The complex roles of m 6 A modifications in neural stem cell proliferation, differentiation, and self-renewal and implications for memory and neurodegenerative diseases.

N6-methyladenosine (m 6 A), the most prevalent and conserved RNA modification in eukaryotic cells, profoundly influences virtually all aspects of mRNA metabolism. mRNA plays crucial roles in neural stem cell genesis and neural regeneration, where it is highly concentrated and actively involved in these processes. Changes in m 6 A modification levels and the expression levels of related enzymatic proteins can lead to neurological dysfunction and contribute to the development of neurological diseases. Furthermore, the proliferation and differentiation of neural stem cells, as well as nerve regeneration, are intimately linked to memory function and neurodegenerative diseases. This paper presents a comprehensive review of the roles of m 6 A in neural stem cell proliferation, differentiation, and self-renewal, as well as its implications in memory and neurodegenerative diseases. m 6 A has demonstrated divergent effects on the proliferation and differentiation of neural stem cells. These observed contradictions may arise from the time-specific nature of m 6 A and its differential impact on neural stem cells across various stages of development. Similarly, the diverse effects of m 6 A on distinct types of memory could be attributed to the involvement of specific brain regions in memory formation and recall. Inconsistencies in m 6 A levels across different models of neurodegenerative disease, particularly Alzheimer's disease and Parkinson's disease, suggest that these disparities are linked to variations in the affected brain regions. Notably, the opposing changes in m 6 A levels observed in Parkinson's disease models exposed to manganese compared to normal Parkinson's disease models further underscore the complexity of m 6 A's role in neurodegenerative processes. The roles of m 6 A in neural stem cell proliferation, differentiation, and self-renewal, and its implications in memory and neurodegenerative diseases, appear contradictory. These inconsistencies may be attributed to the time-specific nature of m 6 A and its varying effects on distinct brain regions and in different environments.

The genetic basis of leaf hair development in upland cotton (Gossypium hirsutum).

Trichomes, which originate from the epidermal cell of aerial organs, provide plants with defense and secretion functions. Although numerous genes have been implicated in trichome development, the molecular mechanisms underlying trichome cell formation in plants remain incompletely understood. Here, we using genome-wide association study (GWAS) across 1037 diverse accessions in upland cotton (Gossypium hirsutum) to identify three loci associated with leaf pubescence (hair) amount, located on chromosome A06 (LPA1), A08 (LPA2) and A11 (LPA3), respectively. GhHD1, a previously characterized candidate gene, was identified on LPA1 and encodes an HD-Zip transcription factor. For LPA2 and LPA3, we identified two candidate genes, GhGIR1 and GhGIR2, both encoding proteins with WD40 and RING domains that act as inhibitors of leaf hair formation. Expression analysis revealed that GhHD1 was predominantly expressed in hairy accessions, whereas GhGIR1 and GhGIR2 were expressed in hairless accessions. Silencing GhHD1 or overexpressing GhGIR1 in hairy accessions induced in a hairless phenotype, whereas silencing GhGIR2 in hairless accessions resulted in a hairy phenotype. We also demonstrated that GhHD1 interact with both GhGIR1 and GhGIR2, and GhGIR1 can interact with GhGIR2. Further investigation indicated that GhHD1 functions as a transcriptional activator, binding to the promoters of the GhGIR1 and GhGIR2 to active their expression, whereas GhGIR1 and GhGIR2 can suppress the transcriptional activation of GhHD1. Our findings shed light on the intricate regulatory network involving GhHD1, GhGIR1 and GhGIR2 in the initiation and development of plant epidermal hairs in cotton.

Solution-Processed Polymer Memcapacitors with Stimulus-Controlled and Evolvable Synaptic Functionalities: From Short-Term Plasticity to Long-Term Plasticity to Metaplasticity.

In the vanguard of neuromorphic engineering, we develop a paradigm of biocompatible polymer memcapacitors using a seamless solution process, unleashing comprehensive synaptic capabilities depending on both the stimulation form and history. Like the human brain to learn and adapt, the memcapacitors exhibit analogue-type and evolvable capacitance shifts that mirror the complex flexibility of synaptic strengthening and weakening. With increasing frequency and intensity of the stimulation, the memcapacitors demonstrate an evolution from short-term plasticity (STP) to long-term plasticity (LTP), and even to metaplasticity (MP) at a higher level. A physical picture, featuring the stimulus-controlled spatiotemporal ion redistribution in the polymer, elaborates the origin of the memcapacitive prowess and resultant versatile synaptic plasticity. The distinctive MP behavior endows the memcapacitors with a dynamic learning rate (LR), which is utilized in an artificial neural network. The superiority of implementing a dynamic LR compared with conventional practices of using constant LR shines light on the potential of the memcapacitors to exploit organic neuromorphic computing hardware.

Trends in diabetic ketoacidosis- and hyperosmolar hyperglycemic state-related mortality during the COVID-19 pandemic in the United States: A population-based study.

BACKGROUND: During the pandemic, a notable increase in diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS), conditions that warrant emergent management, was reported. We aimed to investigate the trend of DKA- and HHS-related mortality and excess deaths during the pandemic. METHODS: Annual age-standardized mortality rates related to DKA and HHS between 2006 and 2021 were estimated using a nationwide database. Forecast analyses based on prepandemic data were conducted to predict the mortality rates during the pandemic. Excess mortality rates were calculated by comparing the observed versus predicted mortality rates. Subgroup analyses of demographic factors were performed. RESULTS: There were 71 575 DKA-related deaths and 8618 HHS-related deaths documented during 2006-2021. DKA, which showed a steady increase before the pandemic, demonstrated a pronounced excess mortality during the pandemic (36.91% in 2020 and 46.58% in 2021) with an annual percentage change (APC) of 29.4% (95% CI: 16.0%-44.0%). Although HHS incurred a downward trend during 2006-2019, the excess deaths in 2020 (40.60%) and 2021 (56.64%) were profound. Pediatric decedents exhibited the highest excess mortality. More than half of the excess deaths due to DKA were coronavirus disease 2019 (COVID-19) related (51.3% in 2020 and 63.4% in 2021), whereas only less than a quarter of excess deaths due to HHS were COVID-19 related. A widened racial/ethnic disparity was observed, and females exhibited higher excess mortality than males. CONCLUSIONS: The DKA- and HHS-related excess mortality during the pandemic and relevant disparities emphasize the urgent need for targeted strategies to mitigate the escalated risk in these populations during public health crises.

Dual-Model Derailment Detection Algorithm Based on Variational Bayesian Kalman Filtering.

A derailment detection algorithm for railway freight cars based on micro inertial measurement units was designed to address the complex issue of the disassembly and assembly of derailment braking devices. Firstly, a horizontal attitude measurement model for freight cars was established, and attitude measurement algorithms based on gyroscopes and accelerometers were introduced. Subsequently, a high-precision attitude measurement algorithm based on variational Bayesian Kalman filtering was proposed, which used acceleration information as the observation data to correct attitude errors. In order to improve the accuracy of derailment detection, a dual-model instantaneous attitude difference measurement technique was further proposed. In order to verify the effectiveness of the algorithm, offline data from simulation experiments and in-vehicle experiments were used to validate the proposed algorithm. The results showed that the proposed algorithm can effectively improve the measurement accuracy of horizontal attitude changes, reducing the error by 89% compared to pure inertial attitude calculation, laying a technical foundation for improving the accuracy of derailment detection.

Protocol for Evaluating the Efficacy and Safety of Radiotherapy for Prostate and Oligometastatic Lesions in Patients With Low-Burden Sensitive Oligometastatic Prostate Cancer: An Open, Exploratory Pilot Clinical Trial.

INTRODUCTION: The existing large prospective study demonstrates the benefits of primary radiotherapy in patients with low-volume oligometastatic prostate cancer (OMPC), and there is additional evidence of the benefits of local metastasis-directed therapy (MDT) for metastatic lesions. However, there are no results from a prospective study to demonstrate the efficacy of radiotherapy for prostate and oligometastases. Therefore, the aim of the protocol is to illustrate the efficacy of radiotherapy for prostate and oligometastatic lesions in patients with low-volume de novo hormone-sensitive OMPC. METHODS AND ANALYSIS: This study involves a prospective, single-center, limited-sample, single-arm exploration of radiotherapy for prostate and oligometastatic lesions in patients diagnosed with low-volume hormone-sensitive OMPC. Eligible participants undergo thorough assessments and treatment involving endocrine therapy alongside radiation targeting metastatic lesions and the pelvic region. The primary site is treated with volumetric modulated arc therapy (VMAT), while metastatic sites are treated with either VMAT or stereotactic body radiation therapy (SBRT) depending on their location. All patients received radiation therapy for both the primary and metastatic lesions combined with endocrine therapy. Endocrine therapy with an antiandrogen (bicalutamide, for 4 weeks) androgen deprivation therapy combined with novel hormonal agents (acetate abiraterone) will be continued for 2 years. The primary objective is to evaluate progression-free survival-2 (PFS-2), while secondary endpoints include androgen deprivation therapy (ADT)-free survival, quality of life (QoL), overall survival, time to castration-resistant prostate cancer (CRPC), radiation-related complications, and endocrine therapy-related adverse events. ETHICS AND DISSEMINATION: Approval was obtained from the ethics committee of the First Affiliated Hospital of Naval Medical University (CHEC2023-220). This is a single-arm exploration pilot trial evaluating radiotherapy for prostate and oligometastatic lesions in patients with OMPC. It aims to disseminate its findings through peer-reviewed journals and relevant medical conferences, with the intention of publication and presentation at these events. TRIAL REGISTRATION NUMBERS: Clinicaltrials.gov identifier NCT06198387.

The strigolactone-gibberellin crosstalk mediated by a distant silencer fine-tunes plant height in upland cotton.

The optimal plant height is crucial in modern agriculture, influencing lodging resistance and facilitating mechanized crop production. Upland cotton (Gossypium hirsutum) is the most crucial fiber crop globally, but the knowledge of the genetic basis underlying plant height still needs to be discovered. Here we conducted a genome-wide association study (GWAS) to identify the major locus controlling plant height (PH1) in upland cotton. The locus encodes gibberellin 2-oxidase 1A (GhPH1), with a 1,133 bp-length structural variation (PAVPH1) located approximately 16 kb upstream of it. The presence or absence of PAVPH1 confers a differential expression of GhPH1, consequently leading to changes in plant height. Further analysis revealed that a gibberellin-regulating transcription factor (GhGARF) recognizes a specific 'CATTTG' motif on the GhPH1 promoter and PAVPH1. This binding event down-regulates GhPH1, indicating that PAVPH1 functions as a distant upstream silencer. Intriguingly, we found that the critical repressor of the strigolactone (SL) signaling pathway, DWARF53 (D53), directly interacts with GhGARF and inhibits its binding to targets. Moreover, our study uncovers a previously unrecognized GA-SL crosstalk mechanism mediated by the GhD53-GhGARF-GhPH1/PAVPH1 module, crucial in regulating the plant height of upland cotton. These findings shed light on the genetic basis and gene interaction network underlying plant height and provide valuable insights for developing semi-dwarf cotton varieties through precise modulation of GhPH1 expression.

Evaluation of feline mesenchymal stem cell susceptibility to feline viruses.

Feline mesenchymal stem cells (fMSCs) are well known for their robust differentiation capabilities and are commonly used in studying immune-related diseases in cats. Despite their importance, the susceptibility of fMSCs to viral infections remains uncertain. This study aimed to assess the susceptibility of feline adipose-derived mesenchymal stem cells (fAD-MSCs) and feline umbilical cord-derived mesenchymal stem cells (fUC-MSCs) to common feline viruses, including feline coronavirus (FCoV), feline herpesvirus type 1 (FHV-1), and feline panleukopenia virus (FPV). The results demonstrated that both FCoV and FHV-1 were able to infect both types of cells, while FPV did not exhibit cytopathic effects on fUC-MSCs. Furthermore, all three viruses were successfully isolated from fAD-MSCs. These findings suggest that certain feline viruses can replicate in fMSCs, indicating potential limitations in using fMSCs for treating viral diseases caused by these specific viruses. This study has important clinical implications for veterinarians, particularly in the management of viral diseases.

Isolation of the Initial Bovine Alphaherpesvirus 1 Isolate from Yanbian, China.

Bovine infectious rhinotracheitis (IBR), caused by bovine alphaherpesvirus 1 (BoAHV1), poses significant challenges to the global cattle industry due to its high contagiousness and economic impact. In our study, we successfully isolated a BoAHV1 strain from suspected infected bovine nasal mucus samples in Yanji city, revealing genetic similarities with strains from Sichuan, Egypt, and the USA, while strains from Xinjiang, Beijing, Hebei, and Inner Mongolia showed more distant associations, indicating potential cross-border transmission. Additionally, our investigation of BoAHV1 infection dynamics within host cells revealed early upregulation of gB, which is critical for sustained infection, while the expression of gC and gD showed variations compared to previous studies. These findings enhance our understanding of BoAHV1 diversity and infection kinetics, underscoring the importance of international collaboration for effective surveillance and control strategies. Furthermore, they lay the groundwork for the development of targeted therapeutics and vaccines to mitigate the impact of IBR on the cattle industry.

Accelerated biological aging elevates the risk of cardiometabolic multimorbidity and mortality.

Associations of biological aging with the development and mortality of cardiometabolic multimorbidity (CMM) remain unclear. Here we conducted a multistate analysis in 341,159 adults of the UK Biobank. CMM was defined as the coexistence of two or three cardiometabolic diseases (CMDs), including type 2 diabetes, ischemic heart disease and stroke. Biological aging was measured using the Klemera-Doubal Method Biological Age and PhenoAge algorithms. Over a median follow-up of 8.84 years, biologically older participants demonstrated robust higher risks from first CMD to CMM and then to death. In particular, adjusted hazard ratios for first CMD to CMM and for CMM to death were 1.15 (95% confidence interval (CI): 1.12, 1.19) and 1.26 (95% CI: 1.17, 1.35) per 1 s.d. increase in PhenoAge acceleration, respectively. Compared with frailty, Framingham Risk Score and Systematic Coronary Risk Evaluation 2 (SCORE2), biological aging measures yielded consistent substantial associations with CMM development. Accelerated biological aging may help identify individuals with CMM risks, potentially enabling early intervention and subclinical prevention.

UPCARE: Urinary Extracellular Vesicles-Derived Prostate Cancer Assessment for Risk Evaluation.

In the quest for efficient tumor diagnosis via liquid biopsy, extracellular vesicles (EVs) have shown promise as a source of potential biomarkers. This study addresses the gap in biomarker efficacy for predicting clinically significant prostate cancer (csPCa) between the Western and Chinese populations. We developed a urinary extracellular vesicles-based prostate score (EPS) model, utilizing the EXODUS technique for EV isolation from 598 patients and incorporating gene expressions of FOXA1, PCA3, and KLK3. Our findings reveal that the EPS model surpasses prostate-specific antigen (PSA) testing in diagnostic accuracy within a training cohort of 234 patients, achieving an area under the curve (AUC) of 0.730 compared to 0.659 for PSA (p = 0.018). Similarly, in a validation cohort of 101 men, the EPS model achieved an AUC of 0.749, which was significantly better than PSA's 0.577 (p < 0.001). Our model has demonstrated a potential reduction in unnecessary prostate biopsies by 26%, with only a 3% miss rate for csPCa cases, indicating its effectiveness in the Chinese population.

Ginsenoside Rg2 Attenuates Aging-Induced Liver Injury via Inhibiting Caspase 8-Mediated Pyroptosis, Apoptosis and Modulating Gut Microbiota.

Aging is an irresistible natural law of the progressive decline of body molecules, organs, and overall function with the passage of time, resulting in eventual death. World Health Organization data show that aging is correlated with a wide range of common chronic diseases in the elderly, and is an essential driver of many diseases. Panax Ginseng C.A Meyer is an ancient herbal medicine, which has an effect of "long service, light weight, and longevity" recorded in the ancient Chinese medicine book "Compendium of Materia Medica." Ginsenoside Rg2, the main active ingredient of ginseng, also exerts a marked effect on the treatment of liver injury. However, it remains unclear whether Rg2 has the potential to ameliorate aging-induced liver injury. Hence, exploring the hepatoprotective properties of Rg2 and its possible molecular mechanism by Senescence Accelerate Mouse Prone 8 (SAMP8) and gut microbiota. Our study demonstrated that Rg2 can inhibit pyroptosis and apoptosis through caspase 8, and regulate the gut-liver axis to alleviate liver inflammation by changing the composition of gut microbiota, thus improving aging-induced liver injury. These findings provide theoretical support for the pharmacological effects of ginsenosides in delaying aging-induced liver injury.

Clean air policy reduces the atherogenic lipid profile levels: Results from China Health Evaluation And risk Reduction through nationwide Teamwork (ChinaHEART) Study.

Evidence of the associations between long-term exposure to PM2.5 and O3 and human blood lipid concentrations is abundant yet inconclusive. Whether clean air policies could improve lipid profiles remains unclear. In total, 2979312 participants from a Chinese nationwide prospective study were included. For cross-sectional analyses, linear mixed-effects models were utilized to assess the associations of pollutants with lipid profiles (TC, LDL-C, TG, HDL-C). For longitudinal analyses, a quasi-experimental design and difference-in-differences models were employed to investigate the impact of China's Clean Air Act. In the cross-sectional analyses, each IQR increase in PM2.5 was associated with 2.49 % (95 % CI: 2.36 %, 2.62 %), 2.51 % (95 % CI: 2.26 %, 2.75 %), 3.94 % (95 % CI: 3.65 %, 4.23 %), and 1.54 % (95 % CI: 1.38 %, 1.70 %) increases in TC, LDL-C, TG, and HDL-C, respectively. For each IQR increase in O3, TC, LDL-C, TG, and HDL-C changed by 1.06 % (95 % CI: 0.95 %, 1.17 %), 1.21 % (95 % CI: 1.01 %, 1.42 %), 1.78 % (95 % CI: 1.54 %, 2.02 %), and -0.63 % (95 % CI: -0.76 %, -0.49 %), respectively. Longitudinal analyses showed that the intervention group experienced greater TC, LDL-C, and HDL-C reductions (1.77 %, 4.26 %, and 7.70 %, respectively). Our findings suggest that clean air policies could improve lipid metabolism and should be implemented in countries with heavy air pollution burdens.

Sensitivity of triple negative breast cancer cells to ATM-dependent ferroptosis induced by sodium selenite.

Targeting ferroptosis, a type of cell death elicited by Fe2+ and lipid reactive oxygen species (L-ROS), provides a novel strategy for cancer therapy. Selenium has the potential to treat cancers by acting as a pro-oxidative agent, thus leading to cancer cell death. Here, we found that the triple negative breast cancer (TNBC) MDA-MB-231 cells were more sensitive to ferroptosis induced by sodium selenite (Na2SeO3) than that of non-TNBC MCF-7 cells. Na2SeO3 significantly elevated the level of L-ROS, MDA and Fe2+, decreased the content of GSH and the enzyme activity of GPx, disrupted the expression of ferroptosis related proteins such as GPx4 and FTH1, as well as compromised mitochondrial morphology in MDA-MB-231 cells. Moreover, ATM was activated by Na2SeO3 in MDA-MB-231 cells. Notably, Na2SeO3-induced ferroptosis was inhibited by ATM kinase inhibitor KU55933 or siATM, suggesting that Na2SeO3-induced ferroptosis was mediated by ATM protein in MDA-MB-231 cells. Our findings suggest a therapeutic strategy by ferroptosis against TNBC and deepened our understanding of ATM function.

Proteomic landscape profiling of primary prostate cancer reveals a 16-protein panel for prognosis prediction.

Prostate cancer (PCa) is the most common malignant tumor in men. Currently, there are few prognosis indicators for predicting PCa outcomes and guiding treatments. Here, we perform comprehensive proteomic profiling of 918 tissue specimens from 306 Chinese patients with PCa using data-independent acquisition mass spectrometry (DIA-MS). We identify over 10,000 proteins and define three molecular subtypes of PCa with significant clinical and proteomic differences. We develop a 16-protein panel that effectively predicts biochemical recurrence (BCR) for patients with PCa, which is validated in six published datasets and one additional 99-biopsy-sample cohort by targeted proteomics. Interestingly, this 16-protein panel effectively predicts BCR across different International Society of Urological Pathology (ISUP) grades and pathological stages and outperforms the D'Amico risk classification system in BCR prediction. Furthermore, double knockout of NUDT5 and SEPTIN8, two components from the 16-protein panel, significantly suppresses the PCa cells to proliferate, invade, and migrate, suggesting the combination of NUDT5 and SEPTIN8 may provide new approaches for PCa treatment.

Sex-specific epigenetic signatures of circulating urate and its increase after BCG vaccination.

Background: Urate concentration and the physiological regulation of urate homeostasis exhibit clear sex differences. DNA methylation has been shown to explain a substantial proportion of serum urate variance, mediate the genetic effect on urate concentration, and co-regulate with cardiometabolic traits. However, whether urate concentration is associated with DNA methylation in a sex-dependent manner is unknown. Additionally, it is worth investigating if urate changes after perturbations, such as vaccination, are associated with DNA methylation in a sex-specific manner. Methods: We investigated the association between DNA methylation and serum urate concentrations in a Dutch cohort of 325 healthy individuals. Urate concentration and DNA methylation were measured before and after Bacillus Calmette-Guérin (BCG) vaccination, used as a perturbation associated with increased gout flares. The association analysis included united, interaction, and sex-stratified analysis. Validation of the identified CpG sites was conducted using three independent cohorts. Results: 215 CpG sites were associated with serum urate in males, while 5 CpG sites were associated with serum urate in females, indicating sex-specific associations. Circulating urate concentrations significantly increased after BCG vaccination, and baseline DNA methylation was associated with differences in urate concentration before and after vaccination in a sex-specific manner. The CpG sites associated with urate concentration in males were enriched in neuro-protection pathways, whereas in females, the urate change-associated CpG sites were related to lipid and glucose metabolism. Conclusion: Our study enhances the understanding of how epigenetic factors contribute to regulating serum urate levels in a sex-specific manner. These insights have significant implications for the diagnosis, prevention, and treatment of various urate-related diseases and highlight the importance of personalized and sex-specific approaches in medicine.

In Vivo Detection of Abscisic Acid in Tomato Leaves Based on a Disposable Stainless Steel Electrochemical Immunosensor.

Abscisic acid (ABA) plays an important regulatory role in plants. It is very critical to obtain the dynamic changes of ABA in situ for botanical research. Herein, coupled with paper-based analysis devices, electrochemical immunoelectrodes based on disposable stainless steels sheet were developed for ABA detection in plants in situ. The stainless steel sheets were modified with carbon cement, ferrocene-graphene oxide-multi walled carbon nanotubes nanocomposites, and ABA antibodies. The system can detect the ABA in the range of 1 nM to 100 µM, with a limit of detection of 100 pM. The ABA content in tomato leaves under high salinity was detected in situ. The trend of ABA changes was similar to the expression of SlNCED1 and SlNCED2. Overall, this study offers an approach for in situ detection of ABA in plants, which will help to study the regulation mechanism of ABA in plants and to promote the development of precision agriculture.