Stroke stands as a major cause of death and disability with increasing prevalence. The absence of clinical improvement after either intravenous thrombolysis (IVT) or mechanical thrombectomy (MT) represents a frequent concern in the setting of acute ischemic stroke (AIS). In an attempt to optimize overall stroke management, it is clinically valuable to provide important insight into functional outcomes after reperfusion therapy among patients presenting with AIS. The aim of the present review is to explore the predictive value of leukoaraiosis (LA) in terms of clinical response to revascularization poststroke. A literature research of two databases (MEDLINE and Scopus) was conducted in order to trace all relevant studies published between 1 January 2012 and 1 November 2022 that focused on the potential utility of LA severity regarding reperfusion status and clinical outcome after revascularization. A total of 37 articles have been traced and included in this review. LA burden assessment is indicative of functional outcome post-intervention and may be associated with hemorrhagic events’ incidence among stroke individuals. Nevertheless, LA may not solely guide decision-making about treatment strategy poststroke. Overall, the evaluation of LA upon admission seems to have interesting prognostic potential and may substantially enhance individualized stroke care. Stroke represents not only the second leading cause of death but also the major cause of acquired disability among adult individuals, mostly accompanied by a considerable unfavorable effect on the long-term functional independence of stroke survivors ,2,3. TakThe beneficial effects of reperfusion therapy following stroke, either with intravenous thrombolysis (IVT) or mechanical thrombectomy (MT), have been well documented. IVT with recombinant tissue plasminogen activator (rt-PA) has emerged as a first-line treatment strategy for patients with acute ischemic stroke (AIS) within 4.5 h of symptom onset . IncreasGiven the fact that prompt forecasting of each patient’s propensity for recovery substantially contributes to the decision-making in terms of poststroke treatment strategy, it becomes essential to be provided with an accurate and timely outcome prognosis . SeveralIntroduced by Hanchski in 1987 , the terConsidering the expected substantial increase in stroke patients with pre-existing LA undergoing reperfusion therapy, as stroke burden rises among the elderly and life expectancy continues to significantly expand in developed countries, it is of key importance to elucidate the potential contribution of LA on forecasting clinical response to IVT or MT poststroke. Thus, the objective of our study was to review all available literature published within the last decade dealing with baseline LA as a prognostic tool following stroke recanalization.The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA registration number: CRD42022369840) were used to guide this study. Our study’s methods were a priori designed. Two investigators conducted literature research on two databases (MEDLINE and Scopus) (SK and AS) to trace all relevant studies published between 1 January 2012, and 1 November 2022. Search terms were as follows: (“leukoaraiosis” OR “white matter hyperintensities” OR “WMHs”) AND (“thrombolysis” OR “thrombectomy” OR “brain revascularization” OR “reperfusion”). The retrieved articles were also hand-searched for any further potential eligible articles. Any disagreement regarding the screening, or selection process, was solved by a third investigator (KV) until a consensus was reached. Only full-text original articles published in the English language were included. Secondary analyses, reviews, guidelines, meeting summaries, comments, unpublished abstracts, or studies conducted in animals were excluded. There was no restriction on study design or sample characteristics.Data extraction was performed using a predefined data form created in Excel. We recorded the authors, year of publication, number of participants, follow-up time, method of leukoaraiosis assessment, time of computed tomography execution, time from symptom onset to recanalization, the scale used to examine stroke severity and clinical outcomes, and the main results of each study.No statistical analysis or meta-analysis was performed due to the high heterogeneity among studies. Thus, the data were only descriptively analyzed. Overall, 262 records were retrieved from the database search. Duplicates and irrelevant studies were excluded; hence, a total of 90 articles were selected. After screening the full text of the articles, 37 studies were eligible for inclusion .A total of 37 publications fulfilled our inclusion criteria, as shown in In total, 20 studies utilized the Fazekas score, 11 the van Swieten scale, three the Age-Related White Matter Change Scale, two differentiated between the presence or absence of LA, one used the CREDOS WMH visual rating scale, and four estimated WMH volume on imaging. In total, all the studies included in this review were longitudinal. They were either retrospective or prospective cohorts.The total number of stroke patients included in all studies ranges from n = 56  to n = 3In none of the 37 included studies, stroke patients are contrasted to demographically-matched healthy individuals and none of the studies include a disease-control group other than stroke patients.National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) have been simultaneously used in 30 studies. NIHSS was the only scale in three studies and mRS exclusively in one study. In two studies NIHSS was combined with the Fugl-Meyer rating scale (FMS) and in one study with the Oxford Handicap Scale (OHS).A literature review over the last decade was conducted in order to elucidate baseline LA prognostic value in AIS patients undergoing reperfusion therapy. A total of 37 full-text original articles dealing with the potential utility of LA evaluation in forecasting stroke survivors’ clinical response to revascularization were identified and classified into three groups based on the implemented revascularization technique.With respect to poststroke outcome after EST, Zhang et al. , having Additionally, Liu et al.  further As far as the role of brain atrophy and LA in forecasting futile recanalization poststroke is concerned, Kaginele et al. , having With regard to clinical and radiographic variables able to act as predictors of futile recanalization among AIS patients undergoing MT, Gilberti et al. , having Regarding the relationship between both LA severity and time to successful reperfusion with 3-month functional outcome in an acute stroke setting, Milkati et al.  exploredWith respect to the occurrence of hemorrhagic transformation (HT), Shi et al.  investigApart from that, Lee et al.  reportedOn the contrary, Atchaneeyasakul et al. , having As for the prognostic utility of LA burden in patients presented with AIS due to large cerebral artery occlusion undergoing intra-arterial therapy (IAT), Giurgiutiu et al. , having With respect to the clinical response to IV rt-PA utilization in ischemic stroke patients in the setting of detectable LA on baseline CT scan, Huang et al.  examinedAdditionally, Zhong et al. , having As far as the role both early ischemic and pre-existing brain imaging signs are to play in terms of predicting clinical response to IVT in ischemic stroke patients, Delcourt et al.  observedConsidering that the assessment of the global burden of small vessel disease (SVD), as reflected by both white matter changes and pre-existing lacunar infarcts, may constitute a more precise marker with valuable prognostic potential in terms of clinical outcome and hemorrhagic complications following IVT among stroke patients, Arba et al.  investigConsidering the influence of pre-existing LA on CT scans of stroke patients admitted for IVT on 3-month functional outcome and risk of symptomatic ICH, Yang et al.  examinedDespite being associated with ICH occurrence and 3-month unfavorable outcome following IVT, LA severity was not reported as an independent prognostic marker of symptomatic ICH, mortality, or clinical outcome in a study conducted by Capuana et al.  within aWith respect to the prognostic significance of LA in terms of tPA-related bleeding events, Willer et al. , having Regarding the occurrence of remote post-thrombolytic hemorrhagic complications of IVT, Chen et al.  exploredAs far as the prognostic potential of LA burden among elderly stroke patients is concerned, Nighoghossian et al. , having Regarding the prognostic potential of endothelial dysfunction markers as the soluble tumor necrosis factor-like inducer of apoptosis (sTWEAK) in an acute ischemic stroke setting, da Silva-Candal et al.  exploredTaking everything into consideration, the present review provides evidence regarding the prognostic significance of LA severity, as evaluated on baseline head imaging within the early phase following stroke. Our findings suggest the significant role LA assessment may play in forecasting clinical response to reperfusion treatment strategy. LA burden, serving as a surrogate marker of biological age and consequently “brain frailty” among stroke patients, appears to be able to yield additional information in terms of cerebral reserve and brain parenchyma resilience to emerging ischemia, thus reliably predicting both reperfusion status and clinical outcome after either IVT or MT. Determining the extent of pre-existing white matter abnormalities may properly guide the decision-making in a setting of acute stroke, as a greater degree of these lesions is usually coupled with unfavorable prognosis and poorer outcomes after the selected intervention is implemented. Additional data support the prognostic value of baseline LA on the potential development of adverse hemorrhagic events after IVT or MT, with a higher LA burden identified on admission head imaging being accompanied by an increased incidence of intervention-related ICH. Nevertheless, LA assessment should be interpreted in a clinical context and may constitute a more powerful tool when being paralleled with other clinical and neuroimaging biomarkers in an attempt to facilitate individualized stroke care. The aforementioned results highlight the need to further investigate LA as a promising imaging marker for clinical outcomes after IVT or MT to enhance patients’ risk stratification and promote overall stroke management. Additional studies among stroke individuals on the linkage between LA burden and prognosis after stroke intervention are recommended in order to provide further insight into this clinically important relationship.


Epigenetic mechanisms and post-translational modifications as novel therapeutic targets in cancer” collected 11 articles on epigenetic mechanisms, post-translational modifications, cell cycle and signaling pathways related to tumorigenesis and development. Our aim is to provide new research directions for targeted cancer therapies and drug development.This Research Topic “Zhou et al. summarized the role and mechanism of the modification related enzymes “Writers” and “Erasers” in cancer, providing a basis for the development of anti-tumor epigenetic drugs. Tang et al. assessed the causal relationship between smoking-related DNA methylation and breast cancer risk by Mendelian randomization. The results suggest that DNA methylation plays an important role in linking smoking to breast cancer, especially the subtype of ER+ breast cancer. Zeng et al. evaluated pyroptosis-related genes in esophageal adenocarcinoma and found that the expressions of GSDMB and ZBP1 were influenced by DNA methylation levels. Huo et al. focused on the role of RNA modification in cancer. They summarized the molecular mechanism of RNA modification in the occurrence and development of head and neck squamous cell carcinoma and discussed the related treatment options. Jing et al. demonstrated that hypoxia induced upregulation of ELFN1-AS1 expression in colorectal cancer cells. As a potential target of competing endogenous RNA, ELFN1-AS1 relieved the inhibition of TRIM14 by sponging miR-191-5p, thus promoting the proliferation and invasion of colorectal cancer cells. Lu et al. elucidated the role of acetylation modification in tumor immunity by focusing on histone acetyltransferases and deacetylases, and discussed the clinical application of acetylation-modified drugs in tumor therapy.Epigenetic modifications affect genetic expression without the sequence change of DNA, and its disorders are closely related to the occurrence and progression of cancer. Methylation is a widely studied form of epigenetic modification. Hou et al. provided evidence that low expression of USP47 in the primary colorectal cancer was associated with disease-free survival. USP47 deubiquitinated and stabilized the expression of transcription elongation factor A3 (TCEA3). Knockdown of UPS47 or TCEA3 can enhance doxorubicin-induced apoptosis and pyrotosis of colorectal cancer cells, which provides a potential target for the treatment of colorectal cancer.Post-translational modifications increase the protein diversity and play critical roles in regulating the protein activity, localization, and interaction with other molecules. Xia et al. identified aminoquinoline as a novel multi-kinase inhibitor of CDK4/6 and PI3K/AKT for the treatment of hepatocellular carcinoma. Zhao et al. revealed that lysophosphatidic acid induced transactivation of EGFR through MMP-dependent pathway, which upregulated geminin expression and promoted DNA replication in gastric cancer cells. Guo et al. found that a natural microbial product, Ilicicolin A, as a novel EZH2 antagonist, inhibited the EZH2-mediated signaling pathway to enhance the sensitivity of castration-resistant prostate cancer cells to enzalutamide. Yang et al. investigated the role of kinesin family member 2C (KIF2C) in cervical cancer. KIF2C expression was significantly upregulated in cervical cancer, promoted cervical cancer cells proliferation, invasion, and migration. Knockdown of KIF2C inhibited the development of cervical cancer by activating p53 signaling pathway, providing a new target for the treatment of cervical cancer.In normal cells, cell cycle and signal transduction are strictly regulated, and their dysregulation and abnormal activation lead to various diseases including cancer. Epigenetic mechanisms and post-translational modifications as novel therapeutic targets in cancer” Research Topic emphasizes that epigenetic and post-translational modification provide new targets for the development of anti-cancer drugs and bring new strategies for treatment of cancer.In conclusion, the “


It is challenging to conduct in-depth research of the molecular mechanisms associated specifically with human age-related diseases, and how internal and external factors are regulating these processes. For these reasons, research has focused on finding innovative therapies that increase the specificity of the treatment and reduce their drawbacks. This Research Topic on “NLiu et al. offered insights into the heterogeneity of osteoarthritis, which provided in-depth understanding of the transcriptomic diversities within synovial tissue. This transcriptional heterogeneity may improve an understanding on osteoarthritis pathogenesis and provide potential molecular therapeutic targets for osteoarthritis. Zhao et al. investigated the aging-based diagnostic gene signature and molecular subtypes with diverse immune infiltrations in atherosclerosis. Huang et al. did comprehensive characterization of ageing-relevant subtypes associated with different tumorigenesis and tumor microenvironment in prostate cancer. The authors proposed that ageing-relevant molecular subtypes and gene signature might be of great significance to determine clinical outcomes and tumor microenvironment features as well as immunotherapeutic responses in prostate cancer. Song et al. identified reliable gene signatures through combination strategies of diverse feature selection methods, which facilitated the early detection of ischemic cardiomyopathy and revealed the underlying mechanisms. Liu et al. developed of a toll-like receptor (TLR)-based gene signature that can predict prognosis, tumor microenvironment, and chemotherapy response for hepatocellular carcinoma. They also proposed that this TLR-based gene signature might assist clinicians to select personalized therapy programs for HCC patients.This Research Topic described some high-throughput methods  for examining age-related molecular signatures. Lin et al. summarized the role of macrophage phenotypic diversity in the progression of the dynamic atherosclerotic plaque, and the possibility of treating atherosclerosis by targeting macrophage microenvironment. Wang et al. reviewed and concluded the AMPK as a potential therapeutic target for intervertebral disc degeneration. The role of sonic hedgehog pathway in the development of the central nervous system and aging-related neurodegenerative diseases was discussed by Yang et al.You at al. investigated the influence of anemia on postoperative cognitive function in patients undergo hysteromyoma surgery. The results from He et al. showed that secoisolariciresinol diglucoside (SDG) can significantly increase mitochondrial DNA copy number and slow down the process of telomere shortening. The authors also indicated that SDG could improve ovarian reserve by inhibiting oxidative stress. Qin et al. discovered that rational design and synthesis of 3-morpholine linked aromatic-imino-1H-indoles as novel Kv1.5 channel inhibitors sharing vasodilation effects. Du et al. found that the 4-methoxydalbergione could inhibit bladder cancer cell growth through inducing autophagy and inhibiting Akt/ERK signaling pathway. Wu et al. suggested that the sevoflurane could alleviate myocardial ischemia reperfusion injury via inhibiting P2X7-NLRP3 mediated pyroptosis. Jia et al. demonstrated that circulating LBX2-AS1 could be an underlying diagnostic marker in multiple myeloma (MM). Targeting LBX2-AS1 suppressed tumor progression by affecting mRNA stability of LBX2 in MM. Hence, LBX2-AS1 could be a novel therapeutic marker against MM. Lan et al. uncovered that the olfactory impairment could be an early indicator to guide early intervention for postoperative cognitive dysfunction.This Research Topic also discussed novel mechanistic insights and targeted therapies for a personalized treatment against various age-related diseases. Xing et al.Lu et al. reviewed the vitamin D and lipid profiles in postmenopausal women and concluded that the vitamin D administration in postmenopausal women could decrease the concentrations of triacylglycerol, and HDL-cholesterol, but have no effects on LDL-cholesterol and total cholesterol. Xu et al. summarized the recent progress in the functions and mechanisms of newly discovered circular RNAs in intervertebral disc degeneration. Zheng et al. stated that ginkgo biloba extract 80 could have cardioprotective properties through the activation of AKT/GSK3β/β-Catenin signaling pathway. Yin et al. investigated the cordyceps militaris-derived polysaccharide CM1 and demonstrated that it could alleviate atherosclerosis in LDLR (−/−) mice by improving hyperlipidemia. Zhou et al. revealed that propofol could ameliorate ox-LDL-induced endothelial damage by enhancing autophagy through PI3K/Akt/m-TOR pathway, which might offer a novel therapeutic strategy in atherosclerosis. A type I collagen-targeted MR imaging probe for staging fibrosis in Crohn’s disease was conducted by Li et al. Their results demonstrates that targeted MRI probe (EP-3533) supplies a better enhanced effect compared to Gd-DTPA and could be a promising method to evaluate the progression and monitor the therapeutic response of bowel fibrosis. Yang et al. found that the sinomenine could suppress development of hepatocellular carcinoma cells through inhibiting MARCH1 and AMPK/STAT3 signaling pathways. This study provides a new support for SIN as a clinical anticancer drug and illustrates that targeting MARCH1 could be a novel treatment strategy in developing anticancer therapeutics.New formulations or new therapeutic molecules useful for increasing anti-aging effectiveness and reducing toxicity are illustrated here. The atheroprotective effects and molecular mechanism of berberine were discussed by Wang et al. found that the aging-related gene signature was in relation to tumor immunity and stromal activation in rectal cancer, which might predict survival outcomes and immuno- and chemotherapy benefits. Li et al. stated that the miR-330–5p in small extracellular vesicles derived from plastrum testudinis-preconditioned bone mesenchymal stem cells could attenuate osteogenesis by modulating Wnt/β-Catenin signaling. Zeng et al. observed that knockdown of miR-615-5p reversed the suppression of circRNA_100146 silence on the proliferation and invasion of prostate cancer cells. The authors also stated that the tumor growth was also suppressed by silencing circRNA_100146 in vivo. Lu et al. identified two osteoarthritis-specific markers HTR2B and SLC5A3 and their knockdown ameliorated apoptosis and inflammation of Osteoarthritis synovial cells. Zhang et al. also discovered that mitomycin C could inhibit esophageal fibrosis by regulating cell apoptosis and autophagy via lncRNA-ATB and miR-200b.Finally, some genes and proteins involved in aging or anti-aging as well as substances that inhibit or rejuvenate aging are also presented in this Research Topic. We believe that researchers could find this Research Topic to be a useful Research Topic of articles on novel molecular mechanisms and innovative therapeutic approaches for age-associated diseases.


Myeloid neoplasms (MN), namely myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), and acute myeloid leukemias (AML) are characterized by disrupted myelopoiesis encompassing increased apoptosis of bone marrow (BM) progenitors, differentiation arrest and increased proliferation . This reBarcellini and Fattizzo asked themselves the “egg or chicken” question as to whether immune phenomena comes before or after MN. They examined their epidemiological association, and discussed that autoimmunity and immunodeficiency are the two faces of a dysregulated immune tolerance and surveillance possibly resulting in tumor escape and infections. Alterations of the microbiota and of mesenchymal stem cells in MN are also discussed to highlight the importance of a permissive microenvironment for tumor growth. Finally, the authors highlight how novel therapies for MN (including checkpoint inhibitors and chimeric antigen receptor T-cells) may increase autoimmune phenomena.Cominal et al., focused on Philadelphia chromosome-negative MPN that display inflammatory alterations of BM niche. They studied BM soluble mediator signatures using a multiplex assay and found a distinctive profile in polycythemia vera with increased levels of chemokines, and growth factors compared to essential thrombocytopenia and primary myelofibrosis. Deregulation of soluble mediators was associated with abnormal blood counts, thrombosis, treatment status and risk stratification and this might represent a therapeutic target. Additionally, JAK inhibitors also affect the levels of inflammatory cytokines in MPN patients, as described by Cattaneo and Iurlo. They also discussed how these drugs affect several components of the innate and adaptive immune systems such as dendritic cells, natural killer cells, T helper cells, and regulatory T cells, resulting in a level of immune deficiency with increased infectious risk.Sciumè et al., focused on another rare “proliferating” condition: systemic mastocytosis. They described a KIT D816V mutated patient who evolved into MN with PDGFRA rearrangement and responded to imatinib therapy; they discuss how immunological mechanisms may play a role in promoting clonal prevalence of one entity (mastocytosis) over the other (MN).Bucelli et al., who described a large series of patients with co-occurrence of myeloid and lymphoid neoplasms. Patients mainly suffered from MPN with associated non-Hodgkin lymphomas; nearly a half required anti-lymphoma therapy and 1/3 experienced a high-grade infection that was significantly associated with mortality.The clinical and prognostic aspects of the concomitant presence of distinct hematological clonal entities was further addressed by Whether the myeloid and lymphoid clones share a common origin or develop autonomously is still debated, and another interesting example is the association of large granular lymphocyte (LGL) expansion with MN and BM failure syndromes. Our group performed a literature review and discussed how LGL clones, found in up to 1/3 of MN, are associated with deeper cytopenia (likely through immune mediated apoptosis) and good response to immunosuppression. Far from being innocent bystander, LGL clones may contribute to immunosurveillance, as their depletion after immunosuppression may favor leukemic escape.Li et al., developed and validated an innovative prognostic model based on a novel immune-17 signature derived from transcriptome data from The Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression (GTEx) databases. They confirmed that immune biology processes and transcriptional dysregulations are critical factors in the development of AML. Interestingly, the incorporation of the immune-17 signature to the ELN2017 risk score improved patient stratification. This immune signature may be therapeutically exploited, as described by Sun Yao et al., that treated an AML patient with PD-1 blockade in combination with azacytidine after allogeneic hematopoietic stem cell transplantation; these strategies that reactivate anti-leukemic immune surveillance may in turn result in devastating autoimmune/autoinflammatory responses, as in the case described who developed fatal graft versus host disease.Focusing on AML, Razanamahery et al., described a case of Erdheim–Chester disease (ECD), a rare histiocytosis, characterized by somatic mutations of MAP-kinase pathway in CD14+ monocytes. They found a correlation between disease activity and increased CD14++CD16− “classical monocyte” and decreased CD14lowCD16++ “non-classical monocyte” highlighting the contribution of a phenotype switch of innate immunity in this rare disease.Moving to innate immunity effectors, Giannotta et al., reported a patient with MPN who developed clinically overt PNH requiring anti-complement therapy. They discuss that the selection and expansion of PNH clones in MPN is likely to be ascribed to the same immunological bottlenecks described in BMF: autoimmunity against BM precursors, toxicity of therapies, and acquirement of cooperative somatic mutations.Another very rare condition associated with autoimmunity and MN is paroxysmal nocturnal hemoglobinuria (PNH). Caprioli et al., described how the use of single-cell technologies represent powerful tools to assess the cellular composition of the complex tumour ecosystem and its immune environment (Finally, ironment Figure 1In conclusion, this Research Topic highlights the multifaceted immunologic aspects of pathogenesis, clinical course, and treatment of MN. This expanding field will increasingly benefit from sophisticated molecular tools to further identify druggable pathways/targets and optimize management of MN and other rare entities.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Aminul Islam et al., RSC Adv., 2022, 12, 7835–7849, DOI: 10.1039/D2RA00768A.Correction for ‘Efficacy of surface-functionalized Mg The authors regret that the name of one of the authors (Md. Mahbubul Haque) was shown incorrectly in the original article. The corrected author list is as shown here.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.


Due to demographic trends, the importance of optimal treatment of proximal femur fractures in elderly patients will undoubtedly continue to increase. The clinical outcome for this vulnerable patient group depends on many factors, some of which we as surgeons may influence . However, patient-specific factors  are also of upmost importance and may raise our suspicion for a complicative course.In this issue, several authors highlight different surgery-related and patient-specific factors that may influence the perioperative course of geriatric patients with proximal femur fractures.Kristen et al.  retrospeIn the context of surgical timing, Forssten et al.  investigIn addition to the above reported impact of timing, Weingärtner et al.  highlighIn their randomized double-blinded trial, Zhang et al.  evaluateA retrospective, observational study evaluated whether beta-blockers therapy provided a survival benefit following hip fracture surgery . Ahl et Finally, Becker et al.  reviewedWe hope that this issue will provide you with useful information regarding your daily practice with this vulnerable patient group.


Management of hemodialysis patients.”Chronic kidney disease (CKD) is a highly prevalent condition affecting >10% of the general population . Though Assessing the efficacy and safety of Juan Bi Tang for dialysis-related myofascial pain in the fistula arm: Study protocol for a randomized cross-over trial,” Hsu et al. outline a protocol for randomizing HD patients to use of the Chinese herbal medicine Juan Bi Tang, to determine if this therapeutic strategy could alleviate dialysis-related myofascial pain. The authors note wide use of Juan Bi Tang in treatment of other musculoskeletal disorders, though efficacy in treatment of fistula-related pain has not been explored. The results of this study could provide a more effective strategy for managing access arm pain in HD patients.Patients who receive HD through an arteriovenous fistula may experience pain during or after dialysis treatments, which can be related to alterations in extremity perfusion . These sFlash glucose monitoring to assess glycemic control and variability in hemodialysis patients: The GIOTTO study”, Mambelli et al. demonstrate the acceptability of flash glucose monitoring in patients on HD. Though further studies are warranted to validate its accuracy and precision in the setting of other comorbidities, the use of flash glucose monitoring in HD patients could provide an additional layer of safety in managing these vulnerable patients.Additionally, HD treatments can induce hyperglycemia and hypoglycemia in ESKD patients . In factKang et al., “Association between alkaline phosphatase and muscle mass, strength, or physical performance in patients on maintenance hemodialysis,” the authors found that high alkaline phosphatase levels were associated with poor physical performance in ESKD patients on HD, as assessed by several tests of muscle mass and function including handgrip strength and a 6-min walk test. High alkaline phosphatase levels in HD patients typically represent high-turnover bone disease, and have been shown to associate with increased risk of hospitalization and death  values are evaluated during HD treatments to predict short-term and long-term changes in PTH levels. This model would use blood and dialysate samples to guide management of mineral bone disease in HD patients, which is highly prevalent and contributes to significant morbidity. We anticipate that big data and mathematical modeling will continue to enable development of prediction models useful in management of HD patients.Given the massive amount of data collected and available from cohort studies such as the Dialysis Outcomes and Practice Patterns Study , advanceDialyzer classification and mortality in hemodialysis patients: A 3-year nationwide study cohort,” Abe et al. report that protein-leaking dialyzers may be associated with a reduction in mortality. Compared to low-flux and high-flux dialyzers, protein-leaking dialyzers in a group of >250,000 patients on HD in Japan were associated with lower mortality , though the exact contributions of β2-microglobulin removal were not evaluated. Further information is needed to clarify relationships between removal of variable dialyzable proteins and outcomes such as mortality (There are also several studies focusing on clinical endpoints in HD patients, such as mortality. Some risk of mortality may be related to HD treatments in themselves. In their study, “ortality .Tylicki et al., “COVID-19 vaccination reduces mortality in patients on maintenance hemodialysis”, provides even more data to support the use of COVID-19 vaccination in patients on HD to reduce mortality.Finally, in the era of an ongoing pandemic, we must also acknowledge that non-dialysis related factors can significantly influence the outcomes of patients with ESKD. A study by Management of hemodialysis patients”, contribute valuable information on assessing and treating some of the variable aspects of increased morbidity and mortality in ESKD patients on hemodialysis.In sum, the seven articles presented in this Research Topic, “DP drafted the editorial. All authors contributed to editing and finalization of the manuscript.


As the first evolutionary group that comprises of innate immunity and adaptive immunity, fish is considered as a supreme model for clarifying the evolutionary and regulatory mechanisms of vertebrate immunity. However, the types and characteristics of fish immune cells are still not quite clear. In this Research Topic, eight articles including six original research articles and two review articles highlight the advance of novel techniques to identify immune cell population in fish.Fei et al. reviewed the reagents (including mAbs of surface markers and immune cells) available for the research of fish immunity. The authors further discussed the potential applications of fluorescence-activated cell sorting and droplet-based microfluidics in screening and identifying antigen-specific B lymphocytes with a high-throughput manner and suggested to incorporate the alternative technologies to promote the production of specific antibodies in a high-throughput and cost-effective way. Similarly, the review article by Chan et al. summarized the protein marker and partial corresponding mAbs of teleost fish immune cells, and presented the interaction of fish T cells, B cells and dendritic cells via surface molecules for modulating adaptive immune response. More importantly, they further reviewed the advance for application of single-cell RNA sequencing (scRNA-seq) in teleost immunology and explored future directions of the methods developed for studying fish immunity at the cellular level. Martín et al. isolated two homologs of mammalian CD38 (CD38A and CD38B) from Rainbow trout (Oncorhynchus mykiss). By using the mAb against CD38A, CD38A+ populations among IgM+ B cells and IgM- leukocytes of head kidney (HK) were screened via flow cytometry. The IgM+ CD38A+ B cells increased post-inactivated Aeromonas salmonicida stimulation in vitro, which produced higher levels of IgM and enhanced B cell differentiation gene transcription than the cells lacking CD38A.The monoclonal antibody (mAb) specific for leukocyte surface markers is the classical approach to identify fish immune cells. Chan et al., already applied to identify previously unknown cell markers of teleost immune cell populations. In anterior kidney (AK) of Nile tilapia (Oreochromis niloticus), Wu et al. identified five distinct immune cell subsets including B cells, T cells, granulocytes, macrophages, and dendritic cells (DCs) and further uncovered different subsets of B-cell  and T cells  based on distinct transcriptional level of the transcription factors (TFs) and cytokines. Additionally, Huang et al. analyzed scRNA-seq data of Orange-spotted grouper (Epinephelus coioides) with a full-length transcriptome as a reference, which was aimed to develop alternative approach for the fish samples without any published genome. In their study, four cell types including T cells, B cells, monocytes/macrophages (Mo/Mφ) and NCC (non-specific cytotoxic cells) were identified and two subsets of Mo/Mφ (M1 and M2 type), as well as four subsets in B cells . Moreover, the finding of syngnathid fish, Syngnathus typhle (a fish species lacking the spleen and major histocompatibility class II (MHC II) pathway) by Parker et al. indicated that the loss of CD4+ T cells accompanied the loss of the MHC II pathwapresencehe present of regulatory T cells and cytotoxic T cells.The scRNA-seq is a newly developed technique that, also reviewed by Smith et al. examined the mRNA transcriptome profiles at different stage of Atlantic salmon  adherent head kidney leukocytes (HKLs) using microarray, and revealed that the adherent HKL cell population differentiates in vitro to become macrophage-like without exogenous stimulation, which might be regulated by miRNA and targeted differentially expressed genes (DEGs) associated with macrophage differentiation and function. Using transcriptome analysis, Park et al. revealed that the macrophage heterogeneity in adherent intestinal cells (AIC) and adherent head kidney cells (AKC), as well as the functional characteristics of mucosal and systemic macrophages in Atlantic salmon. Their data also suggested that interaction of miRNA and mRNAs related to macrophages and epithelial cells were involved in macrophage activation and differentiation.Although the scRNA-seq technique develops rapidly and contributes to the research field of fish immune cell, the analysis of transcriptome profile is still a reliable method to clarify the activity and development of specific immune cell type in fish. In summary, all collected articles in this Research Topic exhibited recent novel works regarding fish immune cell identification and provided new strategy to better uncover the composition and function of teleost immune system, which can also help to expand our understanding for the evolution of the vertebrate immune system.All authors contributed to this editorial insight and approved the submitted version.This work was supported by National Natural Science Foundation of China , Natural Science Foundation of Guangxi (2020GXNSFAA297243), Technology Planning Project of Guangdong Province of China (grant no. 2015A020209181), National Key R&D Program of China (2018YFD0900501), Independent Project of Southern Marine Science and Engineering Guangdong Laboratory (Zhanjiang) (No. ZJW-2019-06), Special Foundation for “Achieving the First Class” of Guangdong Province , The Project of Guangxi Mangrove Coastal Wetland Ecological Protection and Sustainable Utilization Talent Highland (BGMRC202101), Guangdong South China Sea Key Laboratory of Aquaculture for Aquatic Economic Animals, Guangdong Ocean University (No. KFKT2019YB11), the Japan Society for the Promotion of Science KAKENHI Grants .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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


K-edge HERFD-XANES is evaluated in mine waste samples and synthetically generated mixtures of reference compounds.The improvement in As speciation resulting from As  2O3), orpiment (As2S3), getchellite (AsSbS3), arsenopyrite (FeAsS), kaňkite (FeAsO4·3.5H2O), scorodite (FeAsO4·2H2O), sodium arsenate (Na3AsO4), and realgar (As4S4) were selected for their importance in mine waste systems. Statistical methods of principal component analysis and target transformation were employed to determine whether HERFD improves identification of the components in a dataset of mixtures of reference compounds. LCF was performed on HERFD- and total fluorescence yield (TFY)-XANES spectra collected from mine waste samples. Arsenopyrite, arsenolite, orpiment, and sodium arsenate were more accurately identified in the synthetic HERFD-XANES spectra compared with the transmission-XANES spectra. In mine waste samples containing arsenopyrite and either scorodite or kaňkite, LCF with HERFD-XANES measurements resulted in fits with smaller R-factors than concurrently collected TFY measurements. The improved accuracy of HERFD-XANES analysis may provide enhanced delineation of As phases controlling biogeochemical reactions in mine wastes, contaminated soils, and remediation systems.High-energy-resolution fluorescence-detected (HERFD) X-ray absorption near-edge spectroscopy (XANES) is a spectroscopic method that allows for increased spectral feature resolution, and greater selectivity to decrease complex matrix effects compared with conventional XANES. XANES is an ideal tool for speciation of elements in solid-phase environmental samples. Accurate speciation of As in mine waste materials is important for understanding the mobility and toxicity of As in near-surface environments. In this study, linear combination fitting (LCF) was performed on synthetic spectra generated from mixtures of eight measured reference compounds for both HERFD-XANES and transmission-detected XANES to evaluate the improvement in quantitative speciation with HERFD-XANES spectra. The reference compounds arsenolite (As The oxidation of residual As-sulfide minerals or dissolution of As-bearing minerals in mine wastes releases dissolved As. Predicting the geochemical fate of As is important when designing remediation or prevention measures in mine wastes and other contaminated systems. Precipitation of stable and sparingly or insoluble minerals that incorporate or contain As promotes the attenuation of As. Understanding the mechanisms of As adsorption and mineralization processes, as well as the geochemical conditions that favour As attenuation, provides a foundation for the design of As remediation systems.et al., 1998et al., 2009et al., 2013et al., 2005et al., 2005et al., 2009et al., 2009et al., 2016et al., 2004et al., 2006et al., 2018et al., 2019et al., 2020et al., 2021et al., 2022et al., 2010et al., 2009et al., 2017et al., 2018et al., 2019Arsenic mobility in environmental systems has been extensively studied ; (2) low concentrations of elements of interest  wet chemical methods that rely on pre-treatments that convert the solid phase to a liquid- or gas-phase sample, et al., 2009et al., 2002et al., 2002et al., 2006et al., 2007et al., 2009et al., 2009et al., 2011et al., 2014et al., 2017et al., 2018et al., 2014et al., 2021K-edge  was developed to improve the detection limit, increase the resolution of the features in XANES spectra  and principal component analysis (PCA) techniques were employed to evaluate improved spectral-feature resolution in HERFD-XANES compared with transmission-detected XANES for standard compounds. Arsenic speciation analyses, HERFD-XANES, and total fluorescence yield (TFY)-XANES were conducted to determine the impact of detection mode on the quantification of As species in mine waste samples. The findings of this study will allow us to evaluate the benefits of HERFD-XANES over conventional detection modes for As speciation as applied to both standard compounds and environmental samples.2.2.1.2O3) and sodium arsenate (Na3AsO4)  and mineral specimens of orpiment (As2S3), getchellite (AsSbS3), arsenopyrite (FeAsS), kaňkite (FeAsO4·3.5H2O), scorodite (FeAsO4·2H2O), and realgar (As4S4) . The mineral specimens contained a combination of host rock and the mineral of interest, which was visually identified and removed from the host rock with a fine-tipped diamond Dremel to avoid contamination. Environmental samples were collected from Long Lake Mine, an abandoned gold mine in Sudbury, ON, Canada, that operated intermittently from 1909 to 1939. Samples were collected in aluminium tubing using a piston-coring technique . Solid samples were then freeze-dried and stored at 4°C to preserve their mineralogical composition. All samples and reference compounds were finely ground with an agate mortar and pestle in an anaerobic chamber in preparation for analysis. Samples and reference compounds were transported in an anerobic canister and removed immediately prior to analysis.Arsenic reference compounds included reagent-grade arsenic trioxide  was performed to confirm the identities of the arsenic reference compounds. Ground reference compounds were loaded into Kapton capillaries and sealed at both ends with Locktite 454 epoxy for PXRD analysis. Analyses were performed at CMCF-BM at the Canadian Light Source in Saskatoon, SK. Specifications of the beamline and endstation are fully described elsewhere  was used for further data processing, including diffractogram background subtraction and phase identification with the peak search and match algorithm using the COD-Inorg REV218120 2019.09.10 database .Diffraction images were background-subtracted, calibrated, and integrated using 2.3.Hephaetus . The energy resolution of the crystal analyzer is approximately 1 eV. Normally, filters can be applied upstream of the sample to attenuate and lower the intensity of the incident beam to optimize the count rate for fluorescence yield (FY) detection; however, retaining the maximum signal intensity is critical for HERFD. When FY and HERFD were measured simultaneously, the FY count rate was optimized using aluminium foil to directly filter the signal before it entered the detector.All XAS measurements were performed at 20-ID-C at the Advanced Photon Source at the Argonne National Laboratory in Lemont, IL, USA, where monochromatic X-rays in the hard X-ray regime are produced by an insertion device and a monochromator (Si 311). Ground reference compounds were spread thinly on Kapton tape and layered to achieve the appropriate thickness for collection of transmission-detected XAS. The thickness, calculated for each reference mineral using 2.4.LARCH , orpiment (As2S3), getchellite (AsSbS3), arsenopyrite (FeAsS), kaňkite (FeAsO4·3.5H2O), scorodite (FeAsO4·2H2O), sodium arsenate (Na3AsO4), and realgar (As4S4). Computer-generated spectra of mixtures were created with the spectra from each of the reference compounds, measured in both HERFD and transmission. All computer-generated mixtures were a combination of four reference compounds, each with a minimum contribution of 5% of the total mixture; these limitations were selected to represent speciation with a commonly acceptable number of fit components and detection limit. The computer-generated mixtures were analyzed with LCF and PCA. The datasets of mixtures were created with both HERFD and transmission reference compounds and each unique reference compound was included in 3500 synthetic spectra. A dataset was generated for each of the 70 combinations of four reference compounds to decrease sampling bias. A set of 100 random mixture ratios was generated using the NumPy module . LCF analysis on the mine waste samples was completed in Athena . A small shift of −0.5 to −1 eV is observed in white-line energy in HERFD measurements compared with transmission measurements ; variations in set-up angles were minimized by the magnetically positioned sample holder and consistent sample mounting technique ensuring the sample surface position was unchanged between samples and references. This configuration allows comparison of measurements across samples and reference compounds.The resolution increases observed in the HERFD-XANES spectra are similar to other studies , scorodite , and sodium arsenate  reference spectra for both the HERFD and transmission data, but additional components did not further decrease the residual standard deviation. The synthetic mixtures of arsenopyrite, arsenolite, sodium arsenate, and scorodite were selected for PCA and target transformation because each had unique spectral features . The longer air-path to the area detector used for HERFD measurements could attenuate up to 56% of the As Kα fluorescence emission which would decrease the signal-to-noise ratio. A helium bag placed in the air-path would decrease the attenuation and improve the signal-to-noise ratio. However, improved speciation using HERFD-XANES was observed in samples of As-bearing mill tailings collected from the Long Lake mine, which were identified to have a binary mixture of arsenopyrite and scorodite or kankite  and arsenopyrite, scorodite and kankite are likely chemical components of the dataset  whereas getchellite, orpiment, realgar, arsenolite and sodium arsenate are unlikely to be chemical components of the dataset . On average, the LCF on HERFD-XANES spectra obtained from Long Lake samples with binary mixtures resulted in fits with significantly lower R2  than fits on FY XANES spectra obtained from the same samples  could be impacted by over-absorption (self-absorption) that dampens the amplitude of the XAFS oscillations  were not measured on the same samples used for XAS measurements. If over-absorption is present in the samples, the quality of the fits in both HERFD and TFY would be impacted.Sample spectra collected using FY detection were fit with reference compounds measured in transmission detection, which could be a source of misfit between the sample and standard spectra. Spectra collected in HERFD or TFY from thick samples containing high As concentrations (Table S3) showed no improvement in R2  with HERFD-XANES spectra. The lack of improved fit quality may be attributed to reference materials that do not exactly represent, but have similar molecular bonding environments to, the species present in the sample. Getchellite, orpiment and realgar are rare As-sulfide minerals that are not often identified as secondary minerals in oxidized mine waste environments; however, the spectra for these minerals are similar to arsenical pyrite  (arsenopyrite), As(III)–S (getchellite), As(III)–O (arsenolite) and As(V) (sodium arsenate) . Arsenopyrite was identified in some of the tailings samples with conventional XRD measurements, and Fe–As–O-containing phases were previously identified with SEM-EDS  and As(V) sorbed to various relevant iron oxides and iron hydroxy-sulfates, such as goethite, ferrihydrite, jarosite, and hematite. XANES and EXAFS studies show that As sorbs to and is incorporated into secondary precipitates .HERFD-XANES provides resolution of unique spectral features that may not be detectable with transmission-detection XAS analyses, and this additional resolution enhances LCF fitting when the appropriate standards are available. Slight improvements in spectral resolution are also expected when As is dilute or in a complex matrix, which is one of the main benefits of HERFD for environmental samples. Developing a database of environmentally relevant As reference compounds is vital to the application of LCF with HERFD-XANES to quantitatively determine the speciation of As in mine wastes and other hazardous materials. Use of standard spectra from a HERFD-XANES database is critical with respect to the application of this technique (10.1107/S1600577522007068/ye5018sup1.pdfDetails on Datasets 1 and 2. Figures S1 to S15. Tables S1 to S3. DOI:


Vascular disease is now the leading cause of death worldwide, with cardiovascular and cerebrovascular diseases being the main contributors . HoweverYu et al. attempted to illustrate the association between plasma metabolic profiles and cerebral collateral circulation in patients with acute ischemic stroke (AIS). They found that the sphingosine-1-phosphate (S1P) level in plasma showed significant positive correlation with good collateral circulation and which might be a potential diagnostic biomarker for predicting collateral circulation status in patients with AIS. The paper by Xue et al. focused on excavating the potential biomarkers in lacrimal diabetic angiopathy and its potential mechanism. Hub genes App, F5, Fgg, and Gas6 related to the regulation of circulation and coagulation were identified. Meanwhile, certain small molecular compounds were considered that might reverse the altered differentially expressed genes. This study might empower the novel potential targets to treat lacrimal angiopathy and other diabetes-related diseases. The paper by Fan et al. found that myricanol could inhibit proliferation and migration of vascular smooth muscle cells (VSMCs) induced by platelet-derived growth factor-BB by suppressing the platelet-derived growth factor receptor-β and NF-kB p65 translocation. Furthermore, myricanol was found suppressing the intimal hyperplasia in mice with carotid stenosis. The paper by da Costa et al. found the events that HFD-fed leading decreased Nrf2 nuclear accumulation, decreased mRNA expression and activity of Nrf2-regulated enzymes  were prevented in castrated mice. The study indicate that testosterone would downregulate Nrf2, leading to oxidative stress and vascular dysfunction in HFD-fed obese mice.As the dominating part of this Topic, papers of basic research that we primarily collected have revealed some interesting relationships between metabolic abnormalities and vascular diseases. The paper by Hu et al. showed that there was no significant correlation between increased serum uric acid levels and the risk of first stroke in the Chinese adults with hypertension. Meanwhile, risk of the first stroke in patients with hyperuricemia less than 60 years old was significantly higher than control. The paper by Yu et al. was based on bioinformatic analysis of metabolomic and proteomic to reveal that the dysregulation of glutamate and glycine metabolism, upregulated glycolysis and fatty acid synthesis in the endothelial progenitor cells that treated with the oscillatory shear stress.However, papers of clinical research presented in this Topic have significant discoveries as well. The paper by Ning et al. with creative perspective summarized the potential mechanism underlying metabolic perturbation that type 2 diabetes mellitus (DM) affect the hypertension (HTN), what may be involved in the metabolism of insulin and angiotensin II, sympathetic nervous system as well as the energy reprogramming.Meanwhile, the Review paper by


In this Research Topic several studies have analysed the clinical and molecular profile related to cardiovascular disease (CVD) development in a range of inflammatory and systemic autoimmune diseases, including systemic lupus erythematosus (SLE), psoriatic arthritis, rheumatoid arthritis and spondylarthritis among others. Novel molecular mechanisms and biomarkers have been characterized along with clinical tools and approaches to manage this prevalent comorbidity.Quevedo-Abeledo et al., studied the levels of three CVD molecules involved in the metabolism of triglycerides, such as lipoprotein lipase (LPL), angiopoietin-like protein 4 (ANGPLT4), and apolipoprotein C-III (ApoC3), in 185 patients with SLE and 162 healthy donors. Performing a multivariable analysis, they identified that the LPL, ANGPLT4 and ApoC3, axis is altered in SLE and associated with the disease damage score. Wang et al., used public transcriptomic data to gain insight into the involvement of new players and pathways related to the development of atherosclerosis in SLE patients. They identified 5 hub genes  which might promote the monocytes differentiation into macrophages and the pathway of IL-17 signalling as potential mechanisms involved in the atherosclerotic process of SLE patients. Guzman-Martinez et al., reviewed the association of the immune system with the pathogenesis of endothelial damage and atherosclerosis in SLE patients, including inflammatory mediators, specific circulating cell populations and autoantibodies. Additionally, they discussed the utility of the immune system as early CVD biomarkers and therapeutic targets in SLE.In the case of SLE, three studies have explored at the molecular level the underlaying mechanisms associated with CVD. Remuzgo-Martínez et al., analysed the role of the protein irisin as a serological and genetic biomarker of CV risk, disease severity and subclinical atherosclerosis in a cohort of 725 patients with axial spondylarthritis (axSpA). Their results suggested that low levels of irisin in the serum could be considered a marker of high CV risk, more severe disease and the presence of subclinical atherosclerosis, in axSpA patients. Furthermore, they found that irisin may also constitute a biomarker of disease activity in axSpA at the genetic level.On the other hand, Barbarroja et al., reviewed the interplay of hepatic alterations and CVD, analysing different mechanisms where autoimmunity, chronic inflammation, metabolic deregulation and treatments seem to have an key role. They also discussed the latest controversies regarding the effects of anti-inflammatory therapies used in PsA and RA in the liver damage, such as biologics and DMARDs such as, leflunomide or methotrexate. Schwartz et al., also analyzed in a cohort of PsA patients, the associations of metabolic dysregulation and systemic inflammation with coronary artery disease (CAD) measuring traditional CVD risk factors, serum markers of metabolic dysfunction, inflammatory cytokines and inflammation in specific tissues by using positron emission tomography-computed tomography (PET-CT). They identified metabolic and inflammatory players associated with subclinical CAD in PsA, including inflammation in adipose tissue which might be considered as novel target for CVD prevention and treatment in PsA.In the case of inflammatory arthritis like rheumatoid arthritis (RA) and psoriatic arthritis (PsA), Gao et al., using mendelian randomization and genome-wide association study (GWAS). The analysis suggested a potential causal link between CVD and psoriasis.The association between Psoriasis and the risk of CVD was also explored by Lastly, two studies in this issue evaluated the CV involvement in rare systemic autoimmune disorders.Zhou et al., analyzed in anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody-positive dermatomyositis (DM)//clinically amyopathic dermatomyositis (anti-MDA5 Ab+ DM/CADM) the myocardial involvement. Anti-MDA5 dermatomyositis is a rare autoimmune disease, with high prevalence in Japanese patients with clinically amyopathic dermatomyositis and progressive interstitial lung disease. It also shows systemic manifestations affecting skeletal muscle, skin, and other organs.In a cohort of seventy-six hospitalized patients suffering this disorder, this study identified twelve patients with MI (16%), associated with severe cardiovascular complications and adverse evolution of the disease. They concluded that myocardial involvement is an independent poor prognostic factor of patients with anti-MDA5 Ab+ DM/CADM.Huang et al., investigated the efficacy of percutaneous transluminal pulmonary angioplasty (PTPA) in patients with Takayasu arteritis (TA) and pulmonary hypertension (PH) and pulmonary artery stenosis.Takayasu’s arteritis is a rare chronic inflammatory autoimmune condition that impact the largest blood vessels in the body (aorta) and its branches, the supra-aortic trunks.Results of this study, analyzing 183 lesions from 79 surgeries carried out on 32 patients with TA and PH, indicated that PTPA improved clinical symptoms, hemodynamic parameters, and exercise tolerance, in patients with TA pulmonary artery stenosis and PH. Furthermore, reperfusion pulmonary edema was significantly reduced, and no patient died of PTPA-related complications with guidance from the pressure wire.Overall, these findings might be important for healthcare resource planning and preventive approaches. These 9 articles substantial CV-risk observed in autoimmune diseases patients, suggests that strategies to reduce CV-risk should become a routine part of the management of autoimmune disease patients. However, the causes of cardiovascular involvement associated with systemic autoimmune diseases, and their potential therapy, require further research.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Organisms respond and adapt to the internal and external environmental changes through various cell signaling. The abnormal alteration of cell-signaling pathways could disrupt cell homeostasis and cause diseases . For insCell Signaling Status Alteration in Development and Disease, we collected studies providing new insights into the roles of cell signaling in development and disease occurrence and progression. A total of 5 articles, including two reviews, two original researches and one method article, were published in this Research Topic. We summarize and discuss the main findings of these studies in this editorial.Although cell signaling can be measured through development of sequencing technologies and the application of effective bioinformatic tools , many quAbreu de Oliveira et al.). Yang et al. comprehensively reviewed the role of cyclic GMP-AMP synthase (cGAS)—a stimulator of the interferon gene (STING) signaling pathway in various diseases, such as acute injury, pneumonopathy and kidney diseases, providing a theoretical basis for immunotherapy targeting the STING signal pathway . Ma et al. found that miR-654-5p overexpresses in activated human hepatic stellate cells and TGFβ-treated human hepatic LX-2 cells augmented liver fibrosis in mice that were intraperitoneally injected with CCl4 by targeting the RXRα receptor . Zhang et al. proposed a robust method to acquire finely resolved transcriptional programs with few cells from snap-frozen or RNAlater-treated clinical tissues that was sufficient enough to resolve even isoforms based on immunofluorescence-guided laser capture microdissection (immuno-LCM-RNAseq). With this method, the researchers were able to analyze transcriptional networks and signaling pathways during development, pathogenesis, and aging of specific cell types within native tissues . Lou et al. integrated both immune and hypoxia signaling to establish reliable prognostic signatures for lung adenocarcinoma (LUAD) across different omics data, and provided a robust prognosis predictor for the LUAD patients .Wnt signaling plays an important role in the mammary gland development and adult homeostasis in virtually all animal species. Willy et al. provided a systematic review on Wnt signaling involved in breast cancer and explored the impact of Wnt signaling alteration on the tumorigenesis and disease occurrence (The studies published in this Research Topic presented a diversity of intriguing and meaningful results covering a range of cell signals, which could facilitate our understanding of development and disease. We hope that this Research Topic will inspire researchers to systematically investigate development and disease progression from the perspective of cell signal in a systematic way.


Insights in Cardiovascular Therapeutics: 2021” has achieved great success and is attracting interest from the cardiovascular community. Here, we spotlight 12 studies published in our section that related to cell death and cardiovascular injuries, as well as some recent advances in the field that have tremendous potential in cardiovascular therapy. In addition, these highlights may serve as the foundation for some new developments in our Cardiovascular Therapeutics areas. In 2022, we will keep working to create a fantastic platform for cardiologists, translational cardiovascular scientists, and cardiovascular pharmacological scientists to share new results and data in clinical cardiology and translational cardiovascular therapeutics.With the effort and support of the authors, editorial office, and editorial team, the Frontiers in Cardiovascular Medicine, Cardiovascular Therapeutics Section-Research Topic “Wu et al., Liao et al., and Dash et al., atrial fibrillation reported by Lee et al. and Zheng Wang et al., refractory angina reported by Ambari et al., In-stent restenosis reported by Zhu et al., critical limb ischemia reported by Quiroz et al., protein conformational diseases reported by Zheng Song et al., mitochondrial dysfunction reported by Chen et al., and myocardial injury reported by Barbieri et al. and Cao et al.Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide. An estimated 17.9 million people live with CVDs each year with no effective cures –4. In thIn recent decades, new mechanisms that orchestrate various cell death pathways have been discovered, and this field continues to expand. The current well-established forms of cell death pathways include intrinsic or extrinsic apoptosis, necroptosis, pyroptosis, ferroptosis, mitochondrial permeability transition (MPT)-driven necrosis, autophagic cell death (autosis), lysosome-dependent cell death, immunogenic cell death , cellula5 myocytes  production  pathway and has initially discovered in response to viral infections. Following infection with a virus such as influenza A virus (IAV), a master regulator of PANoptosis, Z-DNA-binding protein 1 (ZBP1)  , 42, int1 (ZBP1) . It is b1 (ZBP1) , resulti1 (ZBP1) . PANopto1 (ZBP1) . AlthougWu et al., Zheng et al., Wang et al., Liao et al., Dash et al., Lee et al., Ambari et al., Zhu et al., Quiroz et al., Zheng Song et al., Chen et al., Barbieri et al., and Cao et al. on our Research Topic to illustrate the cutting-edge treatments for different cardiovascular diseases. Readers could use Medical experts and scientists have long searched for potential cardiac disease treatments and surviving and improving patients' lives. The Frontiers in Cardiovascular Medicine -Cardiovascular Therapeutics section has provided a platform for distinguished scientists to communicate, inspire, and seek more potential therapeutic solutions , 47. In KX carried out literature collections, research analyses, and drafted the manuscript. MK, JY, NS, SW, RV-P, and HW provided editing input. XY supervised and edited the manuscript. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.This work was supported by the National Institutes of Health Grants to XY , HW , JY (HL153599), MK (HL135177), and America Heart Association Award to KX (916828).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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Pogostemon cablin ameliorates ethanol-induced acute liver injury in rats via inhibition of oxidative stress and lipid accumulation’ by Qiong-Hui Huang et al., RSC Adv., 2018, 8, 24399–24410.Correction for ‘Patchouli oil isolated from the leaves of  The authors regret that Corrected Fig. 1 caption: GC-MS analysis of patchouli oil. Numbers indicated on peaks correspond to those in The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.


Mesenchymal stromal/stem cell (MSC) therapies are increasingly explored as novel regenerative and immunomodulatory approaches to treat or prevent diseases  is the only curative option available today for several hematological and non-hematological diseases. However, HSCT is associated with several early and late complications, such as low HSPC engraftment and impaired hematopoietic recovery, immune-mediated graft rejection, and GvHD in the case of allotransplantation : a potential game changer for the COVID-19 crisis,” to employ their immunomodulatory and regenerative properties for lung repair. In turn, Yang et al. from the “Center for Respiratory Medicine” at the China-Japan Friendship Hospital in Beijing, China, review “Therapeutic applications of MSCs in IPF.” The authors present an in-depth analysis of relevant factors for the optimization of MSC treatment, including the use of MSCs from different sources for lung repair, different administration routes, timing, dosing, frequency, and potential pretreatment of the clinical MSC products, to guide the design of future clinical research and to identify novel therapeutic options for these complex diseases.Due to the perivascular nature of MSCs surrounding and maintaining the integrity and function of blood vessels : a liver-derived MSC-like population with pro-regenerative properties.” These HLSCs were first described in 2006 as a new stem cell population obtained from the highly vascularized healthy human livers . The most studied MSC types were isolated from umbilical cord (UC-MSCs), adipose tissue (AT-MSCs) and bone marrow (BM-MSCs). The most studied diseases were wounds, ulcers, burns and psoriasis. Montero-Vilchez et al. report in their article “MSC-conditioned medium for skin diseases: a systematic review” that MSC-CCM improved wound healing, hair restoration, skin rejuvenation, atopic dermatitis, and psoriasis, in both animal models and humans, and decreased hypertrophic scars and flap ischemia in animal models, with further studies needed to standardize CCM manufacturing. In addition, Quiñones-Vico et al. reviewed “The role of exosomes derived from MSCs in dermatology” for both in vitro and in vivo models of different skin conditions.The skin is the largest organ of the human body and skin injuries can damage this important barrier. Three review articles were contributed to our topic from researchers at the “Andalusian Network of Design and Translation of Advanced Therapies” at “Virgen de las Nieves University Hospital” in Granada, Spain. These reviews give an excellent overview on the treatment of skin disease with “cell products”  and “cell-conditioned” media (CCM), as well as “MSC-derived exosomes” in dermatology. Khan et al. from “The Interdisciplinary Stem Cell Institute” at the University of Miami share their experiences in their article: “The Interdisciplinary Stem Cell Institute's Use of Food and Drug Administration-Expanded Access Guidelines to Provide Experimental Cell Therapy to Patients With Rare Serious Diseases.”In some cases, patients present a life-threatening condition or serious disease that requires the urgent access to investigational medical product . For those cases, the U.S. Food and Drug Administration (FDA) may authorize expanded access, to gain access to an investigational medical product for treatment outside of clinical trials. An in-depth understanding of the molecular mechanisms underlying MSCs' beneficial therapeutic effects in different clinical indications is essential to manufacture safe and effective therapies tailored to the individual patient need  and endothelial progenitor cells (EPCs) -MSC-derived EVs, thus suggesting that the EVs confer neuroprotection to the damaged hippocampus. De Luna et al. reviewed the role of “MSC-derived EVs as silver linings for cartilage regeneration.” Ghafouri-Fard et al. summarize “The emerging role of exosomes in the treatment of human disorders with a special focus on MSC-derived Exosomes.” Zhong et al. review “The emerging potential of exosomes on adipogenic differentiation MSCs”. Zhang J. et al. review the “Potential networks regulated by MSCs in acute-on-chronic liver failure (ACLF): exosomal miRNAs and intracellular target genes,” identifying beneficial effects of MSC-derived exosomes. Zhang Y. et al. investigated the therapeutic potential of exosomes derived from amniotic fluid stem cells in a rat model of skin wound repair. They found accelerated wound healing and improved regeneration of hair follicles, nerves, vessels, and increased proliferation of cutaneous cells, and more natural distribution of collagen during wound healing, while preventing excessive aggregation of myofibroblasts and the extracellular matrix. Lai et al. found that AT-MSC-derived exosomes decreased cardiomyocyte apoptosis and hypertrophy in the heart of mice with myocardial ischemia/reperfusion injury, concluding that they act as potent cardioprotectors.The production and release of EVs, including exosomes, from MSCs is perceived to be a major mediator of their therapeutic effects for several pathological conditions  influence the secretome of MSCs and their interaction with monocytes from stroke patients to promote the beneficial antiinflammatory effect of MSCs. In turn, Maisonneuve et al. shed light on how human dental pulp derived stromal cells (DPSCs) react toward interaction with Streptococcus mutans, which is involved in dental pulp necrosis and cardiovascular tissue infections. In response to infection, DPSCs adopted a proinflammatory profile, strengthening the establishment of the dental pulp inflammation.in vivo characterization and cell sorting, preconditioning of MSCs, cellular engineering and the use of structural supports/3D systems.Recent research efforts focus on strategies for further improving the therapeutic efficacy and safety of MSCs and their products, thus helping to achieve better treatment outcomes. These entail amongst others improved Valiuliene et al. from the “Life Sciences Center” at Vilnius University in Lithuania studied the “Metabolic profile and neurogenic potential of human amniotic fluid MSC-like stem cells from normal versus fetus-affected gestations.” The authors found some characteristic differences in surface markers, phosphorylation rate, ATP, ROS, and cytokine secretion between the two groups, which may indicate metabolic and phenotypic differences that need to be considered in their clinical use. Xie et al. from Sun Yat-sen University in Guangzhou, China, studied how “Cardiac-derived CD51-positive MSCs enhance cardiac repair through SCF-mediated angiogenesis in mice with myocardial infarction.” Most vascularized tissues contain resident MSCs, but there is no typical marker to identify resident cardiac MSCs, and the authors here identify CD51 as a novel marker for cardiac resident MSCs.Zhao et al. demonstrate that hypoxic culture preconditioning may constitute a promising strategy to enhance cellular viability and angiogenesis of transplanted AT-MSCs. Lucciola et al. have studied the “Impact of sustained TGF-β-receptor inhibition on chromatin accessibility and gene expression in culture human endometrial EM-MSCs.” The authors found that A83-01, a selective TGF-β-receptor inhibitor, promotes the expansion of EM-MSCs in culture by blocking differentiation and senescence, with in-depth analysis of the underlying gene networks and genome-wide chromatin changes. Bai et al. report how “Glycyrrhizic acid promotes osteogenic differentiation of human BM-MSCs by activating the Wnt/β-catenin signaling pathway,” thus indicating the potential of pharmacological pretreatment for improvements in bone repair. Preconditioning of MSCs also modifies the content and secretion of EVs. Peltzer et al. present that “IFN-γ and hypoxia priming have limited effect on the miRNA landscape of human MSC-derived EVs.” Li et al. found that “miRNA-27a-5p is abundant in small EVs derived from epimedium (EPI)-pre-conditioned BM-MSCs stimulate osteogenesis by targeting Atg4B-mediated autophagy.” Feng et al. reviewed the “Effect of melatonin for regulating MSCs and their EVs” in preclinical and clinical studies.An injured tissue constitutes an ischemic and hypoxic environment that damages the implanted therapeutic cells, leading to apoptosis and thus compromising their capacity in the early stages of cell transplantation. Garcia-Bernal et al. from Murcia in Spain studied how “Exofucosylation of AT-MSCs alters their secretome profile.” The authors found that the exofucosylation modification that improves MSC in vivo trafficking also improved their secretome to promote their antiinflammatory properties, which could be beneficial in treatment of autoimmune, inflammatory, and degenerative diseases. Pawitan et al. reviewed the “Enhancement of the therapeutic capacity of MSCs by genetic modification.” Of the 85 articles reviewed, 51 studies focused tumor/cancer/metastasis, while 34 studies focused on non-cancerous pathologies. In line, Han et al. studied how “Knockdown of POSTN inhibits osteogenic differentiation of MSCs from patients with steroid-induced osteonecrosis,” while Zhang W. et al. studied how “Upregulation of PARKIN accelerates osteoblastic differentiation of BM-MSCs and bone regeneration by enhancing autophagy and β-catenin signaling.”Lin et al. from “Tsing Hua University” in Taiwan demonstrate how “3D-spheroids of UC-MSC-derived Schwann Cells (SCs) promote peripheral nerve regeneration.” The authors used a well-defined non-genetic approach to phenotypically, epigenetically, and functionally convert UC-MSCs into SC-like cells that simulated sprouting of neurites from neuronal cells. To enhance their therapeutic effectiveness, the authors assembled the cells in 3D spheroids with a marked increase in their neurotropic, proangiogenic and anti-apoptotic profile. Marinaro et al. from Cáceres in Spain tested “Laparoscopy for the treatment of congenital hernia: Use of surgical meshes and MSCs in a clinically relevant animal model.” The authors combined laparoscopy and stem cells incorporated into a mesh by using a fibrin-sealant solution for the treatment of hernia in a swine model, with improved in vivo performance in the MSC containing group compared to cell-free mesh.Among the strategies to preserve MSC biological functions are those mimicking the natural habitat of MSCs during cell therapy. This multidisciplinary Research Topic has brought together specialists in Stem Cells, Immunology, Bioengineering, and Cellular Neuroscience, to share their knowledge on current therapeutic strategies and the mechanisms underlying the immune modulation and tissue regeneration that are orchestrated by MSCs. The different articles contained in this Research Topic reflect the great interest, knowledge and innovation in these fields. Here, we have given a summary on the latest clinical developments, efforts to refine the understanding on the MoA of MSC therapeutics, and introduced novel strategies to enhance the efficacy of MSCs and their derived products. Importantly, inflammation and the regulation thereof is an essential part of the healing and regenerative cascades in the human body. The modulation of inflammation is an important aspect of MSCs beneficial properties in the healing of tissue injury or suppression of tissue damage. The many studies contained in this Research Topic indicate that MSCs employ a host of mediators and mechanisms to achieve this goal, with great promise for clinical use.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.VC-G receives support of the Consejería de Transformación Económica, Industria, Conocimiento y Universidades co-funded by Fondos FEDER (PY20/00481), the Institute of Health Carlos III co-funded by Fondos FEDER (CP19/00046 and PI20/00341), the Fundación Científica de la Asociación Española Contra el Cáncer (IDEAS20051CAPI), and the Asociación Pablo Ugarte (+VIDA project). VH-P receives funding from the Spanish Ministry of Science, Innovation and Universities (PCI2018-093062) and the Valencian Council for Innovation, Universities Science and Digital Society (PROMETEO/2019/075). Contributions from GM were made possible by the German Research Foundation (DFG) and the German Federal Ministry of Education and Research (BMBF) through the BSRT (GSC203) and BCRT, respectively, and in part supported by the European Union's Horizon 2020 Research and Innovation Program (Horizon 2020 Framework Program) under the Grant Agreements No. 733006 (PACE) and No. 779293 (HIPGEN).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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The literature demonstrates that infections like Borrelia and Lyme, as well as other infections like group A beta-hemolytic streptococcal (GABHS), can cause an autoimmune reaction and associated antibodies target dopaminergic loci in the mesolimbic region of the brain, which interferes with brain function and potentially causes RDS-like symptoms/behaviors. The treatment of PANDAS remains controversial, especially since there have been limited efficacy studies to date. We propose an innovative potential treatment for PANDAS based on previous clinical trials using a pro-dopamine regulator known as KB220 variants. Our ongoing research suggests that achieving “dopamine homeostasis” by precision-guided DNA testing and pro-dopamine modulation could result in improved therapeutic outcomes.Pediatric autoimmune neuropsychiatric disorders associated with group A streptococcal infections (PANDAS) is a concept that is used to characterize a subset of children with neuropsychiatric symptoms, tic disorders, or obsessive-compulsive disorder (OCD), whose symptoms are exacerbated by group A streptococcal (GAS) infection. PANDAS has been known to cause a sudden onset of reward deficiency syndrome (RDS). RDS includes multiple disorders that are characterized by dopaminergic signaling dysfunction in the brain reward cascade (BRC), which may result in addiction, depression, avoidant behaviors, anxiety, tic disorders, and/or OCD. According to research by Blum  Th. Thi.e.,s of RDS .Group A beta-hemolytic streptococcal (GABHS) infections are thought to be the root cause of RDS and a variety of aggressive and depressive behaviors . CumulatThe original concept of PANDAS can be traced back to a clinical trial that was conducted at the National Institutes of Health (NIH) in the US . The nos2.It is currently believed that PANDAS is an autoimmune reaction that, in part, mimics rheumatic fever and differs from the etiological links associated with spectrum disorders  or RDS. As a result, rheumatic fever can be thought of as an autoimmune disorder caused by streptococcal infections in which antibodies affect the brain and induce neuropsychiatric conditions. In their article on Tourette’s Syndrome and OCD, Lombroso & Scahill introduced the idea of “molecular mimicry” as a potential explanation for PANDAS . Accordiet al. in 1998 ..et al. iet al. conducted a study involving 311 subjects  who self-reported neuropsychiatric symptoms and also had concurrent group A streptococcal infection status ..et al. a3.et al. came to the conclusion in 2018 that rigorously conducted research regarding treatments for PANDAS is scarce, and published studies have a significant risk of bias  and other anti-dopaminergic reward gene risk polymorphisms as measured by genetic risk assessment at the DNA level in compromised pre- and post-adolescence children with PANDAS/CANS. Our ongoing work posits a potential positive clinical outcome as a function of the induction of “dopamine homeostasis” with precision-guided DNA testing and pro-dopamine regulation .


SARS-CoV-2 spike protein comprises a conserved hydrophobic pocket that binds linoleic acid (LA). LA supplementation interferes with viral entry into the cell and replication, and thus could be used as an antiviral. The COVID-19 pandemic and concomitant lockdowns presented a global health challenge and triggered unprecedented research efforts to elucidate the molecular mechanisms and pathogenicity of SARS-CoV-2. The spike glycoprotein decorating the surface of SARS-CoV-2 virions is a prime target for vaccine development, antibody therapy and serology as it binds the host cell receptor and is central for viral cell entry. The electron cryo-microscopy structure of the spike protein revealed a hydrophobic pocket in the receptor-binding domain that is occupied by an essential fatty acid, linoleic acid (LA). The LA-bound spike protein adopts a non-infectious locked conformation which is more stable than the infectious form and shields important immunogenic epitopes. Here, the impact of LA binding on viral infectivity and replication, and the evolutionary conservation of the pocket in other highly pathogenic coronaviruses, including SARS-CoV-2 variants of concern (VOCs), are reviewed. The importance of LA metabolic products, the eicosanoids, in regulating the human immune response and inflammation is highlighted. Lipid and fatty-acid binding to a hydrophobic pocket in proteins on the virion surface appears to be a broader strategy employed by viruses, including picornaviruses and Zika virus. Ligand binding stabilizes their protein structure and assembly, and downregulates infectivity. In the case of rhinoviruses, this has been exploited to develop small-molecule antiviral drugs that bind to the hydrophobic pocket. The results suggest a COVID-19 antiviral treatment based on the LA-binding pocket. Spike makes the first contact with the receptor on the host cell, human angiotensin-converting enzyme 2 (ACE2), and mediates infection by virus–host cell membrane fusion . The furin-cleavage site in spike is key to the increased pathogenicity of SARS-CoV-2 . S2 comprises the membrane-fusion machinery, including the fusion peptide (FP), the fusion peptide-proximal region, heptad repeat (HP) 1, a central helix region (CH), HP2, a transmembrane anchor and a cytoplasmic C-terminal tail . The central helices of spike form a coiled-coil trimeric core. When spike interacts with ACE2, the S2 core and a second proteolytic site (S2′) become exposed  leading to an elongated coiled-coil structure formed by HP1, the central helix and HP2 which positions the N-terminal fusion peptide close to the host cell membrane . In the closed conformation of spike the RBDs are all ‘down’, resulting in threefold symmetry. Importantly, the closed conformation of spike is considered to be a non-infectious form because the RBM is inaccessible. ACE2 interacts with spike in open states with one, two or all three RBDs pointing ‘up’ , and it has been suggested that ACE2 interaction enhances the opening of the RBDs  of the RBD is accessible Fig. 1b. In thp’ Fig. 1b, and i2.et al., 2016et al., 2016et al., 2020et al., 2006et al., 2020et al., 2021et al., 2021et al., 2020et al., 2020C3-symmetrized structure reached a resolution of 2.85 Å. Surprisingly, the RBDs moved closer to each other compared with available atomic models. In a pocket of the RBD, additional tube-shaped density was identified which could not be attributed to protein  and LC-MS-MS, the ligand in the RBD was confirmed to be LA  in mammalian cells and stabilization of the spike trimer by a trimerization domain . Notably, the RBM is completely structured, which is not the case in the LA-free closed conformation, where regions including the RBM were disordered. In the presence of LA, the RBM is tucked away between the RBDs and is inaccessible for ACE2 binding , resulting in increased release of LA from the membranes and increased intracellular LA concentration , including LA. The media used for insect-cell culture contain FFAs as additives, thus mimicking the host environment. Secondly, the transfection of a plasmid encoding spike protein into mammalian cells does not faithfully recapitulate SARS-CoV-2 viral infection. The latter causes extensive membrane and lipidome remodelling and cPLA2.1.et al., 2020et al., 2022et al., 2022et al., 2017et al., 2022et al., 2019et al., 2022et al., 2021Sequence alignments of spike proteins of the other human betacoronaviruses SARS-CoV, MERS-CoV, HKU1-hCoV and OC43-hCoV indicated that the hydrophobic pocket in the RBD (named the B domain in HKU1-hCoV and OC43-hCoV) is conserved  application of the force resulted in an opening of the closed spike in the absence of LA. In contrast, only 14% of the LA-bound spikes opened on the application of the same force. This demonstrates that LA binding stabilizes the locked state of spike, increasing the energy required to raise a single RBD and reach an open conformation  simulations were performed to assess the relative stability of the closed and LA-bound locked spike proteins  which coordinates the carboxy headgroup of LA  spike was found to contain a lysine-to-asparagine mutation (K417N) leading to loss of a positive charge at the RBD–RBD interface. This may affect the intersubunit LA–RBD interaction and weaken the stabilization effect of LA in this VOC spike , significantly reduced attachment to human cells was observed compared with mini-virions with apo spike devoid of LA. Importantly, saturated fatty acids such as palmitic acid (PA) did not show this inhibitory effect, and the mini-virions bound with similar efficiency as mini-virions with apo spike , an enzyme target for antiviral drug development  in a negative-feedback mechanism  of SARS-CoV-2 spike (Wuhan) has been shown to bind the heme metabolites bilirubin and biliverdin . Receptor binding to the canyon displaces a hydrophobic ‘pocket factor’ from a pocket in VP1 below the canyon . This ‘pocket factor’ in the VP1 pocket has been suggested to stabilize picornavirus assembly. Receptor recognition and concomitant loss of the ‘pocket factor’ destabilizes the capsid and helps to release the picornavirus RNA genome during infection  and vitamin A were shown to have antiviral activity against SARS-CoV-2. A recent cryo-EM structure reveals that ATRA indeed binds to the hydrophobic pocket of SARS-CoV-2 spike protein . Importantly, ATRA inhibits the entry of SARS-CoV and MERS-CoV pseudoviruses into human cells, confirming the conservation of the hydrophobic pocket  by desaturation and elongation (Hanna & Hafez, 2018M (Richieri & Kleinfeld, 1995M in a so-called fatty acid–lipid storm (Yan et al., 2019et al., 2021et al., 2022et al., 2022et al., 2020et al., 2021et al., 20202s releasing long-chain PUFAs from host cell membranes has been implicated in severe COVID-19 (Barberis et al., 2020et al., 2021et al., 2020et al., 2020Under physiological conditions, the levels of unsaturated FFA are maintained below 0.1 µ2 activation and lipid metabolome remodelling, which are both common elements of viral infection (Goodwin et al., 2015et al., 2019et al., 2019et al., 2015et al., 2015et al., 2020et al., 2020et al., 2001The dysregulation of FFA levels during COVID-19 is suggested to result from cPLA4.2 and lipid remodelling, allowing the formation of viral replication compartments. LA release from the membranes contributes to the later-stage fatty acid–lipid storm caused by pro-inflammatory eicosanoids. Release of PUFAs, including LA, from the membrane by cPLA2 changes the fluidity of the cellular membranes and contributes to pulmonary and cardiovascular disease. Taken together, this suggests that early-stage supplementation of LA, i.e. while the viral infection is localized in the upper airways, may be beneficial to interfere early with SARS-CoV-2 infection, replication and viral transmission. Current insights into the mechanism of SARS-CoV-2 infection further provide a rationale for the development of intranasal, pulmonary or oropharyngeal drug-delivery systems for self-administration, targeting mucosal epithelial cells with high ACE2 concentration. Given worldwide persisting SARS-CoV-2 infections and the conservation of the pocket in spike protein, LA delivery could present a novel and sustainable strategy for early COVID-19 treatment and prophylaxis.LA binding to an evolutionarily conserved hydrophobic pocket of the RBD of SARS-CoV-2 spike protein was discovered in the spike cryo-EM structure and substantiated by LC-MS-MS. LA impacts viral infection and disease progression by several mechanisms. LA stabilizes spike protein in a non-infectious locked conformation, avoiding premature S2′ cleavage and dissociation of the S1 subunit of spike. Important immunogenic epitopes in the RBD of spike, including the RBM, evade immune recognition in the LA-stabilized locked conformation. In the human host cell, LA binding to spike and viral membranes contributes to hyperactivation of cPLA


Prediction and Explanation in Biomedicine using Network-Based Approaches” putting together “prediction”  and “explanation” . Scientific methodology is aware of the different, albeit related, status of the two perspectives since long time , gene expression correlation  and protein-protein interaction networks . In particular, Uversky and Giuliani review the most recent results in terms of hierarchical organization of complex biological systems, remarking the benefits of analyzing such systems in a multi-level fashion, hence going beyond the standard causative model where events originate at molecular level and then show up at the ‘top’ of the hierarchy . Causality is also the key in , where the authors review how causality can help in shaping disease networks, shedding light on using also functional information alongside physical proximity  for a thoughtful modelling. In Tran et al., the authors question the suitability of MCF-7 cell line for in vitro breast cancer research. They use a network-based approach to compare two MCF-7 datasets against a human breast invasive ductal carcinoma dataset taken from The Cancer Genome Atlas (TGCA), showing how they have only minimal similarity in biological processes, hence concluding that using MCF-7 to study breast cancer can hide important gene targets. Finally, TGCA plays an important role also in , where the authors use a network-based approach to find hub genes related to acute lymphoblastic leukemia.Biological systems are the most evident paradigm of complexity, and this is why it is much more productive to focus on the dynamics of their correlation structure with respect to an in-depth analysis of isolated features. In this Research Topic, this point is made evident by papers exploring correlation structures located at different organization layers: contacts between amino-acid residues of a protein molecule  motivated by the solution of relevant biomedical problems. Specifically, Kuznetsov et al. use a variational autoencoder to generate a synthetic 1-cycle ECG which not only looks quite natural, but can also be generated starting from just 25 features automatically learned by the autoencoder. As instead, Nazarenko et al. show an interesting network-based approach based on parenclitic and synolytic networks to describe multidimensional data via a suitable graph that makes the data easier to inspect, visualize and analyze. Tests on synthetic and benchmark data corroborate the competitiveness of using parenclitic and synolytic networks against common machine learning approaches.It is important not to confuse the integration of data analysis and explanatory perspectives with the too-often repeated statement of the substantial irrelevance of the hypothesis-driven approach when in presence of massive amount of data ; the sitChen et al.; Jung et al.; Luo et al.; Thomas et al.), that give us the strong impression that network-based approaches are here to stay. In detail, Thomas et al. review how network biology can help in understanding inflammatory bowel disease by discussing different network modelling , with some examples also on multi-layered networks. Chen et al. build a predictive model based on network analysis and circular miRNA to address recurrent implantation failure (RIF). Luo et al. also aim at characterizing RIF, but the authors exploit network-based approaches (protein-protein interaction and circRNA–miRNA–mRNA networks) to highlight four hub genes that may be involved in the development of RIF. Finally, Jung et al. briefly review computational models based on machine learning, network modelling and genome-scale metabolic models to characterize drug-resistant cancer cells.In this Research Topic, the application potential to biomedical practice of network-based approaches is explored in (After all, this is not surprising at all, “network biology” is nothing else than “biology as such” given any biological system derives its peculiar behaviour from the interaction of many different element players at different organization layers with no privileged causal layer of explanation . This is