More than 50 million individuals worldwide suffer from dementia with ~60–70% affected by Alzheimer's disease (AD). As a progressive and neurodegenerative disorder and the leading cause of dementia in the elderly, AD lacks effective treatments to modify or stop disease progression. Over the past years, studies have identified new molecular mechanisms and modifiable risk factors of AD. Accumulating data suggest that advancing the understanding of AD mechanisms and risk factors may allow the development of targeted interventions to potentially prevent or cure the disease. There are an increasing number of preclinical studies focusing on mechanism-driven therapies, which need to be further characterized before introducing into clinical trials to determine their efficacy.Progress of Translational Medicine in Alzheimer's Disease” in Frontiers in Aging Neuroscience includes a series of 13 articles that discuss recent advances in the field of translational studies in AD and highlight current challenges and outstanding questions requiring further study in order to advance research in this domain. These articles are discussed based on two main specific themes, noted below.Here, the Research Topic “Xing et al. have completed a meta-analysis, combing through discoveries which describe the diagnostic values of exosome-derived biomarkers in AD and MCI (Mild Cognitive Impairment). The meta-analysis includes 19 eligible studies involving 3,742 subjects and supports the potential diagnostic value of exosome-derived biomarkers in AD and MCI, and lays a foundation for future research to further confirm this finding.Emerging evidence has shown that exosome-derived biomarkers are potentially related to early occurrence and development of AD, which requires a consolidated analysis. Vogrinc et al. summarize more than 100 AD risk loci, with many of them potentially serving as biomarkers of AD progression, even in the preclinical stage of the disease. Furthermore, the analysis of GWAS data has led to identification of key pathways underlying AD pathogenesis, including cellular and metabolic processes, biological regulation, localization, transport, regulation of cellular activities, and neurological system processes. Thus, gene clustering into molecular pathways may help identify novel molecular targets and support the development of more tailored and personalized intervention of AD.Over the past decade, numerous genome-wide association studies (GWAS) have identified significant genes associated with increased risk of AD, for which a systemic review to identify potential molecular mechanisms was overdue. In a review article, Homann et al. conduct an analysis of GWAS on AD brain imaging biomarkers and neuropsychological phenotypes using the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery Dataset (EMIF-AD MBD). Their results highlight the power of using quantitative end phenotypes as outcome traits in AD-related GWAS analyses and nominates new loci underlying cognitive decline.Next, Shi et al. investigate plasma proteomic biomarkers associated with AD through a meta-analysis. The study assesses the diagnostic performance of their own group's previously identified blood biomarkers, and identifies proteins significantly associated with AD, including alpha-2-macroglobulin (A2M), ficolin-2 (FCN2) and fibrinogen gamma chain (FGG).Although plasma biomarkers for the diagnosis and stratification of AD have been intensively analyzed, no plasma markers have so far been well-established and confirmed for AD diagnosis. To this end, Logan et al. explore convolutional neural networks (CNN), a class of deep learning algorithms, for classifying multi-modal neuroimaging data such as magnetic resonance imaging (MRI) and positron emission tomography (PET). These networks may successfully enable early detection of AD and provide insight into AD classification using 3D architectures for multi-modal PET/MRI data.Presently, another challenging barrier to understanding AD and related dementias is availbility of suitable artificial intelligence (AI) methodologies for analyzing massive AD datasets. In a comprehensive review, Wu et al. summarize recent findings involving altered gut microbiota of patients with AD, and discuss pathogenetic mechanisms of gut microbiota in AD, suggesting gut microbiota–targeted therapies for AD.Recently, increasing evidence has suggested the involvement of gut microbiota dysbiosis in association with AD. In a through review, Mee Hayes et al. discusses recent progress and potential mechanisms for targeting aggregates with proteasomes and disaggregases in liquid droplets.Despite the long-standing and established findings supporting insoluble protein deposition as pathological hallmarks of AD and other neurodegenerative disorders, studying the reverse process of aggregate disassembly and degradation has only recently gained momentum, following reports of enzymes with distinct aggregate-disassembly activities. A timely review by Stonebarger et al. present an article challenging a major obstacle in understanding the etiology of normative and pathological aged brains in AD—the availability of suitable animal models. This article highlights our current knowledge in the area and examines the use of the rhesus macaque monkey as a pragmatic translational animal model to progress future research in this area.Furthermore, Morgan et al. have performed text-mining and generated an exhaustive, systematic assessment of the breadth and diversity of biological pathways within a corpus of 206,324 dementia publication abstracts. The results of this research may be applicable to the context of the broader AD literature corpus.The issues surrounding the large number of poorly understood underlying functional mechanisms is a major stumbling block in AD research today. Blevins et al. present a review article looking into the AD-related NLRP3 inflammasome, a multiprotein complex that plays a common and pivotal role in regulating innate immunity and inflammation underlying human pathophysiology.Finally, Zhong et al. focusing on D-penicillamine (D-Pen), a water-soluble metal chelator that can reduce Aβ aggregation. The authors report that D-Pen significantly improves the cognitive functions of APP/PS1 mice and reduces Aβ generation with an associated increase in ADAM10 via the non-amyloidogenic processing pathway.The first article that addresses potential therapies for AD is a study by Ma et al. present the results of their study describing the effects and molecular mechanisms of cornel iridoid glycoside (CIG), an active ingredient of the traditional Chinese herb Cornus officinalis, in pathological tau P301S transgenic mice. The data support CIG as a promising molecule for potentially treating AD-related tauopathy.Next, Carranza-Naval et al. analyze liraglutide (LRGT), a glucagon-like peptide-1 agonist, for its effects on reducing pathological changes in the brain of a mixed murine model of AD and T2D (APP/PS1 x db/db mice). These results support the potential for LRGT therapy to reduce AD-associated brain complications.Because type 2 diabetes (T2D) is a major contributor to the development of AD and AD patients with co-occurrence of T2D are regularly observed in the clinical arena, In closing, we would like to thank all the contributing authors and reviewers for their valuable expertise and effort toward successfully compiling this series of research focusing on translational medicine for AD. We realize that although these selected articles cover a good number of studies reporting up to date research findings, future studies will be necessary to better understand the “elephant in the room:” the etiology of AD, which is our primary goal in developing this Research Topic. We sincerely hope that this Research Topic of articles will provide a useful point of reference and stimulate future studies committed to ultimately understanding the complex pathogenesis of AD and advancing the development of useful therapeutics for AD.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.EF has CRADA arrangement with ChromaDex and is consultant to Aladdin Healthcare Technologies, Vancouver Dementia Prevention Center, and Intellectual Labs. The remaining 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.


Formulations from nanotechnology platform promote therapeutic drug delivery and offer various advantages such as biocompatibility, non-inflammatory effects, high therapeutic output, biodegradability, non-toxicity, and biocompatibility in comparison with free drug delivery. Due to inherent shortcomings of conventional drug delivery to cancerous tissues, alternative nanotechnological-based approaches have been developed for such ailments. Ovarian cancer is the leading gynecological cancer with higher mortality rates due to its reoccurrence and late diagnosis. In recent years, the field of medical nanotechnology has witnessed significant progress in addressing existing problems and improving the diagnosis and therapy of various diseases including cancer. Nevertheless, the literature and current reviews on nanotechnology are mainly focused on its applications in other cancers or diseases. In this review, we focused on the nanoscale drug delivery systems for ovarian cancer targeted therapy and diagnosis, and different nanocarriers systems including dendrimers, nanoparticles, liposomes, nanocapsules, and nanomicelles for ovarian cancer have been discussed. In comparison to non-functionalized counterparts of nanoformulations, the therapeutic potential and preferential targeting of ovarian cancer through ligand functionalized nanoformulations’ development has been reviewed. Furthermore, numerous biomarkers such as prostatic, mucin 1, CA-125, apoptosis repeat baculoviral inhibitor-5, human epididymis protein-4, and e-cadherin have been identified and elucidated in this review for the assessment of ovarian cancer. Nanomaterial biosensor-based tumor markers and their various types for ovarian cancer diagnosis are explained in this article. In association, different nanocarrier approaches for the ovarian cancer therapy have also been underpinned. To ensure ovarian cancer control and efficient detection, there is an urgent need for faster and less costly medical tools in the arena of oncology. Then extracellular matrix gets degrade and the dissociation of cells takes place from primary cancer. The dissociated cells become abdominal free-floating cells or clumps together that forms multicellular aggregates.In the context of patient survival, chemotherapy and radiation therapy is under clinical trials to evaluate the ovarian cancer initial stage and approach the benefits of survival (Boevé et al., In the early phase ovarian cancer detection, the current treatment and diagnostic methods are not enough efficient and sensitive as well. Furthermore, delayed diagnosis has been observed as a virtue of non-specified detection and high costs of the applied methods. Recently, nanotechnology is emerged as a growing field in the treatment and diagnosis of ovarian cancer that offers the development of novel and potential strategies to overcome ovarian cancer (Zhou et al., Liposomes exhibit a lipid bilayer that holding hydrophobic interface that enables the attachment of therapeutic and diagnostic agents of both hydrophilic and hydrophobic nature to the geometry of liposomes. The core region of dendrimers is closer to the hydrophobic component and hydrophilic termini that helps in the delivery of hydrophobic payloads within water insoluble domain. On another hand chemical conjugation of moieties with the exterior is take place for its delivery. Adsorption of carbon nanotubes to various agents is take place for consecutive delivery. Micelle provides delivery platform for hydrophobic anticancer drugs with prolong circulation.2.In recent years, ovarian cancer is globally classified as deadly gynecological cancer (Boitano et al., Biomarkers manifest versatile class of biomolecules that indicates a specific disorder or biological function Ueland, . In the 2.1.Optical biosensor utilizes an optical transducer system with sensing features that are used for analysis purposes. It senses and transmits those signals that are directly proportional to the biomarker . These bTo improve the surface glycosylation visibility of sample cells an accelerating technique was used that showed efficient results. During the technique the MUC1 precise glycosylation on the cancer cell surface was pictured through a quantum dots label using the strategy of RMC magnification. This study offers a sort of suggested scheme for protein-specific glycosylation and thus indicates the mentioned technique as a feasible strategy (Yang et al., 2.2.Electrochemical nanosensors have shown potential methodology and role for the precise detection of biomarkers in ovarian cancer and usually have the detection power in minute quantities of biomarkers and other analytes (Parmin et al., Another research group worked on the CA-125, biomarker identification through the development of immuno-based electrochemical nanosensor. The developed nanosensor was composed of multiwall carbon nanotubes, gold nanoparticles and 3D reduced graphene oxide composite. The developed system displayed an excellent detection limit i.e. 6 µU/mL .2.3.Micro fluidic laboratory-on-chip nanosensor integrates easily the various features of multiple sensing systems with less sampling rate and thus pose it a versatile miniaturized system (Jamshaid et al., 2.4.Within a portable system, it is the unique feature of giant magnetoresistive biosensors that it measures multiple biomarkers all together. In addition, other advantages include integrated circuit connectivity, high accuracy and easy biomolecular detection (Xuan et al., 3.In the recent years, many nanoconjugates and nanoformulations as a drug delivery system have been developed and they have improved the therapeutic drug delivery to the target side due to unique features such as biocompatibility, high therapeutic efficacy as compared to free drug, non-toxicity, biodegradability, off-target side effects and ease of manufacturing scale-up (Larrañeta et al., 3.1.Liposomes are nontoxic phospholipids-based sphere-shaped small vesicle ranges in size from 400 nm to 2.5 mm. Liposomes are extensively employed renowned clinically delivered nanosystems with biodegradable nature and have the capability to entrap hydrophobic and hydrophilic biomacromolecules, i.e. RNAs, peptides and proteins without modification in their inherent properties (Sun et al., The co-loading of two chemotherapy agents into a single liposome in clinical trials has shown many advantages but the loading of two chemotherapeutic drugs into a single liposome is quite challenging. In this context, irinotecan and doxorubicin were encapsulated and loaded into liposomal nanoformulations to treat ovarian cancer xenograft. Various ratios between drugs to the drug were used during loading into the liposome. The encapsulation efficiency was 80%, and it was found that after storage for 6 months the liposomal stability attributes significantly influenced the drug encapsulation. After the administration of developed nanosystem via intraperitoneal route considerably enhanced the survival of the animals with tumor, which was attributed to increased exposure of liposomal nanoformulations to the systemic circulation (Shaikh et al., 3.2.Several nano-sized drug delivery systems have been tested in cancer treatment to reduce the side effects of traditional anticancer drugs while increasing the antitumor efficacy of target therapy (Mohammadzadeh et al., In addition to metal nanoparticles, biomacromolecules such as vitamins, nutrients, hydrophobic drugs and phenolic compounds were immensely delivered to multifaceted biological systems using chitosan nanoparticles. Chitosan-a chitin-deacylated biopolymer of natural origin that exhibit useful features such as inertness, biodegradability, biocompatibility and the presence of hydroxyl and amino group that make it a suitable candidate for the drug delivery (Muddineti et al., In another research study, cannabidiol-loaded polymeric nanoparticles were developed and evaluated in ovarian cancer cell for growth inhibition potential. The encapsulation efficiency found was 95% with 240 nm size nanoparticles and displayed controlled release kinetics for cannabidiol after internalization to SKOV-3 ovarian cancer cells for an extended period of 96 hours. After encapsulation, the antiproliferative effect of cannabidiol was found excellent against the SKOV-3 cells. Apoptosis was also induced by the applied drug-loaded nanosystem that was confirmed when PARP protein was found provoked. Importantly, the ovarian tumor growth inhibition was slightly higher for cannabidiol-loaded nanoparticle as compared to free cannabidiol (Fraguas-Sánchez et al., In the arena of ovarian cancer targeted drug delivery epigallocatechin gallate-loaded chitosan base mesoporous silica nanoparticles were developed and evaluated. Furthermore, the fabricated system was attached with AS1411 aptamer through conjugation with the amine group present in the chitosan using electrostatic attraction. The aptamer functionalized nanosystem followed macro-pinocytosis and displayed efficient internalization potential in SKOV-3 cell lines. Consequently, it resulted in an augmented cytotoxic effect in 93% of ovarian cancer cells along with G1 cell cycle arrest and down-regulation of ERK2 expression level (Alizadeh et al., 3.3.Solid-lipid nanoparticles are made up of surfactants, lipids and therapeutic drugs enclosed in spherical shape colloidal nanocarriers exhibiting 50–1000 nm diameters. The lipid core and nano size range of solid-lipid nanoparticles make them versatile drug delivery carriers from nanotechnology platforms. Such nanocarriers have attained greater interest also due to their considerable biocompatibility, excellent circulation time and marked accumulation at the target site (Radhakrishnan et al., 3.4.l-buthionine sulfoximine—a γ-glutamylcysteine ligase inhibitor, the glutathione synthesis was hampered significantly. Systemic toxicity consideration in this context helped in overcoming the issue of carboplatin resistance by using polyurea-based dendrimer formulations (Cruz et al., Dendrimers are spherical nano size, regularly branched, three-dimensional tree-like architectures of high molecular weight in which the branch lengths are stearic limited exhibiting an inner core. The inner microenvironment and surface of dendrimers are composed of functional moieties that help in the attachment of delivering cargoes (Mishra et al., 3.5.Among nanostructured materials micelles represent an intriguing class of nanoarchitecture in which amphiphilic molecules above critical micelle concentration aggregates to form such a versatile class of nanocarriers (Karayianni & Pispas, 3.6.Nanocapsules manifest a nanoscale vesicular system that is composed of central cavity that gives space to the drugs of interest. In addition, an outer polymeric shell is also there surrounding inner core and it helps in the attachment of various targeting ligands and moieties during surface functionalization (Li et al., A summary of various nanosystems is provided in 4.The knowledge and research on nanotechnology-based formulations has bloomed in recent years, however, only few formulations have made their way successfully to clinics. Most of such formulations fail to demonstrate similar results when tested in vivo and halt their progress to clinical trials. For clinical translation, every nanoformulation has particular challenges, however, most of them confront biological, technological, and study-design-related challenges.Biological challenges include lack of routes of administration, tempering biodistribution, hannelling nanosystems across biological barriers, toxicity and degradation (Lv et al., Controlling nanoparticle’s biological fate is difficult and requires focus. There is a possibility of liver, lung, and kidney damage, despite the fact that nanoparticles are made of biosafety materials. Surface area, shape, solubility, particle size and agglomeration are the factors that are reported to cause toxicity (Jia et al., Technological challenges of nanosystems include equal optimization, performance predictions and scale-up synthesis. Most nanoparticles used are produced in small batches, and scaling up is not always possible due to instrumentation and other factors. In animal models, the best lead clinical candidates are not always systematically designed and optimized. To circumvent this, we can employ specific methods that permit the testing of numerous nanoformulation and the selection of a single optimized formulation via selective iterations (Dobrovolskaia et al., N = 1 clinical studies will be needed for personalized medicine. This includes genetic, environmental, and medical history factors (Love et al., Study-design challenges such as study size, intent, and timing of nanoparticle therapies during therapy have a significant impact on clinical studies. The majority of research is based on “cell and animal models,” which may not translate to human trials. Therefore, it is challenging to mimic natural human body reactions using a single model. Metastasis is an important attribute of cancer, so “models of cancer metastasis” should be researched. Nanotechnology enables personalized oncology, in which cancer therapy and diagnosis are tailored to each patient’s tumor molecular profile, and predictive oncology, in which genetic and/or molecular markers predict development and progression of disease and clinical outcomes. The National Cancer Institute in the US has recently allocated funds to eight national Centers of Cancer Nanotechnology Excellence due to its potential impact on cancer research (Misra et al., 5.The precise delivery of therapeutic cargoes into ovarian tumor cells through novel engineered carriers from nano scaffolds has been widely explored in recent years. In the diagnosis and treatment of ovarian cancer, the chemotherapeutic drugs’ adverse effects were significantly curtailed, the site-specific delivery was augmented and solubility issue of hydrophobic cargoes was resolved using numerous nanotechnology-based carrier systems. In ovarian cancer, nanotechnology from nanoscience domain addresses the site-specific delivery and provides new-enhanced and targeted therapy possibilities. Several formulations show interesting results but only a few will make their way to clinical trials and clinics because the progress of most of them is halted in pre-clinical stages due to a number of factors. Regarding clinical translation, each nanoformulation has particular challenges related to either biological, study-design, or technology related. In addition, the toxicity, biotransformation and excretion of nanocarriers-based systems for ovarian cancer will also be a challenging aspect. Therefore, in the design stages, such considerations should be kept in mind for developing biocompatible and nontoxic carrier systems. Numerous nanotechnology-based biosensors have been proposed and tested in recent years for the diagnosis of ovarian cancer. The associated concerns with ovarian cancer diagnosis and treatment could be resolved through these nanomaterials based biosensors due to their high sensitivity and selectivity. However, the development of nanosensors is a time-consuming and complex process and thus often fails in the critical evaluation of biomarkers. Importantly, in the identification of ovarian cancer biomarkers, the demand of portable nanosensors that could be used to rescue subjects outside the clinical settings is of much value. In the scenario of ovarian cancer diagnosis, microfluidic and paper-based nanosensors fabrication offers feasible prospect for biosensors’ commercialization. In a nutshell, in the near future thrilling developments are required for sensing procedure scale-down using nanotechnology platform that hopefully would enable the patients to check their health easily and indeed would open new avenues in the diagnosis and treatment of ovarian cancer.


Dementia-related continuing education opportunities are important for rural primary health care (PHC) professionals given scarce specialized resources. This report explores the initial perceptions and continuing education needs of rural interprofessional memory clinic team members and other PHC professionals related to a short series of dementia-related education webinars. Three webinars on separate topics were delivered over an 8-month period in 2020 in Saskatchewan, Canada. The research design involved analysis of webinar comments and post-webinar survey data. Sixty-eight individuals participated in at least one webinar, and 46 surveys were completed. Rural memory clinic team members accounted for a minority of webinar participants and a majority of survey respondents. Initial perceptions were positive, with webinar topics and interactivity identified as the most effective aspects. Continuing education needs were mainly aligned with professional roles; however, some overlap of interests occurred. Future webinars will further explore learning needs within an interprofessional environment. Meant tet al., et al., et al., et al., et al., IPE in primary care that promotes interaction and learning between different professional groups is important for strengthening collaboration skills and behaviours and fostering collaboration within teams  team members and the developer (DS) of the Primary Care Dementia Assessment and Treatment Algorithm (PC-DATA™), which has been adapted and integrated into the clinic model. Prior to 2020, continuing education was offered periodically to one team at a time, delivered by clinical specialists and other experts via telehealth videoconference. Teams suggested topics in which they were keen to receive further training, which included differential diagnosis, capacity and competency, medication for dementia, and driving assessment. More teams were invited to take part in the sessions as the model spread to other communities. In a recent process evaluation, teams indicated participation in training and continuing education improved self-confidence in abilities and supported implementation of memory clinics (Morgan 1). Each webinar began with a 30–45 minute presentation followed by 30–45 minutes of discussion. Team members had the flexibility to join remotely with their chosen device since they often travel between settings and communities. During the webinars, the presenter’s camera and audio were live and participants could offer written or oral comments at any time; however, participant’s cameras were turned off.In February 2020, the researchers introduced a cross-team dementia-related continuing education series delivered via WebEx. Three webinars were delivered in 2020 on topics suggested by the teams and are included in this analysis .2). Six Likert items and two open-ended questions were adapted from previous evaluations of dementia-related continuing education sessions for health professionals . Regarding webinar content, the majority agreed the sessions were appropriate for their professional needs and new information was learned (96%). Most found the interactive format and webinar environment effective for learning (96%). A majority also intended to apply the information in their practice and appreciated the participation of other PHC teams and professionals; however, these particular items were endorsed by fewer participants (<90%).Among survey respondents across the webinars, overall satisfaction was high (94%)  (data not shown in table). Regarding the first two webinars which were more medication-focused than the third session, some AHPs found themselves engaged although they were not in a prescribing role and did not feel highly knowledgeable about the topic . Illustrative quotations of themes are provided in Supplemental Table This study explored the perceptions and continuing education needs of rural memory clinic team members and other PHC professionals participating in interprofessional dementia-focused webinars. Findings from post-webinar survey evaluations indicated positive initial perceptions of webinar content and format, and education suggestions that mainly corresponded to professional roles.et al., et al., et al., et al., et al., Our findings are consistent with research showing rural health professionals react positively to dementia care learning opportunities delivered remotely . To help improve management capacity, the rural memory clinic model and other task-sharing approaches collaborate with highly qualified and experienced dementia specialists to further train and support PHC professionals (Canadian Academy of Health Sciences, et al., et al., et al., Suggestions by survey respondents for future education topics generally aligned with professional roles. The mutual interest of AHPs and FP/NPs in pharmacological and non-pharmacological management, and emphasis by FP/NPs on management interventions, underscores the challenge of these issues in primary care. Interest in medication-related topics is consistent with recent research showing potentially inappropriate prescribing is associated with higher levels of comorbidity among people living with dementia (Delgado Limitations of this study should be considered. Survey items focused only on a few selected perceptions of webinar content and format. Other measures of content and format, and other domains, may have been pertinent to participant experience but were not included. Survey participation was voluntary; therefore, the results are subject to non-response bias. Respondents may also have tended to agree rather than disagree with statements, reflecting acquiescence bias. Furthermore, the initial findings from a small sample of professionals from one geographic area limit the generalizability of the findings.There have been few published studies of initiatives that offer dementia-related continuing education in an interprofessional setting to PHC professionals. Initial results from this study indicate favourable feedback from rural participants of a short series of interprofessional dementia-related education webinars. The findings also revealed opportunities to seek further input on varying education needs within teams, to inform future webinars and research.


For patients with a variety of severe diseases, including primarily hematopoietic malignancies, immunodeficiency syndromes, and genetic disorders, allogeneic hematopoietic stem cell transplantation (aHSCT) represents a potentially curative therapeutic approach. In this context, despite significant progress in the optimization of aHSCT, the development of graft-versus-host disease (GVHD) remains a challenge to long-term transplant success after aHSCT. It is associated with significant morbidity and mortality and is the major cause of non-relapse mortality.GVHD occurs when donor T cells are primed by recipient antigens subsequently eliciting an inflammatory response against the host. Clinically, two types of GVHD are distinguishable: an acute form (aGVHD), and a chronic form (cGVHD). In brief, the main characteristics: aGVHD occurs in 30-50% of aHSCTs and is a multi-organ disorder resulting from inflammatory cytokines and donor T cells which primarily damage skin, liver, gastrointestinal tract, and eye. cGVHD, with a prevalence of 30-70% of aHSCTs, is induced by T and B cells resulting in a heterogeneous immunological complication affecting virtually every organ.Traditionally, broad immune-suppressive drugs (with considerable toxicities) including calcineurin inhibitors (CNI) (cyclosporin or tacrolimus), together with methotrexate or mycophenolate mofetil (MMF), and mTOR inhibitors (Sirolimus/Rapamycin) are used as GVHD prophylaxis. But despite first success reports, significant GVHD still occurs with these drugs. Other prophylaxis strategies like pre-transplant anti-thymocyte globulin (ATG) are effective in reducing severe GVHD but have no survival benefits and steroids have serious side effects.One of the most critical challenges in aHSCT is the development of less toxic and more targeted therapies that maintain the graft-versus-leukemia/tumor (GVL/T) effect but suppress GVHD while facilitating enhanced immune reconstitution relative to existing strategies. Recently, several prophylaxis strategies for GVHD have been developed and others are currently in development, including, for example in the case of haploidentical HSCT, post-transplant cyclophosphamide (PTCy), which seem to be very promising.In the frame of this specific Research Topic, we aimed to collect recent developments of innovative methods for both prevention and treatment of GVHD, without impairment of GVL. In 8 original research articles and 4 reviews, this edition provides a deep insight into the role of the microbiome and metabolism as well as recent advances of small molecule and cell therapy development.Mohamed et al., summarize metabolic pathways contributing to GVHD and discuss metabolic targets for acute and chronic GVHD in immune and non-immune cell as well as the immunomodulatory function of microbial metabolites. Furthermore, they examine the metabolic effects of co-inhibitory pathway blockade (PD-1) and cellular therapies (Tregs/MSCs/Bregs) in aHSCT. The mini review by Karl et al., provides an overview of metabolic T cell alterations in GVHD and illustrates the impact of conventional GVHD therapy on T cell metabolism.We are glad, that experts in the field highlight the recent progress in the broad field of immune cell metabolism with two comprehensive reviews. Ghimire et al., investigates the role of G-protein coupled receptors (GPR43 and GPR109A) which engage microbial derived metabolites, like short chain fatty acids, in the mitigation of GVHD in intestinal biopsies from patients after allo-HSCT. A second study by Heidrich et al., describes an association of dental biofilm microbiota dysbiosis with the risk of aGVHD.Recent studies have shown the association of microbiome dysbiosis and aGVHD. Here, primary research by Campe and Ullrich. Moreover, Agbogan et al., explore the immunomodulatory effect of adoptively transferred CpG-activated B cell progenitors to alleviate GVHD symptoms. In addition, Scheurer et al., describe an in vitro generated sub-population of CD11b+CD11c+ myeloid-derived suppressor cells (MDSCs) as potent immune modulators leading to the prevention of GVHD without negatively affecting tumor cytotoxicity. Another innovative and attractive strategy using CRISPR/Cas9 has been described by Majumder et al., for genetical engineering of naïve T cells pre transplant as a method for GVHD prevention in a major murine mismatch model.In the context of cell therapy development, the biological relevance of T helper cell lineage defining transcription factors as potential targets for GVHD therapy has been delineated in a review article by Braun and Zeiser thoroughly review the role of kinase inhibition as novel treatment strategies for acute and chronic GvHD after allo-HCT. Thangavelu et al., evaluate the efficacy of a novel agonist of the retinoic X receptor (RXR), IRX4204, to treat cGVHD in two complementary murine models with bronchiolitis obliterans or sclerodermatous manifestations. Primary research by Matos et al., analyzes a possible association of anti-thymocyte globulin (ATG) treatment and serum levels of 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 in 4 HSCT cohorts with different vitamin D3 supplementation. Lastly, Hadjis et al., characterize post-transplant cyclophosphamide as superior in ameliorating pre-clinical GVHD compared to five other optimally dosed chemotherapeutics  that vary in mechanisms of action and drug resistance.In addition, the recent therapeutic advances in the area of drug development, e.g. small molecules and antibodies, are also addressed. Finally, this Research Topic makes us again aware of how complex the regulation of GVDH is and in which fragile balance between GVHD and GVL patients after aHSCT find themselves. We are aware that this issue can only compile a first selection of innovative findings and treatment strategies that are currently being developed for the prevention and treatment of GVHD.GVHD biology and treatment remains a field that is always influenced by current research developments and new advances can be expected in a short time. Therefore, we will continue to monitor the field and provide updates to the authorship of Frontiers in Immunology.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.EU is a member of Phialogics and receives research support from BMS and Gilead. AB is a scientific cofounder of Aamuthera Biotech GmBH and Dualyx NV.The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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.


Fossil-based heteroatom-containing compounds are crucial core scaffolds or key intermediates in a wide range of pharmaceutical molecules, fiber dyes and printing ink , which cLiu et al., Zhu et al., Liu et al., Zhang et al., Sun et al., Yao et al., Zhou et al., Zhao et al., Yang et al., and Zhou et al.), biodiesel production , and green synthesis of heteroatom-containing bioactive compounds and functional materials . Also, the Research Topic provides interesting insights into the green photocatalysis of organic pollutants .This Research Topic is Volume II of a series, and here we present a collection of original research and review articles  with topics on green and sustainable chemistry, including catalytic conversion of biomass feedstocks . Zhang et al. use glycerol waste to comparatively evaluate the ameliorative effect on lignocellulose under microwave or conventional heating method. During fast pyrolysis, levoglucosan produced from microwave-treated samples (32.9%) was far more selective than the conventional heating group (18.8%), and the content of aldehydes (high toxicity to the downstream fermentation) after glycerol waste and microwave pretreatment was decreased by 2.5 times compared with the untreated counterpart. In addition to directly using raw biomass resources, simple sugars like fructose can be efficiently converted to 5-hydroxymethylfurfural (up to 82% yield) by dehydration over a stable Ti-doped SBA-15 catalyst in DMSO at 140°C for 1 h , or to 5-ethoxymethylfurfural (80.4% yield) by cascade dehydration-etherification using a UIO-66-SO3H catalyst in ethanol under the same thermal conditions . Zhang et al. manufacture a biomass-based solid acid catalyst (SiO2@Cs-SO3H) with a large specific surface area (21.82 m2/g) and acidity (3.47 mmol/g) using renewable chitosan as raw material through sulfonation procedure under relatively mild conditions, which is active for esterification of oleic acid and methanol to produce biodiesel (98.2% yield).Original research paper of Chen et al. reports an unprecedented inactivation process of the indanol-derived NHC catalysts bearing N-C6F5 groups, giving an unexpected multi-cyclic complex product from the 3-component reaction with 1-methylcyclopropyl-carbaldehyde, 2,2,2-trifluoroacetophenone and the NHC catalyst. Pan et al. develop an acid-catalyzed 2-alkylation of indole molecules catalyzed by traceless HI, and 2,3-disubstituted indole molecules bearing congested tertiary carbon centers are obtained in moderate to good yields. Some functional catalytic materials such as hierarchical porous SAPO-34 , bimetallic Zn-Zr metal-organic framework , and graphene oxide-silver nanoparticles composite  are prepared in sustainable ways, and found to be efficient for the synthesis of value-added chemicals  or degradation of organic pollutants.The work of Liu et al., Sun et al., Zhou et al., Yang et al., Yao et al., Liu et al., Wu et al., Liu et al., Pan et al., and Zhang et al.). Liu et al. review the application of recyclable heterogeneous non-noble Zr/Hf-containing catalysts  with acid-base bifunctionality for catalytic transfer hydrogenation using the safe liquid hydrogen donor, with emphasis on evaluating the reaction mechanisms and conversion pathways. In a more detailed manner, the research progress of catalytic synthesis of γ-valerolactone from furfural by Zr/Hf-based catalysts is reviewed by Sun et al., and the effects and regulation approaches of Lewis acid-base and Brønsted acid sites in the catalysts on each steps in the reaction process are discussed. Zhou et al. reveal the significance and potential of using titanate nanotubes-based materials as sustainable and environmentally benign solid catalysts/supports for synthesis of various bio-based chemicals, such as glycerol-derived solketal, jet fuel range alkanes precursors, biomass-derived esters, aldehydes, and aromatic compounds. Yang et al. propose the research development trend for improving the institutional mechanism of the utilization of crop straw resources, strengthening technology research and development, exploring the economic model of green cycle agriculture, accelerating the construction of the industrial system, and designing new paths of resource utilization in multiple ways. Yao et al. mainly review some latest studies about the conversion of cellulose to 5-hydroxymethylfurfural catalyzed by solid acids with Brønsted and/or Lewis acidic sites, such as sulfonated solid acids, carbon-based acids, and zeolites. Liu et al. summarize the mechanisms of several important processes of producing 5-ethoxymethylfurfural from lignocellulosic biomass-derived sugars and the research progress of the developed acid catalysts. In addition, advancements in tobacco (Nicotiana tabacum L.) seed oils  and lipid extraction from microalgae using green solvents  for biodiesel production are also collected. For some structurally somplex natural products such as sex pheromones , and momilactones and related 9β-H pimarane skeleton , the recent advances in their synthetic strategies with the involved challenges are overviewed.This Research Topic features several review articles with distinct scopes (We wish this Research Topic attracts interested colleagues, enlightening more eco-friendly and sustainable synthetic procedures, shedding light on renewed catalytic strategies and routes developed for the production of bio-based heteroatom-containing compounds, and providing enthusiasm in research and studies. Enjoy its reading!


Back in 2010, when we first published data on the in vivo nutrigenomic effects of virgin olive oil polyphenols within the frame of the Mediterranean diet [Research is growing at a fast pace, acknowledging that gene–diet interactions play an enormous role in human health and are typically only partially assessed. Healthcare providers, on the other hand, receive scarce knowledge of these interactions, thus jeopardizing the application of precision nutrition ,3. At thThis Special Issue on the effects of gene–diet interactions in human health includes six original research articles showing data that will bring readers closer to the state-of-the-art developments in the field of nutritional genomics. From human intervention studies in Spain and Latin America to large-scale genome-wide association studies (GWAS), such as the UK Biobank, and the study of molecular mechanisms in Drosophila melanogaster, this issue includes the latest advances driving our understanding of gene–diet interactions.A genetic correlation and two-sample mendelian randomization study was performed by Xu et al.  assessinGranado-Serrano et al.  studied Rivera-Iñiqguez et al.  studied A high polygenic risk score for Type 2 diabetes mellitus was used by Lopez-Portillo et al.  to assesDu et al.  used DroGene–diet interactions, once fully incorporated into clinical practice, hold great promise as a precise tool to improve quality of life, health span, and reduce healthcare costs. This special issue added a piece of knowledge in that direction with more precise data and analysis.


Polasa et al. use an extensive set of equilibrium and non-equilibrium molecular dynamics simulations to describe the conformational changes in the YidC during membrane insertion . Similarly, Li et al. consider the effect of cholesterol and membrane composition on C99 dimerization with ramifications in Alzheimer’s disease . Be it atomistic or coarse-grained, molecular dynamics uses a physics-based approach to explicitly describe the interaction between molecular moieties of interest with an outstanding resolution. Aslam and Alvi present a different computational approach based on systems biology. Their mathematical modeling allowed the complete exploration of a novel postsynaptic channel for glutamatergic synaptic transmission and its effector molecules composed of ions, diacylglycerides, and protein kinases (Aslam and Alvi). Unlike molecular dynamics, systems biology works at much larger scales and aims to characterize emergent phenomena from complex and interdependent processes and interactions in biological systems. Advancing our knowledge of membrane-related processes depends on experimental methods as well. The Research Topic includes the purely experimental work by Kurakin et al., who studied lipid vesicle and divalent ion interactions . This process is of paramount importance in signaling and membrane structure. Overall, we show that advancement in membrane research requires synergies from widespread techniques.Our knowledge of cellular membranes and their components’ critical role is recent and so far, unfinished. Bilayers of lipids were proposed less than 100 years ago . “Fluid


Resco de Dios et al. Nature Communications 10.1038/s41467-022-32013-9 (2022)In their letter, Resco de Dios et al. discuss fire regimes in China using a dataset of annual area burned from a satellite product, i.e., the Moderate Resolution Imaging Spectroradiometer (MODIS) Collection 6 (C6) MCD 64 A1. They suggest that: (1) the fraction of burned area in China’s subtropics is low, (2) no dipole pattern exists between the burned area in western and eastern subtropical China, (3) the El Niño-Southern Oscillation (ENSO) has only weak effects on area burned in subtropical China, and (4) the fire suppression policy has little effect on fire activity in subtropical China. Their analysis of satellite-derived annual area burned raises some interesting issues that deserve further discussion.1. Even though MODIS-derived fire products, such as active fires and area burned, have much improved in recent years2, biases still remain in these products because of surface topography, fast vegetation growth rates, and clouds2. In addition to these biases, crop data gaps due to clouds occur in these fire products2 and this is especially the case in cloudy subtropical China. As a result, fire patterns in southwestern China have been found to be inconsistent between MODIS fire products and ground observations3. To address these biases, we calculated fire occurrences from MODIS fire points4 and further distinguished between wildfire and crop fire in the fire occurrence dataset. We find a high fraction of crop fires in the MODIS fire data in northern China, particularly in the North and Northeast China Plains  and Resco de Dios et al. may be the primary reason for the discrepancies between the two studies. We developed the Wildfire Atlas of China (WFAC), a robust ground-truthed fire occurrence dataset, in which fire occurrences were detected by multiple satellites (including MODIS) and carefully validated through surface observations by local forestry departments and Resc1. To support our previous findings, we have now implemented empirical orthogonal function (EOF) analyses on the WFAC field only (Fig. Based on their analysis of the annual area burned, Resco de Dios et al. argue the lack of a dipole pattern in fire activity between western and eastern subtropical China suggested in our study. We detected this pattern based on the co-varying patterns between the coupled fields of fires in WFAC and sea surface temperaturenly Fig. . The firResco de Dios et al. claim that the modulation of ENSO on fire in China is weak. They base their claim on the insignificant correlations they find between gridded area and ENSO indices on individual grid points in China. Unlike their analysis of individual grid points, our analyses were based on the covariance of data on these grid points. Combining all grid points, our correlation analysis increases the degree of freedom, raises the likelihood of a significance test, and therefore is reliable and robust. Fire in individual grid points can be noisy on a local scale, while climate plays a more critical role in modulating large-scale fires.8. Resco de Dios et al. stated that the ENSO could only influence the ignitions and thus has little effect on fire activity. In fact, fuel availability and flammability are also key factors in fire occurrence, particularly for large-scale fires9. This is evidenced by the strong correlations between fire occurrence and interannual climate variability.Many previous studies revealed the dominant impacts of ENSO in different regions of China10.China’s fire policy not only suppresses existing fires but also prevents human-ignited fire occurrences. As revealed in previous studies, the fire suppression policy since 1987 decreased not only burnt areas but also fire occurrencesThe study by Resco de Dios et al. was based on MODIS-derived annual area burned, which differs from our ground-truthed WFAC fire occurrence dataset. The MODIS cannot sufficiently distinguish the wildfire from the frequent crop fires and thus vastly misinterrupt the crop fires as wildfire, especially over the northern plains where forests are rare. Here, we show that the EOF analyses of the WFAC can also reveal the dipole fire pattern between southwestern and southeastern China. We highlight that the dipole fire pattern and ENSO modulation are on large scales. The fire control policy not only suppresses existing fires but also prevents human-ignited fire occurrences, and thus plays an effective role in reducing five activities in China.


Aboo Shuhailath et al., RSC Adv., 2016, 6, 54357–54370, DOI: 10.1039/C6RA07836B.Correction for ‘Photoactive, antimicrobial CeO The corrected list of affiliations is as shown above.The authors regret that the one of the affiliations (affiliation The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.


Epithelial-mesenchymal transition (EMT) is a core cellular program in vertebrate embryonic development where the expression of key junctional and cytoskeletal proteins such as E-Cadherin and Vimentin orchestrate stages of embryogenesis such as gastrulation or morphogenesis . In 2003When epithelial tumors progress, they lose cell–cell contacts and apico–basal polarity, transforming into spindle-shaped mesenchymal structures. Such cells also gain capabilities of motility and invasiveness for metastasis . At metaVuletic et al.). EMT-associated gain of NK cell ligands in cancer cells may enhance NK cell mediated cytotoxicity, whereas an immune suppressive tumor microenvironment (TME) may activate enzymes that lead to a loss of ligands. He et al. show that the expression of PSMC5 altered the type of immune cells in the TME of CRC by suppressing the infiltration of CD8+ T cells and enhancing the infiltration of innate immune cells such as macrophages and neutrophils and was associated with EMT .EMT proteins can have various non-EMT related functions and act in a tissue-specific manner such as acquisition of immunosuppression and cancer stem cell (CSC)-like features . The tumYu et al.). Song et al. show that expression of β-arrestin1 enhanced the motility of CRC cells via the activation of Wingless/integration-1 (Wnt)/β-catenin signaling .EMT may enhance chemoresistance with evidence for enhanced drug efflux, slower cell proliferation and avoiding apoptosis signaling pathways. Slug was implicated in the development of partial EMT and resistance to doxorubicin via upregulation of drug efflux transporters and stemness in liver cancer cell lines . Yu et aReliance on one or two genes to evaluate a process as complex as EMT as well as the use of acute tumor models may not be sufficient to recapitulate the heterogeneity, metabolic idiosyncrasies, and growth pattern of a slow growing tumor . Over thJia et al.). Moreover, modeling experiments suggest that partial EMT can facilitate hybrid metabolic states with combination of glycolysis and oxidative phosphorylation, contrary to primary tumors that mostly rely on glycolysis . The results reported provide new insights into EMT plasticity and its implications in CRC.


For a comprehensive understanding of protein function and dynamics, it is crucial to study their mechanical properties ,9,10,11.Recent progress regarding theoretical AI-based approaches for the prediction of 3D structures  has creaVan der Sleen and Tych  reviewedGala and Žoldák  applied Single-molecule force experiments can explore protein folding and unfolding under mechanical force. However, such experiments are challenging, cost-demanding and require many years of highly specialized expertise. Bauer and Žoldák  describeAtomic force spectroscopy was used to examine the mechanical properties of two peptides on the surfaces of gold nanoclusters (Au NCs) as small as 2 nm . Such smNon-equilibrium pulling data and derived force-dependent kinetic rates measurements show a systematic discrepancy between the total distance between the native (N) and the unfolded state (U) from elastic models and the sum of the measured distances for folding and unfolding kinetics. Rico-Pasto et al.  performeSziklai et al.  applied Microtubule disassembly and protein degradation are essential processes in the cell, which are mediated by highly specialized hexameric nanomachines. Varikoti et al.  conducteTo summarize, as shown by the research articles in this Special Issue, protein nanomechanics is a fruitful emerging concept which describes the internal dynamics of highly mechanically anisotropic proteins. The further development of experimental methods and bioconjugation strategies will strongly contribute to developing our fundamental understanding of complex protein nanomachines and protein behavior at solid interfaces. Based on our knowledge of protein mechanics, we should be able to design and develop nanomachines and proteinaceous surfaces with tailored-made functional and elastic properties.


Studies have identified high rates of mental disorders in refugees, but most used self-report measures of psychiatric symptoms. In this study, we examined the percentages of adult refugees and asylum seekers meeting diagnostic criteria for major depressive disorder (MDD), post-traumatic stress disorder, bipolar disorder (BPD), and psychosis.A systematic literature search in three databases was conducted. We included studies examining the prevalence of MDD, post-traumatic stress disorder, BPD, and psychosis in adult refugees according to a clinical diagnosis. To estimate the pooled prevalence rates, we performed a meta-analysis using the Meta-prop package in Stata (PROSPERO: CRD42018111778).I2= 99%) for MDD, 31%  for post-traumatic stress disorder, 5%  for BPD, and 1%  for psychosis. Subgroup analyses showed significantly higher prevalence rates of MDD in studies conducted in low-middle income countries  than high-income countries studies , and in studies which used the Mini-International Neuropsychiatric Interview  compared to other diagnostic interviews . Studies among convenience samples reported significant (p = 0.001) higher prevalence rates of MDD  and PTSD  than studies among probability-based samples .We identified 7048 records and 40 studies (11 053 participants) were included. The estimated pooled prevalence rates were 32% (95% CI 26–39%; This meta-analysis has shown a markedly high prevalence of mental disorders among refugees. Our results underline the devastating effects of war and violence, and the necessity to provide mental health intervention to address mental disorders among refugees. The results should be cautiously interpreted due to the high heterogeneity. In 2020et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., During the last years, several studies have examined the prevalence of mental disorders in refugees and asylum seekers. However, the resulting prevalence rates in this population present great variability , and psychosis] in refugees and asylum seekers from conflict-affected areas. Serious mental disorders are conditions resulting in serious functional impairment, which interferes with major life activities NIH, . Other det al., et al., v. high-income countries, and among different kind of population sample (convenience samples v. probability-based samples).Similar to previous studies (Fazel www.prisma-statement.org)  statement  from inception to June 4, 2020, by a medical librarian. Search terms included controlled terms  as well as free text terms. The following terms were used (including synonyms and closely related words) as index terms or free-text words: ‘refugees’ and ‘mental illnesses’. A search filter was used to limit the results to adults. The search was performed without date or language restrictions. Duplicate articles were excluded. The full search strategies for all databases can be found in the online Supplementary materials.et al., et al., Studies were considered eligible for this meta-analysis if they examined (a) the prevalence of serious mental disorders , (b) in an adult (⩾18 years) population of refugees and asylum seekers who had to cross their country borders, (c) according to the criteria of Diagnostic and Statistical Manual of Mental Disorders  or International Classification of Diseases (ICD 9 or10) (d) assessed with a structured or semi-structured clinical interview, such as the Structured Clinical Interview – SCID, Mini-International Neuropsychiatric Interview – MINI, or Composite International Diagnostic Interview – CIDI. No cut-off has been considered to evaluate the diagnosis' severity. Disorders have been evaluated serious according with the National Institute of Mental Health (NIH) and GBD considerations  and asylum seekers (a person who seeks protection from persecution or serious harm in a country other than their own) were in agreement with the UNHCR Master Glossary of Terms UNHCR,  and AsylAll title and abstracts were screened by two researchers independently (MP/MS or SG). We retrieved the full texts of all abstracts that seemed eligible for inclusion. Subsequently, we performed a full-text selection according to our pre-specified eligibility criteria. Disagreements between the reviewers were resolved by discussion.For every eligible study, two reviewers independently (MP/MS or SG) extracted data related to the year of publication, the country of data collection, the country of the refugees' origins, the sample size of the population, the age, the gender, the time elapsed as refugees or asylum seekers, the diagnostic tool used. Finally, we extracted the prevalence rates of MDD (current episode and recurrent), PTSD, BPD and psychotic disorder. In the absence of absolute numbers and if allowed by the data reported, the percentages of prevalence rates were converted into numbers. The time since displacement was reported in three different categories: (1) people who have spent more than five years as refugees or asylum seekers (⩾5), (2) people who have spent between 5 years and 1 year as refugees or asylum seekers (>1 < 5) and (3) people who have spent less then 1 year as refugees or asylum seekers. Countries were categorised as low-, middle- (LMIC) and in high-income (HIC) based on the World Bank list of economies 2020  evaluated the assessment of the methodological quality of individual studies using a modified version of the Joanna Briggs tool – JBI Critical Appraisal Checklist for Studies Reporting Prevalence Data . Prevalence rates were calculated per each disorder separately. Pooled rates for subgroups were indicated, when at least three studies were present for each disorder. All statistical analyses were conducted using Meta-prop package in STATA/SE 16.1 for Mac       of MDD between studies conducted in refugees resettled in LMICs  higher prevalence rate of MDD  has been reported in studies  higher prevalence of MDD and PTSD  than studies . The other analyses of the MDD, reMDD and PTSD subgroups, showed no significant differences among prevalence rates and high heterogeneity , followed by PTSD (31%), recurrent episode of MDD (16%), and BPD (5%). The prevalence of psychotic disorders was 1%. Subgroup analyses showed that MDD appeared to be more prevalent (47%) among studies conducted in LMICs than in HICs (28%), and when the MINI (37%) has been used, compared to other diagnostic instruments (26%). PTSD and MDD showed higher prevalence rates (34% and 35% respectively) in studies where participants were from convenience samples in comparison to studies that used probability-based samples. PTSD and MDD were the most frequently evaluated disorders with 36 studies and 32 studies respectively, as opposed to BPD and psychosis of which we had only a few studies.et al., et al., et al., et al., et al., et al., et al., According to previous studies, the world-wide prevalence rate reported for MDD is 4.4% WHO, , the lifet al., et al., et al., et al., Our results are in line with the prevalence rates of the Blackmore and colleagues , and that its administration is shorter and its outcomes therefore potentially less precise.Despite the high heterogeneity and methodological limitations of included studies, a high prevalence of serious mental disorders was found in refugees and asylum seekers diagnosed through structured clinical interviews. However, specific instruments culturally adapted for use across different local cultures and contexts for refugees would be advisable, since no one of the diagnostic instruments currently in use has been developed for the non-western populations, who represent the highest sample of refugees. For this reason, to reduce the high heterogeneity, more rigorous studies, using representative samples and culturally adapted instruments, to measure cultural concepts of distress would be recommended. Moreover, to strengthen the evidence base concerning the more serious mental disorders, further research on the prevalence of psychosis and BPD is imperative. To follow this goal, international and government investments in mental health research, population screening, and specific interventions on asylum seekers and refugees are warranted. However, until we have more rigorous studies and adequate diagnostic tools, due to the high heterogeneity between these studies, our results should be considered with caution.In sum, our systematic review and meta-analysis show that it is imperative that governments and actors across the world acknowledge the devastating effect of war and prosecution on individuals' mental health. In order to prevent cycles of violence and victimisation, effective public mental health responses may be put in place to address worldwide suffering.All the data involved have been included in Tables and Figures of this paper, including online Supplementary materials.


Image and video processing operatons are significant in our life as most electronic devices, such as PCs and mobiles, are all developed by signal processing. Therefore, signal processing can be considered as a part of computer science. Information entropy is very important in signal processing, and it was developed by Claude Shannon and Harry Nyquist who defined data representations of the physical world. Nowadays, deep learning is widely used in signal processing due to its good performance. This Special Issue calls for current studies on several signal (including image and video) processing approaches that are based on information entropy and machine learning. Papers that were both applicative and theoretical in nature were welcomed (both research papers and reviews), and contributions regarding new signal processing tools for the entropy research community were also welcome. Finally, six papers were selected for this Special Issue.In the contribution by Jia et al., “Chaotic Mapping-Based Anti-Sorting Radio Frequency Stealth Signals and Compressed Sensing-Based Echo Signal Processing Technology,” the signal-generating design principle of anti-sequential difference histogram (SDIF) arrangements was studied for the principal arrangement approach of the SDIF . In addiIn the contribution by Bao et al., “PCQNet: A Trainable Feedback Scheme of Precoder for the Uplink Multi-User MIMO Systems,” the authors presented a CNN-based compression network titled PCQNet to minimalize the feedback’s overhead . The autThe contribution by Wang et al., “Efficient Entropic Security with Joint Compression and Encryption Approach Based on Compressed Sensing with Multiple Chaotic Systems”, focused on a novel approach that uses compressed sensing for image compression and encryption concurrently . In thisIn the contribution by Zhao et al., “A Complex-Valued Self-Supervised Learning-Based Method for Specific Emitter Identification,” the authors present a complex self-supervised learning approach to fully examine the unlabeled examples . In the In the contribution by Liu et al., “Multi-Scale Mixed Attention Network for CT and MRI Image Fusion,” the authors present a CNN-based CT and MRI image fusion approach, which uses a pictorial saliency-based plan to reserve more valuable information . In thisIn the contribution by Sun et al., “On Architecture Selection for Linear Inverse Problems with Untrained Neural Networks,” the authors attempted to broaden the application and understanding of untrained neural network priors by exploring the interaction between the choice of architecture and measurement models . The aut


To the Editor: We read with great interest the article by Lima et al. (Melioidosis is not a notifiable disease in India. Even so, from a single tertiary-care teaching hospital at Odisha, we have reported >100 cases of culture-confirmed cases during 2016–2021 (Clinical severity of melioidosis is predominantly a function of host immunity (


Li et al.; Sequencing technologies including bulk and single-cell approaches have been employed broadly to investigate molecular changes and the underlying mechanisms of cancer development, progression, and metastasis . For insThe Application of Sequencing Technologies and Bioinformatics Methods in Cancer Biology, we aimed to collect novel findings and methods in the field of cancer biology related to mining bulk and single-cell sequencing data with bioinformatics approaches for illuminating different types of tumors  and immune checkpoint expression or tumor mutation burden was an effective prognostic biomarker for immunotherapy. Their findings highlighted that SRS could regulate the immune microenvironment of LUAD.Zhou et al. explored the immune-oncology profile of LUAD and identified a set of immune genes significantly correlated with progression-free survival. They also found that the risk signature based on several of these immune genes was associated with neutrophil infiltration. Therefore, these three studies screened out different types of prognostic biomarkers for LUAD patients, which could be useful and promising for survival analysis.Three studies on this Research Topic dissected lung adenocarcinoma (LUAD) from different perspectives and identified a number of potential prognostic biomarkers. For example, Liu et al. identified five CRC survival-related genes  based on hub gene analysis of co-expression and protein-protein interaction networks. They also constructed a promising risk model using three  of them for prognostic prediction. Their results indicated that these hub genes could be correlated with CRC development and the survival of patients. Wang et al. constructed a scoring model based on four necroptosis-related genes , which can effectively predict the prognosis and response of colon cancer patients to chemotherapy and immunotherapy. They also found that the activation of necroptosis-related genes could promote the metastasis of colon cancer. Unlike these two studies, Bartlett et al. investigated the association between miRNAs and immune checkpoint blockade for CRC. They detected a number of miRNAs that were correlated with mutation burden, microsatellite instability, or PD-L1 expression. Among them, three miRNAs  were related to the M1 macrophage polarization state and their targets had the potential to impact the TGF-β pathway.For colorectal cancer (CRC), three studies discovered potential prognostic biomarkers or treatment preditors by analyzing large-scale datasets. For instance, Zhao et al. discovered that loss of ARID1A was strongly correlated with the high expression of CD47 in gastric cancer. They identified CD47 as a potential direct downstream target of ARID1A, while the combination of ARID1A and CD47 would be a promising prognostic biomarker. Pan et al. examined the landscape of papillary thyroid cancer (PTC) at single-cell resolution and detected molecular signatures correlated with the disease-free survival of patients. They also found that dendritic cells and B cells could play critical functions in preventing PTC progression. identified GPX1 as a promising prognostic biomarker for breast cancer  based on whole-exome sequencing and single-cell RNA-seq data. They found that RUNX3 could be a potential driver and therapeutic target for RRMM. Wu et al. detected KIF23 as an effective prognostic biomarker for clear cell renal cell carcinoma (ccRCC). They also revealed that KIF23 could promote the nuclear translocation of β-catenin, while the knockdown of KIF23 would reduce the proliferation, migration, and invasion of ccRCC. For liver cancer, Wu et al. showed that up-regulated expression of POSTN, LAYN, and HTRA3, and down-regulated expression of AANAT and AFM were associated with poorer overall survival of patients. They also found that the gut microbial metabolites of trimethylamine N-oxide TMAO and POSTN were potential targets for liver cancer treatment. Jiang et al. revealed that TMEM176B could be a diagnostic and prognostic biomarker for skin cutaneous melanoma. The expression of TMEM176B was shown to be correlated with tumor-infiltrating lymphocytes, pathological stage, therapy sensitivity to radiation, as well as tumor ulceration.In addition to biomarker exploration articles in lung and colorectal cancer, we received articles that explored biomarkers in gastric, thyroid, breast, and other tumor types. For example, t cancer . They obWu et al. systematically analyzed AP3S1 in diverse tumor types and found that its expression was widely associated with the immunosuppressive microenvironment. They also demonstrated that AP3S1 could be a pan-cancer biomarker for prognosis and immunotherapy. The other study explored the gene expression profiles of 988 cell lines from 20 distinct cancers by employing several computational methods Ding et al. They identified robust pan-cancer biomarkers for differentiating a variety of cancer types. Overall, the aforementioned studies discovered different types of potential biomarkers for diverse tumors, which could be useful for the diagnosis, prognosis, or treatment of corresponding cancers.Another two studies conducted pan-cancer analyses and detected potential biomarkers for the clinical management of cancers. For example, Dai et al. developed a novel model based on the score of cell type compositions (CTCs) for improving the prognostic analysis of acute myeloid leukemia patients (AML). They further showed that the CTC score could potentially benefit the individualized treatment of AML patients. Chen et al. systematically investigated the chromosome instability (CIN) profile of 280 patients with bone metastatic cancer based on the copy number variations inferred from cell-free DNA (cfDNA) sequencing data. They revealed that CIN quantification with cfDNA provided an effective and non-invasive method for predicting the survival of spine metastasis patients. Yuan et al. developed a scoring approach based on 15-DNA repair gene signatures for effectively predicting the prognosis of gastric cancer patients who received immunotherapies. The scoring system developed by them may benefit the tailored immunotherapy of gastric cancers. Chen et al. proposed an efficient strategy for identifying the circular RNAs (circRNAs) with protein-coding potential in CRC. They also suggested that those circRNAs might be functional in promoting proliferation and invasion ability, while the peptides derived from circRNAs could be potential targets for CRC therapy or diagnosis. Hu et al. designed a panel based on 28 breast cancer-related genes for long-read sequencing . They demonstrated that this approach can effectively detect structural variations in breast cancer patients, which could be used in related clinical investigations. Shi et al. systematically evaluated a gene panel containing ∼1,300 key immuno-oncology genes designed for characterizing tumor microenvironments. Based on the analysis of >1,200 formalin-fixed paraffin-embedded tumor samples, they showed that this panel was comparable with orthogonal platforms . The computational strategies developed in these studies were useful and promising for exploring and characterizing various aspects of different cancers.Besides biomarker investigation, several studies on this Research Topic developed new computational strategies for profiling tumors from different aspects. For instance, Taken together, the studies published in this Research Topic presented a diversity of interesting and meaningful results for a range of different cancers, which could facilitate our understanding of cancer biology. It is well known that bulk and single-cell sequencing technologies can respectively obtain whole-system and cellular views of tumors. Multi-omics and multimodal strategies are superior to single-omics methods for dissecting cancers since different types of data could be complementary . Third-g


Micro and nano molding technologies are continuously being developed due to enduring trends such as increasing miniaturization and the higher functional integration of products, devices and systems. Furthermore, with the introduction of high-engineering-performance polymers, feedstocks and composites, new opportunities in terms of materials properties can be exploited, and consequently, more micro product and micro/nano structured surfaces are currently being designed and manufactured.Innovations in micro and nano molding techniques are seen in different processes employed in production ; in the use of new and functional materials including, e.g., nanocomposites; for an ever-increasing number of applications ; in several key enabling technologies that support the successful realization of micro and nano molding processes  and their integration into new manufacturing process chains.Accordingly, this Special Issue seeks to showcase research papers focusing on the latest developments in micro and nano scale manufacturing using molding techniques as well as their related key enabling technologies to produce both micro products and micro/nano structured surfaces.The Special Issues consists of 10 original research papers and 2 review papers, which cover fundamental molding process technology development, key enabling technologies, as well as the design and application of these technologies for the fabrication of micro/nano devices and micro structured components.The papers included in the Special Issue address research, development and recent advancements in four main domains of micro/nano molding: (1) process technology developments and characterization; (2) modeling and simulation; (3) tooling technologies and micro tool design; (4) applications.(1)Process technology developments and characterization. Calaon et al.  analyzed(2)Modeling and simulation. Weng et al.  modeled (3)Tooling technologies and micro tool design. Wang et al.  develope(4)Applications. Kim et al.  presenteWe wish to thank all of the authors who submitted their papers to this Special Issue, entitled “Latest Advancements in Micro Nano Molding Technologies—Process Developments and Optimization, Materials, Applications, Key Enabling Technologies”. We would also like to acknowledge all of the reviewers whose careful and timely reviews ensured the high quality of this Special Issue.http://www.prosurf-project.eu/, accessed on 5 April 2022, 2018–2021, Project ID: 767589), as well as the Marie Skłodowska-Curie Action Innovative Training Networks MICROMAN  and DIGIMAN4.0 , is acknowledged. The support and funding from the Danish Innovation Fund , through the research projects MADE DIGITAL, Manufacturing Academy of Denmark , Work Package WP3 “Digital manufacturing processes” and QRprod  is acknowledged.The support and funding from the European Commission Horizon2020 Framework Programme for Research and Innovation through the ProSurf project (“High Precision Process Chains for the Mass Production of Functional Structured Surfaces”,


Development of a risk assessment profile tool to determine appropriate use of SARS-CoV-2 rapid antigen detection tests for different activities and events in Ireland, since October 2021’ by Mallon et al., published on 20 January 2022, the name of author Aileen Conway was corrected . This change was made on request of the authors on 4 February 2022.In the article ‘


Lane CA, Barnes J, Nicholas JM, et al. Associations between blood pressure across adulthood and late-life brain structure and pathology in the neuroscience substudy of the 1946 British birth cohort (Insight 46): an epidemiological study. Lancet Neurol 18: 942–522019; —The appendix of this Article has been corrected as of June 17, 2020.


Aberrations in epigenetic regulation at various levels, including DNA methylation, chromatin architecture, and regulatory RNAs, are often associated with, and significantly contribute in most carcinogenesis . TranscrParrello et al. discussed the possibility of targeting factors that control global transcriptional regulation. Li et al. discussed the dual roles of CBX7, a component of polycomb repressive complex, in cancer where it can either help in cancer progression by downregulating tumor suppressor genes or help cancer suppression by modulating cell cycle related proteins. CBX7 interacts with various regulatory RNAs, including micro RNAs, long non-coding RNAs, circular RNAs. Regulatory RNAs play a significant role in carcinogenesis, including chemo-resistance . Sun et al. showed that plasma-derived exosomal micro RNA, miR-2276-5p in glioma patients could serve as a potential diagnostic and prognostic marker. Transcriptomics based gene signatures are emerging as promising biomarkers in cancer .Genome-wide transcriptional control is often dysregulated in cancer. In this research topic, Fatima et al. and Raina et al.). Abbas et al. reported that maternal diet rich in omega-3 fatty acid can reprogram epigenetic and transcriptomic landscapes in F1 generation mice and provide resistance to breast cancer development. Pu et al. reported that methylation profiles of zinc finger genes, specially ESR1 and ZNF132, could be potential biomarkers for the early diagnosis of colorectal cancer patients carrying KRAS mutations. Another study by Gua et al. showed that APOA1 gene is downregulated by DNA methylation in hepatocellular carcinoma that could be a potential biomarker to predict survival. Role of NTPCR in epithelial ovarian cancer  and FGFR1–GLI1 axis as a potential therapeutic target in breast cancer  were also reported.Epigenetic landscape is altered in cancer cells that results in transcriptional dysregulation. Various dietary components have ability to modulate epigenetic aberration (Gazova et al. used CRISPR-Cas9 to generate homozygous inactivating mutation in USP16 gene using leukemia cell line and studied how these cells adapt to the extreme selection pressure through compensatory pathways. Authors also cautioned targeting USP16 in leukemia as cancer could develop resistant to USP16 inhibitors. A timely review by Amir et al. discussed the usefulness of combination therapy of tyrosine kinase inhibitors with epigenetic drugs in chronic myeloid leukemia. Leszczynska et al. reviewed the emerging therapeutic approaches against pediatric high-grade gliomas, particularly those having mutations in genes coding for histone 3 variants that result in substitution of lysine at 27 to methionine.In conclusion, epigenetic aberration and transcriptional homeostasis disruptions are associated with cancer. In-depth understanding of these processes and their interdependencies is needed to better understand carcinogenesis and to develop novel and effective therapeutic approaches.


Lüke et al.).The aim of anakoinosis is “tissue editing,” meaning that bioactive, regulatory acting principles are combined to re-establish tissue homeostasis at primary and metastatic tumor sites by communicatively reprogramming tumor tissue and cell recruitment . Pro-anaLüke et al.; Lüke et al.; Heudobler et al.). The clinical responses outline the possibility to specifically activate unique tumor tissue dynamics in response to pro-anakoinotic effectors, either by combining differently acting biomodulatory drugs, or associating DNA damage with fungal infection.This Research Topic highlights differential clinical outcome characteristics in three histologically completely different neoplasia as a response to “tissue editing” when treated either with pro-anakoinotic approaches  or accidentally initiated by severe fungal infection and reduced intensity induction chemotherapy in acute lymphoblastic leukemia (ALL) .DNA damage response following “one shot” chemotherapy in ALL seems to serve as a homeostatic trigger in the case of parallel fungal infection, presumably supervising and amplifying immunological response by the innate immune system, thereby preventing both early relapse and persistence of minimal residual disease, as indicated by long-term continuous complete remission in both described ALL cases .In r/r NSCLC, explorative studies of the randomized trial provide strong hints that pre-treatment with combined biomodulatory therapy may be the basis for successful consecutive immune checkpoint inhibitor (ICPi) therapy: even though the progression-free survival rate of the biomodulatory treatment arm is significantly inferior to that of the ICPi arm, it, however, exerts tissue modifications that render successive ICPi more efficacious. These results stimulate the hypothesis that the addition of ICPi to the biomodulation could be beneficial .The immune-modulatory acting MEPED schedule for r/r cHL resulted in pivotal outcomes in six cases. Whether a patient is frail and does not respond to reduced standard first-line therapy, or patients are r/r after autologous hematopoietic-stem-cell transplant (autoHSCT), or even allogeneic hematopoietic-stem-cell transplant , MEPED may induce complete PET negative remission. The remissions could be maintained by alloHSCT. But even after discontinuation of MEPED in a frail patient, CR continued without any HSCT. Like in NSCLC, a possible beneficial supplementation of the immune-modulatory schedule could be ICPi therapy  has been given by the group of dulators .Favero et al.; Lüke et al.; Lüke et al.; Heudobler et al.). In vitro studies by Del Favero identify novel biological paths induced by bio-physical circumstances, such as shear stress, and give a first hint on how to target respective biologic structures for reprogramming tumor functions. Drugs used in pro-anakoinotic schedules, like mTOR inhibitors, e.g., in cHL, may reprogram a response to shear stress, as experimentally shown .Besides therapeutic modulation of cell metabolism, immune response, or tumor-associated inflammation in neoplasia, as exemplified in cHL, NSCLC, and ALL or GVHD, reprogramming the mechanical properties of tumor and adjacent stromal cells may be an important new therapeutical direction . The ALL studies highlight that clinical courses of malignant diseases may cause tissue alterations that render therapeutically accessible homeostatic disbalances previously hidden .For successful development of combination therapies in the field of anakoinosis, the detailed description of complex tissue functions supporting disease-related, pathophysiologically dysbalanced homeostasis is necessary. This message clearly emerges from the contributions on GVHD, and from the mechanistic analysis of how T24 bladder cancer cells cope with fluid shear stress by modifying their shape .Development and evaluation of biomodulatory drugs is already ongoing .A novel technology for the evaluation of systems biological drug interactions, relevant for anakoinosis research, has been presented by Liao et al.).Gold nanorods, currently studied as potential therapeutics in photothermal therapies, may also contribute to evaluating pathophysiology in tumor tissues, and as such the impact on tissue homeostasis, by identifying specific binding sites of gold nanorods in single-cell compartments (in vitro test systems, as indicated by the Research Topic, may promote the exploration of biomodulatory drugs derived from different pharmacological tools for designing pro-anakoinotically acting combination therapies, particularly for overcoming therapeutic problems with refractory neoplasia and complex non-malignant diseases associated with tissue dysregulated homeostasis (Kumari et al.; Lüke et al.; Lüke et al.; Heudobler et al.; In summary, this research topic provides a novel clinical collection of pro-anakoinotic approaches modifying dysregulated homeostasis in quite different ways for long-term tumor control or even healing of refractory tumor disease. Hopefully, pre-clinical


With interest, we read the recent article by Wang et al. in which their logistic regression analysis identified the use of vasopressor agents, the presence of a neurological disease, high APACHE II and SOFA scores, an acute gastrointestinal injury (AGI) ≥ grade II, and the use of mechanical ventilation or continuous renal replacement therapy (CRRT) as independent risk factors influencing the success rate of placement of a naso-jejunal tube (NJT) . The imp


Cancer is a genetic disease associated with the rapid growth of abnormal cells, which provoked the death of almost 10 million people worldwide during 2020 , placingSanità et al. reviewed the most recent techniques for surface modification and functionalization of nanoparticles in order to improve their biocompatibility and cellular uptake behavior. Similarly, Cheng et al. summarized and analyzed the current research progresses and challenges in tumor microenvironment-responsive shrink-sized drug delivery nanosystems. Cheng et al. also discussed the current implications and knowledge for promoting deep penetration into tumors using nanoparticles. Meanwhile, Chen et al. used two novel HLA-A2-restricted cytotoxic T lymphocyte epitopes (SV95–6 and SV95–7 peptides) derived from survivin , and were then loaded into human dendritic cell/poly(lactic-co-glycolic) acid-based nanoparticles, thus obtaining advanced materials specific against cancer cells. It should also be noted that Chen et al. carried out major histocompatibility complex peptide binding algorithms to predict a range of modified SV95 decamers (from SV95–2 to SV95–10) based on the natural SV95–104 peptide sequence of ELTLGEFLKL. On the other hand, Sharifiaghdam et al. designed and synthesized new layer-by-layer selenium-based nanocomplexes as carriers of small interfering RNA with improved stability and a dual mode of action against tumors: gene silencing and apoptosis induction in cancer cells. To close this research topic, Shah et al. reported theranostic optical imaging probes based on shortwave infrared (SWIR)-emitting rare earth-doped nanoparticles encapsulated with human serum albumin (ReANCs), which demonstrated superior surveillance ability for detecting micro-lesions at depths of 1 cm in an animal models of breast cancer metastasis, thereby promising an ability for follow-up therapy based on SWIR fluorescence measurements from tumor-targeted ReANCs.Traditional cancer treatments have shown several limitations. Nonetheless, diverse technologies based on nanotechnology have shown significant advances with the aim of obtaining a more efficient and safe cancer therapy. Despite this, several key obstacles related to the use of nanoparticles for cancer therapy such as the complexity and heterogeneity of tumor biology, a lack of understanding of nano-bio interactions, as well as chemical, manufacturing and control challenges must be further studied for clinical success. This research topic addresses some novel aspects of engineering that take advantage of our growing understanding of bionano behaviors and interactions to develop more efficient nanotherapies for cancer patients. Keeping this in mind, in this research topic, The role of nanotechnology in cancer research has grown dramatically in recent years. However, only a few dozen nano-based technologies have reached the market so far, primarily cell-scale targeted bionanosystems, and controlled and sustained carries of desired biomolecules. To change this, we must reconsider traditional views and rethink how we conduct translational cancer nanomedicine research.