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.

Discriminative analysis of aroma profiles in diverse cigar products varieties through integrated sensory evaluation, GC-IMS and E-nose.

Cigars, treasured for their rich aromatic profiles, occupy a notable segment in the global consumer market. The objective of this study was to characterize the volatile aroma compounds that shape the flavor profiles of six distinct varieties of Great Wall cigars, contributing to the understanding of cigar aroma analysis. Utilizing HS-GC-IMS and sensory evaluation, the study discerned the aroma profiles of GJ No. 6 (GJ), Animal from the Chinese zodiac (SX), Range Rover No. 3 Classic (JD), Miracle 132 (QJ), Sheng Shi No. 5 (SS), and Red 132 (HS) cigars. The analysis uncovered a spectrum of characteristic aromas, including tobacco, creaminess, cocoa, leather, baking, herbaceous, leathery, woodsy, and fruity notes. A total of 88 compounds were identified, categorized into 11 chemical classes, with their quantities varying among the cigars in a descending order of QJ, JD, GJ, SS, HS, and SX. 24 compounds, such as 2-heptanone, n-butanol, 2,6-dimethylpyrazine and 2-furfuryl methyl sulfide were considered as key differential components. The volatile components were effectively differentiated using principal component analysis (PCA), orthogonal partial least squares-discriminant analysis (OPLS-DA), and cluster analysis, revealing correlations between sensory attributes, key components, and electronic nose (E-nose). This research introduces a novel method for analyzing volatile aroma components in cigars, offering insights to enhance cigar quality and to foster the development of new products with unique aroma profiles.

112-GBaud mode-division-multiplexing IM-DD transmission beyond net 6.4†Tb/s over weakly coupled FMF for optical interconnections.

Weakly coupled mode-division-multiplexing (MDM) systems based on intensity modulation and direct detection (IM-DD) are a good candidate for further improving the capacity of short-reach optical interconnections. However, restrained by the modal crosstalk of the transmission link and the reception of degenerate mode groups (DMGs) utilizing bandwidth-limited multimode photodetectors (PDs), high-speed MDM IM-DD has encountered a capacity bottleneck. In this Letter, we investigate a high-speed weakly coupled MDM IM-DD transmission system utilizing a degenerate mode diversity receiver scheme adopting high-bandwidth single-mode PDs over a multiple-ring-core (MRC) few-mode fiber (FMF) and a low-crosstalk mode multiplexer/demultiplexer (MUX/DMUX). An MDM IM-DD transmission with four DMGs and eight wavelengths is experimentally demonstrated with 112-GBaud four-level pulse-amplitude modulation (PAM4) and probabilistically shaped PAM8 per lane over 200-m weakly coupled MRC-FMF. To the best of our knowledge, this is the first experimental demonstration of the MDM IM-DD transmission system with up to 112-GBaud baud rate and beyond 6.4-Tb/s net rate. Meanwhile, the experimental results show that the proposed MDM IM-DD transmission link has a superior performance only adopting a low-complexity feedforward equalizer, making it a promising candidate for high-speed optical interconnections.

Rupestonic Acid Derivative YZH-106 Promotes Lysosomal Degradation of HBV L- and M-HBsAg via Direct Interaction with PreS2 Domain.

Hepatitis B surface antigen (HBsAg) is not only the biomarker of hepatitis B virus (HBV) infection and expression activity in hepatocytes, but it also contributes to viral specific T cell exhaustion and HBV persistent infection. Therefore, anti-HBV therapies targeting HBsAg to achieve HBsAg loss are key approaches for an HBV functional cure. In this study, we found that YZH-106, a rupestonic acid derivative, inhibited HBsAg secretion and viral replication. Further investigation demonstrated that YZH-106 promoted the lysosomal degradation of viral L- and M-HBs proteins. A mechanistic study using Biacore and docking analysis revealed that YZH-106 bound directly to the PreS2 domain of L- and M-HBsAg, thereby blocking their entry into the endoplasmic reticulum (ER) and promoting their degradation in cytoplasm. Our work thereby provides the basis for the design of a novel compound therapy to target HBsAg against HBV infection.

The long-term effectiveness and mechanism of oncolytic virotherapy combined with anti-PD-L1 antibody in colorectal cancer patient.

Colorectal cancer (CRC) is known to be resistant to immunotherapy. In our phase-I clinical trial, one patient achieved a 313-day prolonged response during the combined treatment of oncolytic virotherapy and immunotherapy. To gain a deeper understanding of the potential molecular mechanisms, we performed a comprehensive multi-omics analysis on this patient and three non-responders. Our investigation unveiled that, initially, the tumor microenvironment (TME) of this responder presented minimal infiltration of T cells and natural killer cells, along with a relatively higher presence of macrophages compared to non-responders. Remarkably, during treatment, there was a progressive increase in CD4+ T cells, CD8+ T cells, and B cells in the responder's tumor tissue. This was accompanied by a significant upregulation of transcription factors associated with T-cell activation and cytotoxicity, including GATA3, EOMES, and RUNX3. Furthermore, dynamic monitoring of peripheral blood samples from the responder revealed a rapid decrease in circulating tumor DNA (ctDNA), suggesting its potential as an early blood biomarker of treatment efficacy. Collectively, our findings demonstrate the effectiveness of combined oncolytic virotherapy and immunotherapy in certain CRC patients and provide molecular evidence that virotherapy can potentially transform a "cold" TME into a "hot" one, thereby improving sensitivity to immunotherapy.

Lactate promotes bone healing by regulating the osteogenesis of bone marrow mesenchymal stem cells through activating Olfr1440.

Bone malunion or nonunion leads to functional and esthetic problems and is a major healthcare burden. Activation of bone marrow mesenchymal stem cells (BMSCs) and subsequent induction of osteogenic differentiation by local metabolites are crucial steps for bone healing, which has not yet been completely investigated. Here, we found that lactate levels are rapidly increased at the local injury site during the early phase of bone defect healing, which facilitates the healing process by enhancing BMSCs regenerative capacity. Mechanistically, lactate serves as a ligand for the Olfr1440 olfactory receptor, to trigger an intracellular calcium influx that in turn activates osteogenic phenotype transition of BMSCs. Conversely, ablation of Olfr1440 delays skeletal repair and remodelling, as evidenced by thinner cortical bone and less woven bone formation in vivo. Administration of lactate in the defect area enhanced bone regeneration. These findings thus revealed the key roles of lactate in the osteogenic differentiation of BMSCs, which deepened our understanding of the bone healing process, as well as provided cues for a potential therapeutic option that might greatly improve bone defect treatment.

Production of Secreted Antibody in Baculovirus Expression Vector System.

Monoclonal antibodies have widespread applications in disease treatment and antigen detection. They are traditionally produced using mammalian cell expression system, which is not able to satisfy the increasing demand of these proteins at large scale. Baculovirus expression vector system (BEVS) is an attractive alternative platform for the production of biologically active monoclonal antibodies. In this chapter, we demonstrate the production of an HIV-1 broadly neutralizing antibody b12 in BEVS. The processes including transfer vector construction, recombinant baculovirus generation, and antibody production and detection are described.

Photoinduced EnT-mediated sulfonamidylimination of alkenes and (hetero)arenes with iminophenylacetic acid oxime esters.

A photoinduced EnT-mediated generation of sulfonamidyl radicals has been accomplished using rationally designed iminophenylacetic acid oxime ester reagents under metal-free conditions. This approach offers a mild, regio- and diastereoselective synthesis of N-sulfonyl diamines via diamination of alkenes and (hetero)arenes.

Effect of Post-transplant Dietary Restriction on Hematopoietic Reconstitution and Maintenance of Reconstitution Capacity of Hematopoietic Stem Cells.

Hematopoietic cell transplantation (HCT) is an important therapy for many hematological malignancies as well as some non-malignant diseases. Post-transplant hematopoiesis is affected by multiple factors, and the mechanisms of delayed post-transplant hematopoiesis remain poorly understood. Patients undergoing HCT often suffer from significantly reduced food intake due to complications induced by preconditioning treatments. Here, we used a dietary restriction (DR) mouse model to study the effect of post-transplant dietary reduction on hematopoiesis and hematopoietic stem cells (HSCs). We found that post-transplant DR significantly inhibited both lymphopoiesis and myelopoiesis in the primary recipient mice. However, when bone marrow cells (BMCs) from the primary recipient mice were serially transplanted into secondary and tertiary recipient mice, the HSCs derived from the primary recipient mice, which were exposed to post-transplant DR, exhibited a much higher reconstitution capacity. Transplantation experiments with purified HSCs showed that post-transplant DR greatly inhibited hematopoietic stem cell (HSC) expansion. Additionally, post-transplant DR reshaped the gut microbiotas of the recipient mice, which inhibited inflammatory responses and thus may have contributed to maintaining HSC function. Our findings may have important implications for clinical work because reduced food intake and problems with digestion and absorption are common in patients undergoing HCT.

Increased stress from compound drought and heat events on vegetation.

Compound drought and heat events (CDHEs), which are frequently occurring compound extreme climate events, have garnered considerable attention because of their detrimental effects on ecosystems. However, the intricacies of the spatial and temporal distributions of different durations of compound events, along with the variability in vegetation responses remain unclear. Here, we delineated the CDHEs based on meteorological observation data and investigated the spatial and temporal characteristics of CDHEs from 1993 to 2020 using the Theil-Sen trend test and Mann-Kendall nonparametric test. Furthermore, we utilized sliding correlation analysis to evaluate the impacts of CDHEs on vegetation among different climatic regions and ecosystems. Our findings indicate significant increasing trends in both the frequency and persistence of CDHEs from 1993 to 2020. The average trend of CDHEs frequency across different duration periods amounted to 13.80 %/decade. The fractional contribution of CDHEs lasting more than three days exhibited a significant increase, with an average trend of 2.00 %/decade. We also observed that vegetation is most significantly affected by compound events lasting 5-9 days. During the study period, the geographical extent of vegetation significantly impacted by CDHEs expanded by 0.89 %, correlation strength increased by 0.02, and lag time decreased by 0.25 months. These insights highlight the growing impact of CDHEs on vegetation under climate change, improving our understanding of vegetation responses to these compound events.

High composite dietary antioxidant index is associated with reduced risk of kidney stones: a cross-sectional analysis of NHANES 2007-2020.

The composite dietary antioxidant index (CDAI) is commonly utilized to assess antioxidant intake across diseases, but its association with kidney stones is unclear. We hypothesized that higher CDAI is associated with reduced kidney stone risk. Using National Health and Nutrition Examination Survey 2007-2020 data, we calculated CDAI based on vitamins A, C, E, selenium, zinc, and carotenoids intake in 29,280 adults. Stone formers had lower CDAI, with significant gender differences. Restricted cubic spline showed an L-shaped curve, with the steepest decline before CDAI of 1.449. In multivariate logistic regression, moderate and high CDAI tertiles were associated with reduced kidney stone odds compared to the lowest tertile (odds ratio [95% CI]): 0.85 [0.73, 0.99], P = .035 and 0.80 [0.66, 0.95], P = .014, respectively). Vitamin C had the highest negative correlation weight with kidney stones. Significant interactions were found for age and diabetes subgroups. In conclusion, higher CDAI may reduce kidney stone risk, especially with adequate vitamin C intake. Further cohort studies are warranted to confirm the causal association.

Assessing sex and gender equity in submission guidelines of radiology journals: A cross-sectional study.

PURPOSE: Our study aimed to determine the current percentage of gender and sex equity promoting (GSEP) radiology journals, defined as satisfying at least one criterion of the Sex and Gender Equity in Research (SAGER) checklist, published by the European Association of Science Editors (EASE). A secondary objective was to compare characteristics of GSEP and non-GSEP journals. METHODS: A cross-sectional analysis between June 24 and July 3, 2023, was conducted. The author submission guidelines of radiology journals with a 2021 Journal Impact Factor (JIF) were assessed according to the SAGER checklist. GSEP journals were defined as satisfying one or more SAGER checklist criteria in their research instructions. Bibliometric data and journal information were collected from the Journal Citation Reports and National Library of Medicine catalogue. RESULTS: Only 39.7 % (52) of 132 journals satisfied at least one SAGER checklist criterion. Median 2021 JIFs were higher in GSEP journals (4.62, IQR: 3.73 - 5.21) than non-GSEP journals (2.70, IQR: 2.32) (p = 0.00). Median 2021 Journal Citation Index (JCI) scores were higher in GSEP (0.64, 0.56 - 0.73) than non-GSEP journals (0.97, 0.83 - 1.10) (p = 0.00). Cited half-life was shorter for GSEP (5.40, 4.80 - 6.50) than non-GSEP journals (6.70, 5.70 - 7.40) (p = 0.05). Elsevier published 33 of 52 of GSEP journals. CONCLUSION: 60.3% of radiology journals with a 2021 JIF do not meet a single SAGER checklist criterion in their author submission guidelines. GSEP journals had higher impact and source metrics and a shorter cited half-life. Publishers may play a significant role in promoting endorsement of the SAGER checklist in the author submission guidelines of radiology journals.

Greater variability in HDL-C was associated with an increased risk of cognitive decline in the middle- and elderly Chinese: A cohort study.

BACKGROUND: Previous studies into relationship between high-density lipoprotein cholesterol (HDL-C) and cognitive decline were constrained to a single measurement, leaving the association between HDL-C variability and risk of cognitive decline unclear. METHODS: We identified 5930 participants from the China Health and Retirement Longitudinal Study (CHARLS) who were devoid for stroke, dementia, and memory-related diseases at baseline and underwent a minimum of 2 sequential health examinations during 2011-2015. Variability in HDL-C was defined as (1) variability independent of the mean (VIM), (2) average real variability (ARV), and (3) standard deviation (SD) of HDL-C change from baseline and follow-up visits. Cognitive function was evaluated in 2018 by Mini-mental state examination (MMSE) in the Chinese version. Logistic regression was employed to explore the association between HDL-C variability and cognitive decline. Odd ratios (OR) and 95 % confidence intervals (CI) were reported. RESULTS: The study included participants from CHARLS, mean age of 57.84±8.44 years and 44 % male. After adjustment for covariates, the highest quartile of VIM was associated with an increased risk of cognitive decline [OR:1.049, 95 %CI: 1.014-1.086] compared to the lowest quartile. For each SD increment of VIM, the OR was 1.015 (95 %CI:1.003-1.027). Strong dose-response relationships were identified (P for trend: 0.005). Consistent results were obtained for other measures of HDL-C variability (ARV and SD). Similar patterns were identified in different dimensions of cognition. CONCLUSIONS: Elevated HDL-C variability was associated with increased cognitive decline risk. Strategies to reducing HDL-C variability may lower the risks of cognitive decline among the general population.

Copper metabolism and its role in diabetic complications: A review.

Disturbances in copper (Cu) homeostasis have been observed in diabetes and associated complications. Cu is an essential micronutrient that plays important roles in various fundamental biological processes. For example, diabetic cardiomyopathy is associated with elevated levels of Cu in the serum and tissues. Therefore, targeting Cu may be a novel treatment strategy for diabetic complications. This review provides an overview of physiological Cu metabolism and homeostasis, followed by a discussion of Cu metabolism disorders observed during the occurrence and progression of diabetic complications. Finally, we discuss the recent therapeutic advances in the use of Cu coordination complexes as treatments for diabetic complications and their potential mechanisms of action. This review contributes to a complete understanding of the role of Cu in diabetic complications and demonstrates the broad application prospects of Cu-coordinated compounds as potential therapeutic agents.

Weight-adaptive joint mixed-precision quantization and pruning for neural network-based equalization in short-reach direct detection links.

Neural network (NN)-based equalizers have been widely applied for dealing with nonlinear impairments in intensity-modulated direct detection (IM/DD) systems due to their excellent performance. However, the computational complexity (CC) is a major concern that limits the real-time application of NN-based receivers. In this Letter, we propose, to our knowledge, a novel weight-adaptive joint mixed-precision quantization and pruning approach to reduce the CC of NN-based equalizers, where only integer arithmetic is taken into account instead of floating-point operations. The NN connections are either directly cutoff or represented by a proper number of quantization bits by weight partitioning, leading to a hybrid compressed sparse network that computes much faster and consumes less hardware resources. The proposed approach is verified in a 50-Gb/s 25-km pulse amplitude modulation (PAM)-4 IM/DD link using a directly modulated laser (DML) in the C-band. Compared with the traditional fully connected NN-based equalizer operated with standard floating-point arithmetic, about 80% memory can be saved at a minimum network size without degrading the system performance. Quantization is also shown to be more suitable to over-parameterized NN-based equalizers compared with NNs selected at a minimum size.

Circular RNA circNIPBL regulates TP53-H179R mutations in NNK-induced bronchial epithelial carcinogenesis.

Exposure to environmental carcinogens is a significant contributor to cancer development, with genetic and epigenetic alterations playing pivotal roles in the carcinogenic process. However, the interplay between epigenetic regulation and genetic changes in carcinogenesis has yet to receive comprehensive attention. This study investigates the impact of continuous exposure to the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) on bronchial epithelial cells, leading to malignant transformation. Our findings reveal the down-regulation of the tumor suppressor-like circular RNA circNIPBL during oncogenic processes concomitant with the accumulation of the TP53-H179R, a single nucleotide variant. Diminished circNIPBL expression enhances the proliferative, distant metastatic, and tumor-forming capabilities of NNK-induced cancerous cells and lung cancer cell lines (A549, H1299), while also promoting the accumulation of TP53-H179R during NNK-induced carcinogenesis. Mechanistic investigations demonstrate that circNIPBL interacts with HSP90α to regulate the translocation of AHR into the nucleus, which may be a potential regulatory mechanism for NNK-induced carcinogenesis and TP53-H179R accumulation. This study introduces a novel perspective on the interplay between genetic alterations and epigenetic regulation in chemical carcinogenesis, which provides novel insight into the etiology of cancer.

Fusarium pseudograminearum biomass and toxin accumulation in wheat tissues with and without Fusarium crown rot symptoms.

Fusarium crown rot (FCR) is an important and devastating disease of wheat (Triticum aestivum) caused by the fungus Fusarium pseudograminearum and related pathogens. Using two distinct susceptible cultivars, we investigated the isolation frequencies of F. pseudograminearum and quantified its biomass accumulation and the levels of the associated toxins deoxynivalenol (DON) and DON-3-glucoside (D3G) in inoculated field-grown wheat plants. We detected F. pseudograminearum in stem, peduncle, rachis, and husk tissues, but not in grains, whereas DON and D3G accumulated in stem, rachis, husk, and grain tissues. Disease severity was positively correlated with the frequency of pathogen isolation, F. pseudograminearum biomass, and mycotoxin levels. The amount of F. pseudograminearum biomass and mycotoxin contents in asymptomatic tissue of diseased plants were associated with the distance of the tissue from the diseased internode and the disease severity of the plant. Thus, apparently healthy tissue may harbor F. pseudograminearum and contain associated mycotoxins. This research helps clarify the relationship between F. pseudograminearum occurrence, F. pseudograminearum biomass, and mycotoxin accumulation in tissues of susceptible wheat cultivars with or without disease symptoms, providing information that can lead to more effective control measures.

[Association between exposure to PM_(2.5) and chronic kidney disease in a population with metabolic syndrome].

OBJECTIVE: To investigate the association between long-term fine particulate matter(PM_(2.5)) exposure and the risk of chronic kidney disease(CKD) in people with abnormal metabolism syndrome(MS) components. METHODS: Based on health checkup data from a hospital in Beijing, a retrospective cohort study was used to collect annual checkup data from 2013-2019. A questionnaire was used to obtain information on demographic characteristics and lifestyle habits. We measured blood pressure, height, weight, waist circumference, concentrations of triglycerides(TG), fasting glucose, and high-density lipoprotein cholesterol(HDL-C). Longitude and latitude were also extracted from the addresses of the study subjects for pollutant exposure data estimation. Logistic regression models were used to explore the estimated effect of long-term PM_(2.5) exposure on the risk of CKD prevalence in people with abnormal MS components. Two-pollutant and multi-pollutant models were developed to test the stability of these result. Subgroup analysis was conducted based on age, the presence of MS, individual MS component abnormalities, and dual-component MS abnormalities. RESULTS: The study included 1540 study subjects with abnormal MS components at baseline, 206 with CKD during the study period. The association between long-term PM_(2.5) exposure and increased risk of CKD in people with abnormal MS fractions was statistically significant, with a 2.26-fold increase in risk of CKD for every 10 µg/m~3 increase in PM_(2.5) exposure(OR=3.26, 95% CI 2.72-3.90). The result in the dual-pollutant models and multi-pollutant models suggested that the association between long-term PM_(2.5) exposure and increased risk of CKD in people with abnormal MS fractions remained stable after controlling for contemporaneous confounding by other air pollutants. The result of subgroup analysis revealed that individuals aged 45 or older, without MS, with TG<1.7 mmol/L, HDL-C≥1.04 mmol/L, without hypertension, and with central obesity and high blood sugar had a stronger association between PM_(2.5) exposure and CKD-related health effects. CONCLUSION: Long-term exposure to PM_(2.5) may increase the risk of CKD in people with abnormal MS components. More attention should be paid to middle-aged and elderly people aged ≥45 years, people with central obesity and hyperglycemia.

Canadian radiology: 2024 update.

Radiology in Canada is advancing through innovations in clinical practices and research methodologies. Recent developments focus on refining evidence-based practice guidelines, exploring innovative imaging techniques and enhancing diagnostic processes through artificial intelligence. Within the global radiology community, Canadian institutions play an important role by engaging in international collaborations, such as with the American College of Radiology to refine implementation of the Ovarian-Adnexal Reporting and Data System for ultrasound and magnetic resonance imaging. Additionally, researchers have participated in multidisciplinary collaborations to evaluate the performance of artificial intelligence-driven diagnostic tools for chronic liver disease and pediatric brain tumors. Beyond clinical radiology, efforts extend to addressing gender disparities in the field, improving educational practices, and enhancing the environmental sustainability of radiology departments. These advancements highlight Canada's role in the global radiology community, showcasing a commitment to improving patient outcomes and advancing the field through research and innovation. This update underscores the importance of continued collaboration and innovation to address emerging challenges and further enhance the quality and efficacy of radiology practices worldwide.