Phenotypic integration among different anatomical parts of the head is a common phenomenon across vertebrates. Interestingly, despite centuries of research into the factors that contribute to the existing variation in brain size among vertebrates, little is known about the role of phenotypic integration in brain size diversification. Here we used geometric morphometrics on the morphologically diverse Tanganyikan cichlids to investigate phenotypic integration across key morphological aspects of the head. Then, while taking the effect of shared ancestry into account, we tested if head shape was associated with brain size while controlling for the potentially confounding effect of feeding strategy.The shapes of the anterior and posterior parts of the head were strongly correlated, indicating that the head represents an integrated morphological unit in Lake Tanganyika cichlids. After controlling for phylogenetic non-independence, we also found evolutionary associations between head shape, brain size and feeding ecology.Geometric morphometrics and phylogenetic comparative analyses revealed that the anterior and posterior parts of the head are integrated, and that head morphology is associated with brain size and feeding ecology in Tanganyikan cichlid fishes. In light of previous results on mammals, our results suggest that the influence of phenotypic integration on brain diversification is a general process. Brain size is highly variable among vertebrates,2. This The cichlids of Lake Tanganyika are an interesting model group to investigate the integration between skull and brain because of their remarkable diversity in both brain size and head morphology. The relative brain size  of Tanganyikan cichlids is correlated with several ecological and social factors such as diet,24, habiAnolis lizards[The high degree of integration between the different parts of the head is widely reported across vertebrates . Intere lizards. These a lizards. Hence,  lizards which wo lizards,15. AlteIn this study, we use landmark-based geometric morphometric phylogenetic analyses to test for the existence of phenotypic integration between various aspects of head morphology and brain size in Lake Tanganyika cichlids. According to our hypothesis, we test two aspects of integration. First, we test if the head is composed of morphologically independent modules or if it represents an integrated morphological unit. We then investigate whether head morphology is integrated with brain size or brain region volumes while considering the potentially confounding effect of prey utilization patterns that may affect head morphology.Benthochromis tricoti) for which we had two specimens  was much higher than within-species between-sex variation  and the interaction between species and sex . Our data should thus be robust against within-species sex differences. Specimens were sacrificed using an overdose of benzocaine. After measuring standard length and head width , the head was severed and preserved in 4% paraformaldehyde in a phosphate buffer for tissue fixation and preservation. Whole brains were obtained from dissected heads following fixation and weighed using a Precisa 125A electronic scale . All cranial nerves, optic nerves and meningeal membranes were removed and the brain was severed from the spinal cord just posterior of the dorsal medulla. Since brain volume and brain weight are highly correlated in our dataset , we use = 0.96,,36. Feed = 0.96,,47. To a = 0.96,. Therefo,[et al., Konings,[et al.,50, Yama,[et al.-53, Yuma,[et al., Takeuchl.[et al., Ochi[5l.[et al..p > 0.62 in all cases). We measured the head length as the distance between the foremost point of the snout and the rearmost point along the operculum using a scale photographed in the background of the images. Using TpsDig version 2.16, we digitized six homologous landmarks and seven semi-landmarks along the edge of the forehead to capture the variation in forehead shape where the largest proportion of variation is concentrated[F550, 2112 = 3.58, p < 0.001) than intraspecific between-sex differences . Generalized Procrustes Analysis (GPA) was performed to mathematically remove the variation of position, size, and rotation of the landmark configurations[Images of the lateral sides of 156 individuals were taken with a reflex digital camera (Nikon D 70 with an AF Micro Nikkor 60 mm 1:2.8 D macro lens). Assuming symmetry, we used the best quality images either from the right or left side. A permutation test using Procrustes distance confirmed that the shape was not different between the photos of the separate sides , 0.08 (PC2), 0.005 (PC3), 0.003 (PC4)), suggesting the use of residuals would not introduce bias in the analysis[λ = 0.95) and PSC (λ = 1), indicating the necessity for phylogenetic correction. PPCA and PSC were performed using the phytools package[In order to control for the allometric effect of body size on brain weight, we used phylogenetic principal component analyses (PPCA). Prior tanalysis. We perf package in R ver package.λ < 0.001). Following Horn’s parallel analysis[λ = 1 for the residuals of the model. Then, we performed mPGLS with λ = 1, i.e. a Brownian motion model, to test the integration between head shape and brain size. We also tested the robustness of our test using overall brain size against structural heterogeneity of the brain by performing mPGLS on size of the six major brain regions  as a predictor variable and head shape (PC1-4) as a response matrix, using overall brain weight to control for the effect of size  and brain size  were correlated with head shape. The direction of the shape change associated with brain size is presented in Figure The associations between head shape  and the three independent variables  are summarized in Table Our study represents one of the first macro-evolutionary studies of phenotypic integration between brain size and head morphology in non-mammalian vertebrates and several insights can be gained from our results. First, we found support for phenotypic integration rather than modularity between the pre-orbital and post-orbital parts of the head. Second, head morphology was linked to prey utilization. Third, when controlling for the association between food utilization and head morphology, we found that brain size in Lake Tanganyika cichlids was closely associated with variation in head morphology. Together, these findings indicate that brain evolution and trophic adaptations may interact through phenotypic integration of brain size and head shape.et al.[et al.[Perissodini) in their dataset while we did not. Second, our choice of landmarks and semi-landmarks are slightly different from Parsons et al.[et al.[et al.[et al.[Our test for modularity did not support the existence of independent modules within the head. Our result therefore disagrees with a previous comparative analysis which suggested the existence of independent modules within the head of East African cichlids. We propet al.. First, l.[et al. includedns et al.. Howeverns et al.,31, diffns et al., while Pl.[et al. investigl.[et al.. It is tl.[et al.,23,60. Hl.[et al. did not l.[et al., it is pInstead, our results indicated phenotypic integration between the pre-orbital parts (which included the skull) and the post-orbital parts (which included the upper and lower jaws) of the head. Given the close association between forehead shape and skull shape this intper se, a round forehead with a downward-pointing mouth are thought to be adaptations for grazing algae from the substrate[Our results confirmed the widely reported evolutionary link between head morphology and feeding ecology in Lake Tanganyika cichlids-37. The ubstrate. Howeverubstrate,24-26.After controlling for the interaction between feeding mode and head morphology, our results confirmed a strong association between head morphology and brain size. We showed that species with a high head profile have larger brains while species with a more elongated head profile have smaller brains. Given that an elongated body shape is associated with a smaller head volume in cichlid fishes, our resOur multivariate phylogenetic comparative study found support for integration of the head morphology of Lake Tanganyika cichlids, and that evolutionary associations exist among head morphology, feeding mode, and brain size. Our study therefore indicates that head-brain phenotypic integration might have played an important role in forming the macro-evolutionary variation of brain size in cichlid fishes, a group which has been an important model system for the study of phenotypic diversification. Given the strong and general association of ecology and head shape in teleost fishes-36, our We declare that we have no competing interests.All authors have read and approved the final manuscript. MT participated in the design of the study, carried out the analyses, and drafted the manuscript. AG-V conducted brain dissections and data collection, assisted in the analyses, and critically revised the manuscript. NK conceived the study, obtained funds, participated in the design of the study and helped to draft the manuscript.Heterogeneity of the brain.Click here for file


Zhao and Devine  exhaustiShevchuk and co-workers  describeOstermeier and collaborators  review eCasagrande and co-workers  focus onAlthough a large body of evidence points out to a negative role of platelet activity during pathological conditions, a protective role is also well-established. Accordingly, due to their enriched cargo in bioactive compounds, including growth factors and anti-inflammatory molecules, platelet preparation lysates represent a successful strategy for treatment of inflammatory conditions and regenerative medicine. By investigating the in vitro anti-inflammatory activity of various platelet-rich fibrin preparations (PRFs), Kargarpour and colleagues  highlighEvodia rutaecarpa), as therapeutic agents against thromboembolic disorders is the focus of two Chinese studies [The potential of two phytochemicals, i.e., pterostilbene  and rutaecarpine (a bioactive component of the well-known Chinese medicine  studies ,9. Lin a studies  find tha2+ channel ORAI and its activating Ca2+ sensor STIM that are associated with platelet activation. These two proteins are upregulated by hyperphosphatemia occurring in chronic kidney disease and the authors reported the beneficial action of MgCl2 and the CaSR agonist GdCl3 in counteracting this detrimental phenomenon, thus suggesting that pharmacological modulation of CaSR by both Mg2+ and Gd3+ might restore calcium homeostasis in blood.Zhou’s group  investigFinally, a rapid and reproducible test for routine laboratory identification of platelet activation is described by Watanabe’s group , who set


Why does Frontiers in Multiple Sclerosis and Neuroimmunology publish Case Reports? There are several reasons. First, we can learn from case reports regarding novel disease entities and rare diseases. Second, case reports can give insight into better pathophysiological understanding of rare diseases. Third, case reports can be of interest regarding translational aspects and modeling in animal models. Fourth, case reports can be important regarding exploration of novel treatment regimen. Possibly, more reasons in favor of case reports can be found, the above indicated are most relevant for the Speciality Chief Editors of Frontiers in Multiple Sclerosis and Neuroimmunology. Of course, it is important that the presented cases bring additional value to the field. The ideal type of case report would contain data regarding the clinical manifestation, immunological, genetic, and pathological aspects of the disease and a novel treatment approach would be presented. Also, the findings should be discussed in the context of the relevant literature. Ideally, there should be two or more similar patients per case report. This is not trivial, especially if the case reports are coming from an individual center. Sometimes, case reports are the entrance into research for the involved physicians especially early in career, since the case has initiated a scientific argument. Therefore, the value of case reports also in gaining scientific thinking should not be underestimated. Frontiers of Multiple Sclerosis and Neuroimmunology is proud to present the “Multiple Sclerosis and Neuroimmunology—Case Report Collection I”. This collection contains 27 case studies that were published between 2021 and 2022. We would like to thank the Associate and Review Editors who have evaluated the manuscripts and significantly contributed with their constructive criticism.The 27 case reports of “Multiple Sclerosis and Neuroimmunology—Case Report Collection I” can be ordered as follows: (1) Reports regarding neurological manifestations of coronavirus disease 2019 (COVID-19). (2) Case reports regarding vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) and nervous-system related side effects. (3) Case reports with novel aspects of the emerging field of autoimmune encephalitis (AE). (4) Case reports of viral encephalitis. (5) Case reports regarding autoimmune peripheral nervous system disease. (6) Reports of cases of neuroimmunological side effects by pharmacological treatment. (7) Case reports regarding rare disease variants leading to demyelination within the central nervous system (CNS). (8) Case reports of rare disease variants successfully treated by immune therapy.Ishaq et al. present a case of a patient with opsoclonus myoclonus syndrome a rare neurological disease entity that was successfully treated with intravenous immunoglobulins (i.v. Ig). Gilio et al. present findings regarding the overlap of functional neurological disorders with long COVID. They indicate that stress and inflammation might drive disease precipitation of functional neurological disorders. Kimura et al. reports a patient with Bickerstaff brainstem encephalitis possibly triggered by COVID-19 and emerging Takotsubo cardiomyopathy (TC). They indicate that TC should be considered early when hemodynamic status remains unstable in patients with Bickerstaff brainstem encephalitis.There are several neurological manifestations that can be associated with COVID-19 and post- and long COVID. Maniscalco et al. present a patient with multiple sclerosis (MS) with a relapse shortly after vaccination with BNT162b2 from Pfizer-BioNTech. Nistri et al. present 16 cases regarding relapse manifestation of MS triggered by vaccination against SARS-COV-2 with 10 patients vaccinated with BNT162b2 from Pfizer-BioNTech, two patients vaccinated with mRNA-1273 from Moderna and four patients vaccinated with ChAdOx1 from AstraZeneca. In a case series by Ancau et al. three patients are reported with acute hemorrhagic encephalomyelitis (AHE) after SARS-COV-2 vaccination with ChAdOx1 from AstraZeneca. The authors indicated that these vaccination-related neurological diseases are rare events. They argue for the need of a robust post-vaccination surveillance.Song et al. report a patient with coexistence of anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor encephalitis and biomarkers of Alzheimer‘s disease. There are AE that are antibody-negative. Possibly, the relevant antigen has not been defined for these disease entities so far. Park and Kim present a patient of antibody negative AE that was successfully treated with B cell depletion by rituximab arguing for an underlying immunological disease-driving pathophysiology. Beside autoimmunity as driver for AE, there is paraneoplasia as disease initiator of AE, mediated by the anti-neoplasia-directed immune response. Gogia et al. report a case with amphiphysin antibody-associated stiff limp syndrome and myelopathy in a patient with breast cancer. Fang, Pan, et al. report a patient with relapses of anti-AMPA encephalitis with progressive brain atrophy and speculate regarding the underlying mechanisms. They observe partial functional recovery even in presence of severe brain atrophy after treatment with immunotherapy. Vaux et al. present a patient that was diagnosed with schizophrenia and was subsequently identified as a patient with anti-N-methyl-D-aspartate (NMDA) receptor encephalitis. Treatment with immune therapy led to improvement of symptoms in this patient. This case argues that patients with psychiatric diagnosis should be routinely explored for AE as a potential cause of their disease. This is important since immunotherapy can lead to improvement of symptoms and can in some patients even result in cure. Hashimoto‘s encephalopathy is a highly debated and questioned disease entity. Amano et al. present a patient with Hashimoto‘s encephalopathy associated with lymphomatosis cerebri and periodic synchronous discharges resembling prion, namely Creutzfeld-Jacob disease.Different types of autoimmune encephalitis (AE) are rare diseases with varying clinical presentations. Much can be learned regarding neurobiology from these diseases. Kolesnik et al. report a patient with herpes simplex virus 2 (HSV-2) encephalitis presenting with the clinical manifestation of chorea. This is a very rare clinical manifestation in HSV-2 encephalitis.Huang et al. report a patient with Guillain-Barré syndrome (GBS) and unilateral facial palsy. They summarize the current literature regarding such clinical presentations and report 28 cases. They speculate regarding the underlying immune response. Belgrado et al. had two patients with GBS and posterior reversible encephalopathy (PRES). They speculate that autoimmune dysregulation associated with GBS may be a trigger factor for co-emergence of PRES. A patient with reported combined central and peripheral demyelination (CCPD) was presented by Alshamrani et al. This patient had the coexistence of radiologically isolated syndrome (RIS) and Miller-Fisher-syndrome (MFS). Most so far reported cases of CCPD were diagnosed as having co-existence of MS and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).Koska et al. (a) report a patient with MS with severe lymphopenia due to treatment with fingolimod. The discontinuation of fingolimod treatment led to clinical deterioration with presence of neuropsychological symptoms that was difficult to overcome. Progressive multifocal leukoencephalopathy (PML) should be also taken early into consideration regarding differential diagnosis in such patients. Tang et al. present a patient with recurrent encephalopathy after treatment with ornidazole. Ornidazole is an antibiotic used for the treatment of protozoan infections. The patient recovered after discontinuation of the treatment with ornidazole. Longitudinal extensive transverse myelitis (LEMS) evolved and novel autoantibodies emerged in a patient treated with pemprolizumab reported by Charabi et al. The humanized antibody pemprolizumab targets programmed cell death protein 1 (PD1) on lymphocytes. Pemprolizumab is used in the treatment of various types of cancers. The emergence of LEMS was B cell mediated. A putative novel autoantigen was hypothesized in this disease condition that has not been defined so far.Baert et al. APRIL provides a favorable environment for plasmocytes in the NMO lesion. In addition, APRIL induces an anti-inflammatory response in the NMO lesion. This indicates that targeting of APRIL by novel immunological therapies should only be executed with extreme caution since there is a dichotomy of APRIL-related functions in the NMO lesion. Differential diagnosis can be challenging in patients with atypical clinical presentations. Fang, Tong, et al. report a patient with primary CNS lymphoma that was initially misdiagnosed with glial fibrillary acidic protein (GFAP) astrocytopathy. Early diagnosis to differentiate these diseases is important, due to grossly different treatment approaches. Gao et al. report a patient with GFAP astrocytopathy associated with an area postrema syndrome. Ma et al. report a patient with bilateral meningo-cortical involvement of anti-myelin-oligodendrocyte-glycoprotein (MOG) IgG associated disease. Štourač et al. present the difficulties in the diagnosis and treatment of progressive tumefactive demyelination. The presented patient had an unfavorable outcome. Neurosarcoidosis can be difficult to diagnose. Braun et al. present a patient with myelopathy that was finally diagnosed with neurosarcoidosis.The expression of a proliferation inducing ligand (APRIL), belonging to the TNF superfamily, in the CNS was investigated in a patient with neuromyelitis optica (NMO) reported by Koska et al. (b) report a patient with Marburg variant of MS who was successfully treated with cyclophosphamide and ocrelizumab. Eculizumab was successfully used to treat a patient with seronegative NMO by Digala et al. This argues for a role of complement in seronegative NMO.The case series “Multiple Sclerosis and Neuroimmunology—Case Report Collection I” demonstrates the power of case studies as well as their limitations. Possibly, the cases will help to gain progress regarding clinical, pathophysiological, immunological, and treatment-related understanding in clinical and research environments dealing with related patient groups and evolving scientific topics in neuroimmunology. Interested physicians, physician-scientist and researchers will possibly have a benefit that will help to transform scientific thinking in medicine to a patient-focused research approach regarding disease biology and rationally well-founded medical and rehabilitative treatments.RW outlined and wrote the editorial.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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.


Neurodegenerative diseases are a heterogeneous group of disorders characterized by gradual progressive neuronal loss in the central nervous system . These iThis Special Issue of Medicina, entitled “Biomarkers in Alzheimer Disease and Other Dementias: What’s Next into Pathophysiology to Support Clinical Practice and Drug Development”, includes seven articles dealing with the role of CSF plasma/serum biomarkers in the understanding the biochemical mechanisms and  diagnosis of dementing disorders, and their drug development.The CSF AD profile  is highly predictive of the progression of cognitively unimpaired subjects to mild cognitive impairment (MCI) and dementia. In their interesting study, Scarmeas et al. [Using ultrasensitive single-molecule array assays (Simoa), it is possible to measure low concentrations of NfL, not only in the CSF but also in blood samples, with very high sensitivity. In this prospective study of patients with AD conducted by Kern et al. , higher In the future, biomarkers should be available not only for early diagnosis, but also for indicating responses to specific therapeutic interventions that help to guide treatment decisionsfor AD. Alharbi et al.  demonstrPrion diseases are rare, irreversible neurodegenerative disorders with rapidly progressive dementia, cerebellar ataxia and myoclonus. Altuna et al.  reviewedα-syn species measured for further validation of these biomarkers in clinical practice.Continuous efforts will be also necessary to establish useful CSF biomarkers for the early diagnosis of dementia with Lewy bodies (DLB). In their review, Foska et al.  highlighCompared to protein-based biomarkers, miRNAs are more stable inbodily fluids; moreover, their easy measurement usingvarious commonly used laboratory methods make them potential biomarkers for atypical dementing disorders such asmultiple system atrophy (MSA) and progressive supranuclear palsy (PSP). In our systematic review , three sPotagas et al.  suggesteOverall, the papers published in this Special Issue contribute to a deeper understanding of biochemical markers in dementing disorders, including neurodegenerative proteinopathies with novel biomarkers. Thereby, this Special Issue might initiate hypothesis-driven refinement of current and novel biomarkers in AD and other dementias.


It is unclear whether seven interventions recommended by Public Health England for preventing and managing common musculoskeletal conditions reduce or widen health inequalities in adults with musculoskeletal conditions.We used citation searches of Web of Science (date of ‘parent publication’ for each intervention to April 2021) to identify original research articles reporting subgroup or moderator analyses of intervention effects by social stratifiers defined using the PROGRESS-Plus frameworks. Randomized controlled trials, controlled before-after studies, interrupted time series, systematic reviews presenting subgroup/stratified analyses or meta-regressions, individual participant data meta-analyses and modelling studies were eligible. Two reviewers independently assessed the credibility of effect moderation claims using Instrument to assess the Credibility of Effect Moderation Analyses. A narrative approach to synthesis was used (PROSPERO registration number: CRD42019140018).Of 1480 potentially relevant studies, seven eligible analyses of single trials and five meta-analyses were included. Among these, we found eight claims of potential differential effectiveness according to social characteristics, but none that were judged to have high credibility.In the absence of highly credible evidence of differential effectiveness in different social groups, and given ongoing national implementation, equity concerns may be best served by investing in monitoring and action aimed at ensuring fair access to these interventions. Studies had to be of adults aged 18 years and over with a relevant musculoskeletal condition  and not restricted only to patients with inflammatory disease or trauma/injury. Protocol papers, editorials, correspondence, conference abstracts and non-English language articles were excluded.Screening of titles and abstracts and review of full-text articles for inclusion were conducted by two independent reviewers with disagreement resolved by consensus, using RayyanData extraction was conducted by one reviewer using a form that we designed before data extraction began. Data extraction was checked by a second reviewer resolving discrepancies through discussion. In addition to standard descriptive fields, we extracted information on (i) baseline distribution of PROGRESS-Plus characteristics; (ii) methods, results  and author conclusions on moderator analyses by each PROGRESS-Plus variable; (iii) selective participation or attrition by PROGRESS-Plus characteristics.We assessed the credibility of potentially relevant treatment effect moderation reported in analyses of a single RCT or in meta-analysis of multiple RCTs using the Instrument to assess the Credibility of Effect Moderation Analyses (ICEMAN).Given heterogeneity in populations, interventions and outcomes, we anticipated a narrative synthesis approach rather than formal meta-analysis. Where available, we sought to summarize both relative and absolute differences in effectiveness of interventions by social stratifier.The citation search yielded 1480 potentially relevant articles after removal of duplicates, of which 12 were included .,,,Six of the 12 included studies were moderator (subgroup) analyses of data from single RCTs, typically the original trial, of the BeST,Within the economic analysis of the BeST trial data,et al.In addition to pre-specified moderator analyses of the BeST trial, Underwood et al.Using latent class analysis of baseline psychological and symptom severity variables in the BeST trial, Barons et al.In a complier average causal effects analysis of the BeST trial data, Knox et al.et al.Bernard et al.Martinez-Calderon et al.P = 0.028) with the beneficial effect of the STarT Back intervention greatest among higher SES participants and least in lower SES participants. This is suspected to be due to a lack of effect of promoting self-management without further face-to-face physiotherapist support in lower SES patients with low health literacy . The interaction term for educational level was in the same direction, suggesting greater benefit among more educated participants, but was statistically non-significant (P = 0.109). Interaction terms for age, sex and employment status were non-significant (P > 0.20).In a secondary analysis of STarT Back trial data, Beneciuk et al.et al.,et al.’s review included Yoga for Healthy Lower Backs trial findings alongside other forms of mindful exercise for chronic low back pain on the outcomes of pain intensity and disability. Martinez-Calderon et al.’s included various exercise intervention trials for low back pain with a focus on self-efficacy outcomes up to 12 months after intervention.Meta-regression analyses by Zou et al.,In pre-specified moderator analyses Salisbury et al.Meta-regression analyses by Niknejad et al.In contrast, Kroon et al.,et al.,et al.,et al.,We applied ICEMANTheoretically informed, pre-specified subgroup analyses of RCT data, adequately powered and appropriately conducted and reported, provide the best available evidence of differential effectiveness of interventions. We found no claims of differential effectiveness of interventions recommended in the PHE ROI tool that met this high bar of evidence. Some evidence that low back pain (LBP) patients of lower occupational class might benefit less from the STarT Back stratified care intervention was judged as moderately credible. However, this was not a pre-specified subgroup analysis in the original trial and, unlike secondary analyses of the BeST intervention,,et al.,,,,The absence of highly credible, ‘confirmatory’ evidence of differential effectiveness of interventions is not unexpected: a similar conclusion was reached in previous reviews in the general medical literature,,,,,The most comprehensive body of research to date has been on therapist-delivered interventions for low back pain, spanning subgroup analysis of the BeST trial,Our review extends previous research to specifically consider equity issues and provide a critical synthesis of currently available evidence on differential effectiveness for the range of interventions recommended in the ROI tool. Despite the high burden of musculoskeletal conditions there has been surprisingly little focus on equity when investigating the effects of interventions. Given the well-recognized challenges in obtaining rigorous evidence on equity effects from quantitative analysis of single and multiple trials, our review underscores the importance of embedding equity considerations across the research cycle including intervention development and process evaluation. While none of the interventions in our review was designed deliberately to be ‘equity focussed’, they have demonstrated overall effectiveness in populations with varying degrees of social diversity and many are now already at fairly advanced stages of implementation. At the time of this review almost 1300 health professionals had been trained to deliver ESCAPE-pain. Prior to COVID-19, it was offered at 295 NHS facilities and leisure/community centres across UK, including some in more deprived neighbourhoods. In total, 19 300 people have taken the programme and an online version has been released .We used a citation search strategy that will tend to miss relevant studies of other similar interventions. We restricted our attention to studies with an appropriate comparison of effect between social groups. There may be other studies, including those excluded at title/abstract stage, which include useful information or discussion on equity-related matters in relation to these or similar interventions, but we think it unlikely that we missed additional rigorous evidence of effect moderation. For example, one systematic reviewWe found no highly credible evidence against the assumption that seven interventions recommended for the prevention and management of musculoskeletal health are equally effective in different social groups. A policy of restricting or targeting these interventions to subpopulations is not supported. Most of these interventions are already being actively implemented, many achieving substantial reach nationally. Equity concerns may be best served by investing in equity-focussed action aimed at ensuring fair access to, and participation in, these interventions. Routine collection of key social variables during implementation should underpin this.Effects_on_health_inequalities_PHE_systematic_review_SUPPLEMENT_fdac014Click here for additional data file.


Direct care workers play a key role in supporting the health and wellbeing of older adults and people with disabilities across care settings—yet their own health risks are largely overlooked. The four papers in this symposium address this critical knowledge gap. First, McCall and colleagues will present a comparative analysis of the health status, health insurance coverage, and healthcare experiences of direct care workers across long-term care using National Health Interview Survey data. Next, Lee et al. will present the trends and characteristics of occupational injuries and illnesses among California’s long-term care workers from 2019 to 2020 using California Workers’ Compensation data, assessing the impact of COVID-19 on their occupational health. Sterling will characterize the physical and mental health of the direct care workforce before and during COVID-19 using data from the CDC's Behavioral Risk Factor Surveillance Survey, as well as drawing on qualitative and survey-based studies of unionized, agency-employed home care workers in New York. Sterling will also present findings from a pilot feasibility study of an intervention aimed at improving home care workers’ well-being. Finally, Quinn et al. will synthesize findings on home care workers’ occupational hazards—including needlesticks, musculoskeletal strain, violence and infections—and examine how preventing these risks can improve safety for both workers and clients. The discussant will draw out themes and implications from across these complementary studies, highlighting the importance of safeguarding direct care workers’ health as a key step toward improving care quality and outcomes for older adults and people with disabilities.


The prevalence of aging-related neuronal diseases is increasing. However, there is still a huge unmet need for diagnosis, treatments, and drug discovery of these diseases. With the development of modern high-throughput omic measurement platforms, vast amounts of biological data have been generated which can be integrated in multi-omics studies to examine the complex molecular underpinnings of diseases, thus impacting the development of aging-related neuronal diseases' therapy.In this editorial, we presented an account of how integrative multi-omics studies have greatly facilitated the diagnosis, treatments, and drug discovery of aging-related neuronal diseases. This editorial is based on 13 research articles and 3 regular reviews which shed light on the power of integrative multi-omics studies to improve aging-related neuronal diseases' therapy including but not limited to Alzheimer's disease (AD), ischemic stroke (IS), and Parkinson's disease (PD).Han et al.'s cross-sectional study, chi square test, correlation analysis, and regression analysis were employed to analyze the influencing factors of cognitive impairment. Consequently, gender, age, education level, hypertension, and LDL-C were found to have significant differences in the incidence of cognitive impairment, providing a basis for the early screening and intervention in the elderly . Two research articles create prediction models based on variables of interest. Kang et al. developed an accurate, efficient nomogram with a model created by Cox regression method and further built a corresponding website to help clinicians improve their assessment of patient outcomes. In Li J. et al.'s study, they applied machine learning classification model light gradient boosting machine (LightGBM) to analyze presurgical variables of endovascular treatment (EVT) for acute ischemic stroke (AIS) induced by large-vessel occlusion (LVO) and construct a unique prediction model which was used to establish feasible and accurate presurgical prediction scale in identifying unfavorable outcomes of AIS after EVT.Several research articles analyze variables for prediction. In Zhang C. et al. first employed the limma R package to the got the significant differentially expressed genes (DGEs) in Depression. These DEGS were then put into weighted gene co-expression network analysis (WGCNA) and protein–protein interaction (PPI) analysis and at last the common gene general transcription factor IIF polypeptide 2 (GTF2F2) which may serve as a promising diagnostic biomarker and treatment target of depression was thus identified . Most of the bioinformatic approaches in this study were implemented in the article of Gu et al., where Stepwise regression and logistic regression analyses were employed to get hub genes and diagnostic model related to Iron Metabolism in AD. They also retrieved eight drugs targeting hub genes from the DrugBank database . A similar study in IS was completed by Wang X. et al. where Boruta algorithm was used for genes' further screening. Importantly, they validated the gene signature with many methods, such as enrichment analyses through GO, KEGG, and GSEA pathways, ROC curves, and immune cell infiltration. Moreover, Li D. et al. demonstrated that gene methylation can also be utilized as signatures. In their research, least absolute shrinkage and selection operator cox regression analysis were carried out to construct a diagnostic signature related to PD . In Zhang W. et al.'s study, the molecular mechanism of Xingnao Kaiqiao Pill in the treatment of perioperative neurocognitive disorder (PND) was investigated from the perspective of network pharmacology and molecular docking technology. They constructed the network of “Xingnao Kaiqiao Pill–traditional Chinese medicine–compound–common target” by Cytoscape software. Molecular docking stimulation was used to further verify the interaction between the active components and key targets . Huang et al. and Chen Y. et al. both performed multi-omics integration analysis based on single cell technology. In their study, scRNA analysis, differential expression analysis, cell-cell communication analyses, and cell trajectory inference analyses were performed to identify candidate ligands or receptors, as well as the corresponding cell types. Combined with molecular docking, Huang et al. found that Quercetin targets VCAM1 to prevent diabetic cerebrovascular endothelial cell injury , while Chen Y. et al. further identified differentially expressed transcription factors in AD associated with exercise using a modified SCENIC method. Chen Y. et al. finally constructed a network of exercise-regulating TFs in monocytes, revealing the mechanism by which exercise regulated monocytes to confer therapeutic benefits against AD and its complications. Furthermore, through target gene's knockdown and bioassays, Xia et al. found that GDF15 effectively alleviated neuronal ferroptosis post Spinal cord injury (SCI) via the p62-Keap1-Nrf2 signaling pathway and promoted locomotor recovery of SCI mice, which is suggested as a potential target on SCI pathogenesis and treatment.Eight research articles capture gene signature (models) by integrating multi-omics information through different bioinformatics analysis and machine learning approaches. Zhu et al. exploited a novel iterative method called linear neighborhood similarity-based protein multifeatures fusion (LNSPF) to predict potential key proteins. The gene expression data downloaded from the benchmark database are used for further optimization through linear neighborhood similarity . To find biologically important imaging genetic relations more powerfully, Wang et al. imposed the GraphNet regularization penalty on the existing model and presented an improved fusion paired group lasso structured sparse canonical correlation analysis algorithm (FGLGNSCCA). Experiment results shown that the new FGLGNSCCA model proposed in their manuscript is superior or equivalent to traditional methods. With FGLGNSCCA algorithm, more AD-related biomarkers can been found .Notably, two research articles focus on the development of computational approaches which can integrate multi-omics information. Based on topological features extracted from a protein-protein interaction (PPI) network and functional features extracted by integrating subcellular localization and homologous information of proteins, Chen W. et al.'s review focuses on optogenetics in neurobiology, including how to use optogenetics to control nerve cells, study neural circuits, and treat diseases by changing the state of neurons. Wang Y. et al. revealed potential protective role of polysaccharides of Neurodegenerative Diseases (NDs), highlighting the contributions of polysaccharides and the prospects of their mechanism studies for the treatment of NDs. Ji et al. concentrated on body fluids biomarkers of early neurological deterioration (END) that have shown potential to be transferred into clinical practice.Finally, three reviews give a comprehensive understanding of the progress in the field of aging-related neuronal diseases from different aspects. In conclusion, the research articles and reviews in this Research Topic show how integrative multi-omics are applied to better understand and treat aging-related neuronal disease. For fully utilizing data from various omics sources to gain insights into disease, multi-omics approaches are becoming more relevant every day.This editorial was designed by MT and XG and written by CS and XL. YL, HZ, and YG had revised it. All authors have made a direct and intellectual contribution to this topic and approved the article for publication.This work was supported by grants from Jiangsu University (19JDG039) and the National Natural Science Foundation of China (32002235).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.


APOE ε4 allele is the greatest genetic determinant for AD and is widely reported to mediate detrimental effects on mitochondria function and mitophagic process. Given the continuity of the physiological process, this review takes the mitochondrial dynamic and mitophagic core events into consideration, which highlights the current knowledge about the molecular alterations from an APOE-genotype perspective, synthesizes ApoE4-associated regulations, and the cross-talk between these signaling, along with the focuses on general autophagic process and several pivotal processes of mitophagy, including mitochondrial dynamic , mitophagic induction . These may shed new light on the link between ApoE4 and AD and provide novel insights for promising mitophagy-targeted therapeutic strategies for AD.Alzheimer's disease (AD) is one of the major worldwide causes of dementia that is characterized by irreversible decline in learning, memory loss, and behavioral impairments. Mitophagy is selective autophagy through the clearance of aberrant mitochondria, specifically for degradation to maintain energy generation and neuronal and synaptic function in the brain. Accumulating evidence shows that defective mitophagy is believed to be as one of the early and prominent features in AD pathogenesis and has drawn attention in the recent few years.  Alzheimer's disease (AD) is the most common and well-known form of dementia and features age-related and progressive recognition impairment, memory loss, and learning failure, accompanied by encephalatrophy, and extracellular amyloid-β (Aβ) plaques, intracellular tangles of hyperphosphorylated Tau  allele remains the strongest genetic risk for sporadic AD , inner mitochondrial membrane (IMM), intermembrane space, and mitochondrial matrix performs diverse essential roles in multiple intracellular homeostasis events, including tricarboxylic acid cycle, β-oxidation of fatty acids, genetic information storage, CaHere, we have reviewed emerging findings for the central and multi-faceted roles that mitophagy plays in the pathogenesis of AD, described physiological changes from the pre-mitophagy events to mitophagy proceeding considering the continuity of the physiological processes, integrated the signaling pathways suggesting the relationships between ApoE4 and mitophagy deficit, and discussed the underlying mechanisms that how ApoE4 triggers these abnormalities and ultimately contributes to AD pathogenesis, while highlighting potential therapeutic targets that may correct these dysfunctions .Autophagy is a ubiquitous event highly conserved from yeast to mammals and functions as a recycling system for maintaining metabolic homeostasis and cellular self-renewal , and mitophagy-specific induction.Mitochondria is a highly dynamic organelle that can form long tubular networks for highly interconnected networks, and continually undergoes the cycle of fusion and fission in response to environmental changes  and higher phosphorylation level of dynamin-related protein1 (DRP1), leading to reductive mitochondria fragmentation and neuronal energy dysfunction  possess pro-fission activation and fusion inhibition  are the most broadly investigated fission regulators network in recent years Chan, . Mitochoin vivo and in vitro, ApoE4 interferes with SIRT1 transcription, expression, and enzyme activity more than ApoE3  in the frontal cortex tissue from AD patients  are growing and the polyubiquitinated level of MFN-2 is reduced, while the fission proteins (FIS1 and GLP1) are not distinctively altered in HEK293 cells overexpressing human Tau, and rat primary hippocampal neurons  machinery, then is cleaved by PARL in a mitochondrial membrane potential (MMP)-dependent manner followed by degradation  and mitophagic genes (BNIP3 and PINK1)  in APOE ε4 carriers. Collectively, ApoE4 mediated full-scale inhibition of mitophagy via FOXO3a signaling, including its expression, activity-dependent on chemical modification, and the induction of its downstream effects.FOXO3a served as a transcription factor highly represented in the brain and a new target of AD diagnosis  is a deacetylase, highly expressed in high-metabolic tissues, and strongly associated with mitochondrial quality (Meng et al., via direct interaction with TOMM40 (Bertolin et al., 2a cells by proteomic profiling (Mise et al., APOE (Simonovitch et al., TOMM40 expression is closely associated with APOE expression (Mise et al., APOE-TOMM40-APOC1 variants are strongly associated with a high instance of AD (Gottschalk et al., APOE ε4 has closely linked to various TOMM40 polymorphisms carried adverse impacts (Roses et al., APOE ε4, and its degradation is blocked under an ApoE4-induced context, which may be helpful to explore the underlying mechanisms of AD.TOMM40, a channel-forming subunit at OMM constituting the TOMM40 complex for protein import into mitochondria (Humphries et al., 2a cells performed by proteomic profiling assays (Orr et al., via double-labeling analysis, and reconfirmed the interaction without isoform-dependent difference via co-IP in H9c2 cells, a type of embryonic rat heart-derived cells (Chen et al., APOE-TR mice or AD model mice, even the APOE ε4 carriers and AD subjects, in order to explore whether the interaction exists in the neuronal system, whether there is a differential interaction between ApoE3 and ApoE4, and whether it is associated with AD pathogenesis. Incidentally, the VDAC1-Aβ and VDAC1-Tau interaction is confirmed by double-labeling analysis and co-IP in the brains of AD subjects and several AD model mice (Manczak and Reddy, VDAC1, a porin protein abundantly located at OMM that mediates ATP production and the trafficking of nucleotide and metabolites, functions as a target for Parkin-directed poly-ubiquitin chains, and regulates Parkin recruitment (Sun et al., Aβ aggregation causes reductive cytosolic Parkin and PINK1 levels in the cytoplasm (Kerr et al., via multi-faced downstream regulators (Sohn et al., Collectively, ApoE4 and PINK1-Parkin comprise a potential mitochondrial signaling cascade response pathway, and these observations indicate ApoE4-mediated inhibition on PINK1-Parkin mitophagy Deficient mitochondrial quality control is established to interfere with cellular bioenergetic metabolisms and neuronal survival, leading to the occurrence and development of neurodegenerative disorders (Chinnery, 2+ (Cereghetti et al., APOE genotype. Third, the neuro-degeneration processes may share a common mechanism with AD and other neurodegenerative diseases. ApoE has been extensively studied in multiple fields and displays new findings, such as the interaction of ApoE4-TFEB promoter (Parcon et al., SIRT1 promoter (Theendakara et al., APOE-genotype perspective, hence, completing a related investigation may be helpful to better understand the complicated alterations in AD (Sun et al., in vivo and in vitro studies and further develop specific therapies.Despite current studies about mitophagic control, some important issues are required to be addressed. First, ApoE4 participates in diverse mitophagic signaling pathways at various processes in direct or indirect manners (Horner et al., In general, mitophagy is a multifunctional event preventing AD pathogenesis along with multiple challenges to its beneficial effects. Current findings of the ApoE4 role of mitophagy in AD seem to be limited to some extent, and remain controversial still need further investigation in detail. Discovering the gaps in the underlying mechanisms are greatly enlightened to screen for possible and predominant mechanisms and open a new avenue of research to facilitate earlier diagnosis or potential neuroprotective therapies for AD.GC had the idea for the article and made the final approval of version to be submitted. HC wrote and critically revised the manuscript the work. YiJ and FC supervised the overall writing and edited the manuscript. GH and LZ performed the literature search, sorting, and integration. FS and MZ provided guidance, helpful discussion, and careful revision. YC and YaJ helped the schematic diagrams. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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 Women in Avian Physiology Research Topic is part of an inclusive Frontiers series across all sections focused on Women in Physiology. The purpose of the series is to showcase physiological research of women and to highlight their achievements. Submissions were welcomed covering all areas of Avian Physiology. Submissions were encouraged from early career researchers and/or where the lead/last author were females. A total of 12 submissions were accepted for publication in this Research Topic covering the areas of: 1. Skeletal Muscle Physiology and Meat Quality; 2. Female Reproduction; 3. Pathobiology; 4. Genetic Selection; and 5. Neurobiology.Swanson et al., Bordini et al., and Xu et al.Swanson et al. reviewed phenotypic plasticity to environmental variation focusing on metabolic rates and skeletal muscle physiology in wild birds. The ultrastructural plasticity of skeletal muscle with regard to thermal variation and increased workload was reviewed and correlated with myostatin, Insulin-like growth factor-1, and satellite cell proliferation. Xu et al. examined the effects of temperature and selection for growth on the proliferation, differentiation, adipogenic potential of turkey myogenic satellite cells through frizzled-7-mediated Wnt planar cell polarity (Wnt/PCP) pathway. It was found that thermal stress altered frizzled-7 regulation of the Wnt/PCP pathway in a growth-dependent manner affecting the growth potential of the breast muscle and protein to fat ratio. Bordini et al. contributed an original Research Topic studying molecular pathways and key genes associated with White Striping and Wooden Breast in chickens. Using Weighted Gene Co-expression Network Analysis to identify clusters of co-expressed genes associated with White Striping and Wooden Breast, they found that endoplasmic reticulum stress may underly the inflammatory condition in affected breast muscles and Collagen type IV may have significant role in the events leading to White Striping and Wooden Breast.Three contributions addressed skeletal muscle physiology and/or meat quality by Hanlon et al. provided a comprehensive review on the roles of 17β-estradiol in non-gonadal tissues and its impact on reproduction in both laying and broiler breeder hens. Estradiol-17β are involved in reproduction, liver metabolism, and medullary bone formation. Thus, this hormone may regulate all aspects of egg formation and hence the timing of estradiol-17β is critical to reproduction which has been altered by genetic selection for intense growth. Mehlhorn et al. investigated how hen line, age and housing affect estradiol-17β on egg laying performance. High performance hen lines had higher estradiol-17ß concentrations compared to low performing hens. Regardless of line, maximal estradiol-17ß concentration was measured at their 49th to their 51st week of age. Furthermore, cages hens had highest estradiol-17β levels compared to floor housed hens. We could show that laying performance is strongly linked with estradiol -17ß concentration. This concentration changes during laying period and is also influenced by the housing system.Salmonella vaccine  was shown to decrease Salmonella enterica serovar enteritidis load in immunized broiler chickens by Acevedo-Villanueva et al.Shanmugasundaram et al. contributed an original Research Topic demonstrating that subclinical doses of combined fumonisins and deoxynivalenol (mycotoxins contaminating poultry diets) predispose Clostridum perfringens inoculated broilers to necrotic enteritis, an economically important disease negatively impacting digestion and absorption of nutrients in broilers.Use of an oral-killed chitosan nanoparticle Bernardi et al. reported on chemerin as a possible genetic selection tool for embryo survivability pending larger scale testing. Research on how the somatotrophic axis has changed with commercial growth selection and its relationship to increased growth was reported by Vaccaro et al. They found the expression of insulin-like growth factors 1 and 2 was greater in the modern commercial chicken and maybe linked with increased breast muscle growth and overall muscle accretion. In broilers divergently selected for ultimate pH, it was found by Beauclercq et al. that there is an association between serum lipid profile, ultimate pH and meat quality. Furthermore, since ultimate pH can be obtained on live birds, it may be a useful marker in genetic selection.Two contributions addressed the effects of genetic selection. Loveland et al. contributed a perspective paper on how inversion variants can affect neural circuitry. This review covered how behavior polymorphisms can evolve from genetic inversions, especially when inversions are associated with sets of genes involved with hormonal regulation. Primary focus was on the three-morph system of the ruff , two alternative morphs (Satellites and Faeders) each with distinct behaviors and low circulating testosterone that is genetically determined by an inverted region on an autosomal chromosome. Franco et al. examined the bird sense of sight and found that broilers raised under blue light were more hyperopic than those raised with white light. The blue light reared broilers had better spatial vision and higher success in selecting the right feeder.


Advances made in the Internet of Things (IoT) and other disruptive technological trends, including big data analytics and edge computing methods, have contributed enabling solutions to the numerous challenges affecting modern communities. With Gartner reporting 14.2 billion IoT devices in 2019 , smart aHowever, there remain practical challenges in large-scale and rapid deployment of sensors for diverse applications, such as problems affecting siting optimization methods and participant recruitment and incentive mechanisms. On a higher level, the deluge of data sources that drive the IoT phenomenon grows every day. With the rise of smartphone-enabled citizen sensing data via social networks or personal health devices, as well as with increasing connectedness in transport, logistics, utilities, or manufacturing domains, this range and complexity of available data calls for even more advanced data processing, mining and fusion methods than those already applied.The goal of this Special Issue was to solicit high-quality original papers aimed at demonstrating effective and efficient deployment of sensor networks in the IoT, encompassing both physical and virtual sensor networks (through modelling) as well as social networks. Related issues of data processing, in addition to challenges of the fusion and visualisation of the resultant IoT big data, are also reflected in the published papers. This Special Issue consists of 11 papers. All submissions were strictly and thoroughly peer-reviewed by experts. These submissions cover many of the relevant research issues. In the following sections, we summarize these articles and highlight their major contributions.In the article entitled “egoDetect: Visual Detection and Exploration of Anomaly in Social Communication Network”, Pu et al . presentThe article entitled “Recognizing Context-Aware Human Sociability Patterns Using Pervasive Monitoring for Supporting Mental Health Professionals”, contributed by Moura et al. , presentZurbuchen et al. , in theiThe article entitled “IoTCrawler: Challenges and Solutions for Searching the Internet of Things” by Iggena et al.  addresseThe paper entitled “Energy Management Expert Assistant, a New Concept” by Linan-Reyes et al.  presentsThe topical theme of user device location privacy is explored in the paper “Perturbed-Location Mechanism for Increased User-Location Privacy in Proximity Detection and Digital Contact-Tracing Applications” by Lohan et al. , which pThe predictive maintenance of sensors is addressed in the article entitled “Providing Fault Detection from Sensor Data in Complex Machines That Build the Smart City” by Gascón et al.  through The application of IoT-enabled services to smart tourism scenarios is explored in the article “An Architecture for Service Integration to Fully Support Novel Personalized Smart Tourism Offerings” by Sabbioni et al. . The artThe use of short texts from social networks as a data source in the IoT is the focus of the article entitled “Investigating the Efficient Use of Word Embedding with Neural-Topic Models for Interpretable Topics from Short Texts”, submitted by Murakami and Chakraborty . The aut“A Novel Privacy Preserving Scheme for Smart Grid-Based Home Area Networks”, submitted by Ali et al. , presentA review article, entitled “Applications of Wireless Sensor Networks and Internet of Things Frameworks in the Industry Revolution 4.0: A Systematic Literature Review” by Majid et al. , complet


Determination of antisuicidal factors (AF) in balance with risk factors for suicidal behavior (SB) is essential for treatment and prophylactic measures.Study AF in a sample of schizophrenic recovered patients  according to operational criteria R.P. Liberman et al. (2002).The content analysis of published self-reports of a sample (n = 13) of Russian and foreign psychiatrists and clinical psychologists with psychotic experience was used as a part of a more extensive qualitative analysis of «wounded healers».In the history of > ½  ex-patients, repeated SPs (aborted suicides), as well as non-suicidal self-harm , were noted during the active period of the disease, and in four of them – during untreated psychosis. Following AFs can be distinguished in recovery state: clinical  social , and existential .AF is an important integral component of recovery in schizophrenia as a process of personality development despite a burden of severe mental disorders.No significant relationships.


Enterobacter faecalis MSI12 and its effect on the disruption of Candida albicans biofilm’ by G. Seghal Kiran et al., RSC Adv., 2015, 5, 71573–71585, DOI: 10.1039/C5RA10302A.Correction for ‘Characterization of an exopolysaccharide from probiont  The authors regret that incorrect versions of Accordingly, the experimental methods followed in the phase contrast microscopy and large-size images of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.


The second volume of the Special Issue on “Micro-Electro Discharge Machining: Principles, Recent Advancements and Applications” confirms the growing interest in the micro-EDM technology as a suitable and efficient technology for machining novel, multi-material components, with demanding requirements in terms of precision, accuracy and productivity.This volume consists of 10 original research papers which involve several approaches to micro-EDM and cover the enhancement of the process performance, such as the material removal rate, surface roughness, or accuracy of the machining, using advanced optimization methods. Some studies also consider several dielectric fluid additives and investigate the processability of new materials. Others investigate the combination of Reverse-micro-EDM with laser beam micromachining or explore new applications for the micro-EDM for fabricating antimicrobial nanosilver colloid.In more detail, in order to improve the machining accuracy of detail features in micro-EDM milling, a theoretical model is developed by Jing et al.  to simulThe influence of the near-dry WEDM technique to reduce the environmental impact of wet WEDM was investigated by Chaudhari et al. . The stuA mathematical–statistical computational (MSC) model for predicting high productivity and quality of the machined area is formulated by Straka et al.  by the aWire-cut electro-discharge machining (Wire-EDM) of polymer composite material (PCM) was studied by Ablyaz et al. . Tests wSidhu et al.  used theAblyaz et al.  investig2O3). The study evaluated effects on material removal rate (MRR), relative electrode wear rate (REWR), and surface roughness on machining (EDM) of ultrafine particle type tungsten carbide and observing single discharge crater and hole machining tests. The results showed that adding CnF enhanced the material removal rate under all conditions. In contrast, Si and Al2O3 powders only improved the machining performance at a high discharge energy of 110 V. Improvement in surface roughness was observed prominently at high voltages for all the powders. However, alumina improved the surface roughness the most among the three powders.Gattu et al.  mixed thEsser et al.  observedReverse-µEDM was considered by Kishore et al.  with theFinally, an alternative study has been performed by Tseng et al.  with theWe thank all the authors who submitted their papers to this Special Issue, “Micro-Electro Discharge Machining: Principles, Recent Advancements and Applications”. We would also like to acknowledge all the reviewers for dedicating their time to providing careful and timely reviews to ensure the quality of this Special Issue.


Research focusing on innovative nanomaterials for applications in biomedicine and bioengineering has steadily gained attention over the last 20 years. This is due to the unique physical and chemical characteristics that can be provided by nanomaterials compared to their bulk counterparts, including augmented surface reactivity; improved mechanical, electrical, magnetic, optical and thermal properties; and their enhanced bioactivity, drug loading capacity or permeability through biological barriers. Advanced nano-biomaterials with tailored surface topography and chemistry can be designed to create environmental conditions favorable for proper protein and consequently for accelerated cell adhesion, proliferation and differentiation ,2. In thNanostructured modifications of metal scaffolds represent a promising approach to accelerate implant osseointegration through the increasing in endothelial commitment of mesenchymal stem cells (MSC). Gardin et al. explored the possibility that exosomes secreted by hMSCs grown on the different nanotubular Ti surfaces  could act as biomimetic tools to modulate the biological properties of human umbilical vein endothelial cells (HUVECs) in vitro . The resNanoscale surface modifications may also have an impact on peri-implant cell fate and implant loading, both of which have an impact on early bone healing. This issue was addressed by De Barros E Lima Bueno et al., who studied how mechanical loading affects healing around implants with nanotopography . At 7 daIn addition to nanotopography, the composition of the composition certainly plays a key role in determining the final performance of biomedical devices. Poly:polystyrene sulfonate (PEDOT:PSS) is a widely used conductive polymers for a plethora of applications, including electroactive scaffolds for bone tissue regeneration. As a viable alternative, PEDOT:Nafion is emerging due to its better electrochemical properties than PEDOT:PSS. However, its biocompatibility has not yet been studied. Guzzo et al. investigated the in vitro cytotoxicity of nanostructured PEDOT:Nafion coatings obtained from a water-based formulation of PEDOT:Nafion, using a primary cell culture of rat fibroblasts . The resMagnetic iron oxide nanoparticles are widely used in applications for targeted anti-cancer radiotherapy and imaging techniques using radioisotopes emitting β+, β−, α, and γ radiation. In this context, Nieciecka et al. demonstrated that the conjugation of iron oxide nanoparticles with terbium ions and guanosine-5′-monophosphate  were more promising for hypothermia-based treatments than standard unconjugated nanoparticles .4:Yb3+/Er3+ UCNPs coated with SiO2 using the hydrothermal method [Up-conversion rare-earth nanoparticles (UCNPs) are an extremely interesting class of materials due to their high fluorescence intensity as well as the possibility to absorb near-infrared radiation and converting into visible light through non-linear optical processes. Zhang et al. reported a new method for synthesizing Ag-NaYFl method . These nA new and promising strategy for cancer therapy is sonodynamic therapy (SDT). In SDT, effective sonosensitizers are of paramount importance. Ma et al. showed that urchin-shaped copper-based metalloporphyrin liposome nanosystem can be considered highly effective sonosensitizer, as it was found to massively generate reactive oxygen species capable to kill 4T1 tumor cells under ultrasound irradiation . In the This Special Issue also contains four review articles on key topics in the field, which can be very interesting and useful, especially for young researchers involved in this multidisciplinary and highly fascinating field of research. The first review by Duta et al. covers the production of biphasic calcium phosphate materials derived from fish wastes , known as fish discards, in the context of material recycling and the circular economy . This woNanomaterials covers a wide range of different nanomaterials, including nanostructured coatings, nanoparticles, nanosystems, biomimetic devices and drug carriers that are expected to be the building blocks of next-generation of biomaterials. Although not fully representative of the huge number of different nanomaterials and solutions available for biomedical applications, this Special Issue manages to provide a quick overview of some of the most promising solutions in this rapidly evolving and interdisciplinary field.In summary, this Special Issue of


F. Duffy et al. Nature Communications 10.1038/s41467-022-32996-5 (2022)P. falciparum transcriptomic datasets with approaches centred on the tight transcriptional pattern governing P. falciparum along its ~48 h intraerythrocytic asexual cycle, and we showed a relation between circulation of more developed parasites within each ~48 h asexual cycle and lower parasitaemias or milder malaria symptoms1. Previously unpublished data from Duffy and colleagues is not fully aligned with our published conclusions. Here we discuss their comments on our recent study.We have recently reanalysed several 1 we included among others, the 2018 publication by Tonkin-Hill et al.2 which at the time did not report individual patients’ parasitaemias, total parasite biomass estimates in the form of Ptot or the levels of HRP2, haematocrit, and weight for its calculation, or that parasitaemias of the subset of the patients whose samples they used for differentially expressed gene (DEG) analysis were significantly different between samples of severe and uncomplicated malaria cases, contrary to their report for the comparison including the entire group of samples2, hence we could not have included these data in our publication.In our manuscript2, we included their reported DEG list in the analyses of our manuscript similarly to what we did for other studies1. We concluded that the comparison between non-severe and severe cases without reported strong parasitaemia differences in Tonkin-Hill et al. resulted in less pronounced differences in peak of expression of DEGs and in proportions of predicted parasite stages. We agree with Duffy et al. that we could have more clearly transmitted to the reader that the normalization efforts originally applied to their dataset would prevent showing such clear trends as the other studies, and accept their criticism. Nevertheless, despite the normalizations implemented, using the reported DEG list by Tonkin-Hill et al. we still estimate higher ring-stage proportion in severe versus non-severe malaria cases ; and we observed gene expression patterns associating with number of housekeeping-gene reads, which we used instead of individual parasite levels, given that those were not originally reported 2. Duffy et al. now report that RNAseq read counts of this housekeeping gene and individual parasitaemias do not correlate, which we had no possible way of knowing at the time of publication of Thomson-Luque et al.1. We do not fully agree with the additional arguments based on correlations proposed by Duffy et al. The proportion of ring- and non-ring- asexual stages is expected to sum up to 1 (or very close to 1 whenever gametocytes are present). Positive correlations to one of the groups imply negative correlations to the other, as in fact Duffy et al. observed. That the correlation found by Duffy et al. is positive with the proportion of rings, supports our rational that severe cases have higher proportion of rings  and higher parasitaemias . The variation of the glycine tRNA ligase shown on PlasmoDB highlights slightly lower expression of the gene at very young ring stages or schizonts, which would lead to proportionally lower normalised glycine tRNA ligase reads in parasites of younger developmental stage, and not reflect youth of parasites as proposed by Duffy and colleagues.Although we were aware of the different efforts Duffy and colleagues performed in Tonkin-Hill et al. to statistically normalize by developmental stage the differential expression between parasites causing severe and non-severe malaria1 as only Lee et al. reported individual values of HRP23 of the ten studies included.In Fig. 5 of Thomson-Luque et al. we have not investigated transcriptome correlates with circulating parasite density within each individual study, as we believe these would be difficult to detect due to small sample size, and short ranges in parasite densities in the vast majority of the included studies. We also did not report nor inferred any correlates between total parasite biomass and circulating parasite age in Thomson-Luque et al.2. At the time of publishing Thomson-Luque et al. we referred to the parasite density comparison reported in Tonkin-Hill et al.2, showing a non-significant difference between severe and uncomplicated malaria cases n = 44 p = 0.87262, and we could not foresee that the authors would now present an analysis of the same cohort with a lower sample number  showing a significant difference .Duffy et al. now report that parasitaemias of the subset of the patients whose samples they analysed for differentially expressed gene (DEG) analysis were significantly different between samples of severe and uncomplicated malaria cases, however, this data is novel and different from the one they published in Tonkin-Hill et al.2. And in Thomson-Luque et al. we wrote: “Tonkin-Hill et al. detected no differences between severe and uncomplicated malaria cases in total number of var gene reads, but identified segregation at the multidomain and individual domain level between severe and uncomplicated disease. However, Tonkin-Hill et al. also found genes involved in PfEMP1 transport and regulation to be downregulated in severe malaria”. We believe we did not interpret Tonkin-Hill data or statement wrongly.Regarding a possible misinterpretation of Tonkin-Hill var gene expression data, objectively, in Tonkin-Hill et al. can be read “genes involved in PfEMP1 transport and a gene involved in regulation of var genes were down-regulated in severe malaria. This suggested that var gene expression was modulated but PfEMP1 surface presentation was reduced.”4, in line with the with the conclusions in Thomson-Luque et al. Nevertheless, we acknowledge that our combination of very different datasets may be a limitation, and we believe that future studies, including parameters like the ones now presented by Duffy and colleagues, alongside novel approaches like single-cell analysis should provide greater resolution of the parasite life-cycle stages. This may help improve interpretations and correct any unintended imperfect conclusion in Thomson-Luque et al. and the other bulk RNAseq-studies.We published a series of observations obtained through multiple approaches and applied to several studies, which we interpreted considering the data included in the original reports, to allow the detection of broad patterns that could otherwise be overseen. Since the publication of Thomson-Luque et al., a study investigating expression profiles of cerebral malaria and uncomplicated malaria isolates from Benin found that the mean parasite age expressed in hour post invasion was statistically lower in cerebral malaria cases, and confirmed the difference by microscopic reading of thin blood smearsFurther information on research design is available in the Reporting Summary


Non-coding RNAs including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are implicated in the regulation of gene expression at transcriptional, posttranscriptional, and epigenetic levels. Several studies in cell lines, animal models, and humans, have revealed that non-coding RNAs play crucial roles in the pathogenesis of Alzheimer's disease (AD). Detailed knowledge on their mechanism of implication in the AD pathogenesis can help to develop novel therapeutic and disease management strategies. The two main pathological hallmarks of AD are amyloid plaques resulting from the β-amyloid accumulation, and neurofibrillary tangles (NFT) due to the phosphorylated tau accumulation. Several lncRNAs and miRNAs play crucial roles in both these hallmarks of the AD pathogenesis and other AD-related pathological procedures such as neuronal and synaptic plasticity, neuroinflammation, neuronal differentiation and neuronal apoptosis. In this review, we outlined the non-coding RNAs and further discussed how they are implicated in these AD-related pathological procedures. Alzheimer's disease (AD) is a devastating neurodegenerative disorder and the most common cause of dementia, accounting for approximately 60 % to 80 % of cases among the elderly worldwide  comprise a class of endogenous regulatory RNA molecules that are over 200 nucleotides (nt) in length, without protein-coding capacity, and make up the largest proportions of the mammalian non-coding transcriptome , and th2O2 increase the expression of lncRNA BACE1-AS, which in turn makes BACE1 mRNA more stable, leading to enhanced APP processing and toxic Aβ production by a post-transcriptional feed-forward mechanism  is an enzyme central to the pathology of AD that contributed to the formation of Aβ peptides and extracellular plaque deposition . BACE1 al., 2008). Producal., 2008) . Besideal., 2008). BACE1-al., 2008; Fotuhi al., 2008).The neuronal sortilin-related receptor 1(SORL1) gene encodes SORLA protein, which is involved in the processing of amyloid-β protein precursor (APP) and decrease Aβ peptides production in neurons . StudieLow density lipoprotein receptor-related protein 1(LRP1), as a receptor is involved in a variety of cellular processes including cell signaling, lipoprotein metabolism, and APP trafficking and processing . LRP1 iOne of the neuropathological features of AD is synaptic dysfunction that occurs in the first stages of the disorder , is widely synthesized in the central nervous system, has a physiological role in synaptic plasticity and survival of neurons . BDNF gal., 2016, 2009[98al., 2012). Guo etal., 2012). It wasal., 2012; Ding etal., 2012), and thal., 2012). More rGlial cell line-derived neurotrophic factor (GDNF) is an important biologically active trophic factor for development and survival of the midbrain dopaminergic neurons . It hasNeuroblastoma differentiation marker 29 (NDM29), a RNA pol II-transcribed lncRNA, mapped to a genomic region of chromosome 11, and its synthesis is regulated by an extragenic type 3 promoter . NDM29 Sox2 is a component of the core transcriptional regulatory network that is essential for maintaining pluripotency of stem cells and neurogenesis . Sox2 oRecently, Magistri et al. used RNA sequencing in order to discover significant alterations in expression profile of the lncRNAs from AD brains and found that lncRNA EBF3-AS is abundantly expressed in the brain of late-onset AD cases compared to control individuals . FurtheLee and colleagues identified 47 upregulated and 158 downregulated lncRNAs in rat model of AD compared with healthy controls using microarray analysis . MoreovMicroRNAs (miRNAs) are endogenous ~22 nucleotide non-coding RNAs, responsible for direct posttranscriptional regulation of gene expression, either by targeting mRNA degradation or by inhibition of protein translation at both mRNA and protein levels . After ′-UTR region of the BACE1 to reduce Aβ accumulation, which makes it as a novel drug target , a rate-limiting enzyme involved in the formation of Aβ, plays a crucial role in AD progression . Similaal., 2014; Zhu et al., 2014). Other al., 2014). Furtheal., 2014). In anoal., 2014). Du et al., 2014). In sum′-UTR of the APP mRNA resulted in decreased level of APP in patients with AD . Intereal., 2020).in vitro and in vivo . Severaal., 2016). Smith al., 2016). It hasal., 2016). Studieal., 2016). Moreoval., 2016).In this review, we summarized the relationship between ncRNAs and AD pathogenesis based on recent evidence. Multiple studies have shown the critical role of ncRNAs in various biological processes, including cell growth, apoptosis, and differentiation, indicating that they might be involved in the occurrence and progress of neurodegenerative diseases including AD  can be used as potential therapeutic targets and biomarkers.Reliable biomarkers for early diagnosis are required to halt the disease development and improve the effects of therapeutic strategies.Authors appreciate the Cognitive Sciences and Technologies Council of Iran for supporting this work.This work was supported by the Cognitive Sciences and Technologies Council of Iran, grant number 6300.The authors have no relevant financial or non-financial interests to disclose.Majid Khodayi-Shahrak performed research and wrote the manuscript; Mohammad Khalaj-Kondori supervised research, reviewed and edited the manuscript; Mohammad Ali Hosseinpour Feizi reviewed and edited the manuscript; Mahnaz Talebi reviewed and edited the manuscript.


Snowdon et al., RSC Adv., 2019, 9, 6752–6761, DOI: 10.1039/C9RA00034H.Correction for ‘Comparative study of the extrinsic properties of poly(lactic acid)-based biocomposites filled with talc  The authors regret that the values given for oxygen and water vapor permeability in The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.


The intensive genetic selection of broiler (meat-type) chickens over the past 80 years has focused narrowly on economically important traits, namely growth rate, feed efficiency, and breast yield . AlthougGrowth rates have dramatically increased by over four times between 1957 and 2005  and modede novo lipogenesis  and/or endogenous (adipogenesis/lipogenesis) sources. As commercial broilers are fed lipid-poor diets (<10%), the majority of the accumulated fat is derived from the liver, which is the main site for ogenesis . Fat metKato et al. showed that two-week intracerebroventricular infusion of neurosecretory protein GM (NPGM) increased body mass, and the mass of abdominal and gizzard fat in chickens, without effects on feed intake. At molecular levels, they showed that NPGM might induce hepatic fat deposition via down regulation of the hepatic PPARα gene expression.At the central level, Massimino et al., on the other hand, used high throughput real-time quantitative PCR to determine the effect of embryonic thermal manipulation on the hepatic lipid and carbohydrate metabolism, stress, cell proliferation, and thyroid hormone pathways in mule ducks. They identified several key genes that might be involved in thermal long-term programming of hepatic metabolism. Surugihalli et al. used mass spectrometry-based metabolomics to evaluate the rapid remodeling of hepatic mitochondrial and cytoplasmic networks in chicken E18 embryo and d3 post-hatch chicks. Several metabolites were profiled in both plasma and liver showing a transition from lipid oxidation in embryonic liver to de novo lipogenesis in neonatal liver. Using forced molting laying hens, cecal metabolomics, and liver transcriptomics, Ruirui (abstract only) identified regulatory intestinal-liver lipid metabolism factors affecting reproductive performance in laying hens.At the peripheral level, the Bonnefont group has used a high throughput metabolomics approach to identify hepatic biomarkers for Foie Gras quality in duck. A total of eighteen quality-associated metabolite signatures were determined, with five specific to liver weight and four specific for technological yield at cooking. Zhao et al. determined the developmental changes of adipocyte differentiation, lipid synthesis, lipolysis, fatty acid β-oxidation, and lipid content from chicken embryo day 12 to day-9 post hatch. They showed that the mitochondrial copy number and fatty acid β-oxidation increased during the post hatch period, indicating that subcutaneous adipose tissue plays an important role in energy supply. Sun et al. used the Iso-Seq technology and identified several long non-coding RNA and alternative splicing in abdominal and subcutaneous adipose tissues of pekin ducks. Na et al. reported several reference genes for real-time quantitative PCR in chicken adipose tissue and adipocytes. Kim et al. determined the effect of in ovo injection of different doses of all-trans retinoic acid on quail embryonic adipogenesis. They found that all-trans retinoic acid promoted hypertrophic fat accretion in quail embryos via upregulation of PPARγ and FABP4 and down regulation of Dlk1. The Gilbert group studied the effect of dietary baicalein supplementation on adipose tissue gene expression profiles during the first week post hatch in chickens. They showed a reduction of growth performance , breast muscle weight, and subcutaneous and abdominal fat weights along with a modulation of several genes involved in adipogenesis and fat storage. In a separate paper, the Cline group reviewed the effects of dietary flavonoids on lipid metabolism in liver, skeletal muscle, and adipose tissue of poultry species. Finally, Kim and Voy provided a thorough review associated with the beneficial effects of n-3 polyunsaturated fatty acids in reducing fat accretion in poultry.In adipose tissue, In summary, the papers within the current Research Topic provide new insights and discoveries related to lipid metabolism in various avian species  and suggest some solutions and perspectives for future investigations aiming to reduce fat accretion in poultry. It is my fervent hope that this ebook and the Research Topic is a great resource for the readers, and we look forward to a second volume to expand more research and knowledge associated with other molecular pathways of lipid metabolism in various other avian species.


Protein kinases regulate nearly every aspect of cell life, and changes in their expression or gene mutations cause cancer and other diseases. As many human diseases result from mutations and overexpression of kinases, this enzyme class symbolizes an important targeted strategy for drug development. Kinases are also essential in signaling pathways that regulate tumor cell functions. Kinase dysregulation causes a number of pathophysiological changes that promote cancer cell proliferation and metastasis. This targeted, structure-based drug design is gaining traction; several anticancer drugs targeting specific kinases are in various stages of clinical trials. When compared to a decade ago, the new opportunities, developments, and results in this field are almost unbelievable.The development of superior drugs that target specific signaling molecules has had a significant impact on the pipelines of pharmaceutical companies, leading to the development of multiple marketed kinase inhibitors. The development of selective small molecules against kinases has the potential to provide greater potency and selectivity than was previously possible.The authors included in this Research Topic discuss how various classes of kinases are used as potential drug targets, with a particular emphasis on anticancer therapy. The content covers both the challenges and opportunities for future kinase inhibitor development for anticancer therapy. Contributions also discuss how the problem of drug resistance to kinase inhibitors is being addressed, as well as the future of kinase drug discovery. Kinases are currently being studied extensively for the treatment of a variety of life-threatening diseases. This Research Topic brings together several reviews and research articles, contributed by scientists and researchers in the fields of medicinal chemistry and molecular biology, as well as new emerging multi-drug targets.Hepatic Rupture as the Initial Presentation of an EGFR-Mutated Lung Adenocarcinoma: A Case Report” by Mirallas et al., which describes a female patient who presented with a metastatic hepatic rupture and was later diagnosed with EGFR-mutated lung adenocarcinoma. Hepatic rupture is a rare complication in patients with solid tumor malignancies, particularly lung adenocarcinomas, and it is associated with a very poor prognosis.This Research Topic starts with a research article on “Alam et al. examining “Bax/Bcl-2’s Cascade Is Regulated by the EGFR Pathway: Therapeutic Targeting of Non-Small Cell Lung Cancer.” The review summarizes recent information on the molecular mechanisms of the Bax/Bcl-2 cascade and the EGFR pathway in NSCLC and targets them for therapeutic implications. This study looked at the therapeutic potential of Bax/Bcl-2/EGFR SMIs, particularly those with higher potency and selectivity, such as gefitinib, EGCG, ABT-737, thymoquinone, quercetin, and venetoclax. Furthermore, they also discuss the EGFR pathway and ongoing in vitro, in vivo, and clinical studies in NSCLC. Exploration of such inhibitors facilitates future NSCLC treatment and management.The next article in this Research Topic is a review by Wu et al. in their contribution, “Lestaurtinib Has the Potential to Inhibit the Proliferation of Hepatocellular Carcinoma Uncovered by Bioinformatics Analysis and Pharmacological Experiments,” identifies a new candidate STAT family. This factor is involved in the development of HCC and new treatment Candidate STAT family genes for HCC were found using bioinformatics web resources such as Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), The Human Protein Atlas (HPA), Tumor Immune Estimation Resource (TIMER), and GSCALite. In this study, the author performed in vitro experiments using lestaurtinib as a treatment for patients with liver cancer and verified that lestaurtinib, a tyrosine kinase inhibitor, can inhibit the growth of liver cancer cells. The author explores the effects of lestaurtinib in hepatocellular carcinoma through in vitro and in vivo systemic studies to provide a new strategy for the treatment of hepatocellular carcinoma. In vivo studies focus on addressing how to limit toxicity at optimal biological doses.Research by Therapeutic Implications of Caffeic Acid in Cancer and Neurological Diseases,” is a review by Alam et al. that focuses on the chemical, physical, and pharmacological properties of caffeine, including its antioxidant, anti-inflammatory, anticancer, and neuroprotective effects. The features, therapeutic potential, and future possibilities of CA are also discussed by the author.The fourth article in this Research Topic, “Chen et al. identified a novel LDLR-ROS1 fusion in patients with resectable stage IIIA NSCLC, entitled “Case Report: Adjuvant Crizotinib Therapy Exerted Favorable Survival Benefit in a Resectable Stage IIIA NSCLC Patient With Novel LDLR-ROS1 Fusion.” After receiving crizotinib as adjuvant therapy, the patient experienced no substantial harmful side effects and maintained recurrence-free survival (RFS) for 29 months. This example supports the use of adjuvant treatment with the ROS1 inhibitor exhibiting clinical survival advantage in ROS1 fusion-positive resected NSCLC, according to the authors’ report of a novel LDLR-ROS1 fusion responding to crizotinib in a patient with lung adenocarcinoma.The fifth article in this Research Topic by Avery et al. on “Onco-immunomodulatory properties of pharmacological interference with RAS-RAF-MEK-ERK pathway hyperactivation.” This article outlines the rationale and concepts for utilizing the immunomodulatory properties of RAS-RAF-MEK-ERK inhibition while emphasizing the role of MEK inhibition in combinatorial and intermittent anemia treatment. The considerable scientific efforts made to address the difficulties encountered during the clinical transition of different therapeutic drugs were also highlighted in the hunt for the most efficient and secure patient- and tumor-tailored treatment strategy.The sixth article in this Research Topic is a review by Case Report: A Lung Adenocarcinoma With Brain Metastasis Harbored Novel MET 14 Skipping Alteration Sensitive to Savolitinib,” was written by Li et al. and describes a 61-year-old woman who had lung adenocarcinoma and was treated with Savolitinib after having a novel MET exon 14 skipping (c.3004). These two MET changes were also validated by the CytoTest MET/CCP7 FISH Probe (c-MET/CCP7 Ratio:1.41 and mean gene copy number:6) and qPCR, which used the ABI 7500. Savolitinib treatment lasted for 2 months, and the clinical assessment showed a partial response (PR). In conclusion, this discovery not only broadened the range of the MET exon14 variation (METex14). Targeted NGS analysis may enhance the ability to detect MET changes in everyday practice.The seventh article in this Research Topic, “RET Signaling Pathway and RET Inhibitors in Human Cancer,” by Regua et al. reviews biological understanding of RET signaling, the effects of RET hyperactivity on tumor progression in a variety of tumor types, and the efficacy of RET inhibitors in preclinical and clinical settings.The final article in this Research Topic, “Kinase Inhibitors in Cancer Therapy.”I would like to thank all authors who contributed to this Research Topic on “


After tBritish Medical Journal, Wallis et al. [Annals of Thoracic Surgery, Rong et al. [Addressing the issue of disparities between men and women can seem redundant, since this dichotomy is well recognized in the professional world. It is nevertheless essential in our surgical field since it is still a male-dominated world: most recent data from the public report of the American Association of Medical Colleges (AAMC) in 2019 on active physicians sex and specialtyindicates that 92% of practicing cardio-thoracic surgeons are men . Despites et al.  reportedg et al.  reported‘I do not wish to give (women) a first place, still less a second one—but the complete freedom to take their true place, whatever it may be’.—Elizabeth BlackwellSadly, despite this documented equality in operative results, the academic career ladder still seems steeper for female surgeons: women with an MD are less likely to author a paper than men with the same degree and instead, a PhD becomes much more essential for women . They alThe Women in Cardio-Thoracic Surgery Committee currently consists of seven female surgeons from various career levels and countries: Prof. Jolanda Kluin (The Netherlands); Dr Indu Deglurkar (UK); Dr Lena Emrich (Germany); Dr Francesca D’Auria ; Dr Julie Cleuziou (Germany); Dr Miia Lehtinen (Finland); and Dr Maroua Eid (France). This heterogeneity seems essential, allowing all female surgeons to relate to the committee.female surgeons [The committee holds an important mission: establishing a network for surgeons . Such coet al. ‘attention should be given to the potential unconscious bias in leadership in cardiothoracic surgery’ [Gender should not intervene in one’s career choices; only abilities and perseverance should be considered. A shift towards an increased representation of female surgeons is to be expected in our field, and as suggested by Shemanski surgery’ . For our


Artificial intelligence (AI) has emerged as a key player in modern healthcare, especially in the pharmaceutical industry for the development of new drugs and vaccine candidates. AI technology has shown promising results in target identification, protein–protein interactions, protein–drug interactions, metabolic pathway identification, drug repurposing, facilitating de novo drug design to combat diseases, and increasing short-term research productivity. This Special Issue highlights recent advances in computational modeling and dynamics simulations for elucidating phosphodiesterase 9 (PDE9) inhibitors with different metal systems; the identification of potential inhibitors of coronavirus disease 2019 (COVID-19); the prediction of convolutional network-based drug–target interaction modules; the building of transformer-based deep neural networks for metabolomics; and the development of autoencoder-based deep learning models for drug repurposing for Alzheimer’s disease. Signal transduction systems such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) regulate cellular functions in organisms, and the dysregulation of these signaling pathways leads to various diseases. To minimize the dysregulation of signaling pathways and the disruption of cellular function, Sivakumar et al.  targetedThe repurposing of ‘existing’ drugs to treat common and emerging diseases increasingly involves the targeting of lower-risk compounds and results in reduced development costs and times. The COVID-19 pandemic has disrupted healthcare systems globally since 2019, calling for new therapeutics that target severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is responsible for the disease. Antiviral treatments have been known to reduce disease spread, infection, and severity for over 30 years. Mohammad et al. [The prediction and identification of compound–protein interactions (CPIs) play an important role in the recent discovery and development of safe drug candidates. Many studies point to the advantages of deep learning models for learning task-related functions from large datasets on compound–protein interactions. Wang et al.  developeIn the past decades, high-throughput screening (HTS) experiments have greatly accelerated the identification of drug–target interactions (DTIs). However, HTS experiments are costly and cumbersome, and cannot meet the need to reveal DTIs for millions of existing drug and target combinations. Jin et al.  developeMass spectrometry (MS) fingerprinting is key to metabolomics . The identification of metabolite molecules is currently performed primarily by comparing MS data with those of a limited number of authentic chemical standard libraries. Only 10% of molecules can typically be identified experimentally from reproducible spectral features of complex matrices , despite many heuristics . To address the above issues, Shrivastava et al.  developeFinally, Chyr et al.  proposedBiomolecules for the opportunity to work with them on this enlightening editorial journey.We hope that the interdisciplinary topics covered in this collection will prompt further discussion among researchers and promote innovation in the field of artificial intelligence for drug design and development. Above all, we would like to thank the authors for their excellent contributions. We also thank the scientific experts in AI, computational modeling, and drug design who offered invaluable comments and suggestions to improve the quality of this Special Issue. Finally, we would like to thank the Editor-in-Chief, Section Managing Editor, and all the editorial staff of MDPI—


Matson et al., RSC Adv., 2021, 11, 32269–32274. DOI: 10.1039/D1RA06151HCorrection for ‘X-ray absorption spectroscopy of exemplary platinum porphyrin and corrole derivatives: metal-  The authors regret that the one of the author affiliations was incorrectly shown in the original manuscript. The corrected list of affiliations is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.