Editorial on the Research TopicYing and Yang Members of the Tumor Necrosis Factor Superfamily: Friends or Foes in Immune-Mediated Diseases and CancerBalomenos et al.; Chakrabandhu and Hueber; Roberts et al.; Saxena et al.; Volpe et al.; Yamada et al.; Yolcu et al.; O’Reilly et al.). Unfortunately, other critical members of the TNF superfamily, including CD40L/CD40, GITR, BAFF, APRIL, TACI, and GITR were beyond the scope of this research topic. However, we refer the reader to scholarly reviews about other members of TNF/TNFR superfamilies that have not been covered here, including their roles in rheumatic diseases , and general aspects of their signaling pathways (Tumor necrosis factor (TNF) and TNF-receptors (TNFR) superfamilies represent one of the earliest immunological systems to be targeted for immunotherapy as typified by the use of anti-TNFα agents for treating Crohn’s disease in patients refractory to corticosteroids and conventional immunosuppressives . It is adiseases , neuroinpathways .The articles published under this research topic help to provide a better understanding of the roles of some of the major members of the TNF/TNFR superfamily in the pathogenesis of several diseases and generate considerable hope that their manipulation could lead to therapeutic interventions:Hamad’s paper on the “Expansion of FasL-Expressing CD5+ B Cells in Type 1 Diabetes Patients” discusses a newly identified subpopulation of FasL+ CD5+ CD19+ B cells that was significantly elevated in Type 1 Diabetes (T1D) subjects. In contrast, to IL-10+ CD5+ B cells that do not express FasL but produce IL-10, FasL+ CD5+ cells do not produce cytokines and are more resistant to activation-induced cell death (AICD). These intriguing findings could lead to better understanding of the mechanisms underlying the pathogenic role of FasL in T1D and cell types expressing it , 5.Yamada et al.; Hamad et al.).Yamada’s group’s paper on the “Dual Role of Fas/FasL-Mediated Signal in Peripheral Immune Tolerance” uses data from research studies on Fas/FasL gene mutations in mice and humans to discuss the dual function of the Fas pathway signaling leading to apoptosis or cell proliferation of immune cells depending on local environmental circumstances, and how mutations and disruptions of this process leads to the pathogenesis of autoimmunity .Yolcu’s paper on “Fas/Fas-Ligand Interaction As a Mechanism of Immune Homeostasis and β-Cell Cytotoxicity: Enforcement Rather Than Neutralization for Treatment of Type 1 Diabetes” focuses on the immunogenic activities of Fas/Fas-L interactions, as well as how TNF functions in both apoptosis and growth signaling, thereby regulating both immune reactions and injury repair. The paper further details how these processes may be involved in the pathogenesis of T1D and presents arguments for and against therapeutic neutralization of Fas and/or FasL to potentially abrogate T1D .Balomenos’s paper, “On How Fas Apoptosis-Independent Pathways Drive T Cell Hyperproliferation and Lymphadenopathy in Volpe et al.).Volpe’s paper, “Fas-Fas Ligand: Checkpoint of T Cell Functions in Multiple Sclerosis,” discusses Fas–Fas ligand interactions, and their involvement in Activation Induced Cell Death (AICD) and negative selection to destroy autoreactive lymphocytes in the context of autoimmune disease and cancer. In particular, this article focuses on the Fas–FasL pathway and how defects in its interaction involving Th17 and Treg can contribute to the pathogenesis of multiple sclerosis (Chakrabandhu and Hueber).Chakrabandhu’s paper, “Fas Versatile Signaling and Beyond: Pivotal Role of Tyrosine Phosphorylation in Context-Dependent Signaling and Diseases,” discusses the role of the Fas/FasL system as an apoptosis activator as well as a source of non-death signals that can promote survival, proliferation, migrations, and cell invasion. This article focuses on the recent identification of tyrosine phosphorylation in the death domain as a regulator of the reversible signaling switch between the two seemingly opposite roles of Fas/FasL, the factors and context that contribute to the switch, and how pathologies can develop in the signaling pathways . Interestingly, upregulation of IL-10 as a result of FasL blockade plays a critical role in preventing islet insulitis in NOD mice bearing a loss-of-function gld mutation of FasL .O’Reilly’s paper “The Janus Face of Death Receptor Signaling during Tumor Immunoediting” addresses the issue of tumor cells’ ability to proliferate and evade immune-mediated elimination by resisting the death ligand-induced apoptotic pathway through cleavage and mutations in death ligand receptors, or overexpression of decoy receptors and pro-survival proteins. The article discusses the role of death receptor signaling, and the early elimination and escape phase of tumor immunoediting as it relates to the tumor cells’ ability to resist cell death and metastasize. The article also discusses the opportunities and challenges of developing death receptor agonists for cancer therapeutics (In summary, diversity of these studies reveal the complex tasks carried out by TNF superfamily members, which provides a great opportunity for identifying therapeutic targets and at the same time, underlines the challenges.AG and RA read and summarized manuscripts published under the Research topic. AH, HY served as associate editors for the Research Topic and TD read, commented, and edited the editorial.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.


Inflammation has been widely demonstrated to be involved in various stimuli, such as oxidative stress, bacterial and virus infection, and some physiological process, while a chronic and excessive inflammatory response is a significant risk factor for developing various human diseases .An increasing number of compelling reports are recently published suggesting that some nutrients, like amino acids, oligosaccharides, and short-chain fatty acids, exhibit anti-inflammatory effect , 3, whicThe articles contained in this special issue include 4 review papers and 10 original research papers that are focused on characterizing the contribution and molecular mechanisms associated with nutrients and inflammation. A brief description of these 14 works is detailed below.Amino acids and their metabolites have been widely demonstrated to exhibit anti-inflammatory effect on various inflammatory models, such as inflammatory bowel disease. X. Bao et al. provide a detailed review of the literature on the relationship between amino acids and inflammatory bowel disease in their paper titled “Roles of Dietary Amino Acids and Their Metabolites in Pathogenesis of Inflammatory Bowel Disease.”In the paper titled “Role of Uric Acid Metabolism-Related Inflammation in the Pathogenesis of Metabolic Syndrome Components Such as Atherosclerosis and Nonalcoholic Steatohepatitis,” A. Kushiyama et al. outline the molecular mechanisms underlying inflammation occurrence in relation to uric acid metabolism.Inflammation contributes to the development of various metabolic diseases, such as obesity and diabetes. S. Chen et al. review the anti-inflammatory properties of quercetin in relation to obesity and type 2 diabetes in the paper titled “Therapeutic Effects of Quercetin on Inflammation, Obesity, and Type 2 Diabetes.”Intestinal microbiota is highly involved in host physiology and pathology through activity of the microbiome and its metabolic products. “Diet-Intestinal Microbiota Axis in Osteoarthritis: A Possible Role” by Y. Li et al. concludes that intestinal microbiota is a major hidden risk factor for osteoarthritis and an important explanation for person-level risk factors.Four groups from R. Garib et al., H. Xiao et al., H. Ni et al., and M. Li et al. investigated the anti-inflammatory effects of amino acids on different inflammatory models. The papers include “Effect of Previous High Glutamine Infusion on Inflammatory Mediators and Mortality in an Acute Pancreatitis Model,” “N-Acetyl-L-cysteine Protects the Enterocyte against Oxidative Damage by Modulation of Mitochondrial Function,” “Effects of Glutamate and Aspartate on Serum Antioxidative Enzyme, Sex Hormones, and Genital Inflammation in Boars Challenged with Hydrogen Peroxide,” and “High-Methionine Diet Attenuates Severity of Arthritis and Modulates IGF-I Related Gene Expressions in an Adjuvant Arthritis Rats Model.”κB signaling pathways involve in the mechanism of anti-inflammatory effects of fatty acids from royal jelly.In the article “In Vitro Anti-Inflammatory Effects of Three Fatty Acids from Royal Jelly,” Y.-F. Chen et al. evaluate and compare the in vitro anti-inflammatory effects of three fatty acids on lipopolysaccharide-stimulated RAW 264.7 macrophages and find that MAPK and NF-Escherichia coli, G. Liu et al. find that dietary chitosan markedly alleviated intestinal inflammation. The paper is titled “Chitosan Modulates Inflammatory Responses in Rats Infected with Enterotoxigenic Escherichia coli.”In rats infected with enterotoxigenic Veronicastrum axillare were collected: “Curcumin Alters Neural Plasticity and Viability of Intact Hippocampal Circuits and Attenuates Behavioral Despair and COX-2 Expression in Chronically Stressed Rats” by G.-Y. Choi et al. and “Veronicastrum axillare Alleviates Lipopolysaccharide-Induced Acute Lung Injury via Suppression of Proinflammatory Mediators and Downregulation of the NF-κB Signaling Pathway” by Q. Ma et al.Traditional medical plants and plant extracts have been widely explored to treat inflammatory diseases. In this issue, two articles about curcumin and A clinical trial titled “The Effect of Immunonutrition on the Postoperative Complications in Thymoma with Myasthenia Gravis” by Y. Xin et al. concludes that preoperative immunonutrition support is effective in reducing postoperative complications in patients of thymoma with myasthenia gravis.High-mobility group box 1 protein (HMGB1) and autophagy are vital to maintain cellular homeostasis and protect against inflammatory response. In the paper titled “Regulation of Autophagy-Related Protein and Cell Differentiation by High Mobility Group Box 1 Protein in Adipocytes” by H. Feng et al., it focuses on the relationship between HMGB1 and autophagy in adipocytes.


As members of the Ca2+ permeable transient receptor potential (TRP), five of the channels (TRPV1-4 and TRPM2) are activated by different heat temperatures, and two of the channels (TRPA1 and TRPM8) are activated by cold temperature. Accumulating evidences indicates that antagonists of TRPA1 and TRPM8 may protect against cisplatin, oxaliplatin, and paclitaxel-induced mitochondrial oxidative stress, inflammation, cold allodynia, and hyperalgesia. TRPV1 was responsible from the cisplatin-induced heat hyperalgesia and mechanical allodynia in the sensory neurons. TRPA1, TRPM8, and TRPV2 protein expression levels were mostly increased in the dorsal root (DRG) and trigeminal ganglia by these treatments. There is a debate on direct or oxaliplatin-induced oxidative cold stress dependent TRPA1 and TRPV4 activation in the DRG. Involvement of molecular pathways such as cysteine groups, glutathione metabolism, anandamide, cAMP, lipopolysaccharide, proteinase-activated receptor 2, and mitogen-activated protein kinase were also indicated in the oxaliplatin and paclitaxel-induced cold allodynia. In this review, we summarized results of five temperature-regulated TRP channels  as novel targets for treating chemotherapy-induced peripheral painAbnormal Ca Chemotherapeutic agents such as taxanes  and platinum analogs  are used in treatment of several cancer types. Taxanes inhibit progression of mitosis through stabilization of tubulin in the treatment of solid tumors  overload plays an important role. Ca2+ enters into cells by different ways including cation channels. Voltage gated calcium channels (VGCC) and chemical channels  are well-known calcium channels  neurons have important roles in the pathobiology of neuropathic pain. There is no barrier between the DRG and blood, and compounds with a high molecular weight can easily diffuse into the DRG  channels .Excessive reactive oxygen species (ROS) and low levels of antioxidants play a pivotal role in the pathobiology of cancers  has a significant role in the development and maintenance of neuropathic pain. The involvement of TRPA1 through activation of p38 MAPK in oxaliplatin-induced acute cold hypersensitivity in mice DRG neuron was recently reported  is a member of PAR subfamily of G protein-coupled receptors and activation of these receptors regulates several pathophysiological processes including inflammation and pain , menthol, icilin  and low-voltage-activated (LVA) channels  are very selective to CaTRPV1 is a member of vanilloid subfamily of the TRP superfamily. The channel was firstly expressed in rats through activation of high temperature and pungent hot chili pepper component (capsaicin) in mice DRG (Caterina et al., ROS are produced in physiological levels as part of normal mitochondrial function and phagocytic activity. During the removal of bacteria and viruses, ROS are produced by anti-inflammatory cells such as macrophages microphages and microglia. Therefore, there is direct relationship between increased levels of ROS and inflammatory hyperalgesia (Oehler et al., Cisplatin-induced TRPV1 channel expressions were investigated in DRG neuron by Hori et al.  and theyReports on cisplatin-induced thermal sensitivity in rodents are conflicting. For example, cutaneous mechanical allodynia and hyperalgesia but not noxious thermal sensitivity was reported by cisplatin treatment (Hori et al., In a study, diameters of TRPV1 remained unchanged in mice DRG neurons following cisplatin treatment, although the occurrence of TRPV1 in the neurons was increased by cisplatin treatment (Khasabova et al., 2+ concentrations induced release of excessive substance P from the central and peripheral nerve terminals of DRG neurons in response to noxious stimuli (Sacerdote and Levrini, Increased intracellular CaThe involvement of oxaliplatin on the release of calcitonin gene-related peptide from rat sensory neurons in culture was recently reported (Pittman et al., Another member of TRP superfamily is the TRPV2 and the channel is also a member of thermosensitive TRP channels and it is activated by a very high-threshold heat temperature (>52°C; Ahluwalia et al., As a member of TRP superfamily, TRPV4 was firstly described with mammalian osmotransducer property (Liedtke et al., Induction of hyperalgesia through activation of α2β1 integrin and Src tyrosine kinase pathways in rat DRG neuron was reported in the TRPV4 knockout mice by paclitaxel treatment (Alessandri-Haber et al., Accumulating evidence suggests that neuropathic pain and painful neurotoxicity in the rodents are increased by selected chemotherapeutic agent through increased sensitization of TRPA1, TRPM8, and TRPV1. In addition, antagonists of TRPA1 and TRPM8 were able to attenuate cisplatin, oxaliplatin, and paclitaxel-induced mitochondrial oxidative stress, inflammation, cold allodynia, and hyperalgesia, although TRPV1 was responsible for cisplatin-induced heat hyperalgesia and mechanical allodynia in sensory neurons. TRPA1, TRPM8, and TRPV2 protein expression levels were mostly increased in the DRG and trigeminal ganglia neurons by chemotherapeutic agents. There is a debate on direct or oxaliplatin-induced oxidative cold stress dependent TRPA1 and TRPV4 activation in the DRG. Involvement of molecular pathways such as cysteine group, GSH, anandamide, cAMP, lipopolysaccharide, proteinase-activated receptor 2, and mitogen-activated protein kinase were also indicated in oxaliplatin and paclitaxel-induced cold allodynia. Therefore, there is growing evidence for the potential role of TRP channel inhibitors as modulators of chemotherapy-induced neuropathic pain in the clinic.A new member of the TRP superfamily is TRPM2. The enzyme ADPR pyrophosphatase in the C-terminal domain of TRPM2 is sensitive to ROS and RNS (Wehage et al., MN formulated the present hypothesis and he was responsible for writing the report. NB made critical revision for the manuscript. The original figures were produced by MN.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.


Editorial on the Research TopicSelf-Eating on Demand: Autophagy in Cancer and Cancer TherapyThe field of autophagy has grown enormously over the past 10–15 years, with rapid advances in our understanding of the regulatory mechanisms that control autophagy pathways in mammalian systems, and an improved understanding of the physiological influences of autophagy in health and disease. Supporting such progress, there has been substantial diversification in assessment and modulation tools . SponsorTransAutophagy comprises five different thematic Working Groups with activities designed to synergize and support translation of our ever-advancing basic autophagy knowledge into biomedical and biotechnological applications . TargetiMathiassen et al. (Cecconi’s lab) discusses mounting evidence for new regulatory intersections between autophagy and the cell cycle, which need to be urgently validated in vivo. At the mechanistic level, the tumor suppressor role of autophagy has been ascribed to its vital cell-autonomous functions in mitigating damage and maintaining cellular integrity during metabolic stress. An emerging and intriguing link, which is discussed in the review of Kania et al. (Bultynck’s/Parys’s labs), is the regulation of autophagy in cancer cells through Ca2+ transfer from the ER to mitochondria via the inositol 1,4,5-trisphosphate receptor (IP3R) at ER–mitochondria contact sites. In a developing research area with enormous potential, the impact of miRNA-mediated autophagy regulation on the tumor microenvironment and cancer growth, and their potential as cancer biomarkers and therapeutic targets, is discussed in the review of Gozuacik et al. (Gozuacik’s lab).The review of Viry et al. (Janji’s lab), cancer cell-associated autophagy in hypoxic tumors plays a crucial role in modulating immunosurveillance and in fostering the immunosuppressive tumor microenvironment, by suppressing key mechanisms of innate and adaptive antitumor immunity, thus favoring tumor outgrow and dissemination. Consistent with this pro-tumorigenic role, advanced tumors often display an “autophagy-lysosomal addiction,” which appears to be required to maintain their energy balance through the recycling of intracellular components into biosynthetic pathways or ATP synthesis and to regulate secretion of pro-tumorigenic factors. In the review of New et al. (Tooze’s lab), the idea that advanced and aggressive mutant KRAS-driven tumors  exploit a heightened autophagy–lysosomal pathway under the transcriptional control of the MiF/TFE factors to support energy metabolism and to allow growth under conditions of energy deficit and metabolic stress is discussed (Iovanna (Iovanna’s lab) highlights the key role played by the pancreatitis-associated vacuolar protein 1 (VMP1) in pancreatic acinar cells and how its elevated expression drives early autophagy and cooperates with the KRAS oncogene to promote carcinogenesis in the pancreas.In established tumors, elevated levels of autophagy are often associated with poorly oxygenated regions where the demand for nutrients and the need to withstand diverse metabolic stresses are increased. As further discussed in the review of iscussed . FurtherKeulers et al. (Rouschop’s lab), is the ability of advanced cancer cells to use autophagy as a trafficking and export mechanism of pro-tumorigenic factors, such as pro-inflammatory/pro-angiogenic cytokines or chemotactic/pro-invasive molecules. This cancer cell-autonomous trait further illustrates the plasticity of tumor-associated autophagy, which can enable and modulate the crosstalk between cancer and stromal cells thereby affecting the tumor microenvironment, a property that needs to be taken into consideration when considering therapeutic approaches. Based on the growing relevance of tumor-associated autophagy, many labs are developing and testing the effects of autophagy modulators in cancer therapy. The recognition of the prevalent—albeit not unique—cytoprotective and stress adaptation roles of autophagy in advanced cancers has led to the assumption—as supported by in vitro and preclinical data—that blocking cancer cell-intrinsic autophagy may curtail cancer cell resistance to chemotherapy, thereby improving therapy outcome. Thus, the first-generation autophagy blockers, e.g., chloroquine and its derivative hydroxychloroquine (Fulda (Fulda’s lab). Finally, although autophagy is a highly dynamic process, the expression of certain autophagy genes in aggressive tumors like melanoma, may provide novel independent prognostic biomarkers for early stage neoplasms, as discussed in the review of Tang et al. (Lovat’s lab). This may help to identify patients at risk of disease progression, thus facilitating earlier patient therapeutic intervention and stratification for personalized therapeutic approaches.Another emerging aspect linking autophagy to tumor progression, discussed in the review of oroquine , 7 are cAuthors contributed equally.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.


International Journal of Molecular Sciences on 11 May 2017 [We read with great interest the article “Circulating Cell-Free DNA and Circulating Tumor Cells as Prognostic and Predictive Biomarkers in Advanced Non-Small Cell Lung Cancer Patients Treated with First-Line Chemotherapy” published by Coco, S. et al. in The authors chose a device  which is simple, inexpensive and allows to study the biological characteristics of CTCs isolated from 3 ml of blood. Nevertheless, Haematoxylin–Eosin (H&E) staining alone does not allow a correct enumeration of CTCs, which would necessitate further molecular characterization for cancer-specific biomarkers, such as, in this case, thyroid transcription factor 1 (TTF-1) for adenocarcinomas and high-molecular weight (HMW) keratins (CK5/6) for squamous-cell carcinomas . Indeed, as early as 2013, El-Heliebi et al. reported that reliable detection of CTCs should be confirmed by immunocytochemical and/or molecular biological methods [Furthermore, the association between a higher number of CTCs and better prognosis is definitely uncommon and would deserve further discussion. Our feeling is that, similarly to what is reported by Juan et al. , the autAs a suggestion, the authors could perform a leukocytes depletion before detecting CTCs by using a ScreenCell Cyto kit  and subsWe hope that our observation and advice will be accepted as a productive analysis.


Editorial on the Research TopicCD4 T Follicular Helper Cells in HIVFH cells could also hold clues to a functional cure for HIV; as reservoirs of latent HIV during antiretroviral therapy (ART), TFH cells facilitate HIV persistence. This special topic “CD4 TFH cells in HIV” synthesizes reviews from experts in the field to explore, discuss, and share recent discoveries on the intricate relationship between TFH cells and HIV. This special topic also seeks to offer perspectives on areas needing further inquiry in this rapidly evolving field.CD4 T follicular helper cells are vital for induction of long-lived humoral immunity; this specialized function makes them highly desirable immunological targets for designing an effective HIV vaccine. Intriguingly, TFH cells during HIV infection. Leong et al. delineate potential cell intrinsic and extrinsic factors driving viral replication within TFH cells during HIV infection. These include lack of cellular host restriction factors within TFH cells, exclusion of cytolytic CD8 T cells from B cell follicles within germinal centers (GCs), and trapped virus on GC follicular dendritic cells; a constellation of factors that create a perfect storm to promote unfettered viral replication within GC TFH cells.Despite the success of ART, achieving a functional cure for HIV, i.e., sustained viral suppression after ART interruption, remains a challenge due to persistence of viral sanctuaries under ART. As a result, there is a critical need to understand the reservoir to devise effective strategies to purge the latent virus and eliminate life-long dependence on ART. In this special topic, experts in the HIV field synthesize and evaluate recent discoveries in humans and non-human primate model systems to understand the complex dynamics of TFH cells are not depleted as dramatically as other CD4 T cell subsets. Zaunders et al. report a clear increase in proportion of TFH cells compared to other CD4 T cell subsets in serial fine-needle aspirates from lymph nodes of SIV-infected macaques. Miles et al. reveal that an increase in interleukin 6 and interferon gamma and a corresponding reduction in IL-2 could promote TFH proliferation. Hong et al. and Wang et al. argue that a relative increase in TFH cell proportions occurs in the face of net decrease in TFH cells numbers. They attribute the decrease in TFH numbers to increased expression of programmed death-ligand 1 on dendritic cells following infection. Hong et al. also state that an increase in transforming growth factor-b-mediated collagen deposition and fibrosis and loss of fibroblastic reticular cells drives disruption of the lymphoid architecture impairing TFH cell numbers and function. Miles et al. state that an increase in T follicular regulatory cells impairs TFH function in HIV infection. While these observations may seem at odds with each other, given the complex immunopathology of HIV infection and progression to AIDS, it is highly likely that TFH cell numbers and function vary widely over the course of infection and between infected animals and humans. Ultimately, B cell responses are impaired with aberrant B cell activation and hypogammaglobulinemia in the face of poor HIV-specific antibody responses. Chiodi et al. raise the possibility that IL-7, a cytokine whose level is elevated during HIV-1 infection, may have a role in increased expression of B cell costimulatory molecules on TFH cells leading to abnormal B cell differentiation and apoptosis.Surprisingly, despite being hotbeds for viral replication, TZaunders et al. contend that not all immune responses are impotent but that effective immune responses drive virus evolution resulting in Envelope divergence and diversification. The generation of neoantigens in the infected host could recruit naive CD4 T cells, which upon activation drive viral replication leading to eventual depletion of CD4 T cells.However, antibody responses are not compromised in all HIV-infected individuals. In some infected individuals, broadly neutralizing antibodies that have acquired extensive hypermutation and even deletion/insertion mutations appear several years after initial infection. Graff-Dubois et al. assert that TFH cell frequency varies widely according to (i) the stage of HIV/SIV infection, (ii) the severity of the disease, and (iii) the ability to develop broadly neutralizing antibodies highlighting that a blanket increase or decrease in TFH cells is not a unifying characteristic of all HIV/SIV infections. Given the intricate link between virus and lymph node cells, blocking HIV replication in lymphoid tissues might be a prerequisite for induction of effective TFH responses and anti-HIV antibodies and could have the benefit of dramatically decreasing seeding of the latent reservoir. While the lymph node has received a great deal of attention, other compartments are also emerging as critical parameters deserving of attention.In their review, Thornhill et al. review what is known about peripheral(p) TFH cells, which are now emerging as valuable surrogates for GC TFH cells and indicate that the preservation of pTFH cells during HIV infection by early ART initiation is associated with better viral suppression and lack of B cell dysfunction. Moukambi et al. highlight the importance of TFH cells in the spleen, the primary organ for B cell activation and differentiation. Their recent observations indicate early and profound loss of splenic TFH cells. There is also emerging interest in studying TFH cells in mucosal compartments—this understanding of the TFH cell response in distinct tissue compartments with differences in viral dynamics will undoubtedly shed further insights in the relationship of CD4 TFH cells and HIV. Thus, there remains a great deal to learn about TFH cells, and as with HIV, these cells are likely to attract the attention of immunologists and virologists alike.The author confirms being a contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Molecular Psychiatry, Huang et al. heroically investigated the cortical functional changes following methamphetamine abuse both in animal model and human addicts -induced motor evoked potential (MEPs) (Huang et al., Motor cortex is commonly a neglected region in addiction field. However, neuroimaging findings demonstrated that craving evoked by drug-associated cues involved motor and sensory regions (Yalachkov et al., Cortical plasticity is affected by a number of factors, such as genetic susceptibility to activity-dependent plasticity, trophic factor expression, neurotransmitters (Li Voti et al., Cortical plasticity impairment, however, is not limited to addiction. Previous studies reported that schizophrenia (Fitzgerald et al., All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.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.


Brain is the most energetically demanding organ of the body, and is thus vulnerable to even modest decline in ATP generation. Multiple neurodegenerative diseases are associated with decline in mitochondrial function, e.g., Alzheimer’s, Parkinson’s, multiple sclerosis and multiple neuropathies. Genetic variances in the mitochondrial genome can modify bioenergetic and respiratory phenotypes, at both the cellular and system biology levels. Mitochondrial haplotype can be a key driver of mitochondrial efficiency. Herein, we focus on the association between mitochondrial haplotype and risk of late onset Alzheimer’s disease (LOAD). Evidence for the association of mitochondrial genetic variances/haplotypes and the risk of developing LOAD are explored and discussed. Further, we provide a conceptual framework that suggests an interaction between mitochondrial haplotypes and two demonstrated risk factors for Alzheimer’s disease (AD), apolipoprotein E (APOE) genotype and chromosomal sex. We posit herein that mitochondrial haplotype, and hence respiratory capacity, plays a key role in determining risk of LOAD and other age-associated neurodegenerative diseases. Further, therapeutic design and targeting that involve mitochondrial haplotype would advance precision medicine for AD and other age related neurodegenerative diseases. A central role of mitochondria in age-related metabolic and neurodegenerative diseases has long been proposed, and an association between mitochondrial dysfunction and Alzheimer’s disease has been long proposed across multiple investigative strategies from analysis of human tissue to cell model systems Beal, . The “miHere we review the link between mitochondrial dysfunction and the risk of AD, the contribution of mitochondrial genetic variances to the risk, and how the risk is modulated by other factors, such as apolipoprotein E (APOE) genotype and sex differences.Unlike many other organelles, mitochondria have their own genome. The human mitochondrial genome is a circular set of 16,569 base pairs encoding 37 genes. Thirteen of these genes encode protein subunits required for four of the five electron transport chain complexes: complex I (NADH ubiquinone oxidoreductase), complex III (cytochrome bc1 complex), complex IV (cytochrome c oxidase), and complex V (ATP synthase); two encode rRNAs for mitochondrial ribosomes 12S and 16S), and 22 encode tRNAs  activity was observed in both platelets and postmortem AD brain  cycle enzymes was observed in AD brain. Autopsy-confirmed AD brain had significantly reduced activity in pyruvate dehydrogenase complex, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase complex, whereas the activity of succinate dehydrogenase and malate dehydrogenase were increased  than non-J participants  and total energy expenditure (TEE) were measured in 294 participants in the health, aging and body composition study . Different sets of haplogroups are identified in different studies and different studies could identify opposite effects of the same mitochondrial haplotype on risk of LOAD. Moreover, multiple studies involving Caucasians of European descendant  did not detect associations between any haplogroup and AD (Chinnery et al., APOEε4 genotype is a widely recognized risk factor for AD, and has been repeatedly confirmed in the studies reviewed herein (Corder et al., In longitudinal studies, APOEε4 carriers had significantly greater rCMRglc decline in the vicinity of temporal, posterior cingulate, and prefrontal cortex, basal forebrain, parahippocampal gyrus, and thalamus (Reiman et al., In vitro studies also suggested that truncated APOEε4 fragment can interact directly with mitochondria and cause mitochondrial dysfunction and neurotoxicity (Chang et al., At the cellular level, APOEε4 gene expression in human was associated with down-regulation of genes involved in mitochondrial oxidative phosphorylation and energy metabolism (Xu et al., After stratifying by APOEε4 status, three interesting modes of interactions between APOEε4 status and mitochondrial haplogroups in modulating the risk of AD were apparent (see Table The first mode is a neutralizing effect of mitochondrial haplogroup on the effect of APOEε4 on risk of AD (see Table The second mode is an enabling effect of APOEε4 on mitochondrial genetic variances as risk factors for AD (see Table A synergistic effect was also observed between APOEε4 and mitochondrial haplotypes (see Table As with the association between mitochondrial haplotype and the risk of late onset AD, the interaction between APOEε4 and mitochondrial genetic variances in modulating the risk of late onset AD remains debatable. Multiple studies failed to identify any correlation between mitochondrial haplogroup and APOEε4 status or failed to identify an interaction between the two on the risk of developing AD (Zsurka et al., Females are at greater lifetime risk for LOAD, and also have higher prevalence and incidence rate than all age-matched males (Brookmeyer et al., While almost all the reviewed studies recognized sex differences on risk of LOAD, only a few studied the effects of mitochondrial genetic variances in each sex (van der Walt et al., In contrast, some variances affected only males (see Table These results indicate that previously observed associations between mitochondrial haplogroups and AD could be driven by sex. Conversely, the effects observed in one sex could be diluted in the whole population, or be neutralized by the other sex, resulting in non-significant associations.Mounting evidence suggested a central role of mitochondrial dysfunction in the etiology of late onset AD. As reviewed above, disruption of mitochondrial bioenergetics, structure and dynamics have all been indicated in AD patients. Given the maternal pattern of inheritance of late onset AD and mitochondrial genome, herein we reviewed the association of mitochondrial genetic variances on bioenergetics, respiratory phenotypes and risk of developing LOAD. While the outcomes remain debatable, a large body of science supports an association between mitochondrial genetic variances and differences in bioenergetics and AD susceptibility. Several factors can help explain the disagreement. First, although most studies were conducted in descendants of European origin, the geographic distribution of participants were drastically different, which could result in diverse nuclear genetic background. Since mitochondria communicate extensively with the nucleus, uncontrolled nuclear background can potentially mask effects of mitochondrial genetic variances. Second, as we have reviewed, observations could be driven by certain subhaplogroups, thus results obtained from different populations may be biased by their dominant subhaplogroup. Third, given the heteroplasmic nature of the mitochondrial DNA, accumulated mutations throughout aging may be haplotype and tissue specific Wallace, , which cThe data also indicate that mitochondrial haplotype is one factor among several that impacts risk of AD. This is consistent with the multifactorial nature of aging trajectories and risk for LOAD. A systems biology approach that integrates mitochondrial genetic variances and risk factors such as APOEε4 genotype and sex is a step towards resolving disparities across studies of mitochondrial haplotype and risk of neurodegenerative diseases associated with mitochondrial dysfunction (see Figure YW and RDB wrote and reviewed the manuscript together.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.


Saccharomyces cerevisiae  biosynthesis in heterologous robust hosts to produce a wide array of compounds  use of fluorescent compounds as acceptor substrates whose fluorescence signal decreases upon sugar conjugation (Gantt et al., E. coli, S. cerevisiae, and Streptomyces. These biosynthesis approaches include de novo pathway engineering, central carbon flux redirection for co-factor or precursor synthesis, the selection of alternative enzymes, protein engineering/mutagenesis, precursor directed mutasynthesis, modular metabolic engineering, system and synthetic biology tools, such as codon optimization, vector, promoter, ribosome binding site engineering, and the engineering and manipulation of other non-protein-coding sequences (Pandey et al., E. coli. This hurdle can be addressed by regulating intermediate consuming pathway genes in the chromosome of host organisms. Several studies have been reported by our group (Malla et al., E. coli by constructing background E. coli mutants (Kim et al., Recently, advances have been made in the construction of robust microbial cells for the synthesis of several biomolecules in in vivo fermentation approach for producing NP glycosides is inadequate for producing a significant amount of glycosides by simple fermentation even though the process can be easily subjected to industrial scale up. To produce future NP glycosides by fermentation, a robust system should be developed that is capable of producing diverse NDP-sugars in the cell cytosol while engineering promiscuous GTs for sugar transfer to acceptor molecules. High level production of target non-natural NP glycosides can be achieved by simple microbial fermentation upon proper implementation of recently developed system/synthetic biology tools for the engineering of microbial host cells. Cumulatively, this approach of GT-mediated exchange of microbial non-natural glycones with exogenous aglycones offers huge combinatorial potential for the biosynthesis of novel future molecules for human use.The RP and JS 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.


Innate lymphoid cells (ILCs) are a newly classified family of immune cells of the lymphoid lineage. While they could be found in both lymphoid organs and non-lymphoid tissues, ILCs are preferentially enriched in barrier tissues such as the skin, intestine, and lung where they could play important roles in maintenance of tissue integrity and function and protection against assaults of foreign agents. On the other hand, dysregulated activation of ILCs could contribute to tissue inflammatory diseases. In spite of recent progress towards understanding roles of ILCs in the health and disease, mechanisms regulating specific establishment, activation, and function of ILCs in barrier tissues are still poorly understood. We herein review the up-to-date understanding of tissue-specific relevance of ILCs. Particularly we will focus on resident ILCs of the skin, the outmost barrier tissue critical in protection against various foreign hazardous agents and maintenance of thermal and water balance. In addition, we will discuss remaining outstanding questions yet to be addressed. ILCs have the property of classic lymphoid cells but lack rearranged antigen-specific receptors  NKp46  cells, ILCs are conventionally divided into three groups based on their differential expression of effector cytokines and developmental requirements for transcription factors  cells were also described   and Peyer’s patches has long been recognized (De Togni et al., + ILC3s, can induce inflammation in the intestines of both mice and humans (Bernink et al., Although ILCs normally play host-protective roles, dysregulated activation of ILCs could lead to inflammatory diseases (Artis and Spits, Chronic ILC2 activation was reported to contribute to a large variety of tissue inflammatory disorders such as asthma in the lung and atopic dermatitis in the skin, which are generally associated with over-production of the type 2 inflammatory cytokines such as IL-4, IL-5, and IL-13. ILC2s expand and produce the type 2 cytokines in mice with allergic lung inflammation (Chang et al., − cells within human colorectal carcinoma tumors (Kirchberger et al., ILC3s could contribute to inflammatory diseases and tumorigenesis in various tissues. IL-17- and IL-22-producing ILC3s have been linked with the inflammatory skin disease psoriasis, inflammatory bowl disease, obesity-associated asthma, and multiple sclerosis (Buonocore et al., in vitro development analysis (Scoville et al., Specific functions of ILCs in homeostasis and inflammation are associated with their unique localization in peripheral tissues. Recently, several groups reported that ILCs are predominantly tissue-resident cells that do not circulate in the body. In parabiotic studies, helper-like ILCs in both non-lymphoid tissues and lymphoid organs such as the small intestine, salivary gland, lung, mensenteric lymph node, and adipose tissue of two joined adult mice with shared blood circulation systems remain locally and do not move from one mouse to another (Gasteiger et al., + ILC1-type cells although their origin and lineage association are not known (Almeida et al., + and NCR− subsets, account for about 50% of total skin ILCs in humans (Dyring-Andersen et al., Skin is the outmost barrier tissue constantly exposed to assaults of various foreign agents. Skin is enriched with ILCs and ILCs of all the three groups could be found in the skin (Yang et al., + dendritic cells are involved in the programming of skin-homing CCR10+ ILCs in skin-draining lymph nodes (Yang et al., Since ILCs share many common regulatory pathways with helper T cells for their development and function, we investigated whether skin-specific ILCs are programmed in skin-draining lymph nodes to acquire their skin-homing property for establishment of their skin residency, paralleling the process by which the skin-homing property of conventional αβ T cells is imprinted in skin-draining lymph nodes (Yang et al., + ILCs in skin-draining lymph nodes, local inflammatory conditions suppress programming of skin-homing CCR10+ ILCs (Yang et al., Dependent on environmental cues of lymphoid organs in which T cells and ILCs are activated, they could be also imprinted to acquire homing properties to other distinct peripheral tissues (Campbell and Butcher, Compared to the healthy skin, ILC2s are increased in the skin of patients with atopic dermatitis (Kim et al., + ILC3s are increased in both lesional and non-lesional skin and NKp44− ILC3s have the potential to differentiate to NKp44+ ILC3s in response to stimulation of IL-1β and IL-23 (Teunissen et al., + RORγt+CD56+ ILC3s were found in the psoriatic skin in a separate study (Dyring-Andersen et al., Increasing evidence implicates involvement of ILC3s in psoriasis, a skin inflammatory disease largely resulting from overproduction of Th17-associated cytokines such as IL-17A (Dyring-Andersen et al., While ILCs are relatively well studied for their participation in development of skin inflammatory diseases, their physiological role in maintenance of the skin homeostasis and host protection is still poorly understood. Since ILC2s are capable of producing amphiregulin, a member of epithelial growth factor family, they could potentially contribute to wound healing (Salimi et al., + T cells and dampen their responses to microbiota (Hepworth et al., + ILCs and T cells plays a critical role in maintaining the immune homeostasis of the skin (Yang et al., Rag1−/− mice that lack T and B cells, there are significantly reduced CCR10+ ILCs in the skin, while transfer of CD4+ T cells could partially restore the homeostatic presence of CCR10+ ILCs (Yang et al., Il2rg−/−Rag2−/− mice, which lack all ILCs as well as T/B cells, donor CD4+ T cells in skin of hosts contain significantly higher percentages of IL-17A-producing Th17 and IL-5-producing Th2 cells but much lower percentages of IFNγ-producing Th1 cells than those transferred into Rag1−/− recipients that have ILCs (Yang et al., Skin ILCs interact with other skin-resident immune cells to maintain the immune homeostatic condition. In the steady-state skin, the preferential interaction of ILC2s and mast cells has been detected (Barnig et al., The research over past several years has started to reveal roles of ILCs in the skin and unravel mechanisms regulating establishment and function of the skin-resident ILCs. However, several major questions remain to be addressed. First, physiological functions of skin-resident ILCs in host protection and immune homeostatic maintenance are still poorly understood. While ILCs have been generally implicated in protection against infection, control of commensal bacteria and regulation of immune activation in various barrier tissues, the function of resident ILCs specifically in the skin is not well studied. Considering that ILCs are maintained locally in different barrier tissues, functions and regulation of ILCs in the skin and other barrier tissues are likely regulated differently with local environmental cues. For example, the CCR10/CCL27 axis is involved in the regulation of resident ILCs in the skin but not other sites (Yang et al., + ILCs are dominant in the healthy skin where they promote balanced maintenance of resident T cells (Yang et al., −/−, Foxp3−/− or topical Calcipotriol-treated wild-type mice, CCR10+ ILCs are decreased while CCR10− ILCs are increased in the skin (Yang et al., + and CCR10− ILCs might be differently involved in skin immune homeostatic regulation and activation (Fig. + and CCR10− skin ILCs are regulated and function should help understand basic biology of the skin-specific ILCs in the health and disease.Second, mechanisms regulating differential involvement of ILCs in the skin homeostasis and inflammation are largely unknown. Studies of ILCs of the skin and other barrier tissues have showed that ILCs could be involved in both homeostatic regulation and tissue inflammatory processes. However, it is currently unknown whether and how ILCs involved in homeostatic regulation are different from ILCs involved in immune inflammatory processes in the skin. Our studies have found that CCR10+ ILC1s to ILC3s (Bernink et al., Third, the involvement of ILCs in promoting diseases has raised interest in modulating ILC functions for the treatment of diseases. In other tissues, antibodies against ILC2-activating cytokines, such as IL-25 and IL-33, as well as those targeting ILC2-produced cytokines, including IL-5 and IL-13, have been found to suppress ILC2 proliferation and function in tissue inflammatory diseases in the lung (Gauvreau et al.,


Phospholipids represent the highly conserved structural basis of biological membranes from bacteria to humans. However, plants and other photoautotrophic organisms are unique in using non-phosphorus galactolipids as primary components of their photosynthetic membranes. In light of the biomass of green tissues as compared with that of the overall plant body and the highly stacked thylakoid membrane structures in chloroplasts, galactolipids are the most abundant membrane lipids on the earth. Historically, the roles of galactolipids have been studied mainly in relation to photosynthesis, and recent advances in molecular biology with Arabidopsis and other model organisms have revealed an essential role of galactolipids in photosynthesis. However, these galactolipids are also abundant in non-photosynthetic organs, especially flowers, which suggests their distinct role apart from photosynthesis. The aim of this mini-review is to describe distinct biochemical properties of flower galactolipids and possible new roles, with a summary of the current understanding of galactolipid biosynthesis in Arabidopsis.The online version of this article (doi:10.1186/1999-3110-54-29) contains supplementary material, which is available to authorized users. Its activity was initially observed as a major DGDG synthetic activity in isolated chloroplasts or envelope preparations (van Besouw and Wintermans, SENSITIVE TO FREEZING 2, a gene essential for freezing tolerance in Arabidopsis, encodes a processive galactosyltransferase that produces oligogalactolipids by transferring galactose groups from MGDG (Moellering et al., Because of the odd enzymatic property of GGGT, its identity has long been an issue. Recently, Moellering and the Benning group found that Petunia hybrid to explore yet-unknown roles of galactolipids in flowers (Figure Given that chloroplasts are differentiated as a form of plastids, an important question was whether galactolipids are unique in chloroplasts or are widely found in different plastids. Biochemical studies found significant levels of MGDG and DGDG in non-photosynthetic organs (Kleinig and Liedvogel, s Figure  (Nakamurs Figure ; (Nakamus Figure ; (Nakamus Figure .Figure 3The level of MGDG in petals is about one third of that in leaves (Nakamura et al., 2003dad1, which is deficient in anther dehiscence, is mutated in a gene encoding lipase that liberates 18:3 fatty acid from the glycerlipid backbone for jasmonic acid synthesis (Ishiguro et al., Among the 3 floral organs, stamens show the highest MGDG levels and the level is about half that in leaves (Nakamura et al., Pistils are the most unique among the floral organs we discuss in terms of predominant DGDG levels relative to that of MGDG (Nakamura et al., Galactolipids can be utilized even during pollen tube growth. Glycerolipid profiling of lily pollen tubes before and after elongation revealed a 5.7-fold increase in DGDG level and 2.8-fold increase in MGDG level (Nakamura et al., mgd1 mutant is challenging because it has a lethal phenotype (Kobayashi et al., Galactolipid biosynthesis is well understood in the model system Arabidopsis. Meanwhile, ample biochemical data from different botanical flowers show intriguing features of galactolipid biosynthesis in floral organs. Although the functional difference between type A and B MGD is clear and type B is more involved in MGDG synthesis in flowers, double knockout of MGD2 and MGD3 does not result in defective flower development nor MGDG level (Kobayashi et al.,


Neuroinflammation plays a critical role in the onset and progression of many neurological disorders, including Multiple Sclerosis, Alzheimer's and Parkinson's diseases. In these clinical conditions the underlying neuroinflammatory processes are significantly heterogeneous. Nevertheless, a common link is the chronic activation of innate immune responses and imbalanced secretion of pro and anti-inflammatory mediators. In light of this, the discovery of robust biomarkers is crucial for screening, early diagnosis, and monitoring of neurological diseases. However, the difficulty to investigate biochemical processes directly in the central nervous system (CNS) is challenging. In recent years, biomarkers of CNS inflammatory responses have been identified in different body fluids, such as blood, cerebrospinal fluid, and tears. In addition, progress in micro and nanotechnology has enabled the development of biosensing platforms capable of detecting in real-time, multiple biomarkers in clinically relevant samples. Biosensing technologies are approaching maturity where they will become deployed in community settings, at which point screening programs and personalized medicine will become a reality. In this multidisciplinary review, our goal is to highlight both clinical and recent technological advances toward the development of multiplex-based solutions for effective neuroinflammatory and neurodegenerative disease diagnostics and monitoring. Neurological disorders account for an increasing number of disability-adjusted life-years worldwide, especially in high-income countries. Alzheimer's disease, Parkinson's disease and Multiple Sclerosis are the most prevalent causes of neurological disability  cleavage of amyloid precursor protein] and its clearance, leading to the formation of toxic oligomers (AβO), subsequent synaptic dysfunction and neuronal cell death  the formation of amyloid plaques is promoted by an increased production of Aβ1−42, while in sporadic AD it is mainly due to impaired Aβ clearance  is a neurodegenerative disorder primarily affecting neocortical regions and characterized by progressive episodic memory loss leading to significant behavioral changes  deposition  imaging. Biomarker analysis, including α-syn, in serum or CSF, is not performed in standard clinical practice , GBA (glucocerebrosidase), PRKN (parkin), and LRRK2 (leucine-rich repeat kinase 2) which are expressed in microglia , the second most common neurodegenerative disorder, is characterized by the early and progressive loss of dopaminergic neurons in the Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disorder of the CNS of unknown etiology but with a genetic predisposition and environmental influence  or “inside-out” (CNS-intrinsic initiation of the inflammatory cascade) models  which specifically recognizes the biomarker  of interest and a transducer which converts biochemical interactions into a quantifiable electrical signal proportional to biomarker concentrations. Biosensors are commonly classified in electrochemical, optical, piezoelectric, or magnetic, based on the signal transduction mechanism. These technologies have broad applications in health  provided by the use of gold nanoparticles (NPs) , which mediates the neuronal binding and toxicity of AβO, was used as a recognition element for the specific detection of the oligomers. The biosensor presented a LOD of 0.5 pM and successfully detected cell-derived AβO from conditioned media of 7PA2 Chinese Hamster Ovary (CHO) cells that naturally secrete AβO  based on its oxidation and subsequent aggregation into NPs (polydopamine) (Yildirim and Bayindir, 2 nanotube arrays for sensitive α-syn quantification with a detection limit of 34 pg/mL (An et al., substancia nigra (Choi et al., 2 NPs (Heydari-Bafrooei et al., Although α-syn has been the most intensely studied and recognized biomarker for PD, its application in biosensing is very limited. A photoelectrochemical biosensor was developed by An et al. based on Au-doped TiOThe heterogeneous nature of MS, characterized by distinct patterns associated with the demyelination process, makes it highly improbable that a single diagnostic marker is capable of covering the full spectrum of MS subtypes (Lucchinetti et al., in situ early diagnostics of neuroinflammatory and neurodegenerative diseases. Altogether, these advantages will surely bring great benefits for both academic and medical fields.An increasing number of studies are uncovering the beneficial and detrimental roles of microglia in neurodegenerative disease onset and progression. Pro-inflammatory cytokines can be used in combination with classical biomarkers for neurodegenerative and neuroinflammatory disease diagnostics and monitoring of disease progression. Technologies for simultaneous detection and quantification of different biomarkers are rapidly developing and future devices are aimed at bringing valuable advantages, specifically related to lower sample volumes, detection time and limits, higher specificity and sensitivity. Decreasing the need for biological samples processing, while integrating biosensing platforms in portable lab-on-a-chip systems would, in turn, allow point-of-care use by semi-skilled operators toward real-time and All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.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 explosive growth of health-related data presented unprecedented opportunities for improving health of a patient. Machine learning plays an essential role in healthcare field and is being increasingly applied to healthcare, including medical image segmentation, image registration, multimodal image fusion, computer-aided diagnosis, image-guided therapy, image annotation, and image database retrieval, where failure could be fatal.The purpose of this special issue is to advance scientific research in the broad field of machine learning in healthcare, with focuses on theory, applications, recent challenges, and cutting-edge techniques.The quality level of the submissions for this special issue was very high. A total of 24 manuscripts were submitted to this issue in response to the call for papers. Based on a rigorous review process, 8 papers (33%) were accepted for the publication in the special issue. Below, we briefly summarize the highlights of each paper.One of the papers of this special issue, “Diagnosis of Alzheimer's Disease Based on Structural MRI Images Using a Regularized Extreme Learning Machine and PCA Features,” R. K. Lama et al. proposes a method and compared Alzheimer disease (AD) diagnosis approaches using structural magnetic resonance (sMR) images to discriminate AD, mild cognitive impairment, and healthy control subjects using a support vector machine (SVM), an import vector machine (IVM), and a regularized extreme learning machine (RELM). By means of experiments on the ADNI datasets, it has been concluded that RELM with the feature selection approach can significantly improve classification accuracy of AD from mild cognitive impairment and healthy control subjects.S. Alam et al. presented a method for distinguishing AD from healthy control using combination of dual-tree complex wavelet transforms, principal coefficients from the transaxial slices of MRI images, linear discriminant analysis, and twin support vector machine in their article “Twin SVM-Based Classification of Alzheimer's Disease Using Complex Dual-Tree Wavelet Principal Coefficients and LDA.”A semisupervised learning approach for cell detection is presented in the third article of this special issue by N. Ramesh et al. in their paper entitled “Cell Detection Using Extremal Regions in a Semisupervised Learning Framework.” The method requires very few examples of cells with simple dot annotations for training.In the paper entitled “Patient-Specific Deep Architectural Model for ECG Classification” by K. Luo et al., a method for ECG classification is proposed. The method is based on time-frequency representation and patient-specific deep learning architectural model, and it uses deep neural network classifier.An automatic method for segmentation of 3D magnetic resonance imaging (MRI) data, useful in the clinical diagnosis of brain tumor, named as Glioma is presented by Z. Li et al. in the article “Low-Grade Glioma Segmentation Based on CNN with Fully Connected CRF.” The method combined a multipathway convolutional neural network (CNN) and fully connected conditional random field (CRF). Experimental results have shown that the method is useful for low-grade glioma.A general system for hybrid disease diagnosis adopting classifier optimization procedure using evolutionary algorithms is presented by M. R. Nalluri et al. in their article “Hybrid Disease Diagnosis Using Multiobjective Optimization with Evolutionary Parameter Optimization.”Y. Chou et al., in their paper “A Real-Time Analysis Method for Pulse Rate Variability Based on Improved Basic Scale Entropy,” proposed a method named sliding window iterative base scale entropy analysis by combining base scale entropy analysis and sliding window iterative theory for analyzing heart rate variability signal.Another paper of this special issue by J.-S. Park et al. titled “R Peak Detection Method Using Wavelet Transform and Modified Shannon Energy Envelope” presents an R peak detection method using the wavelet transform and a modified Shannon energy envelope for rapid ECG analysis.These 8 selected contributions basically can reflect the new achievements in the machine learning applications in healthcare, and we hope they can provide a solid foundation for future new approaches and applications.


Iron (Fe) is an essential plant micronutrient but is toxic in excess. Fe deficiency chlorosis is a major constraint for plant growth and causes severe losses of crop yields and quality. Under Fe deficiency conditions, plants have developed sophisticated mechanisms to keep cellular Fe homeostasis via various physiological, morphological, metabolic, and gene expression changes to facilitate the availability of Fe. Ethylene has been found to be involved in the Fe deficiency responses of plants through pharmacological studies or by the use of ethylene mutants. However, how ethylene is involved in the regulations of Fe starvation responses remains not fully understood. Over the past decade, omics approaches, mainly focusing on the RNA and protein levels, have been used extensively to investigate global gene expression changes under Fe-limiting conditions, and thousands of genes have been found to be regulated by Fe status. Similarly, proteome profiles have uncovered several hallmark processes that help plants adapt to Fe shortage. To find out how ethylene participates in the Fe deficiency response and explore putatively novel regulators for further investigation, this review emphasizes the integration of those genes and proteins, derived from omics approaches, regulated both by Fe deficiency, and ethylene into a systemic network by gene co-expression analysis. Iron (Fe) is an essential element for living organisms including plants. Fe-containing proteins play a variety of vital roles in cellular respiration, intermediary metabolism, oxygen transport, and DNA stability and repair, as well as photosynthesis in plants. In human beings, Fe deficiency causes severe healthy problems, including anemia, which affects billions of people worldwide . The first step in this strategy is the acidification of the rhizosphere mediated by the H+-translocating P-type ATPase AHA2  transcription factor FER-LIKE Fe DEFICIENCY-INDUCED TRANSCRIPTION FACTOR (FIT) , have been carried out in a broad range of plant species, including model strategy I plant Arabidopsis, Medicago, soybean, as well as Strategy II plant rice and others  from the four data sets, herein named Fe deficiency-response core genes, with 61 being up-regulated and 10 down-regulated  from S-adenosylmethionine (SAM), underlying the importance of controlling the expression of NAS genes including NAS1 gene  recycling for ethylene synthesis, is encoded by single gene in Arabidopsis genome, indicating the importance to tightly control its expression  oxygenase family; proteins in this family is generally considered to possess oxidoreductase activity catalysing the 2-oxoglutarate- and Fe(II)-dependent oxidation of an organic substrate using a dioxygen molecule. Previous study showed that the ethylene synthesis protein ACC oxidase also belongs to 2OG-Fe(II) oxygenase superfamily , functioning as ferric iron binding and participating in the cellular iron ion homeostasis, are essential to protect cells against oxidative damage and flowering  was the gene AT3G13610 encoding a Fe (II)- and 2-oxoglutarate-dependent dioxygenase family gene F6'H1  and Fe (II)-dependent oxygenase superfamily protein putatively assumed to be involved in hormone metabolism by MapMan analysis. The gene co-expressed with AT3G12900 is AT5G38820, whose expression is also regulated by ethylene     , and this study does have uncovered new layer of regulation in gene activity in response to Fe deficiency  that were induced in Brassica napus phloem sap upon Fe deficiency, which is consistent with the decrease of ACC content (Gutierrez-Carbonell et al., Medicago truncatula under Fe limitation (Rodriguez-Celma et al., Although nearly no protein with changes in abundance upon Fe deficiency has been uncovered across a wide range of plant species, a comprehensive comparison of these studies indeed has revealed some common elements in proteome under Fe limitation. In brief, proteins associated with “oxidative stress and defense,” “C metabolism,” “N metabolism,” “cell wall,” “secondary metabolism, particularly the phenylpropanoid metabolism,” “energy and ATP-coupled transport processes,” and “protein metabolism” have been identified as differentially accumulated proteins among plant species, which is well-summarized in an excellent review published in 2013 (Lopez-Millan et al., Omic approaches have been widely employed to explore the responses of plant to Fe deficiency, and have uncovered diverse metabolic adaptations upon Fe starvation. A subset of conserved Fe-responsive genes and some common metabolic pathways have been revealed by transcriptome and proteome across a range of plant species. It has been clear that the concordance between the abundance of mRNA and their related proteins is not strong correlated (Lan et al., All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.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.


Stroke is an important cause of morbidity and mortality as well as functional impairment particularly in the elderly people . PredictSeveral previously published studies found an association between high serum CRP level and development of stroke , 8-10. RSimilarly, Ridker et al., found a positive correlation between serum hsCRP and severity of stroke . In a pr


Over the last decade, an increasing number of reports underscored the importance of epigenetic regulations in brain plasticity. Epigenetic elements such as readers, writers and erasers recognize, establish, and remove the epigenetic tags in nucleosomes, respectively. One such regulation concerns DNA-methylation and demethylation, which are highly dynamic and activity-dependent processes even in the adult neurons. It is nowadays widely believed that external stimuli control the methylation marks on the DNA and that such processes serve transcriptional regulation in neurons. In this mini-review, we cover the current knowledge on the regulatory mechanisms controlling in particular DNA demethylation as well as the possible functional consequences in health and disease. Among several other epigenetic tags, methyl tags on the DNA were generally considered as repressive marks. However, an increasing number of studies showed that the DNA methylation at intergenic regions as well as gene regulatory regions might enhance gene expression  in vivo  45 proteins (GADD45A and GADD45B) that in neurons take part in active DNA demethylation processes  was first described in the 1972  or apolipoprotein B mRNA editing complex (APOBEC) is an alternative path to successive oxidation reactions by TET enzymes for the initiation of DNA demethylation Figure . The modBdnf gene that is quite well investigated in the context of synaptic plasticity and learning , methyl CpG binding protein 2 (MeCP2), histone deacetylases (HDAC) 1 and 2. The repressor complex dissociates following phosphorylation of MeCP2 and nitrosylation of HDAC2 in response to Ca+2 influx (Chen et al., Bdnf IV in a stimulus-dependent manner (Ratnu et al., In the long-lived nature of postmitotic neurons, genomic stability needs to be maintained for decades while at the same time their remarkable plasticity has to be kept at a poised state ready to respond (Baker-Andresen et al., Gadd45b gene expression (Keeley et al., Unfortunately, conflicting reports have been published on the role of GADD45B in learning and memory processes. Fear conditioning induces Interestingly, 5hmC is not only an intermediate DNA demethylation form but also an epigenetic mark on its own, which is enriched within promoters and gene bodies (Kaas et al., Another critical issue is cell-type specificity of DNA demethylation. In most studies brain tissue that contains different neuronal and glial cell types was used. The current knowledge on how the DNA demethylation machinery functions in different cell-types and responds to neuronal activity is therefore very limited. DNA methylation patterns vary between neurons and non-neuronal cells. Ventromedial prefrontal cortex neurons have higher global DNA methylation levels compared to non-neuronal cells (Li et al., Bdnf IX promoter was found, which is in line with reduced Bdnf IX expression (Gavin et al., Arc was also associated with reduced levels of GADD45B and DNA demethylation in this stress model (Grassi et al., Bdnf IX promoter methylation level is abolished and mRNA expression is perturbed (Ma et al., Bdnf gene expression (Dong et al., Given the principal functions of chromatin modifications in regulating gene transcription programs, it’s not surprising that the number of studies, which report the involvement of DNA demethylation machinery in neurological disorders, is steadily increasing. Enhanced GADD45B levels were reported in two different cohorts of major psychotic patients (Gavin et al., Based on the initial GADD45B-dependent demethylation hypothesis (Gavin et al., GB and MK are invited to contribute to the article collection for the special issue of the “Epigenetic Mechanisms Regulating Neural Plasticity”. GB outlined the mini review and GB and MK 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.


However, this notion contrasts with the mild phenotype associated with tau deletion. Instead, an analysis of cellular hallmarks common to different tauopathies, including aberrant patterns of protein phosphorylation and early degeneration of axons, suggests that alterations in kinase-based signaling pathways and deficits in axonal transport (AT) associated with such alterations contribute to the loss of neuronal connectivity triggered by pathogenic forms of tau. Here, we review a body of literature providing evidence that axonal pathology represents an early and common pathogenic event among human tauopathies. Observations of axonal degeneration in animal models of specific tauopathies are discussed and similarities to human disease highlighted. Finally, we discuss potential mechanistic pathways other than microtubule destabilization by which disease-related forms of tau may promote axonopathy.Tauopathies are a diverse group of diseases featuring progressive dying-back neurodegeneration of specific neuronal populations in association with accumulation of abnormal forms of the microtubule-associated protein tau. It is well-established that the clinical symptoms characteristic of tauopathies correlate with deficits in synaptic function and neuritic connectivity early in the course of disease, but mechanisms underlying these critical pathogenic events are not fully understood. Biochemical  Proper brain function relies on appropriate connectivity between specific neuronal populations. An essential cellular process underlying such connectivity involves the generation and continued maintenance of molecular constituents within axons and dendrites , frontal temporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick's disease (PiD)  and glial cells (tufted astrocytes and coiled bodies)  is characterized by severe atrophy of the frontal, temporal, and parietal lobes. Cytoplasmic neuronal tau inclusions known as Pick bodies represent the major neuropathological hallmark of PiD, and these are typically found in the dentate gyrus of the hippocampus and frontal and temporal cortices  promoter, which provides relatively selective expression of tau in forebrain neurons  vectors encoding P301L tau into the EC (Siman et al., Collectively, data from various animal models of tauopathy reveal axonal degeneration as a prominent pathological feature, and further suggest there is a contribution to this phenotype from glial cells. Based on their resemblance to this specific aspect of human tauopathies, these animal models may help define mechanisms and specific molecular components mediating the toxic effect of pathogenic tau on axonal maintenance and function.in vitro (Weingarten et al., in vivo has yet to be provided.The initial discovery of tau protein was based on biochemical procedures that revealed its ability to associate with purified microtubules and modulate their dynamic growth behavior in vivo. Furthermore, axonal development is normal in cultured primary neurons obtained from some tau knockout mice (Harada et al., Collectively, data from the available four transgenic tau knockout mouse lines (reviewed in Ke et al., Available experimental evidence suggests that tau performs functions other than microtubule stabilization in neurons. Numerous studies suggest a role for tau in multiple cellular processes and compartments, some of which may not include microtubule interactions. The functional repertoire of tau includes microtubule-actin cytoskeleton interactions (Selden and Pollard, In vitro studies using purified components of the AT system further supported a model where tau would elicit this effect by competing with conventional kinesin heavy chain subunits for microtubule binding (Seitz et al., in vivo extend the conclusions from squid axoplasm studies to mammalian neurons, showing normal AT rates in the optic nerve of tau-overexpressing mice (Yuan et al., The dependence of axons on proper anterograde and retrograde AT is evident because mutations in selected conventional kinesins or cytoplasmic dynein subunits suffice to promote dying-back degeneration of neurons (Morfini et al., in vitro and in situ also appears inconsistent with the notion that tau physically blocks motor proteins (Samsonov et al., The highly dynamic nature of the interaction between tau and microtubules The major motor proteins responsible for AT, conventional kinesin and cytoplasmic dynein, are regulated by specific protein kinases providing a novel mechanism linking pathological forms of tau to deficits in AT (Kanaan et al., 2+ dysregulation may negatively impact axonal connectivity (Figure 2+ from the endoplasmic reticulum, leading to inhibition of synaptic vesicle exocytosis and synaptic transmission through a mechanism involving PAD exposure and GSK3 activation (Figure 2+ imbalance and cell death in induced pluripotent stem cells (Imamura et al., 2+ levels by directly inhibiting plasma membrane Ca2+ ATPase (Berrocal et al., 2+ buffering in cells (Werth and Thayer, 2+ levels (reviewed in Eckert et al., 2+ levels may promote abnormal activation of calcium-activated proteases and proteolysis of critical cytoskeletal protein components (Figure In addition to the mechanisms above, mechanisms linking pathological tau to Cay Figure . For exan Figure . Oligomen Figure  and longn Figure  in cultun Figure . Studiess Figure . Consists Figure , and inhs Figure . Interess Figure . Collect2+ homeostasis, altered glial function, and others (Figure The landscape of tauopathies is marked by significant heterogeneity in clinical presentation, cellular topography, and neuropathological features. Despite this diversity, an examinations of human brains and animal models of tauopathies reveal axonopathy as a common feature of these diverse diseases (Hyman et al., s Figure . DevelopAK, BC, KC, GM, and NK all contributed equally with writing, editing and figure preparation for 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.


Malaria has remained a greatest health and socioeconomic burden in the tropical and subtropical regions of the world. According to World Health Organization, approximately, 429,000 deaths with 212 million cases were reported from malaria in the world , China , and Pakistan  and it shares the shortest land border with Afghanistan (106 Km)  among all the bordering countries of India , China (79%), Nepal (78%), and Bhutan (60%) while its prevalence in Myanmar and Bangladesh is 34 and 7%, respectively  followed by Myanmar (66%), Bhutan (40%), Nepal (22%), Pakistan (19%), China (11%), and Afghanistan (5%)  in the northeast region of India  of hanistan 06 Km  gene in this fatal human malaria parasite  gene  gene amplification were characterized by increased susceptibility to chloroquine but decreased susceptibility to mefloquine (Imwong et al., pvmdr1 in conferring resistance to chloroquine is still elusive and controversial (Faway et al., pvmdr1 gene copies correlated with mefloquine use history, in vivo data showing a direct relationship between mefloquine resistance and pvmdr1 gene amplification form mefloquine-treated patients are needed (Khim et al., P. vivax.i et al. . Howeveri et al. . AccordiKinley Wangdi and colleagues have highlighted the malaria elimination efforts carried out by the neighboring countries, however, they did not mention the Malaria Control Programme of Pakistan bordering Gujarat and Rajasthan, the high malaria transmission western states of India (Wangdi et al., Wangdi and colleagues have overlooked the malaria deaths and prevalence in children. According to WHO, “A child dies of malaria every 2 minutes” (World Health Organization, All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.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.


Shen Yuan et al.  highlighIn the discussion, the authors state: “Our study is the first meta-analysis investigating the protective role of chocolate consumption against diabetes.”However, this represents a slight imprecision; in 2011, Buitrago-Lopez et al. [Another interesting difference between the two studies is that Shen Yang et al. found a chocolate protective effect occurred in the category of moderate chocolate consumption (<6 serving/week), while Buitrago-Lopez et al. found that a higher chocolate consumption (definitions of which vary from the number of servings per week or grams per day) confers the lowest incidence of diabetic and cardiometabolic events. Such differences deserve a detailed exploration in order to delimitate the ideal chocolate recommendation which provides optimal flavonoid amounts for a cardiometabolic protective effect  without


Tsianos et al.  demonstrThe possibility of combining neuroimaging and/or eye-tracking with visual search paradigms offers a promising avenue for cognitive style research. Visual search tasks can investigate the allocation of attention during task completion (i.e., Galpin and Underwood, We also argue that future cognitive styles research would benefit from not only adopting a mixed method experimental approach, but also from investigating other dimensions of cognitive style beyond the visualizer–verbalizer dimension. For instance, it has been shown that individual differences in brain structure and function are related to preferences in field-dependence/field-independence (Hao et al., Whilst some authors argue that cognitive styles are more dynamic than static, so can change or alter Zang, , others A decade has passed since Coffield et al.'s  heavy crRB, opinion concept, main conclusions, article drafting; AG, LM, and SC verification of opinion concept, main conclusions, article drafting.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.


IUCrJ (2017), 4, 108–118] discuss progress on using in-cell NMR in prokaryotic and eukaryotic cell preparations.High-resolution NMR provides increasing possibilities to probe biomolecular structure in the native state. In this issue, Luchinat and Banci [ One of the unique properties of magnetic resonance (MR) has been its ability to non-invasively yield molecular information from the test tube to applications in cells, tissue and even entire organisms. In the context of MR imaging (MRI) or spectroscopy (MRS), water or other small molecules including metabolites can be used as MR-active probes to infer localized chemical information at the micrometre scale.in vitro solution-state or, more recently, solid-state NMR conditions. Applying the full and growing arsenal of such NMR methodology for studying larger molecules in a native  setting has, however, required the development of novel and tailored NMR-based cellular structural biology concepts. Compared to the in vitro case, NMR studies under native conditions have to simultaneously address several challenges. Firstly, adequate spectroscopic sensitivity is of utmost importance as the native cellular environment is usually far more complex than what can be mimicked under well defined test-tube conditions. Another challenge relates to the fact that NMR signals of interest must be detected in a complex, usually dominating, molecular background. In practice, concepts suppressing signals of the surrounding molecular background so far have employed a combination of tailored biochemical, cell biology and spectroscopic methods. Thirdly, studying ‘live’ cell preparations furthermore calls for NMR approaches that allow NMR data to be rapidly acquired or involve instrumental setups that keep cells viable by allowing exchange of nutrients and removal of metabolic byproducts.In parallel, nuclear magnetic resonance (NMR) spectroscopy has become a well established structural biology approach to comprehensively study (at the atomic level) three-dimensional molecular structure and dynamics under IUCrJ, E. Luchinat and L. Banci  and in human cells. In the latter case, Luchinat and Banci discuss various protein delivery methods that allow proteins or other biomolecules to be incorporated into cells as well as intracellular protein expression approaches. With these developments, solution-state NMR has become a powerful tool for studying three-dimensional molecular structure and the effect of molecular crowding at the atomic level. In addition, their review highlights elegant studies probing post-translational modifications and (mis)folding of proteins in living cells.In their review in this issue of et al., 2015et al., 2015et al., 2014et al., 2015et al.  native conditions. Again, promising applications have been seen in recent years. Next to the work discussed by Luchinat and Banci, such studies have targeted large protein complexes embedded in bacterial cell envelopes (Kaplan in vitro and in vivo NMR can be of great value in dissecting molecular structure and interactions in the native state. For example, successful demonstrations included the use of cell lysates (Frederick et al., 2015et al., 2015in vivo extracts (Qiang et al., 2017Finally, hybrid approaches that bridge the gap between


Recen in vivo . Further in vivo  has, howTanda and his colleagues further assessed specificity of the blocking effects ofthe TLR4 antagonists on self-administration of remifentanil or cocaine . ConsistThe more recent results by Tanda et al.  indicate


Sorop Figure 1). However, not all patients have all comorbidities and the unpredictable interplay between different comorbidities is likely to result in multiple HFpEF phenotypes. Indeed, unbiased cluster analysis of densely phenotyped HFpEF patients suggests the presence of distinct ‘phenogroups’ with different clinical characteristics and outcomes.A substantial proportion of patients with heart failure have a left ventricular (LV) ejection fraction (EF) in the ‘normal’ range, a form of the syndrome that is termed heart failure with preserved ejection fraction (HFpEF). Patients with HFpEF have significant morbidity and mortality but unlike heart failure with reduced EF, there are currently no effective validated therapies. HFpEF is therefore an important area for further research. Patients with HFpEF have cardiac and extra-cardiac manifestations, including LV diastolic dysfunction, abnormal heart rate and rhythm, microvascular dysfunction, increased aortic stiffness, and abnormal ventriculo-vascular coupling, which impair systolic and diastolic reserve capacity upon exercise.Clinical studies to investigate the pathomechanisms involved in HFpEF have typically involved small numbers of highly selected patients subjected to invasive physiological assessment and cardiac biopsy-based analyses. A recent extensively-promoted model based on such studies posits that comorbidities induce systemic inflammation and vascular endothelial dysfunction as a consequence of an abnormal balance between reactive oxygen species (ROS) production and nitric oxide (NO) bioavailability.et al.Experimental animal models that allow deeper analysis of the pathogenesis of HFpEF would clearly be valuable. Rodent models that have been employed include the DOCA-salt model of hypertension and models of obesity and/or diabetes.et al.,,et al.et al.’s findings that cardiomyocyte size and body weight were both reduced in their model rather than being increased as might be expected. With regard to inflammation, the authors measured systemic TNFα levels but it would have been informative to also quantify myocardial cytokines and inflammatory cell infiltration.Sorop et al.et al.Figure 1).A more general critique of the model reported by Sorop The work was supported by the British Heart Foundation (BHF CH/1999001/11735) and the Department of Health via a National Institute for Health Research (NIHR) Biomedical Research Centre award to Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust.Conflict of interest: none declared.


Hair cells in the inner ear convert mechanical stimuli provided by sound waves and head movements into electrical signal. Several mechanically evoked ionic currents with different properties have been recorded in hair cells. The search for the proteins that form the underlying ion channels is still in progress. The mechanoelectrical transduction (MET) channel near the tips of stereociliary in hair cells, which is responsible for sensory transduction, has been studied most extensively. Several components of the sensory mechanotransduction machinery in stereocilia have been identified, including the multi-transmembrane proteins tetraspan membrane protein in hair cell stereocilia (TMHS)/LHFPL5, transmembrane inner ear (TMIE) and transmembrane channel-like proteins 1 and 2 (TMC1/2). However, there remains considerable uncertainty regarding the molecules that form the channel pore. In addition to the sensory MET channel, hair cells express the mechanically gated ion channel PIEZO2, which is localized near the base of stereocilia and not essential for sensory transduction. The function of PIEZO2 in hair cells is not entirely clear but it might have a role in damage sensing and repair processes. Additional stretch-activated channels of unknown molecular identity and function have been found to localize at the basolateral membrane of hair cells. Here, we review current knowledge regarding the different mechanically gated ion channels in hair cells and discuss open questions concerning their molecular composition and function. Hair cells of the inner ear are specialized mechanosensory cells, which convert mechanical stimuli provided by sound waves (cochlea) or head movement (vestibular system) into electrical signals. Hair cells are highly polarized cells with extraordinary morphological specialization for sensing mechanical stimuli. The most prominent morphological specialization of a hair cell is the hair bundle. It protrudes from the apical surface of a hair cell and is formed by an array of F-actin based stereocilia that are arranged in a staircase of decreasing heights Figure . The senBesides the sensory MET channels at tip links, a second mechanically activated channel was recently identified in hair cells that is located at their apical cell surface where stereocilia emanate from the cell body Figures . This MEHair cells in the mammalian cochlea come in two flavors, outer hair cells (OHCs) and inner hair cells (IHCs). OHCs have an important function in amplifying input sound signals while IHCs transmit sound information to the CNS  and low in Ca2+ (0.03 mM; Bosher and Warren, +. However, Ca2+ profoundly affects channel function where channel activity is increased when the external Ca2+ is decreased from a mM to a μM concentration (Corey and Hudspeth, The MET channel is non-selective for cations (Corey and Hudspeth, 2+ selectivity and single-channel conductance also show tonotopic characteristics in OHCs but not in IHCs. In 20 μM external Ca2+, single-channel conductance varies from 145 to 210 pS for OHCs along the tonotopic axis but is about 260 pS for IHCs along the entire length of the cochlea (Beurg et al., The organ of Corti in mammals has the ability to separate sound frequencies along its length—high-frequency tones at the proximal end and low-frequency at the distal end of the organ. The Ca2+ either to the MET channel itself or to a binding side near the channel. Slow adaptation is thought to be regulated by a myosin motor complex at the upper insertion site of tip links (Crawford et al., 2+ (Peng et al., 2+ entry and voltage, while channel open probability is modulated by divalent ions interacting with the local lipid environment (Peng et al., 2+ influx (Corns et al., 2+ selectivity (Effertz et al., Sensory MET channels in hair cells adapt to mechanical stimuli, which leads to a decrease in current during a constant stimulus but additional stimulation again increases current. Adaptation is thought to set the resting tension of the transduction channel to position the channel near the most sensitive point of activation, and is important for providing amplification for mechanical signals (reviewed in LeMasurier and Gillespie, 2+, and sensitivity to channel blockers are similar but not identical between the two channels (Beurg et al., 2+ and ~90 pS at 0.07 mM Ca2+ (Beurg et al., During the early development of hair cells, their hair bundles are less directionally sensitive. Transducer currents can be observed by deflection of the hair bundle both towards the shortest and longest stereocilia (Waguespack et al., + and Na+ (Iwasa et al., −, which is thought to regulate prestin function (Oliver et al., Several studies identified stretch activated MET currents in the basolateral membrane of hair cells, but the properties of these currents differed between reports. At least three different currents that are affected by mechanical force have been reported in OHCs. One type of current was activated by stretch and a single-channel conductance of 38–50 pS was determined for the underlying channel. This ion channel was non-selective to cations and had a reversal potential ~ −12 mV (Ding et al., 2+ imaging, it was demonstrated that the sensory MET channel is localized near the lower end of tip links (Beurg et al., The search for the molecular constituents of the MET channel in stereocilia has been in progress for decades. Using high speed CaTmc1 and Tmc2 are members of a gene family consisting in mammals of eight genes (Keresztes et al., Tmc1 and Tmc4 are the main family members that are expressed in adult cochlear hair cells, while Tmc2 is only transiently expressed in the cochlea during early postnatal development but can be detected in vestibular hair cells into adulthood (Kawashima et al., Tmc3 belongs to the same gene subfamily as Tmc1 and Tmc2, it does not appear to be essential for MET by hair cells (Beurg et al., Tmc1/2 deficient hair cells (Kawashima et al., 2+ selectivity and adaptation time constant in developing hair cells lacking either TMC1 alone or TMC2 alone differ (Kim and Fettiplace, 2+ selectivity of IHCs and OHCs lacking TMC2 but not TMC1 is significantly reduced (Kim and Fettiplace, Tmc1 has been reported to reduce Ca2+ permeability and single-channel conductance in IHCs (Pan et al., 2+ selectivity of the MET channel can be explained by variations in the stoichiometry of TMC1/2 (Pan et al., Tmc1 reduces single-channel conductance (Beurg et al., Tmc1 and Tmc2 can be caused by modulating the concentration of PIP2 in hair bundles (Effertz et al., tmc ortholog in the worm has been reported to relate to sodium-sensitive channel for salt sensation (Chatzigeorgiou et al., C. elegans (Zhang et al., Drosophila, TMC was found to play a function in providing sensory feedback for laval locomotion (Guo et al., Drosophila TMC (Zhang et al., However, whether TMC1 and TMC2 form the channel pore is still under debate. It was proposed that the tonotopic gradient in the conductance and CaTmhs/Lhfpl5 mutations cause deafness and lead to a dramatic reduction in mechanotransduction currents in cochlear hair cells of mice (Xiong et al., Tmhs/Lhfpl5-deficient hair cells. Single channel recordings demonstrated that in the absence of TMHS/LHFPL5 the conductance of the MET channel is affected as well as its activation and adaptation kinetics (Table TMHS/LHFPL5 is a second protein that has been implicated to be an integral component of the mechanotransduction channel in hair cells. TMHS/LHFPL5 is a member of a small subfamily within the large superfamily of proteins with four transmembrane domains (Petit et al., cs Table . The toncs Table . Taken tcs Table . Since scs Table . HoweverTmie-deficient cochlear hair cells, no MET currents can be detected, even though tip links remain intact and all known components of the MET machinery including TMC1/2 can travel into stereocilia (Zhao et al., TMIE is a protein with two transmembrane domains and linked to deafness in both human and mice (Mitchem et al., 2+ concentration (Wu et al., The similarities in single-channel conductance and pharmacological properties of the normal and reverse-polarity current in hair cells initially suggest that these two mechanically gated currents are carried by the same channel pore (Kim et al., − influx through a stretch-sensitive channel in the basolateral membrane of OHCs was reported to allosteric modulate prestin, thus potentially functioning in OHC amplification (Oliver et al., Piezo2-deficient hair cells demonstrated that PIEZO2 is not essential for electromotility (Wu et al., We still know next to nothing about the molecular composition of ion channels that carry the stretch activated currents in the basolateral membrane of OHCs (Ding et al., Recent studies have provided compelling evidence that hair cells express several molecularly distinct ion channels with different function. The best studied of these is the sensory MET channel at tips of stereocilia. Substantial evidence suggests that TMC1/2, TMHS and TMIE are integral components of the sensory MET channel Figure  but whicXQ and UM wrote the manuscript. Figures were designed by XQ.UM is a co-founder of Decibel Therapeutics. The other author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.