we defined a mechanistic pathway from developmental exposure to an endocrine disrupting chemical to the development of adult-onset cancer. These findings provide an explanation for how human cancers, which are often associated with abnormal activation of PI3K/AKT signaling, could result from exposure to environmental insults during development.

Esculeoside A Decreases Diabetic Cardiomyopathy in Streptozotocin-Treated Rats by Attenuating Oxidative Stress, Inflammation, Fibrosis, and Apoptosis: Impressive Role of Nrf2.

Background and Objectives: This experiment evaluated the preventative influence of the tomato-derived Esculeoside A (ESA) on diabetic cardiomyopathy in type 1 diabetes mellitus (T1DM) in rats induced by streptozotocin (STZ). It also examined whether the activation of Nrf2 signaling affords this protection. Materials and Methods: Adult male Wistar control nondiabetic rats and rats with T1DM (STZ-T1DM) were given either carboxymethylcellulose as a vehicle or ESA (100 mg/kg) (eight rats/group) orally daily for 12 weeks. A group of STZ-T1DM rats was also treated with 100 mg/kg ESA and co-treated i.p. with 2 mg/kg (twice/week), brusatol, and Nrf2 inhibitors for 12 weeks. Results and Conclusions: Treatment with ESA prevented the gain in heart weight and cardiomyocyte hypertrophy and improved the left ventricular (LV) systolic and diastolic function (LV) in the STZ-T1DM rat group. Likewise, it reduced their serum levels of triglycerides, cholesterol, and low-density lipoproteins (LDL-c), as well as their LV mRNA, cytoplasmic total, and nuclear total levels of NF-κB. ESA also reduced the total levels of malondialdehyde, tumor necrosis factor-α, interleukine-6 (IL-6), Bax, cytochrome-c, and caspase-3 in the LV of the STZ-T1DM rats. In parallel, ESA enhanced the nuclear and cytoplasmic levels of Nrf2 and the levels of superoxide dismutase, glutathione, and heme oxygenase-1, but decreased the mRNA and cytoplasmic levels of keap-1 in the LVs of the STZ-T1DM rats. Interestingly, ESA did not affect the fasting insulin and glucose levels of the diabetic rats. All of these beneficially protective effects of ESA were not seen in the ESA-treated rats that received brusatol. In conclusion, ESA represses diabetic cardiomyopathy in STZ-diabetic hearts by activating the Nrf2/antioxidant/NF-κB axis.

TESTOSTERONE RESTORES BODY COMPOSITION, BONE MASS AND BONE STRENGTH FOLLOWING EARLY PUBERTY SUPPRESSION IN A MOUSE MODEL MIMICKING THE CLINICAL STRATEGY IN TRANS BOYS.

Transgender youth increasingly present at pediatric gender services. Some of them receive long-term puberty suppression with gonadotropin-releasing hormone analogues (GnRHa) before starting gender-affirming hormones (GAH). The impact of GnRHa use started in early puberty on bone composition and bone mass accrual is unexplored. It is furthermore unclear whether subsequent GAH fully restore GnRHa effects, and if the timing of GAH introduction matters. To answer these questions, we developed a mouse model mimicking the clinical strategy applied in trans boys. Prepubertal 4-week-old female mice were treated with GnRHa alone, or with GnRHa supplemented with testosterone (T) from 6 weeks (early puberty) or 8 weeks (late puberty) onwards. Outcomes were analyzed at 16 weeks and compared to untreated mice of both sexes. GnRHa markedly increased total body fat mass, decreased lean body mass and had a modest negative impact on grip strength. Both early and late T administration shaped body composition to adult male levels, while grip strength was restored to female values. GnRHa-treated animals showed lower trabecular bone volume, and reduced cortical bone mass and strength. These changes were reversed by T to female levels (cortical bone mass and strength) irrespective of the time of administration, or even fully up to adult male control values (trabecular parameters) in case of earlier T start. The lower bone mass in GnRHa-treated mice was associated with increased bone marrow adiposity, also reversed by T. In conclusion, prolonged GnRHa use started in prepubertal female mice modifies body composition towards more fat and less lean mass, and impairs bone mass acquisition and strength. Subsequent T administration counteracts GnRHa impact on these parameters, shaping body composition and trabecular parameters to male values while restoring cortical bone architecture and strength up to female but not male control levels. These findings could help guide clinical strategies in transgender care. This article is protected by copyright. All rights reserved.

Saponins of Panax japonicus ameliorates cardiac aging phenotype in aging rats by enhancing basal autophagy through AMPK/mTOR/ULK1 pathway

Heart disease is a significant health concern for elderly individuals, with heart aging being the primary cause. Recent studies have shown that autophagy can play a protective role in preventing cardiac aging. Our previous research confirmed that Chikusetsu saponin IVa, a fundamental component of Saponins of Panax japonics (SPJ), can enhance basic autophagy levels in cardiomyocyte of isoproterenol induced cardiac fibrosis mice. However, it remains unclear whether SPJ possesses a protective effect on cardiac dysfunction during the natural aging process. Rats were randomly divided into four groups: adult control group (6 months old), aging group (24 months old), aging group treated with 10 mg/kg SPJ, and aging group treated with 30 mg/kg SPJ. The heart function, blood pressure, and heart mass index (HMI) were measured. Hematoxylin and eosin staining (H&E) and Wheat Germ Agglutinin (WGA) staining were used to observe the changes in morphology, while Masson staining was used to examine collagen deposition in the rat hearts and CD45 immunohistochemistry was conducted to examine the macrophage infiltration in heart tissues. TUNEL kit was used to detect apoptosis level of cardiomyocyte, and western blot was used to evaluate autophagy-related proteins as well as AMPK/mTOR/ULK1 pathway-related markers. SPJ treatment improved the cardiac function, reduced HMI, attenuated myocardial fiber disorder, inhibited inflammatory cell infiltration, and decreased collagen deposition and cardiomyocyte apoptosis in aging rats. Additionally, SPJ treatment decreased the expression of aging-related proteins and restored the expression of autophagy-related markers. SPJ activated autophagy through the activation of AMPK, which in turn increased the phosphorylation of ULK1(Ser555), while inhibited the phosphorylation of mTOR and ULK1(Ser757). Our study demonstrates that SPJ improves the cardiac function of aging rats by enhancing basal autophagy through the AMPK/mTOR/ULK1 pathway. These results offer a theoretical foundation and empirical evidence to support the clinical advancement of SPJ in enhancing age-related cardiac dysfunction.

The distribution of myeloid-derived suppressor cells subsets and up-regulation of programmed death-1/PD-L1 axis in peripheral blood of adult CAP patients.

Myeloid-derived suppressor cells (MDSCs) have been reported to expand and have a potent ability in the expansion of regulatory T cells in malignant and infectious disease. The current study was performed to investigate the role of MDSCs and possible immune mechanisms in dampening immune responses of community acquired pneumonia (CAP). This was a single-center cross-sectional study. The distribution of MDSCs subsets, the PD-1/PD-L1(L2) level of MDSCs subsets and Tregs in the peripheral blood of adult CAP patients and healthy control were measured by flow cytometry analysis. Peripheral blood mononuclear cells (PBMCs) from 63 adult CAP patients contained an elevated frequency of both G-MDSC (4.92±0.30 vs 2.25±0.21,p<0.0001) and M-MDSC (19.40±1.30 vs 9.64±0.57,p<0.001) compared to healthy controls. Treg in the peripheral blood of CAP patients exhibited increased expression of PD-1 and CTLA-4, accompanied by no difference of their frequency. Moreover, up-regulated expression of PD-L1 on MDSC subsets in the peripheral blood of CAP patients was also revealed. Of note, the frequency of circulating MDSCs subset displayed a positive correlation with neutrophil count percentage in blood in CAP patients. In summary, the significant expansion of circulating MDSCs subsets and the up-regulated expression of PD-1/PD-L1 level in CAP patients may suggest the possible involvement of PD-1/PD-L1axis in MDSCs mediated immune regulation on Treg at least partially in CAP patients.

Analysis of the serum bile acid profile to facilitate diagnosis and differential diagnosis of NA(+)-taurocholate cotransporting polypeptide deficiency

Objective: This study focuses on Na(+)-taurocholate cotransporting polypeptide (NTCP) deficiency to analyze and investigate the value of the serum bile acid profile for facilitating the diagnosis and differential diagnosis. Methods: Clinical data of 66 patients with cholestatic liver diseases (CLDs) diagnosed and treated in the Department of Pediatrics of the First Affiliated Hospital of Jinan University from early April 2015 to the end of December 2021 were collected, including 32 cases of NTCP deficiency (16 adults and 16 children), 16 cases of neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), 8 cases of Alagille syndrome, and 10 cases of biliary atresia. At the same time, adult and pediatric healthy control groups (15 cases each) were established. The serum bile acid components of the study subjects were qualitatively and quantitatively analyzed by ultra-high performance liquid chromatography-tandem mass spectrometry. The data were plotted and compared using statistical SPSS 19.0 and GraphPad Prism 5.0 software. The clinical and bile acid profiles of children with NTCP deficiency and corresponding healthy controls, as well as differences between NTCP deficiency and other CLDs, were compared using statistical methods such as t-tests, Wilcoxon rank sum tests, and Kruskal-Wallis H tests. Results: Compared with the healthy control, the levels of total conjugated bile acids, total primary bile acids, total secondary bile acids, glycocholic acid, taurocholic acid, and glycochenodeoxycholic acid were increased in NTCP deficiency patients (P < 0.05). Compared with adults with NTCP deficiency, the levels of total conjugated bile acids and total primary bile acids were significantly increased in children with NTCP deficiency (P < 0.05). The serum levels of taurochenodeoxycholic acid, glycolithocholate, taurohyocholate, and tauro-α-muricholic acid were significantly increased in children with NTCP deficiency, but the bile acid levels such as glycodeoxycholic acid, glycolithocholate, and lithocholic acid were decreased (P < 0.05). The serum levels of secondary bile acids such as lithocholic acid, deoxycholic acid, and hyodeoxycholic acid were significantly higher in children with NTCP deficiency than those in other CLD groups such as NICCD, Alagille syndrome, and biliary atresia (P < 0.05). Total primary bile acids/total secondary bile acids, total conjugated bile acids/total unconjugated bile acids, taurocholic acid, serum taurodeoxycholic acid, and glycodeoxycholic acid effectively distinguished children with NTCP deficiency from other non-NTCP deficiency CLDs. Conclusion: This study confirms that serum bile acid profile analysis has an important reference value for facilitating the diagnosis and differential diagnosis of NTCP deficiency. Furthermore, it deepens the scientific understanding of the changing characteristics of serum bile acid profiles in patients with CLDs such as NTCP deficiency, provides a metabolomic basis for in-depth understanding of its pathogenesis, and provides clues and ideas for subsequent in-depth research.

Prenatal alcohol alters inflammatory signatures in enteric portal tissues following adult-onset cerebrovascular ischemic stroke

Prenatal alcohol exposure (PAE) impairs recovery from cerebrovascular ischemic stroke in adult rodents. Since the gut becomes dysbiotic following stroke, we assessed links between PAE and enteric portal inflammation. Adult control and PAE rat offspring received a unilateral endothelin-1-induced occlusion of the middle cerebral artery. Post-stroke behavioral disabilities and brain cytokines were assessed. Mesenteric adipose and liver transcriptomes were assessed from stroke-exposed and stroke-naive offspring. We identified, in the liver of stroke-naive animals, a moderate correlation between PAE and a gene network for inflammatory necroptosis. PAE inhibited the acute-phase brain inflammatory cytokine response to stroke. Post-stroke neurological function was correlated with an adipose gene network associated with B-lymphocyte differentiation and nuclear factor κB (NF-κB) signaling and with a liver pro-inflammatory gene network. Collectively, PAE inhibits brain inflammation but results in an inflammatory signature in enteric portal tissues after stroke, suggesting that PAE persistently and adversely impacts the gut-brain axis following adult-onset disease.

Saponins from Panax japonicus improve neuronal mitochondrial injury of aging rats

Context Panax japonicus is the dried rhizome of Panax japonicus C.A. Mey. (Araliaceae). Saponins from Panax japonicus (SPJ) exhibit anti-oxidative and anti-aging effects. Objective We evaluated the neuroprotective effects of SPJ on aging rats. Materials and methods Sprague-Dawley rats (18-months-old) were randomly divided into aging and SPJ groups (n = 8). Five-month-old rats were taken as the adult control (n = 8). The rats were fed a normal chow diet or the SPJ-containing diet (10 or 30 mg/kg) for 4 months. An in vitro model was established by d-galactose (d-Gal) in the SH-SY5Y cell line and pretreated with SPJ (25 and 50 µg/mL). The neuroprotection of SPJ was evaluated via Nissl staining, flow cytometry, transmission electron microscopy and Western blotting in vivo and in vitro. Results SPJ improved the neuronal degeneration and mitochondrial morphology that are associated with aging. Meanwhile, SPJ up-regulated the protein levels of mitofusin 2 (Mfn2) and optic atrophy 1 (Opa1) and down-regulated the protein level of dynamin-like protein 1 (Drp1) in the hippocampus of aging rats (p < 0.05 or p < 0.01 vs. 22 M). The in vitro studies also demonstrated that SPJ attenuated d-Gal-induced cell senescence concomitant with the improvement in mitochondrial function; SPJ, also up-regulated the Mfn2 and Opa1 protein levels, whereas the Drp1 protein level (p < 0.05 or p < 0.01 vs. d-Gal group) was down-regulated. Discussion and conclusions Further research on the elderly population will contribute to the development and utilization of SPJ for the treatment of neurodegenerative disorders.

Extrusion of the medial meniscus under a weight-loading condition in early knee osteoarthritis: an investigation using special upright magnetic resonance imaging

BackgroundWhether the medial meniscus morphology and movement occur under upright loading conditions in early knee osteoarthritis (OA) or medial meniscus posterior root tear (MMPRT) remains unknown. This study aimed to evaluate the medial and anteroposterior extrusion of the medial meniscus under unloaded and upright-loaded conditions in patients with early knee OA.MethodsTwelve patients with early knee OA and 18 healthy adult volunteers participated in this study. Magnetic resonance imaging using special equipment was performed with the participants in the unloaded and upright-loaded conditions. Medial, anterior, and posterior extrusions of the medial meniscus against the tibial edge were evaluated and compared between the early knee OA and healthy adult control groups. Additionally, 12 patients in the early knee OA group were divided into 2 subgroups based on whether MMPRT was observed, and the extrusion of the medial meniscus was compared.ResultsThe amount of medial extrusion of the medial meniscus in both the unloaded and upright-loaded conditions was significantly greater in the early knee OA group than in the control group (unloaded: 2.6 ± 1.0 mm vs 0.7 ± 0.5 mm; upright-loaded: 3.7 ± 0.9 mm vs 1.8 ± 0.8 mm). Similarly, the anterior and posterior extrusion of the medial meniscus in the upright-loaded condition was significantly larger in the early knee OA group (anterior: 4.6 ± 1.0 mm vs 3.7 ± 1.1 mm; posterior: -3.4 ± 1.1 mm vs -4.6 ± 1.6 mm). However, no difference was observed in meniscal extrusion between unloaded and upright-loaded conditions. The posterior extrusion of the medial meniscus in the upright-loaded condition was significantly greater in MMPRT cases than in non-MMPRT cases in the early knee OA group (MMPRT: -2.7 ± 1.1 mm; non-MMPRT -4.1 ± 1.5 mm).ConclusionsIn early knee OA, significantly large meniscal extrusions of the medial meniscus in both unloaded and upright-loaded conditions were found compared with healthy adults. Among patients with early knee OA, those with MMPRT showed a large posterior extrusion of the medial meniscus in the upright-loaded condition compared with those without MMPRT.Level of evidenceLevel IV.

Generation of two human iPSC lines from dermal fibroblasts of adult- and juvenile-onset Huntington's disease patients and two healthy donors

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a mutation in the HTT gene. To generate human-induced pluripotent stem cells (hiPSCs), we used dermal fibroblasts from 1 healthy adult control (K-Pic2), 1 HD manifest patient (M-T2), 1 healthy juvenile control (jK-N1), and 1 juvenile HD patient (jHD-V1). HD stage of patients was assessed by neurological tests and donors were without comorbidities and were non-smokers. Characterization showed that the obtained hiPSCs have the same number of CAG repeats as the parental fibroblast lines, express pluripotency markers and have the ability to differentiate into all 3 germ layers.

Lived experiences constraints of family caregivers in caring for older adults with chronic diseases during the Covid-19 pandemic: a qualitative study of Indonesian perspectives

PurposeThe purpose of this study is to explore the lived experiences of the constraints of older adult family caregivers with chronic diseases in caring for and accessing health services during the COVID-19 pandemic.Design/methodology/approachThis study used the descriptive phenomenology qualitative method. The sampling method was purposive sampling involving 16 older adult family caregivers.FindingsThe results of this study showed three themes such as difficulties in health services in hospitals during the COVID-19 pandemic (complaints of services provided by doctors, older adult treatment control problems and difficulty getting to hospital health facilities); difficulties accompanying taking older adult medicine (older adult non-compliance response to taking medication and older adult medicine assistance); and psychosocial complaints caring for and accompanying the older adult (negative emotions for the older adult, difficulty interacting with the older adult and the economic burden of caring for the older adult).Practical implicationsBarriers to family caregivers in caring for older adults with chronic diseases can help health-care service providers understand and support families caring for and assisting older adults, which may contribute to the quality of life and care for both family caregivers and older adults.Originality/valueThis study showed that Indonesian family caregivers faced difficulties caring for and living with older adults with chronic diseases during the pandemic. Family caregivers’ experiences are essential when developing an intervention to support and manage health care for older adults with chronic illnesses.