Recent advances in the field of molecular pathology and the publication of the revised fourth edition of the WHO Classification of central nervous system (CNS) tumors have significantly reshaped the approach to both diagnosis and therapy of brain tumors . Due to This Research Topic entitled “Molecular Advances in Diagnosis and Treatment of CNS Tumors” includes 22 original research articles and 3 review articles that cover several important themes:Glioblastoma (GBM) is the most common and devastating primary brain tumor in adults. It is therefore essential to identify novel and effective biomarkers or risk signatures for GBM patients. Wang et al. examined differentially expressed genes between GBM and low-grade glioma (LGG) and selected five genes  to construct a risk signature to independently predict the outcome of GBM patients, as well as stratified by radio-chemotherapy, isocitrate dehydrogenase 1 (IDH1) and O6-methylguanine-DNA methyltransferase (MGMT) promoter status. Zhang et al. evaluated the expression level of integrin beta 5 (ITGB5) and the relationship of its elevated expression with glioma progression and poor survival in GBM patients. It appears ITGB5 plays important regulatory roles in angiogenesis and the immune response, and is required for invasion and migration of neoplastic cells and endothelial proliferation in GBM. Zusman et al. discussed how harvesting GBM tissue using traditional surgical approach and the automated resection NICO Myriad™ system may impact the translational research value of the sample. Their study further supports the need to harvest and analyze multiple specimens for each tumor, in order to capture the genomic diversity and maximize the benefits of molecularly-based therapeutics. Zhang et al. demonstrated that Forkhead Box P2 (FOXP2) was the target protein of miR-9-5p. In addition, high expression of miR-9-5p and low expression of FOXP2 were related to better outcome in GBM patients, whereas down regulated FOXP2 expression was capable of inhibiting glioma proliferation through cell cycle arrest. Liu et al. determined the candidate genes that may function as biomarkers to further distinguish patients with IDH-wildtype GBM. The investigators developed a seven-gene-based signature, which allocated each patient to a risk group (low or high). Subsequent bioinformatics analysis predicted that the seven-gene signature was involved in the immune response, inflammatory response, cell adhesion, and apoptotic process. Marchi et al. attempted to correlate the biomolecular aspects of MGMT methylation status in relation to the maximal surgical extent of resection. Interestingly, a positive prognostic value exists only in case of the presence of residual tumor tissue. Dent et al. explored whether a multiple sclerosis drug, Fingolimod would synergize with dimethyl fumarate and its plasma breakdown product MMF to kill GBM neoplastic cells. Indeed, the data demonstrated that the above combination produced reactive oxygen species and killed tumor cells more effectively via death receptor signaling and autophagy induction. Hu et al. conducted a systematic analysis of survival-associated alternative splicing event. The nomogram with age, pharmaceutical and radiation therapy, alternate donor site, and exon skip signatures provided excellent prognostic predictive value.Treatment effectiveness and overall prognosis for glioma patients depend heavily on the genetic and epigenetic factors in each individual tumor. Gates et al. discovered that primary brain tumors are genetically heterogeneous, and the physical distance within a given glioma positively correlates to genomic distance in number of genes, copy number variations, and methylation profiles. They further derived quantitative linear relationships between physical and genomic distances. Su et al. showed that γKlotho  is highly expressed in gliomas epigenetically and its expression is significantly associated with high tumor aggressiveness and poor outcomes for glioma patients. Mechanistically, LCTL might play an important immunosuppressive role via FGF signaling in glioma. Yang et al. performed weighted gene co-expression network analysis in a large public database of glioma samples. The derived brown co-expression module and the biomarker TNFRSF1A were strongly related to glioma grading. Furthermore upregulated TNFRSF1A was tightly associated with clinical features. Zhang et al. systematically analyzed the relationship between methyltransferase-related gene expression profiles and clinical outcomes in glioma patients and identified a novel methyltransferase-related risk signature for predicting the prognosis of gliomas.Recently non-coding types of RNA have been shown to play a vital role in glioma tumorigenesis. Jin et al. characterized a novel non-coding RNA, lipocalin-2-derived circular RNA, in glioma tumorigenesis. The investigators demonstrated that it facilitated glioma progression by sponging miR-661 to increase RAB3D expression. Similarly, Zheng et al. characterized non-coding competitive RNA networks as alternative therapeutic targets in the treatment of GBM. Sun et al. explored the expression profiles and potential relationship between long non-coding RNAs (lncRNAs) and mRNAs in glioma patients. Both lncRNAs and mRNAs exhibited dynamic differential expression profiles, consistent with their roles in critical biological processes and pathways associated with tumor pathogenesis.Several manuscripts cover some of the most fascinating developments in the field. Zhang et al. conducted a meta-analysis to evaluate the prognostic role of connexin protein Cx43 in glioma. The results showed that Cx43 expression was a clearly negative factor with tumor grades and beneficial for survival time, offering evidence that Cx43 is generally a tumor suppressor. Deng et al. explored the influence of IDH1 mutation on the immune microenvironment and developed an IDH1-associated immune prognostic signature to help classify LGG patients into subgroups with distinct outcomes and immunophenotypes. Liu et al. discussed the correlations of soluble PD-L1 (sPD-L1) with clinical features in brain tumors and assessed its diagnostic value in gliomas. Both serum and CSF sPD-L1 showed significant value, but serum sPD-L1 rather than blood-based inflammatory markers had the best diagnostic performance in the diagnosis and stratification of glioma. In addition, a descending trend in the level of serum sPD-L1 was observed in postoperative patients. Hung et al. studied the important question of glioma stem-like cells contributing to drug resistance and tumor recurrence. Their study suggests that a sonic hedgehog (Shh) inhibitor could induce autophagy of CD133+ GSCs through mTOR independent pathway. Therefore, targeting the Shh signal pathway may overcome chemoresistance and provide a therapeutic strategy for patients with malignant gliomas.Informative Review Articles:Tang et al. reviewed the advantages and possible limitations of mRNA-based gene therapy including the in vitro synthesis of mRNA, the feasible methods for synthetic mRNA delivery and clinical therapeutic prospects of mRNA-based gene therapy for glioblastoma. Yu et al. reviewed the regulation of MGMT expression and its role in chemotherapy, especially in glioma. Targeting MGMT seems to be a promising approach to overcome chemoresistance. Hu et al. reviewed the relationship between ferroptosis, a new type of cell death, and temozolomide (TMZ) resistance. Importantly, targeted ferroptosis can be used to reverse TMZ resistance.In summary, management of CNS tumor patients has undergone a molecular revolution driven by the development of high throughput molecular techniques. Molecular testing has become an essential part for the optimal CNS tumor patient workup. At the current stage, a combination of FISH, copy number array, NGS panel and genome-wide methylation profiling can be used to detect molecular alterations in order to provide the best possible patient care. It is true that our ability of amassing molecular data currently surpasses our ability to utilize this information for treatment; however, it is clear that informative molecular biomarkers will guide future clinical trials and lead to the development of new therapeutic strategies.Z-HZ, M-TL, and LC are the coeditors for this Research Topic. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Recently, Johansson and colleagues published an article about the mechanisms causing female reproductive disorders with a special focus on the ovaries (Johansson et al. In recent years, stem cell-based tests have been established where precursor cells are exposed to test compounds during the differentiation period (Krug et al.


In 2015, the World Health Organization (WHO) published the guideline “Sugars intake for adults and children” [The paper presented by Anderson et al.  studied While still more research is needed on the association of both pure fruit juice and ASB consumption with all-cause mortality risk, Anderson et al. provide an important contribution to the current scientific evidence in this field by finding different associations for all-cause mortality between consumption of SSBs and consumption of pure fruit juice. Since the association between SSB consumption and all-cause mortality is well established , 5, 6, i


Short (<200 nt) and long (>200 nt) non-coding (nc) RNAs account for majority of mammalian transcriptional output and encompass RNA species critical for various aspects of development and disease Ambros, . We haveDeeper insight into these enigmatic RNA species clearly requires efforts from both wet-lab and computational avenues of research . One of them, miR-30c, directly repressed cyclin-dependent kinase 12 (CDK12) through a complementary site in the 3′ UTR . Several DNA damage response (DDR) genes were significantly downregulated after introducing miR-30c or repressing CDK12, suggesting that miR-30c regulates embryo development through the DDR pathway .Zhao et al. examined deregulated miRNAs, lncRNAs and circRNAs in the hair follicle cycle of Angora Rabbit (Oryctolagus cuniculus) and provides comprehensive repository of ncRNAs potentially relevant to this process.Mature hair follicles in mammals undergo periodic self-renewal processes called hair follicle cycles. Understanding the molecular regulatory mechanisms of the renewal cycle is important in medicine and developmental biology. Wang et al. profiled lncRNAs in the CD4+ T cells in the mouse model of acute asthma. They found 36 up- and 98 down-regulated lncRNAs in the disease compared with the control samples . The potential functions of deregulated lncRNA were analyzed by performing miRNA binding analysis .Xun et al. proposed an efficient experimental method to find miRNA binding sequences in genomic DNA in vivo, thus potentially identifying miRNA binding sites in the regulatory regions of genes.It has been well-established that miRNAs work by guiding RNA-induced silencing complex (RISC) to their target RNA binding sites in cytoplasm Bartel, . HoweverOu-Yang et al. proposed a novel method called two-side sparse self-representation (TSSR) for predicting lncRNA-disease associations. TSSR significantly outperformed other tested methods and identified some candidate lncRNA-disease associations .Zhang et al. proposed a method called CRlncRC2 for predicting associations between lncRNAs and cancers. More than four hundred cancer-related lncRNA candidates were identified, which were evaluated by examining the Lnc2Cancer database, reviewing literature, and performing statistical analysis of multiple relevant data sources containing information on mutations and differential gene expression in cancers . These results demonstrated that CRlncRC2 is an effective and accurate method for identification of cancer-related lncRNAs .Shen et al. proposed a new method for identifying lncRNA-protein interactions by employing Kernel Ridge Regression, based on Fast Kernel Learning (LPI-FKLKRR). LPI-FKLKRR demonstrated a superior performance compared with a series of other methods as judged by area under precision recall curve.LncRNAs are assumed to realize their functions by interacting with other molecules, such as proteins, chromatin and other RNA species. Huang et al. introduced a computational method to predict interactions between lncRNAs and miRNAs leveraging the information of expression profile data for these transcripts and the graph convolution technique. The proposed model is based on the assumption that the interaction between an lncRNA and a miRNA could be deciphered from their co-expression pattern. Compared with the conventional miRNA-target prediction algorithms based on sequence matching, their work presents a new approach to predict lncRNA:miRNA interactions.Fukunaga et al. introduced a web server, called LncRRIsearch, for predicting lncRNA:lncRNA and lncRNA:mRNA interactions in human and mouse. The tissue-specific expression and cellular localization data of lncRNAs are integrated in this web server to explore tissue-specific or subcellular-localized lncRNA interactions .Li and Liu summarizing recent evidences suggesting that coding and non-coding properties are inherent to both coding and non-coding transcripts. In other words, some lncRNAs and circRNAs could be used to produce short peptides, i.e., have coding capabilities. On the other hand, 3′ and 5′ UTRs of coding genes have non-coding functions such as recruiting RNA-binding proteins (Li and Liu).Smith et al. reviewed the miRNAs and lncRNAs that play key roles in the initiation and progression of pediatric solid tumors. Pediatric tumors, due to lower mutation load compared with adult ones, are assumed to arise from mis-regulation of networks normally functioning during development at transcriptional level . The authors summarized accumulating evidence of involvement of miRNAs and lncRNAs in the regulatory networks functioning during oncogenesis.Watson et al. explored small RNAs in neurodegenerative diseases. This comprehensive review discusses roles of various small RNAs in multiple neurodegenerative diseases, including Alzheimer's, Parkinson's, multiple sclerosis, Amyotrophoic lateral sclerosis, and Huntington's disease.Ramón y Cajal et al. proposed that the interactions between miRNAs and lncRNAs might contribute to the cell-type specific outcomes and to the determination of cell fate. In one model, miRNAs could be competitively sequestered by tissue-specific lncRNAs. In another context, miRNAs released to extracellular space as ligands could interact with lncRNAs in different organs as receptors to either sequester the miRNAs or induce degradation of the miRNAs or the lncRNAs.Recent evidences show that ncRNAs, both miRNAs and lncRNAs, could serve as communication factors between cells (Bayraktar et al., Non-coding RNAs have been associated with various biological processes and human diseases. These phenomena were further expanded and reviewed by several studies in this Research Topic. A number of wet lab and computational methods as well as database resources reported in the Topic should help to refine the connections between ncRNAs and diseases and identify the mechanisms of actions of the former, thus further contributing to the advancement of the ncRNA field.YZ and PK conceived of the work and wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Floral plantings are promoted to foster ecological intensification of agriculture through provisioning of ecosystem services. However, a comprehensive assessment of the effectiveness of different floral plantings, their characteristics and consequences for crop yield is lacking. Here we quantified the impacts of flower strips and hedgerows on pest control (18 studies) and pollination services (17 studies) in adjacent crops in North America, Europe and New Zealand. Flower strips, but not hedgerows, enhanced pest control services in adjacent fields by 16% on average. However, effects on crop pollination and yield were more variable. Our synthesis identifies several important drivers of variability in effectiveness of plantings: pollination services declined exponentially with distance from plantings, and perennial and older flower strips with higher flowering plant diversity enhanced pollination more effectively. These findings provide promising pathways to optimise floral plantings to more effectively contribute to ecosystem service delivery and ecological intensification of agriculture in the future. Our quantitative synthesis of the impacts of floral plantings on pest control, crop pollination and yield reveals that flower strips, but not hedgerows, enhanced pest control services in adjacent fields by 16% on average, while effects on crop pollination and yield were more variable. Our synthesis identifies several important drivers of this variability in effectiveness of plantings: pollination services declined exponentially with distance from plantings, and perennial and older flower strips with higher flowering plant diversity enhanced pollination more effectively, with important implications for the the design and implementation of these measures to effectively promote ecological intensification of agriculture in the future The ‘exporter’ hypothesis  the extent to which flower strips and hedgerows enhance pollination and pest control services in adjacent crops; (2) how service provisioning changes with distance from floral plantings; (3) the role of plant diversity and time since establishment of floral plantings in promoting pollination and pest control services; (4) whether simplification of the surrounding landscape modifies the responses; and (5) whether floral plantings enhance crop yield in adjacent fields.Our synthesis reveals general positive effects of flower strips but not hedgerows on pest control services in adjacent crop fields. Effects on crop pollination, however, depended on flowering plant diversity and age since establishment, with more species‐rich and older plantings being more effective. However, no consistent impacts of flower strips on crop yield could be detected, highlighting the need for further optimisations of plantings as measures for ecological intensification.To identify data sets suitable to address our research questions, we performed a search in the ISI Web of Science and SCOPUS (records published until 31.12.2017 were considered). To minimise potential publication bias  because (1) average z‐scores follow a normal distribution, and (2) the variability present in the raw data is not constrained as in other indices that are bound between 0 and 1  therefore focus on flower strip effects on pollination and pest control services. Information on plant species richness was available in 12 out of 18 pest control studies and 10 out of 17 pollination studies. Whenever available, the species richness of flowering plants was used. Otherwise, for some flower strip studies, the number of sown, potentially flowering plant species (excluding grasses) was used. Time since establishment of flower strips, that is the time span between seeding or planting and data sampling, was available for all studies ranging from 3 to 122 months.et al., et al., The proportional cover of arable crops was available and analysed as a proxy for landscape simplification . Only 10 studies measured services in several years since establishment  linear mixed‐effect models with planting (field with or without planting) were separately fitted for flower strips and hedgerows for the response variables pollination service and pest control service. To test how the effects on service provisioning change with distance  from plantings (question 2) and with landscape simplification (question 4) these explanatory variables and their interactions with the fixed effects described earlier were included in the models. Exploratory analyses showed that neither distance nor landscape simplification effects differed between flower strips and hedgerows; that is no significant interactive effects of planting type with any of the tested fixed effects. We therefore pooled flower strip and hedgerow data in the final models, excluding planting type and its two or three‐way interactions as fixed effects. In addition to linear relationships we tested for an exponential decline of measured response variables from the border of the field by fitting log10(distance) in the linear mixed‐effect models described earlier. In this case, field nested within study was included as a random effect. To test the intermediate landscape complexity hypothesis, we tested for linear as well as hump‐shaped relationships between landscape context, and its interaction with local floral plantings by fitting landscape variables as a quadratic fixed predictor in the models described earlier . To present the ranges covered by the agricultural landscape gradients, we did not standardise measures of landscape simplification within studies  recommended for testing significant effects of , et al. . All staThe provisioning of pest control services in crop fields adjacent to flower strips was enhanced by 16% on average compared to fields without flower strips. On average, pest control services were also increased in crops adjacent to hedgerows, but effects were more variable and overall not statistically significant Fig. ; Table 1Crop pollination effects were more variable across studies and overall not significantly different between crops with or without adjacent floral planting across all studies and within‐field distances Fig ; Table 1Crop pollination services, but not pest control services, tended to increase with flowering plant species richness of the adjacent flower strip . These results indicate that floral plantings have great potential to benefit ecosystem service provision, but to do so will need to be carefully tailored for functioning at specific spatial scales. Flower diversity and strip age are important drivers through which this can be achieved and they should be considered integrally before floral plantings can make a significant contribution to the ecological intensification of agricultural production.sensu Morandin and Kremen, et al., et al., We found positive effects of flower strips on ecosystem service provisioning in support of the ‘exporter’ hypothesis . We fou, et al, .et al., et al., et al., et al., et al., et al., et al., et al., Consistent with previous studies (e.g. Dainese et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Crop yield is affected by a complex interplay of a multitude of agricultural management practices such as fertilisation, level of pesticide use, pest pressures, soil cultivation and other factors such as local soil and climatic conditions (e.g. Bartomeus Our synthesis demonstrates enhanced natural pest control services to crops adjacent flower strips plantings, across a broad suite of regions, cropping systems and types of flower strips studied. However, it also reveals inconsistent and highly variable effects of flower strips and hedgerows on crop pollination services and yield. This highlights a strong need to identify the key factors driving this variability and the effectiveness of different types of floral plantings in contributing to ecosystem service delivery. Informed by such improved understanding, the design, implementation and management of floral plantings can increase their effectiveness as measures for ecological intensification. This synthesis identifies several promising pathways towards more effective floral plantings for the provision of ecosystem services and ecological intensification: the modelled exponential distance‐decay function of pollination service provisioning by floral plantings into crop field helps to predict service provision in crop fields; together with the lack of a strong planting area effect, our findings suggest that a dense spatial network of relatively small plantings will be more effective than a few large ones to optimise pollination service provisioning. Moreover, it identifies important drivers of the effectiveness of floral plantings for delivery of crop pollination services: flowering plant diversity and age. Based on these findings we strongly encourage the establishment, adequate management and restoration of existing perennial floral plantings that ensure the availability of high floral diversity across several years as promising pathways towards optimised measures for ecological intensification.MA and LS designed the study. MA, DK, MT, BRB, RB, AJC, MD, FD, MHE, DG, ADG, DG, HG, HH, FH, RI, KJ, PJ, MJ, EK, CK, DAL, GML, LM, MMK, LM, SCP, SGP, MR, HS, AS, CT, TT, EV, EV, IMGV, AW, DBW, FW, KW, NMW, MW, SW and LS contributed data. MA compiled the dataset. LS and MA analysed the data. MA, LS, DK, MG, SGP and MR interpreted results. MA wrote the paper and all authors contributed to revisionFig S1Click here for additional data file.Table S1Click here for additional data file.Table S2Click here for additional data file.Table S3Click here for additional data file.Table S4Click here for additional data file.Table S5Click here for additional data file.


Cachexia is a metabolic mutiny that directly reduces life expectancy in chronic conditions such as cancer. The underlying mechanisms associated with cachexia involve inflammation, metabolism, and anorexia. Therefore, the need to identify cachexia biomarkers is warranted to better understand catabolism change and assess various therapeutic interventions. Among inflammatory proteins, growth differentiation factor-15 (GDF15), an atypical transforming growth factor-beta (TGF-β) superfamily member, emerges as a stress-related hormone. In inflammatory conditions, cardiovascular diseases, and cancer, GDF15 is a biomarker for disease outcome. GDF15 is also implicated in energy homeostasis, body weight regulation, and plays a distinct role in cachexia. The recent discovery of its receptor, glial cell line-derived neurotrophic factor (GDNF) family receptor α-like (GFRAL), sheds light on its metabolic function. Herein, we critically review the mechanisms involving GDF15 in cancer cachexia and discuss therapeutic interventions to improve outcomes in people living with cancer. Almost eighty percent of advanced cancer patients are affected by involuntary wasting, which is inversely related to handgrip strength, high toxicities of anti-cancer drugs, quality of life, and survival.18Since cachexia preferentially causes loss of LBM more than FM, there is a need for a biomarker for the early diagnosis of cachexia, especially the atrophy in skeletal muscle.et al. demonstrated reversal of cancer cachexia by injecting anti-bodies against Act A and Mstn in mice model leading to prolong survival.et al., demonstrated that GDF15 inhibitors reversed the loss of LBM and FM in mice.In recent years, several markers have been reported to be involved in skeletal muscle atrophy in cancer cachexia.et al. found that cancer-related weight loss was linked to changes in the diet and inflammatory cytokines.Table .In 2005, Fouladiun  et al.'s recommendation in 2000, the protein was coined growth differentiation factor 15 (GDF15).49Almost two decades ago GDF15 was identified as a member of the TGF-β superfamily.et al. injected GDF15 subcutaneously into mice which caused a rapid decrease in food intake and hence, a decline in weight.et al. in 2012 further demonstrated that the overexpression of GDF15 in tumors led to the inhibition of food intake in an animal model which subsequently causes loss of both LBM and FM.58Several studies demonstrated the overexpression of GDF15 in many advanced cancers such as prostate, urothelial, breast, gastric, colorectal, and esophagus.in-vivo and in-vitro studies which were responsible for its anti-tumorigenic effect.et al. demonstrated a strong association of elevated plasma GDF15 levels with metastasis in prostate cancer.46GDF15 may have a context-dependent role in cancers: an antitumorigenic role of GDF15 was observed in early cancer while an association of GDF15 with the induction of tumor growth was observed in advanced cancer depending on a tumor type and its micro-environment.In one animal study, GDF15 was identified as the only biomarker for the loss of skeletal muscle and weight in cancer.65et al. showed an absence of a postprandial increase in GDF15 serum levels in healthy participants suggesting that it is unlikely that this hormone acts as a 'satiety factor'.et al., in 2017 showed that GDF15 serum levels induced a minimal change in response to caloric surpluses or deficits in both mice and humans, differentiating its action from intestinally derived satiety hormones and leptin. Furthermore, the same group showed that GDF15 expression was regulated by the tissue stress response in mice, and its administration triggered conditioned taste aversion suggesting that GDF15 induces an aversive response to nutritional stress.et al. in 2019, also demonstrated that GDF15 administration triggered conditioned taste aversion via GFRAL, while Borner et al. showed that GDF15 Induces anorexia through nausea and emesis in the mouse model. Globally, these findings indicate that GDF15 does not act as an 'anti-hunger' hormone or has any 'satiety effect' but induces an aversive response to nutritional stress. In 2017, the GDF15 receptor was identified as the glial cell-derived neurotrophic factor (GDNF) family receptor alpha-like (GFRAL) expressed in the brainstem.et al. identified novel characteristics of GDF15 in disease tolerance in the context of infection. This group showed in a mouse model that GDF15 is induced in inflammatory diseases through the central induction of metabolic adaptation and contribute to a protective effect in organ damage. This inflammation-induced tolerance effect is achieved by metabolic reprogramming and the production of triglycerides via hepatic sympathetic outflow, hence preventing cardiac damage after an LPS endotoxemic challenge.73It was established in the 1980s that the β adrenergic stimulation causes increase lipolysis and inhibit the activity of the lipoprotein lipase resulting in increased plasma triglycerides.In August 2020, Suriben et al. were the first to link the GDF15/GRFAL sympathetic pathway with the hepatic lipid oxidation in a cancer cachexia mouse model.Despite the breakthrough in inhibiting the GDF15/GFRAL pathway for the treatment of cachexia in the mouse model, several issues concerning interplay between host and tumor must be addressed for cachectic cancer patients.65For most patients with metastatic cancers, the cause of death is due to cachexia more than the direct effect of tumor bulk and organ failure. Based on the absence of any therapy for improving cachexia and on similar mechanistic evidence in the animal model and human, clinical trials testing anti-GDF15/GFRAL treatments appear promising, specifically in patients with elevated circulating GDF15 levels.Beyond its cachectic effect, GDF15 has been also implicated in tumor cell apoptosis and the development of metastasis. In addition, GDF15 can also modulate the tumor microenvironment, innate immune surveillance, and response to immunetherapy.47Globally, considering both host and cancer factors, only the completion of clinical trials using an inhibitor of the GDF15/GFRAL pathway will provide clinical evidence on the merit of reversing this “metabolic signature” to improve the lives of those living with advanced cancer.81GDF15 plasma level correlates with tumor progression and has been considered as a tumor biomarker.


TheFinally, safety is not guaranteed for nutrients, given the known issues with intakes above tolerable upper intake levels (UL). Adverse events were inadequately assessed in the context of purported benefits. Calder et al.’s recommended intakes do not adequately define amounts  or intended population given differences in UL by age/sex . The systematic review of omega-3 fatty acids and antioxidants that they cited could not rule out adverse events .Though recommendations by Calder et al. are made in the context of the COVID-19 pandemic, we note that this review offers no direct evidence to support the claim for dietary supplements for prevention or treatment of COVID-19, per se [


Despite efficient virological suppression on antiretroviral therapy (ART), people living with HIV (PLWH), experience an increased burden of premature co-morbidities, such as cancer and end-organ disease. With remaining challenges in terms of access to therapy, adherence and potential long-term drug toxicity, improving their long-term healthcare outcome, including new strategies for HIV clearance, remains a global priority. There is, therefore, an ongoing need to better characterize and harness the immune response in order to develop new strategies and supplement current therapeutic approaches for a “functional” cure. Current efforts toward HIV eradication to enhance immune recognition and elimination of persistently infected cells have highlighted the need for an optimized “kill” approach. Natural killer (NK) cells play an important role in antiviral defense and by virtue of their innate and adaptive features hold great promise as a focus of “kill” efforts. Galvanized by advances in the cancer field, NK cell exploitation, represents a transformative approach to augment HIV therapeutic modalities, circumventing many of the limitations inherent to T cell approaches. In this review we will discuss recent advances in our understanding of the development of NK cell adaptive/memory responses in HIV infection and highlight new and exciting opportunities to exploit the beneficial attributes of NK cells for HIV immunotherapy. NK cells are multipotent innate effector cells that play pivotal roles in antiviral and tumor immunity  that target the interaction between MHC class I and NK cell inhibitory receptors represents one strategy that is currently used to enhance NK cell anti-tumor activity  .Following the rise of single cell cloning techniques, next-generation anti-HIV-1 broadly neutralizing antibodies (bNAbs) with greater potency/breadth and the ability to suppress viral replication and potential for Fc-mediated clearance of virus-infected cells have now entered the clinical arena  could differentiate into effector NK cells mediating an innate antiviral response and protection against HIV -engineered NK cells offer great promise as a new immunotherapeutic tool in the HIV field. The recent success of CAR NK cells derived from cord blood transduced with a retroviral vector, expressing the genes encoding anti-CD19, IL-15, and a safety switch (inducible caspase 9), in patients with refractory or relapsed CD19 positive cancers, represents a remarkable achievement in the field   (Wang et al., In addition to the influence of CMV co-infection, a recent study demonstrated that the pro-inflammatory milieu in HIV infected patients drives the expansion of a defined NK subset with memory-like properties, characterized by CD94loCD69+T-betloEomeshi signature (Stegmann et al., Antigen-specific NK cells have been reported in rhesus macaques infected with SIV/SHIV (Reeves et al., in vivo persistence they are endowed with enhanced capacity for ADCC (Schlums et al., Adaptive NK cells make a significant proportion of the peripheral NK cell pool in HIV infection (Zhou et al., A concern with utilizing bulk NK cells for immunotherapy is their potential for unwanted immunoregulatory functions, such as regulation of T cell responses (Peppa et al., in vitro expansion capability with predictable selectivity as an alternative or combination strategy for a functional cure. Utilizing HLA-E expressing transfectants has been a successful strategy for obtaining robust proliferation of functional adaptive NK cells, with profound skewing toward a single self KIR, and enhanced NKG2C effector potential against allogeneic acute lymphoblastic leukemia primary blasts (Liu et al., Importantly adaptive NK cells have Indeed, adoptive transfer of cytokine-induced adaptive NK cells are being tested in phase I clinical trials in AML patients (Romee et al., ex vivo expansion for clinical application represents an exciting new avenue for the development of novel therapeutic interventions in the field of HIV infection. These approaches can be combined with therapeutic antibodies improving their efficacy. In addition, the generation of memory NK cell represents a novel goal of new vaccination approaches incorporating targeted adjuvants or through enhancing presentation via HLA-E. Future innovative strategies for cure include manipulation of the metabolic machinery of immune cells and attempts to intrinsically rewire NK cells to improve their immunotherapeutic potential.The study of adaptive NK cell subpopulations and Despite the considerable amount of progress, additional work is required to fully unravel the unique properties of specialized and memory NK cells subsets, especially within key effector sites, along with their potential for functional exhaustion. This knowledge would be critical in order to leverage their distinct features and maximize their therapeutic use in chronic viral infections while offsetting any detrimental effects to adaptive immunity and the host.AA, AO, and EM contributed to writing specific sections. DP edited the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


This special issue is dedicated to entropy-based fatigue, fracture, failure prediction and structural health monitoring. The unification of laws of thermodynamics and Newtonian mechanics has been a pursuit of many scientists since the mid-19th century. Distinguished scientists from around the world who contributed to this special issue all show that unification of Newtonian mechanics with thermodynamics using entropy as a link eliminates the need for phenomenological continuum mechanics, where the second law of thermodynamics is usually imposed only as an external constraint, but is not satisfied at the material level, because derivative of displacement with respect to entropy is assumed to be zero. For example, the theory of elasticity assumes that there is no entropy generation at the material level. As a result, everything is reversible, which violates the second law of thermodynamics.Group from Indian Institute of Technology Madras and University at Buffalo used unified mechanics theory for low cycle fatigue life prediction of Ti-6Al-4V alloys. Bin Jamal et al.  show thaScientists from Belarus State University contributed a noteworthy paper with their recent advances on mechanothermodynamics, which is essentially a theory almost identical to the unified mechanics theory. They both use entropy generation rate for degradation and unification of Newtonian mechanics and thermodynamics laws. Sosnovskiy and Sherbakov  formulatA Purdue University group contributed their outstanding work on using maximum entropy models for fatigue damage in metals with application to low-cycle fatigue of aluminum 2024-T351. Young and Subbarayan [University of Maryland, College Park scientists contributed an excellent study on measures of entropy to characterize fatigue damage in metallic materials. Yun and Modarres  show thaUniversity of Texas at Austin researchers contributed an excellent paper on degradation-entropy generation methodology for system and process characterization and failure analysis. Osara and Bryant  formulatScientists from Northwestern Polytechnical University and Xi’an University of Architecture and Technology contributed an exceptional study titled an entropy-based failure prediction model for the creep and fatigue of metallic materials. Wang and Yao  state th−7 m/cycle. In conclusion, they prove that entropy generation can accurately predict the fatigue crack growth rate of dual-phase steels under spectrum loading.Universiti Kebangsaan Malaysia group, contributed a great study on prediction of fatigue crack growth rate based on entropy generation. Idris et al.  present Researchers from Beihang University and Beijing Aeronautical Science & Technology Research Institute contributed a very interesting study on using copula entropy for quantifying dependence among multiple degradation processes. Sun et al.  studied Scientists from Beihang University and North China University of Water Resources and Electric Power contributed an indirectly related paper on intelligent analysis algorithm for satellite health under time-varying and extremely high thermal loads. Li et al.  present 2FeCoMo0.5V0.2 medium entropy alloy by rotationally accelerated shot peening. Liang et al. [2FeCoMo0.5V0.2 medium-entropy alloy by rotationally accelerated shot peening (RASP). Transmission electron microscopy analysis revealed that deformation twinning and dislocation activities are responsible for the effective grain refinement of the high-entropy alloy. In order to reveal the effectiveness of surface nano-crystallization on the Ni2FeCoMo0.5V0.2 medium-entropy alloy, a common model material, Ni, is used as a reference.Nanjing University of Science and Technology and City University of Hong Kong teams participated with their paper titled effective surface nano-crystallization of Nig et al.  reported


Major depressive disorder and neuroticism (Neu) share a large genetic basis. We sought to determine whether this shared basis could be decomposed to identify genetic factors that are specific to depression.We analysed summary statistics from genome-wide association studies (GWAS) of depression  and compared them with GWAS of Neu (from UK Biobank). First, we used a pairwise GWAS analysis to classify variants as associated with only depression, with only Neu or with both. Second, we estimated partial genetic correlations to test whether the depression's genetic link with other phenotypes was explained by shared overlap with Neu.We found evidence that most genomic regions (25/37) associated with depression are likely to be shared with Neu. The overlapping common genetic variance of depression and Neu was genetically correlated primarily with psychiatric disorders. We found that the genetic contributions to depression, that were not shared with Neu, were positively correlated with metabolic phenotypes and cardiovascular disease, and negatively correlated with the personality trait conscientiousness. After removing shared genetic overlap with Neu, depression still had a specific association with schizophrenia, bipolar disorder, coronary artery disease and age of first birth. Independent of depression, Neu had specific genetic correlates in ulcerative colitis, pubertal growth, anorexia and education.Our findings demonstrate that, while genetic risk factors for depression are largely shared with Neu, there are also non-Neu-related features of depression that may be useful for further patient or phenotypic stratification. Major depressive disorder (MDD) is a leading cause of morbidity worldwide, currently affecting approximately 4% of the world's population , is a robustly and consistently replicated dimension of personality that is relatively stable over time Eysenck, . Neu feaet al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Twin, family and genomic studies have shown that population variation in Neu and liability to depression are conferred by both genetic and environmental risk factors . We compared the depression summary statistics with summary statistics for Neu .We used depression summary statistics from the Psychiatric Genomics Consortium (PGC) ; for Neu we used summary statistics from the UK Biobank sample . We used the munge_sumstats.py tool . Using these filtered summary statistics, the gwas-pw program  and within 3 Mb, then used MAGMA  genes and conducted GWAS catalogue lookups using FUMA . We defined segments that were associated with neither trait as those that had a total posterior probability of association <0.2 and that did not contain any genome-wide hits for either trait. To examine the depression-only signal, we excluded segments associated with Neu or with both traits from the depression summary statistics, clumped single-nucleotide polymorphisms (SNPs) that were in linkage disequilibrium (LD)  with either MDD or Neu. These included psychiatric disorders, personality traits, cardiovascular and inflammatory diseases, anthropometric and life-history traits, education and lifestyle factors. We supplemented this list of traits with BMI since obesity has been identified as a potential stratifying factor for depression  but not with Neu after adjusting for depression (Neu·adjMD). Finally, we identified traits with the opposite patterns of having genetic correlations that were specific to Neu or to Neu after adjusting for depression. We tested whether unadjusted and adjusted correlations were different from zero and whether adjusted correlations were smaller than their unadjusted counterparts and corrected for multiple testing using False Discovery Rate  explained by the genetic architecture shared between depression and Neu (‘neurotic depression’) or (2) specific to depression and independent of Neu (‘non-neurotic depression’) (and vice versa for ‘depressive neuroticism’ and ‘non-depressive neuroticism’). We estimated the genetic covariance among MD, Neu and each trait using GenomicSEM  (We used pairwise GWAS (Pickrell ability) , Table 1et al., p < 2.77 × 10−6) with the partitioned genomic segments. There were 30 genes significantly associated with depression only (online Supplementary Table S3), 203 genes associated with Neu only (online Supplementary Table S4) and 104 genes associated with both depression and Neu (online Supplementary Table S5). We used FUMA  and to coronary heart disease (p = 3.2 × 10−3). Neu-only gene sets were related to traits such as intracranial volume, Parkinson's disease and high-density lipoprotein cholesterol. The gene sets shared by depression and Neu were related to cross-disorder psychiatric traits, coffee consumption and epilepsy, among other traits (online Supplementary S6).We used MAGMA  and with Neu where overlap with depression has been removed (Neu·adjMD) , schizophrenia, bipolar disorder, coronary artery disease and age of first birth. There were three additional traits  that showed a similar pattern of full and partial correlations with MD, but where the effect sizes overlapped with those for Neu, and thus their status of having a specific relationship was less well supported. Finally, there were three traits  that showed specific relationships with Neu after removing shared overlap with MD.RFWD2 (ring finger and WD repeat domain 2), a gene that can promote tumour growth  which is involved in the Krebs cycle; rs4143229 is in an intron of the ecto-NOX disulphide-thiol exchanger 1 gene (ENOX1) which is expressed in the nervous systems and has been implicated in autoimmune disorders  and immune  systems  gene, which has been implicated in childhood asthma  gene. A second association signal (rs12129573) was in the intron of an uncharacterised non-protein coding RNA (LOC105378800). In a further region, a signal was found (97.8–100.6 Mb on chromosome 6) that showed a clear separation between the association signals for each trait . The SNP associated with depression (rs12202410) was near the F-box and leucine-rich repeat protein 4 (FBXL4) gene which is related to energy homoeostasis  contained two association signals for depression. The first signal (rs1460942) was shared with Neu and was close to the neuronal growth regulator 1 (et al., Using a GWAS catalogue lookup with FUMA (Watanabe et al., et al., et al., et al., Differential association of MD with other traits, once shared overlap with Neu was accounted for, was also shown in our analysis of LD score genetic correlations. We found that, unlike Neu, MD was genetically correlated with BMI, triglyceride levels and coronary artery disease, suggesting the atypical depressive subtype related to cardio-metabolic traits (Lasserre et al., et al., et al., et al., et al., et al., et al., et al., One limitation of our study is that by using summary statistics from GWAS, we were only able to assess the overlap in genetic architecture between depression and Neu that arises from common variants. Even biobank-sized samples of millions of participants can be underpowered for detecting associations with rare variants unless such variants have very large effect sizes (Visscher et al., et al., et al., et al., et al., et al., just noisy measures of the same underlying liability. If these differences represent distinct genetic subtypes of depression, then most cases of depression will stem from this Neu–depression nexus, while a smaller proportion may have aetiologies that are distinct from Neu. Some of these associations, such as between depression, chronotype and metabolic phenotypes, are suggestive of endogenous depression's features but do not point to all the characteristics of this previously described subtype. Confirming known depression subtypes and identifying new subtypes will be useful for phenotypic and clinical stratification. The unique associations of triglyceride levels and BMI with depression, but not at all with Neu, confirms that depression with comorbid obesity and other metabolic factors should be studied as a subtype when exploring aetiology and testing treatment efficacy. The partial genetic correlations that ADHD, schizophrenia and bipolar disorder have with depression after adjusting for Neu imply that polygenic risk scores for these other disorders may be useful to screen or stratify participants even if they do not manifest these other disorders.Neu is a major risk factor for depression (Bagby et al., et al., et al., et al., et al., Neither depression (Kendler


Due to their enormous surface area compared to other cell types, neurons face unique challenges in properly handling supply and retrieval of the plasma membrane (PM)—a process termed PM turnover—in their distal areas. Because of the length and extensiveness of dendritic branches in neurons, the transport of materials needed for PM turnover from soma to distal dendrites will be inefficient and quite burdensome for somatic organelles. To meet local demands, PM turnover in dendrites most likely requires local cellular machinery, such as dendritic endocytic and secretory systems, dysregulation of which may result in dendritic pathology observed in various neurodegenerative diseases (NDs). Supporting this notion, a growing body of literature provides evidence to suggest the pathogenic contribution of dysregulated PM turnover to dendritic pathology in certain NDs. In this article, we present our perspective view that impaired dendritic endocytic and secretory systems may contribute to dendritic pathology by encumbering PM turnover in NDs. Dendrites are neuronal compartments essential for receiving electrochemical signals from presynaptic neurons through formed synapses. Accurate neuronal wiring relies critically on the proper establishment of the dendritic field that is achieved by both structural build-ups of dendritic arbors and functional maturation of synapses . This process of PM turnover is mediated primarily by endocytic and secretory pathways. However, due to its highly elaborate dendrites, a typical neuron has a 10,000 times larger surface area than does a typical epithelial cell , such as Alzheimer’s disease (AD), Parkinson’s disease (PD), polyglutamine (polyQ) diseases, and amyotrophic lateral sclerosis  expand or reduce its size; (2) alter its shape; and (3) insert or remove from its PM the membranous lipids and proteins needed to convey both intra- and extra-cellular signals.N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes required for the membrane fusion do not form  neurons, defects in exocytosis-mediated dendritic growth were mitigated by blocking clathrin-mediated endocytosis (CME) using a temperature-sensitive dominant-negative allele of shibire , has a specialized membrane-stacked morphology similar to that of Golgi Gray, ,b. BasedDrosophila , which was first defined in cultured hippocampal neurons  GTPase proteins are among the most compelling candidate molecular machinery that may play crucial roles in (dendritic) PM turnover. Rabs, which were first found in rat brains , Rab GTPase-activating proteins (Rab GAPs), and Rab-GDP dissociation inhibitors (Rab GDIs) control the guanine nucleotide status of Rab  complexes initiate vesicle budding from PM at clathrin-coated pits  pathway, through which membrane vesicles are transported directly from EEs to PM; and the slow recycling (10–20 min) pathway, through which membrane vesicles are transported to PM Rab35 , where membrane fission actively occurs  neurons that mutation of a dynein subunit gene, dlic, led to proximally “bushy” dendrites and that dlic and Rab5 double mutation resulted in greatly simplified dendritic morphology. Interestingly, this double mutant phenotype was similar to those seen in neurons with Rab5 mutation only. These data indicate that Rab5, in a co-operation with dlic, plays a regulatory role in dendrite morphogenesis. Another study on the genetic interaction between Protein Kinase A (PKA) and Rab5 in C4 da neurons showed that PKA could also contribute to the dendritic arbor development by altering Rab5-endosomal transport in dendrites , in primary cortical neurons increased dendritic branches and decreased endolysosomal trafficking in dendrites  seems to be involved. In this section, we will briefly outline the generalized characteristics of the early secretory pathway by describing some of its key regulators and make extensions to the dendritic secretory pathway and NDs where appropriate.Drosophila and yeast are mediated by coat protein complex II (COPII) vesicles (Brandizzi and Barlowe, cis-Golgi (Suda et al., cis-Golgi (Sztul and Lupashin, The secretory pathway comprises the transport of secretory and membranous materials from ER to Golgi and ultimately to PM. ER-to-ERGIC and ERGIC-to-Golgi in mammals and ER-to-Golgi transport in other less-developed species such as via Dsl1 tethering complex in yeast (Andag and Schmitt, The transport process between the ER and Golgi is not unidirectional. The best characterized retrograde transport process from Golgi to ER is the COPI pathway Spang, . COPI coAlthough the origins of dendritic secretory units are mostly unknown, we suspect that they are not entirely discrete from the canonical secretory units in the soma. Indeed, a study reported that GOPs may originate from somatic Golgi in rat hippocampal neurons (Quassollo et al., Drosophila has also provided a link between the dendritic secretory pathway and dendritic pathology. Chung et al. (CrebA mRNA level. Because CrebA is the master regulator of the secretory pathway (Abrams and Andrew, Sec31 (Chung et al., Sar1 in Drosophila da neurons (Ye et al., A recent study on polyQ toxicity in g et al.  showed tLrrk2, Sec16A detached from the dendritic ERES, which led to the impairment of ER-to-Golgi transport and NMDA receptor trafficking in mouse primary hippocampal neurons (Cho et al., Drosophila ortholog of LRRK2, co-localized with somatic Golgi and GOPs in Drosophila da neurons, and that overexpression of a PD-linked mutant form of LRRK2, LRRK2 G2019S, suppressed anterograde movements of GOPs marked by ManII-eGFP. This GOP transport defect may underlie the dendrite degeneration observed in LRRK2 G2019S-expressing Drosophila da neurons (Lin et al., Glutamatergic excitotoxicity involving the NMDA receptor is often observed in animal models of NDs (Lewerenz and Maher, Neuronal dendrites seem to be highly vulnerable to neurotoxic insults, including those that arise in NDs (Luebke et al., Sec31 and nuclear polyQ expression lead to the loss of GOPs, but not somatic Golgi (Chung et al., Sec31, Rab1, and Sar1, all lead to impaired arborization of dendrites, but normal morphology of axons in Drosophila da neurons (Ye et al., Drosophila model for progressive myoclonus epilepsy (Praschberger et al., Drosophila motoneurons (Ryglewski et al., Although the dendritic and the canonical pathways occur in distinct areas of the neuron, they share many of the regulatory molecules. Also, pieces of evidence show that at least parts of the dendritic secretory system, such as GOPs, may be derived from the canonical somatic secretory system (Quassollo et al., In this review article, we presented our perspective view that impaired PM turnover involving dysregulation of the dendritic endocytic and secretory pathways may contribute to dendritic pathology in NDs. Although there is a growing body of evidence for the potential link between impaired PM turnover and dendritic pathology in NDs, our understanding of the exact pathogenic mechanisms remains largely elusive. We propose that dendritic pathology in NDs may involve dysregulation of the regulatory machinery, such as Rab GTPases and COPI/COPII, for the dendritic endocytic and secretory pathways described above. Dysregulation of the dendritic pathways appears to complement cytoskeleton impairment as underlying pathogenic mechanisms for dendritic pathology. Because dendritic defects are often early features of ND, future studies to elucidate the pathogenic mechanisms by which impaired PM turnover contributes to dendritic pathology in NDs will deepen our understanding of the early pathogenesis of NDs.JP, CC, SP and SL conceptualized the theme of the review and wrote the manuscript together. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by amyloid-β (Aβ) plaques and the formation of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. In response to Aβ and tau aggregates, microglia, the primary innate immune cells of the central nervous system (CNS), facilitate Aβ and tau clearance and contribute to neuroinflammation that damages neurons. Microglia also perform a wide range of other functions, e.g., synaptic pruning, within the CNS that require a large amount of energy. Glucose appears to be the primary energy source, but microglia can utilize several other substrates for energy production including other sugars and ketone bodies. Recent studies have demonstrated that changes in the metabolic profiles of immune cells, including macrophages, are important in controlling their activation and effector functions. Additional studies have focused on the role of metabolism in neuron and astrocyte function while until recently microglia metabolism has been considerably less well understood. Considering many neurological disorders, such as neurodegeneration associated with AD, are associated with chronic inflammation and alterations in brain energy metabolism, it is hypothesized that microglial metabolism plays a significant role in the inflammatory responses of microglia during neurodegeneration. Here, we review the role of microglial immunometabolism in AD. Alzheimer’s disease (AD) is an age-related neurodegenerative disorder associated with memory loss and impaired cognitive abilities. AD is a major cause of disability and dependency in the United States and worldwide, causing a significant impact on not only the individual patient, but also their family, community, and the healthcare system , account for 10–15% of the adult glial cell population in the brain  inflammasome is activated by glycolytic enzymes  activity compared to wild-type cells; decreases in mTOR signaling were associated with increased autophagy. Additionally, the metabolic deficiency, and lack of microglial responsiveness, was restored in Trem2−/− 5XFAD mice by increasing microglial energy capacity with cyclocreatine  and glucose metabolism in neurodegeneration has been identified , and acetoacetate Laffel, . Levels To date AD drug discovery research has focused on tauopathy or Aβ reduction. As discussed above, glycolysis is a major factor in maintaining activated microglia, while non-activated microglia rely more on oxidative metabolism (Bernhart et al., Microglia shift to an anti-inflammatory phenotype in response to BHB (Huang et al., APOE4 allele do not see the improvement in cognitive function as subjects administered CT who are not carriers of the APOE4 allele (Reger et al., Medium-chain triglyceride diets have been developed to provide a more palatable alternative to the ketogenic diet (Huttenlocher et al., TREM2 deficiency results in decreased neuroinflammation and protects against neurodegeneration (Leyns et al., TREM2 increases tau pathology (Bemiller et al., Another approach to AD treatment is to target microglial genes important in microglial metabolism. As previously discussed, TREM2 is vital to microglial metabolic fitness (Ulland et al., The emerging field of immunometabolism has provided significant progress in our understanding of how cellular and systemic metabolism affects immune responses. More importantly, these data suggest that targeting immune cell metabolism may be a valuable strategy for the development of advanced therapeutics to treat human disease (Bettencourt and Powell, DS drafted the manuscript. TU reviewed and edited the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Minimal hepatic encephalopathy (MHE), which shows mild cognitive impairment, is a subtle complication of cirrhosis that has been shown to affect daily functioning and quality of life. However, until 2014, relevant guidelines do not give much attention to the diagnosis and treatment of MHE, resulting in patients being ignored and denied the benefits of treatment. In this review, we summarize recent cognition-based research about (1) alteration of nerve cells, including astrocytes, microglial cells and neurons, in mild cognitive impairment in MHE; (2) comparison of methods in detecting cognitive impairment in MHE; and (3) comparison of methods for therapy of cognitive impairment in MHE. We hope to provide information about diagnosis and treatment of cognitive impairment in patients with MHE. Minimal hepatic encephalopathy (MHE), which affects 30–55% of cirrhosis patients, is a subtle complication of cirrhosis that may have a detrimental effect on daily functioning. In the MHE phase, patients show mild cognitive impairment, which lead to deficits of attention, and psychomotor slowing  diagnostic criteria have not been standardized; (2) there is no overt clinical manifestation in patients with MHE; and (3) hyperammonemia is present with inflammation and certain levels of ammonemia  the relationship between cognitive impairment and nerve cell injury; (2) comparison of diagnostic methods for MHE; and (3) comparison of therapeutic methods for MHE.During MHE, the main contributor to cognitive impairment is hyperammonemia. In patients with liver disease, ammonia accumulates in blood due to deficient activity of hepatic urea cycle enzymes. In the brain, nerve cells take up ammonia and cause cognitive impairment. For example, astrocytes take up ammonia and glutamine synthetase detoxifies ammonia into glutamine. The rapid accumulation of glutamine creates an osmotic gradient that results in astrocyte swelling  secretion, play important roles in nerve cell impairment. For example, hyperammonemia significantly reduces long-term potentiation and alters mRNA for DA receptors, which cause deficits in disturbed synaptic plasticity and novelty acquisition in hippocampal and corticostriatal pathways involved in goal-directed and learning behavior -α. Astrocytic TNF-α, which triggers neurodegenerative progression consequently or indirectly, resulting in cognitive impairment. Ding et al. found that low-dose DA (10 μM) produced TNF-α in primary astrocytes, and co-culture of these astrocytes and neurons exhibited neuronal apoptosis compared with control group , which often occurs in cirrhosis patients, contributes to the MHE pathogenesis. Ding et al. found that the final production of neurotrophic factors, including PI3K/AKT signaling pathway to the phosphorylation of N-Methyl-d-Aspartate receptors and downstream activation of the CaMKIV/CREB pathway, was impaired in MHE rats -1β, Toll-like-receptor (TLR)-4 agonist lipopolysaccharide, and TNF-α. These pro-inflammatory microglia are characterized by immune-potentiating abilities, antigen-presenting and microbicidal -E2 and IL-6. And hyperammonemia also caused reduced Anti-inflammatory IL-10 and microglia activation in hippocampus. Increased TNF-α and IL-1β levels and phosphorylation (activity) of p38 cause GABAergic and glutamatergic neurotransmission. For example, membrane expression of GluR2 of AMPA receptor and subunits α1 of etc. GABAA receptor is increased, while expression of subunits GluR1 of AMPA receptors and NR1 and NR2a of NMDA receptors is reduced. These altered membrane expression receptors are associated with hyperammonemia-induced microglial activation. And are responsible for impairment of spatial learning and altered neurotransmission in the radial maze. In turn, these inflammatory injuries contribute to microglial differentiation from anti-inflammatory M2 to pro-inflammatory M1 phenotype  is involved in the perturbation of neural synaptogenesis. Cholinesterase (CHO) overload in combination with DA burden elicits memory loss and cognitive decline via the peroxisome proliferator-activated receptor (PPAR) γ/extracellular signal-regulated kinase (ERK)/CREB pathway in MHE. In turn, DA triggers CHO biosynthesis via activation of the C-Jun N-terminal kinase 3/sterol regulatory element-binding protein 2 signaling pathway in primary cultured astrocytes. Zhuge et al. found that CHO secreted from astrocytes stimulated secretion of DA from primary cultured neurons. PPARγ/pERK/pCREB expression was decreased by DA-induced synergistic leads to synergistic synaptic impairment in   represents the ability to suppress irrelevant motor or cognitive processes, and is useful for diagnosis of MHE (Di Lemma and Field The novel electronic number connection test (eNCT) has test–retest reliability to detect cognitive function and monitor cognitive impairment in patients with cirrhosis. Wuensch et al. found that the eNCT performance was negatively correlated with PHES performance in patients with cirrhosis. Control participants showed significantly faster eNCT completion times compared with cirrhosis patients  in the transition from an unimpaired mental state to HE  applies electromagnetic waves emitted by a graded magnetic field to acquire the internal structure of the objects (Lockwood et al. Different kinds of MRI play an important role in the detection of MHE. Kooka et al. demonstrated magnetic resonance spectroscopy, which shows that reduced magnetization transfer ratio in the whole brain field and an increase in glutamate/glutamine or taurine in chronic HE patients contribute to early and objective diagnosis of MHE. The levels of brain glutamine were significantly lower and the levels of brain myo-inositol were significantly higher in the control group compared with the MHE group (Kale et al. In addition to hyperammonemia, inflammation also modulates neuropsychological function in patients with MHE. For example, Circulating IL-6 is negatively associated with memory function in low-dose endotoxemia (Krabbe et al. Paper-and-pencil test used in PHES is the gold standard for diagnosis of MHE. But the process of diagnosis of PHES is inconvenient and affected by many factors. The diagnostic methods take time, and are affected by demographic factors, and lack ecological validity and language functions, such as verbal memory. PHES focuses on only two cognitive domains but it is not sensitive enough to detect early neurological alterations. Patients classified as without MHE by PHES have a high risk of suffering overt HE. Around 40% of patients without MHE according to PHES fail two other psychometric tests Bajaj . Other kCFF is a noninvasive, rapid, simple test for diagnosis of MHE. Compared with PHES, CFF has a positive predictive value of 93.2 ± 7.44%, specificity of 92.7 ± 7.96%, negative predictive value of 90.4 ± 8.91% and sensitivity of 91.1 ± 8.32%. CFF is excellent for diagnosis of MHE, with an area under the curve of 0.937 (Metwally et al. Neuroimaging studies can detect diffuse abnormal metabolic activity of nerve cells, which is a typical feature of patients with MHE. MRI can provide objective and reliable imaging biomarkers that are necessary to help diagnose or identify MHE (Zhang et al. In addition to hyperammonemia, there is a parallel relationship between inflammatory cytokines and MHE, or a significant correlation between proinflammatory cytokines with MD values on diffusion tensor imaging (Srivastava et al. Recent guidelines suggest that either alternative techniques, such as computerized tests, neurophysiological testing or EEG should be used alongside PHES for multicenter studies (Morgan et al. As mentioned above, nerve cell injury plays an important role in MHE progression, so protection of nerve cells is one way to prevent and treat MHE. Good nutritional status is an important way to relieve nerve cell damage. Myosteatosis and sarcopenia, probably by reducing the handling of ammonia in the muscle, are independently associated with MHE. Venous ammonia is significantly higher in patients with sarcopenia and myosteatosis and inversely correlated with both parameters (Nardelli et al. Reducing neuroinflammation is also an important way to relieve nerve cell damage. Malaguarnera et al. demonstrated that bicuculline decreases anxiety and improves working memory and spatial learning in hyperammonemic rats. Bicuculline can reduce activation of GABAA receptors, which contributes to neuroinflammation. Meanwhile, bicuculline reduces astrocyte activation and not microglial activation. Bicuculline reverses the changes in membrane expression of AMPA and NMDA receptor subunits (Malaguarnera et al. Disorder of intestinal flora and bacterial translocation, which increase production and absorption of intestinal toxins, are closely related to HE. There are different degrees of intestinal flora disorder in patients with chronic liver disease. Beneficial bacteria such as bifidobacteria are decreased while urease-producing bacteria are the source of gut-derived toxins. Production and absorption of intestinal toxins significantly increase, but the liver cannot metabolize these toxins completely, which leads to toxin retention (McPhail et al. Enterococcus and Enterobacteriaceae were significantly decreased while the predominant bacteria were significantly enriched (Xia et al. MHE is also associated with individual microbiota signatures. For example, the relative abundance of Lactobacillaceae is higher in MHE, whereas abundance of autochthonous Lachnospiraceae is higher in those without MHE (Bajaj et al. Probiotics are well-tolerated, natural and safe and appropriate for long-term treatment of MHE (Jiang et al. Rifaximin is a non-absorbed, gut-selective antibiotic with a low resistance profile that is commonly used to treat HE. It achieves high concentrations in the human intestine, where it is active against many enteropathogens (Goel et al. Rifaximin has always been a second-line drug in the treatment of HE, but there are no unified conclusions for treatment of MHE. Bajaj et al. demonstrated that over the 8-week period, MHE patients treated with rifaximin showed significant improvements in avoiding total driving errors, speeding, and illegal turns. Rifaximin also made improvements in the psychosocial dimension of the sickness impact profile and the anti-inflammatory cytokine IL-10 levels (Bajaj et al. LOLA may be administered orally or parenterally. The benefits of LOLA for the treatment of HE have been known for 50 years (Buyeverov et al. Lactulose is a disaccharide composed of galactose and fructose. As early as 1957, the prebiotic properties of lactulose were reported in both adults and infants. Due to promising outcomes, low price and high availability, Lactulose does not undergo cleavage by human gastrointestinal enzymes (Ruszkowski and Witkowski Psychometric tests improved in 75% of MHE patients after treatment with lactulose (El-Karaksy et al. Probiotics, rifaximin, LOLA and lactulose can improve MHE, but they also have some weaknesses Table . ProbiotStreptococcus abundance in the gut (Zuo et al. In recent years, many scientists have compared the efficacy of these drugs in preventing and treating MHE, and there was no difference between probiotics and lactulose (Jiang et al. Given the adverse effects of lactulose, cost of rifaximin and the safety of probiotics, LOLA appears to have beneficial effects in MHE, although its role in therapy is not clearly defined Table .MHE has serious consequences for quality of life, increasing the number of accidents, falls, hospitalizations and associated costs (Llansola et al. Timely and accurate discovery of cognitive impairment is the key to diagnosis of MHE. Psychometric tests, CFF, EEG and MRI are useful to evaluate cognitive function in an intuitive or abstract way. Psychometric tests are irreplaceable now. Compared with other psychometric tests, ANT is little influenced by age and education level. MRI, which can more accurately reflect changes in cognitive function, may be the best option in the future, if the problem of lack of detection accuracy of the measured signal can be resolved. CFF and EEG should be used alongside PHES Table .Timely correction of cognitive impairment is the key to treatment of MHE. One method is to prevent nerve cell injury, through improving the nutritional status of nerve cells, and blocking their injury by inflammatory mediators. Another method is to improve intestinal flora and reduce serum ammonia level. Among the drugs to improve intestinal flora, LOLA has few adverse effects and low cost, which may become the ideal choice in the future Table .


Forster et al.  performeThe median-joining network approach employed in Forster et al.  is a metAs an evolutionary biologist working in a developing country, I have experienced firsthand how sensational findings can influence decision-making processes by diverting time and resources to control virus strains deemed to be “more aggressive.” In the fog of war, scarce resources are allocated in haste, and the developing world does not have well-informed science advisers sitting in every key meeting to help provide balanced scientific viewpoints. The scientific community, as a whole, needs to be extra cautious in interpreting new findings related to coronavirus disease 2019 (COVID-19), and any potential misinformation must be promptly addressed. Scientific discourse is the basic foundation of science, and high-profile publications, especially controversial ones, require constructive dialogues for advancement of science and betterment of society, particularly during an ongoing war against a global pandemic.


Hair cells are the mechanosensory receptors of the inner ear and can be damaged by noise, aging, and ototoxic drugs. This damage often results in permanent sensorineural hearing loss. Hair cells have high energy demands and rely on mitochondria to produce ATP as well as contribute to intracellular calcium homeostasis. In addition to generating ATP, mitochondria produce reactive oxygen species, which can lead to oxidative stress, and regulate cell death pathways. Zebrafish lateral-line hair cells are structurally and functionally analogous to cochlear hair cells but are optically and pharmacologically accessible within an intact specimen, making the zebrafish a good model in which to study hair-cell mitochondrial activity. Moreover, the ease of genetic manipulation of zebrafish embryos allows for the study of mutations implicated in human deafness, as well as the generation of transgenic models to visualize mitochondrial calcium transients and mitochondrial activity in live organisms. Studies of the zebrafish lateral line have shown that variations in mitochondrial activity can predict hair-cell susceptibility to damage by aminoglycosides or noise exposure. In addition, antioxidants have been shown to protect against noise trauma and ototoxic drug–induced hair-cell death. In this review, we discuss the tools and findings of recent investigations into zebrafish hair-cell mitochondria and their involvement in cellular processes, both under homeostatic conditions and in response to noise or ototoxic drugs. The zebrafish lateral line is a valuable model in which to study the roles of mitochondria in hair-cell pathologies and to develop therapeutic strategies to prevent sensorineural hearing loss in humans. IP3Rs in the ER are involved in Ca2+ release into the cytosol and are coupled with mitochondrial VDAC in MAMs  to transiently elevate intracellular Ca2+ levels, they observed increased mitochondrial Ca2+ uptake that corresponded with an increase in mitochondrial transmembrane potential (ΔΨm), suggesting that even transient increases in mitochondrial Ca2+ can affect mitochondrial activity in hair cells. Cumulatively, these results show that under non-pathological conditions mitochondria take up Ca2+ released from the ER and that changes in mitochondrial Ca2+ can alter mitochondrial activity.In conjunction with the mitochondrion, the endoplasmic reticulum (ER) is also a critical regulator of Cah Vance, . In zebrg et al.  combined2+ indicators described earlier, Pickett et al.  collapses, followed by a spike in cytosolic Ca2+  wild-type strain of zebrafish were less vulnerable to gentamicin-induced hair-cell loss than the ABOne consequence of oxidative phosphorylation is the generation of ROS. Mitochondrial ROS are generally produced in the form of superoxide or hydrogen peroxide due to oxidation of metabolic intermediates in the electron transport chain complexes I and III Brand, . Hydroxym and mitochondrial oxidation, as reflected by the indicator mitoSOX (2+ uptake; blocking entry of Ca2+ into the mitochondria with Ru360 reduced ROS levels and mitochondrial oxidation after neomycin exposure. Cumulatively, these data suggest that mitochondrial Ca2+ uptake is an event upstream of neomycin ototoxicity, with ROS playing an additional role.Mitochondrial ROS production may play a role in aminoglycoside ototoxicity. It has been shown that aminoglycosides bind to iron salts and stimulate the production of free radicals by Fenton chemistry (Priuska and Schacht,  mitoSOX . These oin vitro, also protected against neomycin-induced hair-cell loss (Hirose et al., 2DCFDA labeling (Exogenous antioxidants have shown promising otoprotective effects in zebrafish lateral line and mammalian cochlear explants (Ton and Parng, labeling .d-methionine prevented this sonic-induced hair-cell loss, suggesting a role for oxidative stress in this model. Because zebrafish can be exposed to drugs by bath application, they are an optimal system in which to screen for protective or harmful drugs. By screening a redox library for compounds that protected against damage, glutathione, baicalein, d-α-tocopherylquinone, and ferulic acid ethylester were identified as protective agents (Uribe et al., In mammals, it has been shown that ROS are generated in the cochlea after noise exposure, and that antioxidants administered before or after exposure can potentially ameliorate noise-induced damage (Yamane et al., It has been suggested, specifically in the context of aminoglycoside ototoxicity, that hair cells “find a way to die” such that inhibition of one death pathway will lead to the activation of other death pathways, and that it may be necessary to target multiple pathways to fully protect hair cells from ototoxins, such as by using drug cocktails or by using drugs that have multiple modes of action (Vandenabeele et al., Cisplatin is an anti-cancer chemotherapeutic drug that is commonly used to treat a number of different cancers. Notably, cisplatin treatment causes hearing loss in up to 80% of patients (Frisina et al., Similar to work with aminoglycosides, protection against cisplatin ototoxicity using antioxidants and ROS scavengers has been an intriguing topic of recent study. Epicatechin, a ROS scavenger derived from tea leaves, has been shown to protect zebrafish from cisplatin-induced lateral-line hair-cell loss (Kim C. H et al., While acquired hearing loss can be caused by exposure to noise or ototoxic drugs, some hearing loss is inherited (Lenz and Avraham, Zebrafish have been a popular model for genetic studies due to their high fecundity and ease of genetic manipulation. Forward genetic screens in zebrafish have proven useful for identifying genes required for hearing and balance as well as in pathways involved in aminoglycoside-induced death (Nicolson et al., pappaa, which encodes pregnancy-associated plasma protein-aa (Wolman et al., pappaap170 mutant zebrafish were more susceptible to neomycin-induced hair-cell death and had elevated ROS levels in their hair cells. In addition, pappaap170 mutant hair cells had increased mitochondrial Ca2+, hyperpolarized ΔΨm, and reduced expression of the mitochondrial antioxidant genes gpx, sod1, and sod2, all of which could contribute to increased ROS levels. Treatment with the ROS scavenger mitoTEMPO rescued pappaap170 mutant susceptibility to neomycin-induced hair-cell death, suggesting that elevated ROS underlies the enhanced hair-cell death in pappaap170 mutants. The study supports the utility of zebrafish forward genetic screens in identifying novel genes involved in mitochondrial function and hair-cell vulnerability.Forward genetic screens have been particularly useful for identifying novel gene function in the zebrafish lateral line. One such gene identified using forward genetics is mtu1 to study its function in hair cells (Zhang et al., mtu1-deficient zebrafish had deficient thiolation of mitochondrial tRNA, as well as decreased levels of mitochondrial tRNA and mitochondrial proteins (Zhang et al., mtu1−/− zebrafish also had deficient oxidative phosphorylation and reduced ATP. In the lateral line, mtu1−/− zebrafish had fewer hair cells per neuromast. These results support a role for mitochondrial tRNA modification in deafness and demonstrate the value in using reverse genetics to study gene function in hair cells.Another study used CRISPR/Cas9 technology to delete the gene in vivo. Studies utilizing this system have shed light on the roles of mitochondria in calcium homeostasis and synapse regulation as well as supported roles of mitochondria in cell death pathways, particularly in response to ototoxic drugs like aminoglycosides. The strides made from zebrafish studies contribute to the understanding of hearing loss in humans and will lead to development of preventative or protective therapies in the future.The zebrafish lateral line is a valuable model system in which to study hair-cell mitochondria and offers unique tools such as the ability to visualize mitochondrial dynamics MH and LS wrote the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The importance of training in regulating body mass and performance is well known. Physical training induces metabolic changes in the organism, leading to the activation of adaptive mechanisms aimed at establishing a new dynamic equilibrium. However, exercise can have both positive and negative effects on inflammatory and redox statuses. In recent years, attention has focused on the regulation of energy homeostasis and most studies have reported the involvement of peripheral signals in influencing energy and even inflammatory homeostasis due to overtraining syndrome. Among these, leptin, adiponectin, ghrelin, interleukin-6 (IL6), interleukin-1β (IL1β) and tumour necrosis factor a (TNFa) were reported to influence energy and even inflammatory homeostasis. However, most studies were performed on sedentary individuals undergoing an aerobic training program. Therefore, the purpose of this review was to focus on high-performance exercise studies performed in athletes to correlate peripheral mediators and key inflammation markers with physiological and pathological conditions in different sports such as basketball, soccer, swimming and cycling. In elite athletes, there is large disparity among the training protocols; the effects on oxidative stress (OS) and inflammatory cytokines are still not well known. Is important to highlight that excessive training loads are able to trigger the syndrome known as overtraining syndrome (OTS), a phenomenon in which there is an increase in pro-inflammatory markers and consequently a decrease in sport performance . TherefoPeripheral mediators could be used to monitor both long- and short-term effects in elite athletes during training exercise. Leptin, adiponectin and ghrelin exert important effects on the hormonal regulation in response to acute exercise and chronic training and are related to each other. It is interesting to evaluate the effects of specific training on these molecules and on metabolic state in athletes since cytokine responses are linked to changes in physical performance. Jürimäea et al.  found thProfessional cyclists are a class of highly trained athletes subjected to different schedules of training and often to ultra-endurance training. Serrano et al.  reportedNieman et al.  reportedThey suggest a possible link between the increase in adiponectin and the training improvement due to the endurance or resistance training in cyclists. Córdova Martínez et al.  determinIn young well-trained female basketball players, Plinta et al.  found, aThe study of Souglis et al.  reportedUnal et al.  carried Martín-Sánchez et al. , using aIn conclusion, in elite soccer players, more than in other athletes, an intensive and inadequate training program modifies the inflammatory status, and this may be associated with a reduction in performance.Karamouzis et al.  reportedAerobic and anaerobic exercises result in alterations of redox homeostasis in untrained, trained and well-trained athletes. Following intensive physical activity in elite athletes, the source of systemic oxidative stress (OS) is not fully understood but it is proposed that skeletal muscle is the main contributor to the exercise-induced ROS . In this2O2, glutathione disulfide (GSSG) level and catalase (CAT) activity in well-trained female athletes who practice anaerobic/aerobic sports. They conclude that these results could be related to the adaptation mechanisms of antioxidative defense that depends on the type of sport. The results of a study by Souglis et al. [The influence of seasons on training has been analyzed by Balog et al.  measurins et al.  showed ts et al. , we suggs et al.  reportedAltitude exposure can increase markers of OS after acute exercise and this is observed in endurance-trained cyclists. McGinnis et al.  simulateDifferent studies demonstrated damage associated with OS in DNA following exhaustive/high-intensity endurance exercise, eccentric exercise and unaccustomed exercise. However, this effect is recovered after adequate rest. DNA damage is measured with an increase in 8-hydroxy-2′-deoxyguanosine (8-OHdG) plasma levels because the activity of several DNA-repairing enzymes (among them: human 8-oxoguanine DNA glycosylase1 and oxidized purine-nucleoside triphosphate) is increased to protect against exercise-induced DNA damage. Yasuda et al.  determinIn a short report, Lekhi et al.  analyzedIn a recent study, Maleki et al.  reportedDuring the season, elite basketball players train twice a day and play one or two games per week. Even though both aerobic and anaerobic systems are activated, several studies have demonstrated that anaerobic metabolism is the primary energy pathway activated in basketball players because basketball requires movements with variable velocity, continuous accelerations, decelerations, stopping and sudden changes of direction. These authors reported that elite basketball players show good anaerobic power  and modeThe overall duration of a typical basketball match is 40–48 min, in which an athlete carries out a combination of high-intensity actions  interspersed with low-intensity activities  and active or passive recovery . In one 2– and H2O2 remained unchanged. On the other hand, SOD and CAT activity increased, while GSH decreased. Le Moal et al. [The physical demands activity required for soccer players includes: sprints, change of direction and high-intensity running involving both aerobic and anaerobic energy pathways leading to alterations of biological processes such as inflammation, muscle damage and OS. Jakovljević et al.  investigl et al.  followedIn summary, oxidative stress is markedly upregulated after a soccer game and it is correlated with cumulated training loads during the football season.Competitive swimming combines factors such as the simultaneous contribution of arms and legs to propulsion, water immersion and prone position and allows muscles to work in harmony and in accordance with each other, since gravity drops down to almost zero in water. Unlike other popular sports, the OS that occurs in swimming is largely affected by the type of competitions, and swimmers require a sophisticated training for both aerobic (endurance exercises) and anaerobic (short high-effort exercises below 200 m) exercise to increase performance. Several studies indicate that swimming is involved in OS homeostasis changing but the duration and intensity of the stress are strictly correlated with the effort . The stuThe purpose of this review was to focus on high-performance exercise studies performed in athletes to correlate peripheral mediators and key inflammation markers with physiological and pathological conditions in different sports such as basketball, soccer, swimming and cycling. The main source of discrepancies among reviewed studies indeed mainly concerns differences in the type, duration and intensity of training . In well