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 timespecific nature of m^(6)A and its varying effects on distinct brain regions and in different environments.

Mitigation of N_(2)O emissions in water-saving paddy fields:Evaluating organic fertilizer substitution and microbial mechanisms

Water-saving irrigation strategies can successfully alleviate methane emissions from rice fields,but significantly stimulate nitrous oxide(N_(2)O)emissions because of variations in soil oxygen level and redox potential.However,the relationship linking soil N_(2)O emissions to nitrogen functional genes during various fertilization treatments in water-saving paddy fields has rarely been investigated.Furthermore,the mitigation potential of organic fertilizer substitution on N_(2)O emissions and the microbial mechanism in rice fields must be further elucidated.Our study examined how soil N_(2)O emissions were affected by related functional microorganisms(ammonia-oxidizing archaea(AOA),ammonia-oxidizing bacteria(AOB),nirS,nirK and nosZ)to various fertilization treatments in a rice field in southeast China over two years.In this study,three fertilization regimes were applied to rice cultivation:a no nitrogen(N)(Control),an inorganic N(Ni),and an inorganic N with partial N substitution with organic manure(N_(i)+N_(o)).Over two rice-growing seasons,cumulative N_(2)O emissions averaged 0.47,4.62 and 4.08 kg ha^(−1)for the Control,Ni and N_(i)+N_(o)treatments,respectively.In comparison to the Ni treatment,the N_(i)+N_(o)fertilization regime considerably reduced soil N_(2)O emissions by 11.6%while maintaining rice yield,with a lower N_(2)O emission factor(EF)from fertilizer N of 0.95%.Nitrogen fertilization considerably raised the AOB,nirS,nirK and nosZ gene abundances,in comparison to the Control treatment.Moreover,the substitution of organic manure for inorganic N fertilizer significantly decreased AOB and nirS gene abundances and increased nosZ gene abundance.The AOB responded to N fertilization more sensitively than the AOA.Total N_(2)O emissions significantly correlated positively with AOB and nirS gene abundances while having a negative correlation with nosZ gene abundance and the nosZ/nirS ratio across N-fertilized plots.In summary,we conclude that organic manure substitution for inorganic N fertilizer decreased soil N_(2)O emissions primarily by changing the soil NO_(3)^(−)-N,pH and DOC levels,thus inhibiting the activities of ammonia oxidation in nitrification and nitrite reduction in denitrification,and strengthening N_(2)O reduction in denitrification from water-saving rice paddies.

Upregulation of α-ENaC induces pancreatic β-cell dysfunction,ER stress,and SIRT2 degradation

Islet beta cells(β-cells)produce insulin in response to high blood glucose levels,which is essential for preserving glucose homeostasis.Voltage-gated ion channels inβ-cells,including Na+,K+,and Ca2+channels,aid in the release of insulin.The epithelial sodium channel alpha subunit(α-ENaC),a voltage-independent sodium ion channel,is also expressed in human pancreatic endocrine cells.However,there is no reported study on the function of ENaC in theβ-cells.In the current study,we found thatα-ENaC was expressed in human pancreatic glandule and pancreatic isletβ-cells.In the pancreas of db/db mice and high-fat diet-induced mice,and in mouse isletβ-cells(MIN6 cells)treated with palmitate,α-ENaC expression was increased.Whenα-ENaC was overexpressed in MIN6 cells,insulin content and glucose-induced insulin secretion were significantly reduced.On the other hand,palmitate injured isletβ-cells and suppressed insulin synthesis and secretion,but increasedα-ENaC expression in MIN6 cells.However,α-ENaC knockout(Scnn1a−/−)in MIN6 cells attenuatedβ-cell disorder induced by palmitate.Furthermore,α-ENaC regulated the ubiquitylation and degradation of sirtuin 2 inβ-cells.α-ENaC also modulatedβ-cell function in correlation with the inositol-requiring enzyme 1 alpha/X-box binding protein 1(IRE1α/XBP1)and protein kinase RNA-like endoplasmic reticulum kinase/C/EBP homologous protein(PERK/CHOP)endoplasmic reticulum stress pathways.These results suggest thatα-ENaC may play a novel role in insulin synthesis and secretion in theβ-cells,and the upregulation ofα-ENaC promotes isletβ-cell dysfunction.In conclusion,α-ENaC may be a key regulator involved in isletβ-cell damage and a potential therapeutic target for type 2 diabetes mellitus.

WNT7A promotes tumorigenesis of head and neck squamous cell carcinoma via activating FZD7/JAK1/STAT3 signaling

Wnt signaling are critical pathway involved in organ development, tumorigenesis, and cancer progression. WNT7A, a member of the Wnt family, remains poorly understood in terms of its role and the underlying molecular mechanisms it entails in head and neck squamous cell carcinoma (HNSCC). According to the Cancer Genome Atlas (TCGA), transcriptome sequencing data of HNSCC, the expression level of WNT7A in tumors was found to be higher than in adjacent normal tissues, which was validated using Real-time RT-PCR and immunohistochemistry. Unexpectedly, overexpression of WNT7A did not activate the canonical Wnt-β-catenin pathway in HNSCC. Instead, our findings suggested that WNT7A potentially activated the FZD7/JAK1/STAT3 signaling pathway, leading to enhanced cell proliferation, self-renewal, and resistance to apoptosis. Furthermore, in a patient-derived xenograft (PDX) tumor model, high expression of WNT7A and phosphorylated STAT3 was observed, which positively correlated with tumor progression.These findings underscore the significance of WNT7A in HNSCC progression and propose the targeting of key molecules within the FZD7/JAK1/STAT3 pathway as a promising strategy for precise treatment of HNSCC.

TCM-HIN2Vec:A strategy for uncovering biological basis of heart qi deficiency pattern based on network embedding and transcriptomic experiment

Objective To elucidate the biological basis of the heart qi deficiency(HQD)pattern,an in-depth understanding of which is essential for improving clinical herbal therapy.Methods We predicted and characterized HQD pattern genes using the new strategy,TCM-HIN2Vec,which involves heterogeneous network embedding and transcriptomic experiments.First,a heterogeneous network of traditional Chinese medicine(TCM)patterns was constructed using public databases.Next,we predicted HQD pattern genes using a heterogeneous network-embedding algorithm.We then analyzed the functional characteristics of HQD pattern genes using gene enrichment analysis and examined gene expression levels using RNA-seq.Finally,we identified TCM herbs that demonstrated enriched interactions with HQD pattern genes via herbal enrichment analysis.Results Our TCM-HIN2Vec strategy revealed that candidate genes associated with HQD pattern were significantly enriched in energy metabolism,signal transduction pathways,and immune processes.Moreover,we found that these candidate genes were significantly differentially expressed in the transcriptional profile of mice model with heart failure with a qi deficiency pattern.Furthermore,herbal enrichment analysis identified TCM herbs that demonstrated enriched interactions with the top 10 candidate genes and could potentially serve as drug candidates for treating HQD.Conclusion Our results suggested that TCM-HIN2Vec is capable of not only accurately identifying HQD pattern genes,but also deciphering the basis of HQD pattern.Furthermore our finding indicated that TCM-HIN2Vec may be further expanded to develop other patterns,leading to a new approach aimed at elucidating general TCM patterns and developing precision medicine.

Suppression of hepatic steatosis in non-alcoholic steatohepatitis model by modified Xiaoyao San formula:Evidence,mechanisms and perspective

In this letter,we comment on a recent publication by Mei et al,in the World Journal of Hepatology,investigating the hepatoprotective effects of the modified Xiaoyao San(MXS)formula in a male rat model of non-alcoholic steatohepatitis(NASH).The authors found that MXS treatment mitigated hepatic steatosis and inflam-mation in the NASH model,as evidenced by the reduction in lipid droplets(LDs),fibrosis markers and lipogenic factors.Interestingly,these hepatoprotective effects were associated with androgen upregulation(based on metabolomics analysis of male steroid hormone metabolites),adenosine 5’-monophosphate-activated protein kinase(AMPK)activation,and restoration of phosphatase and tensin homolog(PTEN)expression.However,the authors did not clearly discuss the relationships between MXS-induced hepatic steatosis reduction in the NASH model,and androgen upregulation,AMPK activation,and restoration of PTEN expression.This editorial emphasizes the reported mechanisms and explains how they act or interact with each other to reduce hepatic steatosis and inflammation in the NASH model.As a perspective,we propose additional mechanisms(such as autophagy/lipophagy activation in hepatocytes)for the clearance of LDs and suppression of hepatic steatosis by MXS in the NASH model.A proper understanding of the mechanisms of MXS-induced reduction of hepatic steatosis might help in the treatment of NASH and related diseases.

Insights and implications of sexual dimorphism in osteoporosis

Osteoporosis,a metabolic bone disease characterized by low bone mineral density and deterioration of bone microarchitecture,has led to a high risk of fatal osteoporotic fractures worldwide.Accumulating evidence has revealed that sexual dimorphism is a notable feature of osteoporosis,with sex-specific differences in epidemiology and pathogenesis.Specifically,females are more susceptible than males to osteoporosis,while males are more prone to disability or death from the disease.To date,sex chromosome abnormalities and steroid hormones have been proven to contribute greatly to sexual dimorphism in osteoporosis by regulating the functions of bone cells.Understanding the sex-specific differences in osteoporosis and its related complications is essential for improving treatment strategies tailored to women and men.This literature review focuses on the mechanisms underlying sexual dimorphism in osteoporosis,mainly in a population of aging patients,chronic glucocorticoid administration,and diabetes.Moreover,we highlight the implications of sexual dimorphism for developing therapeutics and preventive strategies and screening approaches tailored to women and men.Additionally,the challenges in translating bench research to bedside treatments and future directions to overcome these obstacles will be discussed.

Charcoal Nanoparticles as a Delivery System for Doxorubicin and Sorafenib in Treatment of Hepatocellular Carcinoma

Background: Hepatocellular carcinoma (HCC) is the most common type of liver cancer and one of the leading causes of cancer-related death worldwide. Advanced HCC displays strong resistance to chemotherapy, and traditional chemotherapy drugs do not achieve satisfactory therapeutic efficacy. The delivery of therapeutic compounds to the target site is a major challenge in the treatment of many diseases. Objective: This study aims to evaluate activated charcoal nanoparticles as a drug delivery system for anticancer agents (Sorafenib and Doxorubicin) in Hepatocellular Cancer Stem Cells. Method: The percent efficiency of entrapment (% EE) of the doxorubicin and sorafenib entrapped onto the activated charcoal was obtained by determining the free doxorubicin and sorafenib concentration in the supernatant-prepared solutions. Then the characterizations of nanoparticles were formed by determination of the particle size distribution, zeta potential, and polydispersity index (PDI). The anticancer activity of activated Charcoal, Doxorubicin-ACNP, sorafenib-ACNP, free doxorubicin, and free sorafenib solutions was measured based on cell viability percentage in HepG2 cell lines (ATCC-CCL 75). In vitro RBC’s toxicity of Doxorubicin/sorafenib loaded charcoal was estimated by hemolysis percentage. Results: The synthesized Doxorubicin-ACNP and Sorafenib-ACNP were evaluated and their physiochemical properties were also examined. Essentially, the percent Efficiency of Entrapment (EE %) was found to be 87.5% and 82.66% for Doxorubicin-ACNP and Sorafenib-ACNP, respectively. The loading capacity was 34.78% and 24.31% for Doxorubicin-ACNP and Sorafenib-ACNP. Using the Dynamic Light scattering [DLS] for the determination of the hydrodynamic size and surface zeta potential, a narrow sample size distribution was obtained of (18, 68, and 190 nm for charcoal, 105, 255, and 712 nm for doxorubicin, and 91, 295, and 955 nm for sorafenib), respectively. A surface charge of −13.2, −15.6 and −17 was obtained for charcoal, doxorubicin/charcoal, and sorafenib/charcoal nanoparticles. The cytotoxic activity of Doxorubicin-ACNP and Sorafenib-ACNP was evaluated in-vitro against HepG2 cell lines and it was observed that Drug loaded ACNP improved anticancer activity when compared to Doxorubicin or Sorafenib alone. Moreover, testing the toxicity potential of DOX-ACNP and Sorafenib-ACNP showed a significant reduction in the hemolysis of red blood cells when compared to Doxorubicin and Sorafenib alone. Conclusion: In conclusion, it is notable to state that this study is regarded as the first to investigate the use of Activated charcoal for the loading of Doxorubicin and Sorafenib for further use in the arena of hepatocellular carcinoma. Doxorubicin-ACNP and Sorafenib-ACNP showed noteworthy anticancer activity along with a reduced potential of RBCs hemolysis rendering it as an efficacious carrier with a low toxicity potential.

The Effect of Macronutrient Restrictions on Gut Microbiome and Biochemical Parameters of Wistar Albino Rats

Macronutrients serve as a source of energy for both gut microbiota and its host. An increase or decrease in macronutrients can either increase or decrease the composition of gut microbiota, leading to gut dysbiosis which has been implicated in many diseases state including non-communicable diseases. To achieve this, seven diets were formulated by restricting 60% of each macronutrient. These diets were fed on 42 albino rats (Wistar), divided into 7 groups of 6 rats each. Group 1 was fed on a normal laboratory chow diet (ND), group 2 received a fat-restricted diet (FRD), group 3 received a protein-restricted diet, (PFD), group 4 received a carbohydrate-restricted diet (CRD), group 5 received a protein and fat-restricted diet (PFRD), group 6 re-ceived a carbohydrate and fat-restricted diet (CFRD) and group 7 received a carbohydrate and protein-restricted diet (CPRD). Feed and water intake were given ad libitum and daily weight and food intake were recorded. The experiment went on for 4 weeks after which animals were sacrificed and intestinal content and blood were collected for analysis (gut microbial composition, glucose, insulin levels, serum lipid, and enzyme). Compared to the control group results showed a decrease in Bacteroides (40.50 - 14.00 CFU), HDL (68.20 - 40.40 mg/dl), and AST (66.62 - 64.74 U/L) in FRD. An increase in AST (66.6 - 69.43 U/L), Bifidobacterial (59.50 - 92.00 CFU) and decreased Bacteroides (40.5 - 19.5 CFU) for PRD was also recorded. CRD reduced Lactobacillus (73 - 33.5 CFU), total bacterial count (129 - 48 CFU), HDL (68.2 - 30.8 mg/dl), and cholesterol (121.44 - 88.65 mg/dl) whereas intestinal composition of E. coli (30.5 - 51.5 CFU) increased. PFRD increased Lactobacillus (73.00 - 102.5 CFU), Bifidobacterial (59.5 - 100 CFU), HDL (68.2 - 74.7 mg/dl), and Triglyceride (111.67 - 146.67 mg/dl) concentration. Meanwhile, a reduction in Bifidobacterial (59.5 - 41.5 CFU), and an increasing of AST (66.62 - 70.30 U/l) were recorded for CFRD. However, Bacteroides (40.5 69.5 CFU), LDL (30.95 - 41.98 mg/dl) increased and Bifidobacterial (59.5 - 38.00 CFU) and HDL (68.2 - 53.5 mg/dl) decreased for CPRD. This work, therefore, concludes that macronutrient restriction causes significant changes in serum marker and enzyme profile, and gut microbial composition which can cause gut dysbiosis and later on could expose the host to inflammatory diseases in the long run.

Hyperhomocysteinemia and Associated Biological Markers in a Congolese Population of Type 2 Diabetes Mellitus in Brazzaville

The search for new biomarkers predictive of type 2 diabetes currently constitutes a research avenue in Bioclinical. Total homocysteine remains a preferred target due to its involvement in the occurrence of degenerative complications in type 2 diabetics. The aim of this work was to study hyperhomocysteinemia and other biochemical markers associated with T2D in the Congolese population. This was an analytical case-control study carried out between October 2022 and October 2023. The study population consisted of 150 subjects including 100 T2D patients and 50 control subjects. The main clinical data were collected on a pre-established form. Homocysteine determination was carried out by the sandwich ELISA method. The other biochemical markers were measured by colorimetric enzymatic methods. Hyperhomocysteinemia was present in 27.3% (41/150) of the entire study population. Type 2 diabetics had a frequency of hyperhomocysteinemia of 36% (36/100) and control 10% (5/50) (p = 0.001). The mean hyperhomocysteinemia concentration was 31.9 μmol/l with extremes ranging from 18 to 103 μmol/l. Means of biological markers between diabetics and controls showed a statistically significant difference (p = 0.01). The risk factors associated with this HHcy were: sex (OR = 3.5), age (OR = 9.4), sedentary lifestyle (OR = 3.4) and glycosylated hemoglobin (OR = 12) with a p-value <0.05 respectively. Our results suggest that hyperhomocysteinemia can be considered as a predictive biomarker in the bioclinic of Congolese type 2 diabetic patients.

Phenotypic and Molecular Characterization of Staphylococcaceae and Enterobacteriaceae Species Isolated from Smoked, Dried, and Braised Fish Marketed in Ouagadougou

Background: To preserve its nutritional properties, fish must have good sanitary quality. The objective of this study was to investigate some pathogens contaminating smoked, dried, and braised fish marketed in Ouagadougou. Methodology: Potential pathogens of Enterobacteriaceae and Staphylococcus were screened in eight (8) species of processed fish. The investigation of the germs was carried out following the normative methods of microbiology. The identities of the strains were determined by API 20 E (BioMerieux S.A., France) and API STAPH (BioMerieux S.A., France) kits for Enterobacteriaceae and Staphylococcus species respectively. The uidA gene profile in Escherichia coli isolates was determined by simplex PCR. The identity of Staphylococcus aureus was confirmed by amplification of specific 23S rDNA regions and nuc gene profile with PCR. Results: A total of 235 fish samples were analyzed. A diversity of Enterobacteriaceae and Staphylococcus was detected. Twenty species of Enterobacteriaceae were identified among which, the most frequent were Escherichia coli, Salmonella sp, Raoultella ornithinolytica and Serratia odorifera, respectively in 22.6%, 4.3%, 28.9%, 17.4% of the samples analyzed. However, eleven species of Staphylococcus were identified among which, Staphylococcus xylosus, Staphylococcus aureus, Staphylococcus lugdunensis, and Staphylococcus sciuri were the most frequent with respective percentages of 47.7%, 23.4%, 12.8% and 10.6% of samples. For all the samples, the species frequently isolated were: Raoultella ornithinolytica, Escherichia coli, Serratia odorifera, Staphylococcus aureus, Staphylococcus xylosus, and Staphylococcus lugdunensis. The uidA gene specific to Escherichia coli was detected in 82.85% of strains (29/35). Amplification of the specific 23S rDNA region using staur primers was observed in 98% (49/50) of the isolated Staphylococcus aureus strains and the nuc gene was detected in 86% of Staphylococcus aureus strains. Conclusion: The isolated bacteria are potential pathogens involved in foodborne illnesses and intoxications. Effective sanitary safety systems must be implemented to guarantee the sanitary quality of fish supplied to consumers.

Analysis of the Effects of Different Synthesis and Processing Methods on Circular RNA Integrity,Protein Expression,and Removal of Immunogenic Impurities

Circular RNAs(circRNAs)are emerging as a promising alternative to messenger RNAs(mRNAs)in gene delivery applications due to their enhanced stability and translation.Developing circRNA-based therapeutic platforms requires efficient manufacturing of circRNA with broad scalability.However,the permuted intron-exon(PIE)-based circRNA production commonly used to date involves complex RNA synthesis,circularization,precursor RNA digestion,and impurity removal steps that have limited practical applications.While co-transcriptional circularization could effectively streamline circRNA production,and both cellulose/phosphatase treatment and high-performance liquid chromatography(HPLC)have demonstrated their reliability in mRNA manufacturing,their potential effects on the quality,translation,and reactogenicity of circRNA remained to be fully investigated.Here,using circRNAs systematically manufactured through three independent workflows,we comprehensively examined the utilities of these RNA synthesis and processing methods in circRNA production by comparing the integrity,translation,and immunogenicity of their circRNA products.We began by manufacturing a mNeonGreen(mNG)-encoding circRNA through these workflows and subsequently assessed circRNA integrity via E-gel EX electrophoresis.Protein expression was then monitored in HEK 293T,A549,and DC2.4 cells at 72 hours post-transfection.Finally,we evaluated the immunogenicity of these circRNAs by measuring their interferon beta(IFN-β)induction in A549 cells at 4 hours post-transfection.Using HPLC purification over cellulose and phosphatase treatment resulted in 10-14%higher circRNA enrichment by reducing nicking associated with processing conditions.Protein expression remained consistent across circRNAs from different workflows(P>0.05),demonstrating that co-transcriptional circularization produces circRNA with translation levels comparable to those obtained from the conventional PIE method.Moreover,both cellulose/phosphatase treatment and HPLC purification effectively minimized IFN-βinduction of the purified circRNAs,confirming their reliability in removing immunogenic impurities introduced during in vitro transcription and their compatibility with the co-transcriptional circularization strategy.Collectively,our results provide valuable insights for improving the production efficiency and scalability of circRNA manufacturing that are crucial for addressing key bottlenecks in the development of circRNA-based therapeutic applications.

Altered O-GlcNAcylation and mitochondrial dysfunction,a molecular link between brain glucose dysregulation and sporadic Alzheimer's disease

Alzheimer’s disease is a neurodegenerative disease that affected over 6.5 million people in the United States in 2021,with this number expected to double in the next 40 years without any sort of treatment.Due to its heterogeneity and complexity,the etiology of Alzheimer’s disease,especially sporadic Alzheimer’s disease,remains largely unclear.Compelling evidence suggests that brain glucose hypometabolism,preceding Alzheimer’s disease hallmarks,is involved in the pathogenesis of Alzheimer’s disease.Herein,we discuss the potential causes of reduced glucose uptake and the mechanisms underlying glucose hypometabolism and Alzheimer’s disease pathology.Specifically,decreased O-Glc NAcylation levels by glucose deficiency alter mitochondrial functions and together contribute to Alzheimer’s disease pathogenesis.One major problem with Alzheimer’s disease research is that the disease progresses for several years before the onset of any symptoms,suggesting the critical need for appropriate models to study the molecular changes in the early phase of Alzheimer’s disease progression.Therefore,this review also discusses current available sporadic Alzheimer’s disease models induced by metabolic abnormalities and provides novel directions for establishing a human neuronal sporadic Alzheimer’s disease model that better represents human sporadic Alzheimer’s disease as a metabolic disease.

Oral squamous cell carcinomas:state of the field and emerging directions

Oral squamous cell carcinoma (OSCC) develops on the mucosal epithelium of the oral cavity. It accounts for approximately 90% oforal malignancies and impairs appearance, pronunciation, swallowing, and flavor perception. In 2020, 377,713 OSCC cases werereported globally. According to the Global Cancer Observatory (GCO), the incidence of OSCC will rise by approximately 40% by2040, accompanied by a growth in mortality. Persistent exposure to various risk factors, including tobacco, alcohol, betel quid (BQ),and human papillomavirus (HPV), will lead to the development of oral potentially malignant disorders (OPMDs), which are oralmucosal lesions with an increased risk of developing into OSCC. Complex and multifactorial, the oncogenesis process involvesgenetic alteration, epigenetic modification, and a dysregulated tumor microenvironment. Although various therapeuticinterventions, such as chemotherapy, radiation, immunotherapy, and nanomedicine, have been proposed to prevent or treat OSCCand OPMDs, understanding the mechanism of malignancies will facilitate the identification of therapeutic and prognostic factors,thereby improving the efficacy of treatment for OSCC patients. This review summarizes the mechanisms involved in OSCC.Moreover, the current therapeutic interventions and prognostic methods for OSCC and OPMDs are discussed to facilitatecomprehension and provide several prospective outlooks for the fields.

Cdk5 and aberrant cell cycle activation at the core of neurodegeneration

Neurodegenerative diseases are caused by the progressive loss of specific neurons.The exact mechanisms of action of these diseases are unknown,and many studies have focused on pathways related to abnormal accumulation and processing of proteins,mitochondrial dysfunction,and oxidative stress leading to apoptotic death.However,a growing body of evidence indicates that aberrant cell cycle re-entry plays a major role in the pathogenesis of neurodegeneration.The activation of the cell cycle in mature neurons could be promoted by several signaling mechanisms,including c-Jun N-terminal kinases,p38 mitogen-activated protein kinases,and mitogen-activated protein kinase/extracellular signal-regulated kinase cascades;post-translational modifications such as Tau-phosphorylation;and DNA damage response.In all these events,implicated Cdk5,a proline-directed serine/threonine protein kinase,seems to be responsible for several cellular processes in neurons including axon growth,neurotransmission,synaptic plasticity,neuronal migration,and maintenance of neuronal survival.However,under pathological conditions,Cdk5 dysregulation may lead to cell cycle re-entry in post-mitotic neurons.Thus,Cdk5 hyperactivation,by its physiologic activator p25,hyper-phosphorylates downstream substrates related to neurodegenerative diseases.This review summarizes factors such as oxidative stress,DNA damage response,signaling pathway disturbance,and Ubiquitin proteasome malfunction contributing to cell cycle re-entry in post-mitotic neurons.It also describes how all these factors are linked to a greater or lesser extent with Cdk5.Thus,it offers a global vision of the function of cell cycle-related proteins in mature neurons with a focus on Cdk5 and how this protein contributes to the development of Alzheimer’s disease,Parkinson’s disease,amyotrophic lateral sclerosis,and Huntington’s disease by cell cycle activation.

Columbianetin acetate inhibits the occurrence and development of pancreatic cancer cells by down-regulating the expression of Meiotic nuclear divisions 1

Columbianetin acetate(CE)is one of the effective components of Angelica pubescens.So far,the specific role and molecular mechanism of CE in pancreatic cancer are not clear.Thus,this study aimed to explore the specific mechanism of CE on pancreatic cancer.The target genes combined with CE were predicted through the PharmMapper database and the 3D molecular structure of CE.Then,the Cancer Genome Atlas(TCGA)and Cistrome data browser(DB)databases were used to screen Meiotic nuclear divisions 1(MND1)-related genes,transcription factors,and transcription factor data sets,and the intersection of the above data sets.The“limma”package in the R and gene expression profiling interactive analysis(GEPIA)databases were used to analyze the correlation and survival difference between the target genes and MND1 to predict the degree of association between CE and MND1.Western blotting and RT-PCR experiments revealed the regulatory relationship among CE,E2F1,and MND1 at the cellular level.The specific effects of CE on pancreatic cancer cells were explored through CCK8,wound healing,migration,and flow cycle experiments.E2F1,also the predictive transcription factor of MND1,was also the predictive target protein of CE.At the same time,E2F1 and MND1 were closely related in pancreatic tissue.In the cell function experiment,CE and interference with E2F1 expression could reduce the gene and protein expression of MND1,which was closely associated with cell proliferation,migration,and cycle development.Similarly,interfering with the expression of mnd1 can also inhibit the further development of tumor cells.CE may inhibit the development of pancreatic cancer cells by reducing the expression of MND1.This implies that CE may be a potential novel agent for the treatment of pancreatic cancer.

X-ray imaging of 30 year old wine grape wood reveals cumulative impacts of rootstocks on scion secondary growth and Ravaz index

Annual rings from 30 year old vines in a California rootstock trial were measured to determine the effects of 15 different rootstocks on Chardonnay and Cabernet Sauvignon scions.Viticultural traits measuring vegetative growth,yield,berry quality,and nutrient uptake were collected at the beginning(1995 to 1999)and end(2017 to 2020)of the lifetime of a vineyard initially planted in 1991 and removed in 2021.X-ray Computed Tomography(CT)was used to measure ring widths in 103 vines.Ring width was modeled as a function of ring number using a negative exponential model.Early and late wood ring widths,cambium width,and scion trunk radius were correlated with 27 traits.Modeling of annual ring width shows that scions alter the width of the first rings but that rootstocks alter the decay of later rings,consistently shortening ring width throughout the lifetime of the vine.Ravaz index,juice pH,photosynthetic assimilation and transpiration rates,and instantaneous water use efficiency are correlated with scion trunk radius.Ultimately,our research indicates that rootstocks modulate secondary growth over years,altering physiology and agronomic traits.Rootstocks act in similar but distinct ways from climate to modulate ring width,which borrowing techniques from dendrochronology,can be used to monitor both genetic and environmental effects in woody perennial crop species.

Molecular immune pathogenesis and diagnosis of COVID-19

Coronavirus disease 2019(COVID-19)is a kind of viral pneumonia which is caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).The emergence of SARS-CoV-2 has been marked as the third introduction of a highly pathogenic coronavirus into the human population after the severe acute respiratory syndrome coronavirus(SARS-CoV)and the Middle East respiratory syndrome coro-navirus(MERS-CoV)in the twenty-first century.In this minireview,we provide a brief introduction of the general features of SARS-CoV-2 and discuss current knowledge of molecular immune pathogenesis,diagnosis and treatment of COVID-19 on the base of the present understanding of SARS-CoV and MERS-CoV infections,which may be helpful in offering novel insights and potential therapeutic targets for combating the SARS-CoV-2 infection.

Tau truncation in the pathogenesis of Alzheimer's disease:a narrative review

Alzheimer's disease is characterized by two major neuropathological hallmarks—the extracellularβ-amyloid plaques and intracellular neurofibrillary tangles consisting of aggregated and hyperphosphorylated Tau protein.Recent studies suggest that dysregulation of the microtubuleassociated protein Tau,especially specific proteolysis,could be a driving force for Alzheimer's disease neurodegeneration.Tau physiologically promotes the assembly and stabilization of microtubules,whereas specific truncated fragments are sufficient to induce abnormal hyperphosphorylation and aggregate into toxic oligomers,resulting in them gaining prion-like characteristics.In addition,Tau truncations cause extensive impairments to neural and glial cell functions and animal cognition and behavior in a fragment-dependent manner.This review summarizes over 60 proteolytic cleavage sites and their corresponding truncated fragments,investigates the role of specific truncations in physiological and pathological states of Alzheimer's disease,and summarizes the latest applications of strategies targeting Tau fragments in the diagnosis and treatment of Alzheimer's disease.

Neurofibrillary tangles in Alzheimer＇s disease： elucidation of the molecular mechanism by immunohistochemistry and tau protein phospho-proteomics

As a key contributor to memory storage, the synapse is one of the earliest affected neuronal components in Alzheimer＇s disease （AD）. Under physiological conditions, the synaptic con- nections between neurons undergo activity-dependent func- tional and morphological re-organisation. This dynamic, ＇plastic＇ neural ability critically depends on the structural integrity of the synapse. Thus, proteins that are implicated in preserving the organisation and dynamics of synaptic connections, including microtubules of the cytoskeleton and associated proteins, have attracted much focus for their involvement in the malfunction- ing AD synapse.