Hippocampal PDHA1 gene knockout inhibits the Warburg Effect leading to cognitive dysfunction and attenuates the beneficial effects of ZiBuPiYin Recipe on cognition.

ETHNOPHARMACOLOGICAL RELEVANCE: The attenuation of the Warburg effect is an important pathological feature of cognitive dysfunction, and enhancing the Warburg effect is conducive to improving cognitive function. However, the pathogenic mechanisms underlying cognitive dysfunction remain incompletely elucidated. ZiBuPiYin Recipe (ZBPYR) is a traditional Chinese herbal compound used clinically for the treatment of cognitive dysfunction with significant efficacy. Nonetheless, the molecular mechanism underlying its beneficial effects remains elusive. AIM OF THE STUDY: The objective of this study is to investigate whether the attenuation of the Warburg effect exists in a mouse model of cognitive dysfunction induced by knockout of the pyruvate dehydrogenase E1 component subunit alpha (PDHA1) gene in the hippocampus, as well as the interventional effect of ZBPYR. MATERIALS AND METHODS: Using mice with PDHA1 gene knockout in the hippocampus and their littermate control mice as study subjects, behavioral experiments were conducted to assess the impact of PDHA1 gene knockout on cognitive function and the interventional effect of ZBPYR. We detected the expression of the Warburg effect-associated rate-limiting enzymes and PI3K/AKT pathway-related proteins. Subsequently, in PC12 cells, we explored the effect of the Warburg effect on cell apoptosis as well as the role of PDHA1 in the regulation of the PI3K/AKT-Warburg effect and the potential mechanism of ZBPYR in improving cognitive function. RESULTS: Mice with knockout of the PDHA1 gene in the hippocampus exhibited cognitive dysfunction, inhibition of the PI3K/AKT pathway, reduction of the Warburg effect, and neuronal damage. In vitro experiments indicated that silencing of PDHA1 in the hippocampus inhibited the PI3K/AKT-Warburg effect, leading to cell apoptosis and mediated the effect of ZBPYR in improving cognitive function. CONCLUSION: Our data not only suggest that the hippocampal PDHA1-PI3K/AKT-Warburg effect may be involved in the pathogenesis of cognitive dysfunction, but also demonstrate that PDHA1 knockout can abolish the beneficial effects of ZBPYR on cognition. This research aids in unraveling the cause of cognitive dysfunction and, therefore, offers a promising and innovative therapeutic target for these patients.

Pilot turning behavior cognitive load analysis in simulated flight.

Background: To identify the cognitive load of different turning tasks in simulated flight, a flight experiment was designed based on real "preliminary screening" training modules for pilots. Methods: Heart Rate Variability (HRV) and flight data were collected during the experiments using a flight simulator and a heart rate sensor bracelet. The turning behaviors in flight were classified into climbing turns, descending turns, and level flight turns. A recognition model for the cognitive load associated with these turning behaviors was developed using machine learning and deep learning algorithms. Results: pnni_20, range_nni, rmssd, sdsd, nni_20, sd1, triangular_index indicators are negatively correlated with different turning load. The LSTM-Attention model excelled in recognizing turning tasks with varying cognitive load, achieving an F1 score of 0.9491. Conclusion: Specific HRV characteristics can be used to analyze cognitive load in different turn-ing tasks, and the LSTM-Attention model can provide references for future studies on the selection characteristics of pilot cognitive load, and offer guidance for pilot training, thus having significant implications for pilot training and flight safety.

Blood Pressure Cuff Sizes for Pregnant Women in the United States: Findings from the National Health and Nutrition Examination Survey.

BACKGROUND: The use of correctly-sized blood pressure (BP) cuffs is important to ensure accurate measurement and effective management of hypertension. The goals of this study were to determine the proportions of pregnant women that would require small, adult, large, and extra-large (XL) cuff sizes, and to examine the demographic characteristics associated with need for a large or XL cuff. METHODS: This cross-sectional study analyzed 1,176 pregnant women (≥18 years) included in the National Health and Nutrition Examination Survey (NHANES) 1999-2006 cycles. Recommended BP cuff sizes, based on American Heart Association recommendations, were categorized by mid-arm circumference: small adult (≤26 cm), adult (>26 to ≤34 cm), large (>34 to ≤44 cm), and extra-large (XL) (>44 cm). RESULTS: Among US pregnant women, recommended cuff sizes were: 17.9% small adult, 57.0% adult, and 25.1% for large or XL. About 38.5% of non-Hispanic Black, 21.6% of Mexican American and 21.0% of non-Hispanic White pregnant women required a large or XL cuff. About 81.8% of women in the highest quartile for BMI required large or XL cuffs, which was significantly higher than women in other quartiles. CONCLUSION: Roughly one out of every four pregnant women required large or XL BP cuffs. The requirement for large or XL cuffs was highest among non-Hispanic Black women and women with the highest BMI. For pregnant women, measuring the arm circumference and selecting an appropriately-sized cuff is important to facilitate accurate blood pressure monitoring and hypertension management.

A Lysosome-Targeting hNEU1 Inhibitor Treats Myocardial Infarction: A Potential Therapeutic Breakthrough.

The overexpression of NEU1 has recently been certified as being associated with myocardial infarction. However, the pursuit of an efficacious human NEU1 (hNEU1) inhibitor remains challenging, and viral NEU1 (viNEU1) inhibitor drugs are significantly weaker in terms of hNEU1 inhibition. Recognizing that hNEU1 is located within the lysosome, we designed a series of lysosome-targeting compounds, derived from oseltamivir, aimed at hNEU1 inhibition. Among these compounds, OsMo exhibits the most potent activity. Our findings reveal that OsMo accumulates within lysosomes and releases its pharmacophore via enzymatic catalysis. OsMo enhances hNEU1 inhibition by accumulating pharmacophores at the target site. OsMo exhibits improved regulation of abnormal autophagy during myocardial injury, demonstrating superior efficacy in treating myocardial infarction in vivo. Furthermore, OsMo exhibits acceptable pharmacokinetic parameters. Importantly, the development of molecules with lysosome-targeting abilities represents a promising avenue for addressing myocardial injuries linked to hNEU1 overexpression.

The ultralow viscosity of volatile-rich kimberlite magma: Implications for the water content of primitive kimberlite melts.

The eruption of deeply sourced kimberlite magma offers the fastest route to bring deep-seated volatiles back to the Earth's surface. However, the viscosity of kimberlite magma, a factor governing its migration and eruption dynamics within Earth, remains poorly constrained. We conducted synchrotron in situ falling sphere viscometry experiments to examine kimberlite magma with different volatile contents (0 to 5 wt % H2O and 2 to 8 wt % CO2) under high pressure-temperature conditions. The results reveal that the viscosity of volatile-rich kimberlite magma is ~1 to 2 orders lower than that of mid-ocean ridge basalt (MORB) and comparable to the ultramobile pure carbonate melt. Using the measured viscosity values, we simulated the ascent and eruption process of kimberlite magma. We found that a minimum content of ~0.5 wt % water in the primitive magma is necessary to allow the ultrafast eruption process of kimberlite, thereby enabling the preservation of diamonds and high-pressure mineral inclusions transported by the magma.

Genetic structure and selective sweeps in Kirghiz sheep using SNP50K bead chip.

The objective of this study is to analyze environmental genetic selection signals in large-scale sheep populations with conflicting environmental adaptations, aiming to identify and isolate genes associated with environmental adaptations in sheep populations. Kirghiz sheep, which inhabit high-altitude environments year-round, demonstrate the ability to adapt to extreme conditions. In this study, 42 Kirghiz sheep, 24 Tien-Shan in Kyrgyzstan sheep, 189 Qira black sheep, and 160 Chinese Merino sheep were genotyped using Illumina Ovine SNP50K chip. Regions exhibiting a selection signal threshold of 5%, as well as PI analysis and haplotype statistical scanning gene data were annotated, and intersecting genes were identified as candidate genes. Through Fst and haplotype statistical analysis revealed the key gene PDGFD and its vicinity's impact on fat deposition in sheep tails. Additionally, Fst and PI analysis uncovered genes related to high-altitude adaptation as well as those linked to animal growth and reproduction.Further GO and KEGG enrichment pathway analyses unveiled pathways associated with high-altitude adaptation such as negative regulation of peptidyl-tyrosine phosphorylation and xenobiotic metabolism processes.This investigation into the adaptability of Kirghiz sheep provides theoretical support and practical guidance for the conservation and genetic enhancement of Kirghiz sheep germplasm resources.

Therapeutic potential of Cordyceps sinensis targeting oxidative stress and inflammatory response in the treatment of COPD rats: insights from metabolomics analysis.

This study aimed to investigate the effects of wild Cordyceps sinensis on chronic obstructive pulmonary disease (COPD) rats through metabolomics approach, combined with biochemical parameters evaluations. Consequently, C. sinensis exhibited regulatory effects on the lung's metabolic profiles in COPD rats. Treatment with C. sinensis potentially modulated glycerophospholipid metabolism, glutathione metabolism, and tryptophan metabolism, thereby alleviating oxidative stress (by decreasing MDA and GSSG, while increasing SOD and GSH) and inflammatory response (by inhibiting TNF-α, IL-8, and MMP-9) in COPD rats while improving lung tissue damage.

Corrigendum: Knowledge, attitude, and practice toward delirium and subtype assessment among Chinese clinical nurses and determinant factors: A multicentre cross-section study.

[This corrects the article DOI: 10.3389/fpsyt.2022.1017283.].

KRT19 is regulated by miR-642a-5p and promotes pancreatic cancer progression through the Wnt/ß-catenin pathway.

Pancreatic cancer (PC) has a really poor prognosis, and we urgently need to delve deeper into its molecular mechanisms. In this study, we found that KRT19 expression was significantly increased in PC tissues and cell lines and it was linked to unfavorable outcomes for patients. Overexpression of KRT19 boosted the proliferation, migration, and invasion of PC cells. Additionally, miR-374b-5p targets KRT19, inhibiting the activation of the Wnt/ß-catenin pathway (WBC), which in turn suppresses epithelial-to-mesenchymal transition (EMT) and the progression of PC. Further experiments showed that under hypoxic conditions, HIF1α was positively correlated with KRT19, promoting its expression. The loss of miR-642a-5p and the upregulation of KRT19 induced by hypoxia can significantly favor PC progression. Plus, the increased expression of KRT19 might act as a predictive marker and potential target for PC treatment.

The role of ESM1 in the lipids metabolic reprogramming and angiogenesis of lung adenocarcinoma cells.

Background: Lung adenocarcinoma (LUAD) is one of the respiratory diseases with high mortality and incidence. As an important angiogenic factor, (Endothelial cell-specific molecule 1) ESM1 plays an important role in the occurrence and development of LUAD. However, the role and molecular mechanism of ESM1 on LUAD metabolic reprogramming and angiogenesis remain unclear. Methods: We used multiple databases to analyze the prognostic significance and potential function of ESM1 in patients with LUAD. The expression of ESM1 in LUAD cells was down-regulated/overexpressed by RNA interference, and the effects of ESM1 on the proliferation, migration, lipid metabolism and angiogenesis of LUAD cells in vitro and in vivo were analyzed using MTT, EdU, wound healing, oil red O, tubule formation, xenograft tumor model and chicken embryo allantoic model. Results: ESM1 is closely associated with poor prognosis in LUAD patients. ESM1 promotes LUAD proliferation, migration, fatty acid synthesis and angiogenesis. It also accelerates the proliferation, migration, lipid synthesis and tubule formation of endothelial cells in the tumor microenvironment in the form of secreted protein. Mechanically, ESM1 can promote the activation of AKT signaling pathway and up-regulate the expression of SCD1 and FASN. Conclusion: Our results suggest that ESM1 promotes the proliferation, migration, lipid reprogramming, and angiogenesis of LUAD cells by activating the AKT signaling pathway, suggesting that ESM1 may be a potential therapeutic target and prognostic marker in LUAD patients.

Predicted Heart Age and Life's Essential 8 Among U.S. Adults: NHANES 2015-March 2020.

INTRODUCTION: This study examined the association between American Heart Association's (AHA) cardiovascular health (CVH) metrics, Life's Essential 8 (LE8), and predicted heart age among U.S. adults. METHODS: The sample comprised 7,075 participants aged 30-74 years without CVD and/or stroke from the National Health and Nutrition Examination Survey (NHANES) 2015-March 2020. LE8 was measured according to AHA's metrics (overall score ranging from 0 to 100 points), and nonlaboratory-based Framingham Risk Score was used to estimate predicted heart age. Analyses were completed in June 2024. RESULTS: Median LE8 scores were 62.8 for men and 66.0 for women. Over 80% of participants had less than optimal CVH scores, affecting 141.5 million people and 1-in-6 participants had a low CVH score, impacting 30.0 million people. Mean predicted heart age and excess heart age (EHA, difference between actual and predicted heart age) were 56.6 (95% CI 56.1-57.1) and 8.6 (8.1-9.1) years for men and 54.0 (53.4-54.7) and 5.9 (5.2-6.5) years for women. Participants in the low CVH group (scores<50), had an EHA that was 20.7 years higher than those in the high CVH group (score 80-100). Compared to the high CVH group, participants in low CVH group had 15 times (for men) and 44 times (for women) higher risk of having EHA ≥10 years. The pattern of differences in predicted heart age, EHA, and prevalence of EHA ≥10 years by LE8 groups remained largely consistent across subpopulations. CONCLUSIONS: These findings highlight the importance of maintaining a healthy lifestyle to improve cardiovascular health and reduce excess heart age.

Putative pathogenic factors underlying Streptococcus oralis opportunistic infections.

Streptococcus oralis, belonging to the viridans group streptococci (VGS), has been considered a component of the normal flora predominantly inhabiting the oral cavity. In recent years, a growing body of literature has revealed that dental procedures or daily tooth brushing activities can cause the spread of S. oralis from the oral cavity into various body sites leading to life-threatening opportunistic infections such as infective endocarditis (IE) and meningitis. However, very little is currently known about the pathogenicity of S. oralis. Thus, the aim of this review is to update the current understanding of the pathogenic potential of S. oralis to pave the way for the prevention and treatment of S. oralis opportunistic infections.

TNFSF14+ natural killer cells prevent spontaneous abortion by restricting leucine-mediated decidual stromal cell senescence.

In preparation for a potential pregnancy, the endometrium of the uterus changes into a temporary structure called the decidua. Senescent decidual stromal cells (DSCs) are enriched in the decidua during decidualization, but the underlying mechanisms of this process remain unclear. Here, we performed single-cell RNA transcriptomics on ESCs and DSCs and found that cell senescence during decidualization is accompanied by increased levels of the branched-chain amino acid (BCAA) transporter SLC3A2. Depletion of leucine, one of the branched-chain amino acids, from cultured media decreased senescence, while high leucine diet resulted in increased senescence and high rates of embryo loss in mice. BCAAs induced senescence in DSCs via the p38 MAPK pathway. In contrast, TNFSF14+ decidual natural killer (dNK) cells were found to inhibit DSC senescence by interacting with its ligand TNFRSF14. As in mice fed high-leucine diets, both mice with NK cell depletion and Tnfrsf14-deficient mice with excessive uterine senescence experienced adverse pregnancy outcomes. Further, we found excessive uterine senescence, SLC3A2-mediated BCAA intake, and insufficient TNFRSF14 expression in the decidua of patients with recurrent spontaneous abortion. In summary, this study suggests that dNK cells maintain senescence homeostasis of DSCs via TNFSF14/TNFRSF14, providing a potential therapeutic strategy to prevent DSC senescence-associated spontaneous abortion.

Lipopolysaccharide Triggers Luminal Acidification to Promote Defense Against Bacterial Infection in Vaginal Epithelium.

The vaginal epithelium plays pivotal roles in host defense against pathogen invasion, contributing to the maintenance of an acidic microenvironment within the vaginal lumen through the activity of acid-base transport proteins. However, the precise defense mechanisms of the vaginal epithelium after a bacterial infection remain incompletely understood. This study showed that bacterial lipopolysaccharide (LPS) potentiated net proton efflux by up-regulating the expression of Na+-H+ exchanger 1 (NHE1) without affecting other acid-base transport proteins in vaginal epithelial cells. Pharmacologic inhibition or genetic knockdown of Toll-like receptor-4 and the extracellular signal-regulated protein kinase signaling pathway effectively counteracted the up-regulation of NHE1 and the enhanced proton efflux triggered by LPS in vaginal epithelial cells. In vivo studies revealed that LPS administration led to luminal acidification through the up-regulation of NHE1 expression in the rat vagina. Moreover, inhibition of NHE exhibited an impaired defense against acute bacterial infection in the rat vagina. These findings collectively indicate the active involvement of vaginal epithelial cells in facilitating luminal acidification during acute bacterial infection, offering potential insights into the treatment of bacterial vaginosis.

Experimental study on the performance of the vertical shell-tube indirect evaporative cooler with inner grooved tubes.

The vertical tube indirect evaporative cooler (VTIEC) could be preferred one to air-conditioning buildings if its water film quality could be improved. This paper proposed a new VTIEC with inner grooved tubes to improve the water film quality and obtained its performance by experimental method. The results indicated that inner grooved tubes have positive effects on the water film and performance of the new VTIEC. A low working air enthalpy at inlet can significantly improve the total cooling capacity from evaporation, and then VTIEC performance. In this paper conditions, the velocity ratio of 1.52 of the produced air to the working air is better one condition compared to 1.01 and 2.28. The produced air velocity is positive effect on the cooling capacity per unit area until the produced air velocity of about 4.05 m/s and is negative effect on COP. The maximum unit cooling capacity, wet-bulb efficiency and COP are 307.74W/m2, 81.7% and 44.97.The results will promote the application of the new VTIEC.

Enhanced recovery after surgery for hip and knee arthroplasty: A systematic review and meta-analysis on randomized control trials.

OBJECTIVES: This review aimed to compare the efficacy and safety of enhanced recovery after surgery (ERAS) versus traditional care in patients who underwent total hip arthroplasty (THA) and total knee arthroplasty (TKA). METHODS: All randomized controlled trials (RCTs) were acquired via a comprehensive search of multiple databases. A meta-analysis was performed using Cochrane Collaboration's RevMan 5.4 software to calculate effect sizes. RESULTS: This meta-analysis included 850 patients in the ERAS group and 845 patients in the control group (patients who received traditional care). The outcomes suggested no significant difference in operative time, intraoperative blood loss, visual analogue scale, 30-day readmission rate, and mortality rate between the two groups. However, the ERAS group was associated with a significant decrease in transfusion rate, hospital length of stay, and postoperative complications. Moreover, the ERAS group had higher Hospital for Special Surgery scores and satisfaction rates. CONCLUSIONS: Patients who underwent THA and TKA would benefit more from ERAS than traditional care.

Thermodynamic analysis of adsorption and retention behaviors in normal-phase liquid chromatography.

This study investigated the adsorption mechanisms in a normal-phase system using a cyano-based stationary phase as the sorbent. The minor disturbance method was used to measure the adsorption isotherms of acetone and alcohols with various structures. Excluding data in pure n-hexane revealed that the adsorption behaviors on cyano sites were well described by the Langmuir model. The adsorption equilibrium constants, ranging from 8.86 to 11.15 at 25 °C, showed no significant differences across alcohol structures and decreased with increasing temperature. The saturation adsorption concentration decreased with increasing alcohol molecule size, with branched-chain alcohols showing a lower saturation adsorption amount compared to straight-chain alcohols. The standard state adsorption enthalpies and entropies calculated from the equilibrium constants for various alcohols ranged from -29 to -22 kJ/mol and -78 to -55 J/K·mol, respectively, showing enthalpy-entropy compensation. A discrepancy was observed between these adsorption enthalpies and those obtained from the retention factors of alcohols using pure n-hexane as the mobile phase. This discrepancy may result from the affinity energy distribution of the adsorbent. In pure n-hexane, the adsorption behaviors of adsorbates were considerably affected by high-affinity sites. Moreover, acetone and these alcohol molecules were used as solvent modifiers to investigate the relationship between the retention factor, modifier concentration, and temperature for various solutes with distinct functional groups. The retention curves were converted to enthalpic curves using the van't Hoff equation. A theoretical model was proposed to describe the relationship between the van't Hoff enthalpy change and mobile phase composition. The proposed model effectively described the enthalpic curves, indicating that the enthalpy change follows a saturation curve with increasing modifier concentration. This trend is primarily due to competitive adsorption and complexation behaviors between the solute and modifier molecules.

Non-fused Star-shape Giant Trimer Electron Acceptors for Organic Solar Cells with Efficiency over 19.

Organic solar cells (OSCs) based on giant molecular acceptors (GMAs) have attracted extensive attention due to their excellent power conversion efficiency (PCE) and operation stability. However, the large conjugated plane of GMAs poses great challenges in regulating the solubility, over-size aggregation and yield, which in turn further constrains their development in commercial products. Herein, we employ a non-fused skeleton strategy to develop novel non-fused star-shape trimers (3BTT6F and 3BTT6Cl) for improving device performance. Single-bond linkage can break the rigid planarity to form a 3D architecture, generating multidimensional charge transfer pathways. Importantly, the non-fused skeleton strategy can not only significantly improve solubility and synthesis yield, but also effectively suppress molecular excessive aggregation. Consequently, due to the optimized film-forming process and charge dynamics, 3BTT6F-based binary device obtains a high PCE of 17.52%, which is significantly higher than the reported fully fused trimers. Excitingly, 3BTT6F-based ternary device even obtains a top-level PCE of 19.26%. Furthermore, the non-fused star-shape configuration also endows these acceptors with enhanced intermolecular interaction in the active layer, demonstrating excellent operational stability. Our work emphasizes the potential of non-fused star-shape trimers, providing a new pathway for achieving highly efficient and stable OSCs.

Olfaction modulates cortical arousal independent of perceived odor intensity and pleasantness.

Throughout history, various odors have been harnessed to invigorate or relax the mind. The mechanisms underlying odors' diverse arousal effects remain poorly understood. We conducted five experiments (184 participants) to investigate this issue, using pupillometry, electroencephalography, and the attentional blink paradigm, which exemplifies the limit in attentional capacity. Results demonstrated that exposure to citral, compared to vanillin, enlarged pupil size, reduced resting-state alpha oscillations and alpha network efficiency, augmented beta-gamma oscillations, and enhanced the coordination between parietal alpha and frontal beta-gamma activities. In parallel, it attenuated the attentional blink effect. These effects were observed despite citral and vanillin being comparable in perceived odor intensity, pleasantness, and nasal pungency, and were unlikely driven by semantic biases. Our findings reveal that odors differentially alter the small-worldness of brain network architecture, and thereby brain state and arousal. Furthermore, they establish arousal as a unique dimension in olfactory space, distinct from intensity and pleasantness.

Efficacy of durvalumab plus chemotherapy in advanced biliary duct cancer and biomarkers exploration.

BACKGROUND: The anti-PD-L1 antibody durvalumab has been approved for use in first-line advanced biliary duct cancer (ABC). So far, predictive biomarkers of efficacy are lacking. METHODS: ABC patients who underwent gemcitabine-based chemotherapy with or without durvalumab were retrospectively enrolled, and their baseline clinical pathological indices were retrieved from medical records. Overall (OS) and progression free survival (PFS) were calculated and analyzed. The levels of peripheral biomarkers from 48 patients were detected with assay kits including enzyme-linked immunosorbent assay. Genomic alterations in 27 patients whose tumor tissues were available were depicted via targeted next-generation sequencing. RESULTS: A total of 186 ABC patients met the inclusion criteria between January 2020 and December 2022 were finally enrolled in this study. Of these, 93 patients received chemotherapy with durvalumab and the rest received chemotherapy alone. Durvalumab plus chemotherapy demonstrated significant improvements in PFS (6.77 vs. 4.99 months; hazard ratio 0.65 [95% CI 0.48-0.88]; P = 0.005), but not OS (14.29 vs. 13.24 months; hazard ratio 0.91 [95% CI 0.62-1.32]; P = 0.608) vs. chemotherapy alone in previously untreated ABC patients. The objective response rate (ORR) in patients receiving chemotherapy with and without durvalumab was 19.1% and 7.8%, respectively. Pretreatment sPD-L1, CSF1R and OPG were identified as significant prognosis predictors in patients receiving durvalumab. ADGRB3 and RNF43 mutations were enriched in patients who responded to chemotherapy plus durvalumab and correlated with superior survival. CONCLUSION: This retrospective real-world study confirmed the clinical benefit of durvalumab plus chemotherapy in treatment-naïve ABC patients. Peripheral sPD-L1 and CSF1R are promising prognostic biomarkers for this therapeutic strategy. Presence of ADGRB3 or RNF43 mutations could improve the stratification of immunotherapy outcomes, but further studies are warranted to explore the underlying mechanisms.