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In renal collecting duct (CD) principal cells (PCs), vasopressin (VP) acts through its receptor, V2R, to increase intracellular cAMP leading to phosphorylation and apical membrane accumulation of the water channel aquaporin 2 (AQP2). The trafficking and function of basolaterally located AQP2 is, however, poorly understood. Here we report the successful application of a 3-dimensional Madin-Darby canine kidney (MDCK) epithelial model to study polarized AQP2 trafficking. This model recapitulates the luminal architecture of the CD and bi-polarized distribution of AQP2 as seen in kidney. Without stimulation, AQP2 is located in the subapical and basolateral regions. Treatment with VP, forskolin (FK), or 8-(4-Chlorophenylthio)-2'-O-methyladenosine 3',5'-cyclic monophosphate monosodium hydrate (CPT-cAMP) leads to translocation of cytosolic AQP2 to the apical membrane, but not to the basolateral membrane. Treating cells with methyl-β-cyclodextrin (mβCD) to acutely block endocytosis causes accumulation of AQP2 on the basolateral membrane, but not on the apical membrane. Our data suggest that AQP2 may traffic differently at the apical and basolateral domains in this 3D epithelial model. In addition, application of a panel of phosphorylation specific AQP2 antibodies reveals the polarized, subcellular localization of differentially phosphorylated AQP2 at S256, S261, S264 and S269 in the 3D culture model, which is consistent with observations made in the CDs of VP treated animals, suggesting the preservation of phosphorylation dependent regulatory mechanism of AQP2 trafficking in this model. Therefore we have established a 3D culture model for the study of trafficking and regulation of both the apical and basolaterally targeted AQP2. The new model will enable further characterization of the complex mechanism regulating bi-polarized trafficking of AQP2 in vitro.

There are currently no clinical strategies utilizing tumor gene expression to inform therapeutic selection for patients with head and neck squamous cell carcinoma (HNSCC). One of the challenges in developing predictive biomarkers is the limited characterization of preclinical HNSCC models. Patient-derived xenografts (PDXs) are increasingly recognized as translationally relevant preclinical avatars for human tumors; however, the overall transcriptomic concordance of HNSCC PDXs with primary human HNSCC is understudied, especially in human papillomavirus-associated (HPV+) disease. Here, we characterized 64 HNSCC PDXs (16 HPV+ and 48 HPV-) at the transcriptomic level using RNA-sequencing. The range of human-specific reads per PDX varied from 64.6%-96.5%, with a comparison of the most differentially expressed genes before and after removal of mouse transcripts revealing no significant benefit to filtering out mouse mRNA reads in this cohort. We demonstrate that four previously established HNSCC molecular subtypes found in The Cancer Genome Atlas (TCGA) are also clearly recapitulated in HNSCC PDXs. Unsupervised hierarchical clustering yielded a striking natural division of HNSCC PDXs by HPV status, with C19orf57 (BRME1), a gene previously correlated with positive response to cisplatin in cervical cancer, among the most significantly differentially expressed genes between HPV+ and HPV- PDXs. In vivo experiments demonstrated a possible relationship between increased C19orf57 expression and superior anti-tumor responses of PDXs to cisplatin, which should be investigated further. These findings highlight the value of PDXs as models for HPV+ and HPV- HNSCC, providing a resource for future discovery of predictive biomarkers to guide treatment selection in HNSCC.

The kidney maintains water homeostasis by modulating aquaporin 2 (AQP2) on the plasma membrane of collecting duct principal cells in response to vasopressin (VP). VP mediated phosphorylation of AQP2 at serine 256 is critical for this effect. However, the role of phosphorylation of other serine residues in the AQP2 C-terminus is less well understood. Here, we examined the effect of phosphorylation of S256, S261 and S269 on AQP2 trafficking and association with recycling pathway markers. We used LLC-PK1 cells expressing AQP2(S-D) or (S-A) phospho mutants and a 20°C cold block, which allows endocytosis to continue, but prevents protein exit from the trans Golgi network (TGN), inducing formation of a perinuclear AQP2 patch. AQP2-S256D persists on the plasma membrane during cold block, while wild type AQP2, AQP2-S256A, S261A, S269A and S269D are internalized and accumulate in the patch. Development of this patch, a measure of AQP2 internalization, was most rapid with AQP2-S256A, and slowest with S261A and S269D. AQP2-S269D exhibited a biphasic internalization profile with a significant amount not internalized until 150 minutes of cold block. After rewarming to 37°C, wt AQP2, AQP2-S261A and AQP2-S269D rapidly redistributed throughout the cytoplasm within 20 minutes, whereas AQP2-S256A dissipated more slowly. Colocalization of AQP2 mutants with several key vesicular markers including clathrin, HSP70/HSC70, EEA, GM130 and Rab11 revealed no major differences. Overall, our data provide evidence supporting the role of S256 and S269 in the maintenance of AQP2 at the cell surface and reveal the dynamics of internalization and recycling of differentially phosphorylated AQP2 in cell culture.

Although there have been great advancements in the field of HIV treatment and prevention, there is no cure. There are two types of HIV: HIV-1 and HIV-2. In addition to genetic differences between the two types of HIV, HIV-2 infection causes a slower disease progression, and the rate of new HIV-2 infections has dramatically decreased since 2003. Like HIV-1, HIV-2 is capable of establishing latent infection in CD4+ T cells, thereby allowing the virus to evade viral cytopathic effects and detection by the immune system. The mechanisms underlying HIV latency are not fully understood, rendering this a significant barrier to development of a cure. Using RT-ddPCR, we previously demonstrated that latent infection with HIV-1 may be due to blocks to HIV transcriptional elongation, distal transcription/polyadenylation, and multiple splicing. In this study, we describe the development of seven highly-specific RT-ddPCR assays for HIV-2 that can be applied to the study of HIV-2 infections and latency. We designed and validated seven assays targeting different HIV-2 RNA regions along the genome that can be used to measure the degree of progression through different blocks to HIV-2 transcription and splicing. Given that HIV-2 is vastly understudied relative to HIV-1 and that it can be considered a model of a less virulent infection, application of these assays to studies of HIV-2 latency may inform new therapies for HIV-2, HIV-1, and other retroviruses.

The diversity of living cells, in both size and internal complexity, calls for imaging methods with adaptable spatial resolution. Soft x-ray tomography (SXT) is a three-dimensional imaging technique ideally suited to visualizing and quantifying the internal organization of single cells of varying sizes in a near-native state. The achievable resolution of the soft x-ray microscope is largely determined by the objective lens, but switching between objectives is extremely time-consuming and typically undertaken only during microscope maintenance procedures. Since the resolution of the optic is inversely proportional to the depth of focus, an optic capable of imaging the thickest cells is routinely selected. This unnecessarily limits the achievable resolution in smaller cells and eliminates the ability to obtain high-resolution images of regions of interest in larger cells. Here, we describe developments to overcome this shortfall and allow selection of microscope optics best suited to the specimen characteristics and data requirements. We demonstrate that switchable objective capability advances the flexibility of SXT to enable imaging cells ranging in size from bacteria to yeast and mammalian cells without physically modifying the microscope, and we demonstrate the use of this technology to image the same specimen with both optics.

The forensic examination of AIGC(Artificial Intelligence Generated Content) faces poses a contemporary challenge within the realm of color image forensics. A myriad of artificially generated faces by AIGC encompasses both global and local manipulations. While there has been noteworthy progress in the forensic scrutiny of fake faces, current research primarily focuses on the isolated detection of globally and locally manipulated fake faces, thus lacking a universally effective detection methodology. To address this limitation, we propose a sophisticated forensic model that incorporates a dual-stream framework comprising quaternion RGB and PRNU(Photo Response Non-Uniformity). The PRNU stream extracts the "camera fingerprint" feature by discerning the non-uniform response of the image sensor under varying lighting conditions, thereby encapsulating the overall distribution characteristics of globally manipulated faces. The quaternion RGB stream leverages the inherent nonlinear properties of quaternions and their informative representation capabilities to accurately describe changes in image color, background, and spatial structure, facilitating the meticulous capture of nuanced local distinctions between locally manipulated faces and real faces. Ultimately, we integrate the two streams to establish the exchange of feature information between PRNU and quaternion RGB streams. This strategic integration fully exploits the complementarity between two streams to amalgamate local and global features effectively. Experimental results obtained from diverse datasets underscore the advantages of our method in terms of accuracy, achieving a detection accuracy of 96.81%. [ABSTRACT FROM AUTHOR]

Two related methods, Quasi-ANCOVA and Dual-Centered ANCOVA, have recently been suggested as a way to get greater power when analyzing data from a before and after study. Both methods use group-mean centering where the groups are the treatment and comparison groups. Group-mean centering creates a generated regressor problem. When the estimated standard errors are corrected for the generated regressor problem, there is no longer any gain in power. The corrected Quasi-ANCOVA estimates are identical to those from ANOVA and the corrected Dual-Centered ANCOVA estimates are identical to those from the differences model. These conclusions are derived analytically and also verified using a Monte Carlo simulation. [ABSTRACT FROM AUTHOR]

Background: Shenfu injection (SFI), derived from a traditional Chinese medicine (TCM) prescription, is an effective drug for the treatment of sepsis-induced myocardial injury (SIMI) with good efficacy, but its exact therapeutic mechanism remains unclear. Methods: SwissTargetPrediction and GeneCards database were used to obtain relevant targets for SFI and SIMI. STRING 11.5 and MCODE were used to analyse potential therapeutic targets for SFI. DAVID 6.8 database was used to perform enrichment analysis. In addition, the SIMI model was constructed by cecal ligation and puncture (CLP) on Sprague Dawley rats and the related protein expression levels were verified by AutoDock Vina 1.1.2 and experiment. Results: SFI has a total of 10 main active compounds and treats SIMI through 52 potential targets, among which LGALS3, STAT3, FGF1, and AKT1 were the core targets for treatment. Based on enrichment analysis, STAT3, FGF1, and AKT1 in the core targets were experimentally validated. The experimental results showed that SFI effectively ameliorated the inflammatory response and myocardial injury and inhibited apoptosis in SIMI. And SFI improved SIMI by decreasing caspase-9, STAT3 and phospho-AKT1 (p-AKT1) expression, and enhancing FGF1 expressions. Conclusions: This study showed that SFI effectively reduced the expression of caspase-9, STAT3 and p-AKT1, enhanced the expression of FGF1, reduced the inflammatory response, inhibited apoptosis and attenuated cardiac injury to SIMI. [ABSTRACT FROM AUTHOR]

Predicting Drug-Drug Interactions (DDIs) enables cost reduction and time savings in the drug discovery process, while effectively screening and optimizing drugs. The intensification of societal aging and the increase in life stress have led to a growing number of patients suffering from both heart disease and depression. These patients often need to use cardiovascular drugs and antidepressants for polypharmacy, but potential DDIs may compromise treatment effectiveness and patient safety. To predict interactions between drugs used to treat these two diseases, we propose a method named Multi-Drug Features Learning with Drug Relation Regularization (MDFLDRR). First, we map feature vectors representing drugs in different feature spaces to the same. Second, we propose drug relation regularization to determine drug pair relationships in the interaction space. Experimental results demonstrate that MDFLDRR can be effectively applied to two DDI prediction goals: predicting unobserved interactions among drugs within the drug network and predicting interactions between drugs inside and outside the network. Publicly available evidence confirms that MDFLDRR can accurately identify DDIs between cardiovascular drugs and antidepressants. Lastly, by utilizing drug structure calculations, we ascertained the severity of newly discovered DDIs to mine the potential co-medication risks and aid in the smart management of pharmaceuticals. [ABSTRACT FROM AUTHOR]

The evolutionary model of construction land serves as a fundamental pillar in national spatial development and planning research. However, previous studies have overlooked the "climbing" mode of construction land on three-dimensional terrains. To address this issue, utilizing elevation data and land use data from 2010 to 2020, this study employs slope analysis, intensity analysis, spatio-temporal transformation, and PLUS model to elucidate the spatial expansion process and driving forces of urban construction land in Chongqing from both two-dimensional and three-dimensional perspectives. The findings indicate that: (1) From a three-dimensional topographical standpoint, between 2010 and 2012, construction land gradually expanded towards low-slope areas, whereas between 2012 and 2020, it progressively extended into high-slope regions. (2) Regarding land type conversion patterns, the shift from arable land to construction land demonstrates a systematic inclination, while other transformations exhibit absolute or relative tendencies. Conversely, the conversion from construction land to arable land also displays a systematic pattern. (3) Since 2010, the growth process of construction land has transitioned from slow-equilibrium to rapid-disequilibrium with an expanding spatial disparity. (4) Most areas maintain relatively stable spatial conditions without significant jumps or transitions observed. (5) The expansion of construction land in Chongqing is primarily influenced by terrain, river, tunnel, rail transit, and other factors. The outcomes of this study can provide scientific foundations and decision-making references for rational planning in similar cities characterized by mountainous landscapes intersected by rivers. [ABSTRACT FROM AUTHOR]

Amidst the global restructuring of the semiconductor supply chain, this paper constructs a global semiconductor trade network (2007, 2012, 2017, 2021) encompassing three segments (raw materials, equipment, and finished components), based on the CEPII database. After initially exploring trade flows among different regions, the paper conducts an in-depth analysis of the network's overall structure and the significance of its nodes. Furthermore, the evolution of the trade network's community structure is discussed and its robustness and dynamics over recent years are assessed through computer program simulation. The findings are as follows: First, semiconductor trade flows are concentrated primarily among a few regions in Asia, US, and EU. Second, the network has grown in size and exhibits significant "small-world" characteristics in all segments, deviating from the typical "sparsity" seen in large-scale networks. Third, Japan, the US, and a few European regions wield significant influence in semiconductor materials and equipment trade, while Asian economies such as Chinese mainland, Chinese Taiwan, and Korea dominate semiconductor components trade. Fourth, the raw materials trade network has diversified in recent years, while the trade networks for equipment and finished components remain in a state of continuous "polarization." Fifth, the semiconductor trade network demonstrates robustness against random attacks but collapses quickly under targeted attacks. Among the three segments, the trade network of finished components, being larger in scale, exhibits greater resilience against both random and targeted attacks. This paper not only enhances the construction of the global semiconductor trade network but also introduces a dynamic perspective, offering deeper insights into its structure and robustness. The insights gained from this analysis provide valuable guidance for policymakers and companies, especially amidst rapid technological change and geopolitical tensions. [ABSTRACT FROM AUTHOR]

The modified nanoparticles can significantly improve the insulation characteristics of transformer oil. Currently, there is a lack of research on the actual motion state of particles in nanofluid to further understand the micro-mechanism of nanoparticles improving the insulation characteristics of transformer oil. In this study, the nanofluid containing 0.01g/L of TiO2 with a particle size of 20nm is prepared using the thermal oscillation method. Breakdown voltage tests are carried out. The experimental test results show that adding nanoparticles can significantly reduce the breakdown probability of transformer oil. The more the water content, the less the enhancement effect of the nanofluid on breakdown voltage. The higher the temperature, the stronger the enhancement effect of the nanofluid on breakdown voltage. Finally, the polarization process of nanoparticles and the trajectory of charged particles in the transformer oil under different electric fields are simulated using COMSOL to further analyze the influence mechanism of nanoparticles on the insulation characteristics of transformer oil. The simulation results show that under the action of the electric field, nanoparticles polarize and generate charge shallow traps to adsorb electrons, reducing the high-speed free charges in the oil, and indirectly increasing the breakdown voltage. [ABSTRACT FROM AUTHOR]

Background: Many systematic reviews (SRs) have reported the repetitive transcranial magnetic stimulation (rTMS) for Parkinson' s disease (PD), but the quality of the evidence is unclear. The aim of this study was to summarize the evidence provided by SRs on the effect of rTMS on PD. Methods: A comprehensive search for SRs published from the establishment of the library to March 1, 2024, was conducted in PubMed, EMBASE, Cochrane Library, Web of Science, CNKI, VIP and Wanfang databases. The A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR-2), the Risk of Bias for Systematic Reviews (ROBIS), and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) tool were used to evaluate the methodology quality, risk of bias and evidence quality of SRs, respectively. Results: We identified 16 SRs. According to the results of the AMSTAR-2, 12.5% (2/16) of the SRs rated as high quality, 43.75% (7/16) rated as low quality, and 43.75% (7/16) rated as very low quality. Based on the ROBIS tool, 6 (37.5%) SRs had low risk of bias. The GRADE results suggested that 16.13% (10/62) of the evidence was of moderate quality, 33.87% (21/62) of the evidence was of low quality and 50% (31/62) of the evidence was of very low quality. Moderate-quality results show that rTMS can improve PD motor symptoms. Conclusions: Here we show that rTMS can improve the motor symptoms of PD, but its effectiveness in treating non-motor symptoms of PD is inconsistent. Due to the methodological limitations and diversity in study designs, future studies should focus on addressing these issues by providing thorough methodological details, standardizing rTMS protocols, evaluating side effects, and comparing with other treatments. [ABSTRACT FROM AUTHOR]

As digital healthcare evolves, the security of electronic health records (EHR) becomes increasingly crucial. This study presents the GPT-Onto-CAABAC framework, integrating Generative Pretrained Transformer (GPT), medical-legal ontologies and Context-Aware Attribute-Based Access Control (CAABAC) to enhance EHR access security. Unlike traditional models, GPT-Onto-CAABAC dynamically interprets policies and adapts to changing healthcare and legal environments, offering customized access control solutions. Through empirical evaluation, this framework is shown to be effective in improving EHR security by accurately aligning access decisions with complex regulatory and situational requirements. The findings suggest its broader applicability in sectors where access control must meet stringent compliance and adaptability standards. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the effects of different concentrations of astaxanthin and Bidens Pilosa compound feed additives on the color and hypoxia tolerance of cherry shrimp (Neocaridina davidi var. red). Color parameters were assessed using CIELAB color space, and differential gene expression related to color and stress was analyzed using reverse transcription quantitative polymerase chain reaction (RT-qPCR) to understand the gene regulatory mechanisms affecting color expression and stability. Over a 56-day rearing period, the feed additives AX100 (astaxanthin 100 mg/kg) and AX100+BP (astaxanthin 100 mg/kg + B. pilosa 5 g/kg) significantly reduced the color difference values compared to the standard sample (ΔE*ab), indicating notable color boosting effects. This included a reduction in lightness (L*), a decrease in color hue angle (h*) with AX100, and an increase in redness (a*) and chroma (C*) with AX100+BP. We further designed 22 color-related gene primers, 16 of which amplified the target fragment. Six gene sets exhibited significant differences among all feed treatment groups and were correlated with color expression. After 9 hours of hypoxic stress, body color remained stable in the feed additive groups, especially in the AX100 + BP and AX200 + BP (astaxanthin 200 mg/kg + B. pilosa 5 g/kg) groups, with color differences before and after hypoxic stress remaining below the discernible threshold of the human eye, indicating optimal color stability. Additionally, the CAT gene, among the stress-related genes that successfully amplified, showed significant differences among feed treatment groups and correlated with color stability based on color difference values. In conclusion, the composite addition of 100 mg/kg astaxanthin and 5 g/kg Bidens pilosa (AX100 + BP) was identified as the most effective treatment. This formulation significantly enhanced cherry shrimp color, evidenced by improved parameters such as decreased lightness and increased redness. Moreover, AX100 + BP demonstrated superior color stability under hypoxic conditions, with ΔE*ab values remaining below the discernible threshold of the human eye, highlighting its potential for maintaining optimal color during transportation. Offering a basis for enhancing the commercial value and reducing the sale risks of cherry shrimp. [ABSTRACT FROM AUTHOR]

Objective: Ankylosing spondylitis (AS) patients often present with microscopic signs of gut inflammation. We used proteomic techniques to identify the differentially expressed proteins (DEPs) in the colon tissues of patients with AS and patients with gut inflammation, and then used investigated the influence of NMRAL1 protein on inflammatory cytokines to explore its potential role in the pathogenesis of AS and gut inflammation. Methods: Colonic mucosal tissues were collected from four different groups: healthy individuals (group A), patients with gut inflammation only (group B), patients with AS only (group C), and patients with AS combined with gut inflammation (group D). A total of 20 samples were processed for proteomic analysis, wherein proteins were extracted using SDT lysis, followed by separation via sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE). The proteins were digested using the filter-aided sample preparation (FASP) method and then analyzed using a timsTOF Pro mass spectrometer. The resulting peptide data were used to identify differentially expressed proteins (DEPs) across the different groups. To further explore the inflammation-related function of NMRAL1 protein, the murine monocyte/macrophage cell line RAW264.7 was used. NMRAL1 mRNA expression levels were assessed via RT-qPCR, and inflammatory cytokine levels (TNF-α, IL-1β, IL-17 and IL-23) were measured using ELISA following NMRAL1 siRNA transfection in LPS-treated macrophages. Results: We collected colonic mucosa specimens from 20 patients, including groups A,B, C and D with 5 patients in each group. We established a database of DEPs and identified 107 (63 upregulated and 44 downregulated) between group B and group A, 78 (16 upregulated and 62 downregulated) between group D and group C, 45 (8 upregulated and 37 downregulated) between group D and group B, and 57 (33 upregulated and 24 downregulated) between group C and group A. Further analysis revealed that the NmrA-like family domain containing 1 (NMRAL1) protein was identified as a DEP specifically associated with group D. The results of in vitro results showed a significant decrease in NMRAL1 mRNA expression in LPS-treated cells (P<0.001), which was further reduced in NMRAL1 siRNA-transfected cells (P<0.0001), confirming successful transfection. ELISA results revealed that the levels of key inflammatory cytokines (TNF-α, IL-1β, IL-17 and IL-23) were significantly elevated in the LPS-treated model group (P<0.0001, P<0.001), but these levels were significantly decreased after NMRAL1 siRNA transfection (P<0.0001, P<0.01, P<0.05). Conclusion: NMRAL1 is identified as a key differentially expressed protein in AS patients with gut inflammation. Knockdown of NMRAL1 significantly reduced the levels of inflammatory cytokines, suggesting its potential role in the pathogenesis of AS and gut inflammation, and as a possible therapeutic target. [ABSTRACT FROM AUTHOR]

As China's population continues to age rapidly, smart elderly care has become a crucial strategy for addressing this societal challenge. Smart home systems have the potential to significantly enhance the quality of life, safety, and autonomy of the elderly. However, the adoption rate of these systems in this demographic remains relatively low, requiring an exploration of the key factors influencing the behavioral intention to use such systems. This study developed a comprehensive model based on the Technology Acceptance Model and the Unified Theory of Acceptance and Use of Technology. Through empirical analysis using partial least squares structural equation modeling, this study systematically examined the pathways through which various factors affected the behavioral intentions of the elderly. The findings revealed that perceived usefulness, facilitating conditions, compatibility, and perceived cost had significant direct effects on behavioral intention. Additionally, social influence, perceived trust, facilitating conditions, and compatibility indirectly influenced behavioral intention through perceived usefulness and perceived ease of use. Although perceived trust did not directly affect behavioral intention, it exerted an indirect influence through perceived usefulness. This comprehensive model provides theoretical insights into the behavioral intentions of the elderly toward smart home systems and offers practical guidance for developers, designers, and policymakers in the development, design, and promotion of these systems. [ABSTRACT FROM AUTHOR]

Background: Dexmedetomidine may improve sleep quality after surgery, but conflicting results also exist. Herein, we explored the effects of perioperative dexmedetomidine on postoperative sleep quality in adult patients. Methods: In this systematic review and meta-analysis, randomized controlled trials investigating the effects of perioperative dexmedetomidine on sleep quality after noncardiac surgery were retrieved from Cochrane Library, PubMed, and EMBASE from inception to January 12, 2023, and updated on March 15, 2024. The Cochrane Collaboration's tool was applied to assess risk of bias. A random-effects model was used for meta-analysis. The primary outcome was the subjective sleep quality score on the first night after surgery. Results: A total of 29 trials containing 5610 participants were included. The subjective sleep score on the first postoperative night was lower (better) with dexmedetomidine than with placebo (SMD [standardized mean difference] = -0.8, 95% CI -1.1 to -0.6, p<0.00001; I2 = 93%; 22 trials; n = 4611). Sensitivity analysis showed that overall conclusion was not changed (SMD = -0.8, 95% CI -1.1 to -0.5, p<0.00001; I2 = 93%; 14 trials; n = 3846). Results of polysomnographic monitoring showed improved sleep structure with dexmedetomidine on the first night after surgery, as manifested by increased sleep efficiency index and stage N2 sleep and decreased arousal index and stage N1 sleep. Conclusions: This systematic review suggests that, among patients who underwent noncardiac surgery, perioperative dexmedetomidine administration may improve early postoperative sleep quality pattern. However, the resulting evidence were of low or very low qualities and further studies are required to confirm our results. PROSPERO registration number: CRD42023390972. [ABSTRACT FROM AUTHOR]

The World Health Organization has issued a global alert on Acute Severe Hepatitis of Unknown Aetiology (AS-HEP-UA) since 23 April 2022,and there was still uncertainty regarding the association of AS-HEP-UA with SARS-CoV-2 as well as adenovirus. This study aimed to summarize the infection of SARS-CoV-2 and co-infections with adenovirus, as well as clinical features and outcomes in patients with AS-HEP-UA. PubMed, Embase, Web of Science, and the Cochrane Library were searched from 1 October 2021 to 8 December 2022 for studies about patients with AS-HEP-UA. This study was registered in the PROSPERO database (CRD42023385056). We has included 14 eligible articles. The main clinical features of AS-HEP-UA were jaundice (65%) and vomiting (59%), while other clinical features included diarrhea (45%), abdominal pain (37%), and fever (31%), roughly 10% of the children required liver transplantation. The overall positivity rate for SARS-CoV-2 was 21.6% (95% CI: 0.126–0.319), with 25.5% (95% CI: 0.161–0.358) for previous infections. The positivity rate for adenovirus infection was 58.6% (95% CI:0.429–0.736) while co-infection with SARS-CoV-2 was 17.5% (95% CI: 0.049–0.342). Moreover, we found that the positive rate of SARS-CoV-2 for this hepatitis outbreak was correlated with region by subgroup analysis. In conclusion, the positive rate of adenovirus was higher than SARS-CoV-2, and the relationship between AS-Hep-UA and COVID-19 is not significant. However, it cannot be excluded that the COVID-19 epidemic is an indirect causative agent of AS-Hep-UA, which requires a larger cohort of AS-Hep-UA patients to uncover additional findings. [ABSTRACT FROM AUTHOR]

IntroductionUrocortin 2 (Ucn2) is a 38-amino acid peptide of the corticotropin-releasing factor family. Intravenous (IV) delivery of an adeno-associated virus vector serotype 8 encoding Ucn2 (AAV8.Ucn2) increases insulin sensitivity and glucose disposal in mice with insulin resistance.ObjectiveTo determine the effects of Ucn2 on liver metabolome.MethodsSix-week-old C57BL6 mice were divided into normal chow (CHOW)-fed and high fat diet (HFD)-fed groups. The animals received saline, AAV8 encoding no gene (AAV8.Empt) or AAV8.Ucn2 (2x1013 genome copy/kg, IV injection). Livers were isolated from CHOW-fed and HFD-fed mice and analyzed by untargeted metabolomics. Group differences were statistically analyzed.ResultsIn CHOW-fed mice, AAV8.Ucn2 gene transfer (vs. saline) altered the metabolites in glycolysis, pentose phosphate, glycogen synthesis, glycogenolysis, and choline-folate-methionine signaling pathways. In addition, AAV8.Ucn2 gene transfer increased amino acids and peptides, which were associated with reduced protein synthesis. In insulin resistant (HFD-induced) mice, HFD (vs CHOW) altered 448 (112 increased and 336 decreased) metabolites and AAV8.Ucn2 altered 239 metabolites (124 increased and 115 reduced) in multiple pathways. There are 61 metabolites in 5 super pathways showed interactions between diet and AAV8.Ucn2 treatment. Among them, AAV8.Ucn2 gene transfer reversed HFD effects on 13 metabolites. Finally, plasma Ucn2 effects were determined using a 3-group comparison of HFD-fed mice that received AAV8.Ucn2, AAV.Empt or saline, where 18 metabolites that altered by HFD (15 increased and 3 decreased), but restored levels to that seen in CHOW-fed mice by increased plasma Ucn2.ConclusionsMetabolomics study revealed that AAV8.Ucn2 gene transfer, through increased plasma Ucn2, provided counter-HFD effects in restoring hepatic metabolites to normal levels, which could be the underlying mechanisms for Ucn2 effects on increasing glucose disposal and reducing insulin assistance.

We examined the impact of statins on Yes-associated Protein (YAP) localization, phosphorylation and transcriptional activity in human and mouse pancreatic ductal adenocarcinoma (PDAC) cells. Exposure of sparse cultures of PANC-1 and MiaPaCa-2 cells to cerivastatin or simvastatin induced a striking re-localization of YAP from the nucleus to the cytoplasm and inhibited the expression of the YAP/TEAD-regulated genes Connective Tissue Growth Factor (CTGF) and Cysteine-rich angiogenic inducer 61 (CYR61). Statins also prevented YAP nuclear import and expression of CTGF and CYR61 stimulated by the mitogenic combination of insulin and neurotensin in dense culture of these PDAC cells. Cerivastatin, simvastatin, atorvastatin and fluvastatin also inhibited colony formation by PANC-1 and MiaPaCa-2 cells in a dose-dependent manner. In contrast, the hydrophilic statin pravastatin did not exert any inhibitory effect even at a high concentration (10 μM). Mechanistically, cerivastatin did not alter the phosphorylation of YAP at Ser127 in either PANC-1 or MiaPaCa-2 cells incubated without or with neurotensin and insulin but blunted the assembly of actin stress fiber in these cells. We extended these findings with human PDAC cells using primary KC and KPC cells, (expressing KrasG12D or both KrasG12D and mutant p53, respectively) isolated from KC or KPC mice. Using cultures of these murine cells, we show that lipophilic statins induced striking YAP translocation from the nucleus to the cytoplasm, inhibited the expression of Ctgf, Cyr61 and Birc5 and profoundly inhibited colony formation of these cells. Administration of simvastatin to KC mice subjected to diet-induced obesity prevented early pancreatic acini depletion and PanIN formation. Collectively, our results show that lipophilic statins restrain YAP activity and proliferation in pancreatic cancer cell models in vitro and attenuates early lesions leading to PDAC in vivo.

Citrus tatter leaf virus (CTLV) threatens citrus production worldwide because it induces bud-union crease on the commercially important Citrange (Poncirus trifoliata × Citrus sinensis) rootstocks. However, little is known about its genomic diversity and how such diversity may influence virus detection. In this study, full-length genome sequences of 12 CTLV isolates from different geographical areas, intercepted and maintained for the past 60 years at the Citrus Clonal Protection Program (CCPP), University of California, Riverside, were characterized using next generation sequencing. Genome structure and sequence for all CTLV isolates were similar to Apple stem grooving virus (ASGV), the type species of Capillovirus genus of the Betaflexiviridae family. Phylogenetic analysis highlighted CTLV's point of origin in Asia, the virus spillover to different plant species and the bottleneck event of its introduction in the United States of America (USA). A reverse transcription quantitative polymerase chain reaction assay was designed at the most conserved genome area between the coat protein and the 3'-untranslated region (UTR), as identified by the full genome analysis. The assay was validated with different parameters (e.g. specificity, sensitivity, transferability and robustness) using multiple CTLV isolates from various citrus growing regions and it was compared with other published assays. This study proposes that in the era of powerful affordable sequencing platforms the presented approach of systematic full-genome sequence analysis of multiple virus isolates, and not only a small genome area of a small number of isolates, becomes a guideline for the design and validation of molecular virus detection assays, especially for use in high value germplasm programs.

CD19-targeted chimeric antigen receptor (CAR) T cell therapies have driven a paradigm shift in the treatment of relapsed/refractory B-cell malignancies. However, >50% of CD19-CAR-T-treated patients experience progressive disease mainly due to antigen escape and low persistence. Clinical prognosis is heavily influenced by CAR-T cell function and systemic cytokine toxicities. Furthermore, it remains a challenge to efficiently, cost-effectively, and consistently manufacture clinically relevant numbers of virally engineered CAR-T cells. Using a highly efficient piggyBac transposon-based vector, Quantum pBac™ (qPB), we developed a virus-free cell-engineering system for development and production of multiplex CAR-T therapies. Here, we demonstrate in vitro and in vivo that consistent, robust and functional CD20/CD19 dual-targeted CAR-T stem cell memory (CAR-TSCM) cells can be efficiently produced for clinical application using qPB™. In particular, we showed that qPB™-manufactured CAR-T cells from cancer patients expanded efficiently, rapidly eradicated tumors, and can be safely controlled via an iCasp9 suicide gene-inducing drug. Therefore, the simplicity of manufacturing multiplex CAR-T cells using the qPB™ system has the potential to improve efficacy and broaden the accessibility of CAR-T therapies. [ABSTRACT FROM AUTHOR]

Both a lack of biomarkers and relatively ineffective treatments constitute impediments to management of lupus nephritis (LN). Here we used gene expression microarrays to contrast the transcriptomic profiles of active SLE patients with and without LN to identify potential biomarkers for this condition. RNA isolated from whole peripheral blood of active SLE patients was used for transcriptomic profiling and the data analyzed by linear modeling, with corrections for multiple testing. Results were validated in a second cohort of SLE patients, using NanoString technology. The majority of genes demonstrating altered transcript abundance between patients with and without LN were neutrophil-related. Findings in the validation cohort confirmed this observation and showed that levels of RNA abundance in renal remission were similar to active patients without LN. In secondary analyses, RNA abundance correlated with disease activity, hematuria and proteinuria, but not renal biopsy changes. As abundance levels of the individual transcripts correlated strongly with each other, a composite neutrophil score was generated by summing all levels before examining additional correlations. There was a modest correlation between the neutrophil score and the blood neutrophil count, which was largely driven by the dose of glucocorticosteroids and not the proportion of low density and/or activated neutrophils. Analysis of longitudinal data revealed no correlation between baseline neutrophil score or changes over the first year of follow-up with subsequent renal flare or treatment outcomes, respectively. The findings argue that although the neutrophil score is associated with LN, its clinical utility as a biomarker may be limited.

Monocyte activation and polarization play essential roles in many chronic inflammatory diseases. An imbalance of M1 and M2 macrophage activation (pro-inflammatory and alternatively activated, respectively) is believed to be a key aspect in the etiology of these diseases, thus a therapeutic approach that regulates macrophage activation could be of broad clinical relevance. Methylglyoxal-bis-guanylhydrazone (MGBG), a regulator of polyamine metabolism, has recently been shown to be concentrated in monocytes and macrophages, and interfere with HIV integration into the DNA of these cells in vitro. RNA expression analysis of monocytes from HIV+ and control donors with or without MGBG treatment revealed the only gene to be consistently down regulated by MGBG to be osteopontin (OPN). The elevated expression of this pro-inflammatory cytokine and monocyte chemoattractant is associated with various chronic inflammatory diseases. We demonstrate that MGBG is a potent inhibitor of secreted OPN (sOPN) in cultured monocytes with 50% inhibition achieved at 0.1 μM of the drug. Furthermore, inhibition of OPN RNA transcription in monocyte cultures occurs at similar concentrations of the drug. During differentiation of monocytes into macrophages in vitro, monocytes express cell surface CD16 and the cells undergo limited DNA synthesis as measured by uptake of BrdU. MGBG inhibited both activities at similar doses to those regulating OPN expression. In addition, monocyte treatment with MGBG inhibited differentiation into both M1 and M2 classes of macrophages at non-toxic doses. The inhibition of differentiation and anti-OPN effects of MGBG were specific for monocytes in that differentiated macrophages were nearly resistant to MGBG activities. Thus MGBG may have potential therapeutic utility in reducing or normalizing OPN levels and regulating monocyte activation in diseases that involve chronic inflammation.

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.

Bovine leukemia virus (BLV), a common virus of cattle globally, was believed for decades not to infect humans. More recent techniques (in situ PCR and DNA sequencing) enabled detection of BLV in human breast tissue, and determination of its significant association with breast cancer in a US population. Using similar techniques to study 96 Australian women, we report here detection of retrotranscribed BLV DNA in breast tissue of 40/50(80%) of women with breast cancer versus 19/46(41%) of women with no history of breast cancer, indicating an age-adjusted odds ratio and confidence interval of 4.72(1.71–13.05). These results corroborate the findings of the previous study of US women with an even higher odds ratio for the Australian population. For 48 of the subjects, paired breast tissue samples, removed 3–10 years apart in two unrelated procedures, were available. For 23/31 (74%) of these, in which the first specimen was diagnosed as nonmalignant (benign or premalignant) and the second as malignant, BLV was already present in benign breast tissue years 3–10 years before the malignancy was diagnosed. This is consistent with the supposition of a causative temporal relationship between BLV infection and subsequent development of cancer.

Bone density is controlled by interactions between osteoclasts, which resorb bone, and osteoblasts, which deposit it. The semaphorins and their receptors, the plexins, originally shown to function in the immune system and to provide chemotactic cues for axon guidance, are now known to play a role in this process as well. Emerging data have identified Semaphorin 4D (Sema4D) as a product of osteoclasts acting through its receptor Plexin-B1 on osteoblasts to inhibit their function, tipping the balance of bone homeostasis in favor of resorption. Breast cancers and other epithelial malignancies overexpress Sema4D, so we theorized that tumor cells could be exploiting this pathway to establish lytic skeletal metastases. Here, we use measurements of osteoblast and osteoclast differentiation and function in vitro and a mouse model of skeletal metastasis to demonstrate that both soluble Sema4D and protein produced by the breast cancer cell line MDA-MB-231 inhibits differentiation of MC3T3 cells, an osteoblast cell line, and their ability to form mineralized tissues, while Sema4D-mediated induction of IL-8 and LIX/CXCL5, the murine homologue of IL-8, increases osteoclast numbers and activity. We also observe a decrease in the number of bone metastases in mice injected with MDA-MB-231 cells when Sema4D is silenced by RNA interference. These results are significant because treatments directed at suppression of skeletal metastases in bone-homing malignancies usually work by arresting bone remodeling, potentially leading to skeletal fragility, a significant problem in patient management. Targeting Sema4D in these cancers would not affect bone remodeling and therefore could elicit an improved therapeutic result without the debilitating side effects.

In recent years, the domestic live pig price has risen and fallen rapidly and fluctuated frequently, which has greatly impacted the live pig industry. The level of price volatility in the pig market has served as a significant indication of the progress of the agricultural sector. Identifying the dominant factors affecting the fluctuation of pig prices has become more important. Based on the monthly data of the pig industry from February 2009 to December 2022, this paper constructs an index system of influencing factors of pig price from four aspects: uncertain impact, supply factors, demand factors, and macro-environment factors. By using the transfer model of the Markov regime (MS-VAR), we obtained the probability plot of zone transition for pig price volatility, the impulse response effect diagram of factors affecting pig price, and the cumulated impulse response effect diagram of factors affecting pig price, and analyze the reasons for the ups and downs of pig price according to the above results. The findings indicate prominent features of zone transition in the price fluctuation of China's pig market. From 2017 to 2022, the domestic pig price frequently switches between rising and falling zones, and the "falling pig price stage" and "rising pig price stage" in the non-stationary state last for a relatively short and discontinuous period. There is little probability that the price of live pigs will directly change from rising to falling, and there will be a smooth buffer stage in the price rise and fall process. Among the factors that affect the fluctuation of live pig prices, the dominant factor of frequent and large fluctuation of pig prices is the pig epidemic situation in external factors. Among the internal influencing factors, the changes in farming costs have the greatest significant influence on the fluctuation of pig prices. These results provide a decision-making reference for legislators to carry out epidemic risk prevention and control better, stabilize the market pig price, and provide empirical evidence for market participants to accurately avoid price risks through multiple channels and ways and ensure stable profitability. [ABSTRACT FROM AUTHOR]

Background: Life's Essential 8 (LE8) is the American Heart Association (AHA)'s recently updated assessment of cardiovascular health (CVH). Metabolic syndrome (MetS) is one of the most common chronic noncommunicable diseases associated with CVH impairment and an increased risk of mortality. However, the association of LE8 with all-cause and disease-specific mortality in the MetS population remains unknown. We aimed to explore these associations in a national prospective cohort study from NHANES 2005–2018. Methods: The LE8 was calculated according to the assessment criteria proposed by the AHA, which includes health behavior and health factor domains. LE8 scores were categorized as low CVH (0–49), moderate CVH (50–79), and high CVH (80–100). MetS was assessed according to NCEP-ATP III criteria, and mortality data were obtained through prospective linkage to the National Death Index database. Results: 7839 participants with MetS were included and only 3.5% were in high CVH. In the fully adjusted models, LE8 was negatively associated with both all-cause and cardiovascular disease (CVD) mortality (hazard ratios [HR] and 95% confidence intervals [CI] of 0.978 (0.971,0.984) and 0.972 (0.961,0.984), respectively, both p < 0.0001). Both moderate/high CVH were associated with significantly lower mortality compared to low CVH (both p for trend <0.0001). Health behaviors had a more dominant effect compared to health factors. All-cause and CVD mortality gradually decreased with increasing ideal LE8 metrics. LE8 was not significantly associated with cancer mortality. LE8 and health behaviors were linearly associated with all-cause and CVD mortality, whereas health factors were nonlinearly associated (plateaued after ≥50). Education and chronic kidney disease influenced the association of LE8 with all-cause and CVD mortality, respectively. Conclusions: LE8 scores were negatively associated with all-cause and CVD mortality in the MetS population, while health behaviors had a dominant role. Adherence to higher CVH contributes to the prevention of excessive all-cause and CVD mortality in the MetS population. [ABSTRACT FROM AUTHOR]

Background: This study aims to explore the relationship between urinary phytoestrogen mixed metabolites and the risk of osteoarthritis (OA). Methods: Using data from the National Health and Nutrition Examination Survey (NHANES), a Weighted Quantile Sum (WQS) regression analysis was conducted to determine the dominant metabolites. Additionally, a Bayesian kernel machine regression (BKMR) model was utilized to explore the combined effects of phytoestrogen mixed metabolites on OA. Results: Compared to the lowest quartile group, the highest quartile group of Enterodiol showed a 46% increased risk of OA (OR = 1.46, 95% CI: 1.09–1.96), while the highest quartile group of Enterlactone showed a 30% decreased risk of OA (OR = 0.70, 95% CI: 0.52–0.96). The WQS regression model analysis revealed a positive relationship between urinary phytoestrogen mixed metabolites and OA risk, with Enterodiol found to have the highest weight in this association. The BKMR model indicated that the association between urinary phytoestrogens and OA increased with concentration but did not reach statistical significance. The univariate exposure-response function demonstrated a positive association between Enterodiol and OA. Conclusions: There is a positive relationship between urinary phytoestrogen mixed metabolites and OA, with Enterodiol being an important factor influencing OA risk. [ABSTRACT FROM AUTHOR]

Preventing the progression of acute pancreatitis (AP) to severe acute pancreatitis (SAP) is crucial for AP patients. The use of clinical parameters in laboratory facilities for predicting SAP can be rapid, efficient, and cost-effective. This study aimed to investigate the predictive and prognostic value of collected clinical detection parameters, such as serum alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) levels, and their ratios, such as ALP-to-hemoglobin (Hb) and LDH-to-Hb ratios, for the prediction of SAP occurrence, complications, and mortality. In all, 50 healthy controls (CON), 455 patients with mild acute pancreatitis (MAP), 127 patients with moderately severe acute pancreatitis (MSAP), and 93 patients with SAP were included in the study. Thirty clinical parameters were collected, measured, compared, and analyzed. The ratios of ALP/Hb and LDH/Hb were subsequently calculated and evaluated with respect to gender and age and whether they could predict SAP occurrence, complications, and mortality. The results revealed that 15 parameters were significant for the prediction of AP. Furthermore, the following 6 indicators are associated with the occurrence of SAP: ALP, ALP/Hb, LDH, LDH/Hb, CRP, and blood glucose. Among these parameters, the predictive abilities of ALP/Hb and LDH/Hb for SAP were most effective. However, they fail to differentiate between MAP and MSAP or gender in SAP patients. Positive correlations were only observed between the levels of these indicators and age at onset of SAP. In addition, receiver operating characteristic (ROC) curves were generated to predict SAP incidence rates, complications, and mortality. The area under the curve (AUC) values for the ALP/Hb ratio ranged from 0.7097 to 0.7837, whereas those for the LDH/Hb ratio ranged from 0.5043 to 0.7778. These findings suggest that ALP and LDH alone or in combination with Hb possess unique predictive characteristics that may serve as independent factors for predicting SAP occurrence, complications, and mortality; of these, the ALP/Hb ratio is especially predictive of SAP mortality. [ABSTRACT FROM AUTHOR]

Long-term exposure to a microgravity environment leads to structural and functional changes in hearts of astronauts. Although several studies have reported mechanisms of cardiac damage under microgravity conditions, comprehensive research on changes at the protein level in these hearts is still lacking. In this study, proteomic analysis of microgravity-exposed hearts identified 156 differentially expressed proteins, and ubiquitinomic analysis of these hearts identified 169 proteins with differential ubiquitination modifications. Integrated ubiquitinomic and proteomic analysis revealed that differential proteomic changes caused by transcription affect the immune response in microgravity-exposed hearts. Additionally, changes in ubiquitination modifications under microgravity conditions excessively activated certain kinases, such as hexokinase and phosphofructokinase, leading to cardiac metabolic disorders. These findings provide new insights into the mechanisms of cardiac damage under microgravity conditions. [ABSTRACT FROM AUTHOR]

The ability to efficiently target loci in the Chlamydia trachomatis genome for deletion remains a desirable goal in the field and new strategies need to be developed and refined. Here we describe the development and application of a lambda red recombineering system for Chlamydia. Using a non-replicative plasmid encoding key lambda Red components and targeting sequences, we demonstrate the efficient deletion of numerous gene targets in the model chlamydial strains C. trachomatis L2/434 and C. muridarum. For initial development of the system, we targeted the incA gene of C. trachomatis for deletion. Deletion mutants containing a chloramphenicol resistance marker were recovered within 3 rounds of selection, or 2 rounds of passaging, in McCoy cells and the resulting clones (CTΔincA) were verified by PCR-based genotyping and whole genome sequencing. Phenotypic assessment of host cells infected with CTΔincA was performed by immunofluorescence microscopy and confirmed the lack of IncA expression and the uniform presence of nonfusogenic vacuoles (inclusions) across CTΔincA-infected monolayers. To explore the utility of this system, we deleted 5 additional candidate virulence factors in C. trachomatis and C. muridarum, including deletions of single and multiple genes. We expect lambda Red recombineering to offer a powerful new strategy for making gene deletion and/or replacement mutants in Chlamydia. [ABSTRACT FROM AUTHOR]

Demand response-based load scheduling in smart power grids is currently one of the most important topics in energy optimization. There are several benefits to utility companies and their customers from this strategy. The main goal of this work is to employ a load scheduling controller (LSC) to model and solve the scheduling issue for household appliances. The LSC offers a solution to the primary problems faced during implementing demand response. The goal is to minimize peak-to-average demand ratios (PADR) and electricity bills while preserving customer satisfaction. Time-varying pricing, intermittent renewable energy, domestic appliance energy demand, storage battery, and grid constraints are all incorporated into the model. The optimal adaptive wind-driven optimization (OAWDO) method is a stochastic optimization technique designed to manage supply, demand, and power price uncertainties. LSC creates the ideal schedule for home appliance running periods using the OAWDO algorithm. This guarantees that every appliance runs as economically as possible on its own. Most appliances run the risk of functioning during low-price hours if just the real time-varying price system is used, which could result in rebound peaks. We combine an inclined block tariff with a real-time-varying price to alleviate this problem. MATLAB is used to do a load scheduling simulation for home appliances based on the OAWDO algorithm. By contrasting it with other algorithms, including the genetic algorithm (GA), the whale optimization algorithm (WOA), the fire-fly optimization algorithm (FFOA), and the wind-driven optimization (WDO) algorithms, the effectiveness of the OAWDO technique is supported. Results indicate that OAWDO works better than current algorithms in terms of reducing power costs, PADR, and rebound peak formation without sacrificing user comfort. [ABSTRACT FROM AUTHOR]

Purpose: This study examined the impacts of customer knowledge management and flow experience on customer value co-creation and the mediating role of flow experience in the context of fitness apps. Design/methodology/approach: Using the questionnaire star platform to edit the questionnaire and collect data(n = 450). A structural equation modeling test was conducted to examine the relationships between the variables. Findings: The findings reveal that in a fitness app service scenario, customer knowledge management has a significant positive impact on customer flow experience, customer flow experience has a significant positive impact on customer value co-creation, and customer flow experience plays a partial mediating role in the path from customer knowledge management to customer value co-creation. Practical implications: The results could help fitness-app-related enterprises or service organizations understand the factors influencing and processes of customer participation in value co-creation and thus could help such enterprises and organizations formulate effective marketing strategies to realize customer value co-creation and ultimately to achieve their development goals. Originality/value: Using value co-creation theory and customer-dominant logic, this study analyzed the effects of customer knowledge management, flow experience, and customer value co-creation in the context of fitness apps and examined the mediating role of flow experience. The findings fill a gap in the theoretical research regarding customer value co-creation in the context of fitness apps and expand the scope of research on customer knowledge management and flow experience. [ABSTRACT FROM AUTHOR]

Rabex-5 (also called RabGEF1), a protein originally characterized for its Rab5 GEF function, also has an A20-like E3 ubiquitin ligase domain. We and others reported that Rabex-5 E3 activity promotes Ras mono- and di-ubiquitination to inhibit Ras signaling in Drosophila and mammals. Subsequently, we reported that Rabex-5 inhibits Notch signaling in the Drosophila hematopoietic system. Here we report genetic interactions using Rabex-5 transgenes encoding domain-specific mutations that show that Rabex-5 requires an intact E3 domain to inhibit Notch signaling in the epithelial tissue of the developing wing. Surprisingly, we discovered that Rabex-5 with an impaired E3 domain but active Rab5 GEF domain suppresses Notch loss-of-function phenotypes and enhances both Notch duplication phenotypes and activated Ras phenotypes consistent with a model that the Rab5 GEF activity of Rabex-5 might positively regulate Ras and Notch. Positive and negative regulation of developmental signaling by its different catalytic domains could allow Rabex-5 to precisely coordinate developmental signaling to fine-tune patterning. Finally, we report that Rabex-5 also inhibits the overgrowth due to loss of PTEN or activation of PI3K but not activation of AKT. Inhibition of Ras, Notch, and PI3K signaling may explain why Rabex-5 is deleted in some cancers. Paradoxically, Rabex-5 is reported to be an oncogene in other cancers. We propose that Rabex-5 acts as a tumor suppressor via its E3 activity to inhibit Ras, Notch, and PI3K signaling and as an oncogene via its Rab5 GEF activity to enhance Ras and Notch signaling. [ABSTRACT FROM AUTHOR]

Background: The association between dietary carbohydrate intake and hyperlipidemia remained incompletely understood. This study aimed to explore the association between dietary carbohydrate intake and the risk of hyperlipidemia among reproductive-aged women in the US. Methods: The study utilized data from the National Health and Nutrition Examination Survey (NHANES) conducted from 2005 to 2020. Dietary intake information was assessed via interviews using 24-hour dietary recall interviews, and hyperlipidemia diagnosis adhered to the National Cholesterol Education Program guidelines. Univariate and multivariate logistic regression analyses, along with restricted cubic splines (RCS) and stratified analyses, were conducted to investigate the association between dietary carbohydrate intake and the risk of hyperlipidemia. Results: A total of 6,791 women of reproductive age, with a mean age of 34.87 (±8.57) years, were included in the final analysis. In the multivariate logistic regression model adjusting for covariates, a higher percentage of energy from carbohydrate was positively correlated with the risk of hyperlipidemia (adjusted odds ratio (AOR): 1.014, 95% CI: 1.004–1.024). Analyzing the percentage of energy from carbohydrate as a categorical variable, compared to the lowest quartile, the third quartile (AOR: 1.263, 95% CI: 1.031–1.546) and the highest quartile (AOR: 1.411, 95% CI: 1.083–1.839) were associated with increased hyperlipidemia risk. Additionally, a linear relationship (P for nonlinearity = 0.088) existed between the percentage of energy from carbohydrate and the risk of hyperlipidemia, with an inflection point identified at 49.64. Conclusions: This study found that elevated dietary carbohydrate intake was associated with an increased the risk of hyperlipidemia in reproductive-aged women. These findings implied that reproductive-aged women should pay closer attention to reducing their carbohydrate intake. [ABSTRACT FROM AUTHOR]

Previous studies have shown sleep deprivation is increasingly reported as one of the causes of female infertility. However, how and by what relevant mechanisms it affects female fertility remains unclear. In this study, female mice underwent 72 hours of total sleep deprivation (TSD) caused by rotating wheel or 2 different controls: a stationary wheel, or forced movement at night. Even though, there was no significant difference in the number of eggs ovulated by the TSD mice compared to the control groups. Overall levels of estrogen and FSH were lower throughout the estrus cycle. A total of 42 genes showed significant differential expression in GV oocytes after TSD by RNA sequencing (RNA-Seq). These included genes were enriched in gene ontology terms of mitochondrial protein complex, oxidoreductase activity, cell division, cell cycle G1/S phase transition, as well as others. The increased concentrations of reactive oxygen species (ROS) in germinal vesicle (GV) and metaphase II (MII) oocytes from TSD mice were observed, which might be induced by impaired mitochondrial function caused by TSD. The GV oocytes displayed increased mitochondrial DNA (mtDNA) copy number and a significant transient increase in inner mitochondrial membrane potential (Δψm) from the TSD mice probably due to compensatory effect. In contrast, MII oocytes in the TSD group showed a decrease in the mtDNA copy number and a lower Δψm compared with the controls. Furthermore, abnormal distribution of mitochondria in the GV and MII oocytes was also observed in TSD mice, suggesting mitochondrial dysfunction. In addition, abnormal spindle and abnormal arrangement of chromosomes in MII oocytes were markedly increased in the TSD mice compared with the control mice. In conclusion, our results suggest that TSD significantly alters the oocyte transcriptome, contributing to oxidative stress and disrupted mitochondrial function, which then resulted in oocyte defects and impaired early embryo development in female mice. [ABSTRACT FROM AUTHOR]

This study investigates the economic resilience of cities in Hubei province during the COVID-19 pandemic, utilizing highway nighttime lights as a proxy indicator. By February 2020, the pandemic had caused a significant economic contraction in Hubei. However, by May 2021, a strong recovery was observed, with most cities experiencing growth rates of over 20%. Despite initially similar responses to the crisis, this study reveals significant heterogeneity in economic resilience across the examined cities in Hubei. The spatial distribution follows a core-periphery structure, with Wuhan exhibiting greater resistance to economic shocks compared to peripheral cities. Furthermore, the response capacity within the Wuhan urban agglomeration area exhibits regional variations. In summary, lockdown policies had spatially varied impacts on economic resilience across Hubei's cities. These results offer valuable insights into regional economic resilience and contribute to the formulation of strategies aimed at effectively addressing future unforeseen events. [ABSTRACT FROM AUTHOR]

With rising environmental concerns, accurate air quality predictions have become paramount as they help in planning preventive measures and policies for potential health hazards and environmental problems caused by poor air quality. Most of the time, air quality data are time series data. However, due to various reasons, we often encounter missing values in datasets collected during data preparation and aggregation steps. The inability to analyze and handle missing data will significantly hinder the data analysis process. To address this issue, this paper offers an extensive review of air quality prediction and missing data imputation techniques for time series, particularly in relation to environmental challenges. In addition, we empirically assess eight imputation methods, including mean, median, kNNI, MICE, SAITS, BRITS, MRNN, and Transformer, to scrutinize their impact on air quality data. The evaluation is conducted using diverse air quality datasets gathered from numerous cities globally. Based on these evaluations, we offer practical recommendations for practitioners dealing with missing data in time series scenarios for environmental data. [ABSTRACT FROM AUTHOR]

Obstructive uropathy is a common kidney disease caused by elevated hydrostatic pressure (HP), but relevant molecular and cellular mechanisms have not yet been well understood. In this study, we ex vivo investigated the effects of elevated HP on human renal epithelial cells (HREpCs). Primary HREpCs were subjected to 100 cmH2O HP for 8 or 48 h. Then, the cells were cultured without HP stimulation for another 24 h or 72 h. Cell morphology showed almost no change after 8h HP treatment, but exhibited reversible elongation after 48h HP treatment. HP treatment for 8 h increased the expression of TGFB1 and VEGFA but decreased the expression of CSF2 and TGFB2. On the other hand, HP treatment for 48 h downregulated the expression of CSF2, TGFB2, PDGFB, VEGFA, and VEGFB, while upregulated the expression of TGFB3. Interestingly, all changes induced by 48 h HP treatment were detected more severe compared to 8 h HP treatment. In conclusion, elongated ex vivo HP loading to renal epithelial cells induces reversible changes on cell morphology and disturbs the expression of several growth factors, which provides novel mechanistic insight on elevated HP-caused kidney injury such as obstructive uropathy. [ABSTRACT FROM AUTHOR]

Objective: Sarcopenia and cognitive impairment often coexist in the elderly. In this study, we investigated the causal relationship between sarcopenia-related muscle characteristics and cognitive performance. Methods: We used linkage disequilibrium score regression (LDSC) and Mendelian Randomization (MR) analyses to estimate genetic correlations and causal relationships between genetically predicted sarcopenia-related muscle traits and cognitive function, as well as cognitive function-based discovery samples and replicated samples. Estimated effect sizes were derived from a fixed-effects meta-analysis. Results: Our univariate genome-wide association study (GWAS) meta-analysis indicated a causal relationship between appendicular lean mass (ALM) (β = 0.049; 95% confidence interval (CI): 0.032–0.066, P < 0.001) and walking pace (β = 0.349; 95% CI: 0.210–0.487, P < 0.001) with cognitive function, where a causal relationship existed between ALM in both male and female (βALM-Male(M) = 0.060; 95% CI: 0.031–0.089, PALM-M < 0.001; βALM-Female(F) = 0.045; 95% CI: 0.020–0.069, PALM-F < 0.001) with cognitive function. Low grip strength was not causally associated with cognitive function (β = -0.045; 95% CI: -0.092 - -0.002, P = 0.062). A reverse causality GWAS meta-analysis showed a causal relationship between cognitive function and ALM (β = 0.033; 95% CI: 0.018–0.048, P < 0.001) and walking pace (β = 0.039; 95% CI: 0.033–0.051, P < 0.001), where ALM in both male and female showed a causality (βALM-M = 0.041; 95% CI: 0.019–0.063, PALM-M < 0.001; βALM-F = 0.034; 95% CI: 0.010–0.058, PALM-F = 0.005). Cognitive function was not causally related to low grip strength (β = -0.024; 95% CI: -0.073–0.025, P = 0.344). Multivariable MR1 (MVMR1) analyses showed a significant causal relationship for ALM (β = 0.077; 95% CI: 0.044–0.109, P = 0.000) and walking pace (β = 0.579; 95% CI: 0.383–0.775, P = 0.000) and cognitive function. Multivariable MR2 (MVMR2) multivariate analysis showed that ALM causality remained (β = 0.069; 95% CI: 0.033–0.106, P = 0.000), and walking pace (β = 0.589; 95% CI: 0.372–0.806, P = 0.000). Conclusions: Bidirectional two-sample MR demonstrated that sarcopenia-related muscle characteristics and cognitive performance were positive causal genetic risk factors for each other, while a multivariable MR study demonstrated that low ALM and a slow walking pace were causally involved in reduced cognitive performance. This study suggests a causal relationship between sarcopenia and cognitive impairment in older adults and provide new ideas for prevention and treatment. [ABSTRACT FROM AUTHOR]

Background: The relationship between a nurse and a patient is a key part of nursing that can impact how happy the patient is with the care they receive. It appears that the nurse's mental health can also affect this connection. However, there is little research on this topic. So, the aim of the present study was to determine the correlation of nurse's mental health with nurse–patient relational care and nursing care satisfaction. Methods: A total of 532 nurses and 532 patients from 13 Level-III hospitals of Hubei province (China) completed a China Mental Health Survey, general information questionnaire, the Nursing Care Satisfaction Scale, and Relational Care Scale. Results: Age, nurse working years, and night shift last month were correlated with mental health score (r = -0.142, r = -0.150, r = 0.164, p < 0.05). Nurse's mental health was correlated with relational care score and nursing care satisfaction score (r = -0.177, r = -0.325, p < 0.05). Also, relational care score, patients age and gender were correlated with nursing care satisfaction score (r = 0.584 and r = 0.143, x2 = 11.636, p < 0.05). Descriptive information of nurses had a direct impact on nurses' mental health (direct effect = 0.612, 0.419–0.713). Nurses' mental health had a direct effect on relational care score (direct effect = 0.493, 0.298–0.428) and an indirect effect on nursing care satisfaction score (indirect effect = 0.051, 0.032–0.074). Relational care score and patient's descriptive information had also a direct effect on nursing care satisfaction score (direct effect = 0.232, 0.057–0.172 and 0.057, 0.347–0.493). Conclusion: This study showed that the better the mental health of nurses, the more patients feel satisfied with nursing services. [ABSTRACT FROM AUTHOR]

Deployment of cultivars with genetic resistance is an effective approach to control the diseases of powdery mildew (PM) and yellow rust (YR). Chinese wheat cultivar XK0106 exhibits high levels of resistance to both diseases, while cultivar E07901 has partial, adult plant resistance (APR). The aim of this study was to map resistance loci derived from the two cultivars and analyze their effects against PM and YR in a range of environments. A doubled haploid population (388 lines) was used to develop a framework map consisting of 117 SSR markers, while a much higher density map using the 90K Illumina iSelect SNP array was produced with a subset of 80 randomly selected lines. Seedling resistance was characterized against a range of PM and YR isolates, while field scores in multiple environments were used to characterize APR. Composite interval mapping (CIM) of seedling PM scores identified two QTLs (QPm.haas-6A and QPm.haas-2A), the former being located at the Pm21 locus. These QTLs were also significant in field scores, as were Qpm.haas-3A and QPm.haas-5A. QYr.haas-1B-1 and QYr.haas-2A were identified in field scores of YR and were located at the Yr24/26 and Yr17 chromosomal regions respectively. A second 1B QTL, QYr.haas-1B-2 was also identified. QPm.haas-2A and QYr.haas-1B-2 are likely to be new QTLs that have not been previously identified. Effects of the QTLs were further investigated in multiple environments through the testing of selected lines predicted to contain various QTL combinations. Significant additive interactions between the PM QTLs highlighted the ability to pyramid these loci to provide higher level of resistance. Interactions between the YR QTLs gave insights into the pathogen populations in the different locations as well as showing genetic interactions between these loci.

Animal models of ocular hypertension are important tools for glaucoma studies. Both acute transient models and chronic models of ocular hypertension may be useful to investigate specific aspects of neurodegeneration. In this study, we compare the intraocular pressure (IOP) and inner retinal changes induced by 1) laser photocoagulation of both episcleral veins and limbal vessels and 2) circumlimbal suture in CD-1 mice. The suture group is divided into 3 subgroups depending on the level of the immediate IOP spike (acute > 55 mmHg or chronic < 55 mmHg) and time period of monitoring (7 or 28 days). The laser group is followed for 7 days. IOP data show that it peaks at 5 hours and returns to normal level within 7 days in the laser group. In all suture groups, IOP spikes initially and decreases gradually, but it remains significantly elevated at 7 days. In 7 days, the acute suture model generates rapid loss of retinal nerve fiber layer (RNFL) and retinal ganglion cells (RGCs) when compared to the gradual loss by the chronic suture model, possibly due to retinal ischemia and reperfusion within the first few hours after treatment. The laser model falls between the acute suture and chronic suture models resulting in less RNFL and RGC loss than the acute suture model but significantly more loss than the chronic suture model. These results suggest that when using suture models of IOP elevation, it is critical to take the initial IOP spike into consideration and to choose between the acute and chronic models depending on respective research purposes.

The most efficient method to expand limbal stem cells (LSCs) in vitro for clinical transplantation is to culture single LSCs directly on growth-arrested mouse fibroblast 3T3 cells. To reduce possible xenobiotic contamination from 3T3s, primary human adipose-derived stem cells (ASCs) were examined as feeder cells to support the expansion of LSCs in vitro. To optimize the ASC-supported culture, freshly isolated limbal epithelial cells in the form of single cells (SC-ASC) or cell clusters (CC-ASC) were cultured using three different methods: LSCs seeded directly on feeder cells, a 3-dimensional (3D) culture system and a 3D culture system with fibrin (fibrin 3D). The expanded LSCs were examined at the end of a 2-week culture. The standard 3T3 culture served as control. Expansion of SC-ASC showed limited proliferation and exhibited differentiated morphology. CC-ASC generated epithelial cells with undifferentiated morphology in all culture methods, among which CC-ASC in 3D culture supported the highest cell doubling (cells doubled 9.0 times compared to cells doubled 4.9 times in control) while maintained the percentage of putative limbal stem/progenitor cells compared to the control. There were few cell-cell contacts between cultured LSCs and ASCs in 3D CC-ASC. In conclusion, ASCs support the growth of LSCs in the form of cell clusters but not in single cells. 3D CC-ASC could serve as a substitute for the standard 3T3 culture to expand LSCs.

The 48-basepair (48-bp) variable number tandem repeat (VNTR) polymorphism in exon 3 of the dopamine receptor D4 gene (DRD4) is implicated in the etiology of attention-deficit/ hyperactivity disorder (ADHD). In particular, ADHD in European-ancestry population is associated with an increased prevalence of the 7-repeat (7R) allele of the exon 3 VNTR. However, it is intriguing to note that the 7R allele has been found to be of very low prevalence in the Chinese general population. In a previous case-control study, our research team had found that the 7R allele was similarly absent in Chinese ADHD children in Hong Kong. Instead, there was an increased prevalence of the 2R allele in Chinese ADHD children. Interestingly, in Asian samples, the 2R allele had been found to be an evolutionary derivative of the 7R allele with equivalent biochemical functionality. So, the finding of an association between ADHD and 2R allele in Chinese population does not exactly contradict the original 7R allele finding in European-ancestry population. However, given the potential pitfall of population stratification in the previous case-control design, this current study tested the 2R allele and ADHD association using a methodologically more rigorous family-based approach on 33 Chinese ADHD probands who had favorable clinical responses to stimulant medication (methylphenidate). Haplotype Relative Risk (HRR) analysis and Transmission Disequilibrium Test (TDT) both showed a significant preferential transmission of the 2R allele from the biological parents to ADHD probands (pone-tailed = 0.038, OR = 2.04; pone-tailed = 0.048, OR = 2.29, respectively). A second hypothesis speculates that it is the deviation, including 7R and 2R alleles, from the conserved ancestral 4R allele which confers risk to ADHD. Thus, a preferential transmission of non-4R alleles, against the 4R allele, from biological parents to their ADHD probands is predicted. Both HRR analysis and TDT confirmed such prediction (pone-tailed = 0.029, OR = 2.07; pone-tailed = 0.032, OR = 2.43, respectively). This study re-confirmed the original finding of a previous study that in Chinese population, the 2R allele of the DRD4 exon 3 VNTR was related to ADHD. This endorses the general thesis that DRD4 exon 3 VNTR polymorphism is related to ADHD, despite that the exact length or number of repeats of the associated alleles varies across ethnicity. This in turn supports the dopamine dysregulation theory of ADHD.