The limitations of conventional therapeutic drugs necessitate the importance of developing novel therapeutics to treat diverse diseases. Conventional drugs have poor blood circulation time and are not stable or compatible with the biological system. Nanomaterials, with their exceptional structural properties, have gained significance as promising materials for the development of novel therapeutics. Nanofibers with unique physiochemical and biological properties have gained significant attention in the field of health care and biomedical research. The choice of a wide variety of materials for nanofiber fabrication, along with the release of therapeutic payload in sustained and controlled release patterns, make nanofibers an ideal material for drug delivery research. Electrospinning is the conventional method for fabricating nanofibers with different morphologies and is often used for the mass production of nanofibers. This review highlights the recent advancements in the use of nanofibers for the delivery of therapeutic drugs, nucleic acids and growth factors. A detailed mechanism for fabricating different types of nanofiber produced from electrospinning, and factors influencing nanofiber generation, are discussed. The insights from this review can provide a thorough understanding of the precise selection of materials used for fabricating nanofibers for specific therapeutic applications and also the importance of nanofibers for drug delivery applications. Nanotechnology—the use of nanomaterials for biomedical applications—is an emerging and promising paradigm in biomedical research. Nanomaterials with exceptional physiochemical properties, biocompatibility and minimal biological toxicity, can sense local biological environments and initiate cellular level reprogramming to achieve the desired therapeutic efficacy. Diverse zero dimensional , one-dimensional  and two-dimensional  nanomaterials along with nanosized particles are currently used for diagnosis, imaging and therapy ,2,3. NanElectrospinning is a unique and versatile technique that depends on the electrostatic repulsion between surface charges to constantly draw nanofibers from viscoelastic fluids. Polymers, ceramics, small molecules and their combinations are used as rich materials for the production of nanofibers. In addition to solid nanofibers, a secondary structure of nanofibers—including porous, hollow or core-sheath structures—has been manufactured and the surface of the structure can be functionalized with different molecular moieties, during or after the electrospinning process . ElectroWe have reviewed the most efficient and recent therapeutic applications of electrospun based nanofibers and their future perspectives. Different electrospinning techniques are described here, along with their biomedical applications and suitability. Nanofibers are generally natural or synthetic polymers and they have vast therapeutic applications even though only a limited number reach clinical trials. The application of nanofibers as drug delivery carriers—especially for cancer drugs, antibacterial drugs, nonsteroidal anti-inflammatory drugs, cardiovascular agents, gastrointestinal drugs, antihistamine drugs, contraceptive drugs and palliative drugs delivery—is described here. Nanofibers have promising therapeutic applications for DNA, RNA and growth factors, for example, protein and steroid hormones delivery, which are included in this review. The current scenario for nanofiber based materials is mostly promising for wound dressing, sensor technology and for the catalysis of various reaction pathways in the laboratory . The theElectrospinning is considered a promising, highly productive and simple method for fabricating the nanofibers of polymers, composites, and inorganic materials, including carbides, oxides, nitrides and hybrid composites. In the electrospinning technique, electrostatic forces are utilized to produce nanofibers from a polymer solution . In geneAlthough fibers produced by different electrospinning methods have attracted increasing attention in the field of biomedical applications, challenges persist for the selection of an appropriate method, as well as for optimizing multiple parameters to generate robust cargo loaded nanofibers . ElectroBlend electrospinning is the conventional electrospinning technique, in which the drug/biomolecules are dispersed or dissolved in the polymer solution, resulting in the development of nanofibers with drugs/biomolecules dispersed throughout the fibers . AlthougCo-axial electrospinning is an improvement on conventional blend electrospinning, in which two nozzles are connected to the high voltage source rather than one nozzle. Two different solutions are loaded within each nozzle and are pumped out to generate nanofibers with core-shell morphologies . Both syEmulsion electrospinning requires a setup similar to that of blend electrospinning, in which two immiscible solvents are simultaneously spun to generate core-shell nanofibers. Here, active bioactive molecules, along with surfactants, are initially allowed to form W/O emulsions and are later mixed with the polymer matrix solution . During Melt electrospinning has gained more attention in the electrospinning field, where toxicity and solvent accumulation is a concern. In this process, polymer melt is used instead of a solution, which is transformed from liquid to solid to achieve the desired product on cooling, rather than through solvent evaporation . The polGas jet electrospinning is an improvement on the conventional melt electrospinning technique, in which the conventional electrospinning setup is additionally equipped with a gas jet device. The major limitation of melt electrospinning is that it requires definite control over the temperatures and therefore multiple heating zones must be placed to maintain the polymer melt. This results in generation of thicker nanofibers compared to the solutions. In this technique, the co-axial jet is surrounded by a tube feeding the heated gas, which can provide sufficient heat near the nozzle and delay the process of polymer solidification. For example, Zhmayev et al. spun polylactic acid (PLA) and showed a decrease in the diameter of the nanofibers obtained by gas jet electrospinning compared to normal electrospinning. Interestingly, the heated gas flow-rate had a significant effect on the diameter of the nanofiber. The increased gas flow rate can offer additional drag force to the jet surface which can result in the development of thinner nanofibers. Zhmayev et al.’s result showed a significant decrease in the diameter of the nanofiber, from 350 nm to 183 nm, when the gas flow rate was increased from 5.0 L/m to 15.0 L/m ,40.Most conventional drugs are hydrophobic and suffer from poor bio-distribution, solubility and stability in the biological system. Moreover, these drugs do not have the desired active targeting capabilities, which can result in non-specific systemic toxicity or faster elimination from the body, without achieving the desired therapeutic efficacy. Drug delivery systems (DDS) are approaches, formulations and technologies for transporting therapeutic agents to the targeted therapeutic site in the body . The devOf all delivery routes, the oral route is considered the most preferable and convenient route of administration, which can overcome the problems associated with other routes of administration . HoweverThe oral mucosa has its own subdivisions according to its different regions, namely, buccal, sublingual and gingival. A few years ago, researchers were also interested in designing nanofiber based drug delivery systems for sublingual (under the tongue) or buccal (between the gums and teeth) routes of administration. The sublingual or buccal delivery systems usually allow the drug-loaded electrospun nanofibers to dissolve in the presence of mucus so that the drug can directly penetrate into the small blood vessels. Interestingly, these oromucosal routes of administration are the most studied sites for nanofiber-based therapeutics, offering versatile and multifunctional drugs, DNA, RNA, protein, peptide, growth factors or vaccine delivery platforms . Pediatric patients (aged under 6 months) usually cannot swallow any drug or food supplement. Under such circumstances, the rectal route could be the best alternative to oral drug delivery systems. In addition, the rectal route is also effective in cases of unconscious or vomiting patients. An electrospun nanofiber-based rectal drug delivery system is continually gaining popularity. In the treatment of post-operative peritoneal effusion following rectal/pelvic surgery, electrospun nanofibers could be considered a safe potential biocompatible, and biodegradable sealing fiber. The first clinical trial on the safety and sealing properties of electrospun nanofibers in lymphorrhea following pelvic surgery was published in 2014 . The autElectrospun nanofiber scaffolds targeting vaginal routes have recently been investigated. However, the acidic condition of vaginal mucosa (~pH 4) should be considered before designing vaginal drug delivery systems using nanofibers. For example, Brako et al. fabricated progesterone-encapsulated nanofibers targeting the vaginal route of administration. The authors used a mucoadhesive molecule (carboxymethylcellulose) for the fabrication of electrospun nanofibers. As-synthesized progesterone/carboxymethylcellulose electrospun nanofibers exhibited sustained release properties ,55. AnotCurrently, supramolecular peptides are used to fabricate electrospun nanofiber scaffolds. Electrospun supramolecular peptide nanofibers have proven their potential for intranasal vaccine delivery. For example, Si and coworkers developed intranasal administrated influenza vaccine using peptide nanofibers consisting of virus polymerase. This self-assembled nanofiber could elicit both humoral and cell mediated immune responses against the influenza virus. To be specific, nasal administrated nanofiber vaccine particles were initially ingested by antigen presenting cells in lung-draining mediastinal lymph nodes and activated both Th1 Th2 to produce the antibody against the given antigen. Furthermore, a high immune response was elicited without any use of vaccine adjuvant .Generally, various drops or ointments are used for ocular infection or inflammation. In these cases, those drugs are easily excreted from the eye very quickly. Therefore, to improve therapeutic efficacy and overcome the repetitive administration of an established ocular dosage, nanofiber-based ocular inserts have been considered and compared with eye drops or similar methods of dosage. Drug-loaded nanofiber scaffolds that allow the controlled release of incorporated drugs can be placed into the ocular mucosa. For example, the use of brimonidine tartrate (BT)-loaded electrospun nanofibers as ocular inserts were used to treat ocular infection and inflammation, which is described in detail in Transdermal drug delivery systems (TDDS) deliver a drug locally, avoiding undesired drug distribution and possessing excellent skin permeability. Due to high solubility, great morphology and sustained drug release kinetics, electrospun nanofibers have been developed into TDDS. It has been reported that electrospun nanofibers could enhance solubility and form a transdermal patch for the biopharmaceutics classification systems II drugs with a high therapeutic efficiency and no cytotoxicity. Hydrophilic polymers with great permeation are the strength of TDDS, and several in vitro and in vivo evaluations suggest the possibility of using drug-loaded electrospun nanofibers in establishing TDDS .Producing nanofibers with excellent physico-biochemical characteristics using an electrostatic spinning technique is considered to be an efficient multipurpose drug delivery strategy for delivering various therapeutic agents ranging from nanomedicines to macromolecules, including proteins and nucleic acids. Nanofibers can overcome several key challenges such as low solubility, loading efficiency, short circulation and the plasma half-life of drugs and are effective at improving the bioavailability of drug growth factors, DNA, RNA, and so forth. . Using vDiscovering a new potential treatment strategy against cancer is very difficult due to several drawbacks of anticancer therapeutics such as imperfect solubility, impermanence in the circulatory bloodstream, poor accumulation in cancer cells, highly toxic to normal cells, low working efficiency in solid tumors and excess elimination profile . To surpRecently, electrospun nanofibers have been widely used to ameliorate the solubility of anticancer drugs a. In thiEven though polymeric nanoparticles (NPs) are used as a drug carrier to load anticancer drugs like Paclitaxel, the poor drug-loading efficiency of these systems minimizes the applications in the biological system . On the DOX, 500 nm) and these nanocomposites were injected into a tumor-bearing mice model, it showed 4 times more accumulation in the cancer site and was 3 times more stable in plasma level compared with microspheres. However, small length nanofibers of 2 micrometers in diameter exhibited the most powerful cancer cell apoptosis and necrosis activities with the highest resistance to metastasis -2-methoxybenzamide) is an antidopaminergic benzamide, pharmacologically used as a serotonin receptor agonist. Its inhibitory action on acetylcholinesterase exerts its prokinetic and anti-emetic effect due to its actions on contractility of colonic smooth muscle. Recently, Jaber and co-workers fabricated a core/shell nanofiber using PVA/PCL to load metoclopramide hydrochloride [Metoclopramide  as well as core-shell nanofibers such as PVA/PCL, PVA/PLLA, and PVA/PLGA to investigate the control release behavior of metoclopramide loaded as-synthesized nanofibers. The drug release profile data suggested that the controlled release of hydrophilic entities is possible by using core/shell nanofibers and by verifying the physicochemical properties of core/shell solutions. The result also showed a clear difference according to the release characteristics between the monolithic fibers, which are made of hydrophilic and hydrophobic polymers, and core/shell fibers using PCL, PLLA, and PLGA 80/20 shell polymers. The monolithic fibers cannot control the initial burst release of the hydrophilic drug metoclopramide hydrochloride but core/shell electrospun nanofibers can easily regulate the controlled release of incorporated drugs. Thus, electrospun nanofibers would be a promising gastrointestinal drug carrier to achieve controlled release behavior and protect sensitive drugs in a biological pH .Antihistamine generally works by blocking the physiological activities of histamine, thus, antihistamines are used in the treatment of nasal congestion, sneezing, hives, seasonal hay fever and especially, to relieve the symptoms of various allergies such as dust allergy, cold allergy, allergic rhinitis, indoor and food allergies. For the time being, electrostatic nanofiber scaffolds are being used as a carrier of various antihistamine drugs. One experimental study was designed to incorporate the first-generation antihistamine (H1 receptor antagonist) chlorpheniramine maleate into glutinous rice starch combining polyvinyl alcohol (GRS/PVA) electrospun nanofibers to investigate a drug delivery carrier concept and control release properties of the nanofibers . The hybDevelopment of fast dissolving delivery systems of therapeutics (FDDST) is an excellent and unique concept especially for those patients who have difficulties swallowing pharmaceutical solid dosage forms. FDDST offers very fast-dissolving solid oral dosage forms that take a few minutes for absorption in the patient’s mouth. Thus, FDDST facilitates high drug bioavailability, therapeutic window and exemption of hepatic first-pass elimination. Previously, the electrospinning method was employed to design, develop and evaluate FDDST in which one study proved more than 80% of total ibuprofen release within 20 s  whereas Another example of an antihistamine is Diphenhydramine, a member of the ethanolamine class of histamine H1 receptor antagonists, which is mainly used to treat allergies, nausea, motion sickness, extrapyramidal symptoms and symptoms of a common cold by reversing the effects of histamine on capillaries. It is also used in parkinsonism due to its ability to act as a muscarinic acetylcholine receptor reverse agonist by crossing the blood-brain barrier. In addition, its usage as a sodium channel blocker introduced it as a local anesthetic . HoweverFor the first time, a composite electrospun nanofiber was fabricated by free-surface electrospinning with various microscale geometries as a carrier of physicochemical diverse medicines including the contraceptive drug progestin levonorgestrel . The as-Palliative treatment—also known as comfort or supportive care—aimed to relieve, reduce or control symptoms, side effects and adverse effects such as pain and sickness at any stage of serious diseases, thus enhancing the life expectancy and comfort of a patient even during the last stages of an illness. Nagy et al. used lower molecular weight poly to fabricate the non-woven tissues of a nanofiber with a large surface area for developing an oral fast-dissolving dosage form by applying electrostatic spinning. After loading highly water-soluble Donepezil HCl (which is used to treat dementia-related Alzheimer’s disease) into as-prepared nanofibers, the diameter of the electrospun nanofiber was 100–300 nm even when the polymer-drug ratio was 33 w/w%. Interestingly, in comparison with the release rate of the commercially available Aricept tablet (brand name of Donepezil HCl), the drug-loaded nanofiber took less than 30 s to release whereas the Aricept tablet took ≥30 min. This might be due to the availability of the nanofiber’s large surface area which is directly proportional to the dissolution rate, corresponding to the Noyes and Whitney equation [Among various miscellaneous drugs, caffeine is the most used agent worldwide that binds to adenosine receptors by mimicking natural adenosine, affecting various body functions. At present, electrospinning techniques are being widely used to fabricate caffeine loaded nanofibers as a FDDST facilitating a high surface area and high porosity of nanofibers that can lead to fast-wetting features of the nanofiber surface to ensure quick release properties of incorporated drugs. In these respects, drugs are usually encapsulated into nanofibers either in amorphous or nanocrystal format, ensuring high solubility, dissolution, rapid onset of action and bioavailability of loaded drugs. A study was designed by electrospinning using PVA as the drug nanocarriers of caffeine (CA) and riboflavin (RFN) in which the dissolution time and wetting time were 1.5 s and 4.5 s respectively for both PVA-CA and PVA-RFN. In addition, the release percentages of CA and RFN from PVA filament-forming nanofibers were 100 and 40 respectively within 1 min . In anotDiscovering an effective and potential ophthalmic drug delivery system (ODDS) is still a challenge due to the quick elimination of ocular drugs like eye drops. Thus, rapid peroneal losses of eye drops, even with the high volume of administration resulting in low bioavailability and very short half-life of applied drugs and a lower amount of ophthalmic drugs , can reach into intraocular tissues via penetration through the cornea. To address these problems, Gagandeep et al. (2014), developed a nanopatch using PVA and PCL via electrostatic spinning to load and deliver a combination of timolol maleate and dorzolamide hydrochloride as a model drug against glaucoma. As-developed drug-loaded nanopatches were 200–400 d·nm with almost 100% drug entrapment efficiency—no interaction has been found between polymers and encapsulated drugs. Furthermore, the in vitro drug release experiment alluded an initial burst release of incorporated drug from nanopatches followed by controlled release behavior for up to 24 h . The oveDrug enrichment on the surface of the polymer is only possible if the drug is blended with the polymer solution before electrostatic spinning. This system facilitates an initial burst release of the loaded-drug resulting in rapid onset of action, but it also decreases the potential lifetime of delivery carriers. Hence, to obtain desired results such as sustained therapy, local and controlled release, enhanced activity and retrenchment of side and adverse effects, core-shell nanofibers would be the best option. One study was designed to load brimonidine tartrate (BT) into a first dissolving dendrimer nanofibers (DNF) against glaucoma a. The inThe delivery of nucleic acid molecules such as DNA or interfering RNA, into a target cell to knockout/ knockdown mutated gene expressions, either by gene editing or impeding the mechanism of the mutated gene, has proven its novelty in the field of regenerative disease treatment. In this case, when a gene misbehaves in a protein, gene therapy is able to introduce the new copy of that specific gene for recuperating the function of that protein by adjusting the signal transduction pathway . To dated,l-lactide)–poly(ethylene glycol) type biodegradable synthetic copolymers [However, the encapsulation of a nucleic acid/polymer complex in the core of core/shell nanofiber scaffolds can protect the encapsulated DNA or interfering RNA from biological degradation and denaturation, as well as prolong their release up to several months by controlling it. For instance, non-knitted, membraneous nanofiber scaffolds were fabricated via the electrospinning procedure as a gene delivery carrier, containing plasmid DNA encapsulated with poly(lactide-co-glycolide) and poly), PLGA (poly(lactide-co-glycolide)), LPEI (linear polyethyleneimine), ELP (elastin-like polypeptides), PDLLA ), and many more are used as a nucleic acid carrier [However, the hydrophobic nature and slow degradation properties of PCL are responsible for the slow release properties of encapsulated siRNA ,121. To  carrier ,123,125 Growth factors are naturally occurring endogenous signaling molecules  which are efficient for inciting cellular development, differentiation, regeneration and proliferation by binding to cellular receptors. Recently, marked progress has been made in preparing several types of ultrathin electrospun nanofiber scaffolds to successfully load and deliver several growth factors a as wellThe quick inactivation and very short biological half-life of growth factors are the most important factors hindering their effectual delivery. In addition, it has been noted that the growth factors’ carrier should have slow and sequential releasing properties. The establishment of growth factors into nanofiber scaffolds play very crucial roles in repairing and regenerating damaged tissues by mimicking signal transduction from cell to cell, or from cell to its extracellular matrix . Either Recently, the polysaccharide matrix is being used as a superior nanofiber material to fabricate a growth factor carrier owing to their low toxicity, biocompatibility, and extracellular matrix mimicking capability. However, introducing the sulfation state to the alginate scaffolds ensures the appointed binding and loading of growth factor into the polymer backbone, as well as maintenance of its control release properties. For instance, Mohammadi S, et al. fabricated electrospun scaffolds by blending alginate sulfate and polyvinyl alcohol to load and deliver transforming growth factor-beta1 (TGF-β1) for tissue engineering applications. For the first time, this research revealed that more successful binding, encapsulation and sustain release of heparin-like proteins from electrospun scaffolds could be achieved by the addition of an affinity site to the alginate . A part Usually, the traditional nanofiber scaffolds-based GFs delivery methods such as dip coating and covalent binding are associated with low entrapment efficiency and primary burst release properties. Currently, researchers are looking for new, innovative and stable strategies by focusing on controlled and sustained release properties. To control the release properties of encapsulated GFs, the usage of gelatin particles in nanofiber fabrication is becoming popular. Generally, the in vitro degradation time of gelatin particles is about 240 h, so researchers tend to use gelatin particle-mediated nanofiber scaffolds as a promising GF nanocarrier. The basic advantages of using gelatin particles are their slow degradation and controlled release properties in a biological environment because of introducing cross-linking treatment during fabrication. An example would be the work of Jiang and co-workers who prepared PCL fibrous scaffolds containing vascular endothelial growth factor (VEGF)-incorporated gelatin particles which were able to exhibit both diffusion and degradation mediated release for a long period of time b, differd,l-lactic acid) (PDLLA) nanofiber scaffolds whereas the glial cell line-derived neurotrophic factor was incorporated in poly(lactic-co-glycolic acid) (PLGA) electrospun scaffolds [Biocompatible and biodegradable polymeric nanoparticles and biomimetic hydrogel have gained more attention for encapsulating various types of growth factors and confirming their controlled and prolonged releasing . VEGF ancaffolds . This ducaffolds . The prel-lactide-co-caprolactone) and poly(2-ethyl-2-oxazoline) was able to protect the bioactivity of dual angiogenic basic fibroblast growth factor and vascular endothelial growth factor during and after their physical blending. It is also capable of mimicking the topography and chemical cues of native cardiac tissue structures [d,l-lactic acid) [The time period of sustained release of GFs from its carrier should be proportional to the time period of GFs capability to preserve the nanofiber scaffolds; therefore, this important factor is considered during the design of nanofiber-mediated GFs delivery. Employing several electrospinning techniques, the preservation of GFs’ bioactivity is achieved for the proliferation and migration of specific cells. The heterogeneous electrospun matrix made of biocompatible poly(ructures . The strructures . The priructures . Previouic acid) . This glElectrospinning is a promising technology for manufacturing nanofibers from the laboratory to industrial level. Nanomaterials possess a large surface area and enhanced porosity, which are advantages for drug delivery and many other biomedical applications. Nanofibers can be formed using three different techniques: electrospinning, self-assembly, and phase separation. Electrospinning is the most widely used technique because of its promising results. Electrospun nanofibers have attracted much attention due to their biocompatibility, adhesiveness, sterile nature and their efficiency in diverse applications. Currently, nanofibers are considered suitable candidates for scaffold materials, wound dressing materials, drug delivery systems, filtration membranes, catalysts for reduction and so on. Nanofibers are used for medical applications, batteries and fuel cells as a new material.Though the application of nanofibers is versatile, still more development and research is required for the proper use of nanofibers, especially for biomedical therapeutic delivery. The application of nanofibers in drug delivery, medical implants or tissue engineering is still very limited and most of the materials cannot reach the stage of clinical trials. A thorough investigation on the scaling up of nanofiber technology is required, to make it widely available.


Food intolerances are estimated to affect up to 20% of the population but complete understanding of diagnosis and management is complicated, given presentation and non-immunological mechanisms associated vary greatly. This review aims to provide a scientific update on common food intolerances resulting in gastrointestinal and/or extra-intestinal symptoms. FODMAP sensitivity has strong evidence supporting its mechanisms of increased osmotic activity and fermentation with the resulting distention leading to symptoms in those with visceral hypersensitivity. For many of the other food intolerances reviewed including non-coeliac gluten/wheat sensitivity, food additives and bioactive food chemicals, the findings show that there is a shortage of reproducible well-designed double-blind, placebo-controlled studies, making understanding of the mechanisms, diagnosis and management difficult. Enzyme deficiencies have been proposed to result in other food sensitivities including low amine oxidase activity resulting in histamine intolerance and sucrase-isomaltase deficiency resulting in reduced tolerance to sugars and starch. Lack of reliable diagnostic biomarkers for all food intolerances result in an inability to target specific foods in the individual. As such, a trial-and-error approach is used, whereby suspected food constituents are reduced for a short-period and then re-challenged to assess response. Future studies should aim to identify biomarkers to predict response to dietary therapies. Adverse food reactions are defined as any abnormal reaction following the ingestion of food. The different adverse reactions are described as food hypersensitivity, including food intolerance and food allergy, or food aversion, which is a psychological avoidance by Pavlovian conditioning of adverse reactions . There aThe aim of this narrative review was to critically evaluate and synthesize the key evidence and scientific understanding for the most common food intolerances. Each type of food intolerance assessed presents an overview of the food component and where it is found, a description of the induced response including any prevalence data, an overview of the mechanisms of how the food may induce its response and suggested diagnosis and management. Recent literature was analyzed via search databases including Medline, PubMed and Scopus to conduct this narrative review.Naturally occurring and present in a wide variety of foods are fermentable carbohydrates termed ‘FODMAPs’ (denoting fermentable oligo- di- mono-saccharides and polyols). This group of carbohydrates has been identified to trigger symptoms in patients with functional GI symptoms such as in irritable bowel syndrome (IBS) . The lowConsumption of a high FODMAP diet in sensitive individuals is thought to be associated with lower GI symptoms of abdominal pain, bloating, flatulence, and altered bowel habits. Randomized controlled trials using a low FODMAP diet have noted improvement in overall abdominal symptoms, pain, bloating, and bowel habit ,16,17,18Two main mechanisms of action were originally proposed for the effect of FODMAPs on symptom induction. Firstly, short-chain poorly absorbed carbohydrates present in the small intestinal lumen have an osmotic effect, increasing water delivery to the lumen. This mechanism has been confirmed whereby increased effluent output was shown in ileostomates given a high FODMAP diet , as wellThe low FODMAP diet may be implemented following a diagnosis of IBS based on symptom criteria (Rome IV criteria), with adequate exclusion of organic disease . Prior tFaecalibacterium prausnitzii .,58.57,58Histamine intolerance results from an imbalance of accumulated or ingested histamine and the reduced ability to degrade histamine . In healHistamine occurs in different concentrations in animal and plant foods but is also produced and denatured by the body itself, for example in the intestinal microbiome. Histamine produced in the body seems to have less effect on histamine intolerance, except in situations such as mastocytosis  with an Histamine intolerance remains an exclusion diagnosis, as there are no clear diagnostic criteria nor biomarkers for histamine intolerance. The diagnosis of histamine intolerance is made by a combination of criteria  58]..58].Other food intolerances, GI disease, IgE-mediated food allergies and underlying mastocytosis should be excluded before a diagnosis can be made. If histamine intolerance is still suspected, avoidance of histamine-rich foods for 4 to 6 weeks is undertaken. The measurement of DAO or histamine levels in the blood has been scientifically inconclusive and is not recommended for routine diagnosis or only after well-defined dietary regimens. A recent study has shown increased DAO after histamine restriction, reflecting dietary compliance . Some geA low histamine diet is the first priority in management, which includes a three-stage diet change as shown in Thousands of different food additives are used throughout the food industry for various functions, especially to preserve food and improve taste or appearance. They are generally synthetic and natural substances that cannot be consumed alone as food themselves. Food additives are classified based on their function and property including preservatives, flavors, emulsifiers, thickeners, humectants, firming agents and flavor enhancers. A small number of additives have been implicated in IgE-mediated or other immunological or non-immunological adverse reactions.A low food chemical diet encompasses restriction of a wide range of bioactive food additives and preservatives that occur naturally or are artificially added to foods . The lowSimilar to ‘The Elimination Diet’ other diets low in food chemicals have been proposed and used worldwide although they are poorly studied. For example, ‘The Feingold Diet’ originally designed in the 1970’s to reduce attention deficit hyperactivity disorder (ADHD) in children eliminated artificial sweeteners, colours and preservatives from the diet but one re-challenge study using food colouring was unable to show an effect . The ‘FePrevalence of self-reported symptoms to food additives has been reported to be 0.01–0.23% in adults , and chaDue to the lack of controlled studies, mechanisms of action of food additives in symptom provocation are poorly understood. It is likely that studies of each individual food additive will be required to elucidate their specific pathophysiology, few studies have been conducted to date with some suggestions of potential mechanisms of individual food additives. Inconsistent reports of adverse effects exist for tartrazine (food dye) , sulphitThere are no diagnostic tests available to assess food additive or chemical sensitivity. Despite the lack of efficacy data, the low chemical diet is used in clinical practice . Like otDuring normal carbohydrate digestion, sucrase cleaves the 1-4 linked glucose oligomers of sucrose and maltose, while isomaltase cleaves branched (1-6 linked) α-limit dextrins. Following this enzymatic digestion, the monosaccharides are absorbed across the epithelial barrier . When thIn sucrase-isomaltase deficiency, sucrose and starches present in the lumen act as FODMAPs resulting in symptoms of diarrhea, bloating and abdominal pain, with symptom severity dependent on residual sucrase and isomaltase activity .Sucrase-isomaltase deficiency may occur either due to genetic variants, or as a secondary or acquired event. There have been more than 25 genetic variants identified in the human sucrase gene. Variants can occur on the sucrase or isomaltase subunits, and as such varied degrees of symptom severity occur . SecondaRegardless of the cause of sucrase-isomaltase deficiency, the absence or deficiency in enzyme activity results in undigested sugars in the lumen which then act as FODMAPs. The presence of undigested sugars in the lumen has osmotic effects resulting in hyperosmolar diarrhea, and subsequent fermentation in the colon results in gas production . The disThe gold standard for diagnosis is duodenal or jejunal biopsies, although studies to date have largely been conducted in children . InaccurDietary treatment may include restriction of sugars and starch, followed by gradual re-introduction to determine tolerance, although compliance rates are poor and efficacy of dietary modification have not been well studied . An alteDouble-blind placebo-controlled with cross-over trials are the current gold standard for confirming the dietary factor(s) involved in symptom generation and are therefore required to confirm any food intolerance discussed in the current review. Greater methodological difficulties exist in the design and implementation of clinical dietary trials compared to pharmacological trials. For example, lack of isolation of food components e.g. co-existence of gluten and fructan within the same foods, difficulty in design of placebo diets, and challenges in blinding of participants. Hence, the same criteria for trial methodology used in pharmacological studies may not be appropriate . In ordeOnce food compositional data is available and clear efficacy has been established, further research should investigate the following key factors. Firstly, assess the role of mode of education on symptomatic response i.e., does the efficacy vary depending on how the information is delivered, either via physician, dietitian, nurse, or online and app-based mediums. Secondly, what is the level of dietary restriction required to achieve symptom resolution. For example, a strict gluten-free diet is required in coeliac disease to ensure mucosal healing, but it is unknown if this same level of restriction be necessary for those with NCG/WS to reduce symptoms. Likewise, feeding studies assessing efficacy of the low FODMAP diet reduced intake to 3 g/day , compareThe ability to predict response to dietary therapies would significantly enhance treatment strategies which has been reviewed previously . PredictThe ability to identify ways to predict response to dietary therapies may also lead to improved mechanistic understanding of functional GI conditions and allow for creation of ways to improve tolerance to foods. For example, certain microbiota or metabolomics profiles may indicate that supplementation with a certain pre- pro- or syn-biotic is required, shifting the profile to one in which symptom response to a certain food component is mitigated. Due to the lack of tests available to identify intolerance to specific food components, a trial-and-error approach is used in clinical practice. This approach utilizes strategic short-term removal of food components followed by re-introduction to assess symptom response. Selection of which food components to trial removing may be based on the clinical picture including symptomatic profile, habitual diet, patients suspicions of food intolerances, and where applicable, genetic variations. Appropriate implementation and education about avoidance of food triggers is required across any food intolerance . Patients attempting to modify their diet benefit from guidance by a dietitian, likely due to improved understanding and compliance, resulting in greater symptom response ,32,95. TIn some cases, combination therapies may allow for more personalized and targeted therapies. For example, in a re-analysis of patients within a trial assessing the low FODMAP diet, patients who were carriers of the sucrase-isomaltase hypomorphic variants were less likely to respond to a 4-week low FODMAP diet trial . In thesIt is clear that while there are a large number of suspected food components inducing symptoms, there is a notable shortage of well-designed studies making understanding of the reaction, diagnosis and management difficult. Future studies should use carefully planned double-blind studies with defined inclusion criteria to reduce the knowledge gaps and elucidate clear mechanisms of action of food intolerances.


Chemoresistance is a major problem in cancer therapy as cancer cells develop mechanisms that counteract the effect of chemotherapeutic compounds, leading to relapse and the development of more aggressive cancers that contribute to poor prognosis and survival rates of treated patients. Cancer stem cells (CSCs) play a key role in this event. Apart from their slow proliferative property, CSCs have developed a range of cellular processes that involve drug efflux, drug enzymatic inactivation and other mechanisms. In addition, the microenvironment where CSCs evolve (CSC niche), effectively contributes to their role in cancer initiation, progression and chemoresistance. In the CSC niche, immune cells, mesenchymal stem cells (MSCs), endothelial cells and cancer associated fibroblasts (CAFs) contribute to the maintenance of CSC malignancy via the secretion of factors that promote cancer progression and resistance to chemotherapy. Due to these factors that hinder successful cancer therapies, CSCs are a subject of intense research that aims at better understanding of CSC behaviour and at developing efficient targeting therapies. In this review, we provide an overview of cancer stem cells, their role in cancer initiation, progression and chemoresistance, and discuss the progress that has been made in the development of CSC targeted therapies. In 2018, the World Health Organization (WHO) asserted that cancer is responsible for the death of 9.6 million people worldwide ,4. AlthoChemotherapy induces apoptosis by damaging DNA and/or inhibiting mitotic division. However, this therapeutic option is valid for highly dividing cancer cells and therefore has the potential to “miss out” slow dividing cells, leading to cancer relapse and recurrence in treated patients. Unfortunately, follow up chemotherapy that attempted to destroy refractory cancers cells has been mostly unsuccessful and was associated with a decrease in survival rates of treated cancer patients ,6. Due tIt is well known that the microenvironment or niche is essential for stemness maintenance, and this also applies to CSCs where cell‒cell interactions within the niche are required for CSCs’ role in cancer initiation and progression . The CSC+CD38− AML stem cells that were capable of initiating AML in severe combined immune-deficient (SCID) mice. Although using a different set of markers, populations of CSCs were also found in other types of cancerous tissues, which confirmed their existence within other types of tumours and the role that they play in cancer initiation and progression [“Omnis cellula e cellula” (“every cell stem from another cell”), with those words Rudolf Virchow, a German pathologist, gave the base of the cellular pathology. He had already postulated that the disease is due to changes happening in normal cells and that a tumour originates from immature cells ,13. Howegression ,33,34,35gression ,37. The A major challenge in cancer therapy is associated with chemoresistance and recurrence following chemotherapy ,39. In mChemotherapy targets highly proliferative cells through DNA damage and inhibition of mitotic division; however, its action is limited when it applies to slow and non-dividing cancer cells such as CSCs ,49,50,51This large superfamily of membrane proteins functions in the transmembrane transport of various substrates by converting energy obtained from ATP hydrolysis . Althoug+/CD24−/ALDH+ populations have been shown to possess characteristics of stem cells such as self-renewal, high proliferative potential, clonogenicity and multipotency [This superfamily of enzymes is crucial for the detoxification of endogenous and exogenous aldehyde substrates by catalysing the oxidation of aldehydes to carboxylic acids ,62,63. Tipotency ,68,69,70CCSs have been shown to resist apoptosis mediated by the intrinsic or mitochondria-dependent death pathway, and by the extrinsic cell death receptors pathway . For insATM serine/threonine kinase (ATM) and the DNA damage checkpoint protein kinase (Chk1) in response to ionising radiations [Another survival advantage in stressful conditions is related to CSCs’ capacity to timely activate the DNA damage sensor and repair machinery . This prdiations . Anotherdiations . Mammospdiations . In concStem cell niches represent areas of tissue that provide specific microenvironments, which maintain and promote CSCs’ capacity to self-renew and to generate differentiated progenies . The conAlthough CAFs provide a mechanical supportive role for CSCs via enhanced production of fibrillary collagen, these cells also secrete the cytokine CXCL12 (C-X-C motif chemokine ligand 12) and growth factors such as the hepatocyte growth factor (HGF), the vascular endothelial growth factor (VEGF) and the platelet-derived growth factor (PDGF), which significantly contribute to CSCs’ increased proliferation, invasion and metastasis ,100,101.Several immune cells contribute to the chronic inflammatory status of the CSC microenvironment, which enhances tumour proliferation, invasion and metastasis . For insMSCs are multipotent stromal cells that can differentiate into various cell types such as osteocytes, adipocytes and chondrocytes. These cells can migrate to chronic inflammatory sites such as cancer, where they contribute to metastasis by secreting TGFβ which promotes EMT . An invoAngiogenesis is key for the CSC microenvironment as it delivers nutrients for CSC metabolism that are necessary for their self-renewal, and invasive and metastatic abilities. Through tumour vessels, immune cells such as T regulatory cells (Tregs) are recruited in situ and contribute to immune suppression . EndotheSNAIL, bHLH and ZEB factors [The main interest in investigating CSCs is related to their capacity to resist chemotherapy and radiotherapy, which results in cancer recurrence that is extremely difficult to overcome using currently available therapies. CSCs can re-initiate the tumorigenic process by generating a new tumour via their self-renewal and generation of differentiated cancer progenies. Another important property is their high invasive and metastatic potential, which involves a cellular process named EMT. Epithelial cells are connected to each other via lateral cell-cell junctions that include desmosomes, adherens junctions, tight junctions and gap junctions. During EMT, epithelial cells begin to trans-differentiate and start losing their lateral junctions and express molecules associated with the mesenchymal phenotype, resulting in the generation of mesenchymal cells . These l factors ,125. The factors . Beside  factors . SHH sig factors . Notch s factors . Finally factors ,130,131.Cells require energy to perform their own processes of growth, division and survival. This need is met by the glycolysis metabolic pathway that converts glucose into pyruvate, two energy molecules of ATP and one of NADH (nicotinamide adenine dinucleotide hydrogen) . The pyrCSCs are identified and isolated using cell markers whose expression create tissue-specific signatures. While some markers are commonly expressed by different types of cancer, others are tissue specific . In this+ hematopoietic stem cells [CD133 (cluster of differentiation 133 or human prominin-1), a marker that was first identified on the cell surface of CD34em cells , has alsem cells . CD44 is a cell surface adhesion receptor that is expressed by several types of cancers. The function of CD44 in growth and migration is dependent on its interaction with different ligands such as hyaluronic acid (HA), osteopontin (OPN), collagens and metalloproteases (MMPs) . TargetiThe epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein that is expressed by most human carcinomas . The firThe integrin associated protein (IAP) or CD47 (cluster of differentiation 47) was first identified as a β3 integrin interacting partner and was later found to interact with trombospondin-1 (TSP-1) and signal regulatory protein-alpha (SIRPα). Through these interactions, CD47 is involved in the regulation of various cellular functions such as cell migration, axon extension, cytokine production and T cell activation ,157,158.+) and were administered as a vaccination in adults with glioblastoma multiforme (primary or secondary) (NCT01567202). Finally, EPCAM-targeted CAR-T cells have been generated using genetically modified T cells that express a chimeric antigen receptor (CAR), and that bind to tumour cells expressing the EPCAM protein on the cell surface [Dendritic cells (DCs) are antigen presenting cells that initiate and maintain immune responses through their essential function in anti-cancer immunity . DCs pre surface . These CAlthough progress has been made in developing cancer therapies that target CSCs, the specificity of the targeted antigens remains a challenge. Most of the therapies are directed against biomarkers that are not specifically expressed by CSCs and that are also found in normal cells within the body. This has unfortunate effects on increasing toxicity in treated patients. For instance, therapies that target CD133 resulted in adverse events and treatment-related toxicities in glioblastoma patients who were treated with a CD133-specific dendritic vaccine (NCT02010606). However, other ongoing therapies such as the ones combining two monoclonal antibodies or using EPCAM as a target may lead to better therapies. Making the data of the clinical trials available to the scientific and clinical communities will certainly help in sharing information for the development of more efficient targeting therapies . Although cancer bi-therapies are certainly a better choice, further studies are required to identify more specific targets with a much lower toxicity when tested in clinical trials. Large scale analysis of tumour samples from different patients and cohorts using genomics, proteomics and data mining approaches (Bioinformatics) could lead to the identification of CSC-specific genes or antigen signatures that will allow the development of more efficient CSC targeted therapies with lower associated toxicities for treated patients. Furthermore, these approaches could also provide patient specific signatures that will allow a personalised therapy and reduced cost and toxicity.Another aspect that has not been discussed in this review, is the role of epigenetics in regulating the role of CSCs in cancer initiation and progression. Non-coding RNAs such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) function by regulating the expression of several CSC-specific genes. Other epigenetic regulators involve histone acetyl transferases (HATs) and histone deacetylases, which also play important roles in maintaining CSC stemness and differentiation ,176. TheIn summary, whether using drugs, immunotherapies or gene therapies, the specificity of the targets is key for a successful eradication of CSCs and cancer recurrence.


Immunotherapy is rapidly becoming the fourth arm of cancer treatment, and breakthrough successes have been observed in multiple malignancies. However, despite the potential for impressive anti-tumor effects, on average, only 25% of patients respond, and barriers clearly remain. Hence, uncovering innovative ways to apply immunotherapy and overcome immune resistance remains an unmet need in immuno-oncology. Natural killer (NK) cells are an attractive candidate for extending the promise of immunotherapy, although success to date has been largely limited to hematological cancers. An important study has identified novel ways in which NK cells sense and respond to tumors, and these findings may impact clinical translation of NK cells in cancer immunotherapy. Using the activating receptor NKp44, NK cells were shown to bind platelet-derived growth factor DD (PDGF-DD) which was secreted by tumors. Using transgenic mice, NKp44 binding of tumor-expressed PDGF-DD was able to limit tumor growth, and expression of natural cytotoxicity receptor-associated gene signatures (of which NKp44 is a member) was correlated to clinical outcomes. This study highlights the potential for effector-target interactions to impact immune homeostasis in previously unrecognized ways, while at the same time, underscoring the complexities inherent in pre-clinical/ translational experimental design which may confound clinical application of these interesting results. Immunologists tend to view immune cells principally in the context of immune-mediated signaling (i.e. cytokines or co-stimulatory/inhibitory ligands), and as such, we tend to overlook their general biology as cells residing in an organism responding to continuous cellular and molecular signals, particularly in non-immune tissues. Non-immune mediators such as growth factors, hormones, and adhesion molecules are all utilized by immune cells. Indeed, as immune cells can potentially reside anywhere, it makes sense that these non-immune pathways also play important, possibly critical, roles in immune function. Case in point, a recent study by Barrow et al. demonstrated that a platelet derived growth factor (PDGF) isoform is a putative ligand for the NK cell activating receptor, NKp44 or NCR2 . NKp44 oSeveral important conclusions can be drawn from this study. First PDGF-DD can stimulate activated NK cells by directly binding NKp44. Since NKp44 is only present on activated NK cells, it is important to recognize that clinical application using this approach will require prior NK activation. However, it is of interest that the authors focused on cytokine induction rather than CD107a detection as a readout of NKp44 triggering since previous publications have shown a dominant role of NKp44 in augmenting cytolytic capability , althougA critical issue in attempting to determine the possible in vivo relevance of the human NK cell effects observed in vitro are the striking species differences between mouse and human NK cells, which in the current study centers on the complete absence of NKp44 in mice. Tumor immunology necessitates in vivo validation and this presents a quandary given the numerous immunological differences between mouse and man . For exaYet despite these caveats, the study does open new avenues for further exploring the role of NK cells in cancer. It will be of particular interest to ascertain if the role of NK cells and/or NKp44 is heightened when oncolytic viruses are applied in GBM since NK cells can not only target the tumor but simultaneously limit viral efficacy. Further research is also needed to determine why the PDGF-DD isoform is specifically upregulated in some cancers and selected to be a target of NK cells. Finally, the study raises important questions on the increasing use of targeted therapies for possible unforeseen immune effects. PDGF inhibition has been targeted in cancer with some success , 10. How


Attention Deficit Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder with a complex symptomatology, and core symptoms as well as functional impairment often persist into adulthood. Recent investigations estimate the worldwide prevalence of ADHD in children and adolescents to be ~7%, which is a substantial increase compared to a decade ago. Conventional treatment most often includes pharmacotherapy with central nervous stimulants, but the number of non-responders and adverse effects call for treatment alternatives. Exercise has been suggested as a safe and low-cost adjunctive therapy for ADHD and is reported to be accompanied by positive effects on several aspects of cognitive functions in the general child population. Here we review existing evidence that exercise affects cognitive functions in children with and without ADHD and present likely neurophysiological mechanisms of action. We find well-described associations between physical activity and ADHD, as well as causal evidence in the form of small to moderate beneficial effects following acute aerobic exercise on executive functions in children with ADHD. Despite large heterogeneity, meta-analyses find small positive effects of exercise in population-based control (PBC) children, and our extracted effect sizes from long-term interventions suggest consistent positive effects in children and adolescents with ADHD. Paucity of studies probing the effect of different exercise parameters impedes finite conclusions in this regard. Large-scale clinical trials with appropriately timed exercise are needed. In summary, the existing preliminary evidence suggests that exercise can improve cognitive performance intimately linked to ADHD presentations in children with and without an ADHD diagnosis. Based on the findings from both PBC and ADHD children, we cautiously provide recommendations for parameters of exercise. PrefaceADHD is a neurodevelopmental disorder characterized by inattention and/or hyperactivity and impulsivity diagnosed in children before the age of 12 ,4 and reFor a child to be diagnosed with ADHD, she or he must present at least six of the nine symptoms within either the inattentive and/or the hyperactivity and impulsivity category. According to the American Psychiatric Association’s Diagnostic and Statistical Manual for Mental disorders (DSM-5) , a childThe cardinal symptoms of inattentive ADHD encompass distractibility, forgetfulness, poor organization skills and low perseverance, whereas hyperactivity and impulsivity are associated with impatience for delayed rewards, difficulties in inhibition of untimely and inappropriate motor responses along with inability to dampen motor activities to appropriate levels for a given situation . The linAlthough ADHD is in general associated with lower performance, neuropsychological tests are in isolation unlikely to have sufficient selectivity necessary to entail clinical value . As an eAssessing internal phenomena such as cognitive processes is not straightforward and crude categorization into ‘presentations’ or ‘core symptoms’ may not be of sufficient fidelity to fully describe the idiosyncratic etiology of ADHD. Each core symptom of ADHD assessed through conventional scales  is influenced by several neurocognitive functions typically operationalized as performance on neurocognitive tests. Although, each cognitive construct  involves multiple and overlapping neurophysiological processes and testing these independently is accordingly troublesome , they do provide cut out a middleman and provide a more detailed picture of the pathology. Elucidating the effect of exercise on tests of executive functions and attention  provides vital information on how to target exercise interventions for children with ADHD.Meta-analyses suggest that pediatric ADHD is associated with consistently lower performance in tests of response inhibition, behavioral inhibition, reaction time variability, cognitive flexibility, choice impulsivity (delayed gratification and delay discounting tasks) and WM ,46,47,48bodily movement that results in energy expenditure [exercise along with everyday activities such as commuting on foot. The distinction between PA and exercise feeds into the perspectives dominating the research field; exercise may act as a neuro-enhancer and improve cognitive performance through acute and long-term effect on monoaminergic transmission, neurotrophic signaling and mechanisms of neuroplasticity  and exercise exerts a plethora of beneficial physiological, psychological and neurocognitive effects. These include reductions in stress , anxietyenditure . This bree e.g.,  for reviee e.g., ) could ed og Hedges’ g) vary from 0.19 to 0.54 [During the recent years, there has been an increasing focus on acute effects of a single bout of exercise. Acute exercise increases arousal, which is accompanied by potentiated performance in a wide array of cognitive tasks. Although a single bout of exercise is unlikely to cause long-lasting changes in the cognitive functioning, the immediate effect can be harvested for relevant purposes . Across cognitive domains, meta-analyses point to positive effect of acute exercise in PBC children. For combined EFs, effect sizes , Cook et al. reported that young individuals with ADHD who are unmedicated, are—or are likely to be—sedentary [Activity levels of children are typically measured directly as accelerometer data collected over one or more typical days , indirecedentary . This suedentary .n = 14) activity levels measured over 7 days with an accelerometer were positively related to planning abilities assessed as performance in the Tower of London task [In preadolescent children with a high risk of ADHD , Brassell et al., found a positive correlation between aerobic fitness and accuracy for the incongruent trials in a modified Flanker task as well as lower interference scores, altogether signifying better inhibitory capacity for high fit children . In linedon task . AltogetMeta-analyses of the causal effect of long-term exercise interventions cognitive function in PBC children find small effects on EFs  children with ADHD; one combines effects from cross-sectional, acute and long-term investigations , one sumintensity, length, duration and frequency had beneficial effects for children with ADHD (g = 0.81) [In 2015, Cerrillo-Urbina and coworkers presented evidence from eight randomized controlled trials with a total of 249 children . Of the  = 0.81) . DespiteNotwithstanding the limitations of the available meta-analyses, recent evidence-based practice recommendations suggest moderate to large positive effects of exercise on inattention, impulsivity, hyperactivity and executive functioning . This isAs discussed above, ADHD pathology is complex, and several neurophysiological abnormalities contribute to the low performance in test of NCFs. A qualified discussion of how exercise may improve cognitive functions in children with ADHD warrants an outline of differences in central nervous structures, network activity and brain neurochemical signaling between PBC and children with ADHD as well as an overview of how exercise impacts the CNS. See Structural abnormalities in cortex and midbrain associated with ADHD likely develop slowly over years. Similarly, structural changes in cortical and subcortical regions develops slowly over weeks to months of e.g., motor practice ,127,128,2 receptors in the prefrontal cortex of non-human primates causes hyperactivity and impairs behavioral inhibition [ADHD is associated with wide array of grey matter abnormalities in the brain  to demonstrate that white matter integrity in fronto-temporal bundles is higher in individuals with higher aerobic fitness levels . The resThe grey and white matter deficiencies associated with ADHD are likely to contribute to the aberrant patterns of activity and connectivity observed during resting state and task-based functional MRI (fMRI) and electroencephalography (EEG) assessments . ConversEngaging in meaningful sensorimotor interactions with our surroundings depends on our ability to structure brain activity patterns, which are necessary for planning, initiating and executing movements, perceiving sensory inputs and also the ability to attenuate resting-state central nervous activity characterized by default mode network activity during cognitive processing . IncapacHyperactivity, inattention and impulsivity in children has early on been suggested to be reflected in a cortical slowing of processing in frontal regions i.e., and increase in slow  band activity in EEG recordings ,171 reflNot only EEG recordings but also evidence from fMRI has indicated differences in network activation involving frontal brain regions in ADHD and this is commonly referred to as hypofrontality. Evidence from meta-analyses suggests that hypoactivation of frontostriatal (FSN), frontoparietal (FPN) and ventral attentional (VAN) networks during inhibitory control tasks represent correlates of pediatric ADHD ,181. AltExercise has been demonstrated to change oscillatory activity in the ‘resting’ brain, but also task-related activity across several cerebral loci. Resting EEG measurements demonstrate that in young adults, acute exercise increases resting state alpha peak frequency  and betaAmple evidence in PBC children suggests that acute exercise can change event-related brain responses,  during cognitive tasks taxing executive functions e.g., ,206,207),207206,2In children with ADHD, one study examined EEG-correlates of stimulus processing and attentional resource allocation following a single bout of exercise. Intriguingly, the study revealed increases in the amplitude of the P300 component both in non-medicated children with ADHD and in PBC children following 20 m of moderate intensity treadmill running compared to seated reading . FurtherIn young PBC children, aerobic fitness levels have been associated with hyperactivation of prefrontal regions during an Eriksen flanker-task assessing inhibitory control , albeit Here, we briefly describe experimental findings in support of the monoaminergic hypothesis of ADHD as well as findings linking pediatric ADHD to anomalous BDNF activity. Exercise is theorized to influence ongoing and subsequent cognitive performance through multiple central nervous routes such as changes in cortical monoaminergic transmission, changes in brain neurotrophin levels and changes in cerebral blood flow. Acute exercise increases cerebral oxygenation and while the Kety-Schmidt determined global cerebral blood flow remains largely unchanged during most exercise types , regionaWith a particular focus on dopamine (DA) and brain-derived neurotrophic factor (BDNF), we discuss the mechanisms, which are thought to be involved in mediating effects of exercise on performance in cognitive tests in children.As the ADHD affected networks and cerebral structures described above entail multiple monoaminoceptive regions ,232, it It has been suggested that impaired transmission in motivational- and reward-related pathways contributes to the ADHD pathology . In supThe ameliorating effects of stimulants, which are first-in-line treatment for children with ADHD, support the pivotal role of DA transmission in pediatric ADHD. The over-all effect of MPH and amphetamine is to increase extracellular catecholamine availability and whilst they differ slightly in the potency of the direct effects on monoaminergic reuptake transporters, the effects on ligand availability are comparable , a commonly used rodent model for ADHD, is hyperactive; expresses lower ability to sustain attention and increased impulsivity in the absence of immediate rewards along with increased response variability ,248, whioto Rats  and aberoto Rats ,254.Despite a high hereditability of ADHD, which is estimated to ~75% for both inattentive and hyperactive components and all genders  dopamine concentrations .In terms of attentional control, a system of three interconnected networks with distinct neurochemical circuits subserving attentional processes was proposed early on ,195. The2A agonist in children with ADHD [Aberrant norepinephrine (NE) signaling has been demonstrated in relation to ADHD  andith ADHD .As discussed above, candidate gene studies implicate 5-hydroxytryptalmine (5-HT) i.e., serotonergic signaling in the ADHD pathology , whereaThe neuroendocrine response to exercise is intricate and it is beyond the scope of this review to provide a complete overview of the involved mechanisms and effects . HeLonger lasting adaptations in the monoaminergic systems are evident after long-term exercise. Following weeks of treadmill running increased expression of tyrosine hydroxylase (TH) alongside decreased expression of DRD2 autoceptors in substantia nigra indicate increased DA synthesis and release from midbrain projections . ImpaireIn summary, acute exercise affects the same DA and NE systems as stimulants  has been argued to influence EFs as well as related neural structures in late adulthood , meta-ad , is assd  concentrations relate to central nervous levels as demonstrated by highly correlated ontogenic changes in measures of frontal cortex and serum BDNF concentration . Finding+/-) model with only one functional allele [The interaction between mechanisms involved in BDNF and dopamine signaling provide a likely route of which exercise-induced secretion of BDNF may exerts effects, which can influence executive functions . Despitel allele . FurtherBDNF gene do not affect NCF in children with ADHD. Changes in peripheral BDNF may signify increased central nervous BDNF activity and likely influence DA transmission through its high affinity Trk-B in PFC and striatum. The latter provides a likely route of which BDNF may mediate the beneficial effects of exercise on NCFs.In summary, in contrast to the monoamines, genetic differences in the In this section we discuss effect of exercise on neurotrophic factors in relation to ADHD limited to BDNF. The effects of aerobic exercise on BDNF expression and functions of the medial temporal lobe, which are underlying the enhancing effects on (declarative) memory has been reviewed in depth previously . As ADHIn humans, the BDNF Val66Met SNP has been demonstrated to mediate the relationship between levels of physical activity and working memory . FurtherSince exercise may be structured in numerous different ways with respect to duration, intensity, total volume and activity type  etc., these parameters naturally also differ between the existing studies within the research area. In order to understand the potential effects of exercise on cognitive performance in children and adolescents with ADHD, it is thus important to elucidate if observed effects relate to specific parameters of both acute and long-term exercise. In the analysis performed in the present review, we have identified the existing studies on effects of acute and long-term exercise on cognitive performance in children and adolescents with ADHD and quantified effects on performance within specific cognitive domains and relating to the exercise parameters duration, intensity and volume , frontoparietal (FPN) and ventral attentional (VAN) networks during inhibitory control tasks etc. In both PBC and ADHD children, acute exercise with moderate intensity leads to changes in network activity and furthermore moderate intensity exercise can lead to increased functional connectivity within networks intimately associated with executive and attentional control. Acute exercise may thus provide an avenue to counteract the functional deficiencies observed in cognitive processes in children with ADHD and we thus expected to find positive effects of primarily moderate intensity exercise.In general, the computed effect-sizes appear lower in comparison to those reported in the published meta-analyses of exercise in ADHD see . This maAs illustrated in In line with our previous discussion of potential neurophysiological mechanisms underlying the effects of exercise on ADHD, we expected that cognitive functions supported by frontostriatal, dopaminergic and general tonic monoaminergic transmission would display the largest ESs for acute and long-term interventions respectively. As depicted in alternate use task (categorized as cognitive flexibility), we find small positive effects (0.28 to 0.29) on two of two measures extracted from Ludyga et al. also using the alternate use task [The effect of acute exercise on cognitive flexibility is largely positive (two of five ES < 0). In contrast to Chang et al., who did not find meta-analytic evidence of effects of acute exercise on PBC children’s performance in the use task . Howeveruse task ,82. Alsouse task .We extracted ESs from four studies all pointing to performance enhancing effects of long-term exercise on tests of cognitive flexibility ,111,114.Across both acute and long-term studies Tan et al., previously found similar effects of exercise on inhibition and set-shifting  although only inhibition reached statistical significance. Cornelius et al., Vysniauske et al., and Cerrillo-Urbina et al., did not report measures for the various EF domains individually, but reported larger standard mean differences for attention over EF  and modeWhereas previous meta-analyses have refrained from concluding on quantitative exercise parameters as potential moderators of effects on cognitive functions, the analysis of the present review also detail effects relating to the specified exercise parameters intensity, duration and volume. Tan et al. did not find type or number and duration of sessions to moderate effects in studies including both individuals with ADHD and autism spectrum disorder . InteresIn studies of PBC and ADHD children alike, reports of the intended and actual intensity of the exercise intervention are frequently omitted  [p > 0.2), but Xue et al. found that exercise session durations above 90 m and interventions of >5 weeks resulted in larger effects.When considering the potential effects of exercise duration, Chang et al., pointed to a minimum duration of 11 m to elicit positive effects, whereas de Greeff and coworkers did not find any moderating effects  . For chrIn this review, we hereto refrained from discussing potential interactions between medication and exercise. In brief, whereas subgroup analyses have generally not found medication status to moderate effects of exercise on cognition , the siA noteworthy controversy regards the possible role of the type of physical activity  or coordinative exercise , Ludyga and co-workers reported benefits of both compared to seated rest on general reaction time in a modified flanker task, but slightly superior effects for the biking exercise group compared to the group performing coordinative exercise .To sum up, meta-analyses have addressed the controversy at hand. In children with ADHD, Cornelius and coworkers found positive effects of PA involving an imminent cardiovascular element (‘aerobic’ PA) . In suppBelow we provide recommendations for continued research in the field of exercise and ADHD, while summarizing evidence into preliminary points for real-world application of the different findings, which have been discussed so far.p < 0.05) reported by Xue et al. between body mass index and effects on EF suggests that less fit children and adolescents may benefit more from exercise [Existing meta-analyses have refrained from providing recommendations, but a few studies have addressed the question of who benefits from exercise. A positive meta-relation . FurtheAs evident from the fewer circles in Exercise interventions are inherently limited to single-blinded assessments. To increase quality of studies, attempts to blind participants to the intervention should be routinely implemented . This iIn line with this, it is essential to design appropriate control conditions that allow careful teasing apart of factors associated with potential performance enhancing effects. A large part of the studies conducted in individuals with ADHD utilize resting, passive control conditions that entail no specific change in environment or expectancy of changes in performance. As such, for passive control conditions it remains uncertain whether effects of exercise simply result from being presented with a novel situation or being disposed to a novel environment i.e., the Hawthorne effect. Active control conditions might be suitable to overcome this limitation but need to be carefully designed to control for the factors not being put under the microscope, e.g., matching social interactions or cognitive engagement. Accordingly, effects of exercise interventions ought to be interpreted in relation to the included control conditions. In addition, the improvements in tests of NCFs for resting control groups upon repeated task-exposure  underliBased on the findings from the previous intervention studies and meta-analyses, future studies can additionally explore whether long-term effects are contingent on accumulation of acute effects on ongoing and subsequent cognitive processes or rather reflect the structural and neurophysiological characteristics associated with e.g., higher fitness levels. Finally, future studies should explore the ecological validity of different exercise activities and parameters relating to practice structure, activity type, timing etc. by implementing various models of these e.g., during and after schooldays etc.The incomplete and inconsistent reporting of outcome measures hampers interpretation of the effects of exercise. The construct validity of test of NCFs is contingent on appropriate analysis. Pooling accuracy and reaction time scores  for different task-conditions  or only reporting one of them decreases specificity and occludes potential speed-accuracy trade-offs. As an example of the former, Pontifex and co-workers investigated the effects of a single bout of treadmill exercise in children with and without ADHD. The authors found increased response speed and accuracy following 20-min exercise, but findings were reported across stimuli compatibility, thus reflecting overall enhancement of neurocognitive performance. However, specific effects on inhibitory control, usually expressed as an interference score computed by differences between incongruent and congruent response speeds and accuracies in a Flanker task was not formally tested. This complicates inferences relating to the effects of exercise on performance in specific cognitive domains, e.g., inhibitory control, and effects reported on such ought to be interpreted cautiously.In line with previous research, we find that exercise benefits executive functions and attentional control in children with ADHD. The beneficial effects are comparable to those reported in PBC with substantial and consistent improvement on test of several cognitive functions following particularly long-term exercise. An important notion is also that no study has reported negative or adverse effects of exercise. Outside of the neurocognitive realm and thus the scope of this review, exercise has been reported to, not surprisingly, increase cardiovascular fitness  and moton = 1615) from the general adult German population, retrospective assessment of childhood PA levels and ADHD symptom severity along with current (adult) ADHD symptoms revealed that excessive childhood exercise was associated with not carrying ADHD symptoms into adulthood [We end this narrative with a final note to stress the importance of exercise in children and youth with ADHD. Two reports of special interest support the findings by Åberg et al.,  and Tanddulthood . In suppdulthood . These a


Fabry disease (FD) is a rare X-linked disorder characterised by abnormal progressive lysosomal deposition of globotriaosylceramide in a large variety of cell types. The central nervous system (CNS) is often involved in FD, with a wide spectrum of manifestations ranging from mild symptoms to more severe courses related to acute cerebrovascular events. In this review we present the current knowledge on brain imaging for this condition, with a comprehensive and critical description of its most common neuroradiological imaging findings. Moreover, we report results from studies that investigated brain physiopathology underlying this disorder by using advanced imaging techniques, suggesting possible future directions to further explore CNS involvement in FD patients.• Conventional neuroradiological findings in FD are aspecific.• White matter hyperintensities represent the more consistent brain imaging feature of FD• Abnormalities of the vasculature wall of posterior circulation are also consistent features.• The pulvinar sign is not reliable as a finding pathognomonic for FD.• Advanced imaging techniques have increased our knowledge about brain involvement in FD. GLA gene, which encodes for the α-galactosidase A  enzyme  and WM) loss and visually assessed using conventional MRI sequences, has been reported in the past as a possible neuroradiological feature of FD, although with all the limitations of a qualitative assessment of brain atrophy  . These lDifferent quantitative volumetric MRI studies explored the possibility of brain tissue volume loss in FD patients with mild-to-moderate CNS involvement, determining whether, in the absence of a severe cerebrovascular pathology, global normalised brain tissue volumes are preserved in FD patients. In this light, brain atrophy is likely to occur only in more advanced phases of CNS involvement, characterised by the presence of brain infarcts  and/or a significant WMH load , 65, 73.Possible regional differences in GM volume have also been investigated in FD patients, mostly by means of voxel-based morphometry (VBM) analysis. Different VBM studies have been conducted in FD patients in recent years, mostly showing that no differences in terms of regional GM density were present in FD patients compared to healthy controls , 68, 80.Nevertheless, atrophy of specific brain regions have been reported in FD patients , 62. In Interestingly, a recent study showed the presence of a significant reduction of the entire intracranial volume of FD patients compared to HC . This reAll this evidence, taken together, suggests that FD could be characterised by a harmonious reduction of the intracranial volume, with a relative preservation of fractional brain tissue volumes and regional GM density, although atrophy of specific regions of the brain, such as the thalamus or the hippocampus, has been reported. Future studies are warranted to further elucidate the possible presence of global and regional brain volume differences in FD, conducted with automatic measurements using the most recent software, which are known to provide more accurate estimations of intracranial volumes , 82.The assessment of cerebrovascular damage through the evaluation of WMH using conventional MRI sequences and its grading using semi-quantitative visual rating scales is known to provide a limited accuracy .Conversely, diffusion tensor imaging (DTI) has proved to be a sensitive technique for detecting brain tissue alterations, allowing for an accurate and reproducible quantification of microstructural WM changes .One of the first studies focusing on cerebral diffusivity in FD demonstrated an elevated total brain parenchymal average diffusion constant in FD compared to controls, also in patients without any conventional MRI-detectable WM lesion . AuthorsIn a ROI-based DTI analysis, increased mean diffusivity values in FD patients were found at the level of the frontal, parietal and temporal normal-appearing WM . This inThis extensive pattern of microstructural WM alterations has been also demonstrated using tract-based spatial statistics (TBSS) analyses, which combines the strength of voxel-wise and tractography-based analyses . Indeed,These findings are compatible with the hypothesis that vasculopathy could be the leading physiopathological mechanism underlying brain tissue alterations in FD , with a Although widely used in different other pathological conditions, very few fMRI experiments have been performed to date to investigate the presence of possible functional changes in FD patients. The first study was performed by Gavazzi and colleagues , by meanAlong with the investigation of motor circuits, RS-fMRI has also been used to study the presence of possible FC alteration of the default mode network (DMN), which is involved in the integration and coordination of sensorimotor and cognitive goal-directed activities . An incrAlthough only a limited amount of evidence about fMRI alterations in FD is available, diffuse and significant functional changes seem to occur in this condition, thus suggesting a future central role of fMRI in the investigation of cerebral involvement in FD.Along with the above-mentioned studies, other advanced MRI techniques have also been applied in FD to investigate the physiopathology of CNS involvement in this condition.1H-MRS) offers the possibility to study, detect and quantify in vivo different metabolites in the human brain , variations in regional cerebral blood flow (rCBF) were assessed in a resting condition, showing an increased rCBF of the posterior and periventricular areas [Using a freely diffusible tissue tracer like oxygen-15-labelled water [ar areas  apparentar areas .18F-FDG) positron emission tomography (PET), more pronounced in regions with a higher risk of developing WMH, in the absence of significant global cerebral glucose metabolism changes [This increase in rCBF was later proved to be coupled to a significant reduction of regional cerebral glucose metabolism assessed by 18-fluoro-deoxyglucose ( changes . The aut changes , 37. Thi changes .The normal cerebral glucose metabolism distribution in FD patients suggested by Moore and colleagues  was confConsidering the functional changes present in FD patients, and given the opportunity to simultaneously investigate metabolic demand and functional activity using the hybrid PET/MR scanners , future FD is a multiorgan disorder affecting CNS in a variable degree and extent. Conventional neuroradiological findings in this condition are aspecific, and mainly include the presence of WMH and anomalies of the vasculature wall of posterior circulation. Conversely, the once considered pathognomonic and characteristic T1-weighted hyperintensity of the pulvinar should be considered as a very rare neuroradiological finding in FD patients.The application of different advanced imaging techniques has expanded present knowledge about CNS involvement in this lysosomal storage disorder, shedding new light on the type and mechanisms of cerebral involvement in FD, long considered to be only linked to major cerebrovascular events.However, different domains still remain unexplored in FD. Therefore, a proper use and combination of different conventional and advanced imaging techniques is warranted, to further help our understanding about CNS physiopathology in this complex systemic condition.


Microbes drive critical ecosystem functions and affect global nutrient cycling along with human health and disease. They do so under strong constraints exerted by viruses, which shape microbial communities’ structure and shift host cell metabolism during infection. Microbes drive critical ecosystem functions and affect global nutrient cycling along with human health and disease. They do so under strong constraints exerted by viruses, which shape microbial communities’ structure and shift host cell metabolism during infection. While the majority of viruses and their associated impacts remain poorly characterized, a number of mechanisms by which viruses alter microbial cells and ecosystems have already been revealed. Here I outline how a comprehensive host-resolved mapping of viral sequence space will enable a thorough characterization of virus-encoded mechanisms for microbial manipulation. With soon-to-be millions of virus genomes obtained from metagenomes, one of the major challenges resides in the development of methods for high-throughput and high-resolution virus-host pairing, before multi-omics approaches can be leveraged to fully decipher virus-host dynamics in nature. Beyond novel fundamental biological knowledge, these studies will likely provide new molecular tools enabling a precise engineering of microbial cells and communities. Microbes are now recognized to play key roles in all of Earth’s ecosystems, driving nutrient and energy transfers, and directly influencing human health and disease . These mVibrio cholerae, Clostridium botulinum, or Escherichia coli  , 4. Prophia coli . Meanwhihia coli . Beyond hia coli , but othBecause exploring environmental viral communities has remained a challenging task until very recently, our collective understanding of the molecular mechanisms by which viruses can influence microbial cells is still largely partial, and known examples are mostly derived from a few well-studied cultivated model systems. Interrogating the vast diversity of uncultivated viruses holds tremendous potential for the discovery of entirely novel avenues for microbial manipulation, including strategies tailored to specific hosts and environmental conditions. Fortunately, this type of approach might become viable in a not-too-distant future considering the current pace of progress and improvements in the field of viral ecogenomics. Here I outline the major steps and remaining challenges toward a comprehensive characterization of viral diversity and virus-host interactions in nature and the potential use of this knowledge for manipulation of microbial communities.de novo genome assembly from shotgun metagenomes  of viral diversity must first be achieved. This is the topic that saw the most remarkable improvement in the last few years, especially compared to the exploration of microbial diversity, mainly due to a shift in the methods used. The vast diversity of uncultivated microbes was initially revealed through 16S and 18S amplicon sequencing (agenomes . In contagenomes .https://img.jgi.doe.gov/cgi-bin/vr/main.cgi) is composed of >700,000 uncultivated genome fragments, the overwhelming majority collected in the last 2 years alone  similarity between host and virus genomes . While tOne of the major challenges faced by the field of viral ecogenomics is thus to develop experimental approaches providing high-throughput, high-resolution host linkage for uncultivated viruses. These approaches will most likely rely on high-throughput sequencing of single cells and/or targeted host (sub)populations, sorted and selected via a combination of, e.g., microfluidic separation, microdroplet encapsulation, and/or flow cytometry cell sorting. The codetection of virus and host at the individual cell level should then provide unique insights into strain-resolved host range and infection rates for individual virus genotypes in nature, without cultivation of either the microbial host or the virus. Given that pilot experiments are already ongoing, it seems reasonable to hope for some of these methods to be established and broadly available at some point in the next decade. The data obtained by applying these methods across a large range of biomes and ecological conditions will then enable the construction of a global host-resolved mapping of the virus sequence space.in situ, will be especially relevant in this context. Beyond a treasure trove of fundamental biological discoveries about ecological and evolutionary drivers of virus-host dynamics, these studies would also benefit every approach and biotechnological application leveraging microbes and microbial processes. Specifically, a comprehensive understanding of the broad range of virus-host interactions ongoing in nature would provide a fantastic resource that could be mined for new ways to precisely and predictably engineer microbial cells, including for targeted modification of specific populations within a complex microbial community.Finally, a global host-contextualized mapping of the virosphere would serve as a foundation for multi-omics studies aiming at deciphering virus-host interactions and dynamics in nature. Sample sets such as time series, patient cohorts, and incubations under controlled conditions, either in the laboratory or Inoviridae family, i.e., filamentous phages, are particularly interesting in this framework because they have a small genome which can be expressed in a nonhost cell and relatively simple virions whose properties could likely be modified by mutating only one or a couple of genes.Already, results from isolated viruses can provide a glimpse at the type of mechanisms and solutions for microbial manipulations that could be inspired by or derived from viruses. The first and most obvious application of viruses would be to kill specific microbial strains such as contaminants, either through active viruses, i.e., “phage therapy,” or by using only specific components of virus particles, e.g., tailocins. Viruses can also contain many key genes able to redirect entire metabolic pathways or to fundamentally alter host behavior and fitness, including variants of key cellular enzymes displaying unique properties as well as highly efficient transcriptional and translational regulators. Hence, a global and host-contextualized virus genome database could be used to identify a candidate gene(s) for modulating specific metabolisms or expressing artificial constructs in any target microbe. Finally, some viruses are particularly amenable to genome engineering and could thus be repurposed as custom-targeted delivery mechanisms. Members of the Right now is an exciting time to be part of (or join) the young and highly dynamic field of virus ecogenomics. A lot of the infrastructure and conceptual framework is being built , and dat