MWCNTs. The hybrid nanofluid is under the influence of magnetohydrodynamic effects and chemical reaction with activation energy. The governing partial differential equations (PDEs) are transformed into ordinary differential equations (ODEs) using suitable similarity transform. Homotopy analysis method is used to solve the non-linear system of ODEs and MWCNTs while the mass transfer rate depicts contrasting behavior.Hybrid nanofluids are extensively analyzed in recent studies due to their better performance in numerous areas such as heat and mass transfer enhancement, biological fluid movement, medical equipment, heat exchangers, electronic cooling and automotive industry. In current study the nanoparticle concentration utilized is much important in biomedical industry. Major applications include drug delivery, radio-pharmaceuticals, centrifuging blood to obtain red blood cells and plasma, medical implants, onco therapeutics and photo thermal cancer therapy. In this regard, the primary focus of this study is to simulate a blood based unsteady hybrid nanofluid flow between two rotating, stretching disks and convective boundaries. The two nanoparticles in this study are uranium dioxide  Jabbaripour et al.2 examined a water based three dimensional hybrid nanofluid flow with aluminum and copper nanoparticles at slip boundary conditions. Subhani and Nadeem3 analyzed water based micro-polar hybrid nanofluid flow with copper and titanium oxide nanoparticles over a stretching surface. Khan et al.4 studied the convective flow of Casson-nanofluid with gold nanoparticles through a rotating disk under impact of non-linear thermal radiation. Izaday et al.5 numerically scrutinized a Ag nanoparticles passing through an artery is analyzed by Chahregh and Dianrvand6 to better understand the blood circulation through the respiratory system. Ghasemian et al.7 presented their work on three-dimensional unsteady Maxwell nanofluid. Alghamdi et al.8 examined the flow of a 9 conducted a study on flow of 10 considered MFD viscosity effects on flow of a magnetic nanofluid. Waqas et al.11 simulated the free convective flow of a water based nanofluid. 12 simulated a stagnation point flow of a hybrid nanofluid with respect to the masses of two types of nanoparticles i.e., magnesium oxide and silver. Mansourian et al.13 analyzed the flow of a ferro-hybrid nanofluid passing over a stretching sheet.The nanofluids are formed by adding particles of nano-meter size into base fluid either by directly mixing (one-step method) or synthesizing nanoparticles first and then mixing (two-step method). The nanofluids consist of two-phases, fluid phase (base-fluid) and solid-phase (nanoparticles). Base fluids usually are water, ethylene glycol, blood and engine oil etc. while nanoparticles are mostly metal oxides, carbides or carbon nanotubes CNTs. When two types of nanoparticles are mixed into the base fluid then hybrid nanofluid is formed. Hybrid nanofluids enhance the efficiency of base fluids in terms of effective thermal conductivity, diffusivity, viscosity and heat transfer rates. These fluids are potentially useful in microelectronics, hybrid-powered engines, solar energy collectors, heat exchangers, drug transport and many medical equipment. Due to vast applicability, many researchers have attempted to analyze and simulate various hybrid nanofluid models in most recent studies. Rashidi et al.14. He developed a differential setup to analyze the hydrodynamical flow over an infinite rotating disk. His work was further extended by Griffiths15 where he analyzed generalized Newtonian fluids which provided a comprehensive description to non-Newtonian boundary layer flows. Rashidi et al.16 investigated the slip flow of a nanofluid on a rotating porous disk. Khan et al.17 numerically analyzed Oldroyd-B nanofluid flowing over an exponentially stretched surface with radiative effects. Hayat et al.18 studied a third grade nanofluid flow over a single rotating and stretching disk with thermophoresis and Brownian motion. Shah et al.19 investigated a nanofluid flow between two rotating and stretching disks with silver based CNTs under MHD effects. Usman et al.20 presented work on enhancement of heat transfer in a blood based nanofluid with power-law model and heat source/sink stimulated by two rotating stretchable disks. Convective flow of a Newtonian fluid between co-rotating stretching disks with Soret and Dufour effects is examined by Sharma et al.21. Rauf et al.22 explored the rate of heat transfer in a hybrid ferrofluid boundary layer flow passing over a rotating and non-linearly stretching disk in presence of an alternating magnetic field. Usman et al.23 presented steady flow model of a power law fluid co-axially rotating between two stretchable disks with heat source/sink.Flow originated by rotating stretching disks have gathered researchers’ interest due to their applications in food processing, medical equipment, industrial and engineering sectors. Fruitful outcomes have been drawn through several researches but the pioneering work on rotating disk was presented by Karman24, Salahuddin et al.25, McCash et al.26, Raza et al.27 and Nisar et al.28 explored effects of chemical reaction with activation energy on various non-Newtonian and nanofluid models. Saleem et al.29 studied the effects of chemical reaction on flow of a second-order viscoelastic fluid with heat generation effect. Gowda et al.30 recently analyzed the heat and mass transfer rate in a non-Newtonian second grade nanofluid model undergoing chemical reaction with activation energy. Zaib et al.31 applied binary chemical reaction with MHD effects on Casson nanofluid flowing over a wedge. Khan et al.32 analyzed a chemically reactive nanofluid flow over a moving needle with viscous dissipation. Flow of cross nanofluid with immersed gyrotatic microorganisms is presented by Azam et al.33 under effects of non-linear thermal radiation.Addition of surfactants, stabilizers and various nanoparticles in blood causes major chemical reactions. Activation energy is the minimum amount of energy required to start off that chemical reaction. Arrhenius equation is utilized to describe the change of rate constant with changing temperature in a chemical reaction. These reactions take place mostly in chemical reactors which are most of the time limited through the rate of mass transfer. In this context, it becomes much important to incorporate chemical reaction effects in order to analyze the flow problem in this study. Other researchers including Hamid et al.34 in 2009 pioneered working with convective boundary conditions while investigating the Blasius flow. Afterwards, various authors analyzed different fluid models in this regard. Yao et al.35 analyzed the heat transfer in viscous fluid flow past a stretching/shrinking wall with a convective boundary condition. Hayat et al.36 investigated the stagnation point flow of a Casson fluid with mixed convection over a linearly stretching surface with thermally convective boundary. Wang et al.37 studied the bio-convective flow of a Maxwell nanofluid with slip effects and passing over an exponentially stretched surface. Haq et al.38 investigated the flow behavior of a Casson nanofluid with convective boundaries. Zaib et al.39 simulated flow of a nanofluid with convective boundaries in a Darcy-Brinkman porous medium. Boundary layer flow of a Casson fluid is examined by Hussain et al.40 with convective boundary conditions and flow over a stretching wedge. Furthermore, recent researchers on convective boundaries are presented by various authors including Akhtar et al.41, Anuar et al.42, Mabood et al.43, Becerro et al.44 and Rasheed et al.45.Convective conditions are characterized by interaction between boundaries of the machinery and the surrounding environment. Heat exchange by convection is the main cause of thermal response in the machine tools which is important in describing the fluctuations due to environmental changes or addition of cooling liquid. The heat transfer coefficients (HTCs) in these conditions are the proportionality constants when convective heat flux and temperature difference (between fluid and structure) are related. AzizMWCNTs. The governing unsteady non-linear PDEs are converted into ODEs by applying suitable similarity transformations. The obtained system of ODEs is then solved by using homotopy analysis method (HAM)46. To provide convergence of the solution In light of the literature review stated above, it is observed that an unsteady flow of a blood base hybrid nanofluid between two rotating and stretching disks with chemical reaction and activation energy along with convective boundaries has not been investigated. Moreover, uniqueness and need of present work is discussed in comparison with existing recent literature on unsteady hybrid nanofluid flow in Table We consider an unsteady blood hybrid nanofluid flow between two rotating and stretching disks in cylindrical coordinate system mentclass2pt{minimu, v and w are radial, tangential and axial velocities in r, z directions, respectively. T represents hybrid nanofluid temperature and C is the concentration. Chemical reaction rate is denoted by s is a constant power. Also, b is a positive constant with dimension of k is thermal conductivity and D is the thermal diffusivity. MWCNTs are presented in Table entclass1pt{minima57Pr is the Prandtl number, M is the magnetic interaction parameter.In order to non-dimensionalize the problem and to convert the system of partial differential equations into ordinary ones , the following similarity transforms are introducedmentclass2pt{minim use Eq.  and obtamentclasspt{minimaSkin friction sing Eq.  we obtaiIn order to solve system of highly non-linear ordinary differential equations in Eqs. –11) we  we 11) w The final form of series solution obtained as a result is as followsough Eq.  and geneAfter computing the series form solution through homotopic approach the convergence of results is optimized through entclass1pt{minimaThe flow problem is simulated in the fluid domain to depict the behavior of hybrid nanofluid under various effect and physical parameters. In this regard, each fluid phenomena is discussed in detail for hybrid nanofluid in following sections for velocity, temperature and concentration profile.M. In Fig. M. As M increases, the viscous forces in fluid layers decreases causing increase in velocity in all directions. This increase in velocity results in increased temperature of hybrid nanofluid. The temperature profile is analyzed for both fully convective and non-convective boundaries. It is observed that temperature in fully convective boundaries is higher when compared with thermally non-convective (The ratio of electromagnetic force to the viscous forces in a fluid flow is characterized by magnetic interaction parameter, Unsteadiness parameter, The parameters MWCNTs in blood increases the velocity of the hybrid nanofluid in radial, tangential and axial direction. Temperature of the hybrid nanofluid decreases with increased volume fraction of MWCNTs. It is also observed that fully convective boundaries offer higher temperature than non-convective boundaries in case of increasing volume fraction of carbon nanotubes.In Fig. Pr decrease fluid temperature due to reduced thermal conductivity inside the fluid. Fully convective boundaries offer higher temperature as compared to non-convective disks when Pr is increased. Increase in activation energy parameter Convective and non-convective boundary cases for temperature and concentration are shown in Fig. M increases the skin friction due to enhanced Lorentz forces between fluid particles. Increasing volume fraction of CNTs increases the skin friction as nore solid nanoparticles move through the fluid. Unsteady parameter U and stretching parameter Figure Pr, CNTs increases the heat transfer in Fig. Pr, Rate of heat transfer is the ratio of convective heat transfer and conductive heat transfer during a fluid flow. Figure CNTs volume fraction The ratio of mass transfer by convection and diffusion is the Sherwood number which is the mass transfer rate in the fluid. Figure M and Radial, tangential and axial velocity of the hybrid nanofluid increases with increase in Increase in M and Pr.Temperature of the hybrid nanofluid boosts with higher values of Convective boundary conditions result in higher temperature of hybrid nanofluid when compared with non-convective boundary condition case.Increase in Skin friction increases with increase in both volume fractions The rate of heat transfer decreases with increasing volume fraction CNTs decreases the rate of mass transfer in the hybrid nanofluid.Increase in volume fractions of both nanoparticles Current investigation focuses on simulating an unsteady and convective flow of blood based hybrid nanofluid undergoing chemical reaction with activation energy. A novel semi-analytical approach that is homotopy analysis method is utilized to solve the modeled system of non-linear ODEs. Convergence control parameters


Pharmacoepidemiology, the study of the use and effects of medicines in large human populations, is a bridging science between clinical pharmacology and epidemiology. Pharmacovigilance is “the science and activities related to the detection, evaluation, understanding, and prevention of adverse effects or other problems associated with medicines."This Research Topic contains six manuscripts using pharmacoepidemiological methods, five original research papers, and one perspective paper, including one paper using electronic health records as an information source, two papers using spontaneous reporting systems, and three papers using nationwide medical information based on claims data.Alsowaida et al.). The global epidemic of COVID-19 has made the development of effective drugs for the treatment and prevention of COVID-19 a global priority. Several post-marketing studies have reported significant bradycardia with remdesivir administration, and this article provides validation in an evidence-based source.First, a retrospective cohort study using electronic medical records was reported by  to methotrexate (MTX)-based therapy could help reduce the dose-dependent adverse events of MTX, providing clinical evidence to support the beneficial effect of FA.Lin et al. hypothesize that statins inhibit MSU-induced gout flares through their anti-inflammatory properties, and a cohort study using the 2000 Longitudinal Generation Tracking Database (LGTD 2000), a randomly selected dataset of 2 million NHI recipients, found that statins have chemopreventive potential against MSU.Taiwan’s National Health Insurance (NHI) program covered more than 99.9% of the 14 Taiwanese population by 2014 . The NHIYen et al. recruited participants with type 2 diabetes mellitus (T2DM) and cirrhosis from the NHIRD between 1 January 2000 and 31 December 2017 and followed them until 31 December 2018. This report found that using alpha-glucosidase inhibitors was associated with a reduced risk of mortality, hepatocellular carcinoma, compensated cirrhosis, and liver failure in patients with diabetes and compensated cirrhosis.Shida et al. carefully explained the details of these studies.This type of study has not been conducted exclusively in Taiwan. The Pharmaceuticals and Medical Devices Agency (PMDA), the Japanese regulatory authority, conducts various pharmacoepidemiological studies based on actual data from its medical information database for post-marketing drug safety evaluation. Since various medical information is a source of pharmacoepidemiological studies, researchers should properly characterize the sources and consider the study design.The inverse signals detected by pharmacoepidemiological studies are known to be helpful in the search for drug candidates , and man


Alternative splicing is a major mechanism to increase the number of proteins that can be made from the limited number of genes present in the human genome. During transcription of genes into precursor messenger RNA (pre-mRNA), non-coding introns are spliced out to make a messenger RNA (mRNA) that encodes the functional protein. During the splicing process some exons can be included or excluded and this process is termed alternative splicing. This is a highly regulated process that produces diverse mature mRNA transcripts from a single gene. Alternative splicing is present in almost every gene and is widespread in eukaryotic evolution. Moreover, the majority of genes expressed in the mammalian central nervous system undergo extensive alternative splicing, with some genes capable of contributing to over a thousand isoforms. This results in a variety of proteoforms exhibiting differences in function, binding preferences, catalytic activity, and localization. Disruptions in alternative splicing have been associated with numerous neurological disorders. A comprehensive understanding of its role in healthy and pathological nervous system function is still emerging. It is timely to gather current knowledge, advancement and challenges in this field. With this objective, we brought together several articles that discuss involvement of splicing and associated genetic perturbations in the central nervous system across the evolutionary scale—from fly to human.Feng et al. focuses on the heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), a key RBP associated with neurodegeneration and cancer. The authors discuss hnRNPA1's role in gene transcription, mRNA translation, and stability, highlighting its importance and potential as a therapeutic target. Another study by Titus et al. reveals the functional role of the RBP Caper in Drosophila, emphasizing its significance in sensory and motor neurons development and its regulatory role in Drosophila gravitaxis behavior.Many RNA binding proteins (RBPs) play a crucial role in splicing regulation. The review by Lu Y. Q. et al. reveal the causative role of TANK-binding kinase (TBK1) in Amyotrophic Lateral Sclerosis (ALS) through mutational analysis, emphasizing the importance of intronic sequencing and pre-mRNA splicing analysis in understanding the complex mutational spectrum and pathogenesis of ALS. Reis et al. uncover a severe early onset dementia syndrome caused by an intronic splice donor variant in expanding our understanding of early onset dementia syndromes with a digenic background. Chen et al. identify a de novo splicing variant of the FOXP1 (Forkhead Box P1) gene in a patient with FOXP1 syndrome , providing insights into the genetic basis of global developmental delay, intellectual disability, and language delay. Fan et al. identify a disease-causing and aberrant splicing-inducing variant of TSC complex subunit 2 gene (TSC2) in a Han-Chinese family with Tuberous Sclerosis Complex (TSC), expanding the phenotypic and genetic spectrum of TSC and potentially contributing to its diagnosis and treatment. Wang et al. report a novel heterozygous STXBP1 (Syntaxin Binding Protein 1) splice variant with abnormal intron retention in a patient with Ohtahara syndrome (a rare form of epilepsy), highlighting the significance of splicing defect analysis in understanding the pathophysiology of neurodevelopmental disorders. Levchenko et al. reveal a deep intronic variant in the SNX14 (Sorting Nexin 14) gene in patients with spinocerebellar ataxia type 20, providing insights into the molecular pathogenic mechanism underlying the formation of a novel donor splicing site and potential therapeutic implications.Several studies identify splicing mutations associated with various neurological conditions. Xia et al. assess multiple mutations in three repeat (3R) tau for microtubule binding properties and prion-like aggregation propensity, contributing to the understanding of diverse presentations of tauopathies. Using bioinformatics pipelines, Farhadieh and Ghaedi reveal alternative splicing events (ASEs) in postmortem brain tissue with a cell-specific perspective, providing insights into AD pathology at the cell level. Lu Y. et al. identify several significant AS events in an AD mouse model, offering novel pathological mechanisms mediated by splice changes. Alalwany et al. investigate the neuroprotective effects of VEGF splice isoforms against AD-related neurotoxicity, suggesting potential therapeutic avenues.Tauopathies, including frontotemporal dementia and Alzheimer's disease (AD), are neurodegenerative diseases caused by tau brain aggregates. Tau protein, a microtubule-associated protein, can be disrupted in disease states due to the balance of tau splice isoforms. Winsky-Sommerer et al. analyze the transcriptome and translatome in the female mouse hippocampus at different ages, revealing age-associated splicing changes and their potential role in age-related deficits in hippocampal-dependent behavior. The study provides a comprehensive resource for understanding age-associated splicing changes with implications for neurological diseases.Aging is a major risk factor for neurological disorders including dementia. Baxter et al. explore the correlation between high K+ exposure, delayed-onset NMDA receptor-dependent neuronal death, and exon inclusion levels in neurons and astrocytes in vitro. The study highlights the neurotoxic nature of certain stimulation paradigms and emphasizes the importance of NMDA receptor blockade.Differential splicing of exons in neurons can alter protein properties, including ion channels, neurotransmitter receptors, and synaptic cell adhesion molecules. The Research Topic brings together up-to-date research focused on the biology of splicing and its regulators and associated mutations in neurological diseases. It provides new insights into the pathophysiological role of splicing modulations and offers possible strategies for therapeutic targets.KL-A: Conceptualization, Writing – original draft, Writing – review & editing. MS: Conceptualization, Writing – original draft, Writing – review & editing.


Epidemiological studies indicate an alarming narrowing in the gender gap of alcohol and tobacco use especially in adolescents, which may reflect changes in sociocultural patterns in women. Moreover, women use more often alcohol to cope with stress and negative feelings. Pharmacokinetics and pharmacodynamics differences, reward process specificities, and female hormones play a major role in gender differences. Women’s consumption of alcohol may be associated with serious birth and developmental consequences in newborns.Thibaut F et al. WFSBP and IAWMH Guidelines for the treatment of alcohol use disorders in pregnant women. The World Journal of Biological Psychiatry 2019 20(1):17-50None Declared


Vibrio campbellii is described in the paper by Zhou et al. .A new chitin-active AA10 lytic polysaccharide monooxygenase from the marine bacterium  The longest linker, connecting the CBM73 to the other three domains, has typical features of an extended linker, with low sequence complexity and abundance of proline (four) and glutamate (four). Indeed, based on various observations, including lacking electron density for the CBM73 in one of the et al. have gone a long way in the further characterization of their LPMO domain, thus providing important information for the LPMO field. In particular, their data on binding of various metal ions are unique and shed light on the binding potential of the unique copper binding histidine motif in LPMOs. As a point of warning, the pH and temperature optima for ‘LPMO activity’ described in the paper are based on measuring H2O2 production resulting from an off-pathway oxidase reaction of the LPMO with molecular oxygen  have a role in the pathogenicity-related physiology of Vibrio species. The novel, complete crystal structure of VhLPMO10A and the adjacent functional data provide an excellent starting point for digging deeper into the true biological role of these enzymes. Importantly, GbpA, VhLPMO10A and several other LPMOs with putative roles beyond biomass processing (e.g. Askarian et al., 2021et al., 2022i.e. a polymer of a sugar, N-acetylglucosamine, that is abundant in carbohydrate-containing microbial structures, such as cell walls. It needs to be questioned whether chitin is the true substrate of these LPMOs. In this respect, it is worth noting that the topology of the substrate-binding surfaces of the LPMO domains of GbpA and VhLPMO10A is somewhat different from those of LPMOs known to play a key role in chitin degradation, such as SmLPMO10A (also known as CBP21; see arrows in Fig. 3 in Zhou et al., 2023Zhou et al., the biological function of proteins such as VhLPMO10A and GbpA remains largely enigmatic. From work on GbpA, it seems certain that these proteins are important mediators of the interaction between Vibrio and relevant host surfaces (Kirn et al., 2005et al., 2012Vibrio cells. Interestingly, the GbpA ortholog of the non-pathogenic bacterium Aeromonas veronii Hm21 stimulates epithelial cell proliferation in Zebrafish (Banse et al., 2023VhLPMO10A may have substrates that are yet to be discovered.Despite the structural and functional insights provided by Zhou


The detrimental effects of APOE4, the strongest genetic risk factor for AD, have been characterized in different brain cell types, including oligodendrocytes  isoform encoded by the “C” allele of the rs11136000 polymorphism impairs oligodendrocyte progenitor cell (OPC) proliferation and myelination through paracrine signaling from astrocytes   and microtubule-associated protein tau (MAPT) genes , is expressed in microglia and mediates extracellular lipid sensing (Deczkowska et al., TREM2 and other genetic risk variants specific to microglia, neuroimmune myelinoids can be generated by seeding iPSC-derived microglia onto the myelinoid to allow microglia infiltration and interaction with other cell types in the organoid (The roles of genetic risk factors for AD in myelin homeostasis can be defined by deriving genetically engineered myelinoids that express genetic risk variants, such as APOE4 . As a tres APOE4  (Huang ees APOE4 . Anotherorganoid  (Cerneckorganoid . Given torganoid .+ T cells in the aging mouse brain, leading to oligodendrocyte activation and death (Kaya et al., Peripheral effectors, such as immune cells and serum proteins have been recently implicated in AD pathogenesis as well (Gate et al., in vivo to promote advanced myelinoid maturation and vascularization (in vitro (Mansour et al., Finally, various myelinoids discussed earlier can be transplanted rization . Indeed,It is also important to consider various limitations of the brain organoid technology for modeling AD, so that appropriate experimental controls can be utilized (Cerneckis et al., Although AD has historically been considered a gray matter disease, emerging evidence indicates concurrent white matter dysfunction during AD progression. The versatile myelinoid platform offers unprecedented access to human brain myelination models that can be tailored to address specific hypotheses pertaining to myelin dysfunction in AD. For example, microglia can be incorporated into myelinoids described in JC: Writing—original draft, Writing—review and editing. YS: Writing—review and editing.


The rapid advancement of biomedical sensor technology has revolutionized the field of functional mapping in medicine, offering novel and powerful tools for diagnosis, clinical assessment, and rehabilitation. The ability to collect and analyze various physiological signals, even in real-time, has provided unprecedented insights into the “hidden” functioning of the human body. Biomedical sensors have not only enhanced our understanding of human physiology but have also significantly impacted clinical decision-making, patient management, and the development of personalized medical interventions.This Special Issue presents a collection of 14 papers that showcase the diverse applications of biomedical sensors in the context of functional mapping. The papers can be grouped into three sections, highlighting their contributions to (i) medical diagnosis, detection and prediction; (ii) neurological and rehabilitation assessment; and (iii) medical applications and monitoring. Together, these papers shed light on the transformative role of biomedical sensors in understanding physiological mechanisms and enhancing healthcare practices.This section focuses on the application of biomedical sensors for medical diagnosis, detection and prediction. The papers included in this section have a specific focus on the detection of conditions such as COVID-19 and hand osteoarthritis and the prediction of emotions by biosignals. Furthermore, novel approaches based on artificial intelligence and cutting-edge technologies are described.The paper “COVID-19 Detection Using Photoplethysmography and Neural Networks” [In the paper “Toward Early and Objective Hand Osteoarthritis Detection by Using EMG during Grasps” , researcThe third paper “Applications of Laser-Induced Fluorescence in Medicine”  exploresAdditionally, the paper “Predicting Emotion with Biosignals: A Comparison of Classification and Regression Models for Estimating Valence and Arousal Level Using Wearable Sensors”  delves iThis section explores the applications of biomedical sensors in neurological assessment and rehabilitation. The papers collected in this section describe interesting advancements in the analysis of electroencephalography (EEG), EMG and Near-Infrared Spectroscopy (NIRS) signals for the extraction of biomarkers to characterize individual status in neuromuscular applications that can have a potential impact, for example, on the assessment of rehabilitation effectiveness.The paper “Reliability of Mental Workload Index Assessed by EEG with Different Electrode Configurations and Signal Pre-Processing Pipelines”  evaluateIn the paper “A Novel Approach for Segment-Length Selection Based on Stationarity to Perform Effective Connectivity Analysis Applied to Resting-State EEG Signals” , researcThe paper “Reliable Fast (20 Hz) Acquisition Rate by a TD fNIRS Device: Brain Resting-State Oscillation Studies”  introducThe paper “Combined Use of EMG and EEG Techniques for Neuromotor Assessment in Rehabilitative Applications: A Systematic Review”  presentsNext, the paper “Whole-Body Adaptive Functional Electrical Stimulation Kinesitherapy Can Promote the Restoring of Physiological Muscle Synergies for Neurological Patients”  introducFinally, the paper, “Technology Acceptance Model for Exoskeletons for Rehabilitation of the Upper Limbs from Therapists’ Perspectives”  addresseThis last section emphasizes the role of biomedical sensors in medical applications and monitoring, describing novel technologies and tools to improve health monitoring in different medical scenarios.The paper “Towards a Practical Implementation of a Single-Beam All-Optical Non-Zero-Field Magnetic Sensor for Magnetoencephalographic Complexes”  introducThe paper “Experimental Assessment of Cuff Pressures on the Walls of a Trachea-Like Model Using Force Sensing Resistors: Insights for Patient Management in Intensive Care Unit Settings”  investigContinuing in the realm of prosthetic control, the paper “Questioning Domain Adaptation in Myoelectric Hand Prostheses Control: An Inter- and Intra-Subject Study”  delves iThe last paper in this section, “Multi-Scale Evaluation of Sleep Quality Based on Motion Signal from Unobtrusive Device” , introdu“Biomedical Sensors for Functional Mapping: Techniques, Methods, Experimental and Medical Applications” presents a comprehensive collection of cutting-edge research in the field of biomedical sensors. The papers cover a wide range of applications, including medical diagnosis and detection, neurological assessment and rehabilitation, and medical monitoring. These advancements pave the way for improved healthcare practices, patient outcomes, and personalized medicine. As biomedical sensor technology continues to evolve, the findings from these research studies hold significant promise in revolutionizing medical practices and addressing complex health challenges, ultimately leading to better human health and well-being.The Special Issue


Ocular neurodegeneration including high myopia, glaucoma, macular degeneration, optic nerve atrophy, and retinopathy can lead to blindness without timely and appropriate treatment. As the retina is actually an extension of the brain, studies on the molecular mechanisms by which these eye diseases develop are currently one of the hottest research areas in neuroscience.Novel mechanisms, diagnostic and therapeutic strategies for ocular neurodegeneration” is to extend our knowledge related to retina and vision disorders by bringing together work in ophthalmology, optometry, psychology, neuroscience, and vision science.Investigations on neuronal correction of visual deficits have enriched our knowledge of functional eye diseases including ocular neurodegeneration. Nevertheless, it is urgently needed to further our understanding of how these eye diseases develop. Notably, novel therapies with superstar pharmacological intervention or new methods such as gene therapy or stem cell therapy have been attracted into this research area. The aim of this Research Topic “Molcak et al. have summarized the expression, distribution, functions, and interactions of purinergic receptors in the retina and included potential crosstalk with other systems. Dissection of how these processes are affected will improve our understanding of the mechanisms that drive age-related macular degeneration (AMD).Avrutsky et al. have shown their original research data that caspase-9 inhibition has significant retinal protection from retinal vein occlusion (RVO). To be more specific, they have compared the therapeutic effect of caspase-9 inhibition with VEGF neutralization in an established mouse model of RVO, and they have conducted a series of examinations, including fundus angiography, optical coherence tomography (OCT), and electroretinography (ERG), for analyzing pathological changes.Ye et al. have investigated the long-term safety, efficacy, and binocular balance of monovision surgery using Implantable Collamer Lens (ICL) V4c implantation and Femtosecond Laser-Assisted in situ Keratomileusis (FS-LASIK) for the treatment of myopic patients with presbyopia. The results show that CL V4c implantation and FS-LASIK monovision treatment have long-term safety and binocular visual acuity at various distances.Lan et al. have demonstrated the control ability and characteristics of fixational displacement among healthy adults in a convenient method by using eye-tracking technology. A total of 100 healthy people were recruited for this study, providing an objective view that the fixation stability decreased significantly in the group aged over 50 years old.Chen et al. have reported a non-invasive diagnosis tool to assess blood flow perfusion in a visual pathway for ocular ischemic syndrome (OIS), which is attributable to chronic hypoperfusion caused by marked carotid stenosis. They have detected blood flow perfusion in a visual pathway by 3D pseudocontinuous ASL (3D-pCASL) using 3.0T MRI (magnetic resonance imaging). The results indicate that that there is a lower blood flow perfusion value in the visual pathway in patients with OIS.Velmurugan et al. have summarized different gene therapy methods in Leber hereditary optic neuropathy (LHON), suggesting that a mitochondrially targeted AAV (adeno-associated virus) gene therapy is more efficient than an allotopic AAV gene therapy for rescuing the LHON phenotype.Zheng et al. have presented a surprising treatment for restoring vision in adult amblyopia rats. By using molecular and histological approaches, they have revealed that low-frequency repetitive transcranial magnetic stimulation (rTMS) reinstates the amplitude of visual evoked potentials without influencing the impaired depth perception of amblyopic rats. They conclude that rTMS enhances functional recovery and visual plasticity in an adult amblyopic animal model.Zhang et al. have given a bibliometric analysis of apoptosis in glaucoma. This research will broaden our comprehension about the role of apoptosis in the process of glaucoma and provide guidelines for us in basic research and disease treatment.Zhen et al. have summarized rhodopsin-associated retinal dystrophy and its disease mechanisms and therapeutic strategies. In particular, they emphasize that innovative therapy strategies, such as gene therapy  and stem cell therapy, are promising methods for the future treatment of retina pigmentosa. Nevertheless, greater efforts are needed from basic researchers and clinicians to facilitate the translation of recent research findings from the laboratory into clinical practice.Xiang et al. have interrogated the question of whether children with monocular myopia need to wear glasses. They consider the facts that (1) monocular myopia could lead to the accommodative dysfunction and unbalanced input of binocular visual signals, resulting in myopia progression; (2) monocular myopia may also be accompanied by stereopsis dysfunction, and long-term uncorrected monocular myopia may worsen stereopsis acuity in adulthood; (3) patients with monocular myopia could exhibit stereopsis dysfunction at an early stage; thus, they come to a conclusion that children with monocular myopia must wear glasses to restore binocular balance and visual functions, thereby delaying myopia progression.Boal et al. have presented a study showing that retinal ganglion cells adapt to ionic stress in experimental glaucoma. Their data indicate that in response to prolonged IOP (intraocular pressure) elevation, RGCs  undergo an adaptive process that reduces sensitivity to changes in K+ while diminishing excitability. These experiments give insight into the RGC response to IOP stress and lay the groundwork for mechanistic investigation into targets for neuroprotective therapy.Li et al. have systemically analyzed independent risk factors for the progression of different degrees of diabetic retinopathy and non-diabetic retinopathy among type 2 diabetic patients. They conclude that young age, short axial length, and higher levels of FBG (fasting blood glucose) and urinary albumin creatinine ratio (UACR) were the independent risk factors for the progression of diabetic retinopathy in type 2 diabetes.Wareham et al. have presented data on collagen mimetic peptide repair of the corneal nerve bed in a mouse model of dry eye disease. Their data suggest that repair of underlying collagen in conditions that damage the ocular surface could represent a novel therapeutic avenue in treating a broad spectrum of diseases or injury.Wang and Wang have shown a preliminary study of spectral-domain optical coherence tomography (OCT) combined with ERG in the assessment of conbercept for neovascular age-related macular degeneration (nAMD). Their data suggest that (1) conbercept is useful for the short-term treatment of nAMD; (2) it can safely improve the visual acuity of affected eyes; and (3) it can restore the structure and function of the retina.Zhou et al. have shown that increased intraocular inflammation in retinal vein occlusion is independent of circulating immune mediators and is involved in retinal oedema. Their results suggest that (1) intraocular inflammation in RVO is driven primarily by local factors but not circulating immune mediators; (2) intraocular inflammation may promote macular oedema through the PI3K-Akt, Ras, MAPK, and Jak/STAT signaling pathways in RVO; and (3) systemic factors, including cytokines and lipid levels, may be involved in retinal microvascular remodeling.Wang et al. have assessed the precision and reliability of a novel computerized heterophoria test (CHT). Their data suggest that (1) the CHT can be used to demonstrate excellent inter- and intra-examiner repeatability and good correlation with the POCT ; (2) the differences between the CHT and POCT are within the permissible range of error; and (3) the CHT could provide a precise and reliable measurement for clinical applications.Altogether, this Research Topic of articles emphasizes novel diagnostic and therapeutic approaches for a variety of ocular neurodegeneration diseases, which are necessary to further explore.WW: Funding acquisition, Writing—original draft. WT: Writing—review and editing. YL: Writing—review and editing. TH: Funding acquisition, Writing—review and editing. DW: Writing—review and editing. HL: Conceptualization, Funding acquisition, Writing—original draft, Writing—review and editing.


Worldwide, one new case of dementia is detected every 3 s , Ramer et al. examined whether childhood 24HAC behaviors were associated with executive function or academic performance in adolescence. Self-reported sleep quality, recreational screen time, and actigraphy-assessed physical activity were collected during grade 5 when the children were ~11 years; executive function and academic performance were collected during grade 9 at age ~15 years. Using structural equation modeling, the authors found: (1) adolescent executive functions were negatively affected by greater childhood recreational screen time and positively affected by better sleep quality; and (2) the negative association between childhood recreational screen time and adolescent executive functions were attenuated by greater childhood physical activity. Interestingly, childhood physical activity was negatively associated with adolescent executive functions; however, this relationship was mitigated by greater sleep.In a longitudinal analysis from the United States of data from the National Institute of Child Health and Human Development (NICHD) Longitudinal Study of Early Child Care and Youth Development  to data from the Adult Changes in Thought study  and examined the interactive relationships of 24HAC behaviors with global cognitive function. Physical activity and sedentary behavior were assessed by actigraphy, while sleep was estimated as self-reported time in bed. No significant associations were found across all three analytic methods in this cross-sectional study.Mellow et al. cross-sectionally examined the associations between 24HAC composition and cognitive function among 384 Australian healthy adults, aged 60–70 years. The 24HAC was assessed by actigraphy and by questionnaires. Cognitive measures included global cognition, memory, executive functions, and processing speed. Using compositional data analysis, no association between 24HAC composition and cognitive function was found.Hicks et al. cross-sectionally explored how chronotype—an individuals' preferred activity and sleep pattern—and physical activity were associated with cognitive performance  in 153 American adults aged > 60 years, with and without self-reported sleep disorders. Wrist-worn actigraphy assessed physical activity and chronotype. Using multivariate analysis of covariance, no differences in physical activity or cognitive performance between different chronotypes were found.The results indicate that there is still much we do not understand about the 24HAC and cognitive health relationship. It is difficult to broadly characterize the 24HAC and cognitive health relationship at this time given that: (1) most of the evidence is cross-sectional; and (2) there are few studies on the 24HAC and cognitive health relationship in children, adolescents, younger, or middle-aged adults.Wu et al., Mellow et al., and Hicks et al. all found no association between 24HAC composition and cognitive function in healthy older adults; only Hyodo et al. found an association between 24HAC composition and cognitive function. It is possible that time-use composition fails to capture aspects of the 24HAC  that may be more important for cognitive health.Nevertheless, there are several conclusions we can draw from these studies. Notably, time-use composition of the 24HAC does not appear to be strongly associated with cognitive function in healthy older adults. Ramer et al. used a longitudinal design. We strongly urge that future studies use longer follow-up periods and include wider age-ranges in study samples.There is an obvious lack of longitudinal studies in this emerging field of research. Only Our article collection mainly includes studies in older adults, but does not include any research among clinical populations at risk for, or living with, cognitive decline or dementia . People living with clinical conditions which are associated with cognitive decline are often less active, more sedentary, and have poorer sleep (Falck et al., Finally, it is unclear what modifiable and non-modifiable moderators and mediators can impact the 24HAC and cognitive health relationship. None of the studies in this Research Topic explored sex differences. Females have twice the risk of dementia (Ferretti et al., Preserving cognitive abilities across the lifespan is critical for qualify of life and wellbeing. The 24HAC holds promise as a means of maintaining cognitive health from childhood into older adulthood. Future work is needed to identify the temporal 24HAC and cognitive health relationship, as well as understand how different populations, mediators, and moderators such as sex, may impact this relationship across the lifespan.RF wrote the first draft of the manuscript. TL-A, JV, HM, DM, PG, and HS each provided critical edits and wrote portions of the manuscript. All authors contributed to the article and approved the submitted version.


Viruses are medically important obligatory parasites that can impact the health and quality of life of infected patients. Historically, prophylaxis against viral diseases like poliomyelitis and measles became possible by the successful development and roll out of vaccines in the 1950s and 1960s [Virus Microscopy, Coomer and Padilla-Parra discuss the imaging of HIV-1 virus entry and transmission in organoids of the female genital tract and colorectal tract, using techniques such as two-photon confocal microscopy and light sheet microscopy. Hu and Noda describe the structural analyses of Ebola and Marburg virus (Filoviridae) nucleocapsid structures as dissected by single particle analysis using cryo-electron microscopy. Menke et al. elaborate on techniques such as super-resolution microscopy and quantitative image analysis for investigating the cell entry and infection biology of Orthohantaviruses. Finally, Petkidis et al. highlight the power of label-free microscopy including quantitative phase imaging and atomic force microscopy to investigate virus entry and infection.In this Microscopy special issue


Primary breast neuroendocrine neoplasms (BNENs) are a rare form of breast cancer, accounting for less than 0.1% of all breast malignancies. These neoplasms have a similar clinical presentation as conventional breast carcinomas, differing mainly in their histopathology and expression of neuroendocrine (NE) markers, chromogranin and synaptophysin. Owing to their rarity, current knowledge of these tumours comes mainly from corroborative case reports or retrospective case series. There is hence a lack of randomised data on the treatment of these entities and current protocol suggests similar treatment as that of conventional breast carcinomas. We report the case of a 48-year-old with a breast mass, which on further work-up was diagnosed as locally advanced carcinoma breast, that required a mastectomy and axillary node dissection on the same side and revealed NE differentiation on histopathological examination. Hence, immunohistochemical staining was indicated which confirmed NE differentiation. We discuss the current knowledge on incidence, demographics, diagnosis, histopathological and staining characteristics, prognostic factors and treatment modalities of BNENs. Primary breast neuroendocrine neoplasms (BNENs) constitute an under-recognised subtype of breast malignancies. This entity accounts for less than 0.1% of all cases of carcinoma breast and under 1% of primary neuroendocrine neoplasms (NENs) .The updated WHO Classification of Tumours of the Breast, in 2019, defined BNEN as a tumour with greater than 90% of cells showing NE differentiation, that is, expressing NE markers — chromogranin and synaptophysin (SYN) . First dThe present case report outlines a unique case of a primary BNENs.A 48-year-old nulliparous lady without comorbidities presented with a 3-month history of a lump in the lower outer quadrant of her left breast. On examination, a 2 × 2 cm, irregular, hard lump fixed to the surrounding breast tissue was palpated. Multiple, non-tender enlarged level 1 lymph nodes were also felt in the left axilla.Mammography showed an irregular, infiltrating, Breast Imaging-Reporting and Data System (BIRADS) -V lesion in the posterior aspect of the lower outer quadrant measuring 2 × 2 × 1 cm. Significant left axillary lymphadenopathy was also noted.Fine needle aspiration cytology of a level 1 axillary lymph node revealed metastatic breast cancer. Ultrasound-guided tru-cut biopsy of the breast lump yielded nests of cells with nuclear moulding and coarse chromatin. A provisional diagnosis of carcinoma with NE differentiation was made.A chest X-ray showed normal findings and an ultrasound study of the abdomen and pelvis revealed post-hysterectomy status with no other sonological abnormalities.She underwent a left modified radical mastectomy with axillary node clearance, following the workup.On gross examination, a 3 × 2.5 × 1 cm, grey-white, well-circumscribed, unifocal, firm mass was noted. Histologically, the tumour was composed of densely cellular nests and trabeculae. The cells were arranged as solid sheets with rounded margins with delicate fibrovascular stroma separating them. Neoplastic cells were larger and polygonal, with eosinophilic, granular cytoplasm and coarse and fine nuclear chromatin .in situ (DCIS) was found. Electron microscopy revealed dense core secretory granules. On Immunohistochemistry (IHC), the tumour was hormone receptor- oestrogen and progesterone  positive and negative for HER2/neu (a non-hormone IHC marker for breast cancer that guides treatement options). More than 90% of the cells were strongly positive for neuron-specific enolase (NSE) and SYN  and Cyclophosphamide (600 mg/m2) followed by four cycles of single-agent docetaxel (75 mg/m2). The chemotherapy was followed by adjuvant radiation. 50 Gy of three-dimensional conformational radiation therapy with radical intent was given in 25 fractions without concurrent chemotherapy.She received standard-of-care therapy with four cycles of Adriamycin  show similar round or spindle-shaped cells with palisading of the nucleus, abundant eosinophilic and fine granular cytoplasm, and nuclei with ‘salt and pepper chromatin’. Tumour cells form islands, nests and trabeculae which are surrounded by a delicate fibrovascular stroma. According to the WHO classification of tumours 2019, essential criteria for BNENs include histological and immunohistochemical features of NE differentiation and co-existing DCIS is described as a desirable criterion . In the et al [et al [WHO describes BNENs as tumours with >90% of cells showing histological and IHC features of NE differentiation, mainly the expression of NE markers such as SYN and chromogranin A (CGA). CD56 and NSE may also be positive but are not as specific . In addiet al  found thet al . Previouet al . In our l [et al  noted thAs clinical characteristics and imaging features of BNEN are non-specific, histological features and immunohistochemical staining of tissues remain the cornerstone of diagnosis.As per 2019 WHO classification, well-differentiated BNENs were described as NETs which are considered low to intermediate-grade tumours in the current classification. Poorly differentiated BNENs, earlier described as NECs (neuroendocrine carcinoma) are considered high-grade tumours which include small-cell NEC and large-cell NEC . BNEN paThe differential diagnosis for these primary carcinomas is essentially metastasis from NECs at other sites. Presence of DCIS and the absence of tumours in other organs in radiology help in clinching the diagnosis of primary NEC of the breast . In the In terms of the prognosis of BNENs, the current literature is rather ambiguous with different investigators presenting conflicting reports. This ambiguity can also be attributed to the comparative smaller incidence of these tumours and the lack of larger studies on them.et al [et al [et al [et al [Previously, based on small studies, BNENs were thought to have a prognosis similar  or even et al  and Yangl [et al  suggest l [et al . Cloyd el [et al  have shol [et al  where thl [et al . In the l [et al .Presently, there is limited information to recommend a specific treatment protocol for invasive breast carcinomas with NE differentiation and current guidelines suggest treatment same as that of conventional breast cancer (IDC-NOS).et al [et al [Surgery remains the mainstay of treatment for early-stage BNEN. The type of surgery is decided upon by criteria similar to that of IDC-NOS. Of these, the location of the tumour and its size determines the surgical method. There is no sufficient evidence to date showing the most efficient chemotherapy regimen for these cancers. Generally, chemotherapy used in patients depends on the histological features of the patient’s tumour. Regimens containing platinum-etoposide, usually indicated for small-cell lung cancer, can be used in poorly differentiated small-cell BNENs , while aet al  in 2015 et al . Adjuvanet al . Somatoset al . Studiesl [et al  stated tl [et al .Our patient was surgically treated with a modified radical mastectomy of the affected breast with standard adjuvant chemotherapy indicated for Her2/neu negative breast carcinomas. Afterwards, she was started on adjuvant endocrine therapy and has since been in clinical remission. Treatment given was independent of NE features and according to principles of treatment for IDC-NOS, as indicated in the existing literature.There is an unmet need for further studies into these rare tumours for further understanding of these unusual clinical entities and for developing new treatment interventions. This case strengthens the importance of histopathology and early identification of NE features in patients with invasive breast cancer, which will help in early treatment and improved outcomes.The authors have no conflicts of interest to declare.There was no funding received for publishing this case report.


Autophagy in Inflammation Related Diseases, Volume II” to collect related studies for the discussion of such issue.Autophagy is a vital catabolic mechanism to degrade and recycle long-lived proteins and useless organelles relying on lysosomes . Since iWang et al. revealed that aspirin-triggered Resolvin D1 (AT-RvD1) produced an alleviative effect on neuropathic pain through the induction of autophagy-mediated suppression of the NLRP3 inflammasome. In addition, Pei et al. demonstrated that alantolactone attenuated interleukin (IL)-1β-induced inflammatory responses, relieved cartilage degeneration and promoted impaired autophagy via restraining of signal transducer and activator of transcription 3 (STAT3) and nuclear factor (NF)-κB signaling pathways in osteoarthritis. In a review paper, Feng et al. reported that autophagy was involved in the regulation of heparinase-mediated promotion of coagulation disorder and pulmonary fibrosis in acute respiratory distress syndrome (ARDS). In other two review papers, the role of autophagy in the regulation of fibrosis and immunopathogenesis of inflammatory bowel disease was discussed in detail . In addition, Huang et al. demonstrated the hepato-protective role of autophagy in non-alcoholic fatty liver disease (NAFLD).In our Research Topic, six brilliant studies have been collected and officially published in Frontiers in pharmacology. Among them, Autophagy in Inflammation Related Diseases,” has collected several latest original studies for the exploration of potential targets taking advantage of autophagy in the treatment of several kinds of inflammation-related diseases. Furthermore, several brilliant review papers have discussed the role of autophagy in several inflammation-related disorders through reviewing and summarizing the previous studies. We believe that our Research Topic would bring new insights in the investigation of autophagy in inflammation-related diseases.All in all, our current Research Topic, together with the former one entitled “


Biosensors, “Electrical/Optical Biosensing and Regulating Technology”, presents a collection of papers that describe the latest advances in electrical/optical biosensors and systems. These papers report on the development and application of electrical/optical biosensing and regulating technologies that are expected to significantly enhance biomedical research. By bringing together these cutting-edge technologies and research findings, this Special Issue facilitates the advancement of biosensing and regulatory technology and its impact on the field of biomedical research.Biosensing has emerged as a powerful tool for exploring biomedical mechanisms. Utilizing highly sensitive electrical and optical sensing technologies, biosensors can detect weak signals and trace biomarkers in a dynamic, real-time, and label-free manner. The current Special Issue of Sun and colleagues have extensively reviewed the application of optical and electrical sensors in flexible wearable wound detection . They emZhan et al. conduct a review of electrochemical sensors and their applications in detecting glycated hemoglobin (HbA1c) . This stMicrofluidic paper-based analytical devices (μPADs) have greatly promoted the development of in vitro diagnostics due to their low cost, high efficiency, and ease of use. In their review, Zhang et al. provide an overview of the origin, fabrication methods, detection techniques, and innovative applications of μPADs in in vitro diagnostics . They al2+ is an innovative approach. The detection system has good sensitivity, with a detection limit (LOD) of 1.8 μM in bovine serum samples, and good selectivity, with a recovery rate of 92.8~110.1% and a relative standard deviation (RSD) of 1.72~4.89%. The platform’s advantages of low cost, easy portability, strong operability, high throughput, and good repeatability make it a promising tool for point-of-care testing (POCT) applications.The smartphone-based ratio fluorescence probe (SRFP) platform developed by Wu et al. is promising for the detection and quantification of calcium ions in serum . The useYang et al. have developed an innovative platform for high-throughput biochemical analysis that integrates a spectrophotometer with a high-precision ball screw-driven two-dimensional motion slider . The steFunctional near-infrared spectroscopy (fNIRS) is a non-invasive method that can be utilized to detect cerebral hemodynamic responses and reflect the pattern of brain activity under different levels of stress. This technique can be used to assess individual cognitive abilities and psychological/physical health. Bak et al. conducted a study that focused on utilizing the laterality index (LIS) values calculated by fNIRS to differentiate between different types of stress . The autLiang et al. have proposed a novel method for quantitatively analyzing global DNA methylation using methylation-specific antibodies (5mC) modified magnetic beads (MB) for immune recognition and affinity enrichment . The metTerahertz radiation is a relatively new and unique radiation source that has been widely applied in various fields. In a recent study by Qi et al., the effects of 0.14 THz terahertz radiation on mouse behavior were investigated . The stuElectrical/optical biosensing and regulating technology can provide accurate and real-time measurements of various biological and environmental parameters, which can help researchers and scientists better understand complex biological systems and environmental processes. This Special Issue showcases the progress and potential applications of different sensor technologies in various fields, opening up new avenues for the future development of biosensing.


Mitochondrial bioenergetics and its function in tissue homeostasis are vital for regulating energy processes. As cells age, mitochondrial functions are often disrupted by both intrinsic and extrinsic threats including oxidative stress . AlthougGrün et al.; Zhang et al.) and one on human non-small cell lung cancer  along with a review article by Jagtap et al., collects new knowledge on mitochondrial function and shed light on the role of oxidative stress in altered mitochondrial bioenergetics and its relevance with aging-related pathologies. The aging-related decline in proteomic turnover, protein processing/folding, and quality control processes exaggerates the risk of oxidative stress to mitochondrial energetics  and reduced GO (rGO) that was found to be mediated by oxidative stress, lipid peroxidation, and mitochondrial dysfunction  and altered activities of several enzymes/indicators associated with myocardial activity and lipid peroxidation, respectively. These data revealed evidence of GO and rGO cardiotoxicity to myocardial cells that was mediated by oxidative stress, lipid peroxidation, and mitochondrial dysfunction.function ; 2. UsinLi et al. provided evidence of the anticancer function of ROS, which was essentially promoted by NRF2 inhibition , Li et al. analyzed ethanol fractions of Helicteres angustifolia L.  root and showed that 40% ethanol fraction  produced selective toxicity to NSCLC cells. Mechanistically, this bioactivity of EF40 was found to be linked with reduced expression of NRF2 that abundantly expresses across several cancers. Of note, EF40-led suppression of NRF2-dependent cellular defense response promoted the intracellular accumulation of ROS in the NSCLC cells. The biochemical analyses further explained the activity of EF40 in cell cycle arrest and apoptosis, promoted through the ROS-led DNA damage response. An evident decrease in matrix metalloproteinases (MMPs) and hnRNP-K expression levels in EF40-treated NSCLC cells further suggested its anti-migratory activity, which was corroborated by significantly reduced tumor growth and lung metastasis in an in vivo xenograft mice model. Conclusively, Li et al. provided direct evidence of the utility of ROS function in promoting anticancer activity that also reaffirmed the significance of NRF2-regulated defensive antioxidant response in cell survival.Although the oxidative stress produced by high ROS levels is central to the cardiotoxicity of myocardial cells, its lethality can be seen in cancer cells. In line with this, an original study by hibition ; 3. UsinJagtap et al. in a review report comprehensively discussed the new knowledge and developments in the stream (Protein synthesis, protein processing and folding, and quality control mechanisms are critical cellular processes that are directly linked with mitochondrial homeostatic function, which progressively decline with aging. Although the role of protein homeostasis or ‘proteostasis’ in cellular function is understood, its significance in mitochondrial physiology under neurodegenerative conditions needs to be resolved. To this end, e stream ; 4. The Conclusively, the original research and review articles published under the present Research Topic shed light on the role of oxidative stress in altered mitochondrial bioenergetics and its outcome. It also discusses new knowledge on impaired mitochondrial bioenergetics and its relevance with age-related pathologies.


Mood disorders such as major depressive disorder (MDD) and bipolar disorder (BD) are often resistant to current pharmacological treatment. Therefore, various alternative therapeutic approaches including diets are, therefore, under investigation. Ketogenic diet (KD) is effective for treatment-resistant epilepsy and metabolic diseases, however, only a few clinical studies suggest its beneficial effect also for mental disorders. Animal models are a useful tool to uncover the underlying mechanisms of therapeutic effects. Women have a twice-higher prevalence of mood disorders but very little is known about sex differences in nutritional psychiatry. In this review, we aim to summarize current knowledge of the sex-specific effects of KD in mood disorders. Ketone bodies improve mitochondrial functions and suppress oxidative stress, inducing neuroprotective and anti-inflammatory effects which are both beneficial for mental health. Limited data also suggest KD-induced improvement of monoaminergic circuits and hypothalamus–pituitary–adrenal axis—the key pathophysiological pathways of mood disorders. Gut microbiome is an important mediator of the beneficial and detrimental effects of diet on brain functioning and mental health. Gut microbiota composition is affected in mood disorders but its role in the therapeutic effects of different diets, including KD, remains poorly understood. Still little is known about sex differences in the effects of KD on mental health as well as on metabolism and body weight. Some animal studies used both sexes but did not find differences in behavior, body weight loss or gut microbiota composition. More studies, both on a preclinical and clinical level, are needed to better understand sex-specific effects of KD on mental health. High-fat low-carbohydrate ketogenic diet (KD) was originally introduced into clinical practice for the management of drug-resistant epilepsy nearly 100 years ago Peterman  and is sBesides epilepsy, metabolic and cardiovascular diseases growing amount of data suggest a beneficial effect of KD also in neurodegenerative diseases  is a leading mental disorder affecting up to 300 million people worldwide, producing a huge burden on society’s wellbeing and the world economy , medium-chain FA (MCFA) and long-chain FA (LCFA) , BD, psychotic disorders and schizophrenia , but have not reported their results yet. No RCTs of KD have been performed or started for MDD, while animal studies, case reports and a few small clinical trials suggest its beneficial effect on the mood. A recent small trial found improved depressive symptoms in 6 MDD patients and 12 BD patients after 3 weeks on KD  have been performed for KD in any mental disorder up to date. Few studies are registered on Disturbed monoamine neurotransmission is a key mechanism of depression, schizophrenia, ADHD, ASD and other mental disorders  axis dysregulation is a core symptom of mood and anxiety disorders with elevated cortisol level and disturbed feedback inhibition  and Firmicutes   metabolism in the motor and somatosensory cortex, but not in the midbrain and basal ganglia. However, the total level of dopamine, serotonin and noradrenaline remained unchanged in all brain regions explored in this study  and Firmicutes   better in men compared to pre-menopausal, but not post-menopausal women  gene expression (Salberg et al. Rats fed with a high-fat high-sugar diet for 12 weeks showed opposite changes in HPA axis activity with decreased corticosterone level in males but increased level in females (Sahagun et al. Sex-specific effects of KD on mental health were evaluated almost only in animal studies, although one study with obese volunteers did not find any sex differences in KD-induced changes in mood and cognitive function (Halyburton et al. Still very little is known about sex differences in gut microbiota in general (Reviewed in (Jaggar et al. Sex differences in diet-induced changes in gut microbiota were reported only in a few studies with polyphenol (Most et al. Data from experimental animal models and small clinical studies suggest that the ketogenic diet may have beneficial effects both in MDD patients and in the healthy population. Its repeatedly proven neuroprotective and anti-inflammatory effect is thought to be a key mechanism of its potential antidepressant effect. Moreover, key pathways of MDD pathogenesis, such as HPA axis hyperactivity and brain monoamine circuit disturbances have also been shown to be improved by KD in animal stress models. Recent animal studies using depression models showed synergistic effects of antidepressants combined with omega-3-rich fish oil (Paula Farias Waltrick et al.


NAFLD-MAFLD Conundrum”, is to discuss the current debate on renaming nonalcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated fatty liver disease (MAFLD) and the implications of changing terminology, summarizing the current state of knowledge regarding MAFLD and anticipating the necessity for a new nomenclature which is metabolic dysfunction-associated steatotic liver disease (MASLD)   given inOverall, four original articles, a systematic review and two narrative reviews have been published in this Research Topic.Wen et al. which included 10 cohort studies and showed that patients diagnosed with MAFLD alone had higher cardiovascular mortality than those diagnosed with NAFLD alone.The importance of a new definition is well established in the systematic review by Liao et al., where they observed that the number of publications on MAFLD increased dramatically, especially in the last three years. In particular, gut microbiota became an important research direction for etiological and therapeutic investigations into MAFLD, as well as, insulin resistance, a key factor in studying the development of MAFLD. They concluded that liver fibrosis was an important focus of disease development.Our Research Topic aimed to identify the hot topics and new trends in the gut-liver axis in NAFLD/MAFLD research starting from the bibliometric analysis conducted by Yang et al. confirmed the previous analysis revealing that gut microbiota, inflammation, insulin resistance, short-chain fatty acids, and randomized controlled trials will be the new focus of research in the field.Another bibliometric analysis by Li et al. in a cross-sectional study among 4,195 participants aimed to evaluate the diagnostic efficacy of different anthropometric indices, including body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), waist-to-hip ratio (WHR), cardiometabolic index (CMI), triglyceride-glucose (TyG) index, hepatic steatosis index (HSI), lipid accumulation product (LAP), body roundness index (BRI), visceral fat index (VAI), abdominal volume index (AVI), cone index (CI), and body fat index (BAI), in adults with MAFLD to identify the best cut-off point for diagnosis of MAFLD in United States adults. In particular, the authors concluded that LAP may be a sensitive marker for diagnosing MAFLD in United States adults.Xiao et al. is the skeletal muscle mass (SMM). In the same cohort of Li et al., the authors demonstrated that the distribution of SMM differently affected MAFLD and significant fibrosis in the sex groups. Higher appendicular SMM was associated with a lower risk of MAFLD, while the risk of significant fibrosis in females was increased with the trunk SMM. Concluding the two published reviews focused the attention on molecular characterization of NAFLD/MAFLD  and on the latest treatments .Another important parameter taken into account by We hope that this Research Topic will help to produce new evidence about NAFLD/MAFLD and contribute to better understand the new definition of MASLD, in order to clear the complexity of this disease.AD: Conceptualization, Writing – original draft. RK: Writing – review & editing. SA: Validation, Writing – review & editing.


Obsessive-compulsive disorder (OCD) is a psychiatric disorder characterized by recurrent unwanted thoughts (obsessions) and associated repetitive behaviors (compulsions), affecting around 1.1–1.3% of the global population ; it has been shown to play a key role in neurogenesis and neural development, and possibly in synaptic vesicle transport. In SPRED2-deficient mice, alterations in neural transmission were observed in thalamo-amygdala circuits. Subsequently, it was found that these mice, like those in which SAPAP3 had been deleted, also showed altered ultrasonic vocalizations. These changes were observed in both young and older mice, and appeared to increase with age  of SAPAP3 has been specifically associated with the Contamination/Washing dimension of OCD, as well as with a poor response to serotonin reuptake inhibitors , coding for a protein related to SAPAP3 which is also involved in synaptic connectivity, were significantly associated with clinical OCD  have also been associated with childhood OCD (Gazzellone et al., SAPAP1 has been knocked out exhibit impaired scaffolding at glutamatergic synapses and altered social behavior (Coba et al., BDNF and NTRK2 genes, which are proximal components of the same cellular cascade as SPRED2, may exert a protective effect against OCD; these effects may be mediated by beneficial effects on this particular signaling pathway (Alonso et al., Copy number variants in Taken together, these findings suggest that genes involved in neurodevelopment and synaptic connectivity, when disrupted, induce not just OCD-like behavior but alterations in brain development, sensory processing, cognitive functioning and social behavior in animals. At least one of these genes is also associated with certain facets of OCD in humans. There is evidence from animal research that alterations in these genes are associated with functional changes involving prefrontal, striatal and limbic brain regions. The consistency of these findings across rodents and humans suggests that at least some of the genetic mechanisms underlying OCD could be evolutionarily conserved. The fundamental phenotype involved in this process may represent lower-order deficits arising from alterations in neural development, which could influence higher-order cognitive processes in a “bottom-up” manner (Benzina et al., The argument presented above would gain support if it were possible to demonstrate neurodevelopmental antecedents of OCD in humans. In this case, too, the available evidence suggests that at least some types of OCD have developmental antecedents. The evidence for these developmental alterations has been summarized in recent reviews (Poletti et al., SAPAP3 or SPRED2 knock-out mice.Specific phenotypes have also been linked to these developmental alterations. For example, patients with OCD show evidence of impaired olfaction, which is a marker of brain dysfunction of developmental origin (Crow et al., An endophenotype is a heritable trait that can be measured in an objective manner, and which is present in individuals with a given psychiatric disorder, as well as their unaffected first-degree relatives, at rates significantly higher than in healthy controls or in the general population (Gottesman and Gould, A tentative integration of the findings described above is presented in During the course of cognitive development in early life, alterations in these processes affects “higher-order” cognitive processes such as flexibility and decision-making capacities (Abramovitch et al., The model outlined above represents a tentative yet coherent approach to understanding the mechanisms through which evolutionarily conserved cellular and neurobiological processes could contribute to the development of OCD in humans. Much remains to be learned about the specific association of each process with OCD, their relationship to the different dimensions of OCD, and the opportunities they offer for early intervention, improved treatment, and the identification of specific endophenotypes such as sensory over-sensitivity (Fontenelle et al., The sole author of this work was responsible for the conceptual framework, literature review, writing, editing, and proofreading of this paper.


Neurodegenerative and neurodevelopmental diseases represent neurological disorders that variably affect individuals and produce negative consequences, such as altered social interaction, restricted/repetitive behavior, and other medical and mental health conditions that result in lifelong functional and social impairments with high economic and social costs  and presents a compelling argument in support of salivary biomarkers to diagnose this complex disorder, which currently relies solely on behavioral assessments .The mini review entitled, “Salivary MicroRNA Profiling Dysregulation in Autism Spectrum Disorder: A Pilot Study”, demonstrates how saliva can help clinicians support the ASD diagnostic process through the standardization of conditions used to isolate biomarkers that can robustly detect disease in a more simple way . The second, entitled “Salivary Inflammatory Biomarkers are Predictive of Mild Cognitive Impairment and Alzheimer's Disease in a Feasibility Study,” provides evidence for the feasibility of saliva as a valuable source of biomarkers for the early detection of cognitive impairment in individuals on the AD continuum and potentially other neurodegenerative diseases.This mini review is followed by two original research articles. The first, entitled “Non-Invasive Diagnosis and Monitoring Tool of Children's Mental Health: A Point-of-Care Immunosensor for IL-6 Quantification in Saliva Samples”  and “Multisite Dopamine Sensing with Femtomolar Resolution Using a CMOS Enabled Aptasensor Chip”  provide examples of how point-of-care (POC) biosensors can help societies fast track patient needs in the early diagnostic process. For instance, preliminary analysis of retrospective PoliBiobank data  demonstrates that miRNA and inflammatory molecule biomarkers in saliva samples collected from healthy individuals and those diagnosed with neurodegenerative and neurodevelopmental diseases, using traditional techniques, can be detected via real-time PCR and the MSD platform, respectively (unpublished data).The two remaining studies, “Finally, as we highlighted in Goldoni et al. , our hopAll authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.


Neurological disorders (ND) are now globally recognized as the primary cause of death and disability. The prevalence, incidence, deaths, and disability-adjusted life years (DALY’s) were estimated from 1990 to 2016 in 195 countries for nearly 15 common neurological disorders . Based oThe rapid development of India resulted in an increased burden of neurological disorders, which form a significant proportion of non-communicable diseases. A survey on the burden of neurological disorders in India revealed that non-communicable neurological disorders doubled, whereas communicable neurological disorders reduced to about one-fourth from 1990 to 2019 . The preIn the present era, a significant increase in neurological disorders has been observed throughout the globe due to the COVID-19 pandemic or as co-morbidities of post COVID-19 complications. The partial or complete lockdown situations in the last 2 years have confined everyone in their respective territories, leading to changes in neurological complications like anxiety, depression, stress, and psychological disturbances in the general public, especially in children. It has been reported that isolation and post-traumatic stress was the leading cause of depression and altered mood in post COVID-19 patients . A studyIt is the hour of need to deal with the increasing number of neurological disorders in developing and developed countries with safer and therapeutically efficacious medicines. We can achieve this goal with advanced clinical and translational research and bioinformatics tools on traditionally used and medicinally potential natural products . Considering the need to enrich more information about natural products and neurological disorders, researchers and clinicians working in the Natural Products/Pharmacology field were invited to contribute their valuable research to this Research Topic article collection. Research articles on pre-clinical and clinical studies of Natural Products/Traditional Plants in neurological disorders , Case studies/clinical reports emphasizing the role of natural products in neurological disorders, and Review articles focusing on “Neuropharmacological Studies of Natural Products” covering Clinical and translational research with bioinformatics tools, SAR and molecular docking studies and Mechanistic Insights were considered under the scope of this Research Topic.Puri et al., entitled “Natural product-based pharmacological studies for neurological disorders,” focused on targets associated with neurological disorders, traditional holistic approaches for managing neurological disorders and mechanistic approach of phytoconstituents in treating various neurological disorders. A mini-review entitled “Understanding the role of “sunshine vitamin D” in Parkinson’s disease: A review,” published by Behl et al., explained the role of sunshine vitamin D in Parkinson’s disease. In the systematic review article entitled “The neuroprotective effects of melatonin against diabetic neuropathy: A systematic review of non-clinical studies,” published by Hosseini et al., the authors have critically analyzed the role of melatonin in diabetic neuropathy and explained its mechanisms taking reference from pre-clinical data. A research paper entitled “Evaluation of Mollugo oppositifolia Linn. as cholinesterase and β-Secretase enzymes inhibitor,” published by Das et al., emphasized in vitro neuroprotective effect of Mollugo oppositifolia in Alzheimer’s disease. The authors have identified phytochemicals in bioactive plant extract and performed in silico molecular docking studies to identify more potential and stable metabolites with potential for Alzheimer’s disease targeting. Another research paper, “Long-term oral administration of naringenin counteracts aging-related retinal degeneration via regulation of mitochondrial dynamics and autophagy,” stressed the role of a CNS-acting flavonoid, Naringenin, in counteracting aging-related retinal degeneration.We received ten articles for consideration for publication in the thematic issue. After a thorough review, five articles were accepted out of 10 submitted articles. Amongst these, two articles are original research papers, one systematic review, one review, and one mini-review. A review article published by


The application of glial cell line-derive neurotrophic factor (GDNF) to cell cultures and animal models has demonstrated positive effects upon dopaminergic neuronal survival and development, function, restoration, and protection. On this basis, recombinant GDNF protein has been trialled in the treatment of late-stage human Parkinson’s disease patients with only limited success that is likely due to a lack of viable receptor targets in an advanced state of neurodegeneration. The latest research points to more refined approaches of modulating GDNF signalling and an optimal quantity and spatial regulation of GDNF can be extrapolated using regulation of dopamine as a proxy measure. The basic research literature on dopaminergic effects of GDNF in animal models is reviewed, concluding that a twofold increase in natively expressing cells increases dopamine turnover and maximises neuroprotective and beneficial motor effects whilst minimising hyperdopaminergia and other side-effects. Methodological considerations for measurement of dopamine levels and neuroanatomical distinctions are made between populations of dopamine neurons and their respective effects upon movement and behaviour that will inform future research into this still-relevant growth factor. The discovery of glial cell line-derived neurotrophic factor (GDNF) as a secretion product from the rat B49 glioma cell line in 1993 heralded the arrival of a powerful promotor of dopaminergic cell survival with enormous potential for treating Parkinson’s disease (PD). Lin et al  after biSide- and off-target effects are important to consider for future therapies as they affect the tolerability and utility of GDNF. Side-effects following intracerebroventricular (icv) GDNF injection in humans are documented as principally nausea, vomiting, paresthesias, hyponatremia, anorexia, and weight loss  channels  in addition to striatum (40%). ERK1 and ERK2 phosphorylation were increased in SN and striatum, respectively, and microdialysis showed an increase in DA release in response to K+ and amphetamine  was unchanged following nigral GDNF injection in 4–6 month old rats, yet given a twofold increase in K + -induced DA release, there was calculated to be a 1.75-fold increase in TC (DA clearance) when measured electrochemically in vivo  which fine-tunes behaviour /tTA-responsive promotor system under CAMKIIa to overexpress GDNF at two- to threefold levels in cortex, hippocampus and brainstem in any cells that normally express CAMKIIa  showed increased TH activity and DA synthesis yet, unusually, no increase in K+ -stimulated DA release via microdialysis  of the mouse Gdnf 3′UTR has been excised via Cre-LoxP. Homozygous removal of the 3′UTR resulted in a more than threefold increase in Gdnf mRNA and affected prepulse inhibition in mice, suggesting schizophrenia-like behaviour (Mätlik et al. In further support of the endogenous elevation route, the One important methodological consideration arose in measuring extracellular dopamine levels, as reported in Kumar et al. . ElectroThere is evidence for GDNF signalling via multiple pathways and for unexplored roles in maintaining normal striatal function outside of canonical RET signalling. NCAM1, integrins αv and β1, and N-cadherin induce neurite outgrowth, proliferation, survival, and influence axon guidance (Chao et al. , respectively. This may affect the tolerability of future therapies in humans due to effects upon cognitive and behavioural functions.A clearer framework for working with GDNF in terms of overexpression, localisation, and off-target effects is now evident. This highlights the pitfalls of exogenous application and the benefits of endogenous upregulation as well as the marked effects of GDNF upon DA transport. DA overflow in systems with greatly increased dopamine transporter activity may not be an accurate marker of DA release as accurate measurement may be masked by increased reuptake kinetics see Fig. . This is


RISPR-Cas9, have made zebrafish one of the most powerful model systems for breakthroughs in human diseases and provide the foundation for translational research [Our understanding of fundamental biological mechanisms and the pathogenesis of human diseases has been greatly improved by studying the genetics and genomics of zebrafish . The fieresearch .In this Special Issue of “Zebrafish: a powerful model for genetics and genomics”, we present 16 research articles and reviews concerning zebrafish modeling in genetics and genomics that aid in understanding human diseases. Notable publications include three articles that illustrate the generation of novel transgenic zebrafish, which can be used in addressing important biological questions: (1) Mao et al. created a transgenic zebrafish to visualize adipocyte development, facilitating the characterization of white adipose tissues in vivo and the development of therapeutic interventions to treat metabolic diseases in humans; (2) Li et al. generated an animal system to monitor the in vivo dynamics of spatiotemporal calcium signaling useful for normal animal physiology as well as stressful and pathophysiological conditions; (3) Jeong et al. developed an optogenetic manipulation system for dissecting olfaction-related behaviors and their underlying neural circuitry.In addition to transgenesis, two studies have shown advanced applications of CRISPR-Cas9 technology that could assist users in patient-specific gene tailoring as follows: (1) de Vrieze et al. revealed an improved strategy in developing knock-in zebrafish models; (2) Schellens et al. demonstrated the therapeutic potential using the exon skipping approach for modeling retinitis pigmentosa.ift74 gene, developing gradual photoreceptor degeneration that is distinguishable from other previously published IFT-B mutants in zebrafish. (2) Berlingerio et al. demonstrated that cystinosis, a disease characterized by cystine accumulation in the lysosome resulting in nephropathy and vision problems in humans, was recapitulated in ctns gene mutant zebrafish. (3) Alexandro-Moreno et al. showed that primary congenital glaucoma, mainly associated with CYP1B1 gene mutations, was recapitulated in a cyp1b1 KO zebrafish and displayed a novel pathway involving the dysregulated expression of extracellular matrix genes. (4) Kim et al. identified potential regulators responsible for vanishing white matter disease by performing a comparative proteome between eif2b3 KO zebrafish and the WT control. These all show novel molecular processes that underlie disease etiology and, thus, could provide therapeutic clues for corresponding human diseases.What makes this Special Issue more interesting is the addition of articles that each showed a novel gene knockout (KO) zebrafish that recapitulated clinical symptoms associated with specific human diseases. (1) Zhu et al. induced ciliopathy via a mutation in the Additionally, several articles are included in this Special Issue to provide immediate benefit for researchers in regenerative biology, hematopoiesis, brain–skin communications, or environmental health. Ellman et al. described a tutorial paper for setting up an apex resection model to study heart regeneration in lab settings, providing an improved development model and assessing the heart’s capacity for regeneration using zebrafish. Huang et al. discovered that NELF (negative elongation factor), the promoter-proximal pausing controller of RNA polymerase II, is specifically involved in granulocyte development but not erythrocyte development, emphasizing the importance of NELF in regulating hematopoiesis. In addition, Ren et al. identified a biological mechanism that underlies environmental change, particularly acute cold resistance. Furthermore, Hong et al. developed a platform for screening MSH-related activity, identifying an effective chemical treatment for autism spectrum disorder.FOXC1 and PITX2 and discussed their analyses on the utility of zebrafish with the corresponding gene mutations for dissecting potential molecular mechanisms and therapeutic approaches.Finally, three review articles were included in the Special Issue in order to highlight the current status of disease modeling using zebrafish and the underlying molecular pathogenesis. Specific topics include hematopoiesis, rare neurological disorders, and Axenfeld–Rieger syndrome (ARS): (1) Zhang et al. summarized a comprehensive review on erythropoiesis using zebrafish models to explore human anemias; (2) Son et al. described the disease modeling of rare neurological disorders, focusing on zebrafish models; (3) French C.R. wrote a review on the development of ARS induced by mutations in In summary, this Special Issue is a collection of 16 relevant articles that support the use of zebrafish modeling in genetics and genomics for treating human diseases. To further boost the benefits for the communities of researchers who use zebrafish models, we are accepting original research papers or review articles for the 2.0 version with a setup similar to this Special Issue: “Zebrafish: A Powerful Model for Genetics and Genomics 2.0”.


Recognizing the future leaders of Hematology is fundamental to safeguarding tomorrow's driving force in innovation. Indeed, early career researchers have faced a significant and potential “long” impact from the pandemic , 2.Therefore, this Research Topic aimed to showcase the high-quality work of internationally recognized researchers in the early stages of their careers. We highlighted research by leading scientists of the future across the entire breadth of Hematology, and present advances in theory, experiment and methodology with applications to compelling problems. Contributions to the Research Topic were by invitation only. All Rising Star researchers were suggested by established Editors within the Frontiers board in recognition of their influence on the future directions in their respective fields.All articles submitted to us for this Research Topic underwent a rigorous peer review process. Ultimately, 11 articles were published.Fouquet et al. highlighted the link between genotype and the unusual clinical phenotype.(i) An interesting case report in hematology was presented by analysis of a heterozygous somatic BLNK mutation associated with T-cell LGL (large granular lymphocyte) leukemia and autoimmune diseases. Liang et al. indicated the feasibility of the NGS approach and the evaluation of its therapeutic effect.(ii) Application of metagenomic next-generation sequencing (NGS) in the diagnosis of visceral leishmaniasis and its treatment evaluation was presented by a case report. Fattizzo and Motta covered a broad spectrum of novel and exciting treatment options in rare congenital and acquired anemias.(iii) A review article presented an update on emerging treatment strategies in rare anemias. Fu et al. presented an artificial intelligence method of excellent performance for the diagnosis and potentially automatic detection of malaria in the future.(iv) An original article reported an intelligent detection method for plasmodium based on self-supervised learning and attention mechanism. Selvakumar et al. focused on epidemiology and potential mechanisms for adverse long-term sequelae of iTTP, best practices in survivorship care, and presented a research agenda for the future.(v) A review article on immune thrombotic thrombocytopenic purpura (iTTP) provided up-to-date knowledge on long-term outcomes and survivorship. Ramadas and Sparkenbaugh reported novel insights into the activation of PAR1 by APC and thrombin, the APC-EPCR-PAR1 axis, and their potential roles in SCD.(vi) A mini review article discussed activation of APC-EPCR-PAR1 axis in sickle cell disease (SCD). Kerbauy et al. reviewed literatures on applying these novel techniques in autologous and allogeneic transplantation across different clinical entities.(vii) A review article focused on total marrow irradiation in hematopoietic stem cell transplantation for hematologic malignancies. Lysandrou et al. described the study rationale and design, including patient screening, product manufacturing, infusion, and participant follow-up to data collection, management, and analysis.(viii) A study protocol article presented the phase I/II trial of induced HLA-G+ regulatory T cells in patients undergoing allogeneic hematopoietic cell transplantation from an HLA-matched sibling donor. Ahmed et al. reported that many patients who were eligible for ide-cel were not able to secure a timely slot, with high mortality rates as a result.(ix) A brief research report article highlighted “waitlist mortality” for myeloma patients with limited access to BCMA therapy. Whyte has introduced readers into the world of “thromboinflammation” or “immunothrombosis”.(x) A mini review article explained the interactions of the fibrinolytic and innate immune systems. Shah et al. provided in-depth knowledge of the concept of point-of-care (POC) manufacturing or decentralized in-house production.(xi) A review article delineated promises and challenges of a decentralized CAR T-cell manufacturing model. Considering the multi-thematic character of this Research Topic, our hope is to inspire researchers and physicians to continue their explorations into novel advances in Hematology.EG: Writing – original draft. ML: Writing – review & editing. PC: Writing – review & editing. MA: Writing – review & editing.