Endoplasmic reticulum stress and autophagy in cerebral ischemia/reperfusion injury: PERK as a potential target for intervention.

JOURNAL/nrgr/04.03/01300535-202505000-00028/figure1/v/2024-07-28T173839Z/r/image-tiff Several studies have shown that activation of unfolded protein response and endoplasmic reticulum (ER) stress plays a crucial role in severe cerebral ischemia/reperfusion injury. Autophagy occurs within hours after cerebral ischemia, but the relationship between ER stress and autophagy remains unclear. In this study, we established experimental models using oxygen-glucose deprivation/reoxygenation in PC12 cells and primary neurons to simulate cerebral ischemia/reperfusion injury. We found that prolongation of oxygen-glucose deprivation activated the ER stress pathway protein kinase-like endoplasmic reticulum kinase (PERK)/eukaryotic translation initiation factor 2 subunit alpha (eIF2α)-activating transcription factor 4 (ATF4)-C/EBP homologous protein (CHOP), increased neuronal apoptosis, and induced autophagy. Furthermore, inhibition of ER stress using inhibitors or by siRNA knockdown of the PERK gene significantly attenuated excessive autophagy and neuronal apoptosis, indicating an interaction between autophagy and ER stress and suggesting PERK as an essential target for regulating autophagy. Blocking autophagy with chloroquine exacerbated ER stress-induced apoptosis, indicating that normal levels of autophagy play a protective role in neuronal injury following cerebral ischemia/reperfusion injury. Findings from this study indicate that cerebral ischemia/reperfusion injury can trigger neuronal ER stress and promote autophagy, and suggest that PERK is a possible target for inhibiting excessive autophagy in cerebral ischemia/reperfusion injury.

Introgression of an adult-plant powdery mildew resistance gene Pm4VL from Dasypyrum villosum chromosome 4V into bread wheat.

Powdery mildew caused by Blumeria graminis f. sp. tritici (Bgt) seriously threatens wheat production worldwide. It is imperative to identify novel resistance genes from wheat and its wild relatives to control this disease by host resistance. Dasypyrum villosum (2n = 2x = 14, VV) is a relative of wheat and harbors novel genes for resistance against multi-fungal diseases. In the present study, we developed a complete set of new wheat-D. villosum disomic introgression lines through genomic in situ hybridization (GISH), fluorescence in situ hybridization (FISH) and molecular markers analysis, including four disomic substitution lines (2n=42) containing respectively chromosomes 1V#6, 2V#6, 3V#6, and 6V#6, and four disomic addition lines (2n=44) containing respectively chromosomes 4V#6, 5V#6, 6V#6 and 7V#6. These lines were subsequently evaluated for their responses to a mixture Bgt isolates at both seedling and adult-plant stages. Results showed that introgression lines containing chromosomes 3V#6, 5V#6, and 6V#6 exhibited resistance at both seedling and adult-plant stages, whereas the chromosome 4V#6 disomic addition line NAU4V#6-1 exhibited a high level of adult plant resistance to powdery mildew. Moreover, two translocation lines were further developed from the progenies of NAU4V#6-1 and the Ph1b mutation line NAU0686-ph1b. They were T4DL·4V#6S whole-arm translocation line NAU4V#6-2 and T7DL·7DS-4V#6L small-fragment translocation line NAU4V#6-3. Powdery mildew tests of the two lines confirmed the presence of an adult-plant powdery mildew resistance gene, Pm4VL, located on the terminal segment of chromosome arm 4V#6L (FL 0.6-1.00). In comparison with the recurrent parent NAU0686 plants, the T7DL·7DS-4V#6L translocation line NAU4V#6-3 showed no obvious negative effect on yield-related traits, providing a new germplasm in breeding for resistance.

Exploring the Lagged Correlation Between Baidu Index and Influenza-Like Illness - China, 2014-2019.

Introduction: This study investigated the lagged correlation between Baidu Index for influenza-related keywords and influenza-like illness percentage (ILI%) across regions in China. The aim is to establish a scientific foundation for utilizing Baidu Index as an early warning tool for influenza-like illness epidemics. Methods: In this study, data on ILI% and Baidu Index were collected from 30 provincial-level administrative divisions (PLADs) spanning April 2014 to March 2019. The Baidu Index was categorized into Overall Index, Ordinary Index, Prevention Index, Symptom Index, and Treatment Index based on search query themes. The lagged correlation between the Baidu Index and ILI% was examined through the cross-correlation function (CCF) method. Results: Correlating the Baidu Overall Index of 30 PLADs with ILI% revealed CCF values ranging from 0.46 to 0.86, with a median lag of 0.5 days. Subcategory analysis indicated that the Prevention Index and Symptom Index exhibited quicker responses to ILI%, with median lags of -9 and -0.5 days, respectively, compared to 0 and 3 days for the Ordinary and Treatment Indexes. The median lag days between the Baidu Index and the ILI% were earlier in the northern PLADs compared to the southern PLADs. Discussion: The Prevention and Symptom Indexes show promising predictive capabilities for influenza-like illness epidemics.

Comparison Between Threshold Method and Artificial Intelligence Approaches for Early Warning of Respiratory Infectious Diseases - Weifang City, Shandong Province, China, 2020-2023.

Introduction: Respiratory infectious diseases, such as influenza and coronavirus disease 2019 (COVID-19), present significant global public health challenges. The emergence of artificial intelligence (AI) and big data offers opportunities to improve traditional disease surveillance and early warning systems. Methods: The study analyzed data from January 2020 to May 2023, comprising influenza-like illness (ILI) statistics, Baidu index, and clinical data from Weifang. Three methodologies were evaluated: the adaptive dynamic threshold method (ADTM) for dynamic threshold adjustments, the machine learning supervised method (MLSM), and the machine learning unsupervised method (MLUM) utilizing anomaly detection. The comparison focused on sensitivity, specificity, timeliness, and warning consistency. Results: ADTM issued 37 warnings with a sensitivity of 71% and a specificity of 85%. MLSM generated 35 warnings, with a sensitivity of 82% and a specificity of 87%. MLUM produced 63 warnings with a sensitivity of 100% and specificity of 80%. The initial warnings from ADTM and MLUM preceded those from MLSM by five days. The Kappa coefficient indicated moderate agreement between the methods, with values ranging from 0.52 to 0.62 (P<0.05). Discussion: The study explores the comparison between traditional methods and two machine learning approaches for early warning systems. It emphasizes the validation of machine learning's reliability and underscores the unique advantages of each method. Furthermore, it stresses the significance of integrating machine learning models with various data sources to enhance public health preparedness and response, alongside acknowledging limitations and the need for broader validation.

Body mass index growth trajectories and body composition influencing factors: An ambidirectional preschooler cohort.

OBJECTIVES: The purpose of the present study was to explore the latent growth trajectory of body mass index (BMI) from birth to 24 months and comprehensively analyze body composition development influencing factor in preschool children. METHODS: This ambidirectional cohort study was conducted in Tianjin, China, from 2017 to 2020, and children's regular medical check-up data from birth to 24 months were retrospectively collected. The growth models were used to fit BMI z-score trajectories for children aged 0-24 months. Crossover analysis and interaction model were used to explore the interaction of influencing factors. RESULTS: We analyzed the growth trajectories of 3217 children, of these, 1493 children with complete follow-up data were included in the influencing factors analysis. Trajectories and parental prepregnancy BMI (ppBMI) were independent factors influencing children's body composition. When paternal ppBMI ≥24 kg/m2, regardless of maternal ppBMI, the risk of overweight and obesity in senior-class children was increased. The high trajectories played a partial mediating role in the association between paternal ppBMI and body composition in preschool children. CONCLUSIONS: BMI growth in children aged 0-24 months can be divided into three latent trajectories: low, middle, and high. These trajectories and parental ppBMI were independent and interactive factors influencing children's body composition. The high trajectories played a partial mediating role in the association between paternal ppBMI and body composition in preschool children. It is necessary to pay attention to the BMI growth level of children aged 0-24 months, which plays an important role in the development of body fat in the future.

2D nanomaterials-based delivery systems and their potentials in anticancer synergistic photo-immunotherapy.

As the field of cancer therapeutics evolves, integrating two-dimensional (2D) nanomaterials with photo-immunotherapy has emerged as a promising approach with significant potential to augment cancer treatment efficacy. These 2D nanomaterials include graphene-based 2D nanomaterials, 2D MXenes, 2D layered double hydroxides, black phosphorus nanosheets, 2D metal-organic frameworks, and 2D transition metal dichalcogenides. They exhibit high load capacities, multiple functionalization pathways, optimal biocompatibility, and physiological stability. Predominantly, they function as anti-tumor delivery systems, amalgamating diverse therapeutic modalities, most notably phototherapy and immunotherapy, and the former is a recognized non-invasive treatment modality, and the latter represents the most promising anti-cancer strategy presently accessible. Thus, integrating phototherapy and immunotherapy founded on 2D nanomaterials unveils a novel paradigm in the war against cancer. This review delineates the latest developments in 2D nanomaterials as delivery systems for synergistic photo-immunotherapy in cancer treatment. We elaborate on the burgeoning realm of photo-immunotherapy, exploring the interplay between phototherapy and enhanced immune cells, immune response modulation, or immunosuppressive tumor microenvironments. Notably, the strategies to augment photo-immunotherapy have also been discussed. Finally, we discuss the challenges and future perspectives of these 2D nanomaterials in photo-immunotherapy.

G protein-coupled receptors and traditional Chinese medicine: new thinks for the development of traditional Chinese medicine.

G protein-coupled receptors (GPCRs) widely exist in vivo and participate in many physiological processes, thus emerging as important targets for drug development. Approximately 30% of the Food and Drug Administration (FDA)-approved drugs target GPCRs. To date, the 'one disease, one target, one molecule' strategy no longer meets the demands of drug development. Meanwhile, small-molecule drugs account for 60% of FDA-approved drugs. Traditional Chinese medicine (TCM) has garnered widespread attention for its unique theoretical system and treatment methods. TCM involves multiple components, targets and pathways. Centered on GPCRs and TCM, this paper discusses the similarities and differences between TCM and GPCRs from the perspectives of syndrome of TCM, the consistency of TCM's multi-component and multi-target approaches and the potential of GPCRs and TCM in the development of novel drugs. A novel strategy, 'simultaneous screening of drugs and targets', was proposed and applied to the study of GPCRs. We combine GPCRs with TCM to facilitate the modernisation of TCM, provide valuable insights into the rational application of TCM and facilitate the research and development of novel drugs. This study offers theoretical support for the modernisation of TCM and introduces novel ideas for development of safe and effective drugs.

Discovery of 4-(isopentyloxy)-3-nitrobenzamide derivatives as xanthine oxidase inhibitors through a non-anthraquinone exploration.

In our previous study, we reported a series of N-(9,10-anthraquinone-2-carbonyl) amino acid derivatives as novel inhibitors of xanthine oxidase (XO). Recognizing the suboptimal drug-like properties associated with the anthraquinone moiety, we embarked on a nonanthraquinone medicinal chemistry exploration in the current investigation. Through systematic structure-activity relationship (SAR) studies, we identified a series of 4-(isopentyloxy)-3-nitrobenzamide derivatives exhibiting excellent in vitro potency against XO. The optimized compound, 4-isopentyloxy-N-(1H-pyrazol-3-yl)-3-nitrobenzamide (6k), demonstrated exceptional in vitro potency with an IC50 value of 0.13 µM. Compound 6k showed favorable drug-like characteristics with ligand efficiency (LE) and lipophilic ligand efficiency (LLE) values of 0.41 and 3.73, respectively. In comparison to the initial compound 1d, 6k exhibited a substantial 24-fold improvement in IC50, along with a 1.6-fold enhancement in LE and a 3.7-fold increase in LLE. Molecular modeling studies provided insights into the strong interactions of 6k with critical amino acid residues within the active site. Furthermore, in vivo hypouricemic investigations convincingly demonstrated that 6k significantly reduced serum uric acid levels in rats. The MTT results revealed that compound 6k is nontoxic to healthy cells. The gastric and intestinal stability assay demonstrated that compound 6k exhibits good stability in the gastric and intestinal environments. In conclusion, compound 6k emerges as a promising lead compound, showcasing both exceptional in vitro potency and favorable drug-like characteristics, thereby warranting further exploration.

Neuregulin4-ErbB4 signalling pathway is driven by electroacupuncture stimulation to remodel brown adipose tissue innervation.

AIM: To show that electroacupuncture stimulation (ES) remodels sympathetic innervation in brown adipose tissue (BAT) via the bone morphogenic protein 8B (BMP8B)-neuregulin 4 (NRG4)-ErbB4 axis, with somatotopic dependence. MATERIALS AND METHODS: We established a high-fat diet (HFD) model with C57BL/6J mice to measure the thermogenesis and metabolism of BAT. In addition, the sympathetic nerve activity (SNA) was measured with the electrophysiological technique, and the immunostaining of c-Fos was used to detect the central nervous system sources of sympathetic outflows. Finally, the key role of the BMP8B-NRG4-ErbB4 axis was verified by peripheral specific antagonism of ErbB4. RESULTS: ES at the forelimb and abdomen regions significantly up-regulate SNA, whereas ES at the hindlimb region has a limited regulatory effect on SNA but still partially restores HFD-induced BAT dysfunction. Mechanistically, ES at the forelimb and abdomen regions driving catecholaminergic signals in brown adipocytes depends on neural activities projected from the ventromedial nucleus of the hypothalamus (VMH) to the spinal cord intermediolateral column (IML). Notably, the peripheral suppression of ErbB4 in BAT inhibits the thermogenesis and metabolic function of BAT, as well as significantly hindering the SNA activation and metabolic benefits induced by ES. CONCLUSION: These results suggest that ES appears to be an effective approach for remodeling sympathetic innervation in BAT, which is closely related to neuronal activity in the VMH and the NRG4-ErbB4 signaling pathway.

Anisodamine Hydrobromide ameliorates acute lung injury via inhibiting pyroptosis in murine sepsis model.

OBJECTIVE: Sepsis can have severe implications on lung function, leading to acute lung injury (ALI), a major contributor to sepsis-related mortality. Anisodamine hydrobromide (Ani HBr), a bioactive constituent derived from the root of Scopolia tangutica Maxim, a plant endemic to China, has demonstrated efficacy in treating septic shock. We aim to explore whether Ani HBr can alleviate sepsis-triggered acute lung injury (ALI) and elucidate the fundamental mechanisms involved. MATERIALS AND METHOD: The protective effects of Ani HBr were assessed in two models: in vitro, lipopolysaccharide (LPS)-stimulated RAW264.7 cells, and in vivo, cecal ligation puncture (CLP)-induced sepsis. To measure the cell viability of RAW264.7 cells after Ani HBr treatment, we used the CCK-8 assay. We quantified the levels of pro-inflammatory cytokines expression using ELISA. We also measured the expression of pyrotosis indicators by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), Western blotting, and immunofluorescence. RESULTS: Our study demonstrates that Ani HBr can alleviate pulmonary edema, bleeding, and excessive inflammation induced by CLP. Additionally, it exhibits protective effects against cytotoxicity induced by LPS in RAW264.7 macrophage cells. Furthermore, Ani HBr downregulates the mRNA and protein levels of NLRP3, Caspase-1, GSDMD, IL-18, and IL-1ß in both animal models and cell cultures, thereby inhibiting pyroptosis in a similar mechanism to AC-YVAD-CMK (AYC)'s blockade of Caspase-1. Moreover, Ani HBr suppresses the production and release of proinflammatory cytokines. CONCLUSION: These findings suggest that Ani HBr could serve as a protective agent against sepsis-induced ALI by suppressing pyroptosis.

Rehabilitation for spinal muscular atrophy patients in China: a national cross-sectional study.

BACKGROUND: The management of Spinal Muscular Atrophy (SMA) requires a multidisciplinary treatment approach, wherein rehabilitation constitutes an integral element. In this study, we examined the effects of rehabilitation among Chinese SMA patients and assessed the real-world efficacy of rehabilitation interventions. METHODS: We conducted a cross-sectional online survey on SMA patients from June 9, 2023, to June 30, 2023, through the Meier Advocacy & Support Center using data from the Center's database and electronic questionnaires. The rehabilitation situation of the participants over the past 14 months were investigated. Logistic binary regression was used to analyze the relationship between Pediatric Quality of Life Inventory(PedsQL™) scores and rehabilitation. RESULT: A total of 186 questionnaires were finally analyzed. Only 29 patients did not rehabilitated in the past 14 months. A significant correlation between age and type of rehabilitation, as well as between age and duration of rehabilitation. Patients receiving no rehabilitation or solely home-based rehabilitation exhibited a higher median age of 8.4 compared to those undergoing standard rehabilitation or a combination of standard and home-based rehabilitation, with a median age of 4.9 (z-score = -4.49, p-value < 0.001). In addition, long-term rehabilitation (OR = 0.314, 95%CI = 0.106-0.927, p = 0.04) were negatively correlated with lower PedsQL™ Neuromuscular Module scores, and PedsQL scores in the long-term rehabilitation group were higher than those in the short-term and no-rehabilitation groups (54.2 ± 15.1 vs. 45.9 ± 14.4 and 42.3 ± 14.3, p = 0.01), with the most significant difference observed in the physical function section (59.0 ± 15.8 vs. 46.8 ± 15.2 and 45.6 ± 15.9, p < 0.01). Mobility and exercise (OR = 0.26, 95%CI = 0.08-0.81, p = 0.02), as well as assistive technology (OR = 0.28, 95%CI = 0.10-0.82, p = 0.02), were independently associated with a lower score in a negative direction. CONCLUSION: The study found that long-term rehabilitation was linked to higher PedsQL scores in SMA patients, highlighting the need for standardized rehabilitation programs to enhance function and quality of life.

Vagus Nerve Suppression in Ischemic Stroke by Carotid Artery Occlusion: Implications for Metabolic Regulation, Cognitive Function, and Gut Microbiome in a Gerbil Model.

The vagus nerve regulates metabolic homeostasis and mediates gut-brain communication. We hypothesized that vagus nerve dysfunction, induced by truncated vagotomy (VGX) or carotid artery occlusion (AO), would disrupt gut-brain communication and exacerbate metabolic dysregulation, neuroinflammation, and cognitive impairment. This study aimed to test the hypothesis in gerbils fed a high-fat diet. The gerbils were divided into four groups: AO with VGX (AO_VGX), AO without VGX (AO_NVGX), no AO with VGX (NAO_VGX), and no AO without VGX (NAO_NVGX). After 5 weeks on a high-fat diet, the neuronal cell death, neurological severity, hippocampal lipids and inflammation, energy/glucose metabolism, intestinal morphology, and fecal microbiome composition were assessed. AO and VGX increased the neuronal cell death and neurological severity scores associated with increased hippocampal lipid profiles and lipid peroxidation, as well as changes in the inflammatory cytokine expression and brain-derived neurotrophic factor (BDNF) levels. AO and VGX also increased the body weight, visceral fat mass, and insulin resistance and decreased the skeletal muscle mass. The intestinal morphology and microbiome composition were altered, with an increase in the abundance of Bifidobacterium and a decrease in Akkermansia and Ruminococcus. Microbial metagenome functions were also impacted, including glutamatergic synaptic activity, glycogen synthesis, and amino acid biosynthesis. Interestingly, the effects of VGX were not significantly additive with AO, suggesting that AO inhibited the vagus nerve activity, partly offsetting the effects of VGX. In conclusion, AO and VGX exacerbated the dysregulation of energy, glucose, and lipid metabolism, neuroinflammation, and memory deficits, potentially through the modulation of the gut-brain axis. Targeting the gut-brain axis by inhibiting vagus nerve suppression represents a potential therapeutic strategy for ischemic stroke.

AUF1-mediated inhibition of autophagic lysosomal degradation contributes to CagA stability and Helicobacter pylori-induced inflammation.

CagA, a virulence factor of Helicobacter pylori (H. pylori), is known to drive inflammation in gastric epithelial cells and is typically degraded through autophagy. However, the molecular mechanism by which CagA evades autophagy-mediated degradation remains elusive. This study found that H. pylori inhibits autophagic flux by upregulating the expression of AU-rich element RNA-binding factor 1 (AUF1). We confirmed that AUF1 does not affect autophagy initiation but instead hampers lysosomal clearance, as evidenced by treatments with 3-MA, CQ and BafA1. Upregulated AUF1 stabilizes CagA protein levels by inhibiting the autolysosomal degradation of intracellular CagA in H. pylori-infected gastric epithelial cells. Knocking down AUF1 promotes CagA degradation, an effect that can be reversed by the lysosome inhibitor BafA1 and CQ. Transcriptome analysis of AUF1-knockdown gastric epithelial cells infected with H. pylori indicated that AUF1 regulates the expression of lysosomal-associated hydrolase genes, specifically CTSD, to inhibit autolysosomal degradation. Moreover, we observed that knockdown of AUF1 enhanced the stability of CTSD mRNA and identified AUF1 binding to the 3'UTR region of CTSD mRNA. AUF1-mediated downregulation of CTSD expression contributes to CagA stability, and AUF1 overexpression leads to an increase in CagA levels in exosomes, thus promoting extracellular inflammation. In clinical gastric mucosa, the expression of AUF1 and its cytoplasmic translocation are associated with H. pylori-associated gastritis, with CagA being necessary for the translocation of AUF1 into the cytoplasm. Our findings suggest that AUF1 is a novel host-positive regulator of CagA, and dysregulation of AUF1 expression increases the risk of H. pylori-associated gastritis.

Pre-existing sleep disturbances and risk of COVID-19: a meta-analysis.

Background: Sleep disturbances are widespread but usually overlooked health risk factors for coronavirus disease 2019 (COVID-19). We aimed to investigate the influence of pre-existing sleep disturbances on the susceptibility, severity, and long-term effects of COVID-19. Methods: We searched PubMed, Web of Science, and Embase for relevant articles from inception to October 27, 2023 and updated at May 8, 2024. Sleep disturbances included obstructive sleep apnea (OSA), insomnia, abnormal sleep duration, night-shift work, and any other sleep disturbances. Outcomes were COVID-19 susceptibility, hospitalization, mortality, and long COVID. The effect sizes were pooled odds ratios (ORs) and 95% confidence intervals (95% CIs). This study is registered with PROSPERO (CRD42024503518). Findings: A total of 48 observational studies (n = 8,664,026) were included. Pre-existing sleep disturbances increased the risk of COVID-19 susceptibility (OR = 1.12, 95% CI 1.07-1.18), hospitalization (OR = 1.25, 95% CI 1.15-1.36), mortality (OR = 1.45, 95% CI 1.19-1.78), and long COVID (OR = 1.36 95% CI 1.17-1.57). Subgroup analysis showed that younger individuals with sleep disturbances were associated with higher susceptibility and hospitalization and a lower risk of mortality than older individuals. Males with sleep disturbances were associated with higher mortality. For specific sleep disturbances, the susceptibility and hospitalization of COVID-19 were associated with OSA, abnormal sleep duration, and night-shift work; mortality of COVID-19 was linked to OSA; risk of long COVID was related to OSA, abnormal sleep duration and insomnia. Interpretation: Pre-existing sleep disturbances, especially OSA, increased the risk of COVID-19 susceptibility, hospitalization, mortality, and long COVID. Age and sex played important roles in the effect of sleep disturbances on COVID-19. Funding: The National Natural Science Foundation of China and the Key Laboratory of Respiratory Diseases of Liaoning Province.

Comparison of selective laser melting and stereolithography etching templates for guided endodontics.

Background: With the increasing application of guided endodontics to treat complex root canal treatment, the entire process of root canal treatment has become more precise, reducing damage to tooth structure and improving success rates. However, due to the limitations of the operating space, the use of guided endodontic templates in posterior root canal treatment is less common. This study aims to compare the accuracy and reliability of selective laser melting (SLM) and traditional stereolithography etching (SLA) guided endodontic templates for posterior root canals, providing better treatment strategies for posterior root canal treatment. Methods: The teeth were randomly assigned to either SLM or SLA group. Preoperative cone-beam computed tomography (CBCT) and a three-dimensional (3D) scanner were used to establish the 3D root canal system and the accurate occlusal models of the teeth. The virtual access to the canal access was designed using Mimics 19.0 and 3-Matic 11.0. The endodontic access was performed based on either SLM or SLA templates. The accuracy of endodontic preparation was measured in three-dimensions by calculating deviations from planned accesses. The template height and tooth substance loss rates in each group were measured. Results: SLM-guided templates have a low average deviation at the entry point and apical portion of the bur of total posterior teeth (including premolars and molars) and individual molars (P < 0.05). Moreover, there was a significant difference in angular deviations and height of template in total posterior teeth and individual molars (P < 0.05). The mean substance loss rate of the SLA group was slightly greater than that of the SLM group, but the difference was not statistically (P > 0.05). Conclusions: SLM-guided endodontics provides a more predictable and precise location of root canal orifice for the treatment of posterior teeth.

Core microbiome-associated proteins associated with ulcerative colitis interact with cytokines for synergistic or antagonistic effects on gut bacteria.

Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is associated with a loss or an imbalance of host-microorganism interactions. However, such interactions at protein levels remain largely unknown. Here, we applied a depletion-assisted metaproteomics approach to obtain in-depth host-microbiome association networks of IBD, where the core host proteins shifted from those maintaining mucosal homeostasis in controls to those involved in inflammation, proteolysis, and intestinal barrier in IBD. Microbial nodes such as short-chain fatty acid producer-related host-microbial crosstalk were lost or suppressed by inflammatory proteins in IBD. Guided by protein-protein association networks, we employed proteomics and lipidomics to investigate the effects of UC-related core proteins S100A8, S100A9, and cytokines (IL-1ß, IL-6, and TNF-α) on gut bacteria. These proteins suppressed purine nucleotide biosynthesis in stool-derived in vitro communities, which was all reduced in IBD stool samples. Single species study revealed that S100A8, S100A9, and cytokines can synergistically or antagonistically alter gut bacteria intracellular and secreted proteome, with combined S100A8 and S100A9 potently inhibiting beneficial Bifidobacterium adolescentis. Furthermore, these inflammatory proteins only altered the extracellular but not intracellular proteins of Ruminococcus gnavus. Generally, S100A8 induced more significant bacterial proteome changes than S100A9, IL-1ß, IL-6, and TNF-α. But gut bacteria degrade significantly more S100A8 than S100A9 in the presence of both proteins. Among the investigated species, distinct lipid alterations were only observed in Bacteroides vulgatus treated with combined S100A8, S100A9, and cytokines. These results provided a valuable resource of inflammatory protein centric host-microbial molecular interactions.

lncRNA signature mediates mitochondrial permeability transition-driven necrosis in regulating the tumor immune microenvironment of cervical cancer.

Mitochondrial permeability transition (MPT)-driven necrosis (MPTDN) was a regulated variant of cell death triggered by specific stimuli. It played a crucial role in the development of organisms and the pathogenesis of diseases, and may provide new strategies for treating various diseases. However, there was limited research on the mechanisms of MPTDN in cervical cancer (CESC) at present. In this study, Weighted Gene Co-expression Network Analysis (WGCNA) was performed on differentially expressed genes in CESC. The module MEyellow, which showed the highest correlation with the phenotype, was selected for in-depth analysis. It was found that the genes in the MEyellow module may be associated with the tumor immune microenvironment (TIME). Through COX univariate regression and LASSO regression analysis, 6 key genes were identified. These genes were further investigated from multiple perspectives, including their independent diagnostic value, prognostic value, specific regulatory mechanisms in the tumor immune microenvironment, drug sensitivity analysis, and somatic mutation analysis. This study provided a comprehensive exploration of the mechanisms of action of these 6 key genes in CESC patients. And qRT-PCR validation was also conducted. Through COX univariate regression and LASSO coefficient screening of the MEyellow module, 6 key genes were identified: CHRM3-AS2, AC096734.1, BISPR, LINC02446, LINC00944, and DGUOK-AS1. Evaluation of the independent diagnostic value of these 6 key genes revealed that they can serve as independent diagnostic biomarkers. Through correlation analysis among these 6 genes, a potential regulatory mechanism among them was identified. Therefore, a risk prognostic model was established based on the collective action of these 6 genes, and the model showed good performance in predicting the survival period of CESC patients. By studying the relationship between these 6 key genes and the tumor microenvironment of CESC patients from multiple angles, it was found that these 6 genes are key regulatory factors in the tumor immune microenvironment of CESC patients. Additionally, 16 drugs that are associated with these 6 key genes were identified, and 8 small molecule drugs were predicted based on the lncRNA-mRNA network. The 6 key genes can serve as independent biomarkers for diagnosis, and the Risk score of these genes when acting together can be used as an indicator for predicting the clinical survival period of CESC patients. Additionally, these 6 key genes were closely related to the tumor immune microenvironment of CESC patients and were the important regulatory factors in the tumor immune microenvironment of CESC patients.

Natural course and predictors of consciousness recovery in children with prolonged disorder of consciousness.

Prolonged disorder of consciousness (DoC) is a rising challenge. Pediatric data on diagnosis and prognosis of prolonged DoC were too limited and heterogeneous, making it difficult to define the natural course and evaluate the prognosis. The present study explored the emergence from the Minimally Conscious State (eMCS) incidence at different months postinjury drawing the natural course, and detected the predictors of the incidence in children with prolonged DoC. A hospital-based prospective cohort study was conducted. Kaplan-Meier curves, as well as univariate and multivariate COX regression analysis, were performed. The study enrolled 383 pediatric DoC individuals, including 220 males (57.4%), with an average age of 3.9 (1.9-7.3) years. The median duration between onset and rehabilitation is 30.0 (21.0-46.0) days. At enrollment, the ratio of vegetative state/unresponsive wakefulness syndrome (VS/WUS) to MCS is 78.9%-21.1%. Traumatic brain injury and infection are the major etiologies (36.8% and 37.1%, respectively), followed by hypoxia cerebral injury (12.3%). For children with prolonged DoC, the cumulative incidence of eMCS at months 3, 6, 12, and 24 was 0.510, 0.652, 0.731, 0.784 VS 0.290, 0.418, 0.539, 0.603 in the traumatic VS non-traumatic subgroup, respectively. For children in a persistent vegetative state (PVS), the cumulative incidence of emergence at months in 3, 6, 12, 24, 36 and 48 was testified as 0.439, 0.591, 0.683, 0.724, 0.743 and 0.743 in the traumatic subgroup, and 0.204, 0.349, 0.469, 0.534, 0.589 and 0.620 in the non-traumatic subgroup. Participants who exhibit any of the following four demographical and/or clinical characteristics-namely, older than 4 years at onset, accepted rehabilitation within 28 days of onset, remained MCS at enrollment, or with etiology of traumatic brain injuries-had a significantly positive outcome of consciousness recovery (eMCS). Moreover, both prolongation of the central somatosensory conductive time (CCT) (level 2) and absence of N20 (level 3) independently predict a negative outcome. In children with prolonged DoC, we found that 12 months postinjury was critical to eMCS, and a preferred timepoint to define chronic vegetative state (VS). The characteristics including age, etiology, time before rehabilitation, consciousness state, and SEP results were useful predictors of conscious recovery.Trial registration Registered 06/11/2018, the registration number is chiCTR1800019330 (chictr.org.cn). Registered prospectively.

Genome-Wide Identification of the PIP5K Gene Family in Camellia sinensis and Their Roles in Metabolic Regulation.

Spider mite infestation has a severe impact on tea growth and quality. In this study, we conducted a deep exploration of the functions and regulations of the CsPIP5K gene family using chromosomal localization and collinearity analysis. Additionally, we carefully examined the cis elements within these genes. To fully understand the metabolic response of CsPIP5K under spider mite infection, we integrated previously published metabolomic and transcriptomic data. Our analysis revealed that multiple CsPIP5K genes are associated with phospholipid metabolism, with CsPIP5K06 showing the strongest correlation. Therefore, we employed qPCR and subcellular localization techniques to determine the expression pattern of this gene and its functional location within the cell. Overall, this study not only comprehensively elucidated the characteristics, structure, and evolution of the CsPIP5K gene family but also identified several candidate CsPIP5K genes related to phospholipid biosynthesis and associated with spider mites based on previously published data. This research makes a significant contribution to enhancing the resistance of tea to spider mite and maintaining optimal tea quality.

Effects of Ultrasound-Assisted Soy Lecithin Addition on Rehydration Behavior and Physical Properties of Egg White Protein Powder.

This study investigated the effects of ultrasound-assisted soybean lecithin (SL) on the rehydration behavior and physical properties of egg white protein powder (EWPP) and its ability to enhance the efficacy of EWPP instant solubility. The results of rehydration, including wettability and dispersibility, indicated that ultrasound (200 W)-assisted SL (5 g/L) addition had the shortest wetting time and dispersion time, which were 307.14 ± 7.00 s and 20.95 ± 2.27 s, respectively. In terms of powder properties, the EWPP with added SL had lower lightness, moisture content and bulk density. In addition, the increase in average particle size, net negative charge, free sulfhydryl group content and surface hydrophobicity indicated that ultrasound treatment facilitated the protein structures unfolding and promoted the formation of SL-EWP complexes. Overall, our study provided a new perspective for the food industry regarding using ultrasound technology to produce instant EWPP with higher biological activity and more complete nutritional value.