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Abstract Metabolic imbalance leading to inflammatory hypoxia and stabilization of hypoxia-inducible transcription factors (HIFs) is a hallmark of inflammatory bowel diseases. We hypothesize that HIF could be stabilized in CD4+ T cells during intestinal inflammation and alter the functional responses of T cells via regulation of microRNAs. Our assays reveal markedly increased T cell-intrinsic hypoxia and stabilization of HIF protein during experimental colitis. microRNA screen in primary CD4+ T cells points us towards miR-29a and our subsequent studies identify a selective role for HIF-2α in CD4-cell-intrinsic induction of miR-29a during hypoxia. Mice with T cell-intrinsic HIF-2α deletion display elevated T-bet (target of miR-29a) levels and exacerbated intestinal inflammation. Mice with miR-29a deficiency in T cells show enhanced intestinal inflammation. T cell-intrinsic overexpression of HIF-2α or delivery of miR-29a mimetic dampen TH1-driven colitis. In this work, we show a previously unrecognized function for hypoxia-dependent induction of miR-29a in attenuating TH1-mediated inflammation.

Abstract Background The efficacy of surgical treatment for benign prostatic hyperplasia (BPH) patients with detrusor underactivity (DU) remains controversial. Methods To summarize relevant evidence, three databases (PubMed, Embase, and Web of Science) were searched from database inception to May 1, 2023. Transurethral surgical treatment modalities include transurethral prostatectomy (TURP), photoselective vaporization of the prostate (PVP), and transurethral incision of the prostate (TUIP). The efficacy of the transurethral surgical treatment was assessed according to maximal flow rate on uroflowmetry (Q max), International Prostate Symptom Score (IPSS), postvoid residual (PVR), quality of life (QoL), voided volume, bladder contractility index (BCI) and maximal detrusor pressure at maximal flow rate (PdetQmax). Pooled mean differences (MDs) were used as summary statistics for comparison. The quality of enrolled studies was evaluated by using the Newcastle–Ottawa Scale. Sensitivity analysis and funnel plots were applied to assess possible biases. Results In this study, 10 studies with a total of 1142 patients enrolled. In BPH patients with DU, within half a year, significant improvements in Q max (pooled MD, 4.79; 95% CI, 2.43–7.16; P

Objective: The primary objective of this study was to investigate the immediate effects of two doses (Dose1 and Dose2,D1 and D2) of inertial Flywheel Eccentric Overload (FEOL), Eccentric Hook (EH), and High-intensity Half Squat (HHS) on muscle explosiveness in male sprinters. Methods: Twenty-one sub-elite male sprinters were randomly assigned to three groups: the FEOL group (n=7), the EH group (n=7), and the HSS group (n=7),Measurements of athletes' explosive jumps (CMJ, SJ, SLJ) heights, relative peak power indices, and 30-m sprint times were collected before and 6 min after the intervention. Results: At D1 loading dose, CMJ, SJ jump height, and relative peak power increased significantly (p 0.05). At D2 loading dose, CMJ, SJ jump height, and relative peak power increased significantly (p 0.05). CMJ vertical jump height and relative peak power were significantly higher after D2FEOL and D2EH interventions than after D1HHS (P

Background: We aimed to clarify whether differences in food group intake according to household income have changed over the last decade in Japanese people aged 20 years or older. Methods: This cross-sectional study was based on the 2010, 2014, and 2018 National Health and Nutrition Surveys in Japan. Food intake was assessed using a 1-day semi-weighed household dietary record. The participants were categorized into three groups based on their income. The mean of each food intake according to the income group was estimated by adjusting for age, occupation, and number of participants from the same household. The significance of the interaction terms between income and survey year was evaluated to assess the change in income-related differences in food intake over time. Results: Cereal intake was lower in the middle- and the highest-income groups than in the lowest-income group, regardless of sex, and the interaction between income and year was nonsignificant for cereal intake. In the former two surveys, vegetable intake was higher among the highest-income women, while in the 2018 survey, the vegetable intake decreased in the women in the middle- and the highest-income groups. The interaction between income and year was significant for vegetable intake among the women. For other foods, the differences in intake among the income groups did not significantly change over time. Conclusion: The tendency for lower cereal intake in the higher-income groups was consistent over time in both the sexes, and the tendency for higher vegetable intake in the highest income women disappeared over time.

The Mg-8.75Gd-2.85Y (wt%) alloy processed by surface mechanical attrition treatment (SMAT) was annealed at 350 °C followed by peak-ageing. Recrystallization occurred in the surface layer of the specimen induced by the annealing treatment. The obtained heterostructure contained a fine-grained (FG) layer with thickness of about 350 μm on the top and a coarse-grained (CG) layer at the bottom. The sample exhibited a reversely-gradient distribution in hardness, in which the FG layer showed lower values than the CG layer. It was related to the different behaviors of recrystallization and precipitation. Compared with the homogeneous CG alloy, the heterostructured sample exhibited enhancement in both strength and ductility. The increase of yield strength was mainly ascribed to grain boundary strengthening and dislocation strengthening. The random texture of the FG layer and the synergetic effect of the heterostructure were beneficial to the improvement of ductility. This work provides valuable insights for developing gradient-structured Mg-RE alloys for high performance in engineering applications such as automotive, aerospace and defense industries.

Abstract Background Highly processed food (HPF) consumption is increasing globally and has become a prominent public health concern. However, the relationship between HPF consumption and food choice values and food literacy is unknown. This study aimed to examine the association of HPF consumption with food choice values and food literacy. Methods This cross-sectional study used data from a nationwide questionnaire survey conducted in 2018 among 2232 Japanese adults aged 18–80 years. We assessed eight food choice values (accessibility, convenience, health/weight control, tradition, sensory appeal, organic, comfort, and safety) using a 25-item scale, and food literacy characterised by nutrition knowledge (using a validated 143-item questionnaire), cooking and food skills (using 14- and 19-item scales, respectively), and eight eating behaviours (hunger, food responsiveness, emotional overeating, enjoyment of food, satiety responsiveness, emotional undereating, food fussiness, and slowness in eating, using the 35-item Adult Eating Behavior Questionnaire). HPF consumption was estimated using a validated brief diet history questionnaire. The associations between HPF consumption and age, body mass index, energy intake, and each score on food choice values and food literacy were evaluated by multiple linear regression. Results In males, one standard deviation increase in scores for cooking skill and satiety responsiveness was associated with an increase in HPF consumption by 22.1 g/4184 kJ (95% confidence interval (CI): 6.6 to 37.5) and 15.4 g/4184 kJ (95% CI: 6.0 to 24.7), respectively. In females, one standard deviation increase in age and scores for safety and nutrition knowledge corresponded to a decrease in HPF consumption by − 16.4 g/4184 kJ (95% CI: − 23.4 to − 9.3), − 9.9 g/4184 kJ (95% CI: − 19.1 to − 0.7), and − 11.1 g/4184 kJ (95% CI: − 17.0 to − 5.3), whereas one standard deviation increase in the satiety responsiveness score corresponded to an increase in HPF consumption by 13.1 g/4184 kJ (95% CI: 6.8 to 19.4). Conclusions This cross-sectional study suggests that several aspects of food choice values and food literacy were associated with HPF consumption in Japanese adults. Further studies are needed to confirm our findings in a broader context.

Viruses are a leading cause of infectious diseases. Well-developed animal models are valuable for understanding the immune responses to viral infections and the pathogenesis of viral diseases. Zebrafish is a commonly used small vertebrate model organism with strong reproductive ability, a short life cycle, and rapid embryonic development. Moreover, zebrafish and human genomes are highly similar; they have approximately 70 % homology in protein-coding genes, and 84 % of genes associated with human diseases have zebrafish counterparts. Recent years, different groups have developed zebrafish models for human viral infections and diseases, offering new insights into the molecular mechanisms of human viral pathogenesis as well as the development of antiviral strategies. The zebrafish model has become a simple and effective model system for understanding host-virus interaction. This review provides a comprehensive summary of the use of zebrafish models in human viral research, particularly in SARS-CoV-2.

This study aimed to evaluate and compare the effects of inertial flywheel training and accentuated eccentric loading training on the neuromuscular performance of well-trained male college sprinters. Fourteen sprinters were recruited and randomly assigned to either the flywheel training (FWT, n = 7) group or the accentuated eccentric loading training (AELT, n = 7) group. The FWT group completed four sets of 2 + 7 repetitions of flywheel squats, whereas the AELT group performed four sets of seven repetitions of barbell squats (concentric/eccentric: 80%/120% 1RM). Both groups underwent an eight-week squat training program, with two sessions per week. A two-way repeated ANOVA analysis was used to find differences between the two groups and between the two testing times (pre-test vs. post-test). The results indicated significant improvements in all measured variables for the FWT group: 1RM (5.0%, ES = 1.28), CMJ (13.3%, ES = 5.42), SJ (6.0%, ES = 2.94), EUR (6.5%, ES = 4.42), SLJ (2.9%, ES = 1.77), and 30 m sprint (−3.4%, ES = −2.80); and for the AELT group: 1RM (6.3%, ES = 2.53), CMJ (7.4%, ES = 3.44), SJ (6.4%, ES = 2.21), SLJ (2.2%, ES = 1.20), and 30 m sprint (−3.0%, ES = −1.84), with the exception of EUR (0.9%, ES = 0.63, p = 0.134), showing no significant difference. In addition, no significant interaction effects between group and time were observed for 1RM back squat, SJ, SLJ, and 30 m sprint (p > 0.05). Conversely, a significant interaction effect between group and time was observed for both CMJ and EUR (p < 0.001); post hoc analysis revealed that the improvements in CMJ and EUR were significantly greater in the FWT group compared to the AELT group (p < 0.001). These findings indicate that both FWT and AELT are effective at enhancing lower-body strength, power, and speed in well-trained male college sprinters, with FWT being particularly more effective in promoting elastic energy storage and the full utilization of the stretch–shortening cycle.

Background: This systematic review and meta-analysis aimed to analyze whether isoinertial flywheel training (FWT) is superior to traditional resistance training (TRT) in enhancing maximal strength and muscle power in healthy individuals. Methods: Electronic searches were conducted in the Web of Science, PubMed, Cochrane Library, SPORTDiscus, and Scopus databases up to 21 April 2024. Outcomes were analyzed as continuous variables using either a random or fixed effects model to calculate the standardized mean difference (SMD) and 95% confidence intervals (CI). Results: A total of sixteen articles, involving 341 subjects, met the inclusion criteria and were included in the statistical analyses. The pooled results indicate no statistically significant differences between FWT and TRT in developing maximal strength in healthy individuals (SMD = 0.24, 95% CI [−0.26, 0.74], p = 0.35). Additionally, the pooled outcomes showed a small-sized effect in muscle power with FWT (SMD = 0.47, 95% CI [0.10, 0.84]), which was significantly higher than that with TRT (p = 0.01) in healthy individuals. Subgroup analysis revealed that when the total number of FWT sessions is between 12 and 18 (1–3 times per week), it significantly improves muscle power (SMD = 0.61, 95% CI [0.12, 1.09]). Significant effects favoring FWT for muscle power were observed in both well-trained (SMD = 0.58, 95% CI [0.04, 1.13]) and untrained individuals (SMD = 1.40, 95% CI [0.23, 2.57]). In terms of exercise, performing flywheel training with squat and lunge exercises significantly enhances muscle power (SMD = 0.43; 95% CI: 0.02–0.84, and p = 0.04). Interestingly, FWT was superior to weight stack resistance training (SMD = 0.61, 95% CI [0.21, 1.00]) in enhancing muscle power, while no significant differences were found compared to barbell free weights training (SMD = 0.36, 95% CI [−0.22, 0.94]). Conclusions: This meta-analysis confirms the superiority of FWT compared to TRT in promoting muscle power in both healthy untrained and well-trained individuals. Squats and lunges for FWT are more suitable for improving lower limb explosive power. It is recommended that coaches and trainers implement FWT for six weeks, 2–3 times per week, with at least a 48 h interval between each session. Although FWT is not superior to free weights training, it is advisable to include FWT in sport periodization to diversify the training stimuli for healthy individuals.

[This corrects the article DOI: 10.1371/journal.pone.0243659.].

This study aimed to compare the differences in the intake of food groups and nutrients between Japanese adults who consumed the recommended daily vegetable intake (350 g/day) and those who did not. Dietary information was obtained from one-day dietary records collected from the 2016 National Health and Nutrition Survey, which was conducted in 46 prefectures in Japan. The participants aged ≥20 years (n = 21,606; 53.8% women) were classified into the < and ≥350 g/day groups. Inter-group differences for 17 food groups and 27 nutrients were assessed as percentages of consumers (food groups only) and energy-adjusted intake (units/MJ/d or % of total energy intake). Overall, 29% of participants consumed ≥350 g/day of vegetables. The ≥350 g/day group had a higher percentage of consumers and energy-adjusted intakes for all vegetable subgroups than the

This scoping review aimed to identify questionnaire-based dietary assessment methods for use in the National Health and Nutrition Survey (NHNS) in Japan. The search was conducted in three databases (PubMed, Web of Science, and Ichushi) to identify questionnaire such as food frequency questionnaire and dietary history questionnaire validated against dietary recalls or food records for the intakes of both food groups and nutrients among Japanese adults. Study quality was assessed based on previously developed criteria. We extracted the questionnaire characteristics and the design and results of the validation studies. We identified 11 questionnaires, with the number of food items ranging from 40 to 196, from 32 articles of good quality. In the validation studies, participants were aged 30–76 years and 90% of the articles used ≥3 d dietary records as reference. The number of nutrients and food groups with a group-level intake difference within 20% against the reference method ranged from 1 to 30 and 1 to 11, respectively. The range of mean correlation coefficients between questionnaire and reference methods were 0.35–0.57 for nutrients and 0.28–0.52 for food groups. When selecting a survey instrument in the NHNS from the 11 existing questionnaires identified in this study, it is important to select one with high group-level comparison and correlation coefficient values on the intended assessment items after scrutinizing the design and results of the validation study. This review may serve as a reference for future studies that explore dietary assessment tools used for assessing dietary intake in specific representative populations.

The human respiratory and circulatory systems collaborate intricately to ensure oxygen delivery to all cells, which is vital for ATP production and maintaining physiological functions and structures. During limited oxygen availability, hypoxia-inducible factors (HIFs) are stabilized and play a fundamental role in maintaining cellular processes for hypoxia adaptation. First discovered during investigations of erythropoietin production regulation, HIFs influence physiological and pathological processes, including development, inflammation, wound healing, and cancer. HIFs promote extracellular adenosine signaling by enhancing adenosine generation and receptor signaling, representing an endogenous feedback mechanism that curbs excessive inflammation, supports injury resolution, and enhances hypoxia tolerance. This is especially important for conditions that involve tissue hypoxia, such as acute respiratory distress syndrome (ARDS), which globally poses significant health challenges without specific treatment options. Consequently, pharmacological strategies to amplify HIF-mediated adenosine production and receptor signaling are of great importance.

Brain hypoxia is associated with a wide range of physiological and clinical conditions. Although oxygen is an essential constituent of maintaining brain functions, our understanding of how specific brain cell types globally respond and adapt to decreasing oxygen conditions is incomplete. In this study, we exposed mouse primary neurons, astrocytes, and microglia to normoxia and two hypoxic conditions and obtained genome-wide transcriptional profiles of the treated cells. Analysis of differentially expressed genes under conditions of reduced oxygen revealed a canonical hypoxic response shared among different brain cell types. In addition, we observed a higher sensitivity of neurons to oxygen decline, and dissected cell type-specific biological processes affected by hypoxia. Importantly, this study establishes novel gene modules associated with brain cells responding to oxygen deprivation and reveals a state of profound stress incurred by hypoxia.

Abstract Background Symptom networks can provide empirical evidence for the development of personalized and precise symptom management strategies. However, few studies have explored the symptom networks of multidimensional symptom experiences in cancer survivors. The objectives of this study were to generate symptom networks of multidimensional symptom experiences in cancer survivors and explore the centrality indices and density in these symptom networks Methods Data from 1065 cancer survivors were obtained from the Shanghai CANcer Survivor (SCANS) Report. The MD Anderson Symptom Inventory was used to assess the prevalence and severity of 13 cancer‐related symptoms. We constructed contemporaneous networks with all 13 symptoms after controlling for covariates. Results Distress (rs = 9.18, rc = 0.06), sadness (rs = 9.05, rc = 0.06), and lack of appetite (rs = 9.04, rc = 0.06) had the largest values for strength and closeness. The density of the “less than 5 years” network was significantly different from that of the “5–10 years” and “over 10 years” networks (p

Previous studies implicate extracellular adenosine signaling in attenuating myocardial ischemia and reperfusion injury (IRI). This extracellular adenosine signaling is terminated by its uptake into cells by equilibrative nucleoside transporters (ENTs). Thus, we hypothesized that targeting ENTs would function to increase cardiac adenosine signaling and concomitant cardioprotection against IRI. Mice were exposed to myocardial ischemia and reperfusion injury. Myocardial injury was attenuated in mice treated with the nonspecific ENT inhibitor dipyridamole. A comparison of mice with global Ent1 or Ent2 deletion showed cardioprotection only in Ent1–/– mice. Moreover, studies with tissue-specific Ent deletion revealed that mice with myocyte-specific Ent1 deletion (Ent1loxP/loxP Myosin Cre+ mice) experienced smaller infarct sizes. Measurements of cardiac adenosine levels demonstrated that postischemic elevations of adenosine persisted during reperfusion after targeting ENTs. Finally, studies in mice with global or myeloid-specific deletion of the Adora2b adenosine receptor (Adora2bloxP/loxP LysM Cre+ mice) implied that Adora2b signaling on myeloid-inflammatory cells in cardioprotection provided by ENT inhibition. These studies reveal a previously unrecognized role for myocyte-specific ENT1 in cardioprotection by enhancing myeloid-dependent Adora2b signaling during reperfusion. Extension of these findings implicates adenosine transporter inhibitors in cardioprotection against ischemia and reperfusion injury.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense desmoplastic stroma that impedes drug delivery, reduces parenchymal blood flow, and suppresses the anti-tumor immune response. The extracellular matrix and abundance of stromal cells result in severe hypoxia within the tumor microenvironment (TME), and emerging publications evaluating PDAC tumorigenesis have shown the adenosine signaling pathway promotes an immunosuppressive TME and contributes to the overall low survival rate. Hypoxia increases many elements of the adenosine signaling pathway, resulting in higher adenosine levels in the TME, further contributing to immune suppression. Extracellular adenosine signals through 4 adenosine receptors (Adora1, Adora2a, Adora2b, Adora3). Of the 4 receptors, Adora2b has the lowest affinity for adenosine and thus, has important consequences when stimulated by adenosine binding in the hypoxic TME. We and others have shown that Adora2b is present in normal pancreas tissue, and in injured or diseased pancreatic tissue, Adora2b levels are significantly elevated. The Adora2b receptor is present on many immune cells, including macrophages, dendritic cells, natural killer cells, natural killer T cells, γδ T cells, B cells, T cells, CD4+ T cells, and CD8+ T cells. In these immune cell types, adenosine signaling through Adora2b can reduce the adaptive anti-tumor response, augmenting immune suppression, or may contribute to transformation and changes in fibrosis, perineural invasion, or the vasculature by binding the Adora2b receptor on neoplastic epithelial cells, cancer-associated fibroblasts, blood vessels, lymphatic vessels, and nerves. In this review, we discuss the mechanistic consequences of Adora2b activation on cell types in the tumor microenvironment. As the cell-autonomous role of adenosine signaling through Adora2b has not been comprehensively studied in pancreatic cancer cells, we will also discuss published data from other malignancies to infer emerging therapeutic considerations for targeting the Adora2b adenosine receptor to reduce the proliferative, invasive, and metastatic potential of PDAC cells.

Acute lung injury (ALI) is a severe form of lung inflammation causing acute respiratory distress syndrome in patients. ALI pathogenesis is closely linked to uncontrolled alveolar inflammation. We hypothesize that specific enzymes of the glycolytic pathway could function as key regulators of alveolar inflammation. Therefore, we screened isolated alveolar epithelia from mice exposed to ALI induced by injurious ventilation to assess their metabolic responses. These studies pointed us toward a selective role for isoform 3 of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3). Pharmacologic inhibition or genetic deletion of Pfkfb3 in alveolar epithelia (Pfkfb3loxP/loxP SPC-ER-Cre+ mice) was associated with profound increases in ALI during injurious mechanical ventilation or acid instillation. Studies in genetic models linked Pfkfb3 expression and function to Hif1a. Not only did intratracheal pyruvate instillation reconstitute Pfkfb3loxP/loxP or Hif1aloxP/loxP SPC-ER-Cre+ mice, but pyruvate was also effective in ALI treatment of wild-type mice. Finally, proof-of-principle studies in human lung biopsies demonstrated increased PFKFB3 staining in injured lungs and colocalized PFKFB3 to alveolar epithelia. These studies reveal a specific role for PFKFB3 in counterbalancing alveolar inflammation and lay the groundwork for novel metabolic therapeutic approaches during ALI.

Summary: Background: Coronavirus Disease 2019 (COVID-19) can lead to the development of acute respiratory distress syndrome (ARDS). In some patients with non-resolvable (NR) COVID-19, lung injury can progress rapidly to the point that lung transplantation is the only viable option for survival. This fatal progression of lung injury involves a rapid fibroproliferative response and takes on average 15 weeks from initial symptom presentation. Little is known about the mechanisms that lead to this fulminant lung fibrosis (FLF) in NR-COVID-19. Methods: Using a pre-designed unbiased PCR array for fibrotic markers, we analyzed the fibrotic signature in a subset of NR-COVID-19 lungs. We compared the expression profile against control lungs (donor lungs discarded for transplantation), and explanted tissue from patients with idiopathic pulmonary fibrosis (IPF). Subsequently, RT-qPCR, Western blots and immunohistochemistry were conducted to validate and localize selected pro-fibrotic targets. A total of 23 NR-COVID-19 lungs were used for RT-qPCR validation. Findings: We revealed a unique fibrotic gene signature in NR-COVID-19 that is dominated by a hyper-expression of pro-fibrotic genes, including collagens and periostin. Our results also show a significantly increased expression of Collagen Triple Helix Repeat Containing 1(CTHRC1) which co-localized in areas rich in alpha smooth muscle expression, denoting myofibroblasts. We also show a significant increase in cytokeratin (KRT) 5 and 8 expressing cells adjacent to fibroblastic areas and in areas of apparent epithelial bronchiolization. Interpretation: Our studies may provide insights into potential cellular mechanisms that lead to a fulminant presentation of lung fibrosis in NR-COVID-19. Funding: National Institute of Health (NIH) Grants R01HL154720, R01DK122796, R01DK109574, R01HL133900, and Department of Defense (DoD) Grant W81XWH2110032 to H.K.E. NIH Grants: R01HL138510 and R01HL157100, DoD Grant W81XWH-19-1-0007, and American Heart Association Grant: 18IPA34170220 to H.K.-Q. American Heart Association: 19CDA34660279, American Lung Association: CA-622265, Parker B. Francis Fellowship, 1UL1TR003167–01 and The Center for Clinical and Translational Sciences, McGovern Medical School to X.Y.

PurposeWe conducted the first meta-analysis to determine the diagnostic value of non-invasive methods for diagnosing bladder outlet obstruction (BOO) in men with lower urinary tract symptoms (LUTS).MethodsWe searched a range of databases for relevant publications up to June 2022, including PubMed, Embase, Web of Science, and the Cochrane Library. Retrieved studies were then reviewed for eligibility and data were extracted. The risk of bias (RoB) was assessed using the QUADAS-2 tool. We then performed a formal meta-analysis to evaluate the accuracy of various non-invasive methods for diagnosing BOO in men.ResultsWe identified 51 eligible studies including 7,897 patients for meta-analysis. The majority of the studies had a low overall RoB. Detrusor wall thickness (DWT) (pooled sensitivity (SSY): 71%; specificity (SPY): 88%; diagnostic odds ratio (DOR): 17.15; area under curve (AUC) 0.87) and the penile cuff test (PCT) (pooled SSY: 87%; SPY: 78%; DOR: 23.54; AUC: 0.88) showed high accuracy for diagnosing BOO. Furthermore, data suggested that DWT had the highest pooled SPY (0.89), DOR (32.58), and AUC (0.90), when using 2 mm as the cut-off.ConclusionOf the non-invasive tests tested, DWT and PCT had the highest levels of diagnostic accuracy for diagnosing BOO in men with LUTS. DWT, with a 2 mm cut-off, had the highest level of accuracy. These two methods represent good options as non-invasive tools for evaluating BOO in males.

The transcription factor hypoxia-inducible factor HIF1A induces cardioprotection from ischemia and reperfusion injury. Here, we investigate tissue-specific pathways that are critical for HIF1A-elicited tissue protection. Initial studies showed that mice with induced global Hif1a deletion (Hif1aloxP/loxP UbiquitinCre+) have exaggerated myocardial injury during in situ ischemia and reperfusion. Surprisingly, this phenotype was mirrored only in mice with myeloid-specific Hif1a deletion (Hif1aloxP/loxP LysM Cre+). In contrast, mice with myocardial specific (Hif1aloxP/loxP Myosin Cre+), or vascular Hif1a deletion (Hif1aloxP/loxP VEcadherin Cre+) experienced similar levels of injury as controls. Subsequent studies using adoptive transfer of Hif1a-deficient polymorphonuclear neutrophils (PMNs) prior to myocardial injury demonstrated increased reperfusion injury. On the contrary, the adoptive transfer of PMNs treated ex vivo with the hypoxia inducible factor (HIF) stabilizer dimethyloxalylglycine (DMOG) was associated with attenuated myocardial injury. Furthermore, DMOG-mediated cardioprotection was abolished in Hif1aloxP/loxP LysM Cre+ mice, but not in Hif2aloxP/loxP LysM Cre+ mice. Finally, studies of PMN-dependent HIF1A target genes implicated the neuronal guidance molecule netrin-1 in mediating the cardioprotective effects of myeloid HIF1A. Taken together, the present studies identified a functional role for myeloid-expressed HIF1A in providing cardioprotection during ischemia and reperfusion injury, which is mediated, at least in part, by the induction of the netrin-1 neuronal guidance molecule in neutrophils.

During hypoxia or inflammation, extracellular adenosine levels are elevated. Studies using pharmacologic approaches or genetic animal models pertinent to extracellular adenosine signaling implicate this pathway in attenuating hypoxia-associated inflammation. There are four distinct adenosine receptors. Of these, it is not surprising that the Adora2b adenosine receptor functions as an endogenous feedback loop to control hypoxia-associated inflammation. First, Adora2b activation requires higher adenosine concentrations compared to other adenosine receptors, similar to those achieved during hypoxic inflammation. Second, Adora2b is transcriptionally induced during hypoxia or inflammation by hypoxia-inducible transcription factor HIF1A. Studies seeking an alternative adenosine receptor activation mechanism have linked netrin-1 with Adora2b. Netrin-1 was originally discovered as a neuronal guidance molecule but also functions as an immune-modulatory signaling molecule. Similar to Adora2b, netrin-1 is induced by HIF1A, and has been shown to enhance Adora2b signaling. Studies of acute respiratory distress syndrome (ARDS), intestinal inflammation, myocardial or hepatic ischemia and reperfusion implicate the netrin-Adora2b link in tissue protection. In this review, we will discuss the potential molecular linkage between netrin-1 and Adora2b, and explore studies demonstrating interactions between netrin-1 and Adora2b in attenuating tissue inflammation.

Traumatic neuromuscular injury to the pudendal nerve and urethra during childbirth does not regenerate well and contributes to stress urinary incontinence in women. Mesenchymal stem cells (MSCs) can improve neuroregeneration via their secretions, or secretome, which includes brain-derived neurotrophic factor (BDNF). In this study, we investigated whether BDNF is a key factor in the secretome of MSCs for the facilitation of functional recovery following a dual simulated childbirth injury. BDNF knockdown (KD) MSCs were created using an anti-BDNF shRNA lentivirus vector. A scrambled sequence was used as a transduction control (scrambled). Cells were cultured for 24 h before media was concentrated 50x to create concentrated conditioned media (CCM) containing MSC secretome. CCM of unmanipulated MSCs was screened for high BDNF expression (high BDNF CCM). Concentrated control media (CM) was created by concentrating media not conditioned by cells. Female Sprague-Dawley rats underwent bilateral pudendal nerve crush and vaginal distension (Injury) or sham injury. One hour and 1 week after injury, sham injured rats received CM, and injured rats received CM, high BDNF CCM, KD CCM, or scrambled CCM (300 μl intraperitoneally). Three weeks after injury, rats underwent leak point pressure (LPP) and pudendal nerve sensory branch potential (PNSBP) recordings. The urethra and pudendal nerve were harvested for anatomical assessment. ANOVA followed by the Student-Newman-Keuls test determined significant differences between groups (p < 0.05). BDNF KD CCM had significantly decreased BDNF concentration compared to scrambled CCM, while the concentration in high BDNF CCM was significantly increased. LPP was significantly decreased in CM and KD CCM treated animals compared to sham injury, but not with scrambled or high BDNF CCM. PNSBP firing rate showed a significant decrease with CM treatment compared to sham injury. Neuromuscular junctions in the urethral sphincter in KD CCM, scrambled CCM, and high BDNF CCM were healthier than CM treated rats. While anatomical and nerve function tests demonstrate regeneration of the pudendal nerve with any CCM treatment, LPP results suggest it takes longer to recover continence with reduced BDNF in CCM. BDNF in MSC CCM is an important factor for the acceleration of recovery from a dual nerve and muscle injury.

Abstract Background Although the importance of capacity building for public health nutrition (PHN) has been increasing globally, reports on the current status of training programs for PHN in East-Asia including Japan are limited. The aim of this study was to compare the current status of education and research activities in the field of PHN in Japan with those in South Korea, Taiwan, and mainland China. Methods Necessary information was collected by internet search and telephone inquiry. Collection focused on the number of departments in colleges and universities with PHN as a compulsory subject in the 2016 academic year, and the number of articles and information related to these articles published in the journal Public Health Nutrition between 2007 and 2016. Results The number of departments with PHN as a compulsory subject was the highest in Japan (n = 137), followed by mainland China (n = 32), Taiwan (n = 18) and South Korea (n = 7). Using the classification list of education in each country and region, the majority of these departments were classified as home economics, natural science, health and welfare, and medical science in Japan, South Korea, Taiwan, and mainland China, respectively. Regarding publications, most of the articles were written in colleges and universities not having PHN as a compulsory subject in Japan, South Korea, and Taiwan. The number of articles per department among departments with compulsory PHN education was lowest in Japan (n = 0.3) compared to Taiwan, mainland China, and South Korea (n = 1.2, 2.7, and 3.7, respectively). Conclusions Japan has a much higher number of departments with PHN as a compulsory subject than neighboring East Asian states and relatively low research activities in the field of PHN. This suggests that current university education may not lead to active PHN research in Japan. Further studies are warranted to explore the reasons for this.

Despite increasing availability and more successful interventional approaches to restore coronary reperfusion, myocardial ischemia-reperfusion injury is a substantial cause of morbidity and mortality worldwide. During myocardial ischemia, the myocardium becomes profoundly hypoxic, thus causing stabilization of hypoxia-inducible transcription factors (HIF). Stabilization of HIF leads to a transcriptional program that promotes adaptation to hypoxia and cellular survival. Transcriptional consequences of HIF stabilization include increases in extracellular production and signaling effects of adenosine. Extracellular adenosine functions as a signaling molecule via the activation of adenosine receptors. Several studies implicated adenosine signaling in cardioprotection, particularly through the activation of the Adora2a and Adora2b receptors. Adenosine receptor activation can lead to metabolic adaptation to enhance ischemia tolerance or dampen myocardial reperfusion injury via signaling events on immune cells. Many studies highlight that clinical strategies to target the hypoxia-adenosine link could be considered for clinical trials. This could be achieved by using pharmacologic HIF activators or by directly enhancing extracellular adenosine production or signaling as a therapy for patients with acute myocardial infarction, or undergoing cardiac surgery.

Hypoxia and inflammation often coincide in pathogenic conditions such as acute respiratory distress syndrome (ARDS) and chronic lung diseases, which are significant contributors to morbidity and mortality for the general population. For example, the recent global outbreak of Coronavirus disease 2019 (COVID-19) has placed viral infection-induced ARDS under the spotlight. Moreover, chronic lung disease ranks the third leading cause of death in the United States. Hypoxia signaling plays a diverse role in both acute and chronic lung inflammation, which could partially be explained by the divergent function of downstream target pathways such as adenosine signaling. Particularly, hypoxia signaling activates adenosine signaling to inhibit the inflammatory response in ARDS, while in chronic lung diseases, it promotes inflammation and tissue injury. In this review, we discuss the role of adenosine at the interphase of hypoxia and inflammation in ARDS and chronic lung diseases, as well as the current strategy for therapeutic targeting of the adenosine signaling pathway.

Pile-anchor retaining structures are widely used in excavation engineering. The evaluation of lateral displacements, the internal forces of piles are extremely important for the performance of the structure. Most of the existing methods are empirical, semiempirical or FEM methods, while analytic calculation methods for this evaluation are rare. This paper presents an analytic method to calculate the displacements and internal forces of anchored retaining piles based on the existing design code. In the calculation method, the singular function is applied to evaluate the effect of segmented loading on the deflection of a beam with a nonuniform cross section. The load concentration function, expressed by the singular function, can describe the segmented load and be integrated without a complicated procedure for determining the integral constants. The method is applied to a structure in Wenzhou, China, and the calculation results are compared to the field measurement results. This method is only valid for pre-failure predictions.

Many states in the United States allow a “belief exemption” for measles, mumps, and rubella (MMR) vaccines. People’s opinion on whether or not to take the vaccine can have direct consequences in public health. Social media has been one of the dominant communication channels for people to express their opinions of vaccination. Despite governmental organizations’ efforts of disseminating information of vaccination benefits, anti-vaccine sentiment is still gaining momentum. Studies have shown that bots on social media (i.e., social bots) can influence opinion trends by posting a substantial number of automated messages. The research presented here investigates the communication patterns of anti- and pro-vaccine users and the role of bots in Twitter by studying a retweet network related to MMR vaccine after the 2015 California Disneyland measles outbreak. We first classified the users into anti-vaccination, neutral to vaccination, and pro-vaccination groups using supervised machine learning. We discovered that pro- and anti-vaccine users retweet predominantly from their own opinion group. In addition, our bot analysis discovers that 1.45% of the corpus users were identified as likely bots which produced 4.59% of all tweets within our dataset. We further found that bots display hyper-social tendencies by initiating retweets at higher frequencies with users within the same opinion group. The article concludes that highly clustered anti-vaccine Twitter users make it difficult for health organizations to penetrate and counter opinionated information while social bots may be deepening this trend. We believe that these findings can be useful in developing strategies for health communication of vaccination.

Purine nucleotides and nucleosides are at the center of biologic reactions. In particular, adenosine triphosphate (ATP) is the fundamental energy currency of cellular activity and adenosine has been demonstrated to play essential roles in human physiology and pathophysiology. In this review, we examine the role of purinergic signaling in acute and chronic pulmonary inflammation, with emphasis on ATP and adenosine. ATP is released into extracellular space in response to cellular injury and necrosis. It is then metabolized to adenosine monophosphate (AMP) via ectonucleoside triphosphate diphosphohydrolase-1 (CD39) and further hydrolyzed to adenosine via ecto-5′-nucleotidase (CD73). Adenosine signals via one of four adenosine receptors to exert pro- or anti-inflammatory effects. Adenosine signaling is terminated by intracellular transport by concentrative or equilibrative nucleoside transporters (CNTs and ENTs), deamination to inosine by adenosine deaminase (ADA), or phosphorylation back into AMP via adenosine kinase (AK). Pulmonary inflammatory and hypoxic conditions lead to increased extracellular ATP, adenosine diphosphate (ADP) and adenosine levels, which translates to increased adenosine signaling. Adenosine signaling is central to the pulmonary injury response, leading to various effects on inflammation, repair and remodeling processes that are either tissue-protective or tissue destructive. In the acute setting, particularly through activation of adenosine 2A and 2B receptors, adenosine signaling serves an anti-inflammatory, tissue-protective role. However, excessive adenosine signaling in the chronic setting promotes pro-inflammatory, tissue destructive effects in chronic pulmonary inflammation.

The research presented in this paper proposes a thematic network approach to explore rich relationships between places. We connect places in networks through their thematic similarities by applying topic modeling to the textual volunteered geographic information (VGI) pertaining to the places. The network approach enhances previous research involving place clustering using geo-textual information, which often simplifies relationships between places to be either in-cluster or out-of-cluster. To demonstrate our approach, we use as a case study in Manhattan (New York) that compares networks constructed from three different geo-textural data sources—TripAdvisor attraction reviews, TripAdvisor restaurant reviews, and Twitter data. The results showcase how the thematic similarity network approach enables us to conduct clustering analysis as well as node-to-node and node-to-cluster analysis, which is fruitful for understanding how places are connected through individuals’ experiences. Furthermore, by enriching the networks with geodemographic information as node attributes, we discovered that some low-income communities in Manhattan have distinctive restaurant cultures. Even though geolocated tweets are not always related to place they are posted from, our case study demonstrates that topic modeling is an efficient method to filter out the place-irrelevant tweets and therefore refining how of places can be studied.

BACKGROUND:Although several reports concerning the association of iodine excess and thyroid disease have appeared, no systematic review of the association between iodine excess intake and thyroid diseases, especially hyperthyroidism and hypothyroidism, has yet been reported. METHOD:We conducted a systematic search of Ovid MEDLINE, PubMed, Cochrane Central Register of Controlled Trials databases, Ichushi-Web and CiNii database for intervention trials and observational studies. Search terms were constructed from related words for excess AND iodine intake or excretion AND thyroid hormones or diseases AND study designs. After considering the qualitative heterogeneity among studies, a meta-analysis was conducted and odds ratios and 95% confidence intervals (CI) were estimated in random-effects models. A protocol was registered with PROSPERO (No. CRD42015028081). RESULTS:50 articles were included, including three intervention trials, six case-control studies, six follow-up studies and 35 cross-sectional studies. Three cross-sectional studies in adults included in meta-analysis. Odds ratio of overt and subclinical hypothyroidism between excess and adequate populations were 2.78 (CI:1.47 to 5.27) and 2.03 (CI:1.58 to 2.62) in adults, respectively. Source of excess iodine status was mainly iodized salt or water in included studies. CONCLUSION:Although universal salt iodization has improved goiter rates, chronic exposure to excess iodine from water or poorly monitored salt are risk factors for hypothyroidism in free-living populations. Monitoring of both iodine concentration in salt as well as the iodine concentration in local drinking water are essential to preventing thyroid diseases. Hypothyroidism should be also carefully monitored in areas with excess iodine. Because of the low quality and limited number of included studies, further evidence and review are required.

Chronic inhalation of cigarette smoke is the major cause of sterile inflammation and pulmonary emphysema. The effect of carbon black (CB), a universal constituent of smoke derived from the incomplete combustion of organic material, in smokers and non-smokers is less known. In this study, we show that insoluble nanoparticulate carbon black (nCB) accumulates in human myeloid dendritic cells (mDCs) from emphysematous lung and in CD11c+ lung antigen presenting cells (APC) of mice exposed to smoke. Likewise, nCB intranasal administration induced emphysema in mouse lungs. Delivered by smoking or intranasally, nCB persisted indefinitely in mouse lung, activated lung APCs, and promoted T helper 17 cell differentiation through double-stranded DNA break (DSB) and ASC-mediated inflammasome assembly in phagocytes. Increasing the polarity or size of CB mitigated many adverse effects. Thus, nCB causes sterile inflammation, DSB, and emphysema and explains adverse health outcomes seen in smokers while implicating the dangers of nCB exposure in non-smokers.

Asthma is one of the most common of medical illnesses and is treated in part by drugs that activate the beta-2-adrenoceptor (β2-AR) to dilate obstructed airways. Such drugs include long acting beta agonists (LABAs) that are paradoxically linked to excess asthma-related mortality. Here we show that LABAs such as salmeterol and structurally related β2-AR drugs such as formoterol and carvedilol, but not short-acting agonists (SABAs) such as albuterol, promote exaggerated asthma-like allergic airway disease and enhanced airway constriction in mice. We demonstrate that salmeterol aberrantly promotes activation of the allergic disease-related transcription factor signal transducer and activator of transcription 6 (STAT6) in multiple mouse and human cells. A novel inhibitor of STAT6, PM-242H, inhibited initiation of allergic disease induced by airway fungal challenge, reversed established allergic airway disease in mice, and blocked salmeterol-dependent enhanced allergic airway disease. Thus, structurally related β2-AR ligands aberrantly activate STAT6 and promote allergic airway disease. This untoward pharmacological property likely explains adverse outcomes observed with LABAs, which may be overcome by agents that antagonize STAT6.

The human respiratory and circulatory systems collaborate intricately to ensure oxygen delivery to all cells, which is vital for ATP production and maintaining physiological functions and structures. During limited oxygen availability, hypoxia-inducible factors (HIFs) are stabilized and play a fundamental role in maintaining cellular processes for hypoxia adaptation. First discovered during investigations of erythropoietin production regulation, HIFs influence physiological and pathological processes, including development, inflammation, wound healing, and cancer. HIFs promote extracellular adenosine signaling by enhancing adenosine generation and receptor signaling, representing an endogenous feedback mechanism that curbs excessive inflammation, supports injury resolution, and enhances hypoxia tolerance. This is especially important for conditions that involve tissue hypoxia, such as acute respiratory distress syndrome (ARDS), which globally poses significant health challenges without specific treatment options. Consequently, pharmacological strategies to amplify HIF-mediated adenosine production and receptor signaling are of great importance. [ABSTRACT FROM AUTHOR]