Comprehensive analysis of the gut microbiome and posttranslational modifications elucidates the route involved in microbiota-host interactions

The gut microbiome interacts with the host to maintain body homeostasis,with gut microbial dysbiosis implicated in many diseases.However,the underlying mechanisms of gut microbe regulation of host behavior and brain functions remain unclear.This study aimed to elucidate the influence of gut microbiota on brain functions via post-translational modification mechanisms in the presence or absence of bacteria without any stimulation.We conducted succinylome analysis of hippocampal proteins in germ-free(GF)and specific pathogen-free(SPF)mice and metagenomic analysis of feces from SPF mice.These results were integrated with previously reported hippocampal acetylome and phosphorylome data from the same batch of mice.Subsequent bioinformatics analyses revealed 584 succinylation sites on 455 proteins,including 54 up-regulated succinylation sites on 91 proteins and 99 down-regulated sites on 51 proteins in the GF mice compared to the SPF mice.We constructed a panoramic map of gut microbiota-regulated succinylation,acetylation,and phosphorylation,and identified cross-talk and relative independence between the different types of post-translational modifications in modulating complicated intracellular pathways.Pearson correlation analysis indicated that 13 taxa,predominantly belonging to the Bacteroidetes phylum,were correlated with the biological functions of post-translational modifications.Positive correlations between these taxa and succinylation and negative correlations between these taxa and acetylation were identified in the modulation of intracellular pathways.This study highlights the hippocampal physiological changes induced by the absence of gut microbiota,and proteomic quantification of succinylation,phosphorylation,and acetylation,contributing to our understanding of the role of the gut microbiome in brain function and behavioral phenotypes.

Implications of electrode modifications in aqueous organic redox flow batteries

Aqueous organic redox flow batteries(RFBs)exhibit favorable characteristics,such as tunability,multielectron transfer capability,and stability of the redox active molecules utilized as anolytes and catholytes,making them very viable contenders for large-scale grid storage applications.Considerable attention has been paid on the development of efficient redox-active molecules and their performance optimization through chemical substitutions at various places on the backbone as part of the pursuit for high-performance RFBs.Despite the fact that electrodes are vital to optimal performance,they have not garnered significant attention.Limited research has been conducted on the effects of electrode modifications to improve the performance of RFBs.The primary emphasis has been given on the impact of electrode engineering to augment the efficiency of aqueous organic RFBs.An overview of electron transfer at the electrode-electrolyte interface is provided.The implications of electrode modification on the performance of redox flow batteries,with a particular focus on the anodic and cathodic half-cells separately,are then discussed.In each section,significant discrepancies surrounding the effects of electrode engineering are thoroughly examined and discussed.Finally,we have presented a comprehensive assessment along with our perspectives on the future trajectory.

Stem cell-based ischemic stroke therapy:Novel modifications and clinical challenges

Ischemic stroke(IS)causes severe disability and high mortality worldwide.Stem cell(SC)therapy exhibits unique therapeutic potential for IS that differs from current treatments.SC’s cell homing,differentiation and paracrine abilities give hope for neuroprotection.Recent studies on SC modification have enhanced therapeutic effects for IS,including gene transfection,nanoparticle modification,biomaterial modification and pretreatment.Thesemethods improve survival rate,homing,neural differentiation,and paracrine abilities in ischemic areas.However,many problems must be resolved before SC therapy can be clinically applied.These issues include production quality and quantity,stability during transportation and storage,as well as usage regulations.Herein,we reviewed the brief pathogenesis of IS,the“multi-mechanism”advantages of SCs for treating IS,various SC modification methods,and SC therapy challenges.We aim to uncover the potential and overcome the challenges of using SCs for treating IS and convey innovative ideas for modifying SCs.

Systematic Analysis of Post-Translational Modifications for Increased Longevity of Biotherapeutic Proteins

Protein-based therapeutics (PPTs) are drugs used to treat a variety of different conditions in the human body by alleviating enzymatic deficiencies, augmenting other proteins and drugs, modulating signal pathways, and more. However, many PPTs struggle from a short half-life due to degradation caused by irreversible protein aggregation in the bloodstream. Currently, the most researched strategies for improving the efficiency and longevity of PPTs are post-translational modifications (PTMs). The goal of our research was to determine which type of PTM increases longevity the most for each of three commonly-used therapeutic proteins by comparing the docking scores (DS) and binding free energies (BFE) from protein aggregation and reception simulations. DS and BFE values were used to create a quantitative index that outputs a relative number from −1 to 1 to show reduced performance, no change, or increased performance. Results showed that methylation was the most beneficial for insulin (p < 0.1) and human growth hormone (p < 0.0001), and both phosphorylation and methylation were somewhat optimal for erythropoietin (p < 0.1 and p < 0.0001, respectively). Acetylation consistently provided the worst benefits with the most negative indices, while methylation had the most positive indices throughout. However, PTM efficacy varied between PPTs, supporting previous studies regarding how each PTM can confer different benefits based on the unique structures of recipient proteins.

Variations of Atmospheric ELF/VLF Radio Noise Due to Seismogenic Modifications in Tropospheric Conductivity

We suggest a possible explanation of the influence of pre-seismic activity on the registration rate of natural ELF(extremely low frequency)/VLF(very low frequency) pulses and the changes of their characteristics. The main idea is as follows. The distribution of the electric field around a thundercloud depends on the conductivity profile of the atmosphere. Quasi-static electric fields of a thundercloud decrease in those tropospheric regions where an increase of air conductivity is generated by pre-seismic activities due to emanation of radioactive gas and water into the lower atmosphere. The electric field becomes reduced in the lower troposphere, and the probability decreases of the cloud-to-ground (CG) strokes in such “contaminated” areas. Simultaneously, the electric field grows inside and above the thunderclouds, and hence, we anticipate a growth in the number of horizontal and tilted inter-cloud (or intra-cloud) (both termed as IC discharges) strokes. Spatial orientation of lightning strokes reduces vertical projection of their individual amplitudes, while the rate (median number strokes per a unit time) of discharges grows. We demonstrate that channel tilt of strokes modifies the spectral content of ELF/VLF radio noise and changes the rate of detected pulses during the earthquake preparation phase.

Successful lifestyle modifications may underlie umbilical cordmesenchymal stromal cell effects in type 2 diabetes mellitus

Type 2 diabetes mellitus(T2DM)is a lifelong condition and a grave threat to human health.Innovative efforts to relieve its detrimental effects are acutely needed.The sine qua non in T2DM management is consistent adherence to a prudent lifestyle and nutrition,combined with aerobic and resistance exercise regimens,together repeatedly shown to lead to complete reversal and even longterm remission.Non-adherence to the above lifestyle adjustments condemns any treatment effort and ultimately the patient to a grim fate.It is thus imperative that every study evaluating the effects of innovative interventions in T2DM objectively compares the novel treatment modality to lifestyle modifications,preferably through double-blind controlled randomization,before claiming efficacy.

Peanut proteins:Extraction,modifications,and applications:A comprehensive review

As naturally sourced proteins,peanut proteins have garnered significant attention from the food industry,owing to their numerous advantages,such as easy extraction,non-pungency,and high bioavailability.Furthermore,peanut proteins are highly digestible in the gastrointestinal tract and boast a high net protein utilization rate,making them an appealing protein source in food products and a promising alternative to animal protein.In this paper,the recent works on the extraction method,modification method,and application of peanut proteins were reviewed.Both advantages and disadvantages of current extraction and modification were discussed.Recently updated information about peanut protein research was summarized.Based on these,the prospection of peanut proteins research was presented,which may be instructive for future research in this field.Future research is still needed for accessible modification methods to develop the functional properties of peanut proteins.

Redox and metabolic regulation of epigenetic modifications:an emerging toxic action mechanism

Epigenetic modifications modulate conformational structure of chromatin and consequently gene expression by enzyme-mediated chemical modifications of DNA and histones.The activities of epigenetic modifying enzymes depend on many co-substrates and cofactors,such as 2-oxoglutarate(2-OG),iron,S-adenosylmethionine(SAM),nicotinamide adenine dinucleotide(NAD+),flavin adenine dinucleotide(FAD),and acetyl-CoA.These factors are inter-connecting molecules that integrate cellular nutrient metabolism and redox homeostasis,two key regulators of cell proliferation,cell survival,and cell functions.Dysregulation of such delicate regulatory network has been implicated in many pathological conditions and also been increasingly recognized as an emerging mechanism responsible for environmental pollutant-induced adverse effects.In this review,we first summarize DNA and histone modifying enzymes and their essential factors,then discuss the metabolic sources and the redox regulatory roles of these enzymatic factors,and finally elaborate the mechanisms of how targeting such factors by environmental pollutants influences epigenetic regulation and perturbs cellular functions.

Epigenetic modifications and metabolic memory in diabetic retinopathy:beyond the surface

Epigenetics focuses on DNA methylation,histone modification,chromatin remodeling,noncoding RNAs,and other gene regulation mechanisms beyond the DNA sequence.In the past decade,epigenetic modifications have drawn more attention as they participate in the development and progression of diabetic retinopathy despite tight control of glucose levels.The underlying mechanisms of epigenetic modifications in diabetic retinopathy still urgently need to be elucidated.The diabetic condition facilitates epigenetic changes and influences target gene expression.In this review,we summarize the involvement of epigenetic modifications and metabolic memory in the development and progression of diabetic retinopathy and propose novel insights into the treatment of diabetic retinopathy.

Current Strategies of Surface Modifications to Polyurethane Biomaterials for Vascular Grafts

As the number of patients suffering from cardiovascular diseases and peripheral vascular diseases rises,the constraints of autologous transplantation remain unavoidable.As a result,artificial vascular grafts must be developed.Adhesion of proteins,platelets and bacteria on implants can result in stenosis,thrombus formation,and postoperative infection,which can be fatal for an implantation.Polyurethane,as a commonly used biomaterial,has been modified in various ways to deal with the adhesions of proteins,platelets,and bacteria and to stimulate endothelium adhesion.In this review,we briefly summarize the mechanisms behind adhesions,overview the current strategies of surface modifications of polyurethane biomaterials used in vascular grafts,and highlight the challenges that need to be addressed in future studies,aiming to gain a more profound understanding of how to develop artificial polyurethane vascular grafts with an enhanced implantation success rate and reduced side effect.

Compared discharge characteristics and film modifications of atmospheric pressure plasma jets with two different electrode geometries

Atmospheric pressure plasma jet shows great potential for polymer film processing. The electrode geometry is the key factor to determine discharge characteristics and film modification of jets. In this paper, we compared the discharge characteristics and the film modifications of atmospheric pressure plasma jets with needle-ring electrode(NRE) and doublering electrode(DRE). The results show that jet with NRE has stronger electric field intensity and higher discharge power,making it present more reactive oxygen particles and higher electron temperature, but its discharge stability is insufficient.In contrast, the jet with DRE has uniform electric field distribution of lower field intensity, which allows it to maintain stable discharge over a wide range of applied voltages. Besides, the modification results show that the treatment efficiency of PET film by NRE is higher than that by DRE. These results provide a suitable atmospheric pressure plasma jets device selection scheme for polymer film processing process.

Histone modifications and alcohol-induced liver disease:Are altered nutrients the missing link?

Alcoholism is a major health problem in the United States and worldwide,and alcohol remains the single most significant cause of liver-related diseases and deaths.Alcohol is known to influence nutritional status at many levels including nutrient intake,absorption,utilization,and excretion,and can lead to many nutritional disturbances and deficiencies.Nutrients can dramatically affect gene expression and alcohol-induced nutrient imbalance may be a major contributor to pathogenic gene expression in alcohol-induced liver disease(ALD).There is growing interest regarding epigenetic changes,including histone modifications that regulate gene expression during disease pathogenesis.Notably,modifications of core histones in the nucleosome regulate chromatin structure and DNA methylation,and control gene transcription.This review highlights the role of nutrient disturbances brought about during alcohol metabolism and their impact on epigenetic histone modifications that may contribute to ALD.The review is focused on four critical metabolites,namely,acetate,S-adenosylmethionine,nicotinamide adenine dinucleotide and zinc that are particularly relevant to alcohol metabolism and ALD.

Post-translational modifications of prostaglandin-endoperoxide synthase 2 in colorectal cancer:An update

The biosynthesis of prostanoids is involved in both physiological and pathological processes. The expression of prostaglandin-endoperoxide synthase 2(PTGS2; also known as COX-2) has been traditionally associated to the onset of several pathologies, from inflammation to cardiovascular, gastrointestinal and oncologic events. For this reason, the search of selective PTGS2 inhibitors has been a focus for therapeutic interventions. In addition to the classic non-steroidal anti-inflammatory drugs, selective and specific PTGS2 inhibitors, termed coxibs, have been generated and widely used. PTGS2 activity is less restrictive in terms of substrate specificity than the homeostatic counterpart PTGS1, and it accounts for the elevated prostanoid synthesis that accompanies several pathologies. The main regulation of PTGS2 occurs at the transcription level. In addition to this, the stability of the mRNA is finely regulated through the interaction with several cytoplasmic elements, ranging from specificmicroR NAs to proteins that control mR NA degradation. Moreover, the protein has been recognized to be the substrate for several post-translational modifications that affect both the enzyme activity and the targeting for degradation via proteasomal and non-proteasomal mechanisms. Among these modifications, phosphorylation, glycosylation and covalent modifications by reactive lipidic intermediates and by free radicals associated to the proinflammatory condition appear to be the main changes. Identification of these post-translational modifications is relevant to better understand the role of PTGS2 in several pathologies and to establish a correct analysis of the potential function of this protein in diseases progress. Finally, these modifications can be used as biomarkers to establish correlations with other parameters, including the immunomodulation dependent on molecular pathological epidemiology determinants, which may provide a better frame for potential therapeutic interventions.

Acetylcholinesterase inhibitor modifications: a promising strategy to delay the progression of Alzheimer's disease

Alzheimer＇s disease （AD）, a fatal, progressive, neurodegener- ative disorder, is the most common cause of old-age demen- tia, accounting for 50-75% of dementia patients. Early stages of AD are marked by vocabulary shrinkage, spatial disori- entation, depression, apraxia, and deterioration of recent forms of declarative memory. In course of time, the patients require close supervision due to the loss of cognitive and functional abilities, and at the terminal stages of the disease, all forms of memory are severely impaired with the patients needing nursing home care （World Alzheimer Report, 2013）.

Syntheses,challenges and modifications of single-crystal cathodes for lithium-ion battery

Single-crystal cathodes(SCCs)are promising substitute materials for polycrystal cathodes(PCCs)in lithium-ion batteries(LIBs),because of their unique ordered structure,excellent cycling stability and high safety performance.Cathode materials with layered(LiCoO_(2),LiNi_xCo_yMnzO_(2),LiNi_xCo_yAl_(2)O_(2))and spinel structure(LiMn_(2)O_(4),LiNi_(0.5)Mn_(1.5)O_(4))show a relatively stable electrochemical performance,but still lack of sufficient attention in research field.In this review,we begin with the definition,structural features and electrochemical advantages of SCCs.Common SCCs synthesis methods and the thermodynamic growth mechanism of SCCs with oriented facet exposure are summarized in the following part.Then we introduce the problems and challenges of SCCs faced and the corresponding modification strategies.Finally,the industrialization progress of SCCs is brifly outlined.We intend to tease out the difficulties and advances of SCCs to provide insights for future development of high-performance SCCs for practical LIBs.

Post-translational modifications of hepatitis C viral proteins and their biological significance

Replication of hepatitis C virus(HCV)depends on the interaction of viral proteins with various host cellular proteins and signalling pathways.Similar to cellular proteins,post-translational modifications(PTMs)of HCV proteins are essential for proper protein function and regulation,thus,directly affecting viral life cycle and the generation of infectious virus particles.Cleavage of the HCV polyprotein by cellular and viral proteases into more than 10 proteins represents an early protein modification step after translation of the HCV positivestranded RNA genome.The key modifications include the regulated intramembranous proteolytic cleavage of core protein,disulfide bond formation of core,glycosylation of HCV envelope proteins E1 and E2,methylation of nonstructural protein 3(NS3),biotinylation of NS4A,ubiquitination of NS5B and phosphorylation of core and NS5B.Other modifications like ubiquitination of core and palmitoylation of core and NS4B proteins have been reported as well.For some modifications such as phosphorylation of NS3 and NS5A and acetylation of NS3,we have limited understanding of their effects on HCV replication and pathogenesis while the impact of other modifications is far from clear.In this review,we summarize the available information on PTMs of HCV proteins and discuss their relevance to HCV replication and pathogenesis.

Evaluation of biomarkers, genetic mutations, and epigenetic modifications in early diagnosis of pancreatic cancer

BACKGROUND Pancreatic cancer(PC)is one of the deadliest malignancies with an alarming mortality rate.Despite significant advancement in diagnostics and therapeutics,early diagnosis remains elusive causing poor prognosis,marred by mutations and epigenetic modifications in key genes which contribute to disease progression.AIM To evaluate the various biological tumor markers collectively for early diagnosis which could act as prognostic biomarkers and helps in future therapeutics of PC in Kashmir valley.METHODS A total of 50 confirmed PC cases were included in the study to evaluate the levels of carbohydrate antigen 19-9(CA 19-9),tissue polypeptide specific antigen(TPS),carcinoembryonic antigen(CEA),vascular endothelial growth factor-A(VEGF-A),and epidermal growth factor receptor(EGFR).Mutational analysis was performed to evaluate the mutations in Kirsten rat sarcoma(KRAS),Breast cancer type 2(BRCA-2),and deleted in pancreatic cancer-4(DPC-4)genes.However,epigenetic modifications(methylation of CpG islands)were performed in the promoter regions of cyclin-dependent kinase inhibitor 2A(p16;CDKN2A),MutL homolog 1(hMLH1),and Ras association domain-containing protein 1(RASSF1A)genes.RESULTS We found significantly elevated levels of biological markers CA 19-9(P≤0.05),TPS(P≤0.05),CEA(P≤0.001),and VEGF(P≤0.001).Molecular genetic analysis revealed that KRAS gene mutation is predominant in codon 12(16 subjects,P≤0.05),and 13(12 subjects,P≤0.05).However,we did not find a mutation in DPC-4(1203G>T)and BRCA-2(617delT)genes.Furthermore,epigenetic modification revealed that CpG methylation in 21(P≤0.05)and 4 subjects in the promoter regions of the p16 and hMLH1 gene,respectively.CONCLUSION In conclusion,CA 19-9,TPS,CEA,and VEGF levels were significantly elevated and collectively have potential as diagnostic and prognostic markers in PC.Global data of mutation in the KRAS gene commonly in codon 12 and rare in codon 13 could augment the predisposition towards PC.Additionally,methylation of the p16 gene could also modulate transcription of genes thereby increasing the predisposition and susceptibility towards PC.

Chemical Modifications of Layered Double Hydroxides in the Supercapacitor

Layered double hydroxides are one class or kind of 2 D layered materials that are considered promising for use in the supercapacitor.Although there have been many studies on the structure,composition,properties,and electrode fabrication of layered double hydroxides,none summarize the effects of various modification methods on the structure and performance of layered double hydroxides in the supercapacitor.In a bid to fill this gap,in this review,we summarize the progress of modification methods such as exfoliation,intercalation,vacancy,doping,phase transformation,and composition regulation of layered double hydroxides in the field of the supercapacitor and put forward some opinions regarding the progress of research on the methods used in modifying the layered double hydroxides.

Validation of the eighth edition of the AJCC staging system for patients with pancreatic adenocarcinoma initially receiving chemoradiotherapy and proposal of modifications

Objective:To validate the eighth edition of the AJCC staging system in patients with pancreatic adenocarcinoma receiving only stereotactic body radiation therapy and chemotherapy,and to propose modifications to improve prognostic accuracy.Methods:Patients with pathologically confirmed pancreatic adenocarcinoma without metastasis who were undergoing only chemoradiotherapy were included and staged according to the seventh and eighth editions of the AJCC staging system.Meanwhile,another group of stage T4 patients from the above enrollment with only portal vein involvement with or without tumor thrombi(PV±PVTT)were retrieved for survival comparisons.Modifications were proposed according to the survival comparisons.A cohort from the SEER database was used for external validation of the modified staging system.Results:A total of 683 patients were included.Patients with N2 or N1 but different T stages had significantly different survival outcomes according to the eighth edition.The survival of patients with(PV±PVTT)was comparable to that of patients with T4 tumors.The concordance index of the seventh and eighth editions,and the modified staging system was 0.744(95%CI:0.718—0.769),0.750(95%CI:0.725—0.775),and 0.788(95%CI:0.762-0.813),respectively.For external validation,the concordance index was 0.744(95%CI:0.718-0.770),0.750(95%CI:0.724-0.776),and 0.788(95%CI:0.762-0.814),respectively.Conclusions:The modified staging system is suggested to have the m ost accurate prognostic value.Hence,PV土PVTT should be added to the definition of T4 tumors regardless of tumor size.Patients with N2 or N1 in different T stages could be regrouped into different substages.Additionally,stage III should be subclassified into IIIA(T3N 2 and T4N 0)and IIIB(T4N 1-2).

Lipid accumulation and protein modifications of Bruch’s membrane in age-related macular degeneration

Age-related macular degeneration(AMD)is a progressive retinal disease,which is the leading cause of blindness in western countries.There is an urgency to establish new therapeutic strategies that could prevent or delay the progression of AMD more efficiently.Until now,the pathogenesis of AMD has remained unclear,limiting the development of the novel therapy.Bruch’s membrane(BM)goes through remarkable changes in AMD,playing a significant role during the disease course.The main aim of this review is to present the crucial processes that occur at the level of BM,with special consideration of the lipid accumulation and protein modifications.Besides,some therapies targeted at these molecules and the construction of BM in tissue engineering of retinal pigment epithelium(RPE)cells transplantation were listed.Hopefully,this review may provide a reference for researchers engaged in pathogenesis or management on AMD.