Brain-wide correspondence of neuronal epigenomics and distant projections.

Single-cell analyses parse the brain's billions of neurons into thousands of 'cell-type' clusters residing in different brain structures1. Many cell types mediate their functions through targeted long-distance projections allowing interactions between specific cell types. Here we used epi-retro-seq2 to link single-cell epigenomes and cell types to long-distance projections for 33,034 neurons dissected from 32 different regions projecting to 24 different targets (225 source-to-target combinations) across the whole mouse brain. We highlight uses of these data for interrogating principles relating projection types to transcriptomics and epigenomics, and for addressing hypotheses about cell types and connections related to genetics. We provide an overall synthesis with 926 statistical comparisons of discriminability of neurons projecting to each target for every source. We integrate this dataset into the larger BRAIN Initiative Cell Census Network atlas, composed of millions of neurons, to link projection cell types to consensus clusters. Integration with spatial transcriptomics further assigns projection-enriched clusters to smaller source regions than the original dissections. We exemplify this by presenting in-depth analyses of projection neurons from the hypothalamus, thalamus, hindbrain, amygdala and midbrain to provide insights into properties of those cell types, including differentially expressed genes, their associated cis-regulatory elements and transcription-factor-binding motifs, and neurotransmitter use.

Epigenomic diversity of cortical projection neurons in the mouse brain.

Neuronal cell types are classically defined by their molecular properties, anatomy and functions. Although recent advances in single-cell genomics have led to high-resolution molecular characterization of cell type diversity in the brain1, neuronal cell types are often studied out of the context of their anatomical properties. To improve our understanding of the relationship between molecular and anatomical features that define cortical neurons, here we combined retrograde labelling with single-nucleus DNA methylation sequencing to link neural epigenomic properties to projections. We examined 11,827 single neocortical neurons from 63 cortico-cortical and cortico-subcortical long-distance projections. Our results showed unique epigenetic signatures of projection neurons that correspond to their laminar and regional location and projection patterns. On the basis of their epigenomes, intra-telencephalic cells that project to different cortical targets could be further distinguished, and some layer 5 neurons that project to extra-telencephalic targets (L5 ET) formed separate clusters that aligned with their axonal projections. Such separation varied between cortical areas, which suggests that there are area-specific differences in L5 ET subtypes, which were further validated by anatomical studies. Notably, a population of cortico-cortical projection neurons clustered with L5 ET rather than intra-telencephalic neurons, which suggests that a population of L5 ET cortical neurons projects to both targets. We verified the existence of these neurons by dual retrograde labelling and anterograde tracing of cortico-cortical projection neurons, which revealed axon terminals in extra-telencephalic targets including the thalamus, superior colliculus and pons. These findings highlight the power of single-cell epigenomic approaches to connect the molecular properties of neurons with their anatomical and projection properties.

Engineered exosomes for studies in tumor immunology.

Exosomes are a type of extracellular vesicle (EV) with diameters of 30-150 nm secreted by most of the cells into the extracellular spaces and can alter the microenvironment through cell-to-cell interactions by fusion with the plasma membrane and subsequent endocytosis and release of the cargo. Because of their biocompatibility, low toxicity and immunogenicity, permeability (even through the blood-brain barrier (BBB)), stability in biological fluids, and ability to accumulate in the lesions with higher specificity, investigators have started making designer's exosomes or engineered exosomes to carry biologically active protein on the surface or inside the exosomes as well as using exosomes to carry drugs, micro RNA, and other products to the site of interest. In this review, we have discussed biogenesis, markers, and contents of various exosomes including exosomes of immune cells. We have also discussed the current methods of making engineered and designer's exosomes as well as the use of engineered exosomes targeting different immune cells in the tumors, stroke, as well as at peripheral blood. Genetic engineering and customizing exosomes create an unlimited opportunity to use in diagnosis and treatment. Very little use has been discovered, and we are far away to reach its limits.

Adenosine A2A receptor blockade prevents cisplatin-induced impairments in neurogenesis and cognitive function.

Chemotherapy-induced cognitive impairment (CICI) has emerged as a significant medical problem without therapeutic options. Using the platinum-based chemotherapy cisplatin to model CICI, we revealed robust elevations in the adenosine A2A receptor (A2AR) and its downstream effectors, cAMP and CREB, by cisplatin in the adult mouse hippocampus, a critical brain structure for learning and memory. Notably, A2AR inhibition by the Food and Drug Administration-approved A2AR antagonist KW-6002 prevented cisplatin-induced impairments in neural progenitor proliferation and dendrite morphogenesis of adult-born neurons, while improving memory and anxiety-like behavior, without affecting tumor growth or cisplatin's antitumor activity. Collectively, our study identifies A2AR signaling as a key pathway that can be therapeutically targeted to prevent cisplatin-induced cognitive impairments.

Morbidity and mortality of common femoral endarterectomy.

OBJECTIVE: Common femoral endarterectomy (CFE) comprises the current standard-of-care for symptomatic common femoral artery occlusive disease. Although it provides effective inflow revascularization via a single incision, it remains an invasive procedure in an often-frail patient population. The purpose of this retrospective clinical study was to assess the morbidity and mortality of CFE in a contemporary cohort. METHODS: Consecutive CFEs performed at a large, urban hospital were reviewed. Six-month mortality, local complications (hematoma, lymphatic leak, pseudoaneurysm, wound infection, and/or dehiscence), and systemic complications were analyzed using univariate and multivariate analyses. RESULTS: A total of 129 isolated CFEs were performed over 7 years for claudication (36%), rest pain (16%), tissue loss (29%), or acute on chronic limb ischemia (21%). Mean age was 75 ± 9 years, and 68% of patients were male. Comorbidities were prevalent, including coronary artery disease (54%), diabetes (41%), chronic pulmonary disease (25%), and congestive heart failure (22%). The majority of CFEs were performed under general anesthesia (98%) with patch angioplasty using bovine pericardium (73% vs 27% Dacron). Twenty-two patients (17%) sustained local complications following the procedure; their occurrence was significantly associated with obesity (P = .002) but no technical or operative factors. Nineteen patients (15%) sustained serious systemic complications; their occurrence was significantly associated with chronic limb-threatening ischemia (P < .001), and a high American Society of Anesthesiologists (ASA) class (P = .002). By 6 months, 17 patients (13%) had died. Being on dialysis, presenting with chronic limb-threatening ischemia, and being in a high ASA class at the time of operation were all associated with 6-month mortality; a high ASA class at the time of operation was independently predictive of mortality (odds ratio, 3.08; 95% confidence interval, 1.03-9.24; P = .044). CONCLUSIONS: Although commonly performed, CFE is not a benign vascular procedure. Disease presentation, anesthetic risk, and expected longevity play an important role in clinical outcomes. Evolving endovascular approaches to the common femoral artery could serve to reduce morbidity and mortality in the future.

Perovskenes: two-dimensional perovskite-type monolayer materials predicted by first-principles calculations.

Inspired by the successful transfer of freestanding ultrathin films of SrTiO3 and BiFeO3 onto various substrates without any thickness limitation, in this study, using density functional theory (DFT), we assessed the structural stability of a group of two-dimensional perovskite-type materials which we call perovskenes. Specifically, we analyzed the stability of 2D SrTiO3, SrZrO3, BaTiO3, and BaZrO3 monolayers. Our simulations revealed that the 2D monolayers of SrTiO3, BaTiO3, and BaZrO3 are at least meta-stable, as confirmed by cohesive energy calculations, evaluation of elastic constants, and simulation of phonon dispersion modes. With this information, we proceeded to investigate the electronic, optical, and thermoelectric properties of these perovskenes. To gain insight into their promising applications, we investigated the electronic and optical properties of these 2D materials and found that they are wide bandgap semiconductors with significant absorption and reflection in the ultraviolet (UV) region of the electromagnetic field, suggesting them as promising materials for use in UV shielding applications. In addition, evaluating their thermoelectric factors revealed that these materials become better conductors of electricity and heat as the temperature rises. They can, hence, convert temperature gradients into electrical energy and transport electrical charges, which is beneficial for efficient power generation in thermoelectric devices. This work opens a new window for designing a novel family of 2D perovskite type materials termed perovskenes. The vast variety of different perovskite compounds and their variety of applications suggest deeper studies on the perovskenes materials for use in innovative technologies.

Thiazolobenzamide-Naphthalene Hybrids as Potent Anticancer agents compared to Doxorubicin: Design, Synthesis, SAR, In-silico and Toxicity Analysis.

In order to determine whether thiazolobenzamide molecules connected to naphthalene could inhibit the growth of three different tumor cell lines, MCF7 (breast carcinoma), A549 (pulmonary carcinoma), and DU145 (prostatic adenocarcinoma) a novel series of ten molecules, designated TA 1-10, was designed, synthesized, and tested. Among these compounds, TA7 showed promising results against cell lines, especially showing exceptional efficacy against breast cancer. Antioxidant activity tests consistently showed the best performance from the TA7 molecule. Furthermore, when a dose of 50 to 500 mg/kg of the total mass of rats is given, the most effective chemical, TA7, did not exhibit any harmful effects during acute oral toxicity tests. The biochemical indicators (SGOT and SGPT) for hepatotoxicity associated with compound TA7 were found to be fairly similar to those of the control group. The findings from molecular docking, XP visualization, and MM-GBSA dG binding investigations are in agreement with the outcomes of in-vitro tests of antioxidant and anticancer capabilities. TA7 was the most effective compound among those that were docked; it bound free energy and had adequate properties for metabolism (biochemical processes), distribution (dispersion), absorption (assimilation), and excretion (elimination). This study found that the TA7 molecule, a thiazole ring system derivative connected to naphthalene, is to be a promising and possible anticancer agent and its efficacy may be further explored in clinical studies.

Significance of Triazole in Medicinal Chemistry: Advancement in Drug Design, Reward and Biological Activity.

One of the triazole tautomers, 1,2,4-triazole derivatives, has a wide range of biological activities that suggest its potential therapeutic utility in medicinal chemistry. These actions include anti-inflammatory, anti-cancer, anti-bacterial, anti-tuberculosis, and anti-diabetic effects. Using computational simulations and models, we investigate the structure-activity relationships of 1,2,4-triazoles, showing how various modifications to the triazole core yield a variety of clinical therapeutic benefits. The review highlights the anti-inflammatory effect of 1,2,4-triazoles in relation to their ability to disrupt significant inflammatory mediators and pathways. We present in-silico data that illuminate the triazoles' capacity to inhibit cell division, encourage apoptosis, and stop metastasis in a range of cancer models. This review looks at the bactericidal and bacteriostatic properties of 1,2,4-triazole derivatives, with a focus on their potential efficacy against multi-drug resistant bacterial infections and their usage in tuberculosis therapy. In order to better understand these substances' potential anti-diabetic benefits, this review also looks at how they affect glucose metabolism regulation and insulin responsiveness. Coordinated efforts are required to translate the efficacy of 1,2,4-triazole compounds in preclinical models into practical therapeutic benefits. Based on the information provided, it can be concluded that 1,2,4-triazole derivatives are a promising class of diverse therapeutic agents with potential utility in a range of disorders. Their development and improvement might herald a new era of medical care that will be immensely advantageous to both patients and the medical community as a whole. This comprehensive research, which is further reinforced by in-silico investigations, highlights the great medicinal potential of 1,2,4-triazoles. Additionally, this study encourages more research into these substances and their enhancement for use in pharmaceutical development.

A simple, inexpensive and portable on-farm test for pregnancy diagnosis and ovary status in cows via chemical analysis of urine.

Ovary dysfunction causes an aberrant endocrine surge at various reproductive cycle stages, negatively impacting fertility and economic profit. Optimizing dairy cow performance requires determining ovarian status and detecting early pregnancy. Still, little to no information is available about the diagnosis of the ovarian condition using urine chemical analysis at the field level in Bangladesh. This study aimed to develop a simple, inexpensive and portable on-farm technique for pregnancy diagnosis and ovary status determination in cows via chemical urine analysis. Fifty reproductively healthy cows were recruited from different donor farms. Prior to artificial insemination (AI), all selected cows were placed in a single ovsynch program. TAI (timed artificial insemination) was carried out. Urine was routinely collected from Day 0-55 days at estrus cycle stages for routine chemical analysis using barium chloride (BaCl2), followed by commercially available protein strip tests. The developed techniques for pregnancy and ovary status diagnosis in cows were validated with rectal palpation (RP). Barium chloride (BaCl2) analysis of urine revealed white precipitation corresponding to a mature follicle in the ovary during estrus and colorless precipitation corresponding to the corpus luteum during the diestrus period. Positive pregnancy was indicated by the presence of a colorless precipitate in the BaCl2 test, and a protein value of less than 100 mg/dl was found in the protein strip test. The maximum accuracy (42/50, 84%) was observed between 25 and 35 days, as confirmed by RP. Perplexing results were seen 45-55 days after AI, between pregnancies and luteal cystic disease. In both cases, we discovered that the BaCl2 precipitation was colorless. However, the protein value in the context of luteal cystic disease was found to be higher than 100 mg/dl. The barium chloride test, followed by protein strip tests, is a simple and portable way to diagnose pregnancy and determine ovarian status in cows at the field level.

Nanotechnology Approaches for Prevention and Treatment of Chemotherapy-Induced Neurotoxicity, Neuropathy, and Cardiomyopathy in Breast and Ovarian Cancer Survivors.

Nanotechnology has emerged as a promising approach for the targeted delivery of therapeutic agents while improving their efficacy and safety. As a result, nanomaterial development for the selective targeting of cancers, with the possibility of treating off-target, detrimental sequelae caused by chemotherapy, is an important area of research. Breast and ovarian cancer are among the most common cancer types in women, and chemotherapy is an essential treatment modality for these diseases. However, chemotherapy-induced neurotoxicity, neuropathy, and cardiomyopathy are common side effects that can affect breast and ovarian cancer survivors quality of life. Therefore, there is an urgent need to develop effective prevention and treatment strategies for these adverse effects. Nanoparticles (NPs) have extreme potential for enhancing therapeutic efficacy but require continued research to elucidate beneficial interventions for women cancer survivors. In short, nanotechnology-based approaches have emerged as promising strategies for preventing and treating chemotherapy-induced neurotoxicity, neuropathy, and cardiomyopathy. NP-based drug delivery systems and therapeutics have shown potential for reducing the side effects of chemotherapeutics while improving drug efficacy. In this article, the latest nanotechnology approaches and their potential for the prevention and treatment of chemotherapy-induced neurotoxicity, neuropathy, and cardiomyopathy in breast and ovarian cancer survivors are discussed.

Risk factors for disease severity among children with Covid-19: a clinical prediction model.

BACKGROUND: Children account for a significant proportion of COVID-19 hospitalizations, but data on the predictors of disease severity in children are limited. We aimed to identify risk factors associated with moderate/severe COVID-19 and develop a nomogram for predicting children with moderate/severe COVID-19. METHODS: We identified children ≤ 12 years old hospitalized for COVID-19 across five hospitals in Negeri Sembilan, Malaysia, from 1 January 2021 to 31 December 2021 from the state's pediatric COVID-19 case registration system. The primary outcome was the development of moderate/severe COVID-19 during hospitalization. Multivariate logistic regression was performed to identify independent risk factors for moderate/severe COVID-19. A nomogram was constructed to predict moderate/severe disease. The model performance was evaluated using the area under the curve (AUC), sensitivity, specificity, and accuracy. RESULTS: A total of 1,717 patients were included. After excluding the asymptomatic cases, 1,234 patients (1,023 mild cases and 211 moderate/severe cases) were used to develop the prediction model. Nine independent risk factors were identified, including the presence of at least one comorbidity, shortness of breath, vomiting, diarrhea, rash, seizures, temperature on arrival, chest recessions, and abnormal breath sounds. The nomogram's sensitivity, specificity, accuracy, and AUC for predicting moderate/severe COVID-19 were 58·1%, 80·5%, 76·8%, and 0·86 (95% CI, 0·79 - 0·92) respectively. CONCLUSION: Our nomogram, which incorporated readily available clinical parameters, would be useful to facilitate individualized clinical decisions.

Human Variation in Error-Based and Reinforcement Motor Learning Is Associated With Entorhinal Volume.

Error-based and reward-based processes are critical for motor learning and are thought to be mediated via distinct neural pathways. However, recent behavioral work in humans suggests that both learning processes can be bolstered by the use of cognitive strategies, which may mediate individual differences in motor learning ability. It has been speculated that medial temporal lobe regions, which have been shown to support motor sequence learning, also support the use of cognitive strategies in error-based and reinforcement motor learning. However, direct evidence in support of this idea remains sparse. Here we first show that better overall learning during error-based visuomotor adaptation is associated with better overall learning during the reward-based shaping of reaching movements. Given the cognitive contribution to learning in both of these tasks, these results support the notion that strategic processes, associated with better performance, drive intersubject variation in both error-based and reinforcement motor learning. Furthermore, we show that entorhinal cortex volume is larger in better learning individuals-characterized across both motor learning tasks-compared with their poorer learning counterparts. These results suggest that individual differences in learning performance during error and reinforcement learning are related to neuroanatomical differences in entorhinal cortex.

Prodrug Rewards in Medicinal Chemistry: An Advance and Challenges Approach for Drug Designing.

This article emphasizes the importance of prodrugs and their diverse spectrum of effects in the field of developing novel drugs for a variety of biological applications. Prodrugs are chemicals that are supplied inactively, but then go through enzymatic and chemical transformation in vivo to release the active parent medication that can have the desired pharmacological effect. By adding an inactive chemical moiety, prodrugs are improved in a number of ways that contribute to their potency and durability. For the purpose of illustrating the usefulness of the prodrug approach, this review covers examples of prodrugs that have been made available or are now undergoing human trials. Additionally, it included lists of the most common functional groups, carrier linkers, and reactive chemicals that can be used to create prodrugs. The current study also provides a brief introduction, several chemical methods and modifications for creating prodrugs and mutual prodrugs, as well as an explanation of recent advancements and difficulties in the field of prodrug design. The primary chemical carriers employed in the creation of prodrugs, such as esters, amides, imides, NH-acidic carriers, amines, alcohols, carbonyl, carboxylic, and azo-linkages, are also discussed. This review also discusses glycosidic and triglyceride mutually activated prodrugs, which aim to deliver the drugs after bioconversion at the intended site of action. The article also discusses the extensive chemistry and wide variety of applications of recently approved prodrugs, such as antibacterial, anti-inflammatory, cardiovascular, antiplatelet, antihypertensive, atherosclerotic, antiviral, etc. In order to illustrate the prodrug and mutual drug concept's various applications and highlight its many triumphs in overcoming the formulation and delivery of problematic pharmaceuticals, this work represents a thorough guide that includes the synthetic moiety for the reader.

Phytochemical and Biological Investigation of an Indigenous Plant of Bangladesh, Gynura procumbens (Lour.) Merr.: Drug Discovery from Nature.

Gynura procumbens (Lour.) Merr. (Family: Asteraceae) is a tropical Asian medicinal plant found in Thailand, China, Malaysia, Indonesia, and Vietnam. It has long been utilized to treat a variety of health concerns in numerous countries around the world, such as renal discomfort, constipation, diabetes mellitus, rheumatism, and hypertension. The chemical investigation resulted in the isolation and characterization of six compounds from the methanol (MeOH) extract of the leaves of Gynura procumbens, which were identified as phytol (1), lupeol (2), stigmasterol (3), friedelanol acetate (4), ß-amyrin (5), and a mixture of stigmasterol and ß-sitosterol (6). In-depth investigations of the high-resolution 1H NMR and 13C NMR spectroscopic data from the isolated compounds, along with comparisons to previously published data, were used to clarify their structures. Among these, the occurrence of Compounds 1 and 4 in this plant are reported for the first time. The crude methanolic extract (CME) and its different partitionates, i.e., petroleum ether (PESF), chloroform (CSF), ethyl acetate (EASF), and aqueous (AQSF) soluble fractions, were subjected to antioxidant, cytotoxic, thrombolytic, and anti-diabetic activities. In a DPPH free radical scavenging assay, EASF showed the maximum activity, with an IC50 value of 10.78 µg/mL. On the other hand, CSF displayed the highest cytotoxic effect with an LC50 value of 1.94 µg/mL compared to 0.464 µg/mL for vincristine sulphate. In a thrombolytic assay, the crude methanolic extract exhibited the highest activity (63.77%) compared to standard streptokinase (70.78%). During the assay for anti-diabetic activity, the PESF showed 70.37% of glucose-lowering activity, where standard glibenclamide showed 63.24% of glucose-reducing activity.

The link of ERCC2 rs13181 and ERCC4 rs2276466 polymorphisms with breast cancer in the Bangladeshi population.

BACKGROUND: Breast cancer (BC) is the most common disease in women and the leading cause of death from cancer globally. Epidemiological studies examined that nucleotide excision repair genes ERCC2 (rs13181) and ERCC4 (rs2276466) SNPs might increase cancer risk. Based on the previous investigation, this study was conducted to explore the correlation between these polymorphisms and BC susceptibility in Bangladeshi women. METHODS AND RESULTS: Between January 2019 and January 2020, 140 blood samples were collected from female patients histologically diagnosed with BC, and 111 female controls were recruited from non-cancer subjects. Genotyping was performed applying the PCR-RFLP method, and all statistical analyzes were conducted using SPSS, version 25.0. Comparison of characteristics and clinicopathological features between ERCC2 rs13181 and ERCC4 rs2276466 carriers and non-carriers showed no significant link with BC. Analysis of ERCC2 rs13181 with the risk of BC showed that the GG genotype and G allele carriers showed a fourfold and 1.78-fold higher risk (OR 4.00, P = 0.001 and OR 1.78, P = 0.002) that are statistically significant. In addition, the patients with combined TG+GG genotype revealed a 2.09-fold increased chance (OR 2.09, P = 0.020) BC development. Analysis of recessive model (GG vs. TT+TG) also depicted 2.74-times significantly higher risk (OR 2.74, P = 0.002). On the other hand, ERCC4 rs2276466 polymorphism did not show any significant association with BC (P > 0.05). CONCLUSIONS: Our findings show that ERCC2 rs13181 is linked to an elevated risk of BC. Our study also shows that ERCC4 rs2276466 polymorphism has no substantial risk of BC in the Bangladeshi population.

Systemic interleukin-6 inhibition ameliorates acute neuropsychiatric phenotypes in a murine model of acute lung injury.

Acute neuropsychiatric impairments occur in over 70% of patients with acute lung injury. Mechanical ventilation is a well-known precipitant of acute lung injury and is strongly associated with the development of acute delirium and anxiety phenotypes. In prior studies, we demonstrated that IL-6 mediates neuropathological changes in the frontal cortex and hippocampus of animals with mechanical ventilation-induced brain injury; however, the effect of systemic IL-6 inhibition on structural and functional acute neuropsychiatric phenotypes is not known. We hypothesized that a murine model of mechanical ventilation-induced acute lung injury (VILI) would induce neural injury to the amygdala and hippocampus, brain regions that are implicated in diverse neuropsychiatric conditions, and corresponding delirium- and anxiety-like functional impairments. Furthermore, we hypothesized that these structural and functional changes would reverse with systemic IL-6 inhibition. VILI was induced using high tidal volume (35 cc/kg) mechanical ventilation. Cleaved caspase-3 (CC3) expression was quantified as a neural injury marker and found to be significantly increased in the VILI group compared to spontaneously breathing or anesthetized and mechanically ventilated mice with 10 cc/kg tidal volume. VILI mice treated with systemic IL-6 inhibition had significantly reduced amygdalar and hippocampal CC3 expression compared to saline-treated animals and demonstrated amelioration in acute neuropsychiatric behaviors in open field, elevated plus maze, and Y-maze tests. Overall, these data provide evidence of a pathogenic role of systemic IL-6 in mediating structural and functional acute neuropsychiatric symptoms in VILI and provide preclinical justification to assess IL-6 inhibition as a potential intervention to ameliorate acute neuropsychiatric phenotypes following VILI.

Experimental Performance Analysis of a Scalable Distributed Hyperledger Fabric for a Large-Scale IoT Testbed.

Blockchain technology, with its decentralization characteristics, immutability, and traceability, is well-suited for facilitating secure storage, sharing, and management of data in decentralized Internet of Things (IoT) applications. Despite the increasing development of blockchain platforms, there is still no comprehensive approach for adopting blockchain technology in IoT systems. This is due to the blockchain's limited capability to process substantial transaction requests from a massive number of IoT devices. Hyperledger Fabric (HLF) is a popular open-source permissioned blockchain platform hosted by the Linux Foundation. This article reports a comprehensive empirical study that measures HLF's performance and identifies potential performance bottlenecks to better meet the requirements of blockchain-based IoT applications. The study considers the implementation of HLF on distributed large-scale IoT systems. First, a model for monitoring the performance of the HLF platform is presented. It addresses the overhead challenges while delivering more details on system performance and better scalability. Then, the proposed framework is implemented to evaluate the impact of varying network workloads on the performance of the blockchain platform in a large-scale distributed environment. In particular, the performance of the HLF is evaluated in terms of throughput, latency, network size, scalability, and the number of peers serviceable by the platform. The obtained experimental results indicate that the proposed framework can provide detailed real-time performance evaluation of blockchain systems for large-scale IoT applications.

Ethnobotanical Uses, Phytochemistry, Toxicology, and Pharmacological Properties of Euphorbia neriifolia Linn. against Infectious Diseases: A Comprehensive Review.

Medicinal plants have considerable potential as antimicrobial agents due to the presence of secondary metabolites. This comprehensive overview aims to summarize the classification, morphology, and ethnobotanical uses of Euphorbia neriifolia L. and its derived phytochemicals with the recent updates on the pharmacological properties against emerging infectious diseases, mainly focusing on bacterial, viral, fungal, and parasitic infections. The data were collected from electronic databases, including Google Scholar, PubMed, Semantic Scholar, ScienceDirect, and SpringerLink by utilizing several keywords like 'Euphorbia neriifolia', 'phytoconstituents', 'traditional uses', 'ethnopharmacological uses', 'infectious diseases', 'molecular mechanisms', 'COVID-19', 'bacterial infection', 'viral infection', etc. The results related to the antimicrobial actions of these plant extracts and their derived phytochemicals were carefully reviewed and summarized. Euphol, monohydroxy triterpene, nerifoliol, taraxerol, ß-amyrin, glut-5-(10)-en-1-one, neriifolione, and cycloartenol are the leading secondary metabolites reported in phytochemical investigations. These chemicals have been shown to possess a wide spectrum of biological functions. Different extracts of E. neriifolia exerted antimicrobial activities against various pathogens to different extents. Moreover, major phytoconstituents present in this plant, such as quercetin, rutin, friedelin, taraxerol, epitaraxerol, taraxeryl acetate, 3ß-friedelanol, 3ß-acetoxy friedelane, 3ß-simiarenol, afzelin, 24-methylene cycloarenol, ingenol triacetate, and ß-amyrin, showed significant antimicrobial activities against various pathogens that are responsible for emerging infectious diseases. This plant and the phytoconstituents, such as flavonoids, monoterpenoids, diterpenoids, triterpenoids, and alkaloids, have been found to have significant antimicrobial properties. The current evidence suggests that they might be used as leads in the development of more effective drugs to treat emerging infectious diseases, including the 2019 coronavirus disease (COVID-19).

Chemical and Pharmacological Profiling of Wrightia coccinea (Roxb. Ex Hornem.) Sims Focusing Antioxidant, Cytotoxic, Antidiarrheal, Hypoglycemic, and Analgesic Properties.

The aim of the study was to conduct phytochemical and pharmacological investigations of Wrightia coccinea (Roxb. ex Hornem.) Sims via several in vitro, in vivo, and in silico models. A total of four compounds were identified and isolated from the methanol extract of the bark and the methanol extract of the seed pulp of W. coccinea through successive chromatographic techniques and were characterized as 3ß-acetyloxy-olean-12-en-28-ol (1), wrightiadione (2), 22ß-hydroxylupeol (3), and ß-sitosterol (4) by spectroscopic analysis. The aqueous fraction of the bark and chloroform fraction of the fruits provided the most potent antioxidant capacity (IC50 = 7.22 and 4.5 µg/mL, respectively) in DPPH free radical scavenging assay compared with the standard ascorbic acid (IC50 = 17.45 µg/mL). The methanol bark extract and the methanol fruit coat extract exerted anti-diarrheal activity by inhibiting 74.55 ± 0.67% and 77.78 ± 1.5% (mean ± SEM) of the diarrheal episode in mice, respectively, after four hours of loading the samples. In the hypoglycemic test, the methanol bark extract and the methanol fruit coat extract (400 mg/kg) produced a significant (p < 0.05) reduction in the blood glucose level in mice. Both doses of the plant extracts (200 mg/kg and 400 mg/kg) used in the study induced a significant (p < 0.05) increase in pain reaction time. The in vitro and in vivo findings were supported by the computational studies. The isolated compounds exhibited higher binding affinity compared with the standard drugs towards the active binding sites of glutathione reductase, epidermal growth factor receptor (EGFR), kappa opioid receptor, glucose transporter 3 (GLUT 3), Mu opioid receptor, and cyclooxygenase 2 (COX-2) proteins due to their potent antioxidant, cytotoxic, anti-diarrheal, hypoglycemic, and central and peripheral analgesic properties, respectively. The current findings concluded that W. coccinea might be a potential natural source for managing oxidative stress, diarrhea, hyperglycemia, and pain. Further studies are warranted for extensively phytochemical screening and establishing exact mechanisms of action.

Phenolic Constituents from Wendlandia tinctoria var. grandis (Roxb.) DC. Stem Deciphering Pharmacological Potentials against Oxidation, Hyperglycemia, and Diarrhea: Phyto-Pharmacological and Computational Approaches.

Wendlandia tinctoria var. grandis (Roxb.) DC. (Family: Rubiaceae) is a semi-evergreen shrub distributed over tropical and subtropical Asia. The present research intended to explore the pharmacological potential of the stem extract of W. tinctoria, focusing on the antioxidant, hypoglycemic, and antidiarrheal properties, and to isolate various secondary metabolites as mediators of such activities. A total of eight phenolic compounds were isolated from the dichloromethane soluble fraction of the stem extract of this plant, which were characterized by electrospray ionization (ESI) mass spectrometric and 1H NMR spectroscopic data as liquiritigenin (1), naringenin (2), apigenin (3), kaempferol (4), glabridin (5), ferulic acid (6), 4-hydroxybenzoic acid (7), and 4-hydroxybenzaldehyde (8). The dichloromethane soluble fraction exhibited the highest phenolic content (289.87 ± 0.47 mg of GAE/g of dried extract) and the highest scavenging activity (IC50 = 18.83 ± 0.07 µg/mL) against the DPPH free radical. All of the isolated compounds, except 4-hydroxybenzaldehyde, exerted a higher antioxidant effect (IC50 = 6.20 ± 0.10 to 16.11 ± 0.02 µg/mL) than the standard butylated hydroxytoluene (BHT) (IC50 = 17.09 ± 0.01 µg/mL). Significant hypoglycemic and antidiarrheal activities of the methanolic crude extract at both doses (200 mg/kg bw and 400 mg/kg bw) were observed in a time-dependent manner. Furthermore, the computational modeling study supported the current in vitro and in vivo findings, and the isolated constituents had a higher or comparable binding affinity for glutathione reductase and urase oxidase enzymes, glucose transporter 3 (GLUT 3), and kappa-opioid receptor, inferring potential antioxidant, hypoglycemic, and antidiarrheal properties, respectively. This is the first report of all of these phenolic compounds being isolated from this plant species and even the first demonstration of the plant stem extract's antioxidant, hypoglycemic, and antidiarrheal potentials. According to the current findings, the W. tinctoria stem could be a potential natural remedy for treating oxidative stress, hyperglycemia, and diarrhea. Nevertheless, further extensive investigation is crucial for thorough phytochemical screening and determining the precise mechanisms of action of the plant-derived bioactive metabolites against broad-spectrum molecular targets.