Dexamethasone induces trabecular meshwork cell myofibroblast transdifferentiation through ARHGEF26.

Glucocorticoid use may cause elevated intraocular pressure, leading to the development of glucocorticoid-induced glaucoma (GIG). However, the mechanism of GIG development remains incompletely understood. In this study, we subjected primary human trabecular meshwork cells (TMCs) and mice to dexamethasone treatment to mimic glucocorticoid exposure. The myofibroblast transdifferentiation of TMCs was observed in cellular and mouse models, as well as in human trabecular mesh specimens. This was demonstrated by the cytoskeletal reorganization, alterations in cell morphology, heightened transdifferentiation markers, increased extracellular matrix deposition, and cellular dysfunction. Knockdown of Rho guanine nucleotide exchange factor 26 (ARHGEF26) expression ameliorated dexamethasone-induced changes in cell morphology and upregulation of myofibroblast markers, reversed dysfunction and extracellular matrix deposition in TMCs, and prevented the development of dexamethasone-induced intraocular hypertension. And, this process may be related to the TGF-ß pathway. In conclusion, glucocorticoids induced the myofibroblast transdifferentiation in TMCs, which played a crucial role in the pathogenesis of GIG. Inhibition of ARHGEF26 expression protected TMCs by reversing myofibroblast transdifferentiation. This study demonstrated the potential of reversing the myofibroblast transdifferentiation of TMCs as a new target for treating GIG.

Arf1 promotes porcine intestinal epithelial cell proliferation via the mTORC1 signaling pathway.

The promotion of gut health, a pervasive problem in modern animal husbandry, positively affects organismal health, productivity, and economics. Porcine intestinal epithelial cells (IPEC-J2) continuously proliferate to maintain intestinal homeostasis, including barrier, immune, and absorptive functions. Gut homeostasis is fundamental to organismal health. ADP-ribosylation factor 1 (Arf1), a small GTPase, plays a crucial role in coordinating mTORC1 in response to nutrients, especially amino acid availability in the gut. mTORC1 is the central hub of proliferation. Thus, it seems likely that Arf1 promotes IPEC-J2 cell proliferation. However, the exact role of Arf1 in the porcine gut remains unclear. Therefore, we evaluated the functional role and possible mechanisms of Arf1 in the porcine intestine through Arf1 overexpression and knockdown in IPEC-J2 cells. Arf1 overexpression and knockdown significantly enhanced and inhibited, respectively, IPEC-J2 cell viability, and PCNA expression varied with Arf1 expression. Moreover, the proportion of Ki67-positive cells was significantly greater in the Arf1-overexpressing group than in the control group. These results suggest that Arf1 improves IPEC-J2 cell proliferation. The underlying mechanism was explored by Western blotting. Arf1 overexpression and knockdown significantly enhanced and suppressed, respectively, the levels of p-S6K1 and p-RPS6, which are key downstream targets of the mTORC1 signaling pathway. Collectively, our findings reveal the role of the Arf1-mTORC1 axis in IPEC-J2 cell proliferation and its potential function in regulating intestinal homeostasis and health.

Redistribution and fusion of protein-lipid assemblies within the egg yolk sphere under slight non-destructive deformation causing a change in thermal gel properties.

Egg yolk production processed after separating egg white is a common method to shorten cycle, but its taste quality will change even the vitelline membrane is intact. This might be related to the slight non-destructive deformation causing redistribution and fusion of protein-lipid assemblies within the egg yolk spheres. We investigated the mechanism of the change in thermal gel properties under slight deformation. The results of microscopic structural morphology revealed that the whole boiled egg yolk (WEY) underwent a transition in protein-lipid assembly morphology within yolk spheres, which changed from local aggregation to disordered fusion in shaken boiled egg yolks (SEYs). The spectroscopic and physicochemical properties analysis demonstrated that the redistribution of protein-lipid assemblies gave rise to marked changes in water migration, texture properties, molecular interactions, and oral sensation simulation of egg yolk thermal gels. This is benefit to guide the regulation of the taste quality egg yolk products in industry.

Suppression of CDK1/Drp1-mediated mitochondrial fission attenuates dexamethasone-induced extracellular matrix deposition in the trabecular meshwork.

AIMS: Deposition of extracellular matrix (ECM) in the trabecular meshwork (TM), as induced by dexamethasone (DEX), is believed to play an important role in the onset of glucocorticoid-induced glaucoma (GIG). Abnormal ECM deposition is a consequence of mitochondrial dysfunction. We aimed to clarify how mitochondrial dysfunction leads to ECM deposition within the TM and to support the development of novel therapeutic strategies. RESULTS: In primary human TM cells (pHTMCs) and a dexamethasone acetate-induced murine model of GIG, glucocorticoid administration stimulated both mitochondrial fission and ECM deposition. Excessive mitochondrial fission leads to dysfunction and the overexpression of ECM proteins in pHTMCs. Notably, when pHTMCs were treated with the Drp1 inhibitor Mdivi-1 or with Drp1 siRNA, we observed a marked reduction in DEX-induced mitochondrial damage and ECM proteins in vitro. Furthermore, in C57BL/6J mice, treatment with Mdivi-1 mitigated mitochondrial damage and blocked ECM deposition within the TM. We then employed Ro3306 to inhibit the CDK1-mediated phosphorylation of Drp1 at Ser 616, which restored mitochondrial function and diminished DEX-induced ECM protein expression in pHTMCs. INNOVATION: This study illuminates the pathogenic mechanism linking mitochondrial dysfunction to ECM deposition in GIG. Our innovative approach revealed that DEX stimulates mitochondrial fission via CDK1-mediated p-Drp1s616 overexpression, which drives ECM accumulation. It offered a novel therapeutic strategy for reducing ECM protein expression by inhibiting excessive mitochondrial fission and restoring mitochondrial function. CONCLUSION: By targeting the CDK1/Drp1-driven mitochondrial fission process, we can counteract DEX-induced ECM deposition in the TM both in vivo and in vitro.

Supraclavicular lymph node metastasis should not be defined as regional lymph node metastasis in cervical and upper thoracic esophageal squamous cell carcinoma.

The importance of supraclavicular lymph node (SCLN) metastasis in cervical and upper thoracic esophageal squamous cell carcinoma (ESCC) has not been determined. The aim of the present study was to provide a detailed definition of the range of SCLN regions and to explore whether SCLNs should be considered as a regional lymph nodes for patients with cervical and upper thoracic ESCC. A retrospective analysis was performed on 230 patients with locally advanced cervical or upper thoracic ESCC who underwent radical radiotherapy and chemotherapy. The range of SCLN regions was defined in detail on contrast enhanced computed tomography images of the neck. According to whether the patient had lymph node metastasis in the supraclavicular region, the included patients were divided into two groups, and the survival differences and reasons for treatment failure between the two groups were analyzed. Of the 230 patients with ESCC, 71 (30.87%) exhibited lymph node metastases in the supraclavicular region. The median overall survival time of ESCC patients with and without SCLN metastasis was 17 and 30 months, respectively (P<0.001). After propensity score matching (PSM), the median overall survival time of ESCC patients with and without SCLN metastasis was 17 and 28 months, respectively (P<0.001). During the follow-up period, there were a total of 101 cases of failure of treatment in the irradiation field, 6 cases had esophageal metastasis in the non-irradiated field and 27 cases had regional lymph node metastasis in the non-irradiated field. In addition, there were 33 cases of metastasis to the distant lymph nodes or organs. There was no significant difference in the local treatment failure rate between the groups with or without SCLN metastasis in both the irradiation field and the non-irradiation field, but the probability of distant metastasis in the SCLN metastasis group was significantly higher than that in the group without SCLN metastasis (P=0.025). In conclusion, patients with cervical and upper thoracic ESCC with SCLN metastasis have a poor prognosis and the median overall survival time is closer to that of metastatic ESCC than ESCC with regional lymph node metastasis; therefore, SCLNs should not be defined as regional lymph nodes in patients with cervical and upper thoracic ESCC.

Optimal N management affects the fate of urea-15N and improves N uptake and utilization of wheat in different rotation systems.

Rice-wheat and maize-wheat rotations are major cropping systems in the middle and lower reaches of Yangtze River in China, where high nitrogen (N) inputs and low N efficiency often exacerbate resource waste and environmental pollution. Due to the changes in factors such as soil properties and moisture content, the N fate and the N utilization characteristics of wheat in different rotations are significantly different. Efficient N management strategies are thus urgently required for promoting maximum wheat yield in different rotation systems while reducing N loss. A 2-year field experiment using isotopic (15N) tracer technique was conducted to evaluate the fate of 15N-labeled urea in wheat fields and the distribution characteristics of N derived from different sources. The wheat yield and N use efficiency under various N rates (180 and 240 kg ha-1, abbreviated as N180 and N240) and preceding crops (rice and maize, abbreviated as R-wheat and M-wheat) were also investigated. The results showed that N240 increased N uptake and grain yield by only 8.77-14.97% and 2.51-4.49% compared with N 180, but decreased N agronomic efficiency (NAE) and N physiological efficiency (NPE) by 14.78-18.79% and 14.06-31.35%. N240 also decreased N recovery in plants by 2.8% on average compared with N180, and increased N residue in soil and N loss to the environment. Compared with that of basal N, the higher proportion of topdressing N was absorbed by wheat rather than lost to the environment. In addition, the accumulation of topdressing N in grain was much higher than that of basal N. Compared with that in R-wheat treatment, plants in M-wheat treatment trended to absorb more 15N and reduce unaccounted N loss, resulting in higher yield potential. Moreover, the M-wheat treatment increased N recovery in 0-20 cm soil but decreased 80-100 cm soil compared with R-wheat treatment, indicating a lower risk of N loss in deeper soil. Collectively, reducing N application rate and increasing the topdressing ratio is an effective way to balance sustainable crop yield for a secure food supply and environmental benefit, which is more urgent in rice-wheat rotation.

PM2.5 triggers tau aggregation in a mouse model of tauopathy.

The aggregation and prion-like propagation of tau are the hallmarks of Alzheimer's disease (AD) and other tauopathies. However, the molecular mechanisms underlying the assembly and spread of tau pathology remain elusive. Epidemiological data show that exposure to fine particulate matter (PM2.5) is associated with an increased risk of AD. However, the molecular mechanisms remain unknown. Here, we showed that PM2.5 triggered the aggregation of tau and promoted the formation of tau fibrils. Injection of PM2.5-induced tau preformed fibrils (PFFs) into the hippocampus of tau P301S transgenic mice promoted the aggregation of tau and induced cognitive deficits and synaptic dysfunction. Furthermore, intranasal administration of PM2.5 exacerbated tau pathology and induced cognitive impairment in tau P301S mice. In conclusion, our results indicated that PM2.5 exposure promoted tau pathology and induced cognitive impairments. These results provide mechanistic insight into how PM2.5 increases the risk of AD.

Association of polygenic risk scores with Alzheimer's disease and plasma biomarkers among Chinese older adults: A community-based study.

INTRODUCTION: We examined the associations of polygenic risk score (PRS) with Alzheimer's disease (AD) and plasma biomarkers in the Chinese population. METHODS: This population-based study used baseline data from MIND-China (2018; n = 4873) and follow-up data from dementia-free individuals (2014-2018; n = 2117). We measured AD-related plasma biomarkers in a subsample (n = 1256). Data were analyzed using logistic and Cox regression models. RESULTS: We developed PRS with (PRSAPOE) and without (PRSnon- APOE) apolipoprotein E (APOE) gene. In the longitudinal analysis, PRSAPOE was associated with a multivariable-adjusted hazards ratio of 1.91 (95% CI = 1.13-3.23) for AD. PRSAPOE in combination with demographics yielded discriminative (area under the curve [AUC]) and predictive(C-statistic) accuracy of 0.80 (95% confidence interval [CI] = 0.77-0.84) and 0.80 (0.77-0.82), respectively. PRSnon- APOE showed an association with AD risk similar to PRSAPOE. PRSAPOE, but not PRSnon- APOE, was associated with reduced plasma Aß42/Aß40 ratio and increased Neurofilament light chain (NfL) (p < 0.05). DISCUSSION: The PRS with and without APOE gene, in combination with demographics, shows good discriminative and predictive ability for AD. The AD-related pathologies underlie AD risk associated with PRSAPOE. HIGHLIGHTS: The PRSAPOE and PRSnon- APOE were associated with AD risk in the Chinese population. The PRSAPOE and PRSnon- APOE, in combination with demographics, showed good discriminative and predictive ability for AD. The AD-related pathologies underlie the AD risk associated with PRSAPOE but not PRSnon- APOE.

Utilizing machine learning to tailor radiotherapy and chemoradiotherapy for low-grade glioma patients.

BACKGROUND: There is ongoing uncertainty about the effectiveness of various adjuvant treatments for low-grade gliomas (LGGs). Machine learning (ML) models that predict individual treatment effects (ITE) and provide treatment recommendations could help tailor treatments to each patient's needs. OBJECTIVE: We sought to discern the individual suitability of radiotherapy (RT) or chemoradiotherapy (CRT) in LGG patients using ML models. METHODS: Ten ML models, trained to infer ITE in 4,042 LGG patients, were assessed. We compared patients who followed treatment recommendations provided by the models with those who did not. To mitigate the risk of treatment selection bias, we employed inverse probability treatment weighting (IPTW). RESULTS: The Balanced Survival Lasso-Network (BSL) model showed the most significant protective effect among all the models we tested (hazard ratio (HR): 0.52, 95% CI, 0.41-0.64; IPTW-adjusted HR: 0.58, 95% CI, 0.45-0.74; the difference in restricted mean survival time (DRMST): 9.11, 95% CI, 6.19-12.03; IPTW-adjusted DRMST: 9.17, 95% CI, 6.30-11.83). CRT presented a protective effect in the 'recommend for CRT' group (IPTW-adjusted HR: 0.60, 95% CI, 0.39-0.93) yet presented an adverse effect in the 'recommend for RT' group (IPTW-adjusted HR: 1.64, 95% CI, 1.19-2.25). Moreover, the models predict that younger patients and patients with overlapping lesions or tumors crossing the midline are better suited for CRT (HR: 0.62, 95% CI, 0.42-0.91; IPTW-adjusted HR: 0.59, 95% CI, 0.36-0.97). CONCLUSION: Our findings underscore the potential of the BSL model in guiding the choice of adjuvant treatment for LGGs patients, potentially improving survival time. This study emphasizes the importance of ML in customizing patient care, understanding the nuances of treatment selection, and advancing personalized medicine.

Enhancing the cytological features and diagnostic significance of cerebrospinal fluid in bacterial meningitis.

Objective: The objective of this study was to investigate the cytological features and diagnostic significance of cerebrospinal fluid (CSF) in bacterial meningitis (BM). Material and Methods: Patients diagnosed with BM at the First Affiliated Hospital of Nanchang University Hospital between August 2021 and April 2022 were enrolled. Clinical, cranial imaging, CSF-next-generation sequencing, CSF examination, and CSF cytology data were retrospectively analyzed. CSF cytology samples were prepared using a CSF cell pelletizer (precipitation method) and stained using the May-Grunwald-Glemsa (MGG) method. The χ2 test was employed to compare the positive rate of routine CSF count and CSF cytology. Results: Eight patients (four males and four females), aged 41-67 years, were included. Among them, two patients had undergone brain surgery within the past 4 months, one patient had an 8-year history of otitis media, and two patients had a history of sudden toothache. Clinical manifestations included fever, headache, sudden disturbance of consciousness, and neck stiffness. CSF cytology revealed abnormal inflammatory changes dominated by neutrophils in seven patients. Routine CSF cell counts exceeded 100/uL in only four cases, indicating a higher positive rate of CSF cytology for detecting CSF inflammatory reactions compared to routine cell count. Conclusion: Comparative detection of bacteria through the observation of CSF cytology inflammatory status in BM patients are more useful for diagnosing BM than routine CSF counts.

A preliminary investigation into the impact of soft tissue augmentation-based periodontal phenotype modification therapy for patients exhibiting class III decompensation.

BACKGROUND: Patients with skeletal angle Class III malocclusion usually have inadequate hard and soft tissue volume at the mandibular anterior teeth. The labial proclination at the teeth may lead to gingival recession. The purpose of this study was to explore whether periodontal phenotype modification therapy with soft tissue augmentation (PhMT-s) can prevent gingival recession in these patients. METHODS: Four patients with skeletal Class III malocclusion and a thin periodontal phenotype underwent surgical-orthodontic treatment. Prior to tooth movement, they underwent a minimally invasive vestibular incision with subperiosteal tunnel access combined with autogenous connective tissue grafts for periodontal phenotype modification with soft tissue augmentation (PhMT-s). The labial gingival thickness of the anterior mandibular teeth was measured at three distinct levels: at the cementoenamel junction (GT0), 3 mm apical to the CEJ (GT3), and 6 mm apical to the CEJ (GT6). These measurements were taken at baseline, three months following PhMT-s, and after tooth decompensation. Additionally, a biopsy sample was obtained from the PhMT-s site of one patient. All sections were subsequently stained using hematoxylin and eosin, Masson trichrome, Sirius Red, and immunohistochemistry. RESULTS: The thickness of the labial gingiva was increased about 0.42 to 2.00 mm after PhMT-s. At the end of pre-orthognathic surgical orthodontic treatment, the thickness of the labial gingiva was increased about - 0.14 to 1.32 mm compared to the baseline and no gingival recession occurred after the pre-orthognathic surgical orthodontic treatment. The histologic results demonstrated that the grafts obtained from the PhMT-s site exhibited increased deposition of collagen fibers. Moreover, the proportion of type III collagen increased and the grafts displayed significantly reduced positive expression of CD31 and OCN. CONCLUSIONS: PhMT-s increased the thickness of the soft tissue, stabilizing the gingival margin for teeth exhibiting a thin periodontal phenotype and undergoing labial movement. This is attributed to the increased deposition of collagen fibers.

Approaching crystal's limit of thermoelectrics by nano-sintering-aid at grain boundaries.

Grain boundary plays a vital role in thermoelectric transports, leading to distinct properties between single crystals and polycrystals. Manipulating the grain boundary to realize good thermoelectric properties in polycrystals similar as those of single crystals is a long-standing task, but it is quite challenging. Herein, we develop a liquid-phase sintering strategy to successfully introduce Mg2Cu nano-sintering-aid into the grain boundaries of Mg3(Bi, Sb)2-based materials. The nano-aid helps to enlarge the average grain size to 23.7 µm and effectively scatter phonons, leading to excellent electrical transports similar as those of single crystals and ultralow lattice thermal conductivity as well as exceptional thermoelectric figure of merit (1.5 at 500 K) and conversion efficiency (7.4% under temperature difference of 207 K). This work provides a simple but effective strategy for the fabrication of high-performance polycrystals for large-scale applications.

Complement Factor B (CFB) inhibits the malignant progression of lung adenocarcinoma by downregulating the Ras/MAPK signaling pathway.

Lung adenocarcinoma (LUAC) as the most common lung cancer, and its incidence is increasing. Complement factor B (CFB) is an important factor in the alternative complement pathway. CFB has been reported to be involved in the progression of many cancers, including in pancreatic cancer, cutaneous squamous cell carcinoma, and nasopharyngeal carcinoma, but the function and molecular mechanism of CFB in LUAC remains unclear. The present study aimed to explore the role of CFB in LUAC malignant progression. In our previous study, we found that CFB was downregulated expression in LUAC clinical samples. Here, we firstly detected the cell function in vitro. Cell proliferation and migration were increased, while cell apoptosis and cell cycle arrest were suppressed after CFB knockdown. Overexpression of CFB repressed the malignant progression of LUAC in vitro. Besides, in vivo experiments revealed that upregulation of CFB inhibited tumor growth and Ki67 expression. Additionally, our data indicated that CFB negatively regulated Ras/mitogen-activated protein kinase (MAPK) signaling pathway. Furthermore, upregulation of CFB inhibited the progression of LUAC was reversed by Ras/MAPK pathway activators (ML-098 or C16-PAF). Our study uncovered that CFB acts as a tumor suppressor repressed tumorigenesis of LUAC through inhibiting the Ras/MAPK pathway, suggesting that CFB may be a potential biomarker and therapeutic target for LUAC.

Preparation and characterization of starch carbamate modified natural sodium alginate composite hydrogel blend formulation and its application for slow-release fertilizer.

The exploration of environmentally friendly slow-release fertilizer (SRF) based on natural bio-polymers is of great importance in the development of modern agriculture and horticulture. Herein, a novel starch carbamate (SC) modified sodium alginate (SA) hydrogel (SC/SAH) was prepared utilizing as-synthesized SC and natural SA through the cationic ions crosslinking method and ultimately the corresponding slow-release fertilizer (SC/SAH-SRF) was successfully developed by immersing the dried SC/SAH matrix into saturated urea solution. Due to the low gelation temperature and high viscosity of the synthesized SC, the formed SC/SAH exhibits significantly enhanced properties including excellent water absorbency up to 8.02 g/g with considerable repeatability, abundant pore structure and high hydrophilicity compared with the neat SAH and natural starch based hydrogel (NS/SAH). Accordingly, the SC/SAH leads to higher urea loading amount âˆ¼ 1.28 g/g. Importantly, the resultant SC/SAH-SRF also shows superior slow-release performance, yielding a cumulative urea release of only 61.6 % within 10 h and almost completely release >16 h in water, what's more, only 58.5 % of the urea releases within 25 days and exceeding 50 days for complete release in soil column assays. The slow-release of urea from SC/SAH-SRF well complies for the first-order kinetics and accomplishes via a non-Fickian diffusion process. Moreover, the pot experiment demonstrates that the SC/SAH-SRF has higher growth promotion role for the maize seedlings than those of others. Consequently, this work provides a novel strategy for preparing environmentally friendly SRF by blending modified starch and hydrogel.

A single amino acid substitution in the AAA-type ATPase LRD6-6 activates immune responses but decreases grain quality in rice.

Plant spotted leaf (spl) mutants are useful to reveal the regulatory mechanisms of immune responses. Thus, in crop plants, their agronomic traits, especially the grain quality are usually ignored. Here, we characterized a rice spl mutant named spl-A (spotted leaf mutant from A814) that shows autoimmunity, broad-spectrum disease resistance and growth deterioration including decreased rice quality. A single nucleotide mutation of C1144T, which leads to change of the 382nd proline to serine, in the gene encoding the ATPases associated with diverse cellular activities (AAA)-type ATPase LRD6-6 is responsible for the phenotype of the spl-A mutant. Mechanistically, this mutation impairs LRD6-6 ATPase activity and disrupts its interaction with endosomal sorting complex required for transport (ESCRT)-III subunits OsSNF7.1/7.2/7.3. And thus, leading to compromise of multivesicular bodies (MVBs)-mediated vesicle trafficking and accumulation of ubiquitinated proteins in both leaves and seeds of spl-A. Therefore, the immune response of spl-A is activated, and the growth and grain quality are deteriorated. Our study identifies a new amino acid residue that important for LRD6-6 and provides new insight into our understanding of how MVBs-mediated vesicle trafficking regulates plant immunity and growth, including grain quality in rice.

Landrace introgression contributed to the recent feralization of weedy rice in East China.

This study leveraged knowledge of the specific known cultivar progenitor "Nanjing11" of a weedy rice population from East China, and discovered that the landrace introgression greatly contributed to the recent feralization of modern cultivars, including the introduction of the Rc gene that confers key weedy traits such as red pericarp and seed dormancy.

Mechanical ventilation guided by driving pressure optimizes local pulmonary biomechanics in an ovine model.

Mechanical ventilation exposes the lung to injurious stresses and strains that can negatively affect clinical outcomes in acute respiratory distress syndrome or cause pulmonary complications after general anesthesia. Excess global lung strain, estimated as increased respiratory system driving pressure, is associated with mortality related to mechanical ventilation. The role of small-dimension biomechanical factors underlying this association and their spatial heterogeneity within the lung are currently unknown. Using four-dimensional computed tomography with a voxel resolution of 2.4 cubic millimeters and a multiresolution convolutional neural network for whole-lung image segmentation, we dynamically measured voxel-wise lung inflation and tidal parenchymal strains. Healthy or injured ovine lungs were evaluated as the mechanical ventilation positive end-expiratory pressure (PEEP) was titrated from 20 to 2 centimeters of water. The PEEP of minimal driving pressure (PEEPDP) optimized local lung biomechanics. We observed a greater rate of change in nonaerated lung mass with respect to PEEP below PEEPDP compared with PEEP values above this threshold. PEEPDP similarly characterized a breaking point in the relationships between PEEP and SD of local tidal parenchymal strain, the 95th percentile of local strains, and the magnitude of tidal overdistension. These findings advance the understanding of lung collapse, tidal overdistension, and strain heterogeneity as local triggers of ventilator-induced lung injury in large-animal lungs similar to those of humans and could inform the clinical management of mechanical ventilation to improve local lung biomechanics.

Visual selective attention in individuals with age-related hearing loss.

Evidence from epidemiological studies suggests that hearing loss is associated with an accelerated decline in cognitive function, but the underlying pathophysiological mechanism remains poorly understood. Studies using auditory tasks have suggested that degraded auditory input increases the cognitive load for auditory perceptual processing and thereby reduces the resources available for other cognitive tasks. Attention-related networks are among the systems overrecruited to support degraded auditory perception, but it is unclear how they function when no excessive recruitment of cognitive resources for auditory processing is needed. Here, we implemented an EEG study using a nonauditory visual attentional selection task in 30 individuals with age-related hearing loss (ARHLs, 60-73 years) and compared them with aged (N = 30, 60-70 years) and young (N = 35, 22-29 years) normal-hearing controls. Compared with their normal-hearing peers, ARHLs demonstrated a significant amplitude reduction for the posterior contralateral N2 component, which is a well-validated index of the allocation of selective visual attention, despite the comparable behavioral performance. Furthermore, the amplitudes were observed to correlate significantly with hearing acuities (pure tone audiometry thresholds) and higher-order hearing abilities (speech-in-noise thresholds) in aged individuals. The target-elicited alpha lateralization, another mechanism of visuospatial attention, demonstrated in control groups was not observed in ARHLs. Although behavioral performance is comparable, the significant decrease in N2pc amplitude in ARHLs provides neurophysiologic evidence that may suggest a visual attentional deficit in ARHLs even without extra-recruitment of cognitive resources by auditory processing. It supports the hypothesis that constant degraded auditory input in ARHLs has an adverse impact on the function of cognitive control systems, which is a possible mechanism mediating the relationship between hearing loss and cognitive decline.

TMEM16F Expressed in Kupffer Cells Regulates Liver Inflammation and Metabolism to Protect Against Listeria Monocytogenes.

Infection by bacteria leads to tissue damage and inflammation, which need to be tightly controlled by host mechanisms to avoid deleterious consequences. It is previously reported that TMEM16F, a calcium-activated lipid scramblase expressed in various immune cell types including T cells and neutrophils, is critical for the control of infection by bacterium Listeria monocytogenes (Lm) in vivo. This function correlated with the capacity of TMEM16F to repair the plasma membrane (PM) damage induced in T cells in vitro, by the Lm toxin listeriolysin O (LLO). However, whether the protective effect of TMEM16F on Lm infection in vivo is mediated by an impact in T cells, or in other cell types, is not determined. Herein, the immune cell types and mechanisms implicated in the protective effect of TMEM16F against Lm in vivo are elucidated. Cellular protective effects of TMEM16F correlated with its capacity of lipid scrambling and augment PM fluidity. Using cell type-specific TMEM16F-deficient mice, the indication is obtained that TMEM16F expressed in liver Kupffer cells (KCs), but not in T cells or B cells, is key for protection against Listeria in vivo. In the absence of TMEM16F, Listeria induced PM rupture and fragmentation of KCs in vivo. KC death associated with greater liver damage, inflammatory changes, and dysregulated liver metabolism. Overall, the results uncovered that TMEM16F expressed in Kupffer cells is crucial to protect the host against Listeria infection. This influence is associated with the capacity of Kupffer cell-expressed TMEM16F to prevent excessive inflammation and abnormal liver metabolism.

Novel genotypes and phenotypes in Snijders Blok-Campeau syndrome caused by CHD3 mutations.

Background: Snijders Blok-Campeau syndrome (SNIBCPS) is a rare genetic disorder characterized by facial abnormalities, hypotonia, macrocephaly, and global developmental delay (GDD) caused by mutations in CHD3 gene. There is limited information on SNIBCPS and few studies on its pathogenic gene CHD3. Methods: We utilized whole-exome sequencing, in vitro minigene splicing assay analysis, and construction of protein models to validate the suspected pathogenic mutation. In addition, the PubMed database was searched using the keywords "Snijders Blok-Campeau syndrome," "CHD3," or "SNIBCPS" to summarize the gene mutations and clinical phenotypic characteristics of children with SNIBCPS. Results: We identified a non-frameshift variant c.3592_c.3606delGCCAAGAGAAAGATG, a splice site variant c.1708-1G>T, and two missense variants, c. 2954G>C (p.Arg985Pro) and c.3371C>T (p.A1124V), in CHD3 variants with SNIBCPS. Importantly, the c.3592_c.3606delGCCAAGAGAAAGATG, c.1708-1G>T, and c.3371C > T (p.A1124V) loci were not reported, and the children in this study also had phenotypic features of unibrow, transverse palmar creases, tracheal bronchus, and hypomelanosis of Ito (HI). The c.1708-1G>T classical splicing mutation leads to abnormal shearing of mRNA, forming a truncated protein that ultimately affects gene function. Conclusion: Our findings have expanded the spectrum of genetic variants and clinical features in children with SNIBCPS. Splicing analysis of CHD3 is an important method to understand the pathogenesis of spliced cells.