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Clozapine is an atypical antipsychotic used in refractory schizophrenia, also efficient in alleviating dyskinesia in Parkinson’s disease. Despite its potency, this drug is associated with severe metabolic side effects, including increased risk for diabetes. We report the case of a 45-year-old overweight woman with Parkinson’s disease who presented with rapid-onset hyperglycaemia within 2 months after starting clozapine for refractory dyskinaesia. She had a history of gestational diabetes. At presentation, her blood glucose level was 505 mg/dL and glycated haemoglobin 12.4%, with no catabolic symptoms. Clozapine was suspended and metformin was started, but adequate glycaemic control was achieved only with insulin therapy, along with exenatide and empagliflozin afterwards. We assume that clozapine acted as a trigger for rapid deterioration of glycaemic control through direct pathophysiological mechanisms, rather than an indirect slowly evolving weight gain-related metabolic syndrome pathway. Clinicians should be aware of this complication, enabling timely diagnosis and proper treatment.

Results of computational analysis and visualization of differences in gene structures using polarization coding are presented. A two-dimensional phase screen, where each element of which corresponds to a specific basic nucleotide (adenine, cytosine, guanine, or thymine), displays the analyzed nucleotide sequence. Readout of the screen with a coherent beam characterized by a given polarization state forms a diffracted light field with a local polarization structure that is unique for the analyzed nucleotide sequence. This unique structure is described by spatial distributions of local values of the Stokes vector components. Analysis of these distributions allows the comparison of nucleotide sequences for different strains of pathogenic microorganisms and frequency analysis of the sequences. The possibilities of this polarization-based technique are illustrated by the model data obtained from a comparative analysis of the spike protein gene sequences for three different model variants (Wuhan, Delta, and Omicron) of the SARS-CoV-2 virus. Various modifications of polarization encoding and analysis of gene structures and a possibility for instrumental implementation of the proposed method are discussed.

Glucagon-like peptide-1(GLP-1) is a multifunctional polypeptide throughout the lifespan via activating Glucagon-like peptide-1 receptor (GLP-1R).GLP-1 can affect food ingestion, enhance the secretion of insulin from pancreatic islets induced by glucose and be utilized to treat type 2 diabetes mellitus(T2DM).But, accumulating evidences from the decades suggest that activation GLP-1R can not only regulate the blood glucose, but also sustain the homeostasis of intracellular environment and protect neuron from various damaged responses such as oxidative stress, inflammation, excitotoxicity, ischemia and so on. And more and more pre-clinical and clinical studies identified that GLP-1 and its analogues may play a significant role in improving multiple central nervous system (CNS) diseases including neurodegenerative diseases, epilepsy, mental disorders, ischemic stroke, hemorrhagic stroke, traumatic brain injury, spinal cord injury, chronic pain, addictive disorders, other diseases neurological complications and so on. In order to better reveal the relationship between GLP-1/GLP-1R axis and the growth, development and survival of neurons, herein, this review is aimed to summarize the multi-function of GLP-1/GLP-1R axis in CNS diseases.

Objective Patients with systemic lupus erythematosus (SLE) display symptoms that are not always related to disease activity and may distort clinical trial results. Recently, a clinical categorization based on the presence of type 1 (inflammatory manifestations) and/or type 2 (widespread pain, fatigue, depression) symptoms has been proposed in SLE. Our aim was to develop a type 2 score derived from the Short-Form health survey (SF-36) to categorize SLE patients and to compare immunological and transcriptomic profiles between groups. Methods Seventeen items from the SF-36 were selected to build a type 2 score for 50 SLE patients (100 visits; LUPUCE cohort) and the SLEDAI was used to define type 1 symptoms. Patients were categorized in four groups: minimal (no symptoms), type 1, type 2 and mixed (both type 1 and type 2 symptoms). Clinical, immunological and transcriptomic profiles were compared between the groups. Results Type 2 scores ranged from 0 to 31, with a cut-off value of 14 (75th percentile). The sample categorization was: minimal in 39%, type 1 in 37%, type 2 in 9% and mixed in 15%. Type 2 patients were older than minimal patients and had a longer disease duration than type 1 and mixed patients. Immunological data and modular interferon signatures did not differ between the groups. Conclusion Patients with SLE can be categorized into four clinical groups using the SLEDAI score and our SF-36-derived type 2 score. This categorization is non-redundant with immunological or transcriptomic profiles and could prove useful to stratify patients in clinical trials.

Many current bioinformatics algorithms have been implemented in parallel programming code. Some of them have already reached the limits imposed by Amdahl’s law, but many can still be improved. In our paper, we present an approach allowing us to generate a high-performance code for calculating the number of RNA pairs. The approach allows us to generate parallel tiled code of the maximal dimension of tiles, which for the discussed algorithm is 3D. Experiments carried out by us on two modern multi-core computers, an Intel(R) Xeon(R) Gold 6326 (2.90 GHz, 2 physical units, 32 cores, 64 threads, 24 MB Cache) and Intel(R) i7(11700KF (3.6 GHz, 8 cores, 16 threads, 16 MB Cache), demonstrate a significant increase in performance and scalability of the generated parallel tiled code. For the Intel(R) Xeon(R) Gold 6326 and Intel(R) i7, target code speedup increases linearly with an increase in the number of threads. An approach presented in the paper to generate target code can be used by programmers to generate target parallel tiled code for other bioinformatics codes whose dependence patterns are similar to those of the code implementing the counting algorithm.

Diabetic mellitus is a worldwide endocrine and metabolic disorder with insulin insensitivity or deficiency or both whose prevalence could rise up to 592 million by 2035. Consistent hyperglycemia leads to one of the most common comorbidities like Diabetic Peripheral Neuropathy (DPN). DPN is underlined with unpleasant sensory experience, such as tingling and burning sensation, hyperalgesia, numbness, etc. Globally, 50-60% of the diabetic population is suffering from such symptoms as microvascular complications. Consistent hyperglycemia during DM causes activation/inhibition of various pathways playing important role in the homeostasis of neurons and other cells. Disruption of these pathways results into apoptosis and mitochondrial dysfunctions, causing neuropathy. Among these, pathways like Polyol and PARP are some of the most intensively studied ones whereas those like Wnt pathway, Mitogen activated protein kinase (MAPK), mTOR pathway are comparatively newly discovered. Understanding of these pathways and their role in pathophysiology of DN underlines a few molecules of immense therapeutic value. The inhibitors or activators of these molecules can be of therapeutic importance in the management of DPN. This review, hence, focuses on these underlying molecular mechanisms intending to provide therapeutically effective molecular targets for the treatment of DPN.

Genel olarak biyoloji bilgisinin bilgisayar aracılığıyla incelenmesi ve işlenmesi olarak tanımlanabilen biyoinformatik günümüzde hızla gelişen bir bilim dalıdır. Biyoinformatik, biyoteknoloji, sağlık, tarım, kimya, genom araştırmaları ve çok sayıda alanda giderek artan uygulamalarıyla dünyada biyoloji öğretiminin önemli bir parçası hâline gelmektedir. Bu bakımdan Türkiye'de biyoinformatik konusunda yetişmiş insan alt yapısının oluşturulması açısından öğretmen adaylarının konuya ilişkin görüşlerinin belirlenmesi önem kazanmaktadır. Bu araştırmanın amacı biyoloji öğretmen adaylarının biyoinformatik ve öğretimi konusunda görüşlerinin incelenmesidir. Nitel araştırma yöntemlerinden bütüncül tek durum deseninin kullanıldığı araştırmanın çalışma grubunu, bir devlet üniversitesinin eğitim fakültesi ve pedagojik formasyon programlarında öğrenimlerine devam eden 105 biyoloji öğretmen adayı oluşturmaktadır. Araştırmanın verileri ilgili alanyazın taramaları ve uzman görüşlerinin alınması aşamalarından sonra araştırmacılar tarafından geliştirilen yarı yapılandırılmış görüşme formu kullanılarak elde edilmiştir. Araştırma sonucunda elde edilen veriler betimsel ve içerik analizi bir arada kullanılarak çözümlenmiştir. Araştırma sonunda elde edilen sonuçlara göre öğretmen adaylarının konuya ilişkin olumlu görüşlere sahip olmalarının yanında, yeterli teorik ve uygulama bilgilerinin olmadığı belirlenmiştir. Bu kapsamda biyoinformatik eğitiminin mevcut öğretim programlarına entegrasyonu, ders içerikleri ve materyallerin oluşturulması önerilmektedir., Bioinformatics, which is generally defined as the study and processing of biology information through computers, is a rapidly developing scientific field today. It is becoming an important part of biology education worldwide with its increasing applications in biotechnology, health, agriculture, chemistry, genome research, and many other fields. Therefore, it is important to determine the views of teacher candidates on bioinformatics in Turkey in terms of creating a human infrastructure trained in the field. The purpose of this research is to examine the views of pre-service biology teachers’ on bioinformatics and its instruction. The study group of the research, which uses the holistic single case design among the qualitative research methods, consists of 105 pre-service biology teachers who are studying at the Faculty of Education and pedagogical formation programs of a state university. The data of the research were obtained using a semi-structured interview form developed by the researchers after the relevant literature search and obtaining expert opinions. The data obtained as a result of the research were analyzed by using descriptive and content analysis together. According to the results obtained at the end of the research, it was determined that the pre-service teachers did not have sufficient theoretical and practical knowledge, besides having positive views on the subject. Within this scope, it is recommended to integrate bioinformatics education into existing curricula, and to create learning contents and materials accordingly.

In this recent publication review the authors aimed to collect evidence of impact of nonsynonymous single nucleotide polymorphisms (nsSNP) in the renin–angiotensin–aldosterone system on patients’ phenotype not only regarding arterial hypertension and its complications, but also the impact on other diseases of interest outside the field of cardiovascular medicine. PubMed database records published between 2017–2020 were searched and all positive case-control studies or positive studies with human DNA were selected. The search identified 104 articles, of which 22 were included on the basis of the inclusion criteria. This paper presents the impact of 44 nsSNPs in panels for genes of renin, angiotensinogen, angiotensin-converting enzyme, angiotensin receptor and aldosterone on the clinical picture of investigated cohorts or on the peptide-protein interactions as consequence of nsSNPs. Genetic variability in nsSNPs of the RAAS is involved in the pathogenesis of arterial hypertension and its complications, and surprisingly also in the pathogenesis of conditions not associated with elevated blood pressure, like neoplasms or inflammatory diseases.

Inflammation is a natural process that occurs in the organism in response to harmful external agents. Despite being considered beneficial, exaggerated cases can cause severe problems for the body. The main inflammatory manifestations are pain, increased temperature, edema, decreased mobility, and quality of life for affected individuals. Diseases such as arthritis, cancer, allergies, infections, arteriosclerosis, neurodegenerative diseases, and metabolic problems are mainly characterized by an exaggerated inflammatory response. Inflammation is related to two categories of substances: pro- and anti-inflammatory mediators. Among the pro-inflammatory mediators is Tumor Necrosis Factor-α (TNF-α). It is associated with immune diseases, cancer, and psychiatric disorders which increase its excretion. Thus, it becomes a target widely used in discovering new antiinflammatory drugs. In this context, secondary metabolites biosynthesized by plants have been used for thousands of years and continue to be one of the primary sources of new drug scaffolds against inflammatory diseases. To decrease costs related to the drug discovery process, Computer-Aided Drug Design (CADD) techniques are broadly explored to increase the chances of success. In this review, the main natural compounds derived from alkaloids, flavonoids, terpene, and polyphenols as promising TNF-α inhibitors will be discussed. Finally, we applied a molecular modeling protocol involving all compounds described here, suggesting that their interactions with Tyr59, Tyr119, Tyr151, Leu57, and Gly121 residues are essential for the activity. Such findings can be useful for research groups worldwide to design new anti-inflammatory TNF-α inhibitors.

Contains fulltext : 286883.pdf (Publisher’s version ) (Open Access) The levels of the thousands of metabolites in the human plasma metabolome are strongly influenced by an individual's genetics and the composition of their diet and gut microbiome. Here, by assessing 1,183 plasma metabolites in 1,368 extensively phenotyped individuals from the Lifelines DEEP and Genome of the Netherlands cohorts, we quantified the proportion of inter-individual variation in the plasma metabolome explained by different factors, characterizing 610, 85 and 38 metabolites as dominantly associated with diet, the gut microbiome and genetics, respectively. Moreover, a diet quality score derived from metabolite levels was significantly associated with diet quality, as assessed by a detailed food frequency questionnaire. Through Mendelian randomization and mediation analyses, we revealed putative causal relationships between diet, the gut microbiome and metabolites. For example, Mendelian randomization analyses support a potential causal effect of Eubacterium rectale in decreasing plasma levels of hydrogen sulfite-a toxin that affects cardiovascular function. Lastly, based on analysis of the plasma metabolome of 311 individuals at two time points separated by 4 years, we observed a positive correlation between the stability of metabolite levels and the amount of variance in the levels of that metabolite that could be explained in our analysis. Altogether, characterization of factors that explain inter-individual variation in the plasma metabolome can help design approaches for modulating diet or the gut microbiome to shape a healthy metabolome.

Clozapine-induced myocarditis or any clozapine-induced inflammation may be a hypersensitivity reaction due to titration that was too rapid for the patient's clozapine metabolism. Clozapine metabolism is influenced by ancestry, sex, smoking and the presence of confounders including obesity, infections, and inhibitors (e.g., valproate) causing the patient to behave as a clozapine poor metabolizer (PM). A published study in a Turkish hospital identified 1 case of clozapine-induced pancreatitis and hepatitis and 9 cases of clozapine-induced myocarditis. To explore the hypothesis that the 10 patients were clozapine PMs, their serum clozapine concentrations were investigated using concentration-to-dose (C/D) ratios and their titrations carefully reviewed.Dividing the trough serum concentration by the dose produces the clozapine C/D ratio. The dose required to reach 350ng/ml was considered the minimum therapeutic dosage and was used to classify patients according to clozapine PM status. Titration speed was assessed.All 10 patients were possibly clozapine PMs (3 of them had as minimum therapeutic doses: 72, 82 or 83mg/day). Nine of the 10 patients may have behaved as clozapine PMs due to obesity and/or valproate co-prescription during titration. One also had an undiagnosed infection. Of the 10 patients, 9 had at least 1 of 3 factors: too-rapid titration in the first or second weeks, or a final dosage that was too high.Future studies using clozapine levels and considering the role of clozapine PM status should explore whether or not all cases of clozapine-induced inflammation could be explained by lack of individualized titration.

Background: Stroke is a serious neurovascular problem and the leading cause of disability and death worldwide. The disrupted demand to supply ratio of blood and glucose during cerebral ischemia develops hypoxic shock, and subsequently necrotic neuronal death in the affected regions. Multiple causal factors like age, sex, race, genetics, diet, and lifestyle play an important role in the occurrence as well as progression of post-stroke deleterious events. These biological and environmental factors may be contributed to vasculature variable architecture and abnormal neuronal activity. Since recombinant tissue plasminogen activator is the only clinically effective clot bursting drug, there is a huge unmet medical need for newer therapies for the treatment of stroke. Innumerous therapeutic interventions have shown promise in the experimental models of stroke but failed to translate it into clinical counterparts. Methods: Original publications regarding pathophysiology, preclinical experimental models, new targets and therapies targeting ischemic stroke have been reviewed since the 1970s. Results: We highlighted the critical underlying pathophysiological mechanisms of cerebral stroke and preclinical stroke models. We discuss the strengths and caveats of widely used ischemic stroke models, and commented on the potential translational problems. We also describe the new emerging treatment strategies, including stem cell therapy, neurotrophic factors and gut microbiome-based therapy for the management of post-stroke consequences. Results : We highlighted the critical underlying pathophysiological mechanisms of cerebral stroke and preclinical stroke models. We discuss the strengths and caveats of widely used ischemic stroke models, and commented on the potential translational problems. We also describe the new emerging treatment strategies, including stem cell therapy, neurotrophic factors and gut microbiome-based therapy for the management of post-stroke consequences. Conclusion: There are still many inter-linked pathophysiological alterations with regards to stroke, animal models need not necessarily mimic the same conditions of stroke pathology and newer targets and therapies are the need of the hour in stroke research.

There is increasing evidence that dsyregulated epigenetic mechanisms of gene expression are involved in the pathogenesis of attention deficit hyperactivity disorder (ADHD). This review presents a comprehensive summary of the current state of research on the role of epigenetics in the pathogenesis of ADHD. The potential role of epigenetic drugs in the treatment of ADHD is also reviewed. Several studies suggest there are epigenetic abnormalities in preclinical models of ADHD and in ADHD patients. Regarding DNA methylation many studies have reported DNA hypermethylation. There is evidence that there is increased histone deacetylation in ADHD patients. Abnormalities in the expression of microRNAs (miRNAs) in ADHD patients have also been found. Some currently used drugs for treating ADHD, in addition to their more well established mechanisms of action, have been shown to alter epigenetic mechanisms of gene expression. Clinical trials of epigenetic drugs in patients with ADHD are reporting favorable results. These data suggest that abnormal epigenetic mechanisms of gene expression may be involved in the pathogenesis of ADHD. Drugs acting on epigenetic mechanisms may be a potential new class of drugs for treating ADHD.

Congenital cataract can be caused by several systemic diseases and differential diagnosis should be done between infections, genetic or metabolic diseases. We present a case of a 12-month-old girl with bilateral nuclear cataracts that was referred for investigation. Since she did not present a family history of congenital cataracts or metabolic diseases, and her physical examination was normal, a systemic evaluation was performed. Biochemical studies disclosed abnormal galactose metabolism signs. The diagnosis of galactokinase (GALK1) deficiency was considered and the study of the GALK1 gene allowed identifying a pathogenic genetic variant and a predictably pathogenic missense mutation, previously not described. Dietary measures were imposed with a good evolution.

Abstract: Ketogenic diet and ketone bodies gained significant attention in recent years due to their ability to influence the specific energy metabolism and restoration of mitochondrial homeostasis that can help in hindering the progression of many metabolic diseases, including diabetes and neurodegenerative diseases. A ketogenic diet consists of high fat and low carbohydrate contents, which makes the body glucose deprived and rely on alternative sources (ketone bodies) for energy. It has been initially designed and supplemented for the treatment of epilepsy, and, later, its influence on many energyderiving biochemical pathways made it a highly sorted food supplement for many metabolic diseases and even for bodybuilding and calorie restriction in healthy individuals. Among the reported therapeutic action over a range of diseases, neurodegenerative disorders, especially Alzheimer’s disease, gained the attention of many researchers and clinicians because of the higher benefits of the ketogenic diet on this disease. Complex pathology and multiple influencing factors of Alzheimer’s disease make exploration of its therapeutic strategies a demanding task. It was a common phenomenon that energy deprivation in neurological disorders, including Alzheimer’s disease, progress rapidly. The ability of ketone bodies to stabilize the mitochondrial energy metabolism makes it a suitable intervening agent. In this review, we will discuss various research progress made with regards to ketone bodies/ketogenic diet for the management of Alzheimer’s disease and elaborate in detail about the mechanisms that are influenced during their therapeutic action.

Background:Septic shock is sepsis accompanied by hemodynamic instability and high clinical mortality.Material and Methods:GSE95233, GSE57065, GSE131761 gene-expression profiles of healthy control subjects and septic shock patients were downloaded from the Gene-Expression Omnibus (GEO) database, and differences of expression profiles and their intersection were analysed using GEO2R. Function and pathway enrichment analysis was performed on common differentially expressed genes (DEG), and key genes for septic shock were screened using a protein-protein interaction network created with STRING. Also, data from the GEO database were used for survival analysis for key genes, and a meta-analysis was used to explore expression trends of core genes. Finally, high-throughput sequencing using the blood of a murine sepsis model was performed to analyse the expression of CD247 and FYN in mice.Results:A total of 539 DEGs were obtained (p < 0.05). Gene ontology analysis showed that key genes were enriched in functions, such as immune response and T cell activity, and DEGs were enriched in signal pathways, such as T cell receptors. FYN and CD247 are in the centre of the protein-protein interaction network, and survival analysis found that they are positively correlated with survival from sepsis. Further, meta-analysis results showed that FYN could be useful for the prognosis of patients, and CD247 might distinguish between sepsis and systemic inflammatory response syndrome patients. Finally, RNA sequencing using a mouse septic shock model showed low expression of CD247 and FYN in this model.Conclusion:FYN and CD247 are expected to become new biomarkers of septic shock.

Spontaneous subarachnoid hemorrhage (SAH) accounts for 5-10% of all strokes and is a subtype of hemorrhagic stroke that places a heavy burden on health care. Despite great progress in surgical clipping and endovascular treatment for ruptured aneurysms, cerebral vasospasm (CVS) and delayed cerebral ischemia (DCI) threaten the long-term outcomes of patients with SAH. Moreover, there are limited drugs available to reduce the risk of DCI and adverse outcomes in SAH patients. New insight suggests that early brain injury (EBI), which occurs within 72 h after the onset of SAH, may lay the foundation for further DCI development and poor outcomes. The mechanisms of EBI mainly include excitotoxicity, oxidative stress, neuroinflammation, blood-brain barrier (BBB) destruction, and cellular death. Mitochondria are a double-membrane organelle, and they play an important role in energy production, cell growth, differentiation, apoptosis, and survival. Mitochondrial dysfunction, which can lead to mitochondrial membrane potential (ΔΨm) collapse, overproduction of reactive oxygen species (ROS), release of apoptogenic proteins, disorders of mitochondrial dynamics, and activation of mitochondria-related inflammation, is considered a novel mechanism of EBI related to DCI as well as post-SAH outcomes. In addition, mitophagy is activated after SAH. In this review, we discuss the latest perspectives on the role of mitochondria in EBI and DCI after SAH. We emphasize the potential of mitochondria as therapeutic targets and summarize the promising therapeutic strategies targeting mitochondria for SAH.

Depression is one of the major disorders of the central nervous system worldwide and causes disability and functional impairment. According to the World Health Organization, around 265 million people worldwide are affected by depression. Currently marketed antidepressant drugs take weeks or even months to show anticipated clinical efficacy but remain ineffective in treating suicidal thoughts and cognitive impairment. Due to the multifactorial complexity of the disease, single-target drugs do not always produce satisfactory results and lack the desired level of therapeutic efficacy. Recent literature reports have revealed improved therapeutic potential of multi-target directed ligands due to their synergistic potency and better safety. Medicinal chemists have gone to great extents to design multitarget ligands by generating structural hybrids of different key pharmacophores with improved binding affinities and potency towards different receptors or enzymes. This article has compiled the design strategies of recently published multi-target directed ligands as antidepressant agents. Their biological evaluation, structural-activity relationships, mechanistic and in silico studies have also been described. This article will prove to be highly useful for the researchers to design and develop multi-target ligands as antidepressants with high potency and therapeutic efficacy.

Abstract: The prevalence of obesity continues to increase to the extent that it became a worldwide pandemic. An accumulating body of evidence has associated obesity with the development of different types of cancer, including colorectal cancer, which is a notorious disease with a high mortality rate. At the molecular level, colorectal cancer is a heterogenous disease characterized by a myriad of genetic and epigenetic alterations associated with various forms of genomic instability (detailed in Supplementary Materials). Recently, the microenvironment has emerged as a major factor in carcinogenesis. Our aim is to define the different molecular alterations leading to the development of colorectal cancer in obese patients with a focus on the role of the microenvironment in carcinogenesis. We also highlight all existent molecules in clinical trials that target the activated pathways in obesity-associated colorectal cancer, whether used as single treatments or in combination. Obesity predisposes to colorectal cancer via creating a state of chronic inflammation with dysregulated adipokines, inflammatory mediators, and other factors such as immune cell infiltration. A unifying theme in obesity-mediated colorectal cancer is the activation of the PI3K/AKT, mTOR/MAPK, and STAT3 signaling pathways. Different inhibitory molecules towards these pathways exist, increasing the therapeutic choice of obesity-associated colon cancer. However, obese patients are more likely to suffer from chemotherapy overdosing. Preventing obesity through maintaining a healthy and active lifestyle remains to be the best remedy.

More than half of cancer patients need radiotherapy during the course of their treatment. Despite the beneficial aspects, the destructive effects of radiation beams on normal tissues lead to oxidative stress, inflammation, and cell injury. Kidneys are affected during radiotherapy of abdominal malignancies. Radiation nephropathy eventually leads to the release of factors triggering systemic inflammation. Currently, there is no proven prophylactic or therapeutic intervention for the management of radiation-induced nephropathy. This article reviews the biomarkers involved in the pathophysiology of radiation-induced nephropathy and its underlying molecular mechanisms. The efficacy of compounds with potential radioprotective properties on amelioration of inflammation and oxidative stress is also discussed. By outlining the approaches for preventing and treating this critical side effect, we evaluate the potential treatment of radiation-induced nephropathy. Available preclinical and clinical studies on these compounds are also scrutinized.

Major depressive disorder (MDD) is a disease associated with many factors; specifically, environmental, genetic, psychological, and biological factors play critical roles. Recent studies have demonstrated that histone modification may occur in the human brain in response to severely stressful events, resulting in transcriptional changes and the development of MDD. In this review, we discuss five different histone modifications, histone methylation, histone acetylation, histone phosphorylation, histone crotonylation and histone β-hydroxybutyrylation, and their relationships with MDD. The utility of histone deacetylase (HDAC) inhibitors (HDACis) for MDD treatment is also discussed. As a large number of MDD patients in China have been treated with traditional Chineses medicine (TCM), we also discuss some TCM therapies, such as Xiaoyaosan (XYS), and their effects on histone modification. In summary, targeting histone modification may be a new strategy for elucidating the mechanism of MDD and a new direction for MDD treatment.

The caspase family is commonly involved in the pathophysiology of acute brain injury (ABI) through complex apoptotic, pyroptotic, and inflammatory pathways. Current translational strategies for caspase modulation in ABI primarily focus on caspase inhibitors. Because there are no caspase-inhibiting drugs approved for clinical use on the market, the development of caspase inhibitors remains an attractive challenge for researchers and clinicians. Therefore, we conducted the present review with the aim of providing a comprehensive introduction of caspases in ABI. In this review, we summarized the available evidence and potential mechanisms regarding the biological function of caspases. We also reviewed the therapeutic effects of caspase inhibitors on ABI and its subsequent complications. However, various important issues remain unclear, prompting further verification of the efficacy and safety regarding clinical application of caspase inhibitors. We believe that our work will be helpful to further understand the critical role of the caspase family and will provide novel therapeutic potential for ABI treatment.

Background: Oxidative stress is one of the main contributing factors involved in cerebral biochemical impairment. The higher susceptibility of the central nervous system to reactive oxygen species mediated damage could be attributed to several factors. For example, neurons use a greater quantity of oxygen, many parts of the brain have higher concentraton of iron, and neuronal mitochondria produce huge content of hydrogen peroxide. In addition, neuronal membranes have polyunsaturated fatty acids, which are predominantly vulnerable to oxidative stress (OS). OS is the imbalance between reactive oxygen species generation and cellular antioxidant potential. This may lead to various pathological conditions and diseases, especially neurodegenerative diseases such as, Parkinson’s, Alzheimer’s, and Huntington’s diseases. Objectives: In this study, we explored the involvement of OS in neurodegenerative diseases. Methods: We used different search terms like “oxidative stress and neurological disorders” “free radicals and neurodegenerative disorders” “oxidative stress, free radicals, and neurological disorders” and “association of oxidative stress with the name of disorders taken from the list of neurological disorders. We tried to summarize the source, biological effects, and physiologic functions of ROS. Results: Finally, it was noted that more than 190 neurological disorders are associated with oxidative stress. Conclusion: More elaborated studies in the future will certainly help in understanding the exact mechanism involved in neurological diseases and provide insight into revelation of therapeutic targets.

Abstract: Epilepsy affects more than 40 million people worldwide, constituting one of the most debilitating disorders of the Central Nervous System (CNS). It results from an imbalance in the electrical activity of neurons, which is primarily mediated by calcium ions. In many cases, treatment with Antiepileptic Drugs (AEDs) that regulate calcium channel activity results in successful seizure control. However, AEDs frequently cause adverse effects that range in severity from minimal impairment of the CNS to death from aplastic anemia or hepatic failure. Moreover, 30% of epileptic patients show drug-resistant epilepsy and do not respond to any form of medical treatment. In this context, nanotechnology has emerged as an excellent tool to overcome AEDs limitations. Numerous nano-strategies have been proposed as therapeutics and diagnostics for epilepsy through inhibition of different calcium channel types in the brain. In addition, limited brain access of classical AEDs in patients showing refractory epilepsy could be improved through the design of targeted drug delivery nanosystems. This report presents a review of the nanocarriers developed so far that could facilitate the interaction with calcium channels in the brain and the transport of AEDs through the blood-brain-barrier, mapping out a potential future direction in the research of epilepsy treatment.

Chronic pain is a common distressing neurological disorder and about 30% of the global population suffers from it. In addition to being highly prevalent, chronic pain causes a heavy economic and social burden. Although substantial progress has been achieved to dissect the underlying mechanism of chronic pain in the past few decades, the incidence and treatment of this neurological illness is yet not properly managed in clinical practice. While nerve injury-, chemotherapy- or inflammation-induced functional regulation of gene expression in the dorsal root ganglion and spinal cord are extensively reported to be involved in the pathogenic process of chronic pain, the specific mechanism of these altered transcriptional profile still remains unclear. Recent studies have shown that epigenetic mechanisms, including DNA/RNA methylation, histone modification and circular RNAs regulation, are involved in the occurrence and development of chronic pain. In this review, we provide a description of research on the role of epigenetic mechanism in chronic pain, summarize the latest clinical and preclinical advance in this field, and propose the potential directions for further research to elucidate the molecular mechanism underlying the pathogenesis of chronic pain.

Although early recognition of sepsis is essential for timely treatment and can improve sepsis outcomes, no marker has demonstrated sufficient discriminatory power to diagnose sepsis. This study aimed to compare gene expression profiles between patients with sepsis and healthy volunteers to determine the accuracy of these profiles in diagnosing sepsis and to predict sepsis outcomes by combining bioinformatics data with molecular experiments and clinical information. We identified 422 differentially expressed genes (DEGs) between the sepsis and control groups, of which 93 immune-related DEGs were considered for further studies due to immune-related pathways being the most highly enriched. Key genes upregulated during sepsis, including S100A8, S100A9, and CR1, are responsible for cell cycle regulation and immune responses. Key downregulated genes, including CD79A, HLA-DQB2, PLD4, and CCR7, are responsible for immune responses. Furthermore, the key upregulated genes showed excellent to fair accuracy in diagnosing sepsis (area under the curve 0.747–0.931) and predicting in-hospital mortality (0.863–0.966) of patients with sepsis. In contrast, the key downregulated genes showed excellent accuracy in predicting mortality of patients with sepsis (0.918–0.961) but failed to effectively diagnosis sepsis. In conclusion, bioinformatics analysis identified key genes that may serve as biomarkers for diagnosing sepsis and predicting outcomes among patients with sepsis.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease with multifactorial pathogenesis; histone demethylases (HDMs) are emerging as attractive targets. We identified HDM genes (including KDM5C, KDM6B, KDM8, KDM4A, and JMJD7) that were differentially expressed in NAFLD and normal samples by exploring gene expression profiling datasets. There was no significant difference in the expression of genes related to histone demethylation between mild and advanced NAFLD. In vitro and in vivo studies indicated that KDM6B and JMJD7 were upregulated at the mRNA level in NAFLD. We explored the expression levels and prognostic values of the identified HDM genes in hepatocellular carcinoma (HCC). KDM5C and KDM4A were upregulated in HCC compared to normal tissue, while KDM8 showed downregulation. The abnormal expression levels of these HDMs could provide prognostic values. Furthermore, KDM5C and KDM4A were associated with immune cell infiltration in HCC. HDMs were associated with cellular and metabolic processes and may be involved in the regulation of gene expression. Differentially expressed HDM genes identified in NAFLD may provide value to understanding pathogenesis and in the development of epigenetic therapeutic targets. However, on the basis of the inconsistent results of in vitro studies, future in vivo experiments combined with transcriptomic analysis are needed for further validation.

Circadian rhythmicity in renal function suggests rhythmic adaptations in renal metabolism. To decipher the role of the circadian clock in renal metabolism, we studied diurnal changes in renal metabolic pathways using integrated transcriptomic, proteomic, and metabolomic analysis performed on control mice and mice with an inducible deletion of the circadian clock regulator Bmal1 in the renal tubule (cKOt). With this unique resource, we demonstrated that approximately 30% of RNAs, approximately 20% of proteins, and approximately 20% of metabolites are rhythmic in the kidneys of control mice. Several key metabolic pathways, including NAD+ biosynthesis, fatty acid transport, carnitine shuttle, and β-oxidation, displayed impairments in kidneys of cKOt mice, resulting in perturbed mitochondrial activity. Carnitine reabsorption from primary urine was one of the most affected processes with an approximately 50% reduction in plasma carnitine levels and a parallel systemic decrease in tissue carnitine content. This suggests that the circadian clock in the renal tubule controls both kidney and systemic physiology.

Transcription factors responsive to small molecules are essential elements in synthetic biology designs. They are often used as genetically encoded biosensors with applications ranging from the detection of environmental contaminants and biomarkers to microbial strain engineering. Despite our efforts to expand the space of compounds that can be detected using biosensors, the identification and characterisation of transcription factors and their corresponding inducer molecules remain labour- and time-intensive tasks. Here, we introduce TFBMiner, a new data mining and analysis pipeline that enables the automated and rapid identification of putative metabolite-responsive transcription factor-based biosensors (TFBs). This user-friendly command line tool harnesses a heuristic rule-based model of gene organisation to identify both gene clusters involved in the catabolism of user-defined molecules and their associated transcriptional regulators. Ultimately, biosensors are scored based on how well they fit the model, providing wet-lab scientists a ranked list of candidates that can be experimentally tested. We validated the pipeline using a set of molecules for which TFBs have been reported previously, including sensors responding to sugars, amino acids, and aromatic compounds, among others. We further demonstrated the utility of TFBMiner by identifying a biosensor for S-mandelic acid, an aromatic compound for which a responsive transcription factor had not been found previously. Using a combinatorial library of mandelate-producing microbial strains, the newly identified biosensor was able to distinguish between low- and high-producing strain candidates. This work will aid in the unravelling of metabolite-responsive microbial gene regulatory networks and expand the synthetic biology toolbox to allow for the construction of more sophisticated self-regulating biosynthetic pathways.

Cardiovascular complications combined with COVID-19 (SARS-CoV-2) lead to a poor prognosis in patients. The common pathogenesis of ischemic cardiomyopathy (ICM) and COVID-19 is still unclear. Here, we explored potential molecular mechanisms and biomarkers for ICM and COVID-19. Common differentially expressed genes (DEGs) of ICM (GSE5406) and COVID-19 (GSE164805) were identified using GEO2R. We performed enrichment and protein–protein interaction analyses and screened key genes. To confirm the diagnostic performance for these hub genes, we used external datasets (GSE116250 and GSE211979) and plotted ROC curves. Transcription factor and microRNA regulatory networks were constructed for the validated hub genes. Finally, drug prediction and molecular docking validation were performed using cMAP. We identified 81 common DEGs, many of which were enriched in terms of their relation to angiogenesis. Three DEGs were identified as key hub genes (HSP90AA1, HSPA9, and SRSF1) in the protein–protein interaction analysis. These hub genes had high diagnostic performance in the four datasets (AUC > 0.7). Mir-16-5p and KLF9 transcription factor co-regulated these hub genes. The drugs vindesine and ON-01910 showed good binding performance to the hub genes. We identified HSP90AA1, HSPA9, and SRSF1 as markers for the co-pathogenesis of ICM and COVID-19, and showed that co-pathogenesis of ICM and COVID-19 may be related to angiogenesis. Vindesine and ON-01910 were predicted as potential therapeutic agents. Our findings will contribute to a deeper understanding of the comorbidity of ICM with COVID-19.

Leishmaniasis represents a complex of diseases with a broad clinical spectrum and epidemiological diversity, considered a major public health problem. Although there is treatment, there are still no vaccines for cutaneous leishmaniasis. Because Leishmania spp. is an intracellular protozoan with several escape mechanisms, a vaccine must provoke cellular and humoral immune responses. Previously, we identified the Leishmania homolog of receptors for activated C kinase (LACK) and phosphoenolpyruvate carboxykinase (PEPCK) proteins as strong immunogens and candidates for the development of a vaccine strategy. The present work focuses on the in silico prediction and characterization of antigenic epitopes that might interact with mice or human major histocompatibility complex class I. After immunogenicity prediction on the Immune Epitope Database (IEDB) and the Database of MHC Ligands and Peptide Motifs (SYFPEITHI), 26 peptides were selected for interaction assays with infected mouse lymphocytes by flow cytometry and ELISpot. This strategy identified nine antigenic peptides (pL1-H2, pPL3-H2, pL10-HLA, pP13-H2, pP14-H2, pP15-H2, pP16-H2, pP17-H2, pP18-H2, pP26-HLA), which are strong candidates for developing a peptide vaccine against leishmaniasis.

Emerging evidence shows that peripheral systemic inflammation, such as inflammatory bowel disease (IBD), has a close even interaction with central nervous disorders such as Alzheimer’s disease (AD). This study is designed to further clarify the relationship between AD and ulcerative colitis (UC, a subclass of IBD). The GEO database was used to download gene expression profiles for AD (GSE5281) and UC (GSE47908). Bioinformatics analysis included GSEA, KEGG pathway, Gene Ontology (GO), WikiPathways, PPI network, and hub gene identification. After screening the shared genes, qRT-PCR, Western blot, and immunofluorescence were used to verify the reliability of the dataset and further confirm the shared genes. GSEA, KEGG, GO, and WikiPathways suggested that PPARG and NOS2 were identified as shared genes and hub genes by cytoHubba in AD and UC and further validated via qRT-PCR and Western blot. Our work identified PPARG and NOS2 are shared genes of AD and UC. They drive macrophages and microglia heterogeneous polarization, which may be potential targets for treating neural dysfunction induced by systemic inflammation and vice versa.

The sigma (σ) factor of RNA holoenzymes is essential for identifying and binding to promoter regions during gene transcription in prokaryotes. σ54 promoters carried out various ancillary methods and environmentally responsive procedures; therefore, it is crucial to accurately identify σ54 promoter sequences to comprehend the underlying process of gene regulation. Herein, we come up with a convolutional neural network (CNN) based prediction tool named “iProm-Sigma54” for the prediction of σ54 promoters. The CNN consists of two one-dimensional convolutional layers, which are followed by max pooling layers and dropout layers. A one-hot encoding scheme was used to extract the input matrix. To determine the prediction performance of iProm-Sigma54, we employed four assessment metrics and five-fold cross-validation; performance was measured using a benchmark and test dataset. According to the findings of this comparison, iProm-Sigma54 outperformed existing methodologies for identifying σ54 promoters. Additionally, a publicly accessible web server was constructed.

The human kidney is known to possess renal progenitor cells (RPCs) that can assist in the repair of acute tubular injury. The RPCs are sparsely located as single cells throughout the kidney. We recently generated an immortalized human renal progenitor cell line (HRTPT) that co-expresses PROM1/CD24 and expresses features expected on RPCs. This included the ability to form nephrospheres, differentiate on the surface of Matrigel, and undergo adipogenic, neurogenic, and osteogenic differentiation. These cells were used in the present study to determine how the cells would respond when exposed to nephrotoxin. Inorganic arsenite (iAs) was chosen as the nephrotoxin since the kidney is susceptible to this toxin and there is evidence of its involvement in renal disease. Gene expression profiles when the cells were exposed to iAs for 3, 8, and 10 passages (subcultured at 1:3 ratio) identified a shift from the control unexposed cells. The cells exposed to iAs for eight passages were then referred with growth media containing no iAs and within two passages the cells returned to an epithelial morphology with strong agreement in differential gene expression between control and cells recovered from iAs exposure. Results show within three serial passages of the cells exposed to iAs there was a shift in morphology from an epithelial to a mesenchymal phenotype. EMT was suggested based on an increase in known mesenchymal markers. We found RPCs can undergo EMT when exposed to a nephrotoxin and undergo MET when the agent is removed from the growth media.

The persistent impact of the COVID-19 pandemic and heterogeneity in disease manifestations point to a need for innovative approaches to identify drivers of immune pathology and predict whether infected patients will present with mild/moderate or severe disease. We have developed a novel iterative machine learning pipeline that utilizes gene enrichment profiles from blood transcriptome data to stratify COVID-19 patients based on disease severity and differentiate severe COVID cases from other patients with acute hypoxic respiratory failure. The pattern of gene module enrichment in COVID-19 patients overall reflected broad cellular expansion and metabolic dysfunction, whereas increased neutrophils, activated B cells, T-cell lymphopenia, and proinflammatory cytokine production were specific to severe COVID patients. Using this pipeline, we also identified small blood gene signatures indicative of COVID-19 diagnosis and severity that could be used as biomarker panels in the clinical setting.

Funding Information: The following grant information was disclosed by the authors: European Commission, the Food Quality and Safety Priority of the Sixth Framework Program: FP6-2005-513946. Finnish Diabetes Research Foundation. Academy of Finland: 335443, 314383, 272376 and 266286. Sigrid Jusélius Foundation. Academy of Finland Center of Excellence in Research on Mitochondria, Metabolism and Disease (FinMIT): 272376. Finnish Medical Foundation. Gyllenberg Foundation. Novo Nordisk Foundation: NNF20OC0060547, NNF17OC0027232 and NNF10OC1013354. Gyllenberg Foundation. Finnish Diabetes Research Foundation. Finnish Foundation for Cardiovascular Research. Funding Information: The Diogenes study was supported by the European Commission, the Food Quality and Safety Priority of the Sixth Framework Program (FP6-2005-513946). Birgitta W. van der Kolk was supported by the Finnish Diabetes Research Foundation. Kirsi H. Pietiläinen was funded by the Academy of Finland (grant numbers 335443, 314383, 272376 and 266286), Sigrid Jusélius Foundation, the Academy of Finland Center of Excellence in Research on Mitochondria, Metabolism and Disease (FinMIT; grant number 272376), the Finnish Medical Foundation, the Gyllenberg Foundation, the Novo Nordisk Foundation (grant numbers NNF20OC0060547, NNF17OC0027232 and NNF10OC1013354), Gyllenberg Foundation, the Finnish Diabetes Research Foundation, the Finnish Foundation for Cardiovascular Research, Government Research Funds, the University of Helsinki and Helsinki University Hospital. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Funding Information: At the time of the study, Armand Valsesia was a full-time employee at Nestlé Institute of Health Sciences SA. W. H. Saris discloses the receipt of research support from several food companies such as Nestlé, DSM, Unilever, Nutrition et Sante and Danone as well as pharmaceutical companies including GSK, Novartis and Novo Nordisk; he is also an unpaid scientific advisor for the International Life Science Institute (ILSI) Europe. Arne Astrup discloses grants and personal fees received from Gelesis, USA; personal fees from Acino, Switzerland; BioCare Copenhagen, DK; Dutch Beer Institute, NL; Groupe Éthique et Santé, France; IKEA Food Scientific Health Advisory Board, SE; McCain Foods Limited, USA; Navamedic, DK; Novo Nordisk, DK; Pfizer, USA; Saniona, DK; Weight Watchers, USA & Zaluvida, Switzerland; and grants from DC-Ingredients Denmark, which lie beyond the scope of the work reported here. Ellen E. Blaak received financial support from food industry, such as DSM, Danone, Friesland Campina, Avebe and Sensus, partly within the context of public–private consortia and has received funding from pharmaceutical companies including Novartis. She is involved in several task forces and expert groups related to ILSI Europe.g interests. Publisher Copyright: Copyright 2023 Oghabian et al. Background: Weight loss effectively reduces cardiometabolic health risks among people with overweight and obesity, but inter-individual variability in weight loss maintenance is large. Here we studied whether baseline gene expression in subcutaneous adipose tissue predicts diet-induced weight loss success. Methods: Within the 8-month multicenter dietary intervention study DiOGenes, we classified a low weight-losers (low-WL) group and a high-WL group based on median weight loss percentage (9.9%) from 281 individuals. Using RNA sequencing, we identified the significantly differentially expressed genes between high-WL and low-WL at baseline and their enriched pathways. We used this information together with support vector machines with linear kernel to build classifier models that predict the weight loss classes. Results: Prediction models based on a selection of genes that are associated with the discovered pathways ‘lipid metabolism’ (max AUC = 0.74, 95% CI [0.62–0.86]) and ‘response to virus’ (max AUC = 0.72,95% CI [0.61–0.83]) predicted the weight-loss classes high-WL/low-WL significantly better than models based on randomly selected genes (P < 0.01). The performance of the models based on ‘response to virus’ genes is highly dependent on those genes that are also associated with lipid metabolism. Incorporation of baseline clinical factors into these models did not noticeably enhance the model performance in most of the runs. This study demonstrates that baseline adipose tissue gene expression data, together with supervised machine learning, facilitates the characterization of the determinants of successful weight loss.

Insomnia is a common, impairing, and difficult-to-treat comorbidity in children with neurodevelopmental disorders (NDDs). Behavioral interventions can be challenging because of developmental and behavioral features that interfere with treatment. Medication management also can be difficult due to a high burden of side effects, a high rate of paradoxical responses, and frequent treatment resistance. Therefore, new treatment options for insomnia in children with NDDs are needed. Dual orexin receptor antagonists (DORAs) are a relatively new class of pharmacotherapeutics that induce sleep by inhibiting the orexin signaling pathway. To date, there is little safety or efficacy data on the use of DORAs in children with NDDs. We present four patients with NDDs and insomnia that we treated with the DORA, suvorexant. We found that patients had a wide range of responses, with one patient displaying a robust improvement in sleep onset and maintenance, while another had significant improvement in insomnia symptoms on combination therapy with trazodone. Our final two patients had mild or no benefit from suvorexant therapy. Further research is necessary to establish the safety and efficacy of DORAs in this population and to identify predictive factors, such as specific neurogenetic diagnoses or clinical features, of a positive treatment response.

Oral squamous cell carcinoma (OSCC) is one of the most common cancers in the world, and the incidence and death rate of OSCC in men is twice that of women. CD47 is a ubiquitous cell surface transmembrane protein, also known as integrin-related protein (IAP). Previous studies have pointed out that CD47 can inhibit the growth of OSCC, but the detailed mechanism is not clear. This study aimed to explore the effect of CD47 gene expression profiles in OSCC. The OSCC cell lines, OECM-1 and OC-2, overexpressed CD47, and the expression profiles of mRNAs were analyzed through next-generation sequencing (NGS) with a bioinformatic approach. A total of 14 differentially expressed genes (DEGs) were listed. In addition, ingenuity pathway analysis (IPA) was used to analyze the molecular function (MF), biological process (BP), and cellular component (CC) network signaling. The human protein atlas (HPA) database was used to analyze gene expression and the survivability of human cancer. The results found that HSPA5, HYOU1, and PDIA4 were involved in the IPA network and when highly expressed, mediated the survivability of cancer. In addition, HSPA5 was positively and significantly correlated with CD47 expression (p < 0.0001) and induced by CD47-overexpression in the OECM-1 and OC-2 OSCC cancer cell lines. These findings provide important insights into possible new diagnostic strategies, including unfolded protein for OSCC-targeting CD47.

An important step in the proteomic analysis of missing proteins is the use of a wide range of tissues, optimal extraction, and the processing of protein material in order to ensure the highest sensitivity in downstream protein detection. This work describes a purification protocol for identifying low-abundance proteins in human chorionic villi using the proposed “1DE-gel concentration” method. This involves the removal of SDS in a short electrophoresis run in a stacking gel without protein separation. Following the in-gel digestion of the obtained holistic single protein band, we used the peptide mixture for further LC–MS/MS analysis. Statistically significant results were derived from six datasets, containing three treatments, each from two tissue sources (elective or missed abortions). The 1DE-gel concentration increased the coverage of the chorionic villus proteome. Our approach allowed the identification of 15 low-abundance proteins, of which some had not been previously detected via the mass spectrometry of trophoblasts. In the post hoc data analysis, we found a dubious or uncertain protein (PSG7) encoded on human chromosome 19 according to neXtProt. A proteomic sample preparation workflow with the 1DE-gel concentration can be used as a prospective tool for uncovering the low-abundance part of the human proteome.

Natural products are compounds isolated from plants that provide a variety of lead structures for the development of new drugs by the pharmaceutical industry. The interest in these substances increases because of their beneficial effects on human health. Alzheimer's disease (AD ) affects occur in about 80% of individuals aged 65 years. AD is the most common cause of dementia in elderly people, is characterized by progressive neurodegenerative alterations, as decrease of cholinergic impulse, increased toxic effects caused by reactive oxygen species and the inflammatory process that the amyloid plaque participates. In silico studies is relevant in the process of drug discovery; through technological advances in the areas of structural characterization of molecules, computational science and molecular biology have contributed to the planning of new drugs used against neurodegenerative diseases. Considering the social impairment caused by increased incidence of disease and that there is no chemotherapy treatment effective against the AD; several compounds are studied. In the researches for effective neuroprotectants as potential treatments for Alzheimer's disease, natural products that have been extensively studied in various AD models. This study aims to carry out a literature review with articles that address the In silico studies of natural products aimed at potential drugs against alzheimer's disease (AD) in the period from 2015 to 2021.

Background Withania somnifera (WS), also known as Ashwagandha, is commonly used in Ayurveda and other traditional medicine systems. WS has seen growing, worldwide use by the public due to its reputation as an adaptogen. This popularity has elicited increased scientific study of its biological effects, including a potential application for neuropsychiatric and neurodegenerative disorders. Objective This review aims to provide a comprehensive summary of preclinical and clinical studies examining the neuropsychiatric effects of WS, specifically its application in stress, anxiety, depression, and insomnia. Methods Reports of human trials and animal studies of WS were collected primarily from the PubMed, Scopus, and Google Scholar databases. Results WS root and leaf extracts exhibited noteworthy anti-stress and anti-anxiety activity in animal and human studies. WS also improved symptoms of depression and insomnia, though fewer studies investigated these applications. WS may alleviate these conditions predominantly through modulation of the hypothalamic-pituitary-adrenal and sympathetic-adrenal medullary axes, as well as through GABAergic and serotonergic pathways. While some studies link specific withanolide components to its neuropsychiatric benefits, there is evidence for the presence of additional, yet unidentified, active compounds in WS. Conclusion While benefits were seen in the reviewed studies, significant variability in the WS extracts examined prevents a consensus on the optimum WS preparation or dosage to treat neuropsychiatric conditions. WS appears generally safe for human use; however, it will be important to investigate potential herb-drug interactions involving WS if used alongside pharmaceutical interventions. Further elucidation of active compounds of WS is also needed.

The natural lifespan of the ovary is occasionally interrupted by pathological processes; some are known, but many are unknown. Premature ovarian insufficiency (POI) can be a devastating diagnosis for an adolescent or for someone who has yet to start a family. Common causes of POI include genetic and chromosomal defects, autoimmune damage, and cancer treatments. Knowledge of the pathogenesis of this condition and an awareness of contemporary hormone replacement and fertility options are required to design a multidisciplinary therapeutic approach comprising reproductive medicine, endocrinology, clinical psychology, and assisted fertility expertise.

With the emergence of immune-modulating therapies, brain tumors present significant diagnostic imaging challenges. These challenges include planning personalized treatment and adjudicating accurate monitoring approaches and therapeutically specific response criteria. This has been due, in part, to the reliance on nonspecific imaging metrics, such as gadolinium-contrast-enhanced MRI or FDG PET, and rapidly evolving biologic understanding of neuroinflammation. The importance of the tumor-immune interaction and ability to therapeutically augment inflammation to improve clinical outcomes necessitates that the radiologist develop a working knowledge of the immune system and its role in clinical neuroimaging. In this article, we review relevant biologic concepts of the tumor microenvironment of primary and metastatic brain tumors, these tumors' interactions with the immune system, and MRI and PET methods for imaging inflammatory elements associated with these malignancies. Recognizing the growing fields of immunotherapeutics and precision oncology, we highlight clinically translatable imaging metrics for the diagnosis and monitoring of brain tumor neuroinflammation. Practical guidance is provided for implementing iron nanoparticle imaging, including imaging indications, protocol, interpretation, and pitfalls. A comprehensive understanding of the inflammatory mechanisms within brain tumors and their imaging features will facilitate the development of innovative non-invasive prognostic and predictive imaging strategies for precision oncology.

OBJECTIVE Developmental and epileptic encephalopathy (DEE) is characterized by refractory seizures, developmental delay or intellectual disability, which may be caused by gene mutation. In this study, we explored the clinical phenotype and long-term outcome in children with genetic early-infantile-onset DEEs. METHODS Next-generation sequencing was performed on 470 patients diagnosed with early-infantile-onset DEE between 2010 and 2020. The genetic variation in all cases was classified and evaluated to identify pathogenic variants. The identified variants were further verified by Sanger sequencing. RESULTS A total of 118 and 10 patients were found to have putative disease-causing gene mutations and copy number variations, respectively. SCN1A mutations were detected in 38 patients (38/118, 32.2%), representing the largest proportion. In patients with early-infantile-onset DEE with burst suppression, KCNQ2 mutation was found in six patients, and the remaining mutations were reported in SCN2A (n=2) and STXBP1 (n=1). Seven patients with dyskinesia were described. In patients with non-syndromic genetic early-infantile-onset DEEs, we detected possible rare pathogenic variants in SETBP1, DPYD, CSNK2B, and H3F3A. With regards to inheritance pattern, de novo heterozygous mutations accounted for the majority (104/118; 88.1%). Three patients with SMC1A mutations responded well to ketogenic diet add-on therapy. Addition of valproic acid showed good therapeutic effects against KCNB1 and PACS2 encephalopathy. SIGNIFICANCE We detected four possible rare pathogenic gene variants as non-syndromic genetic causes of early-infantile-onset DEEs. Although early-infantile-onset DEEs responded poorly to antiseizure medication treatment, we found that specific antiseizure medications showed good therapeutic effects in some patients with early-infantile-onset DEEs harbouring gene variants.

Tourette syndrome (TS) is a frequently observed developmental neuropsychological disorder occurring in children. The pathophysiology involves both genetic and environmental factors. In this review, clinical characteristics, pathophysiology, and treatment approaches based on the pathophysiology of TS are presented. The pathophysiology is the acceleration of developmental decrement of dopamine (DA) activity at the terminal of nigro-striatal (NS)-DA system causing DA D2 receptor up-ward regulation. Serotonergic neurons involving in development of the biphasic sleep-wake-rhythm, and locomotion may be involved. Pharmacological treatments constitute an important part in managing TS. Small dose of levodopa and aripiprazole showed the good effect controlling the tics, without side effects. Intervention with enhancing the day time activity and keeping the regular sleep-wake-rhythm, and encouraging locomotion are important. The data from Yoshiko Nomura Neurological Clinic for Children regarding the clinical features and outcomes, medication effects, and OCD and outcomes are shown. To discuss about the environmental factor, how the COVID-19 pandemic affected the TS patients is also presented.