CD40 is an immune checkpoint regulator that potentiates myocardial inflammation through activation and expansion of CCR2 + macrophages and CD8 T-cells.

Novel immune checkpoint therapeutics including CD40 agonists have tremendous promise to elicit antitumor responses in patients resistant to current therapies. Conventional immune checkpoint inhibitors (PD-1/PD-L1, CTLA-4 antagonists) are associated with serious adverse cardiac events including life-threatening myocarditis. However, little is known regarding the potential for CD40 agonists to trigger myocardial inflammation or myocarditis. Here, we leveraged genetic mouse models, single cell sequencing, and cell depletion studies to demonstrate that an anti-CD40 agonist antibody reshapes the cardiac immune landscape through activation of CCR2 + macrophages and subsequent recruitment of effector memory CD8 T-cells. We identify a positive feedback loop between CCR2 + macrophages and CD8 T-cells driven by IL12b, TNF, and IFN-γ signaling that promotes myocardial inflammation and show that prior exposure to CD40 agonists sensitizes the heart to secondary insults and accelerates LV remodeling. Collectively, these findings highlight the potential for CD40 agonists to promote myocardial inflammation and potentiate heart failure pathogenesis.

Effects of immunosuppression-associated gga-miR-146a-5p on immune regulation in chicken macrophages by targeting the IRKA2 gene.

Stress-induced immunosuppression (SIIS) is one of the common problems in intensive poultry production, which brings enormous economic losses to the poultry industry. Accumulating evidence has shown that microRNAs (miRNAs) were important regulators of gene expression in the immune system. However, the miRNA-mediated molecular mechanisms underlying SIIS in chickens are still poorly understood. This study aimed to investigate the biological functions and regulatory mechanism of miRNAs in chicken SIIS. A stress-induced immunosuppression model was successfully established via daily injection of dexamethasone and analyzed miRNA expression in spleen. Seventy-four differentially expressed miRNAs (DEMs) was identified, and 229 target genes of the DEMs were predicted. Functional enrichment analysis the target genes revealed pathways related to immunity, such as MAPK signaling pathway and FoxO signaling pathway. The candidate miRNA, gga-miR-146a-5p, was found to be significantly downregulated in the Dex-induced chicken spleen, and we found that Dex stimulation significantly inhibited the expression of gga-miR-146a-5p in Chicken macrophages (HD11). Flow cytometry, 5-ethynyl-2'-deoxyuridine (EdU), cell counting kit-8 (CCK-8) and other assays indicated that gga-miR-146a-5p can promote the proliferation and inhibit apoptosis of HD11 cells. A dual-luciferase reporter assay suggested that the Interleukin 1 receptor associated kinase 2 (IRAK2) gene, which encoded a transcriptional factor, was a direct target of gga-miR-146a-5p, gga-miR-146a-5p suppressed the post-transcriptional activity of IRAK2. These findings not only improve our understanding of the specific functions of miRNAs in avian stress but also provide potential targets for genetic improvement of stress resistance in poultry.

Bidirectional associations between sleep quality/duration and multimorbidity in middle-aged and older people Chinese adults: a longitudinal study.

BACKGROUND: Multimorbidity and sleep disorder possess high incidence rates in the middle-aged and older people populations, posing a significant threat to quality of life and physical and mental health. However, investigators have previously only analysed the unidirectional association between sleep status and multimorbidity. We aimed to investigate bidirectional associations between sleep quality or duration and multimorbidity in middle-aged and older Chinese adults from a longitudinal perspective. METHOD: We enrolled a total of 9823 participants 45 years and older from the China Health and Retirement Longitudinal Study from 2015 to 2018 in our study. Multimorbidity was defined as two or more coexisting chronic diseases in the same individual based on 14 self-reported disease questions. Sleep quality was classified as "good" (restless < 1 day per week) and "poor" (restless ≥ 1 days per week); and sleep duration was divided into short (< 6 h), medium (6-9 h), and long (> 9 h). The bidirectional association between multimorbidity and sleep condition was examined using multivariate logistic regression models with adjustments for covariates. RESULTS: Individuals with poor sleep quality showed a significantly higher prevalence of multimorbidity in the future. The adjusted OR (95% CI) values of individuals with poor sleep quality with respect to developing two diseases, three diseases, and ≥ 4 diseases were 1.39 (1.19, 1.63), 1.56 (1.23, 2.03), and 2.36 (1.68, 3.33), respectively. In addition, individuals with multimorbidity exhibited a significantly higher risk of poor sleep quality in the future. Short sleep duration led to multimorbidity in the future (OR = 1.49; 95 CI%, 1.37-1.63), while multimorbidity contributed to short sleep duration (< 6 h) in the future (OR = 1.39; 95% CI, 1.27-1.51) after full adjustment. CONCLUSIONS: There was a bidirectional association between sleep quality or short sleep duration and multimorbidity in middle-aged and older Chinese adults. We recommend that greater attention be given to clinical management among adults with sleep disorders or physical multimorbidities.

The zinc finger protein CG12744 regulates intestinal stem cells in aged Drosophila through the EGFR and BMP pathways.

AIM: Aging is a process characterized by a time-dependent decline in the functionality of adult stem cells and is closely associated with age-related diseases. However, understanding how aging promotes disease and its underlying causes is critical for combating aging. MAIN METHODS: The offspring of UAS-Gal4 and CG12744RNAiDrosophila were cultured for 33 days to evaluate the role of CG12744 in the aging intestine. Immunofluorescence was performed to detect specific cell type markers for assessing proliferation and differentiation. qRT-PCR was used to observe the changes in signaling regulating intestinal homeostasis in the aging intestine after CG12744 knockdown. 16S rRNA-seq analysis was also conducted to elucidate the role of gut microbes in CG12744-mediated intestinal dysfunction. KEY FINDINGS: The mRNA levels of CG12744 were significantly increased in the aged midguts. Knockdown of CG12744 in progenitor cells further exacerbates the age-related intestinal hyperplasia and dysfunction. In particular, upon depletion of CG12744 in progenitors, enteroblasts (EBs) exhibited an increased propensity to differentiate along the enteroendocrine cell (EE) lineage. In contrast, the overexpression of CG12744 in progenitor cells restrained age-related gut hyperplasia in Drosophila. Moreover, CG12744 prevented age-related intestinal stem cell (ISC) overproliferation and differentiation by modulating the EGFR, JNK, and BMP pathways. In addition, the inhibition of CG12744 resulted in a significant increase in the gut microbial composition in aging flies. SIGNIFICANCE: This study established a role for the CG12744 in regulating the proliferation and differentiation of adult stem cells, thereby identifying a potential therapeutic target for diseases caused by age-related dysfunction stem cell dysfunction.

The role of epithelial cells in the immunopathogenesis of Sjögren's syndrome.

Sjögren's syndrome is a systemic autoimmune disease characterized by dysfunction of the affected exocrine glands. Lymphocytic infiltration within the inflamed glands and aberrant B-cell hyperactivation are the two salient pathologic features in Sjögren's syndrome. Increasing evidence indicates that salivary gland epithelial cells act as a key regulator in the pathogenesis of Sjögren's syndrome, as revealed by the dysregulated innate immune signaling pathways in salivary gland epithelium and increased expression of various proinflammatory molecules as well as their interaction with immune cells. In addition, salivary gland epithelial cells can regulate adaptive immune responses as nonprofessional antigen-presenting cells and promote the activation and differentiation of infiltrated immune cells. Moreover, the local inflammatory milieu can modulate the survival of salivary gland epithelial cells, leading to enhanced apoptosis and pyroptosis with the release of intracellular autoantigens, which further contributes to SG autoimmune inflammation and tissue destruction in Sjögren's syndrome. Herein, we reviewed recent advances in elucidating the role of salivary gland epithelial cells in the pathogenesis of Sjögren's syndrome, which may provide rationales for potential therapeutic targeting of salivary gland epithelial cells to alleviate salivary gland dysfunction alongside treatments with immunosuppressive reagents in Sjögren's syndrome.

Dual Oxytocin Receptor-G Protein Signaling in the Autoregulation of Activities of Oxytocin Neurons.

Oxytocin (OT), a hypothalamic nonaneuropeptide, can extensively modulate mental and physical activities; however, the regulation of its secretion from hypothalamic OT neurons remains poorly understood. OT neuronal activity is generally modulated by neurochemical environment, synaptic inputs, astrocytic plasticity, and interneuronal interactions. By changing intracellular signals and ion channel activity, these extracellular factors dynamically regulate OT neuronal activity and OT release in a microdomain-specific manner. In this process, OT receptor (OTR) and OTR-coupled G proteins are pivotal, typically observed during lactation. Suckling-elicited somatodendritic release of OT causes sequential activation of Gq and Gs proteins to increase the firing rate gradually and trigger burst firing transiently, and then of Gi/o protein to cause post-burst inhibition as a result of potential bolus somatodendritic release of OT during the burst-like discharges. Under chronic social stress like mother-baby separation and cesarean section, excessive somatodendritic secretion of OT and over-excitation of OT neurons cause post-excitation inhibition of OT neuronal activity and reduction of OT secretion. In this process, dominance of G protein that couples to OTR is switched from Gq to Gi/o type because of inhibition of OTR-Gq signaling following negative feedback of downstream Gq signaling or crosstalk of Gq with Gs and Gi signals. This review summarizes our current understandings of OT/OTR signaling in the autoregulation of OT neuronal activity under physiological and pathological conditions.

Responses of photosynthesis-related genes in Sargassum horneri to high temperature stress.

Golden tide outbreak threatened the marine ecological environment. Sargassum horneri is a single dominant species of the Yellow Sea golden tide, which growth and development are affected by changes in sea water temperature. This study investigated the photosynthetic physiology of copper algae and found that the growth rate, chlorophyll a content, carotenoid content, Fv/Fm, and maximum electron transfer efficiency were significantly reduced, indicating that Sargassum horneri was under stress under high temperature. In this study, high-throughput sequencing was used to analyze the response mechanisms of photosynthesis-related genes in S. horneri under high temperature stress. The results showed that most of the photosynthesis-related genes in S. horneri were downregulated and photosynthesis was inhibited under high temperature stress. However, the expression levels of ferredoxin, ferredoxin-NADP reductase, light-harvesting protein complexes, and oxygen-evolving complex genes were significantly upregulated (P ≤ 0.05) after five days of high temperature treatment. This study found that photosynthesis related genes play a crucial role in regulating the photosynthetic response of S. horneri to high temperature stress.

A survey of fecal virome and bacterial community of the diarrhea-affected cattle in northeast China reveals novel disease-associated ecological risk factors.

Limited information on the virome and bacterial community hampers our ability to discern systemic ecological risk factors that cause cattle diarrhea, which has become a pressing issue in the control of disease. A total of 110 viruses, 1,011 bacterial genera, and 322 complete viral genomes were identified from 70 sequencing samples mixed with 1,120 fecal samples from 58 farms in northeast China. For the diarrheic samples, the identified virome and bacterial community varied in terms of composition, abundance, diversity, and geographic distribution in relation to different disease-associated ecological factors; the abundance of identified viruses and bacteria was significantly correlated with the host factors of clinical status, cattle type, and age, and with environmental factors such as aquaculture model and geographical location (P < 0.05); a significant interaction occurred between viruses and viruses, bacteria and bacteria, as well as between bacteria and viruses (P < 0.05). The abundance of SMB53, Butyrivibrio, Facklamia, Trichococcus, and Turicibacter was significantly correlated with the health status of cattle (P < 0.05). The proportion of BRV, BCoV, BKV, BToV, BoNoV, BoNeV, BoAstV, BEV, BoPV, and BVDV in 1,120 fecal samples varied from 1.61% to 12.05%. A series of significant correlations were observed between the prevalence of individual viruses and the disease-associated ecological factors. A genome-based phylogenetic analysis revealed high variability of 10 bovine enteric viruses. The bovine hungarovirus was initially identified in both dairy and beef cattle in China. This study elucidates the fecal virome and bacterial community signatures of cattle affected by diarrhea, and reveals novel disease-associated ecological risk factors, including cattle type, cattle age, aquaculture model, and geographical location.IMPORTANCEThe lack of data on the virome and bacterial community restricts our capability to recognize ecological risk factors for bovine diarrhea disease, thereby hindering our overall comprehension of the disease's cause. In this study, we found that, for the diarrheal samples, the identified virome and bacterial community varied in terms of composition, abundance, diversity, configuration, and geographic distribution in relation to different disease-associated ecological factors. A series of significant correlations were observed between the prevalence of individual viruses and the disease-associated ecological factors. Our study aims to uncover novel ecological risk factors of bovine diarrheal disease by examining the pathogenic microorganism-host-environment disease ecology, thereby providing a new perspective on the control of bovine diarrheal diseases.

Macrocyclic-Albumin Conjugates for Precise Delivery of Radionuclides and Anticancer Drugs to Tumors.

Precise delivery of radionuclides and anticancer drugs to tumor tissue is crucial to ensuring drug synergism and optimal therapeutic effects in radionuclide-based combination radio-chemotherapy. However, current codelivery vectors often rely on physical embedment/adsorption to load anticancer drugs, which lacks precise mechanisms for drug loading and release, resulting in unpredictable combination effects. Herein, a macrocyclic-albumin conjugate (MAC) that enables precise loading and controlled release of anticancer drugs is presented. By conjugating multiple macrocyclic hosts (sulfonate azocalix[4]arenes, SAC4A) to albumin molecules, the MAC facilitates the precise loading of anticancer drugs through host-guest interactions and site-specific labeling of radionuclides. Furthermore, the MAC degrades under hypoxic conditions, enabling the release of loaded drugs upon reaching tumor tissues. Through precise loading and targeted delivery of radionuclides and anticancer drugs, MAC achieves efficient cancer diagnosis and combined radio-chemotherapy in breast cancer cell (4T1)-bearing mice. Considering that SAC4A can load many anticancer drugs, MAC may provide a promising platform for effective combination radio-chemotherapy.

Intestinal homeostasis in the gut-lung-kidney axis: a prospective therapeutic target in immune-related chronic kidney diseases.

In recent years, the role of intestinal homeostasis in health has received increasing interest, significantly improving our understanding of the complex pathophysiological interactions of the gut with other organs. Microbiota dysbiosis, impaired intestinal barrier, and aberrant intestinal immunity appear to contribute to the pathogenesis of immune-related chronic kidney diseases (CKD). Meanwhile, the relationship between the pathological changes in the respiratory tract (e.g., infection, fibrosis, granuloma) and immune-related CKD cannot be ignored. The present review aimed to elucidate the new underlying mechanism of immune-related CKD. The lungs may affect kidney function through intestinal mediation. Communication is believed to exist between the gut and lung microbiota across long physiological distances. Following the inhalation of various pathogenic factors (e.g., particulate matter 2.5 mum or less in diameter, pathogen) in the air through the mouth and nose, considering the anatomical connection between the nasopharynx and lungs, gut microbiome regulates oxidative stress and inflammatory states in the lungs and kidneys. Meanwhile, the intestine participates in the differentiation of T cells and promotes the migration of various immune cells to specific organs. This better explain the occurrence and progression of CKD caused by upper respiratory tract precursor infection and suggests the relationship between the lungs and kidney complications in some autoimmune diseases (e.g., anti-neutrophil cytoplasm antibodies -associated vasculitis, systemic lupus erythematosus). CKD can also affect the progression of lung diseases (e.g., acute respiratory distress syndrome and chronic obstructive pulmonary disease). We conclude that damage to the gut barrier appears to contribute to the development of immune-related CKD through gut-lung-kidney interplay, leading us to establish the gut-lung-kidney axis hypothesis. Further, we discuss possible therapeutic interventions and targets. For example, using prebiotics, probiotics, and laxatives (e.g., Rhubarb officinale) to regulate the gut ecology to alleviate oxidative stress, as well as improve the local immune system of the intestine and immune communication with the lungs and kidneys.

Interplay between Tradition and Modernity: Stress and Coping Experiences among Parents of Children with Autism in Beijing, China.

In traditional Chinese culture, specific beliefs and values can influence parents' experiences of stress and coping while raising children with autism. However, as China undergoes rapid social changes amid globalization, are these cultural influences still significant for today's parents of young children with autism? This study delves into this question through 12 in-depth interviews with parents of children with autism in Beijing. Content analysis indicated that while influences from traditional culture remain, modern parents often diverge from them. They adopt Western views on autism to mitigate stigma, establish boundaries with grandparents to ensure effective early interventions, address imbalanced professional dynamics, adjust authoritarian parenting styles, and broaden their social networks. A mix of traditional and contemporary parenting characterizes their experiences. The discussion elaborates on the findings, emphasizing the importance of family support.

Characteristics of multi-channel intermuscular directional coupling based on time-varying partial directional coherence analysis.

The human body transmits directional information between muscles during upper limb movements, and this will be particularly evident when the dominant muscle changes during movement transitions. By capturing the electromyography (EMG) signals of wrist flexion and extension continuous transition movements, we investigated the characteristics of multichannel intermuscular directional coupling and directional information transmission, and consequently explored the control mechanism of Central nervous system (CNS) and the coordination mechanism of motor muscles. Multi-channel EMG was collected from 12 healthy subjects under continuous translational movements of wrist flexion and extension, and the time-varying biased directional coherence analysis (TVPDC) model was constructed using partial directional coherence analysis (PDC) frequency domain directionality to study the directional information transfer characteristics in the time-frequency domain, screen closely related muscle pairs and perform directional coupling significance analysis. Palmaris longus (PL) played a dominant role under wrist flexion movements(WF), Extensor Carpi Radialis (ECR) played a dominant role under wrist extension movements(WE), and the remaining muscles responded to them with information and Biceps Brachii (BB) played a responsive role throughout the movement; flexor pairs had the highest positive coupling values in the beta band during Conversion action1 (MC1) and WF phases, and extensor pairs had the highest positive coupling values in the gamma band during Conversion action2(MC2) phase and the highest coupling values in the beta band during WE phase. TVPDC can effectively analyze the multichannel intermuscular directional coupling and information transmission relationship of surface electromyography under wrist flexion and extension transition movements, providing a reference for exploring the control mechanism of CNS and abnormal control mechanism in patients with motor dysfunction in a new perspective.

Modulation of the proteostasis network promotes tumor resistance to oncogenic KRAS inhibitors.

Despite substantial advances in targeting mutant KRAS, tumor resistance to KRAS inhibitors (KRASi) remains a major barrier to progress. Here, we report proteostasis reprogramming as a key convergence point of multiple KRASi-resistance mechanisms. Inactivation of oncogenic KRAS down-regulated both the heat shock response and the inositol-requiring enzyme 1α (IRE1α) branch of the unfolded protein response, causing severe proteostasis disturbances. However, IRE1α was selectively reactivated in an ER stress-independent manner in acquired KRASi-resistant tumors, restoring proteostasis. Oncogenic KRAS promoted IRE1α protein stability through extracellular signal-regulated kinase (ERK)-dependent phosphorylation of IRE1α, leading to IRE1α disassociation from 3-hydroxy-3-methylglutaryl reductase degradation (HRD1) E3-ligase. In KRASi-resistant tumors, both reactivated ERK and hyperactivated AKT restored IRE1α phosphorylation and stability. Suppression of IRE1α overcame resistance to KRASi. This study reveals a druggable mechanism that leads to proteostasis reprogramming and facilitates KRASi resistance.

Isotopic and proteomic evidence for communal stability at Pre-Pottery Neolithic Jericho in the Southern Levant.

As one of the key, long-term occupied sites in the Southern Levant, Jericho was one of the most important early Neolithic centres to witness social and economic changes associated with the domestication of plants and animals. This study applies strontium (87Sr/86Sr), oxygen (δ18O) and carbon (δ13C) isotope analyses to the enamel of 52 human teeth from Pre-Pottery Neolithic (PPN) layers of Jericho to directly study human diet and mobility and investigate the degree of consolidation and the flexibility of social organization of Jericho society in the PPN period. The results indicate only two non-local individuals out of the 44 sampled inhabitants identified by strontium isotope analysis and are consistent with the presence of a largely sedentary community at PPN Jericho with no evidence for large-scale migration. We also construct strontium spatial baselines (87Sr/86Sr map) with local 87Sr/86Sr signatures for the sites across the Southern Levant based on systematic compilation and analysis of available data. In addition, we apply proteomic analysis of sex-specific amelogenin peptides in tooth enamel for sex estimation of the sampled individuals (n = 44), the results of which showed a sex-biased ratio (more male than female detected in this sample pool) in Jericho society during the PPN period, which may be due to the limited sample size or selective ritual practices like particular burial zones used for specific groups. We also pretreated a batch of human bone samples recovered from PPNB Jericho for stable carbon and nitrogen isotope analyses for dietary investigations. However, the extracted collagen showed poor preservation and no valid δ13C or δ15N data were obtained.

A high-efficiency gene silencing in plants using two-hit asymmetrical artificial MicroRNAs.

MicroRNAs (miRNAs) are small non-coding RNA molecules that play a crucial role in gene regulation. They are produced through an enzyme-guided process called dicing and have an asymmetrical structure with two nucleotide overhangs at the 3' ends. Artificial microRNAs (amiRNAs or amiRs) are designed to mimic the structure of miRNAs and can be used to silence specific genes of interest. Traditionally, amiRNAs are designed based on an endogenous miRNA precursor with certain mismatches at specific positions to increase their efficiency. In this study, the authors modified the highly expressed miR168a in Arabidopsis thaliana by replacing the single miR168 stem-loop/duplex with tandem asymmetrical amiRNA duplexes that follow the statistical rules of miRNA secondary structures. These tandem amiRNA duplexes, called "two-hit" amiRNAs, were shown to have a higher efficiency in silencing GFP and endogenous PDS reporter genes compared to traditional "one-hit" amiRNAs. The authors also demonstrated the effectiveness of "two-hit" amiRNAs in silencing genes involved in miRNA, tasiRNA, and hormone signalling pathways, individually or in families. Importantly, "two-hit" amiRNAs were also able to over-express endogenous miRNAs for their functions. The authors compare "two-hit" amiRNA technology with CRISPR/Cas9 and provide a web-based amiRNA designer for easy design and wide application in plants and even animals.

Flexible use of commercial rhenium disulfide for various theranostic applications.

Rhenium disulfide (ReS2) with distinct physicochemical properties has shown promising potential in disease theranostics, such as drug delivery, computed tomography (CT), radiotherapy, and photothermal therapy (PTT). However, the synthesis and post-modification of ReS2 agents for different application scenarios are time- and energy-consuming, which seriously hinders the clinical translation of ReS2. Herein, we proposed three facile excipient strategies for different theranostic applications of ReS2 just through the flexible use of commercial ReS2 powder. Three excipients, including sodium alginate (ALG), xanthan gum (XG), and ultraviolet-cured resin (UCR), were used to prepare different dosage forms of commercial ReS2 powder, like hydrogel, suspension, and capsule, respectively. These dosage forms of ReS2 with distinct characteristics showed great potential for second near-infrared window PTT against tumours, gastric spectral CT imaging, and functional evaluation of the digestive tract in vivo. In addition, these ReS2 formulations exhibited good biocompatibility both in vitro and in vivo, showing a promising prospect for clinical transformation. More importantly, the facile excipient strategies for commercial agents pave a bridge to the development and wide bioapplication of many other theranostic biomaterials.

A Joint Acoustic Emission Source Localization Method for Composite Materials.

Damage localization methods for composite materials are a popular research topic at present. The time-difference-blind localization method and beamforming localization method are often individually utilized in the localization of the acoustic emission sources of composite materials. Based on the performances of the two methods, a joint localization method for the acoustic emission sources of composite materials is proposed in this paper. Firstly, the performance of the time-difference-blind localization method and the beamforming localization method were analyzed. Then, with the advantages and disadvantages of these two methods in mind, a joint localization method was proposed. Finally, the performance of the joint localization method was verified using simulations and experiments. The results show that the joint localization method can reduce the localization time by half compared with the beamforming localization method. At the same time, compared with the time-difference-blind localization method, the localization accuracy can be improved.

Interactions between the Astrocytic Volume-Regulated Anion Channel and Aquaporin 4 in Hyposmotic Regulation of Vasopressin Neuronal Activity in the Supraoptic Nucleus.

We assessed interactions between the astrocytic volume-regulated anion channel (VRAC) and aquaporin 4 (AQP4) in the supraoptic nucleus (SON). Acute SON slices and cultures of hypothalamic astrocytes prepared from rats received hyposmotic challenge (HOC) with/without VRAC or AQP4 blockers. In acute slices, HOC caused an early decrease with a late rebound in the neuronal firing rate of vasopressin neurons, which required activity of astrocytic AQP4 and VRAC. HOC also caused a persistent decrease in the excitatory postsynaptic current frequency, supported by VRAC and AQP4 activity in early HOC; late HOC required only VRAC activity. These events were associated with the dynamics of glial fibrillary acidic protein (GFAP) filaments, the late retraction of which was mediated by VRAC activity; this activity also mediated an HOC-evoked early increase in AQP4 expression and late subside in GFAP-AQP4 colocalization. AQP4 activity supported an early HOC-evoked increase in VRAC levels and its colocalization with GFAP. In cultured astrocytes, late HOC augmented VRAC currents, the activation of which depended on AQP4 pre-HOC/HOC activity. HOC caused an early increase in VRAC expression followed by a late rebound, requiring AQP4 and VRAC, or only AQP4 activity, respectively. Astrocytic swelling in early HOC depended on AQP4 activity, and so did the early extension of GFAP filaments. VRAC and AQP4 activity supported late regulatory volume decrease, the retraction of GFAP filaments, and subside in GFAP-VRAC colocalization. Taken together, astrocytic morphological plasticity relies on the coordinated activities of VRAC and AQP4, which are mutually regulated in the astrocytic mediation of HOC-evoked modulation of vasopressin neuronal activity.

A visual colorimetric assay based on phage T156 and gold nanoparticles for the sensitive detection of Salmonella in lettuce.

In this study, a new technique was developed for visual and precise identification of Salmonella using phage T156-mediated aggregation of gold nanoparticles. The phage binds to gold nanoparticles in a dispersed and stable state under high NaCl concentrations. When Salmonella is introduced, the phage specifically recognizes and adsorbs the targeted bacteria, causing the AuNPs to undergo a discoloration reaction resulting in aggregation, which enables Salmonella visualization. The method has a detection range of 3.8 × 101-3.8 × 109 CFU/mL and a limit of detection of 38 CFU/mL and can produce results in approximately 80 min. The technique was also tested on field samples, including spiked lettuce, and was found to be accurate with a recovery rate of 81.0-119.2% and relative standard deviations ranging from 3.3% to 14.7%. Notably, this technique utilizes phages as recognition elements in colorimetric methods, offering simplicity, speed, and the ability to effectively distinguish between live and dead Salmonella. It demonstrates remarkable sensitivity, specificity, and accuracy. Furthermore, it presents a novel avenue for the rapid detection of other pathogenic bacteria.

Oxidative Stress Initiates Receptor-Interacting Protein Kinase-3/Mixed Lineage Kinase Domain-Like-Mediated Corneal Epithelial Necroptosis and Nucleotide-Binding Oligomerization Domain-Like Receptor Protein 3 Inflammasome Signaling during Fungal Keratitis.

Fungal keratitis remains a major cause of severe visual loss in developing countries because of limited choices of therapy. The progression of fungal keratitis is a race between the innate immune system and the outgrowth of fungal conidia. Programmed necrosis (necroptosis), a type of proinflammatory cell death, has been recognized as a critical pathologic change in several diseases. However, the role and potential regulatory mechanisms of necroptosis have not been investigated in corneal diseases. The current study showed, for the first time, that fungal infection triggered significant corneal epithelial necroptosis in human/mouse/in vitro models. Moreover, a reduction in excessive reactive oxygen species release effectively prevented necroptosis. NLRP3 knockout did not affect necroptosis in vivo. In contrast, ablation of necroptosis via RIPK3 knockout significantly delayed migration and inhibited the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in macrophages, which enhanced the progression of fungal keratitis. Taking these findings together, the study indicated that overproduction of reactive oxygen species in fungal keratitis leads to significant necroptosis in the corneal epithelium. Furthermore, the necroptotic stimuli-mediated NLRP3 inflammasome serves as a driving force in host defense against fungal infection.