Human Disorders Research Articles

Short tandem repeat expansions in cortical layer-specific genes implicate in phenotypic severity and adaptability of autism spectrum disorder.

Short tandem repeats (STRs) are repetitive DNA sequences and highly mutable in various human disorders. While the involvement of STRs in various genetic disorders has been extensively studied, their role in autism spectrum disorder (ASD) remains largely unexplored. In this study, we aimed to investigate genetic association of STR expansions with ASD using whole genome sequencing (WGS) and identify risk loci associated with ASD phenotypes. We analyzed WGS data of 634 ASD families and performed genome-wide evaluation for 12,929 STR loci. We found rare STR expansions that exceeded normal repeat lengths in autism cases compared to unaffected controls. By integrating single cell RNA and ATAC sequencing datasets of human postmortem brains, we prioritized STR loci in genes specifically expressed in cortical development stages. A deep learning method was used to predict functionality of ASD-associated STR loci. In ASD cases, rare STR expansions predominantly occurred in early cortical layer-specific genes involved in neurodevelopment, highlighting the cellular specificity of STR-associated genes in ASD risk. Leveraging deep learning prediction models, we demonstrated that these STR expansions disrupted the regulatory activity of enhancers and promoters, suggesting a potential mechanism through which they contribute to ASD pathogenesis. We found that individuals with ASD-associated STR expansions exhibited more severe ASD phenotypes and diminished adaptability compared to non-carriers. Short tandem repeat expansions in cortical layer-specific genes are associated with ASD and could potentially be a risk genetic factor for ASD. Our study is the first to show evidence of STR expansion associated with ASD in an under-investigated population.

Primary Cilia are Required for Cell-Type Determination and Angiogenesis in Pituitary Development.

The functional maturation of the pituitary gland requires adequate cell differentiation and vascular network formation. Although spatiotemporal signaling and transcription factors are known to govern pituitary development, the involvement of primary cilia, nonmoving hair-like organelles, remains unclear. In this study, we uncovered the contribution of primary cilia to cell-type determination and vascular network formation during pituitary development. Homozygous knockout mice lacking a ciliary kinase, Dyrk2-/-, exhibit abnormalities in ciliary structure and pituitary hypoplasia, accompanied by varying degrees of failure in differentiation among all types of hormone-producing cells in the anterior lobe. Aberrations in cell differentiation in Dyrk2-/- mice arise from a decrease in the expression of crucial transcription factors, Lhx4, Lhx3, and Prop1, resulting from the inactivity of Hedgehog (Hh) signaling during the early stages of development. Furthermore, the loss of Dyrk2 results in vascular system abnormalities during the middle to late stages of development. Mechanistically, transcriptome analyses revealed the downregulation of vitronectin-integrin αvβ3-VEGFR2 signaling, essential for orchestrating vascular development. Collectively, our findings demonstrate that primary cilia play a pivotal role as critical regulators of cell survival, cell determination, and angiogenesis during pituitary gland development through the activation of Hh signaling. These findings expand our understanding of the potential link between pituitary dysfunction in human disorders and ciliopathies.

Reference-informed prediction of alternative splicing and splicing-altering mutations from sequences.

Alternative splicing plays a crucial role in protein diversity and gene expression regulation in higher eukaryotes, and mutations causing dysregulated splicing underlie a range of genetic diseases. Computational prediction of alternative splicing from genomic sequences not only provides insight into gene-regulatory mechanisms but also helps identify disease-causing mutations and drug targets. However, the current methods for the quantitative prediction of splice site usage still have limited accuracy. Here, we present DeltaSplice, a deep neural network model optimized to learn the impact of mutations on quantitative changes in alternative splicing from the comparative analysis of homologous genes. The model architecture enables DeltaSplice to perform "reference-informed prediction" by incorporating the known splice site usage of a reference gene sequence to improve its prediction on splicing-altering mutations. We benchmarked DeltaSplice and several other state-of-the-art methods on various prediction tasks, including evolutionary sequence divergence on lineage-specific splicing and splicing-altering mutations in human populations and neurodevelopmental disorders, and demonstrated that DeltaSplice outperformed consistently. DeltaSplice predicted ∼15% of splicing quantitative trait loci (sQTLs) in the human brain as causal splicing-altering variants. It also predicted splicing-altering de novo mutations outside the splice sites in a subset of patients affected by autism and other neurodevelopmental disorders (NDDs), including 19 genes with recurrent splicing-altering mutations. Integration of splicing-altering mutations with other types of de novo mutation burdens allowed the prediction of eight novel NDD-risk genes. Our work expanded the capacity of in silico splicing models with potential applications in genetic diagnosis and the development of splicing-based precision medicine.

CTCF mutation at R567 causes developmental disorders via 3D genome rearrangement and abnormal neurodevelopment

The three-dimensional genome structure organized by CTCF is required for development. Clinically identified mutations in CTCF have been linked to adverse developmental outcomes. Nevertheless, the underlying mechanism remains elusive. In this investigation, we explore the regulatory roles of a clinically relevant R567W point mutation, located within the 11th zinc finger of CTCF, by introducing this mutation into both murine models and human embryonic stem cell-derived cortical organoid models. Mice with homozygous CTCFR567W mutation exhibit growth impediments, resulting in postnatal mortality, and deviations in brain, heart, and lung development at the pathological and single-cell transcriptome levels. This mutation induces premature stem-like cell exhaustion, accelerates the maturation of GABAergic neurons, and disrupts neurodevelopmental and synaptic pathways. Additionally, it specifically hinders CTCF binding to peripheral motifs upstream to the core consensus site, causing alterations in local chromatin structure and gene expression, particularly at the clustered protocadherin locus. Comparative analysis using human cortical organoids mirrors the consequences induced by this mutation. In summary, this study elucidates the influence of the CTCFR567W mutation on human neurodevelopmental disorders, paving the way for potential therapeutic interventions.

Insights into Prime Editing Technology: A Deep Dive into Fundamentals, Potentials, and Challenges.

As the most versatile and precise gene editing technology, prime editing (PE) can establish a durable cure for most human genetic disorders. Several generations of PE have been developed based on an editor machine or prime editing guide RNA (pegRNA) to achieve any kind of genetic correction. However, due to the early stage of development, PE complex elements need to be optimized for more efficient editing. Smart optimization of editor proteins as well as pegRNA has been contemplated by many researchers, but the universal PE machine's current shortcomings remain to be solved. The modification of PE elements, fine-tuning of the host genes, manipulation of epigenetics, and blockage of immune responses could be used to reach more efficient PE. Moreover, the host factors involved in the PE process, such as repair and innate immune system genes, have not been determined, and PE cell context dependency is still poorly understood. Regarding the large size of the PE elements, delivery is a significant challenge and the development of a universal viral or nonviral platform is still far from complete. PE versions with shortened variants of reverse transcriptase are still too large to fit in common viral vectors. Overall, PE faces challenges in optimization for efficiency, high context dependency during the cell cycling, and delivery due to the large size of elements. In addition, immune responses, unpredictability of outcomes, and off-target effects further limit its application, making it essential to address these issues for broader use in nonpersonalized gene editing. Besides, due to the limited number of suitable animal models and computational modeling, the prediction of the PE process remains challenging. In this review, the fundamentals of PE, including generations, potential, optimization, delivery, invivo barriers, and the future landscape of the technology are discussed.

Traditional Persian Medicine and Autophagy: Integrating Ancient Health Principles with Modern Cellular Mechanisms

Autophagy, a cellular process responsible for maintaining cellular homeostasis through the degradation and recycling of intracellular components, has a complex relationship with various human diseases, including cancer, neurodegenerative disorders, and infections. Traditional Persian Medicine (TPM), with a 10,000-year history, emphasizes health preservation through six essential principles: physical activity, nutrition, sleep, psychological well-being, air quality, and the excretion of body waste. This review examines the intersection of these principles with autophagy, highlighting the potential of TPM in modern health practices. Recent studies have shown that physical activity induces autophagy, aiding in the prevention and treatment of diseases such as Alzheimer's and diabetes. Nutritional management, another key TPM principle, influences autophagy through practices like intermittent fasting, which can improve insulin sensitivity and prolong life. Sleep, critical for bodily functions and waste disposal, affects autophagy, with disruptions linked to conditions like sleep apnea and cardiovascular diseases. Excretion and retention of necessary materials are crucial for health, with autophagy playing a role in managing obesity, renal function, and gastrointestinal health. Clean air is essential for well-being, and studies indicate that air pollution can stimulate autophagy, potentially leading to liver steatosis. Psychological states also significantly impact autophagy, with stress and emotional well-being influencing cellular processes. This review suggests that the non-pharmacologic modulators of autophagy inherent in TPM's six essential principles could precede pharmaceutical interventions due to their simplicity, safety, and affordability. Health authorities are encouraged to consider these principles in policies for disease treatment and health improvement, leveraging the potential of autophagy modulation for better health outcomes.

Emergence of the ZNF675 Gene During Primate Evolution-Influenced Human Neurodevelopment Through Changing HES1 Autoregulation.

In this study, we investigated recurrent copy number variations (CNVs) in the 19p12 locus, which are associated with neurodevelopmental disorders. The two genes in this locus, ZNF675 and ZNF681, arose via gene duplication in primates, and their presence in several pathological CNVs in the human population suggests that either or both of these genes are required for normal human brain development. ZNF675 and ZNF681 are members of the Krüppel-associated box zinc finger (KZNF) protein family, a class of transcriptional repressors important for epigenetic silencing of specific genomic regions. About 170 primate-specific KZNFs are present in the human genome. Although KZNFs are primarily associated with repressing retrotransposon-derived DNA, evidence is emerging that they can be co-opted for other gene regulatory processes. We show that genetic deletion of ZNF675 causes developmental defects in cortical organoids, and our data suggest that part of the observed neurodevelopmental phenotype is mediated by a gene regulatory role of ZNF675 on the promoter of the neurodevelopmental gene Hes family BHLH transcription factor 1 (HES1). We also find evidence for the recently evolved regulation of genes involved in neurological disorders, microcephalin 1 and sestrin 3. We show that ZNF675 interferes with HES1 auto-inhibition, a process essential for the maintenance of neural progenitors. As a striking example of how some KZNFs have integrated into preexisting gene expression networks, these findings suggest the emergence of ZNF675 has caused a change in the balance of HES1 autoregulation. The association of ZNF675 CNV with human developmental disorders and ZNF675-mediated regulation of neurodevelopmental genes suggests that it evolved into an important factor for human brain development.

RDR100: A Robust Computational Method for Identification of Krüppel-like Factors

Background: Krüppel-like factors (KLFs) are a family of transcription factors containing zinc fingers that regulate various cellular processes. KLF proteins are associated with human diseases, such as cancer, cardiovascular diseases, and metabolic disorders. The KLF family consists of 18 members with diverse expression profiles across numerous tissues. Accurate identification and annotation of KLF proteins is crucial, given their involvement in important biological functions. Although experimental approaches can identify KLF proteins precisely, large-scale identification is complicated, slow, and expensive. Methods: In this study, we developed RDR100, a novel random forest (RF)-based framework for predicting KLF proteins based on their primary sequences. First, we identified the optimal encodings for ten different features using a recursive feature elimination approach, and then trained their respective model using five distinct machine learning (ML) classifiers. Results: The performance of all models was assessed using independent datasets, and RDR100 was selected as the final model based on its consistent performance in cross-validation and independent evaluation. Conclusion: Our results demonstrate that RDR100 is a robust predictor of KLF proteins. RDR100 web server is available at https://procarb.org/RDR100/.

An Insight into Different Experimental Models used for Hepatoprotective Studies: A Review.

Numerous factors, including exposure to harmful substances, drinking too much alcohol, contracting certain hepatitis serotypes, and using specific medicines, contribute to the development of liver illnesses. Lipid peroxidation and other forms of oxidative stress are the main mechanisms by which hepatotoxic substances harm liver cells. Pathological changes in the liver include a rise in the levels of blood serum, a decrease in antioxidant enzymes, as well as the formation of free radical radicals. It is necessary to find pharmaceutical alternatives to treat liver diseases to increase their efficacy and decrease their toxicity. For the development of new therapeutic medications, a greater knowledge of primary mechanisms is required. In order to mimic human liver diseases, animal models are developed. Animal models have been used for several decades to study the pathogenesis of liver disorders and related toxicities. For many years, animal models have been utilized to investigate the pathophysiology of liver illness and associated toxicity. The animal models are created to imitate human hepatic disorders. This review enlisted numerous hepatic damage in vitro and in vivo models using various toxicants, their probable biochemical pathways and numerous metabolic pathways via oxidative stressors, different serum biomarkers enzymes are discussed, which will help to identify the most accurate and suitable model to test any plant preparations to check and evaluate their hepatoprotective properties.

Effect of cannabidiol as a neuroprotective agent on neurodevelopmental impairment in rats with neonatal hypoxia

ObjectiveThis study aims to investigate the neuroprotective effects of cannabidiol (CBD) on neurodevelopmental impairments in rats subjected to neonatal hypoxia, specifically examining its potential to mitigate motor and sensory deficits without the confounding effects of ischemia. MethodsNeonatal Sprague-Dawley rats were allocated to one of four groups: Control, Control-CBD, Hypoxia, and Hypoxia-CBD. Hypoxia was induced on postnatal days 0 and 1. CBD (50 mg/kg) was administered orally for 14 days starting at postnatal day 0. Neurodevelopmental outcomes were assessed using the Neurodevelopmental Reflex Testing in Neonatal Rat Pups scale and the Revised Neurobehavioral Severity Scale for rodents. Statistical analyses were conducted using two-way and one-way ANOVA, with Tukey’s post-hoc tests for group comparisons. ResultsPup weights were recorded on specified postnatal days, with no significant differences observed across the groups (p = 0.1834). Significant neurological impairments due to hypoxia were noted in the Control group compared to the Hypoxia group, particularly in hindlimb grasping on postnatal day 3 (p = 0.0025), posture on postnatal day 12 (p = 0.0073), and in general balance and sound reflex on postnatal day 20 (p = 0.0016 and p = 0.0068, respectively). Additionally, a statistically significant improvement in posture was observed in the Hypoxia-CBD group compared to the Hypoxia group alone (p = 0.0024). ConclusionOur findings indicate that CBD possesses neuroprotective properties that significantly counteract the neurodevelopmental impairments induced by neonatal hypoxia in rats. This study not only supports the therapeutic potential of CBD in managing conditions characterized by neurodevelopmental challenges due to hypoxia but also underscores the necessity for further investigation into the specific molecular mechanisms driving CBD’s neuroprotective effects. Further research is essential to explore CBD’s clinical applications and its potential role in treating human neurodevelopmental disorders.

Biological Importance of Phellodendrine in Traditional and Modern Medicines: An Update on Therapeutic Potential in Medicine.

Herbal medicines have been used for the preparation of numerous pharmaceutical products for the treatment of human disorders. Plant-derived products have been used in medicine, nutraceuticals, perfumery, beverages, and cosmetics industries for different purposes. Herbal medicines are mainly derived from different parts of plant materials. Phellodendron bark has been widely known as one of the fundamental herbs of traditional Chinese medicine. Phellodendron bark contains phellodendrine as a main active phytochemical. Phellodendrine ((7S,13aS)-3,10-dimethoxy-7-methyl-6,8,13,13atetrahydro-5H-isoquinolino[2,1-b]isoquinolin-7- ium-2,11-diol), is a quaternary ammonium alkaloid. This present study aimed to investigate the biological potential and therapeutic effectiveness of phellodendrine in medicine through scientific data analysis of different research works on phellodendrine. The therapeutic value of phellodendrine was analyzed in the present work through scientific data available in Google, Google Scholar, ScienceDirect, and PubMed. All the scientific data on phellodendrine were collected from these databases using the terms herbal drugs and phellodendrine. Pharmacological and analytical data of phellodendrine were analyzed in the present work in order to know the medicinal importance of phellodendrine. Scientific data analysis of phellodendrine in the present work signified the biological importance of phellodendrine in medicine. Phellodendrine has numerous beneficial aspects in medicine due to its potential benefits in ulcerative colitis, inflammation, pancreatic cancer, nephritis, immune response, acetylcholinesterase activity, psoriasis, arthritis, atopic dermatitis, and oxidative stress. However, it also has significant effects on eicosanoid generation, neuraminidase-1, inflammasome generation, cytochrome p450, taste receptors, and hepatic gluconeogenesis. Furthermore, scientific data has indicated the presence of phellodendrine in different natural sources, including Phellodendri cortex. Analytical data on phellodendrines has signified their importance in the isolation and separation of pure phytochemicals in medicine. Pharmacokinetic parameters have highlighted the tissue distribution of phellodendrine in different tissue of human beings and higher animals. In the present work, scientific data analysis has indicated the biological importance, pharmacological activities, and analytical aspects of phellodendrine in medicine.

Iron biofortification in cereal crops: Recent progress and prospects

AbstractMicronutrient malnutrition is one of the major causes of human disorders in the developing world. Iron (Fe) is an important micronutrient due to its use in human metabolism such as immune system and energy production. Estimates indicate that above 30% of the global population is at risk of Fe deficiency, posing a particular threat to infants and pregnant women. Plants have adapted various strategies for uptake, transport, accumulation, and storage of Fe in tissues and organs which later can be consumed by humans. Biofortification refers to increase in micronutrient concentration in edible parts of plants and understanding the pathways for Fe accumulation in plants. Conventional plant breeding, transgenics, agronomic interventions, and microbe‐mediated biofortification are all potential methods to address Fe deficiency. This review article critically evaluates key aspects pertaining to Fe biofortification in cereal crops. It encompasses an in‐depth analysis of the holistic presence of Fe, its significance in both human and plant contexts, and the diverse strategies employed in Fe uptake, transport, accumulation, and storage in plant parts destined for human consumption. Additionally, the article explores the bioavailability of Fe and investigates strategies for biofortification, with a specific emphasis on both traditional methods and recent breakthroughs aimed at enhancing the Fe content in food crops. Keeping in view the significance of Fe for human life, appropriate biofortification strategies may serve better to eliminate hidden hunger rather than its artificial supplementation.

Preclinical Evidence and Underlying Mechanisms of Polygonum multiflorum and Its Chemical Constituents Against Cognitive Impairments and Alzheimer's Disease.

Cognitive impairments, ranging from mild to severe, adversely affect daily functioning, quality of life, and work capacity. Despite significant efforts in the past decade, more than 200 promising drug candidates have failed in clinical trials. Herbal remedies are gaining interest as potential treatments for dementia due to their long history and safety, making them valuable for drug development. This review aimed to examine the mechanisms behind the effect of Polygonum multiflorum on cognitive function. This study focused primarily on the effects of Polygonum multiflorum and its chemical constituents on cognitive behavioral outcomes including the Morris water maze, the passive avoidance test, and the Y maze, as well as pathogenic targets of cognitive impairment and Alzheimer's disease (AD) like amyloid deposition, amyloid precursor protein, tau hyperphosphorylation, and cognitive decline. Additionally, a thorough evaluation of the mechanisms behind Polygonum multiflorum's impact on cognitive function was conducted. We reviewed the most recent data from preclinical research done on experimental models, particularly looking at Polygonum multiflorum's effects on cognitive decline and AD. According to recent research, Poligonum multiflorum and its bioactive components, stilbene, and emodin, influence cognitive behavioral results and regulate the pathological target of cognitive impairment and AD. Their mechanisms of action include reducing oxidative and mitochondrial damage, regulating neuroinflammation, halting apoptosis, and promoting increased neurogenesis and synaptogenesis. This review serves as a comprehensive compilation of current experiments on AD and other cognitive impairment models related to the therapeutic effects of Polygonum multiflorum. We believe that these findings can serve as a basis for future clinical trials and have potential applications in the treatment of human neurological disorders.

A modified glycosylase base editor without predictable DNA off-target effects.

Glycosylase base editor (GBE) can induce C-to-G transversion in mammalian cells, showing great promise for the treatment of human genetic disorders. However, the limited efficiency of transversion and the possibility of off-target effects caused by Cas9 restrict its potential clinical applications. In our recent study, we have successfully developed TaC9-CBE and TaC9-ABE by separating nCas9 and deaminase, which eliminates the Cas9-dependent DNA off-target effects without compromising editing efficiency. We developed a novel GBE called TaC9-GBEYE1, which utilizes the deaminase and UNG-nCas9 guided by TALE and sgRNA, respectively. TaC9-GBEYE1 showed comparable levels of on-target editing efficiency to traditional GBE at 19 target sites, without any off-target effects caused by Cas9 or TALE. The TaC9-GBEYE1 is a safe tool for gene therapy.

Recent Developments in the Role of Protein Tyrosine Phosphatase 1B (PTP1B) as a Regulator of Immune Cell Signalling in Health and Disease.

Protein tyrosine phosphatase 1B (PTP1B) is a non-receptor tyrosine phosphatase best known for its role in regulating insulin and leptin signalling. Recently, knowledge on the role of PTP1B as a major regulator of multiple signalling pathways involved in cell growth, proliferation, viability and metabolism has expanded, and PTP1B is recognised as a therapeutic target in several human disorders, including diabetes, obesity, cardiovascular diseases and hematopoietic malignancies. The function of PTP1B in the immune system was largely overlooked until it was discovered that PTP1B negatively regulates the Janus kinase-a signal transducer and activator of the transcription (JAK/STAT) signalling pathway, which plays a significant role in modulating immune responses. PTP1B is now known to determine the magnitude of many signalling pathways that drive immune cell activation and function. As such, PTP1B inhibitors are being developed and tested in the context of inflammation and autoimmune diseases. Here, we provide an up-to-date summary of the molecular role of PTP1B in regulating immune cell function and how targeting its expression and/or activity has the potential to change the outcomes of immune-mediated and inflammatory disorders.

Depletion of TDP-43 exacerbates tauopathy-dependent brain atrophy by sensitizing vulnerable neurons to caspase 3-mediated endoproteolysis of tau in a mouse model of Multiple Etiology Dementia.

TDP-43 proteinopathy, initially disclosed in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), coexists with tauopathy in a variety of neurodegenerative disorders, termed multiple etiology dementias (MEDs), including Alzheimer's Disease (AD). While such co-pathology of TDP-43 is strongly associated with worsened neurodegeneration and steeper cognitive decline, the pathogenic mechanism underlying the exacerbated neuron loss remains elusive. The loss of TDP-43 splicing repression that occurs in presymptomatic ALS-FTD individuals suggests that such early loss could facilitate the pathological conversion of tau to accelerate neuron loss. Here, we report that the loss of TDP-43 repression of cryptic exons in forebrain neurons (CaMKII-CreER;Tardbp f/f mice) is necessary to exacerbate tauopathy-dependent brain atrophy by sensitizing vulnerable neurons to caspase 3-dependent cleavage of endogenous tau to promote tauopathy. Corroborating this finding within the human context, we demonstrate that loss of TDP-43 function in iPSC-derived cortical neurons promotes early cryptic exon inclusion and subsequent caspase 3-mediated endoproteolysis of tau. Using a genetic approach to seed tauopathy in CaMKII-CreER;Tardbp f/f mice by expressing a four-repeat microtubule binding domain of human tau, we show that the amount of tau seed positively correlates with levels of caspase 3-cleaved tau. Importantly, we found that the vulnerability of hippocampal neurons to TDP-43 depletion is dependent on the amount of caspase 3-cleaved tau: from most vulnerable neurons in the CA2/3, followed by those in the dentate gyrus, to the least in CA1. Taken together, our findings strongly support the view that TDP-43 loss-of-function exacerbates tauopathy-dependent brain atrophy by increasing the sensitivity of vulnerable neurons to caspase 3-mediated endoproteolysis of tau, resulting in a greater degree of neurodegeneration in human disorders with co-pathologies of tau and TDP-43. Our work thus discloses novel mechanistic insights and therapeutic targets for human tauopathies harboring co-pathology of TDP-43 and provides a new MED model for testing therapeutic strategies.

Evolutionary and biomedical implications of sex differences in the primate brain transcriptome

Humans exhibit sex differences in the prevalence of many neurodevelopmental disorders and neurodegenerative diseases. Here, we generated one of the largest multi-brain-region bulk transcriptional datasets for the rhesus macaque and characterized sex-biased gene expression patterns to investigate the translatability of this species for sex-biased neurological conditions. We identify patterns similar to those in humans, which are associated with overlapping regulatory mechanisms, biological processes, and genes implicated in sex-biased human disorders, including autism. We also show that sex-biased genes exhibit greater genetic variance for expression and more tissue-specific expression patterns, which may facilitate rapid evolution of sex-biased genes. Our findings provide insights into the biological mechanisms underlying sex-biased disease and support the rhesus macaque model for the translational study of these conditions.

Geneapp: A web application for visualizing alternative splicing for biomedicine

Alternative Splicing (AS) is an essential mechanism for eukaryotes. However, the consequences of deleting a single exon can be dramatic for the organism and can lead to cancer in humans. Additionally, alternative 5′ and 3′ splice sites, which define the boundaries of exons, also play key roles to human disorders. Therefore, Investigating AS events is crucial for understanding the molecular basis of human diseases and developing therapeutic strategies. Workflow for AS event analysis can be sampling followed by data analysis with bioinformatics to identify the different AS events in the control and case samples, data visualization for curation, and selection of relevant targets for experimental validation. The raw output of the analysis software does not favor the inspection of events by bioinformaticians requiring custom scripts for data visualization. In this work, we propose the Geneapp application with three modules: GeneappScript, GeneappServer, and GeneappExplorer. GeneappScript is a wrapper that assists in identifying AS in samples compared in two different approaches, while GeneappServer integrates data from AS analysis already performed by the user. In GeneappExplorer, the user visualizes the previous dataset by exploring AS events in genes with functional annotation. This targeted screens that Geneapp allows to perform helps in the identification of targets for experimental validation to confirm the hypotheses under study. The Geneapp is freely available for non-commercial use at https://geneapp.net to advance research on AS for bioinformatics.

A Study on In-vitro Anti-Inflammatory and Antioxidant Activity of Aqueous Extract of Terminalia chebula

During ancient times, naturally occurring herbs were a remedy for various ailments in the human body. The deciduous trees of Terminalia species are native to south Asia to southeast China, known as black-chebulic myrobalan. Parts of Terminalia chebula are comprehensively used as medicinal properties. Antioxidants play a noteworthy role by hindering the oxidation reaction, which prompts neurodegenerative disorders in humans. Antioxidant and anti-inflammatory qualities originate from plants. T. chebula has lavish phytochemical properties such as tannins, flavones, essential oils, and phenolic compounds, which give rise to countless possessions like anticancer, antibacterial, anti-inflammatory, and antioxidant activity. The antioxidative capacity of T. chebula fruit aqueous extracts have been assessed using the DPPH scrutiny. The purpose of the study is to get an aqueous extract of T. chebula that contains anti-inflammatory and antioxidant compounds. The concentrations were measured by using absorbance at wavelength 517 nm. The aqueous extracts of T. chebula fruits were considered with a 10 to 50 mL range (5 concentrations). Using %inhibition, 55% at the lowest concentration (10 μL) and 84% at high concentration (50 μL) shows antioxidant activity. The active extracts of T. chebula fruits demonstrate the anti-inflammatory effects of using BSA as a reagent. This assay measured the activity using 5 concentrations (10–50 mL). 75% at 10 μL and 90% at 50 μL concentration attained the anti-inflammatory activity. The study exhibits that the higher the concentration, the higher the activity. The extraction of these active compounds has active principles and novel research activities on anti-inflammatory and antioxidant properties..

The roles and mechanisms of the NF-κB signaling pathway in tendon disorders.

Both acute and chronic tendon injuries are the most frequently occurring musculoskeletal diseases in human and veterinary medicine, with a limited repertoire of successful and evidenced-based therapeutic strategies. Inflammation has been suggested as a key driver for the formation of scar and adhesion tissue following tendon acute injury, as well as pathological alternations of degenerative tendinopathy. However, prior efforts to completely block this inflammatory process have yet to be largely successful. Recent investigations have indicated that a more precise targeted approach for modulating inflammation is critical to improve outcomes. The nuclear factor-kappaB (NF-κB) is a typical proinflammatory signal transduction pathway identified as a key factor leading to tendon disorders. Therefore, a comprehensive understanding of the mechanism or regulation of NF-κB in tendon disorders will aid in developing targeted therapeutic strategies for human and veterinary tendon disorders. In this review, we discuss what is currently known about molecular components and structures of basal NF-κB proteins and two activation pathways: the canonical activation pathway and the non-canonical activation pathway. Furthermore, we summarize the underlying mechanisms of the NF-κB signaling pathway in fibrosis and adhesion after acute tendon injury, as well as pathological changes of degenerative tendinopathy in all species and highlight the effect of targeting this signaling pathway in tendon disorders. However, to gain a comprehensive understanding of its mechanisms underlying tendon disorders, further investigations are required. In the future, extensive scientific examinations are warranted to full characterize the NF-κB, the exact mechanisms of action, and translate findings into clinical human and veterinary practice.