The complex roles of m6A modifications in neural stem cell proliferation, differentiation, and self-renewal and implications for memory and neurodegenerative diseases.

ABSTRACT: N6-methyladenosine (m6A), 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 m6A 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 m6A in neural stem cell proliferation, differentiation, and self-renewal, as well as its implications in memory and neurodegenerative diseases. m6A has demonstrated divergent effects on the proliferation and differentiation of neural stem cells. These observed contradictions may arise from the time-specific nature of m6A and its differential impact on neural stem cells across various stages of development. Similarly, the diverse effects of m6A on distinct types of memory could be attributed to the involvement of specific brain regions in memory formation and recall. Inconsistencies in m6A 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 m6A levels observed in Parkinson's disease models exposed to manganese compared to normal Parkinson's disease models further underscore the complexity of m6A's role in neurodegenerative processes. The roles of m6A 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 m6A and its varying effects on distinct brain regions and in different environments.

A novel gene-based model for prognosis prediction of head and neck squamous cell carcinoma.

Background: Head and neck squamous cell carcinoma (HNSCC) is a significant global health challenge. The identification of reliable prognostic biomarkers and construction of an accurate prognostic model are crucial. Methods: In this study, mRNA expression data and clinical data of HNSCC patients from The Cancer Genome Atlas were used. Overlapping candidate genes (OCGs) were identified by intersecting differentially expressed genes and prognosis-related genes. Best prognostic genes were selected using the least absolute shrinkage and selection operator Cox regression based on OCGs, and a risk score was developed using the Cox coefficient of each gene. The prognostic power of the risk score was assessed using Kaplan-Meier survival analysis and time-dependent receiver operating characteristic analysis. Univariate and multivariate Cox regression were performed to identify independent prognostic parameters, which were used to construct a nomogram. The predictive accuracy of the nomogram was evaluated using calibration plots. Functional enrichment analysis of risk score related genes was performed to explore the potential biological functions and pathways. External validation was conducted using data from the Gene Expression Omnibus and ArrayExpress databases. Results: FADS3, TNFRSF12A, TJP3, and FUT6 were screened to be significantly related to prognosis in HNSCC patients. The risk score effectively stratified patients into high-risk group with poor overall survival (OS) and low-risk group with better OS. Risk score, age, clinical M stage and clinical N stage were regarded as independent prognostic parameters by Cox regression analysis and used to construct a nomogram. The nomogram performed well in 1-, 2-, 3-, 5- and 10-year survival predictions. Functional enrichment analysis suggested that tight junction was closely related to the cancer. In addition, the prognostic power of the risk score was validated by external datasets. Conclusions: This study constructed a gene-based model integrating clinical prognostic parameters to accurately predict prognosis in HNSCC patients.

The Association between Obstructive Sleep Apnea and Venous Thromboembolism: A Bidirectional Two-Sample Mendelian Randomization Study.

BACKGROUND: Despite previous observational studies linking obstructive sleep apnea (OSA) to venous thromboembolism (VTE), these findings remain controversial. This study aimed to explore the association between OSA and VTE, including pulmonary embolism (PE) and deep vein thrombosis (DVT), at a genetic level using a bidirectional two-sample Mendelian randomization (MR) analysis. METHODS: Utilizing summary-level data from large-scale genome-wide association studies in European individuals, we designed a bidirectional two-sample MR analysis to comprehensively assess the genetic association between OSA and VTE. The inverse variance weighted was used as the primary method for MR analysis. In addition, MR-Egger, weighted median, and MR pleiotropy residual sum and outlier (MR-PRESSO) were used for complementary analyses. Furthermore, a series of sensitivity analyses were performed to ensure the validity and robustness of the results. RESULTS: The initial and validation MR analyses indicated that genetically predicted OSA had no effects on the risk of VTE (including PE and DVT). Likewise, the reverse MR analysis did not find substantial support for a significant association between VTE (including PE and DVT) and OSA. Supplementary MR methods and sensitivity analyses provided additional confirmation of the reliability of the MR results. CONCLUSION: Our bidirectional two-sample MR analysis did not find genetic evidence supporting a significant association between OSA and VTE in either direction.

Non-targeted screening and photolysis transformation of tire-related compounds in roadway runoff.

Roadway runoff serves as a crucial pathway for transporting contaminants of emerging concern (CECs) from urban environments to receiving water bodies. Tire-related compounds originating from tire wear particles (TWPs) have been frequently detected, posing a potential ecological threat. Yet, the photolysis of tire-related compounds within roadway runoff remains inadequately acknowledged. Addressing this deficit, our study utilized high-resolution mass spectrometry (HRMS) to characterize the chemical profile of roadway runoff across eight strategically selected sites in Guangzhou, China. 219 chemicals were identified or detected within different confidence levels. Among them, 29 tire-related contaminants were validated with reference standards, including hexa(methoxymethyl)melamine (HMMM), 1,3-diphenylguanidine (DPG), dicyclohexylurea (DCU), and N-cyclohexyl-2-benzothiazol-amine (DCMA). HMMM exhibited with the abundance ranging from 2.30 × 104-3.10 × 106, followed by DPG, 1.69 × 104-8.34 × 106. Runoff sample were exposed to irradiation of 500 W mercury lamp for photodegradation experiment. Photolysis results indicated that tire-related compounds with a low photolysis rate, notably DCU, DCMA, and DPG, are more likely to persist within the runoff. The photolytic rates were significantly correlated with the spatial distribution patterns of these contaminants. Our findings underscore TWPs as a significant source of pollution in water bodies, emphasizing the need for enhanced environmental monitoring and assessment strategies.

Trends and drivers of Arctic-boreal fire intensity between 2003 and 2022.

Climate change has disproportional effects on Arctic-boreal ecosystems, as the increase of air temperatures in these northern regions is several times higher than the global average. Ongoing warming and drying have resulted in recent record-breaking fire years in Arctic-boreal ecosystems, resulting in substantial carbon emissions that might accelerate climate change. While recent trends in Arctic-boreal burned area have been well documented, it is still unclear how fire intensity has changed. Fire intensity relates to the energy release from combustion and to a large extent drives the impact of a fire on the vegetation and soils, the emission of various gasses and the combustion completeness of different fuels. Here, we used the active fire product from the Moderate Resolution Imaging Spectroradiometer (MODIS) to examine trends in fire radiative power (FRP) over the entire Arctic-boreal region. We found a significant increase in annual median fire intensity between 2003 and 2022 in Eurasian boreal forests, for both daytime (increase of 0.392 MW/km2 per year, R2 = 0.56, p < 0.001) and nighttime fires (increase of 0.175 MW/km2 per year, R2 = 0.47, p < 0.001), while no general trend in FRP was observed in boreal North America. This increase in FRP in Eurasian boreal forests was strongly associated with simultaneous increases in air temperature, vapour pressure deficit, fire weather and fuel availability. We estimated that for Eurasia with each degree increase in air temperature, annual median daytime FRP increases with 1.58 MW/km2 in the tundra and 0.94 MW/km2 in the taiga. Climate change has thus resulted in a widespread and clear increase in fire intensity in central and eastern Eurasia while we could not discern clear trends in Arctic-boreal North America. Arctic-boreal fire intensity may further increase with climate change, with potentially major consequences for fire regimes, carbon emissions and society.

Purification, structural characterization, and immunomodulatory activity of two polysaccharides from Portulaca oleracea L.

In present study, two water-soluble polysaccharides designated as POL-1 and POL-2 were purified from purslane and their structural characteristics as well as immunomodulatory activity were investigated. The weight-average molecular weight (Mw) of POL-1 and POL-2 were determined to be 64,100 Da and 21,000 Da, respectively. Comprehensive techniques including UV, IR, GC-MS, and NMR were applied to deduced that POL-1 was a pectin polysaccharide homogalacturonan (HG) consisting of →4)-α-GalpA-(1→ with methyl ester degree of 9.71 % and acetylation degree of 0.34 %, while POL-2 was composed of a 1, 4-linked ß-Galp backbone substituted by short side chain →4)-α-Glcp-(1→ and →6)-α-Glcp-(1→. The →4)-α-Glcp-(1→ was attached at the O-6 position of →4)-ß-Galp-(1→. TEM further revealed that POL-1 was non-branched single chains, while POL-2 was entangled microstructure with side chains. Moreover, POL-2 significantly promoted macrophage phagocytosis as well as the secretion of NO and cytokines (TNF-α, IL-6) through activating NF-κB signaling pathway, thus demonstrating potential immunomodulatory activity. These findings suggested that purslane may be exploited as a potential adjuvant and dietary supplement with immunostimulatory purpose.

Advances in inhibitor development targeting the PWWP domain.

The PWWP domain binds to both histone and DNA of a nucleosome in a bivalent way. PWWP domain-containing proteins are involved in different biological processes, and their aberrant expression is implicated in various human diseases. Here, we discuss the recent developments and challenges in targeting the PWWP domain for therapeutic intervention.

High-resolution Tandem Mass Spectrometry for Studying Chemical Constituents of Gynura bicolor DC.

The separation and analysis of the desired chemical components are important subjects for the fundamental research of traditional Chinese medicine (TCM). Ultra-high-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS) has gradually become a leading technology for the identification of TCM ingredients. Gynura bicolor DC. (BFH), a perennial stemless herb used for medicine and food in China has medicinal effects such as clearing heat, moistening the lung, relieving cough, dispersing stasis, and relieving swelling. Polyphenols and flavonoids contain numerous isomers, which hinder the identification of the complex compounds in BFH. This paper presents a systematic protocol for studying chemical constituents of BFH based on solvent extraction and integrated data via UPLC-Q-TOF-MS. The method described here includes systematic protocols for sample pretreatment, MS calibration, MS acquisition, data processing, and analysis of results. Sample pretreatment includes collection, cleaning, drying, crushing, and extraction. MS calibration consists of multipoint and single-point correction. Data processing includes data importing, method establishment, analysis processing, and result presentation. Representative results of the typical fragmentation pattern of phenolic acids, esters, and glycosides in Gynura bicolor DC. (BFH) are presented in this paper. In addition, organic solvent selection, extraction, data integration, collision energy selection, and method improvement are discussed in detail. This universal protocol can be widely used to identify complex compounds in TCM.

Estimation of potential wildfire behavior characteristics to assess wildfire danger in southwest China using deep learning schemes.

Accurate estimation of potential wildfire behavior characteristics (PWBC) can improve wildfire danger assessment. However, wildfire behavior has been estimated by most fire spread models with immeasurable uncertainties and difficulties in large-scale applications. In this study, a PWBC estimation model (named PWBC-QR-BiLSTM) was proposed by coupling the Bi-directional Long Short-Term Memory (BiLSTM) and quantile regression (QR) methods. Multi-source data, including fuel, weather, topography, infrastructure, and landscape variables, were input into the PWBC-QR-BiLSTM model to estimate the potential rate of spread (ROS) and fire radiative power (FRP) over western Sichuan of China, and then to estimate the probability density of ROS and FRP. Daily ROS and FRP were extracted from the Global Fire Atlas and the MOD14A1/MYD14A1 product. The optimal PWBC-QR-BiLSTM model was determined using the Non-dominated Sorting Genetic Algorithm Ⅱ (NAGA-Ⅱ). Results showed that the PWBC-QR-BiLSTM performed well in estimating potential ROS and FRP with high accuracy (ROS: R2 > 0.7 and MAPE<30%, FRP: R2 > 0.8 and MAPE<25%). The modal PWBC values extracted from the estimated probability density were closer to the observed values, which can be regarded as a good indicator for wildfire danger assessment. The variable importance analysis also verified that fuel and infrastructure variables played an important role in driving wildfire behavior. This study suggests the potential of utilizing artificial intelligence to estimate PWBC and its probability density to improve the guidance on wildfire management.

Efficacy of Cognitive Behavioral Therapy Combined with Pharmacotherapy Versus Pharmacotherapy Alone in Adult ADHD: A Systematic Review and Meta-Analysis.

BACKGROUND: ADHD diagnosis rates are rising; however, currently, no effective treatment method that has been identified. This study compared the efficacy of CBT + M with M for adult ADHD. METHODS: PubMed, Embase, WOS, and Cochrane Library databases were searched up to July 29, 2023. Literature screening and data analysis were conducted. RESULTS: The six randomized controlled studies included. Meta-analysis showed that CBT + M was more effective than M in improving ADHD symptoms. Subgroup analysis showed developed countries significant in ADHD symptoms improvement. At the 3-month, CBT + M was superior to M, but at the 6 and 9 months, no statistically significant differences were observed. CONCLUSION: CBT + M is more effective than M in improving adult ADHD symptoms and maintains an advantage for at least 3 months. It is recommended to intensifying CBT treatment after 3 months. Country and economy may influence results. Combined therapy for ADHD should be prioritized in developed countries.

Taurine alleviates high-fat-high-glucose-induced pancreatic islet ß-cell oxidative stress and apoptosis in rat.

The effect of taurine (TAU) as a specific regulatory mediator on pancreatic function in obese rats induced by a high-fat-high-glucose (HFHG) diet was investigated. We fed male Sprague-Dawley rats under different conditions, namely the control, HFHG, TAU, and HFHG + TAU treatment groups for 4 months. Compared with the HFHG group, TAU supplementation significantly reduced malondialdehyde levels and increased superoxide dismutase, total antioxidant capacity, and glutathione levels in the rat pancreas. In addition, TAU significantly decreased the level of reactive oxygen species, and markedly increased the activity of heme oxygenase 1 (HO-1), Kelch-like ECH-associated protein 1 (KEAP-1), and nuclear factor erythrocyte-2-related factor 2 (Nrf2) in the rat pancreas. Notably, HFHG diet could induce pancreatic injury in the rats through the Nrf2/HO-1 signaling pathway and activate the mitochondrial channel-mediated apoptotic signaling pathway. The addition of TAU significantly improved the pancreatic tissue injury induced by the HFHG diet in the rats and reduced the protein expression of Caspase-3, Cleaved-caspase-3, Caspase-9 and Bcl-2 associated protein X (BAX), and increased the protein expression of B-cell lymphoma-2 (Bcl-2). In conclusion, this experiment confirmed that TAU could alleviate the oxidative stress and apoptosis induced by the HFHG diet in rat pancreatic ß-cells.

Exquisitely Constructing a Robust MOF with Dual Pore Sizes for Efficient CO2 Capture.

Developing metal-organic framework (MOF) adsorbents with excellent performance and robust stability is of critical importance to reduce CO2 emissions yet challenging. Herein, a robust ultra-microporous MOF, Cu(bpfb)(bdc), with mixed ligands of N, N'-(1,4-phenylene)diisonicotinamide (bpfb), and 1,4-dicarboxybenzene (bdc) was delicately constructed. Structurally, this material possesses double-interpenetrated frameworks formed by two staggered, independent frameworks, resulting in two types of narrow ultra-micropores of 3.4 × 5.0 and 4.2 × 12.8 Å2, respectively. The above structural properties make its highly selective separation at 273~298 K with a CO2 capacity of 71.0~86.2 mg/g. Its adsorption heat over CO2 and IAST selectivity were calculated to be 27 kJ/mol and 52.2, respectively. Remarkably, cyclic breakthrough experiments corroborate its impressive performance in CO2/N2 separation in not only dry but also 75% RH humid conditions. Molecular simulation reveals that C-H···OCO2 in the pores plays a pivotal role in the high selectivity of CO2 adsorption. These results point out the huge potential application of this material for CO2/N2 separation.

A case of Smith-Magenis syndrome with skin manifestations caused by a novel locus mutation in the RAI1 gene.

We report the clinical features and genetic testing of a child with Smith-Magenis syndrome (SMS) to improve the understanding of this disease. The clinical data and molecular genetic test results of a child with SMS caused by a novel mutation in the retinoic acid-induced-1 (RAI1) gene were reviewed. A female patient aged 12 years and 9 months presented to the clinic because her mental and motor development was lagging behind that of her peers. The child had learning difficulties, poor motor coordination, temper tantrums, and self-injurious behaviors, such as skin scratching. She had a peculiar facial appearance, dry skin with scattered eczema, low hairline, wide forehead, flat face, collapsed nasal bridge, turned out upper lip, and deep palmar lines on the right hand through the palm. Wechsler's IQ test score was 48. Her electroencephalogram was normal. The diagnosis of SMS was confirmed by a heterozygous mutation in exon 3 of the RAI1 gene on chromosome chr-1717696650 at locus c.388C>T (P.Q130X). In addition, this patient had severe eczema on the skin. The RAI1 mutation c.388C>T (P.Q130X) is a newly reported variant that will help in the clinical identification of SMS and the precise localization of more phenotypically related genes.

Copper-containing titanium alloys promote the coupling of osteogenesis and angiogenesis by releasing copper ions.

Previous investigations have reported on the ability of copper (Cu)-bearing biomaterials to accelerate vascular formation and bone regeneration. However, few studies have explored the effects of Cu-bearing materials on the interactions between angiogenesis and osteogenesis. Therefore, in this study, we prepared Cu-containing alloys using selective laser melting (SLM) technology and investigated the impact of preosteoblasts seeded on Ti6Al4V-4.5Cu alloy on angiogenesis. Our results indicated that Ti6Al4V-4.5Cu alloys increased the expression of proangiogenic genes and proteins in preosteoblasts, which further stimulated vascular formation in endothelial cells. Besides, we discovered that the biological effects of the Ti6Al4V-4.5Cu alloy were partly attributed to the release of Cu ions. In short, our research demonstrated the ability of Ti6Al4V-4.5Cu alloys to promote the coupling of angiogenesis and osteogenesis by releasing Cu ions.

Alternative Splicing for Leucanthemella linearis NST1 Contributes to Variable Abiotic Stress Resistance in Transgenic Tobacco.

Leucanthemella linearis is a marsh plant in the family Compositae. It has good water and moisture resistance and ornamental properties, which makes it one of the important materials for chrysanthemum breeding and genetic improvement. The NST1 (NAC secondary wall enhancement factor 1) gene is associated with the thickening of the secondary walls of fiber cells in the plant ducts and the secondary xylem and plays an important role in plant stress resistance. In this study, two variable spliceosomes of the NST1 gene were identified from a chrysanthemum plant by using bioinformatics, qRT-PCR, transgene, and paraffin section methods to explore the molecular mechanism of the variable splicing of NST1 under abiotic stress. The results show that only three amino acids were found to be different between the two LlNST1 variants. After being treated with salt, drought, and low temperatures, analysis of the expression levels of the LlNST1 and LlNST1.1 genes in Ll showed that LlNST1.1 could respond to low temperatures and salt stress and had a weak response to drought stress. However, the expression level of LlNST1 under the three treatments was lower than that of LlNST1.1. LlNST1 transgenic tobacco showed increased saline-alkali resistance and low-temperature resistance at the seedling stage. LlNST1.1 transgenic tobacco also showed enhanced saline-alkali resistance and drought resistance at the seedling stage. In conclusion, the functions of the two variable spliceosomes of the NST1 gene are very different under abiotic stress. Therefore, this study verified the function of the variable spliceosome of NST1 and improved the stress resistance of the chrysanthemum plant under examination by regulating the expression of the NST protein, which lays a material foundation for the improvement of plant stress resistance materials and has important significance for the study of the resistance of chrysanthemum plants to abiotic stress.

Early-stage oral cancer diagnosis by artificial intelligence-based SERS using Ag NWs@ZIF core-shell nanochains.

Surface-enhanced Raman spectroscopy (SERS) has great potential in the early diagnosis of diseases by detecting the changes of volatile biomarkers in exhaled breath, because of its high sensitivity, rich chemical molecular fingerprint information, and immunity to humidity. Here, an accurate diagnosis of oral cancer (OC) is demonstrated using artificial intelligence (AI)-based SERS of exhaled breath in plasmonic-metal organic framework (MOF) nanoparticles. These plasmonic-MOF nanoparticles were prepared using a zeolitic imidazolate framework coated on Ag nanowires (Ag NWs@ZIF), which offers Raman enhancement from the plasmonic nanowires and gas enrichment from the ZIF shells. Then, the core-shell nanochains of Ag NWs@ZIF prepared with 0.5 mL Ag NWs were selected to capture gaseous methanethiol, which is a tumor biomarker, from the exhalation of OC patients. The substrate was used to collect a total of 400 SERS spectra of exhaled breath of simulated healthy people and simulated OC patients. The artificial neural network (ANN) model in the AI algorithm was trained with these SERS spectra and could classify them with an accuracy of 99%. Notably, the model predicted OC with an area under the curve (AUC) of 0.996 for the simulated OC breath samples. This work suggests the great potential of the combination of breath analysis and AI as a method for the early-stage diagnosis of oral cancer.

Neuronal TRPV1-CGRP axis regulates bone defect repair through Hippo signaling pathway.

Transient receptor potential vanilloid type 1 (TRPV1) is highly expressed on sensory neurons where it serves as a polymodal receptor for detecting physical and chemical stimuli. However, the role of TRPV1 in bone metabolism remains largely unclear. This study aimed to investigate the underlying mechanism of neuronal TRPV1 in regulating bone defect repair. In vivo experiment verified that TRPV1 activation could trigger dorsal root ganglion (DRG) producing the neuropeptide calcitonin gene-related peptide (CGRP) in mice. The accelerated bone healing of femoral defect in this process was observed compared to the control group (p < 0.05). Conversely, Trpv1 knockdown led to reduced CGRP expression in DRG and nerves innervating femur bone tissue, following impaired bone formation and osteogenic capability in the defect region (p < 0.05), which could be rescued by local CGRP treatment. In vitro, results revealed that TRPV1 function in DRG neurons contributed essentially to the regulation of osteoblast physiology through affecting the production and secretion of CGRP. The capsaicin-activated neuronal TRPV1-CGRP axis could enhance the proliferation, migration and differentiation of osteoblasts (p < 0.05). Furthermore, we found that the promoting role of neuronal TRPV1 in osteogenesis was associated with Hippo signaling pathway, reflected by the phosphorylation protein level of large tumor suppressor 1 (LATS1), MOB kinase activator 1 (MOB1) and Yes-associated protein (YAP), as well as the subcellular location of YAP. Our study clarified the effects and intrinsic mechanisms of neuronal TRPV1 on bone defect repair, which might offer us a therapeutic implication for bone disorders.