Upregulation of the WNK4 signaling pathway inhibits epithelial sodium channels of mouse tracheal epithelial cells after influenza A infection

Influenza virus has a significant impact on the respiratory system. The mechanism of how influenza virus impairs the fluid transport in airway is not fully understood. We examined its effects on epithelial sodium channels (ENaC), which are very important for water and salt transport in the respiratory system. We focused on the impacts of influenza virus on ENaC activity in mouse tracheal epithelial cells (MTECs) and applied Ussing chamber apparatus for recording the short-circuit currents in primary cultured MTECs. Expressions of α and γ-ENaC were measured at the protein and mRNA levels by western blot and quantitative real-time polymerase chain reaction, respectively. Roles of the with-no-lysine-kinase-4 (WNK4) pathway were considered in participating influenza virus-involved ENaC regulation by using siRNA to knockdown WNK4 and the physical properties of airway surface liquid (ASL) were detected by confocal microscopy. Our results showed that influenza virus reduced ENaC activity, and the expressions of α and γ-ENaC were decreased at the protein and mRNA levels, respectively. WNK4 expression increased time-dependently at the protein level after influenza virus infection, while knockdown of WNK4 rescued the impact of influenza virus on ENaC and ASL height increased obviously after MTECs were treated with influenza virus. Taken together, these results suggest that influenza virus causes the changes of biophysical profile in the airway by altering the ENaC activity at least partly via facilitating the expression of WNK4

Modeling multirotor wake interference in quadrotor eVTOL flight dynamics and handling qualities

This study presents a good-fidelity flight dynamics model for a quadrotor eVTOL aircraft, with a particular focus on the effects of multirotor aerodynamic interference on vehicle stability and handling qualities. A dynamic vortex tube model, enhanced to account for aircraft angular motions, is developed and integrated with dynamic inflow theory to compute rotor-induced and interference velocities efficiently. The model is validated against wind tunnel data and benchmark trim results, demonstrating strong predictive accuracy. Incorporating this interference model into a 6-DoF flight dynamics framework reveals that multirotor wake interference significantly modify both static and dynamic stability characteristics, especially in low-to-medium speed regimes. Moreover, aerodynamic interference degrades incidence stability, reduces pitch and heave damping, and adversely affects phugoid behavior. In the lateral-directional axes, it destabilizes the spiral mode and introduces non-monotonic variations in Dutch roll stability. Handling qualities analysis using ADS-33E-PRF metrics shows that interference reduces pitch bandwidth from Level 1 to Level 2 and marginally deteriorates pitch and roll dynamic stability, while improving pitch-axis quickness. These findings demonstrate that multirotor aerodynamic interference is not merely a performance issue but a critical factor influencing flight control design and certification. The proposed modeling approach offers a computationally efficient yet physically grounded method for assessing multirotor eVTOL handling qualities across the full flight envelope.This research was supported by the China Aerodynamics Research and Development Center NO: RAL202302-3; National Natural Science Foundation of China, NO: 11902052; the Natural Science Foundation of Chongqing, NO: CSTB2022NSCQ-MSX1592.Aerospace Science and Technolog

Distribution of Serum Uric Acid Concentration and Its Association With Lipid Profiles: A Single-Center Retrospective Study in Children Aged 3 to 12 Years With Adenoid and Tonsillar Hypertrophy

BACKGROUND: Presently, there is no consensus regarding the optimal serum uric acid (SUA) concentration for pediatric patients. Adenoid and tonsillar hypertrophy is considered to be closely associated with pediatric metabolic syndrome and cardiovascular risk and is a common condition in children admitted to the hospital. Therefore, we aimed to evaluate the relationship between SUA and dyslipidemia and propose a reference range for SUA concentration that is associated with a healthy lipid profile in hospitalized children with adenoid and tonsillar hypertrophy. METHODS: Preoperative data from 4922 children admitted for elective adenoidectomy and/or tonsillectomy surgery due to adenoid and tonsillar hypertrophy were collected. SUA concentrations were scaled to standard deviation (SD), and SUA deviations were expressed as SD from the mean SUA of children without dyslipidemia. RESULTS: The mean SUA concentration of the participants was 4.27 ± 1.01 mg/dL, and the prevalence of hyperuricemia was 1.6% when it was defined using an SUA of ≥ 7.0 mg/dL. Participants with dyslipidemia (856, 17.4%) had a higher prevalence of hyperuricemia (3.4% vs. 1.2%, P \u3c 0.001) and higher SUA concentrations (4.51 ± 1.15 vs. 4.22 ± 0.97 mg/dL, P \u3c 0.001) than those with ortholiposis. The circulating lipid status of participants with SUAs \u3c 1 SD below the mean value for the participants with ortholiposis (range 1.80-3.28 mg/dL) was more normal. Each 1-SD increase in SUA was associated with a 27% increase in the risk of dyslipidemia (OR = 1.270, 95% CI, 1.185-1.361). Adjustment for a number of potential confounders reduced the strength of the relationship, but this remained significant (OR = 1.125, 95% CI, 1.042-1.215). The higher risk of dyslipidemia was maintained for participants with SUAs \u3e 1 SD above the mean value of the participants with ortholiposis. CONCLUSIONS: SUA was independently associated with dyslipidemia in children with adenoid and tonsillar hypertrophy, and an SUA \u3c 1 SD below the mean value for patients with ortholiposis was associated with a healthy lipid profile

Learning List-Level Domain-Invariant Representations for Ranking

Domain adaptation aims to transfer the knowledge learned on (data-rich) source domains to (low-resource) target domains, and a popular method is invariant representation learning, which matches and aligns the data distributions on the feature space. Although this method is studied extensively and applied on classification and regression problems, its adoption on ranking problems is sporadic, and the few existing implementations lack theoretical justifications. This paper revisits invariant representation learning for ranking. Upon reviewing prior work, we found that they implement what we call item-level alignment, which aligns the distributions of the items being ranked from all lists in aggregate but ignores their list structure. However, the list structure should be leveraged, because it is intrinsic to ranking problems where the data and the metrics are defined and computed on lists, not the items by themselves. To close this discrepancy, we propose list-level alignment -- learning domain-invariant representations at the higher level of lists. The benefits are twofold: it leads to the first domain adaptation generalization bound for ranking, in turn providing theoretical support for the proposed method, and it achieves better empirical transfer performance for unsupervised domain adaptation on ranking tasks, including passage reranking.Comment: NeurIPS 2023. Comparison to v1: revised presentation and proof of Corollary 4.

Development of a peptide drug restoring AMPK and adipose tissue functionality in cancer cachexia

Cancer cachexia is a severe systemic wasting disease that negatively affects quality of life and survival in patients with cancer. To date, treating cancer cachexia is still a major unmet clinical need. We recently discovered the destabilization of the AMP-activated protein kinase (AMPK) complex in adipose tissue as a key event in cachexia-related adipose tissue dysfunction and developed an adeno-associated virus (AAV)-based approach to prevent AMPK degradation and prolong cachexia-free survival. Here, we show the development and optimization of a prototypic peptide, Pen-X-ACIP, where the AMPK-stabilizing peptide ACIP is fused to the cell-penetrating peptide moiety penetratin via a propargylic glycine linker to enable late-stage functionalization using click chemistry. Pen-X-ACIP was efficiently taken up by adipocytes, inhibited lipolysis, and restored AMPK signaling. Tissue uptake assays showed a favorable uptake profile into adipose tissue upon intraperitoneal injection. Systemic delivery of Pen-X-ACIP into tumor-bearing animals prevented the progression of cancer cachexia without affecting tumor growth and preserved body weight and adipose tissue mass with no discernable side effects in other peripheral organs, thereby achieving proof of concept. As Pen-X-ACIP also exerted its anti-lipolytic activity in human adipocytes, it now provides a promising platform for further (pre)clinical development toward a novel, first-in-class approach against cancer cachexia

Trends of hypercholesterolemia change in Shenzhen, China during 1997-2018

To demonstrate the trends of hypercholesterolemia change in Shenzhen, China from 1997 to 2018. Participants were residents aged 18 to 69 years in Shenzhen, China, and were recruited using multi-stage cluster sampling. All participants were surveyed about their socio-demographics, lifestyle, occupation, mental health, and social support. Physical measurements and blood samples for subsequent measurements were collected according to a standardized protocol. A total of 26,621 individuals participated in the three surveys with 8,266 in 1997, 8,599 in 2009, and 9,756 in 2018. In both women and men, there was a significant downward linear trend in age-adjusted mean high-density lipoprotein-cholesterol (HDL-C) from 1997 to 2018 (women: 0.17 ± 0.06, p = 0.008 vs. men: 0.21 ± 0.04, p < 0.001). In contrast, the age-adjusted total triglycerides and total cholesterol in both sexes have demonstrated an increasing trend in the past two decades. However, no significant changes in age-adjusted low-density lipoprotein-cholesterol (LDL-C) in both men and women between 2009 and 2018 were found (women: 0.00 ± 0.02, p = 0.85 vs. men 0.02 ± 0.03, p = 0.34). The age-adjusted prevalence of hypercholesterolemia observed a rapid rise from 1997 to 2009 and appeared to be stabilized in 2018, which was similar to the trend of the prevalence of high total triglycerides in women. Changes in trends were varied by different types of lipids traits. Over the observed decades, there was a clear increasing trend of prevalence of low HDL-C (<1.04 mmol/L) in both sexes (women: 8.8% in 1997 and doubled to reach 17.5% in 2018 vs. men was 22.1% in 1997 and increased to 39.1% in 2018), particularly among younger age groups. Hence, a bespoke public health strategy aligned with the characteristics of lipids epidemic considered by sex and age groups needs to be developed and implemented

Microbial community dynamics in the soil-root continuum are linked with plant species turnover during secondary succession

Grazing exclusion and land abandonment are commonly adopted to restore degraded ecosystems in semiarid and arid regions worldwide. However, the temporal variation in the soil- versus root-associated microbiome over plant species turnover during secondary succession has rarely been quantified. Using the chronosequence restored from fenced grassland and abandoned farmlands on the Loess Plateau of China, we characterized the dynamics of the soil- and root-associated microbiome of host plant with different dominance statuses during secondary succession from 0 to 40&nbsp;years. Our results revealed that the root microhabitat, the host plant and their interactions were the main contributors to the bacterial community shift (R2 = 15.5%, 8.1%, and 22.3%, respectively), and plant interspecies replacement had a greater effect on the shift in the root-associated microbial community than intraspecies replacement did during succession. The root-associated bacterial community of pioneer plants was particularly responsive to succession, especially the endosphere community. Endosphere microbial diversity was positively correlated with host plant coverage change, and the diversity and abundance of taxon recruitment into the endosphere of pioneer plants from the surrounding environment decreased as succession progressed. The community assembly processes also indicated that the endosphere microbiota are strongly selected in younger host plants, whereas stochastic processes dominate in aged host plants. Our study provides evidence of the unique response of the root-associated microbiome to the replacement of plant species during secondary succession, and the function of endosphere microbes should be considered when studying plant-microbe feedback

Reliability and Validity of Simplified Chinese Version of Roland-Morris Questionnaire in Evaluating Rural and Urban Patients with Low Back Pain

OBJECTIVE: The causes of low back pain in China and Western countries are extremely different. We attempted to analyze the risk factors of low back pain in urban and rural patients under the dual economy with the simplified Chinese version of Roland-Morris disability questionnaire (SC-RMDQ) to demonstrate that SC-RMDQ could evaluate patients with low back pain arising from different causes. METHODS: Roland-Morris disability questionnaire was translated into SCRMDQ according to international guidelines for questionnaire adaptation. In this study, causes of low back pain of 187 outpatients and inpatients (99 urban patients and 88 rural patients) were analyzed. All patients underwent simplified Chinese version of Roland-Morris disability questionnaire (SC-RMDQ), simplified Chinese Oswestry disability index (SCODI) and visual analogue scale (VAS). Reliability was tested using reproducibility (intraclass coefficient of correlation--ICC) and internal consistency (Cronbach's alpha). Validity was tested using Pearson correlation analysis. RESULTS: The leading causes for low back pain were sedentariness (38.4%) and vibration (18.1%) in urban patients and waist bending (48.9%) and spraining (25%) in rural patients. Although causes of low back pain in the two groups of population were completely different, SCRMDQ had high internal consistency (Cronbach's α value of 0.874 in urban patients and 0.883 in rural patients) and good reproducibility (ICC value of .952 in urban patients and 0.949 in rural patients, P<0.01). SCRMDQ also showed significant correlation with Simplified Chinese version of Oswestry disability index (SCODI) and visual analogue scale (VAS) in rural areas (SCRMDQ-SCODI r = 0.841; SCRMDQ-VAS: r = 0.685, P<0.01) and in urban areas (SCRMDQ-SCODI: r = 0.818, P<0.01; SCRMDQ-VAS: r = 0.666, P<0.01). CONCLUSIONS: Although causes of low back pain are completely different in rural and urban patients, SCRMDQ has a good reliability and validity, which is a reliable clinical method to evaluate disability of rural and urban patients

CDK7 in Adipose Tissue Metabolism

Adipose tissue is a central metabolic organ in the régulation of whole-body energy homeostasis and has profound effects on physiology and pathophysiology. There has been an upsurge of interest in the adipose tissue coincident with the onset of the obesity épidémie. Adipocytes represent the primary cell type of adipose tissue and can be divided into différent subtypes based on color, from white, beige to brown. Cyclin-dependent kinase 7 (CDK7) is a member of the cyclin-dependent protein kinases (CDKs) family, which is an important regulator of cell cycle progression and more recently, metabolism. It forms a trimeric complex with cyclin H and MAT1 (Ménage-à-trois 1), which functions as a Cdk-activating kinase (CAK). It is also an essential component of the transcription factor TFIIH, which is involved in transcription initiation, and DNA repair. This protein is thought to serve as a direct link between the régulation of transcription and the cell cycle. Our laboratory showed that members of the CDK family, such as CDK4 and CDK9, respond to nutritional status and are key factors in the régulation of metabolism independently from cell prolifération. As a CAK member, it is still unknown whether CDK7 has a rôle in adipose tissue metabolism and if yes, is it other CDKs dépendent or not? In our project, we first generated CDK7 adipose tissue-specific knockout mice (CDK7 adKO) to study the rôle of CDK7 in adipose tissue. We found that knockout mice have decreased body weight and fat mass compared with control mice. These mice did not exhibit insulin or glucose intolerance. We also found BAT of knockout mice are smaller and more "white", which indicated an impaired BAT function. However, we found this knockout mice model is not that specific, apart from the ablation of CDK7 in both white and brown adipose tissue, CDK7 is also knockdown in the brain. We do observe some phenotypes which are related to the brain, like decreased food intake and physical activity, which could interfere with phenotypes characterization. It will be interesting to study the rôle of CDK7 in the brain in the context of energy homeostasis régulation. On the other hand, In vitro culture of SVF cells from subeutaneous WAT has impaired differentiation capacity, which confirmed a cell autonomous rôle of CDK7 in white adipose tissue. Currently, a more "clean" adipose tissue spécifie CDK7 khockout mice model is generating. To further analyze the rôle of CDK7 specifically in brown adipose tissue, we generate the brown adipose tissue spécifié CDK7 knockout mice (CDK7 bKO). We found that disruption of CDK7 in BAT does not prédisposé mice to systemic metabolic dysregulation. Compared with control littermates, CDK7 bKO animais had similar body weight and fat mass, indistinguishable basai energy expenditure, locomoter activity, and food intake. To our surprise, with acute cold test, CDK7 bKO mice develop hypothermia only during fasting state, which was accompanied by a marked réduction in blood glucose and in stores of triacylglycerols in BAT. Thus, CDK7 is uniquely required for preparing mice for acute cold exposure. RNAseq gave us a global view of the genes that are affected by CDK7 knockout in BAT. We found loss of CDK7 disrupts the expression of metabolic genes in mitochondrial in response to cold. CHIP-seq will be a powerful tool to explore the mechanism of CDK7 régulation in control metabolic genes in BAT. In summary, our data clearly demonstrated that CDK7 is an important regulator in white adipose tissue development and brown fat thermogenesis. -- Le tissu adipeux est un organe métabolique central dans la régulation de l'homéostasie énergétique du corps entier qui a des effets profonds sur la physiologie et la physiopathologie. Il y a eu un regain d'intérêt pour le tissu adipeux coïncidant avec le début de l'épidémie d'obésité. Les adipocytes représentent le principal type de cellules du tissu adipeux et peuvent être divisés en différents sous-types basés sur leur couleur, du blanc au brun en passant par le beige. La kinase cycline-dépendante 7 (CDK7) est un membre de la famille des protéines kinases cycline-dépendantes (CDK) qui sont des régulateurs importants de la progression du cycle cellulaire et, comme démontré plus récemment, du métabolisme. CDK7 forme un complexe trimérique avec la cycline H et MAT1, qui fonctionne comme une kinase activatrice de Cdk (CAK). C'est aussi un composant essentiel du facteur de transcription TFIIH, impliqué dans l'initiation de la transcription et la réparation de l'ADN. Il a été décrit que cette protéine sert de lien direct entre la régulation de la transcription et le cycle cellulaire. Notre laboratoire a montré que les membres de la famille CDK, tels que CDK4 et CDK9, répondent à l'état nutritionnel et sont des facteurs clés dans la régulation du métabolisme indépendamment de la prolifération cellulaire. En tant que membre de la famille des CAK, on ne sait pas encore si CDK7 joue un rôle dans le métabolisme du tissu adipeux et, si oui, si cela est dépendant ou non d'autres CDKs. Dans notre projet, nous avons d'abord généré des souris présentant une délétion de CDK7 spécifiquement dans le tissu adipeux (CDK7 adKO) pour étudier le rôle de CDK7 dans ce tissu. Nous avons constaté que les souris CDK7 adKO ont un poids corporel et une masse grasse diminués par rapport aux souris témoins. Ces souris ne présentent pas d'intolérance à l'insuline ou au glucose. Nous avons également constaté que le tissu adipeux brun (BAT) des souris knock-out sont plus petits et plus «blancs», ce qui indique une altération de la fonction du BAT. Cependant, nous avons trouvé ce modèle de souris knock-out n'est pas suffisamment spécifique. En effet, au-delà de l'ablation de CDK7 dans les tissus adipeux blanc et brun, CDK7 est également invalidé dans le cerveau. Nous observons certains phénotypes qui sont liés au cerveau, comme une diminution de l'apport alimentaire et de l'activité physique, qui pourraient interférer avec la caractérisation du modèle. Il sera intéressant d'étudier le rôle de CDK7 dans le cerveau dans le contexte de la régulation de l'homéostasie énergétique. D'autre part, la culture in vitro de cellules de la fraction stroma-vasculaire du tissu adipeux sous-cutané montre une altération de la capacité de différenciation, ce qui a confirmé un rôle cellulaire spécifique de CDK7 dans le tissu adipeux blanc. Actuellement, un modèle plus spécifique de souris n'exprimant pas CDK7 dans le tissu adipeux est généré. Pour analyser plus spécifiquement le rôle de CDK7 dans le BAT, nous avons généré des souris avec une délétion spécifique de CDK7 dans le tissu adipeux brun (CDK7 bKO). Nous avons constaté que l'absence de CDK7 dans le BAT ne prédispose pas les souris à un dérèglement métabolique systémique. Comparativement aux souris témoins, les animaux CDK7 bKO ont un poids corporel, une masse grasse, une dépense énergétique basale une activité locomotrice et un apport alimentaire similaires. À notre grande surprise, lors d'une exposition au froid de courte durée, les souris CDK7 bKO développent une hypothermie à jeun accompagnée d'une réduction marquée de la glycémie et des réserves de triacylglycérols dans le BAT. Ainsi, CDK7 est nécessaire uniquement pour préparer des souris à une exposition aiguë au froid. Une analyse transcriptomique par RNAseq nous a donné une vision globale des gènes qui sont affectés par l'invalidation de CDK7 dans BAT. Nous avons trouvé que la perte de CDK7 perturbe l'expression des gènes du métabolisme mitochondrial en réponse au froid. Des expériences de CHIP-seq seront un outil puissant pour explorer le mécanisme de régulation des gènes métaboliques par CDK7 dans le contrôle du métabolisme du BAT. En résumé, nos données ont clairement démontré que CDK7 est un régulateur important dudéveloppement du tissu adipeux blanc et de la thermogenèse dans la graisse brune