A spontaneous hyperglycaemic cynomolgus monkey presents cognitive deficits, neurological dysfunction and cataract.

Chronic hyperglycaemia is a chief feature of diabetes mellitus and complicates with many systematic anomalies. Non-human primates (NHPs) are excellent for studying hyperglycaemia or diabetes and associated comorbidities, but lack behavioural observation. In the study, behavioural, brain imaging and histological analysis were performed in a case of spontaneously hyperglycaemic (HGM) Macaca fascicularis. The results were shown that the HGM monkey had persistent body weight loss, long-term hyperglycaemia, insulin resistance, dyslipidemia, but normal concentrations of insulin, C-peptide, insulin autoantibody, islet cell antibody and glutamic acid decarboxylase antibody. Importantly, an impaired working memory in a delayed response task and neurological dysfunctions were found in the HGM monkey. The tendency for atrophy in hippocampus was observed by magnetic resonance imaging. Lenticular opacification, lens fibres disruptions and vacuole formation also occurred to the HGM monkey. The data suggested that the spontaneous HGM monkey might present diabetes-like characteristics and associated neurobehavioral anomalies in this case. This study first reported cognitive deficits in a spontaneous hyperglycaemia NHPs, which might provide evidence to use macaque as a promising model for translational research in diabetes and neurological complications.

Targeting Fatty Acid Desaturase I Inhibits Renal Cancer Growth Via ATF3-mediated ER Stress Response.

Monounsaturated fatty acids (MUFAs) play a pivotal role in maintaining endoplasmic reticulum (ER) homeostasis, an emerging hallmark of cancer. However, the role of polyunsaturated fatty acid (PUFAs) desaturation in persistent ER stress driven by oncogenic abnormalities remains elusive. Fatty Acid Desaturase 1 (FADS1) is a rate-limiting enzyme controlling the bioproduction of long-chain PUFAs. Our previous research has demonstrated the significant role of FADS1 in cancer survival, especially in kidney cancers. We explored the underlying mechanism in this study. We found that pharmacological inhibition or knockdown of the expression of FADS1 effectively inhibits renal cancer cell proliferation and induces cell cycle arrest. The stable knockdown of FADS1 also significantly inhibits tumor formation in vivo. Mechanistically, we show that while FADS1 inhibition induces ER stress, its expression is also augmented by ER-stress inducers. Notably, FADS1-inhibition sensitized cellular response to ER stress inducers, providing evidence of FADS1's role in modulating the ER stress response in cancer cells. We show that, while FADS1 inhibition-induced ER stress leads to activation of ATF3, ATF3-knockdown rescues the FADS1 inhibition-induced ER stress and cell growth suppression. In addition, FADS1 inhibition results in the impaired biosynthesis of nucleotides and decreases the level of UPD-N-Acetylglucosamine, a critical mediator of the unfolded protein response. Our findings suggest that PUFA desaturation is crucial for rescuing cancer cells from persistent ER stress, supporting FADS1 as a new therapeutic target.

Vesicular translocation of PARP-1 to cytoplasm causes ADP-ribosylation and disassembly of vimentin filaments during microglia activation induced by LPS.

ADP-ribosylation plays a significant role in various biological processes including genomic stability maintenance, transcriptional regulation, energy metabolism, and cell death. Using macrodomain pull-down assay with microglia lysates and MALDI-TOF-MS analysis, we identified vimentin as a major protein highly ADP-ribosylated by the poly(ADP-ribose) polymerases-1 (PARP-1) in response to LPS. ABT-888, a potent inhibitor of PARP-1/2 blocks the disassembly and ADP-ribosylation of vimentin. PARP-1 is a highly abundant nuclear protein. Its nuclear functions in repairing DNA damages induced by various stress signals, such as inflammatory stresses, have been well studied. In contrast, limited studies have been done on the cytoplasmic role(s) of PARP-1. Our study focuses on the cytoplasmic role of PARP-1 during microglia activation. Using immunofluorescence microscopy and Western blotting, we showed that a significant amount of PARP-1 is present in the cytosol of microglia cells stimulated and activated by LPS. Live cell imaging showed the translocation of nuclear PARP-1-EGFP to the cytoplasm in vesicular structures upon LPS stimulation. ABT-888 and U0126 can block this translocation. Immunofluorescence staining with various organelle marker antibodies revealed that PARP-1 vesicles show colocalization with Lamin A/C, suggesting they might be derived from the nuclear envelope through nuclear envelope budding. In conclusion, we demonstrated that PARP-1 is translocated from the nucleus to cytoplasm via vesicles upon LPS stimulation and that cytoplasmic PARP-1 causes ADP-ribosylation and disassembly of vimentin filaments during microglia activation induced by LPS.

Protocol for identifying stressed granulocytes from septic mice.

Sepsis trains stressed granulocytes to boost nonspecific response and trigger a new wave of inflammation when facing secondary infection. Here, we present a protocol for a murine model of sepsis with secondary infection. We describe steps for cecal ligation and puncture operation and rechallenging with lipopolysaccharide or Pseudomonas aeruginosa during the recovery phase. We also detail steps to characterize the stressed granulocytes by assessing their functional phenotypes and effect on the mortality of rechallenged mice. For complete details on the use and execution of this protocol, please refer to Wang et al.1.

The acute toxic effect of Chinese medicine Fuzi is exacerbated in kidney yang deficiency mice due to metabolic difference.

ETHNOPHARMACOLOGICAL RELEVANCE: The proper application of toxic medicines is one of the characteristics of traditional Chinese medicines, and the use of traditional Chinese medicines follows the principle of dialectical treatment. It is necessary to combine different "syndrome" or "disease" states with the toxicity of traditional Chinese medicines to form a reliable toxicity evaluation system. Fuzi, the lateral root of Aconitum carmichaelii Debx, is recognized as a panacea for kidney yang deficiency syndrome, however, its toxic effects significantly limit its clinical application. AIM OF THE STUDY: Herein, our research aimed to explore the toxic effects of Fuzi on syndrome models, and tried to reveal the underlying mechanisms. MATERIALS AND METHODS: Firstly, the mouse model of kidney yang deficiency syndrome was established through intramuscular injection of 25 mg/kg hydrocortisone per day for 10 consecutive days. Then, the acute toxicity of Fuzi in normal mice and kidney yang deficiency model mice was explored. Finally, the plasma metabolite concentrations and liver CYP3A4 enzyme activity were analyzed to reveal the possible mechanisms of the different pharmacological and toxicological effects of Fuzi in individuals with different physical constitutions. RESULTS: It was found that the treatment with Fuzi (138 g/kg) had serious toxic effects on kidney yang deficiency mice, leading to the death of 80% of the mice, whereas it showed no lethal toxicity in normal mice. This indicates that Fuzi induced greater toxicity in kidney yang deficiency mice than in normal ones. The liver CYP3A4 enzyme activity in kidney yang deficiency mice was decreased by 20% compared to the controls, resulting in slower metabolism of the toxic diester diterpenoid alkaloids in Fuzi. CONCLUSION: In conclusion, our study showed that changes of the metabolic enzyme activity in individuals with different syndromes led to different toxic effects of Chinese medicines, emphasizing the crucial importance of considering individual physical syndromes in the clinical application of traditional Chinese medicine, and the significance of conducting safety evaluations and dose predictions on animal models with specific syndromes for traditional Chinese medicines.

Targeting STING elicits GSDMD-dependent pyroptosis and boosts anti-tumor immunity in renal cell carcinoma.

While Stimulator-of-interferon genes (STING) is an innate immune adapter cruicial for sensing cytosolic DNA and modulating immune microenvironment, its tumor-promoting role in tumor survival and immune evasion remains largely unknown. Here we reported that renal cancer cells are exceptionally dependent on STING for survival and evading immunosurveillance via suppressing ER stress-mediated pyroptosis. We found that STING is significantly amplified and upregulated in clear cell renal cell carcinoma (ccRCC), and its elevated expression is associated with worse clinical outcomes. Mechanically, STING depletion in RCC cells specifically triggers activation of the PERK/eIF2α/ATF4/CHOP pathway and activates cleavage of Caspase-8, thereby inducing GSDMD-mediated pyroptosis, which is independent of the innate immune pathway of STING. Moreover, animal study revealed that STING depletion promoted infiltration of CD4+ and CD8+ T cells, consequently boosting robust antitumor immunity via pyroptosis-induced inflammation. From the perspective of targeted therapy, we found that Compound SP23, a PROTAC STING degrader, demonstrated comparable efficacy to STING depletion both in vitro and in vivo for treatment of ccRCC. These findings collectively unveiled an unforeseen function of STING in regulating GSDMD-dependent pyroptosis, thus regulating immune response in RCC. Consequently, pharmacological degradation of STING by SP23 may become an attractive strategy for treatment of advanced RCC.

UPK3A+ umbrella cell damage mediated by TLR3-NR2F6 triggers programmed destruction of urothelium in Hunner-type interstitial cystitis/painful bladder syndrome.

Urothelial damage and barrier dysfunction emerge as the foremost mechanisms in Hunner-type interstitial cystitis/bladder pain syndrome (HIC). Although treatments aimed at urothelial regeneration and repair have been employed, their therapeutic effectiveness remains limited due to the inadequate understanding of specific cell types involved in damage and the lack of specific molecular targets within these mechanisms. Therefore, we harnessed single-cell RNA sequencing to elucidate the heterogeneity and developmental trajectory of urothelial cells within HIC bladders. Through reclustering, we identified eight distinct clusters of urothelial cells. There was a significant reduction in UPK3A+ umbrella cells and a simultaneous increase in progenitor-like pluripotent cells (PPCs) within the HIC bladder. Pseudotime analysis of the urothelial cells in the HIC bladder revealed that cells faced challenges in differentiating into UPK3A+ umbrella cells, while PPCs exhibited substantial proliferation to compensate for the loss of UPK3A+ umbrella cells. The urothelium in HIC remains unrepaired, despite the substantial proliferation of PPCs. Thus, we propose that inhibiting the pivotal signaling pathways responsible for the injury to UPK3A+ umbrella cells is paramount for restoring the urothelial barrier and alleviating lower urinary tract symptoms in HIC patients. Subsequently, we identified key molecular pathways (TLR3 and NR2F6) associated with the injury of UPK3A+ umbrella cells in HIC urothelium. Finally, we conducted in vitro and in vivo experiments to confirm the potential of the TLR3-NR2F6 axis as a promising therapeutic target for HIC. These findings hold the potential to inhibit urothelial injury, providing promising clues for early diagnosis and functional bladder self-repair strategies for HIC patients. © 2024 The Pathological Society of Great Britain and Ireland.

Value of the modified Patient-Generated Subjective Global Assessment in indicating the need for nutrition intervention and predicting overall survival in patients with malignant tumors in at least two organs.

BACKGROUND: Although the Patient-Generated Subjective Global Assessment (PG-SGA) is a reference standard used to assess a patient's nutrition status, it is cumbersome to administer. The aim of the present study was to estimate the value of a simpler and easier-to-use modified PG-SGA (mPG-SGA) to evaluate the nutrition status and need for intervention in patients with malignant tumors present in at least two organs. METHODS: A total of 591 patients (343 male and 248 female) were included from the INSCOC study. A Pearson correlation analysis was conducted to assess the correlation between the mPG-SGA and nutrition-related factors, with the optimal cut-off defined by a receiver operating characteristic curve (ROC). The consistency between the mPG-SGA and PG-SGA was compared in a concordance analysis. A survival analysis was used to determine the effects of nutritional intervention among different nutrition status groups. Univariable and multivariable Cox analyses were applied to evaluate the association of the mPG-SGA with the all-cause mortality. RESULTS: The mPG-SGA showed a negative association with nutrition-related factors. Individuals with an mPG-SGA ≥ 5 (rounded from 4.5) were considered to need nutritional intervention. Among the malnourished patients (mPG-SGA ≥ 5), the overall survival (OS) of those who received nutrition intervention was significantly higher than that of patients who did not. However, the OS was not significantly different in the better-nourished patients (mPG-SGA < 5). CONCLUSION: Our findings support that the mPG-SGA is a feasible tool that can be used to guide nutritional interventions and predict the survival of patients with malignant tumors affecting at least two organs.

Subcortical structure alteration in patients with drug-induced parkinsonism: Evidence from neuroimaging.

Parkinson's Disease (PD) and Drug-induced parkinsonism (DIP) are the most common subtypes of parkinsonism, yet no studies have reported that the subcortical volume alterations in DIP patients. This study aimed to identify specific alterations of subcortical structures volume in DIP patients, and investigate association between the subcortical structure modifications and clinical symptoms. We recruited 27 PD patients, 25 DIP patients and 30 healthy controls (HCs). The clinical symptom-related parameters (Unified Parkinson's Disease Rating Scale, UPDRS) were evaluated. Structural imaging was performed on a 3.0 T scanner, and volumes of subcortical structures were obtained using FreeSurfer software. Analysis of covariance (ANCOVA) and partial correlation analysis were performed. DIP group had significantly smaller volume of the thalamus, pallidum, hippocampus and amygdala compared to HCs. ROC curve analysis demonstrated that the highest area under curve (AUC) value was in the right pallidum (AUC = 0.831) for evaluating the diagnostic efficacy in DIP from HCs. Moreover, the volumes of the putamen, hippocampus and amygdala were negatively correlated with UPDRSII in the DIP patients. The volume of the amygdala was negatively correlated with UPDRSIII. The present study provides novel information regarding neuroanatomical alteration of subcortical nuclei in DIP patients, suggesting that these methods might provide the basis for early diagnosis and differential diagnosis of DIP.

COVID-19 pandemic waves: Identification and interpretation of global data.

The mention of the COVID-19 waves is as prevalent as the pandemic itself. Identifying the beginning and end of the wave is critical to evaluating the impact of various COVID-19 variants and the different pharmaceutical and non-pharmaceutical (including economic, health and social, etc.) interventions. We demonstrate a scientifically robust method to identify COVID-19 waves and the breaking points at which they begin and end from January 2020 to June 2021. Employing the Break Least Square method, we determine the significance of COVID-19 waves for global-, regional-, and country-level data. The results show that the method works efficiently in detecting different breaking points. Identifying these breaking points is critical for evaluating the impact of the economic, health, social and other welfare interventions implemented during the pandemic crisis. Employing our method with high frequency data effectively determines the start and end points of the COVID-19 wave(s). Identifying waves at the country level is more relevant than at the global or regional levels. Our research results evidenced that the COVID-19 wave takes about 48 days on average to subside once it begins, irrespective of the circumstances.

Association of possible sarcopenia with all-cause mortality in patients with solid cancer: A nationwide multicenter cohort study.

OBJECTIVES: The concept of possible sarcopenia (PS) was recently introduced to enable timely intervention in settings without the technologies required to make a full diagnosis of sarcopenia. This study aimed to investigate the association between PS and all-cause mortality in patients with solid cancer. DESIGN: Retrospective observational study. SETTING AND PARTICIPANTS: 13,736 patients with 16 types of solid cancer who were ≥18 years old. MEASUREMENTS: The presence of both a low calf circumference (men <34 cm or women <33 cm) and low handgrip strength (men <28 kg or women <18 kg) was considered to indicate PS. Harrell's C-index was used to assess prognostic value and the association of PS with mortality was estimated by calculating multivariable-adjusted hazard ratios (HRs). RESULTS: The study enrolled 7207 men and 6529 women (median age = 57.8 years). During a median follow-up of 43 months, 3150 deaths occurred. PS showed higher Harrell's C-index (0.549, 95%CI = [0.541, 0.557]) than the low calf circumference (0.541, 95%CI = [0.531, 0.551], P = 0.037) or low handgrip strength (0.542, 95%CI = [0.532, 0.552], P = 0.026). PS was associated with increased mortality risk in both univariate (HR = 1.587, 95%CI = [1.476, 1.708]) and multivariable-adjusted models (HR = 1.190, 95%CI = [1.094, 1.293]). Sensitivity analyses showed that the association of PS with mortality was robust in different covariate subgroups, which also held after excluding those patients who died within the first 3 months (HR = 1.162, 95%CI = [1.060, 1.273]), 6 months (HR = 1.150, 95%CI = [1.039, 1.274]) and 12 months (HR = 1.139, 95%CI = [1.002, 1.296]) after enrollment. CONCLUSION: PS could independently and robustly predict all-cause mortality in patients with solid cancer. These findings imply the importance of including PS assessment in routine cancer care to provide significant prognostic information to help mitigate sarcopenia-related premature deaths.

Negative emotionality downregulation affects moral choice but not moral judgement of harm: a pharmacological study.

Previous neuroscientific research has expounded on the fundamental role played by emotion during moral decision-making. Negative emotionality has been observed to exert a general inhibitory effect towards harmful behaviors against others. Nevertheless, the downregulation of negative affects at different levels of moral processing (e.g. impersonal versus personal moral dilemmas) alongside its possible interactions with other factors (e.g. perspective taking) hasn't been directly assessed; both of which can assist in predicting future moral decision-making. In the present research, we empirically test (Study 1, N = 41) whether downregulating negative emotionality through pharmacological interventions using lorazepam (a GABA receptor agonist), modulate the permissibility of harm to others -i.e. if participants find it more morally permissible to harm others when harm is unavoidable (inevitable harm moral dilemmas), than when it may be avoided (evitable harm moral dilemmas). Furthermore, using another sample (Study 2, N = 31), we assess whether lorazepam's effect is modulated by different perspective-taking conditions during a moral dilemma task -e.g. "is it morally permissible for you to […]?" (1st person perspective), relative to "is it morally permissible for [x individual] to […]?" (3rd person perspective)-, where the outcome of the different scenarios is controlled. The results of both studies converge, revealing an emotion-dependent, rather than an outcome-dependent, pharmacological modulation. Lorazepam only influenced interpersonal moral judgments when not modulated by the evitable/inevitable condition. Furthermore, there was a significant interaction between perspective-taking and drug administration, as lorazepam exerted a larger effect in modulating moral choices rather than moral judgements.

A sensory signature of unaffected biological parents predicts the risk of autism in their offspring.

AIM: Despite the emphasis on sensory dysfunction phenotypes in the revised diagnostic criteria for autism spectrum disorder (ASD), there has been limited research, particularly in the field of neurobiology, investigating the concordance in sensory features between individuals with ASD and their genetic relatives. Therefore, our objective was to examine whether neurobehavioral sensory patterns could serve as endophenotypic markers for ASD. METHODS: We combined questionnaire- and lab-based sensory evaluations with sensory fMRI measures to examine the patterns of sensory responsivity in 30 clinically diagnosed with ASD, 26 matched controls (CON), and 48 biological parents for both groups (27 parents of individuals with ASD [P-ASD] and 21 for individuals with CON [P-CON]). RESULTS: The ASD and P-ASD groups had higher sensory responsivity and rated sensory stimuli as more unpleasant than the CON and P-CON groups, respectively. They also exhibited greater hemodynamic responses within the sensory cortices. Overlapping activations were observed within these sensory cortices in the ASD and P-ASD groups. Using a machine learning approach with robust prediction models across cohorts, we demonstrated that the sensory profile of biological parents accurately predicted the likelihood of their offspring having ASD, achieving a prediction accuracy of 71.4%. CONCLUSIONS: These findings provide support for the hereditary basis of sensory alterations in ASD and suggest a potential avenue to improve ASD diagnosis by utilizing the sensory signature of biological parents, especially in families with a high risk of ASD. This approach holds promising prospects for early detection, even before the birth of the offspring.

Predicting recurrence and survival in patients with non-metastatic renal-cell carcinoma after nephrectomy: a prospective population-based study with multicenter validation.

BACKGROUND: Accurate prognostication of oncological outcomes is crucial for the optimal management of patients with renal cell carcinoma (RCC) after surgery. Previous prediction models were developed mainly based on retrospective data in the Western populations, and their predicting accuracy remains limited in contemporary, prospective validation. We aimed to develop contemporary RCC prognostic models for recurrence and overall survival (OS) using prospective population-based patient cohorts and compare their performance with existing, mostly utilized ones. METHODS: In this prospective analysis and external validation study, the development set included 11  128 consecutive patients with non-metastatic RCC treated at a tertiary urology center in China between 2006 and 2022, and the validation set included 853 patients treated at 13 medical centers in the USA between 1996 and 2013. The primary outcome was progression-free survival (PFS), and the secondary outcome was OS. Multivariable Cox regression was used for variable selection and model development. Model performance was assessed by discrimination [Harrell's C-index and time-dependent areas under the curve (AUC)] and calibration (calibration plots). Models were validated internally by bootstrapping and externally by examining their performance in the validation set. The predictive accuracy of the models was compared with validated models commonly used in clinical trial designs and with recently developed models without extensive validation. RESULTS: Of the 11  128 patients included in the development set, 633 PFS and 588 OS events occurred over a median follow-up of 4.3 years [interquartile range (IQR) 1.7-7.8]. Six common clinicopathologic variables (tumor necrosis, size, grade, thrombus, nodal involvement, and perinephric or renal sinus fat invasion) were included in each model. The models demonstrated similar C-indices in the development set (0.790 [95% CI 0.773-0.806] for PFS and 0.793 [95% CI 0.773-0.811] for OS) and in the external validation set (0.773 [0.731-0.816] and 0.723 [0.731-0.816]). A relatively stable predictive ability of the models was observed in the development set (PFS: time-dependent AUC 0.832 at 1 year to 0.760 at 9 years; OS: 0.828 at 1 year to 0.794 at 9 years). The models were well calibrated and their predictions correlated with the observed outcome at 3, 5, and 7 years in both development and validation sets. In comparison to existing prognostic models, the present models showed superior performance, as indicated by C-indices ranging from 0.722 to 0.755 (all P <0.0001) for PFS and from 0.680 to 0.744 (all P <0.0001) for OS. The predictive accuracy of the current models was robust in patients with clear-cell and non-clear-cell RCC. CONCLUSIONS: Based on a prospective population-based patient cohort, the newly developed prognostic models were externally validated and outperformed the currently available models for predicting recurrence and survival in patients with non-metastatic RCC after surgery. The current models have the potential to aid in clinical trial design and facilitate clinical decision-making for both clear-cell and non-clear-cell RCC patients at varying risk of recurrence and survival.

Pseudocapacitance-Dominated MnNb2 O6 -C Nanofiber Anode for Li-Ion Batteries.

MnNb2 O6 anode has attracted much attention owing to its unique properties for holding Li ions. Unluckily, its application as a Li-ion battery anode is restricted by low capacity because of the inferior electronic conductivity and limited electron transfer. Previous studies suggest that structure and component optimization could improve its reversible capacity. This improvement is always companied by capacity increments, however, the reasons have rarely been identified. Herein, MnNb2 O6 -C nanofibers (NFs) with MnNb2 O6 nanoparticles (~15 nm) confined in carbon NFs, and the counterpart MnNb2 O6 NFs consisting of larger nanoparticles (40-100 nm) are prepared by electrospinning for clarifying this phenomenon. The electrochemical evaluations indicate that the capacity achieved by the MnNb2 O6 NF electrode presents an activation process and a degradation in subsequence. Meanwhile, the MnNb2 O6 -C NF electrode delivers high reversible capacity and ultra-stable cycling performance. Further analysis based on electrochemical behaviors and microstructure changes reveals that the partial structure rearrangement should be in charge of the capacity increment, mainly including pseudocapacitance increment. This work suggests that diminishing the dimensions of MnNb2 O6 nanoparticles and further confining them in a matrix could increase the pseudocapacitance-dominated capacity, providing a novel way to improve the reversible capacity of MnNb2 O6 and other intercalation reaction anodes.

Safety, pharmacokinetics and pharmacodynamics of HRS-7535, a novel oral small molecule glucagon-like peptide-1 receptor agonist, in healthy participants: A phase 1, randomized, double-blind, placebo-controlled, single- and multiple-ascending dose, and food effect trial.

AIM: To assess the safety, tolerability, pharmacokinetics (PKs) and pharmacodynamics of HRS-7535, a novel glucagon-like peptide-1 receptor agonist (GLP-1RA), in healthy participants. MATERIALS AND METHODS: This phase 1 trial consisted of single-ascending dose (SAD), food effect (FE) and multiple-ascending dose (MAD) parts. In the SAD part, participants were randomized (6:2) to receive HRS-7535 (at doses of 15, 60 and 120 mg; administered orally once daily) or placebo. In the FE part, participants were randomized (8:2) to receive a single dose of 90-mg HRS-7535 or placebo, in both fed and fasted states. In the MAD part, participants were randomized (18:6) to receive daily HRS-7535 (120 mg [30/60/90/120-mg titration scheme]) or placebo for 28 days. The primary endpoints were safety and tolerability. RESULTS: Nausea and vomiting were the most frequently reported AEs across all three parts. In the SAD part, the median Tmax was 5.98-5.99 hours and the geometric mean t1/2 was 5.28-9.08 hours across the HRS-7535 dosing range. In the MAD part, the median Tmax was 5.98-10.98 hours and the geometric mean t1/2 was 6.48-8.42 hours on day 28 in participants on HRS-7535. PKs were approximately dose-proportional. On day 29 in the MAD part, the mean (percentage) reduction in body weight from baseline was 4.38 kg (6.63%) for participants who received HRS-7535, compared with 0.8 kg (1.18%) for those participants who received a placebo. CONCLUSIONS: HRS-7535 exhibited a safety and tolerability profile consistent with other GLP-1RAs and showed PKs suitable for once-daily dosing. These findings support further clinical development of HRS-7535 for type 2 diabetes.

Rapamycin attenuates pyroptosis by suppressing mTOR phosphorylation and promoting autophagy in LPS-induced bronchopulmonary dysplasia.

PURPOSE/AIM: Bronchopulmonary dysplasia (BPD) is associated with poor survival in preterm infants. Intrauterine infection can aggravate the degree of obstruction of alveolar development in premature infants; however, the pathogenic mechanism remains unclear. In this study, we sought to determine whether pyroptosis could be inhibited by downregulating mammalian target of rapamycin (mTOR) activation and inducing autophagy in BPD-affected lung tissue. MATERIALS AND METHODS: We established a neonatal rat model of BPD induced by intrauterine infection via intraperitoneally injecting pregnant rats with lipopolysaccharide (LPS). Subsequently, mTOR levels and pyroptosis were evaluated using immunohistochemistry, immunofluorescence, TUNEL staining, and western blotting. The Shapiro-Wilk test was employed to assess the normality of the experimental data. Unpaired t-tests were used to compare the means between two groups, and comparisons between multiple groups were performed using analysis of variance. RESULTS: Pyroptosis of lung epithelial cells increased in BPD lung tissues. After administering an mTOR phosphorylation inhibitor (rapamycin) to neonatal rats with BPD, the level of autophagy increased, while the expression of autophagy cargo adaptors, LC3 and p62, did not differ. Following rapamycin treatment, NLRP3, Pro-caspase-1, caspase-1, pro-IL-1ß, IL-1ß, IL-18/Pro-IL-18, N-GSDMD/GSDMD, Pro-caspase-11, and caspase-11 were negatively regulated in BPD lung tissues. The opposite results were observed after treatment with the autophagy inhibitor MHY1485, showing an increase in pyroptosis and a significant decrease in the number of alveoli in BPD. CONCLUSIONS: Rapamycin reduces pyroptosis in neonatal rats with LPS-induced BPD by inhibiting mTOR phosphorylation and inducing autophagy; hence, it may represent a potential therapeutic for treating BPD.

Kinetically well-matched porous framework dual carbon electrodes for high-performance sodium-ion hybrid capacitors.

Sodium-ion hybrid capacitors (SIHCs) have attracted extensive interest due to their applications in sodium-ion batteries and capacitors, which have been considered expectable candidates for large-scale energy storage systems. The crucial issues for achieving high-performance SIHCs are the reaction kinetics imbalances between the slow Faradic battery-type anodes and fast non-Faradaic capacitive cathodes. Herein, we propose a simple self-template strategy to prepare kinetically well-matched porous framework dual-carbon electrodes for high-performance SIHCs, which stem from the single precursor, sodium ascorbate. The porous framework carbon (PFC) is obtained by direct calcination of sodium ascorbate followed by a washing process. The sodium-ion half cells with PFC anodes exhibit high reversible capacity and fast electrochemical kinetics for sodium storage. Moreover, the as-obtained PFC can be further converted to porous framework activated carbon (PFAC) with rich porosity and a high specific surface area, which displays high capacitive properties. By using kinetically well-matched battery-type PFC anodes and capacitive PFAC cathodes, dual-carbon SIHCs are successfully assembled, which can work well in 0-4 V. The optimal PFC//PFAC SIHC exhibits high energy density (101.6 Wh kg-1 at 200 W kg-1), power density (20 kW kg-1 at 51.1 Wh kg-1), and cyclic performance (71.8 % capacitance attenuation over 10,000 cycles).

A heterozygous pathogenic variant in the ATP6V1A gene triggering epilepsy in a large Chinese pedigree.

Epilepsy is one of the most common disorders in children, with an incidence rate of approximately 5%. Although an increasing number of genes have been demonstrated to be pathogenic factors in epilepsy, evidence for a potential pathogenic role of ATP6V1A remains limited. Herein, the clinical and genetic data of a 5-year-old boy who experienced seizures at 9 months of age are collected. Genetic variants are screened using whole-exome sequencing (WES), and the effects of the candidate variants are further validated at both the RNA and protein levels. WES reveals a heterozygous variant [NM_001690.4: c .1132 C>T, p.Leu378Phe] of the ATP6V1A gene. This variant is not reported in the public database, but is predicted to be deleterious by multiple software packages, and classified as a variant of unknown significance following the American College of Medical Genetics and Genomics guidelines. Quantitative PCR and western blotting further confirm its down-regulatory role in both the RNA and protein expression of ATP6V1A. This case report confirms the pathogenicity of ATP6V1A in epilepsy with solid experimental evidence, thereby expanding the phenotype spectrum of ATP6V1A variants. More importantly, we show that seizures triggered by ATP6V1A variants could be controlled by Levetiracetam, crucially rescuing the development of the patient.