Case report: A novel TLK2 variant with a neuropsychiatric phenotype from a Chinese family.

Background: Tousled-like kinase 2 (TLK2) gene variant-related neurodevelopmental disorder was recently described. The haploinsufficiency of TLK2 was considered the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. So far, only four studies, conducted on 49 patients from North America and Europe, have been reported. Case presentation: In this study, we reported a Chinese family with a TLK2-related neuropsychiatric phenotype. The proband, a boy aged 2 years and 6 months, presented with temper tantrums, mood lability, aggressiveness, congenital astigmatism, and distinctive facial dysmorphism. Whole-exome sequencing identified a novel heterozygous variation in TLK2 gene (c.49dupG, p. E17Gfs*10) in them. His father carried the same TLK2 gene variant and exhibited anxiety and irritability. The parental grandparents and other family members had no such variation. Moreover, the proband was found to have global developmental delay, autism-like symptoms, and mild elevated homo-vanillic acid (HVA) and 2,3-dihydroxy-2-methylbutyric acid levels tested in urine. Conclusion: Herein, we identified a novel TLK2 variant from a Chinese family and reported a new neuropsychiatric phenotype. This study also expanded the genotype profile of the newly defined TLK2-related neurodevelopmental disorder.

Well-Being and Cardiovascular Health: Insights From the UK Biobank Study.

BACKGROUND: Cardiovascular diseases (CVDs) are a leading global health concern. Emerging evidence suggests a potential protective role of well-being in reducing CVD risk. METHODS AND RESULTS: We conducted a cohort analysis using the UK Biobank data set, encompassing 121 317 participants. We assessed the well-being of participants using a well-being index derived from baseline questionnaires. Well-being categories were derived by latent class analysis using general happiness and satisfaction with family, friendships, health, and finance situations. The relationship between well-being and 4 major CVDs was analyzed using Cox proportional hazards models and Mendelian randomization. The study also examined the impacts of well-being on lifestyle factors and inflammatory markers, and its mediating role in the well-being-CVD relationship. Higher well-being was associated with a significantly reduced risk of various CVDs. Latent class analysis identified 4 distinct well-being groups (low, variable, moderate-to-high, and high satisfaction), with higher satisfaction levels generally associated with lower risk of CVDs. Mendelian randomization suggested potential causal relationships between well-being and reduced risk of CVDs. Participants with greater well-being demonstrated healthier behaviors and lower levels of inflammatory markers. Mediation analysis indicated that lifestyle and inflammatory markers partially mediated the relationship between well-being and CVDs. CONCLUSIONS: This study demonstrates a robust inverse association between well-being and the risks of CVDs, suggesting that enhancing well-being may be a viable strategy for CVD prevention. The role of lifestyle factors and inflammation as a mediator provides insight into possible biological pathways linking psychological states and cardiovascular health.

Relationship between infection, physical and mental health and exercise habits of some Chinese residents after recovery from COVID-19.

This study aimed to determine the infection status, exercise habits, anxiety levels, and sleep quality in Chinese residents who recovered from infection during the period of coronavirus disease 2019 (COVID-19) period. It also aimed to investigate the influencing factors of recovery status and aid in improving intervention measures for COVID-19 recovery. This study is a sub-study nested within a cross-sectional investigation of infection and physical and mental health among partially recovered residents in all 34 provincial areas of China during the COVID-19 pandemic. A total of 1 013 participants (374 males and 639 females) completed the study. Cardiopulmonary endurance was significantly lower after infection than before infection (p â€‹< â€‹0.001). Women (3.92 â€‹± â€‹4.97) exhibited higher levels of anxiety than men (3.33 â€‹± â€‹4.54, p â€‹= â€‹0.015). The sleep score was significantly higher after infection (8.27 â€‹± â€‹7.05) than before infection (4.17 â€‹± â€‹4.97, p â€‹< â€‹0.001). The active and regular exercise groups exhibited significantly shorter durations of fever than the sedentary and irregular groups (p â€‹= â€‹0.033; p â€‹= â€‹0.021). Additionally, the active group demonstrated significantly fewer recovery days ([7.32 â€‹± â€‹3.24] days) than the sedentary group ([7.66 â€‹± â€‹3.06] days, p â€‹= â€‹0.035). We found a correlation between age and the recovery time of symptoms after COVID-19. We noted that a greater number of symptoms corresponded to poorer cardiopulmonary fitness and sleep quality. Individuals who engage in sedentary lifestyles and irregular exercise regimens generally require prolonged recovery periods. Therefore, incorporating moderate exercise, psychological support, sleep hygiene and other health interventions into post-COVID-19 recovery measures is imperative.

Towards Evidence-Based Food Safety Governance with Wastewater-Based Epidemiology (WBE) Technology in China.

Pesticide residues in food pose significant risks to public health and have long been a major concern in Chinese cities. The management of these risks is influenced by various factors, including the characteristics of responsible officials. This study tests the relationship between the levels of pesticide residues and the responsible officials' interdisciplinary backgrounds and their tenure cycles, which is crucial for improving food safety governance in Chinese cities. Based on wastewater-based epidemiology (WBE) and data from 32 Chinese cities, it was found that the interdisciplinary backgrounds of officials had a significant negative relationship with urban pesticide residues in wastewater, indicating that the interdisciplinary knowledge background or working experience of officials in food safety-related agencies was associated with the supervision and control of urban pesticide residues. This study also generated evidence-based knowledge on how to improve food safety through assigning younger and interdisciplinary officials to the responsible governmental agencies, where WBE is more likely to be adopted.

Electrostatic doping tunable magnetic transition and half-metallicity in the monolayer CrCTe3.

The electrical manipulation of the magnetic transition and spin-polarized states has attracted extensive attention in the field of spintronics. In this work, we perform a detailed study on the electronic and magnetic properties of the carrier-doped monolayer CrCTe3by using first-principles calculation. It is found that, the magnetic transition from Néel-antiferomagnetic (nAFM) to ferromagnetic (FM) is observed in the case of the electron doping, while for hole doping a magnetic transition sequence of nAFM→zigzag-AFM→FM is observed in the monolayer CrCTe3. Interestingly, the carrier doping induced FM ground state always exhibits half-metallicity with full spin polarization. Moreover, the spin polarity of the half-metallic electronic states is opposite for electron and hole doping, meaning that the spin polarization direction can be tuned by manipulating a gate voltage. The Monte Carlo calculations show that the magnetic transition temperature of the doped FM CrCTe3is rapidly increased with the increasing doping concentration and is extremely expected to achieve room temperature at a suitable doping concentration. These findings demonstrate that the monolayer AFM system possesses a potential application in spintronic devices with electrically tunable spin polarization.

Inhibition of Microglial Activation Ameliorates Inflammation, Reduced Neurogenesis in the hippocampus, and Impaired Brain Function in a Rat Model of Bilirubin Encephalopathy.

Hyperbilirubinemia is one of the most common occurrence in newborns and is toxic to the brain, resulting in neurological sequelae such as auditory impairment, with potential to evolve to chronic bilirubin encephalopathy and long-term cognitive impairment in adults. In the early postnatal period, neurogenesis is rigorous and neuroinflammation is detrimental to the brain. What are the alterations in neurogenesis and the underlying mechanisms of bilirubin encephalopathy during the early postnatal period? This study found that, there were a reduction in the number of neuronal stem/progenitor cells, an increase in microglia in the dentate gyrus (DG) and an inflammatory state in the hippocampus, characterized by increased levels of IL-6, TNF-α, and IL-1ß, as well as a decreased level of IL-10 in a rat model of bilirubin encephalopathy (BE). Furthermore, there was a significant decrease in the number of newborn neurons and the expression of neuronal differentiation-associated genes (NeuroD and Ascl1) in the BE group. Additionally, cognitive impairment was observed in this group. The administration of minocycline, an inhibitor of microglial activation, resulted in a reduction of inflammation in the hippocampus, an enhancement of neurogenesis, an increase in the expression of neuron-related genes (NeuroD and Ascl1), and an improvement in cognitive function in the BE group. These results demonstrate that microglia play a critical role in reduced neurogenesis and impaired brain function resulting from bilirubin encephalopathy model, which could inspire the development of novel pharmaceutical and therapeutic strategies.

The GARP family transcription factor MtHHO3 negatively regulates salt tolerance in Medicago truncatula.

High salinity is one of the detrimental environmental factors restricting plant growth and crop production throughout the world. This study demonstrated that the GARP family transcription factor MtHHO3 is involved in response to salt stress and abscisic acid (ABA) signaling in Medicago truncatula. The transcription of MtHHO3 was repressed by salt, osmotic stress, and ABA treatment. The seed germination assay showed that, overexpression of MtHHO3 in Arabidopsis thaliana caused hypersensitivity to salt and osmotic stress, but increased resistance to ABA inhibition. Overexpression of MtHHO3 in M. truncatula resulted in decreased tolerance of salinity, while loss-of-function mutants mthho3-1 and mthho3-2 were more resistant to salt stress compared with wild-type plants. qRT-PCR analyses showed that MtHHO3 downregulated the expression of genes in stress and ABA responsive pathways. We further demonstrated that MtHHO3 repressed the transcription of the pathogenesis-related gene MtPR2 by binding to its promoter. Overall, these results indicate that MtHHO3 negatively regulates salt stress response in plants and deepen our understanding of the role of the GARP subfamily transcription factors in modulating salt stress and ABA signaling.

Bilirubin impairs neuritogenesis and synaptogenesis in NSPCs by downregulating NMDAR-CREB-BDNF signaling.

Neonatal jaundice is one of the most common disorders in the first 2 wk after birth. Unconjugated bilirubin (UCB) is neurotoxic and can cause neurological dysfunction; however, the underlying mechanisms remain unclear. Neurogenesis, neuronal growth, and synaptogenesis are exuberant in the early postnatal stage. In this study, the impact of UCB on neuritogenesis and synaptogenesis in the early postnatal stage was evaluated both in vitro and in vivo. Primary culture neuronal stem and progenitor cells (NSPCs) were treated with UCB during differentiation, and then the neurite length and synapse puncta were measured. In the bilirubin encephalopathy (BE) animal model, DCX+-marked developing neurons were used to detect apical length and dendritic arborization. According to the data, UCB significantly reduced neurite length and synapse density, as well as decreased the apical dendrite length and dendritic arborization. Furthermore, the NMDAR subunit NR2B was downregulated in NSPCs, while pCREB expression in the hippocampus progressively decreased during disease progression in the BE model. Next, we tested the expression of NR2B, pCREB, mBDNF, and p-mTOR in NSPCs in vitro, and found that UCB treatment reduced the expression of these proteins. In summary, this suggests that UCB causes chronic neurological impairment and is related to the inhibition of NMDAR-CREB-BDNF signaling in NSPCs, which is associated with reduced neuritogenesis and synaptogenesis. This finding may inspire the development of novel pharmaceuticals and treatments.

An integrative pan-cancer analysis of WWC family genes and functional validation in lung cancer.

The WW and C2 domain containing (WWC) protein family functions as scaffolds regulating cell proliferation and organ growth control through the Hippo signaling pathway. However, their pan-cancer dysregulation and mechanistic roles in signaling transduction have remained unclear. We performed integrated pan-cancer analyses of WWC family gene expression using data from The Cancer Genome Atlas (TCGA) across 33 different cancer types. Prognostic relevance was evaluated by survival analyses. WWC genetic alterations, DNA methylation, pathway activities, drug response, and tumor immunology were analyzed using online databases. Furthermore, we examined the functional roles of WWCs in lung cancer cells. We observed aberrant WWC expression in various cancers, which associated with patient prognosis. WWC hypermethylation occurred in many cancers and exhibited negative correlation with expression, alongside mutations linked to poor outcomes. Pathway analysis implicated WWCs as Hippo pathway scaffolds, while drug sensitivity analysis suggested associations with diverse chemotherapies. Additionally, pan-cancer analyses elucidated vital immunomodulatory roles for WWC through heterogeneous correlations with immune cell infiltrates, checkpoint molecules, tumor mutation burden, microsatellite instability, and chemokine pathways across cancers. Experimentally, WWCs suppressed lung cancer cell proliferation, migration, and invasion while enhancing apoptosis and paclitaxel chemosensitivity. Mechanistically, WWCs bound large tumor suppressor 1 and 2 (LATS1/2) kinases to stimulate phosphorylation cascades, thereby inhibiting nuclear translocation of the Yes-associated protein (YAP) oncoprotein. Taken together, our multi-omics characterization provides comprehensive evidence for WWCs as putative tumor suppressors across cancers via Hippo pathway modulation. WWCs may serve as prognostic markers and therapeutic targets in lung cancer.

Lead activates neutrophil degranulation to induce early myocardial injury in mice.

Lead (Pb) is a pervasive toxic metal contaminant associated with a high risk of myocardial injury. However, the precise mechanism underlying Pb-induced myocardial injury has yet to be fully elucidated. In this study, a murine model of Pb exposure (0, 1, 5, and 10 mg/kg) was employed to investigate the involvement of neutrophil degranulation in the induction of myocardial injury. Notably, serum levels of cardiac troponin I (cTnI) and creatine kinase-MB (CK-MB) increased significantly in Pb-exposed mice, whereas cTnI levels in cardiomyocytes decreased, suggesting that Pb exposure may cause early myocardial injury. Moreover, Pb exposure was found to promote neutrophil degranulation, as evidenced by elevated myeloperoxidase (MPO) and neutrophil elastase (NE) concentrations in both the serum of Pb-exposed workers and Pb-exposed mice, as well as the extracellular supernatant of neutrophils following exposure. However, we found that serum level of cTnI enhanced by Pb exposure is associated with increased NE levels in the serum, but not with MPO levels. Upon treatment with NE inhibitor (sivelestat), the serum level of cTnI markedly reduced in Pb-exposed mice, we found that early myocardial injury is associated with NE levels in the serum. At the molecular level, western blotting analysis revealed an upregulation of ERK1/2 expression in vitro following Pb exposure, suggesting that the activation of the ERK1/2 signaling pathway may underlie the participation of neutrophil degranulation in Pb-induced myocardial injury. In summary, our findings demonstrate that Pb exposure can initiate early myocardial injury by promoting the neutrophil degranulation process, thereby highlighting the potential role of this process in the pathogenesis of Pb-associated myocardial injury.

An EMT-related genes signature as a prognostic biomarker for patients with endometrial cancer.

BACKGROUND: The epithelial-mesenchymal transition (EMT) plays an indispensable role in the development and progression of Endometrial cancer (EC). Nevertheless, little evidence is reported to uncover the functionality and application of EMT-related molecules in the prognosis of EC. This study aims to develop novel molecular markers for prognosis prediction in patients with EC. METHODS: RNA sequencing profiles of EC patients obtained from The Cancer Genome Atlas (TCGA) database were used to screen differential expression genes (DEGs) between tumors and normal tissues. The Cox regression model with the LASSO method was utilized to identify survival-related DEGs and to establish a prognostic signature whose performance was evaluated by Kaplan-Meier curve, receiver operating characteristic (ROC) and calibration curve. Eventually, functional enrichment analysis and cellular experiments were performed to reveal the roles of prognosis-related genes in EC progression. RESULTS: A total of 540 EMT-related DEGs in EC were screened, and subsequently a four-gene risk signature comprising SIRT2, SIX1, CDKN2A and PGR was established to predict overall survival of EC. This risk signature could serve as a meaningfully independent indicator for EC prognosis via multivariate Cox regression (HR = 2.002, 95%CI = 1.433-2.798; P < 0.001). The nomogram integrating the risk signature and clinical characteristics exhibited robust validity and performance at predicting EC overall survival indicated by ROC and calibration curve. Functional enrichment analysis revealed that the EMT-related genes risk signature was associated with extracellular matrix organization, mesenchymal development and cellular component morphogenesis, suggesting its possible relevance to epithelial-mesenchymal transition and cancer progression. Functionally, we demonstrated that the silencing of SIX1, SIRT2 and CDKN2A expression could accelerate the migratory and invasive capacities of tumor cells, whereas the downregulation of PGR dramatically inhibited cancer cells migration and invasion. CONCLUSIONS: Altogether, a novel four-EMT-related genes signature was a potential biomarker for EC prognosis. These findings might help to ameliorate the individualized prognostication and therapeutic treatment of EC patients.

Self-assembled super-small AIEgen nanoprobe for highly sensitive and selective detection of protamine and trypsin.

Amphiphilic aggregation-induced emission (AIE) molecules show superior potential for fabricating novel ultrasmall nanoprobes. Here, an anionic dipyridyl tetraphenylethene (TPE) derivative is rationally designed and a super-small self-assembled AIEgen nanoprobe (TPE-2Py-SO3NaNPs, ca. 2.48 nm) is thus conveniently constructed for the supersensitive detection of protamine and trypsin. In HEPES/DMSO solution (8 : 2, v/v, pH = 7.4), negatively charged TPE-2Py-SO3NaNPs exhibited an AIE effect in the presence of positively charged protamine, presenting a fluorescence enhancement at 498 nm together with a large Stokes shift of 150 nm and a low detection limit of 8.0 ng mL-1. In addition, the in situ formed TPE-2Py-SO3Na/protamine nanocomposite can be dissociated by trypsin due to the highly selective degradation of protamine via enzymatic hydrolysis, achieving a detection limit for trypsin as low as 5.0 ng mL-1.

STING mediates microglial pyroptosis via interaction with NLRP3 in cerebral ischaemic stroke.

BACKGROUND: Ischaemia-evoked neuroinflammation is a critical pathogenic event following ischaemic stroke. Gasdermin D (GSDMD)-associated pyroptosis represents a type of inflammation-associated programmed cell death, which can exacerbate neuroinflammatory responses and brain damage. Stimulator of interferon genes (STING) was recently described as a vital innate immune adaptor protein associated with neuroinflammation. Nevertheless, the regulatory effects of STING on microglial pyroptosis post-stroke have not been well elaborated. METHODS: STING-knockout and wild-type (WT) mice were subjected to middle cerebral artery occlusion (MCAO). STING small interfering RNA (siRNA) was transfected into BV2 cells before oxygen-glucose deprivation/reoxygenation (OGD/R). STING-overexpressing adeno-associated virus (AAV) and NOD-like receptor family pyrin domain containing 3 (NLRP3) siRNA were administered by stereotaxic injection. 2,3,5-Triphenyl tetrazolium chloride (TTC) staining, TdT-mediated dUTP nick end labeling (TUNEL) staining, Fluoro-Jade C (FJC) staining, neurobehavioural tests, immunohistochemistry, cytokine antibody array assay, transmission electron microscopy, immunoblot, Enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR) were carried out. Co-immunoprecipitation assays were used to investigate the interplay between STING and NLRP3. RESULTS: STING expression was increased after MCAO and mainly detected on microglia. STING deletion alleviated brain infarction, neuronal damage and neurobehavioural impairment in mice subjected to MCAO. STING knockout suppressed microglial activation and the secretion of inflammatory chemokines, accompanied by mitigation of microglial pyroptosis. Specific upregulation of microglial STING by AAV-F4/80-STING aggravated brain injury and microglial pyroptosis. Mechanistically, co-immunoprecipitation showed that STING bound to NLRP3 in microglia. Supplementation of NLRP3 siRNA reversed AAV-F4/80-STING-induced deterioration of microglial pyroptosis. CONCLUSIONS: The current findings indicate that STING modulates NLRP3-mediated microglial pyroptosis following MCAO. STING may serve as a therapeutic target in neuroinflammation induced by cerebral ischaemic/reperfusion (I/R) injury.

Novel Topological Motifs and Superconductivity in Li-Cs System.

In this work, we determined the phase diagram and electronic properties of the Li-Cs system by using an evolutionary crystal structure prediction algorithm coupled with first-principles calculations. We found that Li-rich compounds are more easily formed in a wide range of pressures, while the only predicted Cs-rich compound LiCs3 is thermodynamically stable at pressures above 359 GPa. A topological analysis of crystal structures concludes that both Li6Cs and Li14Cs have a unique topology that has not been reported in existing intermetallics. Of particular interest is the fact that four Li-rich compounds (Li14Cs, Li8Cs, Li7Cs, and Li6Cs) are found to be superconductors with a high critical temperature (∼54 K for Li8Cs at 380 GPa), due to their peculiar structural topologies and notable charge transfer from Li to Cs atoms. Our results not only extend an in-depth understanding of the high-pressure behavior of intermetallic compounds but also provide a new route to design new superconductors.

Microglial Priming in Bilirubin-Induced Neurotoxicity.

Neuroinflammation is a major contributor to bilirubin-induced neurotoxicity, which results in severe neurological deficits. Microglia are the primary immune cells in the brain, with M1 microglia promoting inflammatory injury and M2 microglia inhibiting neuroinflammation. Controlling microglial inflammation could be a promising therapeutic strategy for reducing bilirubin-induced neurotoxicity. Primary microglial cultures were prepared from 1-3-day-old rats. In the early stages of bilirubin treatment, pro-/anti-inflammatory (M1/M2) microglia mixed polarization was observed. In the late stages, bilirubin persistence induced dominant proinflammatory microglia, forming an inflammatory microenvironment and inducing iNOS expression as well as the release of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1ß. Simultaneously, nuclear factor-kappa B (NF-κB) was activated and translocated into the nucleus, upregulating inflammatory target genes. As well known, neuroinflammation can have an effect on N-methyl-D-aspartate receptor (NMDAR) expression or function, which is linked to cognition. Treatment with bilirubin-treated microglia-conditioned medium did affect the expression of IL-1ß, NMDA receptor subunit 2A (NR2A), and NMDA receptor subunit 2B (NR2B) in neurons. However, VX-765 effectively reduces the levels of proinflammatory cytokines TNF-α, IL-6, and IL-1ß, as well as the expressions of CD86, and increases the expressions of anti-inflammatory related Arg-1. A timely reduction in proinflammatory microglia could protect against bilirubin-induced neurotoxicity.

Draft Genome Sequence of Fusobacterium vincentii CNGBCC1850030, Isolated from Healthy Human Feces.

Fusobacterium vincentii usually inhabits the oral cavity and plays an important role in periodontal diseases. Here, we report the draft genome sequence of F. vincentii strain CNGBCC1850030, isolated from healthy human feces.

Elabela-APJ axis mediates angiogenesis via YAP/TAZ pathway in cerebral ischemia/reperfusion injury.

Angiogenesis helps to improve neurological recovery by repairing damaged brain tissue and restoring cerebral blood flow (CBF). The role of the Elabela (ELA)-Apelin receptor (APJ) system in angiogenesis has gained much attention. We aimed to investigate the function of endothelial ELA on post-ischemic cerebral angiogenesis. Here, we demonstrated that the endothelial ELA expression was upregulated in the ischemic brain and treatment with ELA-32 mitigated brain injury and enhanced the restoration of CBF and newly formed functional vessels following cerebral ischemia/reperfusion (I/R) injury. Furthermore, ELA-32 incubation potentiated proliferation, migration, and tube formation abilities of the mouse brain endothelial cells (bEnd.3 cells) under oxygen-glucose deprivation/reoxygenation (OGD/R) condition. RNA sequencing analysis indicated that ELA-32 incubation had a role in the Hippo signaling pathway, and improved angiogenesis-related gene expression in OGD/R-exposed bEnd.3 cells. Mechanistically, we depicted that ELA could bind to APJ and subsequently activate YAP/TAZ signaling pathway. Silence of APJ or pharmacological blockade of YAP abolished the pro-angiogenesis effects of ELA-32. Together, these findings highlight the ELA-APJ axis as a potential therapeutic strategy for ischemic stroke by showing how activation of this pathway promotes post-stroke angiogenesis.

Bilirubin Induces A1-Like Reactivity of Astrocyte.

Astrocytes play an important role in the pathogenesis of bilirubin neurotoxicity, and activated astrocytes might be potential mediators of neuroinflammation processes contributing to neuronal cell death and tissue injury. Recent studies have reported that activated microglia induce two types of reactive astrocytes. A1 astrocytes could cause neuronal death and synaptic damage, as well as impaired phagocytosis. Therefore, the purpose of this study was to investigate whether unconjugated bilirubin (UCB)-induced A1-like astrocytes take on a neuroinflammation type and the underlying regulatory mechanisms. In this study, primary cortical astrocytes were treated with UCB in vitro. We detected the expression of complement component 3 (C3), S100 calcium binding protein A10 (S100A10), nuclear factor kappa B (NF-κB), NLR family pyrin domain containing 3 (NLRP3), activated caspase-1, gasdermin D N-terminal (GSDMD-N), PSD95, synaptophysin (SYP), the transcription levels of interleukin (IL)-1ß and IL-18, and the survival rate of astrocytes after UCB treatment. The results showed that an increase in C3 was accompanied by a decrease in S100A10, and that A1-like astrocytes were functionally expressed after UCB stimulation. Meanwhile, the NF-κB and caspase-1 pathways were activated after UCB stimulation. After adding the NF-κB-specific inhibitor trans-activator of transcriptional-NEMO-binding domain (TAT-NBD) and caspase-1 specific inhibitor VX-765, the survival rate of astrocytes and neurons increased, whereas the protein expression of C3, NF-κB, NLRP3, activated caspase-1, and GSDMD-N decreased, and the mRNA levels of IL-1ß and IL-18 reduced. Thus, we concluded that UCB stimulates the activation of A1-like astrocytes. Inhibition of NF-κB and caspase-1 alleviated A1-like astrocytes and exerted anti-inflammatory protective effects.

'Stress hyperglycemia ratio and in-hospital prognosis in non-surgical patients with heart failure and type 2 diabetes.

OBJECTIVE: To evaluate the impact of stress hyperglycemia on the in-hospital prognosis in non-surgical patients with heart failure and type 2 diabetes. RESEARCH DESIGN AND METHODS: We identified non-surgical hospitalized patients with heart failure and type 2 diabetes from a large electronic medical record-based database of diabetes in China (WECODe) from 2011 to 2019. We estimated stress hyperglycemia using the stress hyperglycemia ratio (SHR) and its equation, say admission blood glucose/[(28.7 × HbA1c)- 46.7]. The primary outcomes included the composite cardiac events (combination of death during hospitalization, requiring cardiopulmonary resuscitation, cardiogenic shock, and the new episode of acute heart failure during hospitalization), major acute kidney injury (AKI stage 2 or 3), and major systemic infection. RESULTS: Of 2875 eligible Chinese adults, SHR showed U-shaped associations with composite cardiac events, major AKI, and major systemic infection. People with SHR in the third tertile (vs those with SHR in the second tertile) presented higher risks of composite cardiac events ([odds ratio, 95% confidence interval] 1.89, 1.26 to 2.87) and major AKI (1.86, 1.01 to 3.54). In patients with impaired kidney function at baseline, both SHR in the first and third tertiles anticipated higher risks of major AKI and major systemic infection. CONCLUSIONS: Both high and low SHR indicates poor prognosis during hospitalization in non-surgical patients with heart failure and type 2 diabetes.

A female case with novel KDM5C heterozygous variation presenting with Claes-Jensen type-like phonotype.

BACKGROUND: Lysine(K)-specific demethylase 5C (KDM5C) dysfunction causes X-linked syndromic intellectual developmental disorder Claes-Jensen type in male patients. The clinical presentations of female individuals with heterozygous KDM5C variations vary widely and are only now beginning to be characterized in detail. CASE PRESENTATION: Herein, we identified a novel de novo heterozygous nonsense variation of KDM5C (c.3533C > A, p.S1178X) in a sporadic 4-year-old Chinese girl, who presented with Claes-Jensen type-like phenotypes, such as moderate developmental delay, serious expressive language delay, short stature, microcephaly, and typical facial particularities. Moreover, X-chromosome inactivation (XCI) analysis showed no significant skewed X-inactivation. CONCLUSION: The report expands the genotype of KDM5C variation in female patients, delineates the phenotype of affected females in this well-known X-linked disorder, and also reinforces the necessity to consider this X-linked gene, KDM5C, in sporadic female patients.