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.

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.

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.

Technical modifications & management innovations in exporting nuclear reactor projects

As a main channel for the foreign economic cooperation of China nuclear industry,China Zhongyuan Engineering Corporation (CZEC) has been constantly engaged in technical modifications and management innovations in its exporting nuclear reactor projects.In the implementation of heavy water research reactor contract in Algeria,CZEC had established a complete and adequate design standards system in compliance with the international standards,and made significant modifications to the reference reactor in the aspects of reactor power and reactor safety,solved quite some technical issues which affected the reactor technical performance.The modifications and improvements enabled the technical parameters,safety features,reactor multipurpose application to attain to the advanced level in the world.In the 300 MWe PWR NPPs in Pakistan,safety features had been updated in line with upgrading regulatory requisites.The design philosophy and technology application demonstrated CZEC's creation and innovation on basis of constant safety enhancement of nuclear power projects.Efforts had also been made by CZEC in promoting China made equipment items and components exportation.

Modifications on default probability calculation methods of commercial banks in China

This paper analyses two methods of calculating default probability adopted by foreign companies. Then, the paper suggests several methods of calculating loan default probability applicable to commercial banks in China, and gives the inadequacy of historic data in China.

Effect of Surfactant-lnduced Modifications on CuCoMn Catalysts for Higher Alcohol Synthesis

A series of surfactant-modified CuCoMn-based catalysts were prepared for higher alco- hol synthesis from biomass-based syngas. Three typical surfactants, cetyltrimethylammonium bromide （CTAB）, sodium dodecyl sulfate （SDS） and pluronic P123 triblock copolymer （EO20PO70EO20）, were employed. Compared to surfactant-free CuCoMn catalyst, CO conversion increased from 17.4% to 29.7% over SDS-modified CuCoMn catalyst, and the selectivity of higher alcohols increased from 22.0% to 41.2% over CTAB-modified catalyst. Besides, the proportions of higher alcohols in total alcohols increased over all surfactantmodified catalysts. The catalysts were characterized by N2 adsorption/desorption, XRD, XPS and IR analysis. The results showed that several more favorable features rendered the CTAB-modified CuCoMn catalyst to be suitable for higher alcohol production, such as the larger pore size, better crystallinity of CuCoMnO4 spinel. moderate surface atomic distribution and lower valence of metallic ions. In addition, it was verified that CTAB addition at the metal precipitation stage was beneficial to higher alcohol synthesis. Surfactant-induced modification provides a promising alternative method for catalyst improvement in synthesis of higher alcohols.

Complex interactomes and post-translational modifications of the regulatory proteins HABP4 and SERBP1 suggest pleiotropic cellular functions

The 57 kDa antigen recognized by the Ki-1 antibody,is also known as intracellular hyaluronic acid binding protein 4 and shares 40.7%identity and 67.4%similarity with serpin mRNA binding protein 1,which is also named CGI-55,or plasminogen activator inhibitor type-1-RNA binding protein-1,indicating that they might be paralog proteins,possibly with similar or redundant functions in human cells.Through the identification of their protein interactomes,both regulatory proteins have been functionally implicated in transcriptional regulation,mRNA metabolism,specifically RNA splicing,the regulation of mRNA stability,especially,in the context of the progesterone hormone response,and the DNA damage response.Both proteins also show a complex pattern of post-translational modifications,involving Ser/Thr phosphorylation,mainly through protein kinase C,arginine methylation and SUMOylation,suggesting that their functions and locations are highly regulated.Furthermore,they show a highly dynamic cellular localization pattern with localizations in both the cytoplasm and nucleus as well as punctuated localizations in both granular cytoplasmic protein bodies,upon stress,and nuclear splicing speckles.Several reports in the literature show altered expressions of both regulatory proteins in a series of cancers as well as mutations in their genes that may contribute to tumorigenesis.This review highlights important aspects of the structure,interactome,post-translational modifications,sub-cellular localization and function of both regulatory proteins and further discusses their possible functions and their potential as tumor markers in different cancer settings.

Dissemination paradox:how contextual realities influence smallholder farmers'modifications of agroforestry technologies in Uganda's Mt.Elgon region

This study was intended to understand how smallholder farmers’modifications improved agroforestry technologies’usability in Uganda’s Mt.Elgon region.We used a case study approach to understand how smallholder farmers’contextual realities informed their modifications and enhanced the usability of agroforestry technologies.Data was collected over four months of frequent and regular interaction with the cases using formal and informal methods that included in-depth interviews,conversations,discussions,and direct observations.Emerging themes and patterns were identified from the comprehensively reduced data.In addition,respondents’direct quotes were used to emphasize the reasons for the modifications.The findings showed that smallholder farmers modified the recommended technologies to suit their biophysical and socio-economic realities.Differences and similarities in modifications existed among cases across the agroforestry technologies.The modifications were mainly done to diversify tree uses,optimize space utilization,and minimize production costs for farming households.These findings imply a need to critically examine the smallholder farmers’modifications to make agroforestry technologies applicable and compliant to their contexts.This will inform the re-invention of technologies that will quickly diffuse into the community for broader impact.Findings also emphasize the need to rethink the linear model of technology transfer mainly applied in agroforestry technology development and dissemination because it offers limited space for the much-needed feedback from smallholder farmers.