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Th is study offers empirical insights into investor behavior and its correlation with various behavioral biases in the context of investment decisions in the Pakistan Stock Exchange (PSX). Data was collected through a structured questionnaire from 261 individual investors in Pakistan. The study employs hierarchical regression analysis to test the hypothesis. It considers several behavioral biases, and statistically, anchoring and adjustment, overconfidence, and herding show a significant impact. The study uses financial literacy to examine its moderating effects on these biases, and the result suggests that it significantly influences behavioral biases related to investment decisions. The results underscore the unique investment behaviors in emerging markets, contrasting with established norms in well-developed financial markets. These findings can inform policymakers and stock market authorities about investor decision-making in emerging economies. more...

This study explains workplace conflicts (interpersonal and task-related) as antecedents of knowledge-hiding behaviors. Moreover, a relational psychological contract breach is a mediator between workplace conflicts and knowledge-hiding behavior. For empirical evidence, data were collected from research and development institutions in Pakistan. The results confirm the significant association between conflicts and knowledge-hiding behaviors and the mediating role of relational psychological contract breach.The objective of this study is to investigate the impact of workplace conflicts (interpersonal conflict and task-related conflict) on knowledge-hiding behaviors (evasive hiding, playing dumb, and rationalized hiding). Besides, a relational psychological contract breach is used as a mediator between workplace conflicts and knowledge-hiding behaviors. By using a simple random sampling technique and time lag strategy, the data were collected from 408 employees working in research and development institutions in Pakistan. For analyses, this study employed partial least squares structural equation modeling statistical technique by using SmartPls-3 software. The results of the study confirm the significant relationship between workplace conflicts and knowledge-hiding behaviors. Relational psychological contract breach also significantly mediates the relationship between conflicts and knowledge-hiding behaviors. However, this study found an insignificant association between interpersonal conflict and evasive knowledge hiding. more...

This study investigates the impact of financial development and economic growth on energy consumption by controlling variables such as urbanization and globalization in developing countries of Asia for the era of 1991-2019. Data related to financial development, economic growth, energy consumption and urbanization is collected from World Development Indicator and data related to globalization is collected from Konjunkturforschungsstelle (KOF) index of globalization. In this research Dynamic seemingly unrelated regression model is applied to test the hypothesis. According to the outcomes of DSUR the impact of financial development on energy consumption is positively substantial as increase of 1 unit in financial development brings 3.07% rise in energy consumption, the effect of GDP on energy consumption is positively influential as increase of 1 unit in GDP brings 0.29% increase in energy consumption and the influence of globalization is unfavorable but substantial as increase of 1 unit in globalization brings decrease of 15.57% in energy consumption. Moreover, the influence of urbanization on energy consumption is positive and considerable, as increase of 1 unit in urbanization brings 11.54% increase in energy consumption. Moreover, there is two way connections among GDP and financial development. Moreover, Asian countries should adopt energy conservation policies. more...

The present study shows that environmental degradation and environmental sustainability are two distinct domains of environmental quality. Regrettably, existing researchers interpret the impact of different factors on environmental sustainability as their findings are based on the explicit measure of the environment (CO2 or GHG emissions). Therefore, this study contributes to the ongoing environment debate by analyzing the role of human capital, information communication technologies, and research and development expenditures on environmental sustainability. The study further tests financial development's moderating role concerning human capital, information communication technologies, R&D expenditures, and environmental sustainability. In this regard, the study collects the annual time series data from the panel of four South Asian Economies (Pakistan, India, Sri Lanka, and Nepal) during 1996-2018 from WDI and Penn world databases. The findings of DOLS show that human capital, information, communication technologies, and R&D expenditures positively contribute to environmental sustainability and financial development, further intensifying the relationship between human capital and environmental sustainability, information and communication technologies, and R&D expenditures environmental sustainability. The study recommends that increasing human capital, information, and communication technologies, R&D expenditures, and financial development play a major role in promoting environmental sustainability more...

This paper aimed to provide empirical evidence on the behavior of the investor toward mutual funds by considering its relationship with risk perception (RP), return perception (Return P), investment criteria (IC), mutual fund awareness (MFA), and financial literacy (FL). Data were collected using a questionnaire from 500 mutual fund investors, from which 460 questionnaires were used for the analysis. In addition, the snowball sampling technique was used to collect data from different cities in Pakistan. The result showed that RP, Return P, and MFA are insignificant and negatively affect the behavior of mutual fund investors. Investment criteria have a negative and significant effect on the behavior of mutual fund investors. Financial literacy has a positive and insignificant effect on the behavior of mutual fund investors. The results provide better information and guidance to investors and policymakers on the factors that affect the behavior of mutual fund investors. more...

The World Health Organization has acknowledged coronavirus disease 2019 (COVID-19) disease as a pandemic. Efforts are being made all over the world to raise awareness to prevent the spread of the disease. The goal of this study was to assess the attitude, perception, and knowledge of Pakistani people toward COVID-19 disease. We conducted a cross-sectional survey in which a questionnaire of 17 questions was transformed online on Google forms and was sent to random individuals online. A total of 1,000 questionnaires from individuals throughout Pakistan were evaluated. The results revealed that 42.9% of the participants knew about COVID-19 through social media, the largest source of information. Most of the participants (48.3%) started working from home amid the lockdown; 39.9% of the participants reported that they wash their hands every hour, and 56.9% participants are using a surgical mask. About thermal scanners, 30.5% of the people answered they may be effective, and 46.0% of the people think COVID-19 is a bioweapon; 59% of the participants think everyone is susceptible, whereas 83.9% of the people recognize fever as a primary symptom; 65.2% of the people are practicing social distancing, whereas 85.1% of the people think social gatherings causes spread of the disease. In general, participants had a good knowledge about the disease and a positive attitude toward protective measures. The effective measures are being taken by the government and the public; still, there remains a need for further awareness campaigns and knowledge of safe interventions to combat the spread of disease. more...

NOise Reduction with DIstribution Corrected (NORDIC) principal component analysis (PCA) has been shown to selectively suppress thermal noise and improve the temporal signal-to-noise ratio (tSNR) in human functional magnetic resonance imaging (fMRI). However, the feasibility to improve data quality for rodent fMRI using NORDIC PCA remains uncertain. NORDIC PCA may also be particularly beneficial for improving topological brain mapping, as conventional mapping requires precise spatiotemporal signals from large datasets (ideally ~1 hour acquisition) for individual representations. In this study, we evaluated the effects of NORDIC PCA compared with "Standard" processing in various rodent fMRI contexts that range from task-evoked optogenetic fMRI to resting-state fMRI. We also evaluated the effects of NORDIC PCA on human resting-state and retinotopic mapping fMRI via population receptive field (pRF) modeling. In rodent optogenetic fMRI, apart from doubling the tSNR, NORDIC PCA resulted in a larger number of activated voxels and a significant decrease in the variance of evoked brain responses without altering brain morphology. In rodent resting-state fMRI, we found that NORDIC PCA induced a nearly threefold increase in tSNR and preserved task-free relative cerebrovascular reactivity (rCVR) across cortical depth. NORDIC PCA further improved the detection of TGN020-induced aquaporin-4 inhibition on rCVR compared with Standard processing without NORDIC PCA. NORDIC PCA also increased the tSNR for both human resting-state and pRF fMRI, and for the latter also increased activation cluster sizes while retaining retinotopic organization. This suggests that NORDIC PCA preserves the spatiotemporal precision of fMRI signals needed for pRF analysis, and effectively captures small activity changes with high sensitivity. Taken together, these results broadly demonstrate the value of NORDIC PCA for the enhanced detection of neural dynamics across various rodent and human fMRI contexts. This can in turn play an important role in improving fMRI image quality and sensitivity for translational and preclinical neuroimaging research., Competing Interests: All authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published under a Creative Commons Attribution 4.0 International (CC BY 4.0) license.) more...

Central insulin resistance, the diminished cellular sensitivity to insulin in the brain, has been implicated in diabetes mellitus, Alzheimer's disease and other neurological disorders. However, whether and how central insulin resistance plays a role in the eye remains unclear. Here, we performed intracerebroventricular injection of S961, a potent and specific blocker of insulin receptor in adult Wistar rats to test if central insulin resistance leads to pathological changes in ocular structures. 80 mg of S961 was stereotaxically injected into the lateral ventricle of the experimental group twice at 7 days apart, whereas buffer solution was injected to the sham control group. Blood samples, intraocular pressure, trabecular meshwork morphology, ciliary body markers, retinal and optic nerve integrity, and whole genome expression patterns were then evaluated. While neither blood glucose nor serum insulin level was significantly altered in the experimental or control group, we found that injection of S961 but not buffer solution significantly increased intraocular pressure at 14 and 24 days after first injection, along with reduced porosity and aquaporin 4 expression in the trabecular meshwork, and increased tumor necrosis factor α and aquaporin 4 expression in the ciliary body. In the retina, cell density and insulin receptor expression decreased in the retinal ganglion cell layer upon S961 injection. Fundus photography revealed peripapillary atrophy with vascular dysregulation in the experimental group. These retinal changes were accompanied by upregulation of pro-inflammatory and pro-apoptotic genes, downregulation of anti-inflammatory, anti-apoptotic, and neurotrophic genes, as well as dysregulation of genes involved in insulin signaling. Optic nerve histology indicated microglial activation and changes in the expression of glial fibrillary acidic protein, tumor necrosis factor α, and aquaporin 4. Molecular pathway architecture of the retina revealed the three most significant pathways involved being inflammation/cell stress, insulin signaling, and extracellular matrix regulation relevant to neurodegeneration. There was also a multimodal crosstalk between insulin signaling derangement and inflammation-related genes. Taken together, our results indicate that blocking insulin receptor signaling in the central nervous system can lead to trabecular meshwork and ciliary body dysfunction, intraocular pressure elevation, as well as inflammation, glial activation, and apoptosis in the retina and optic nerve. Given that central insulin resistance may lead to neurodegenerative phenotype in the visual system, targeting insulin signaling may hold promise for vision disorders involving the retina and optic nerve., Competing Interests: None more...

Background: Socioeconomic status and ethnicity are not explicitly incorporated as risk factors in the four SCORE2 cardiovascular disease (CVD) risk models developed for country-wide implementation across Europe (low, moderate, high and very-high model). The aim of this study was to evaluate the performance of the four SCORE2 CVD risk prediction models in an ethnic and socioeconomic diverse population in the Netherlands., Methods: The SCORE2 CVD risk models were externally validated in socioeconomic and ethnic (by country of origin) subgroups, from a population-based cohort in the Netherlands, with GP, hospital and registry data. In total 155,000 individuals, between 40 and 70 years old in the study period from 2007 to 2020 and without previous CVD or diabetes were included. Variables (age, sex, smoking status, blood pressure, cholesterol) and outcome first CVD event (stroke, myocardial infarction, CVD death) were consistent with SCORE2., Findings: 6966 CVD events were observed, versus 5495 events predicted by the CVD low-risk model (intended for use in the Netherlands). Relative underprediction was similar in men and women (observed/predicted (OE-ratio), 1.3 and 1.2 in men and women, respectively). Underprediction was larger in low socioeconomic subgroups of the overall study population (OE-ratio 1.5 and 1.6 in men and women, respectively), and comparable in Dutch and the combined "other ethnicities" low socioeconomic subgroups. Underprediction in the Surinamese subgroup was largest (OE-ratio 1.9, in men and women), particularly in the low socioeconomic Surinamese subgroups (OE-ratio 2.5 and 2.1 in men and women). In the subgroups with underprediction in the low-risk model, the intermediate or high-risk SCORE2 models showed improved OE-ratios. Discrimination showed moderate performance in all subgroups and the four SCORE2 models, with C-statistics between 0.65 and 0.72, similar to the SCORE2 model development study., Interpretation: The SCORE 2 CVD risk model for low-risk countries (as the Netherlands are) was found to underpredict CVD risk, particularly in low socioeconomic and Surinamese ethnic subgroups. Including socioeconomic status and ethnicity as predictors in CVD risk models and implementing CVD risk adjustment within countries is desirable for adequate CVD risk prediction and counselling., Funding: Leiden University Medical Centre and Leiden University., Competing Interests: All authors declare no competing interests., (© 2023 The Author(s).) more...

Background: Emergence of the new SARS-CoV-2 variant B.1.1.529 worried health policy makers worldwide due to a large number of mutations in its genomic sequence, especially in the spike protein region. The World Health Organization (WHO) designated this variant as a global variant of concern (VOC), which was named "Omicron." Following Omicron's emergence, a surge of new COVID-19 cases was reported globally, primarily in South Africa., Objective: The aim of this study was to understand whether Omicron had an epidemiological advantage over existing variants., Methods: We performed an in silico analysis of the complete genomic sequences of Omicron available on the Global Initiative on Sharing Avian Influenza Data (GISAID) database to analyze the functional impact of the mutations present in this variant on virus-host interactions in terms of viral transmissibility, virulence/lethality, and immune escape. In addition, we performed a correlation analysis of the relative proportion of the genomic sequences of specific SARS-CoV-2 variants (in the period from October 1 to November 29, 2021) with matched epidemiological data (new COVID-19 cases and deaths) from South Africa., Results: Compared with the current list of global VOCs/variants of interest (VOIs), as per the WHO, Omicron bears more sequence variation, specifically in the spike protein and host receptor-binding motif (RBM). Omicron showed the closest nucleotide and protein sequence homology with the Alpha variant for the complete sequence and the RBM. The mutations were found to be primarily condensed in the spike region (n=28-48) of the virus. Further mutational analysis showed enrichment for the mutations decreasing binding affinity to angiotensin-converting enzyme 2 receptor and receptor-binding domain protein expression, and for increasing the propensity of immune escape. An inverse correlation of Omicron with the Delta variant was noted (r=-0.99, P <.001; 95% CI -0.99 to -0.97) in the sequences reported from South Africa postemergence of the new variant, subsequently showing a decrease. There was a steep rise in new COVID-19 cases in parallel with the increase in the proportion of Omicron isolates since the report of the first case (74%-100%). By contrast, the incidence of new deaths did not increase (r=-0.04, P >.05; 95% CI -0.52 to 0.58)., Conclusions: In silico analysis of viral genomic sequences suggests that the Omicron variant has more remarkable immune-escape ability than existing VOCs/VOIs, including Delta, but reduced virulence/lethality than other reported variants. The higher power for immune escape for Omicron was a likely reason for the resurgence in COVID-19 cases and its rapid rise as the globally dominant strain. Being more infectious but less lethal than the existing variants, Omicron could have plausibly led to widespread unnoticed new, repeated, and vaccine breakthrough infections, raising the population-level immunity barrier against the emergence of new lethal variants. The Omicron variant could have thus paved the way for the end of the pandemic., Competing Interests: Conflicts of Interest: None declared., (©Ashutosh Kumar, Adil Asghar, Himanshu N Singh, Muneeb A Faiq, Sujeet Kumar, Ravi K Narayan, Gopichand Kumar, Prakhar Dwivedi, Chetan Sahni, Rakesh K Jha, Maheswari Kulandhasamy, Pranav Prasoon, Kishore Sesham, Kamla Kant, Sada N Pandey. Originally published in JMIR Bioinformatics and Biotechnology (https://bioinform.jmir.org), 10.01.2023.) more...

Optic nerve health is essential for proper function of the visual system. However, the pathophysiology of certain neurodegenerative disease processes affecting the optic nerve, such as glaucoma, is not fully understood. Recently, it was hypothesized that a lack of proper clearance of neurotoxins contributes to neurodegenerative diseases. The ability to clear metabolic waste is essential for tissue homeostasis in mammals, including humans. While the brain lacks the traditional lymphatic drainage system identified in other anatomical regions, there is growing evidence of a glymphatic system in the central nervous system, which structurally includes the optic nerve. Named to acknowledge the supportive role of astroglial cells, this perivascular fluid drainage system is essential to remove toxic metabolites from the central nervous system. Herein, we review existing literature describing the physiology and dysfunction of the glymphatic system specifically as it relates to the optic nerve. We summarize key imaging studies demonstrating the existence of a glymphatic system in the optic nerves of wild-type rodents, aquaporin 4-null rodents, and humans; glymphatic imaging studies in diseases where the optic nerve is impaired; and current evidence regarding pharmacological and lifestyle interventions that may help promote glymphatic function to improve optic nerve health. We conclude by highlighting future research directions that could be applied to improve imaging detection and guide therapeutic interventions for diseases affecting the optic nerve., Competing Interests: None more...

Glaucoma is a group of ophthalmologic conditions characterized by progressive retinal ganglion cell death, optic nerve degeneration, and irreversible vision loss. While intraocular pressure is the only clinically modifiable risk factor, glaucoma may continue to progress at controlled intraocular pressure, indicating other major factors in contributing to the disease mechanisms. Recent studies demonstrated the feasibility of advanced diffusion magnetic resonance imaging (dMRI) in visualizing the microstructural integrity of the visual system, opening new possibilities for non-invasive characterization of glaucomatous brain changes for guiding earlier and targeted intervention besides intraocular pressure lowering. In this review, we discuss dMRI methods currently used in visual system investigations, focusing on the eye, optic nerve, optic tract, subcortical visual brain nuclei, optic radiations, and visual cortex. We evaluate how conventional diffusion tensor imaging, higher-order diffusion kurtosis imaging, and other extended dMRI techniques can assess the neuronal and glial integrity of the visual system in both humans and experimental animal models of glaucoma, among other optic neuropathies or neurodegenerative diseases. We also compare the pros and cons of these methods against other imaging modalities. A growing body of dMRI research indicates that this modality holds promise in characterizing early glaucomatous changes in the visual system, determining the disease severity, and identifying potential neurotherapeutic targets, offering more options to slow glaucoma progression and to reduce the prevalence of this world's leading cause of irreversible but preventable blindness. more...

More than one and a half years have elapsed since the commencement of the coronavirus disease 2019 (COVID-19) pandemic, and the world is struggling to contain it. Being caused by a previously unknown virus, in the initial period, there had been an extreme paucity of knowledge about the disease mechanisms, which hampered preventive and therapeutic measures against COVID-19. In an endeavor to understand the pathogenic mechanisms, extensive experimental studies have been conducted across the globe involving cell culture-based experiments, human tissue organoids, and animal models, targeted to various aspects of the disease, viz. , viral properties, tissue tropism and organ-specific pathogenesis, involvement of physiological systems, and the human immune response against the infection. The vastly accumulated scientific knowledge on all aspects of COVID-19 has currently changed the scenario from great despair to hope. Even though spectacular progress has been made in all of these aspects, multiple knowledge gaps are remaining that need to be addressed in future studies. Moreover, multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have emerged across the globe since the onset of the first COVID-19 wave, with seemingly greater transmissibility/virulence and immune escape capabilities than the wild-type strain. In this review, we narrate the progress made since the commencement of the pandemic regarding the knowledge on COVID-19 mechanisms in the human body, including virus-host interactions, pulmonary and other systemic manifestations, immunological dysregulations, complications, host-specific vulnerability, and long-term health consequences in the survivors. Additionally, we provide a brief review of the current evidence explaining molecular mechanisms imparting greater transmissibility and virulence and immune escape capabilities to the emerging SARS-CoV-2 variants., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kumar, Narayan, Prasoon, Kumari, Kaur, Kumar, Kulandhasamy, Sesham, Pareek, Faiq, Pandey, Singh, Kant, Shekhawat, Raza and Kumar.) more...

Purpose: To characterize the visual pathway integrity of five glaucoma animal models using diffusion tensor imaging (DTI)., Methods: Two experimentally induced and three genetically determined models of glaucoma were evaluated. For inducible models, chronic IOP elevation was achieved via intracameral injection of microbeads or laser photocoagulation of the trabecular meshwork in adult rodent eyes. For genetic models, the DBA/2J mouse model of pigmentary glaucoma, the LTBP2 mutant feline model of congenital glaucoma, and the transgenic TBK1 mouse model of normotensive glaucoma were compared with their respective genetically matched healthy controls. DTI parameters, including fractional anisotropy, axial diffusivity, and radial diffusivity, were evaluated along the optic nerve and optic tract., Results: Significantly elevated IOP relative to controls was observed in each animal model except for the transgenic TBK1 mice. Significantly lower fractional anisotropy and higher radial diffusivity were observed along the visual pathways of the microbead- and laser-induced rodent models, the DBA/2J mice, and the LTBP2-mutant cats compared with their respective healthy controls. The DBA/2J mice also exhibited lower axial diffusivity, which was not observed in the other models examined. No apparent DTI change was observed in the transgenic TBK1 mice compared with controls., Conclusions: Chronic IOP elevation was accompanied by decreased fractional anisotropy and increased radial diffusivity along the optic nerve or optic tract, suggestive of disrupted microstructural integrity in both inducible and genetic glaucoma animal models. The effects on axial diffusivity differed between models, indicating that this DTI metric may represent different aspects of pathological changes over time and with severity. more...

Glaucoma is a neurodegenerative disease that causes progressive, irreversible vision loss. Currently, intraocular pressure (IOP) is the only modifiable risk factor for glaucoma. However, glaucomatous degeneration may continue despite adequate IOP control. Therefore, there exists a need for treatment that protects the visual system, independent of IOP. This study sought, first, to longitudinally examine the neurobehavioral effects of different magnitudes and durations of IOP elevation using multi-parametric magnetic resonance imaging (MRI), optokinetics and histology; and, second, to evaluate the effects of oral citicoline treatment as a neurotherapeutic in experimental glaucoma. Eighty-two adult Long Evans rats were divided into six groups: acute (mild or severe) IOP elevation, chronic (citicoline-treated or untreated) IOP elevation, and sham (acute or chronic) controls. We found that increasing magnitudes and durations of IOP elevation differentially altered structural and functional brain connectivity and visuomotor behavior, as indicated by decreases in fractional anisotropy in diffusion tensor MRI, magnetization transfer ratios in magnetization transfer MRI, T1-weighted MRI enhancement of anterograde manganese transport, resting-state functional connectivity, visual acuity, and neurofilament and myelin staining along the visual pathway. Furthermore, 3 weeks of oral citicoline treatment in the setting of chronic IOP elevation significantly reduced visual brain integrity loss and visual acuity decline without altering IOP. Such effects sustained after treatment was discontinued for another 3 weeks. These results not only illuminate the close interplay between eye, brain, and behavior in glaucomatous neurodegeneration, but also support a role for citicoline in protecting neural tissues and visual function in glaucoma beyond IOP control., (© 2021. The American Society for Experimental NeuroTherapeutics, Inc.) more...

Purpose: Immunohistological investigations have given rise to divergent perspectives about adult hippocampal neurogenesis in humans. Therefore, this study aimed to examine whether a comprehensive transcriptomic analysis of signature markers of neurogenesis, supplemented with markers of gliogenesis, vasculogenesis, cell proliferation, and apoptosis, may help discern essential aspects of adult hippocampal neurogenesis in humans., Materials and Methods: RNA expression data for salient marker genes of neurogenesis, gliogenesis, vasculogenesis, and apoptosis in post-mortem human hippocampal tissue [from prenatal (n = 15), child (n = 5), adolescent (n = 4), and adult (n = 6) brains] were downloaded from the Allen Human Brain Atlas database (http://www.brainspan.org/rnaseq/search/index.html). Gene expression data was categorized, median values were computed, and age group-specific differential expression was subjected to statistical analysis (significance level, α = 0.01)., Results: With the exception of the genes encoding GFAP, BLBP, SOX2, and PSA-NCAM (unchanged), and the post-mitotic late maturation markers CALB1, CALB2, MAP2, and NEUN as well as the pan-neuronal marker PROX1 which were persistently expressed throughout, expression of all other genes associated with neurogenesis was steeply and progressively downregulated between perinatal life and adulthood. Interestingly, expression of the classical proliferation marker KI67 and a progenitor cell marker TBR2 were found to have reached baseline expression levels (zero expression score) at adolescence while the expression of immature neuronal, post-mitotic early and late maturation markers remained at a constant level after childhood. In contrast, markers of gliogenesis (other than PDGFRA and Vimentin ) were significantly upregulated between prenatal life and childhood. Expression of the vasculogenesis markers VEGFA and FGF2 did not differ across any of the age groups studied, whereas the expression of apoptotic markers was progressively decreased after prenatal life., Conclusions: Our findings indicate that the progression of neurogenesis from progenitor cells is highly restricted in the human brain from childhood onwards. An alternative possibility that limited neurogenesis may be continued in adolescents and adults from a developmentally arrested pool of immature neurons needs to be examined further through experimental studies., Competing Interests: None., (© 2020 The Author(s).) more...

Introduction: The conventional model of abdominal anatomy described multiple mesenteries. Dissection techniques were based on this. Recent studies demonstrate the mesentery is continuous from duodenojejunal flexure to anorectal junction. Given this, it is important to update dissection techniques related to the mesentery in the cadaveric setting. Materials and Methods: A technique of mesenteric dissection was developed and tested in a cohort of 20 adult human cadavers (12 male and 8 female). As the technique enabled excision of the mesentery as a single unit, it was possible to characterize the anatomy of the ex vivo mesentery. Results: The technique developed enabled dissection of an intact and continuous mesentery in all cadavers examined. Examination of the ex vivo mesentery demonstrated that a mesoduodenum was present in all cases. The mesentery was continuous from the mesoduodenum to the mesorectum and ended at the level of the anorectal junction. Conclusions: A technique was developed that reproducibly enabled dissection of an intact and continuous mesentery from the duodenum to the anorectal junction. A mesoduodenum was consistently observed and noted to be in continuity with the remainder of the mesentery., (Copyright © 2020 Kumar, Faiq, Krishna, Kishan, Raj, Coffey and Jacob.) more...

Background: The etiology of schizophrenia is extensively debated, and multiple factors have been contended to be involved. A panoramic view of the contributing factors in a genome-wide study can be an effective strategy to provide a comprehensive understanding of its causality. Materials and Methods: GSE53987 dataset downloaded from GEO-database, which comprised mRNA expression data of post-mortem brain tissue across three regions from control (C) and age-matched subjects (T) of schizophrenia (N = Hippocampus [HIP]: C-15, T-18, Prefrontal cortex [PFC]: C-15, T-19, Associative striatum [STR]: C-18, T-18). Bio-conductor-affy-package used to compute mRNA expression, and further t-test applied to investigate differential gene expression. The analysis of the derived genes performed using the PANTHER Classification System and NCBI database. Further, a protein interactome analysis of the derived gene set was performed using STRING v10 database (https://string-db.org/) Results: A set of 40 genes showed significantly altered (p < 0.01) expression across all three brain regions. The analyses unraveled genes implicated in biological processes and events, and molecular pathways relating basic neuronal functions. Conclusions: The aberrant expression of genes maintaining basic cell machinery explains compromised neuronal processing in SCZ., (Copyright © 2019 Kumar, Pareek, Singh, Faiq, Narayan, Raza and Kumar.) more...

Apart from their established role in embryonic development, neurotrophins (NTs) have diverse functions in the nervous system. Their role in the integration of physiological and biochemical aspects of the nervous system is currently attracting much attention. Based on a systematic analysis of the literature, we here propose a new paradigm that, by exploiting a novel role of NTs, may help explain the genesis of stress-related psychiatric disorders, opening new avenues for better management of the same. We hypothesize that NTs as an integrated network play a crucial role in maintaining an indivdual's psychological wellbeing. Given the evidence that stress can induce chronic disruption of the hypothalamic-pituitary-adrenal (HPA) axis which, in turn, is causally linked to several psychiatric disorders, this function may be mediated through the homeostatic mechanisms governing regulation of this axis. In fact, NTs, such as nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) are known to participate in neuroendocrine regulation. Recent studies suggest epigenetic modification of NT-HPA axis interplay in the precipitation of psychiatric disorders. Our article highlights why this new knowledge regarding NTs should be considered in the etiogenesis and treatment of stress-induced psychopathology., (Copyright © 2019 Elsevier B.V. All rights reserved.) more...

Glaucoma is the world's leading cause of irreversible blindness, and falls are a major public health concern in glaucoma patients. Although recent evidence suggests the involvements of the brain toward advanced glaucoma stages, the early brain changes and their clinical and behavioral consequences remain poorly described. This study aims to determine how glaucoma may impair the brain structurally and functionally within and beyond the visual pathway in the early stages, and whether these changes can explain visuomotor impairments in glaucoma. Using multi-parametric magnetic resonance imaging, glaucoma patients presented compromised white matter integrity along the central visual pathway and around the supramarginal gyrus, as well as reduced functional connectivity between the supramarginal gyrus and the visual occipital and superior sensorimotor areas when compared to healthy controls. Furthermore, decreased functional connectivity between the supramarginal gyrus and the visual brain network may negatively impact postural control measured with dynamic posturography in glaucoma patients. Taken together, this study demonstrates that widespread structural and functional brain reorganization is taking place in areas associated with visuomotor coordination in early glaucoma. These results implicate an important central mechanism by which glaucoma patients may be susceptible to visual impairments and increased risk of falls. more...

In the last few years, a cluster of anatomical discoveries has been reported which overturned the long existing dogmas about the structure and function of human body. First to come was the discovery that established the existence of a lymphatic system pertaining to the central nervous system (CNS). CNS was believed to be anatomically immune privileged owing to the absence of any lymphatics and presence of the blood-brain barrier around it, but latest research has established beyond any reasonable doubt that true lymphatic channels carry immune cells in meninges thus challenging the existing theory. Studies also supported the presence of a 'Glymphatic system' (created by the perivascular spaces lined with the leptomeninges and a sheath of glial cells) in the CNS draining interstitial metabolic waste from CNS. The second discovery unraveled the previously unknown parts of the human mesentery in adult and established that it is a continuous entity all along the intra-abdominal gut tube against the previous notion that it is fragmented in the adult humans. A very recently reported third discovery demonstrated a previously unknown tissue component-'interstitium'-a networked collagen bound fluid-filled space existent in a number of human organs. All these structures bear considerable applied importance towards the pathogenesis, prognostic and diagnostic investigations and management of human diseases. This article attempts to present a brief review of all three remarkable discoveries and emphasizes their applied importance within the realm of medical sciences., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For permissions, please email: journals.permissions@oup.com.) more...

Understanding the mechanisms of vision in health and disease requires knowledge of the anatomy and physiology of the eye and the neural pathways relevant to visual perception. As such, development of imaging techniques for the visual system is crucial for unveiling the neural basis of visual function or impairment. Magnetic resonance imaging (MRI) offers non-invasive probing of the structure and function of the neural circuits without depth limitation, and can help identify abnormalities in brain tissues in vivo . Among the advanced MRI techniques, manganese-enhanced MRI (MEMRI) involves the use of active manganese contrast agents that positively enhance brain tissue signals in T1-weighted imaging with respect to the levels of connectivity and activity. Depending on the routes of administration, accumulation of manganese ions in the eye and the visual pathways can be attributed to systemic distribution or their local transport across axons in an anterograde fashion, entering the neurons through voltage-gated calcium channels. The use of the paramagnetic manganese contrast in MRI has a wide range of applications in the visual system from imaging neurodevelopment to assessing and monitoring neurodegeneration, neuroplasticity, neuroprotection, and neuroregeneration. In this review, we present four major domains of scientific inquiry where MEMRI can be put to imperative use - deciphering neuroarchitecture, tracing neuronal tracts, detecting neuronal activity, and identifying or differentiating glial activity. We deliberate upon each category studies that have successfully employed MEMRI to examine the visual system, including the delivery protocols, spatiotemporal characteristics, and biophysical interpretation. Based on this literature, we have identified some critical challenges in the field in terms of toxicity, and sensitivity and specificity of manganese enhancement. We also discuss the pitfalls and alternatives of MEMRI which will provide new avenues to explore in the future. more...

Neurogenesis in adult humans remains a controversial area of research among neuroscientists. Methodological challenges have hampered investigators from conducting high-quality, in-vivo studies that can help elucidate the presence and/or activity of neurogenesis in human brains. Additionally, the studies that have been done in humans report conflicting results, further adding to the ambiguity surrounding the concept of adult neurogenesis in humans. In this review article, the authors seek to help clarify the concept of adult neurogenesis by providing an overview of the basic concept, as we currently understand it, including its historical birth and evolution. The authors also review and discuss current key studies (pro and con) on adult neurogenesis in humans and animals, as well as research challenges with potential solutions. Finally, the authors discuss the clinical implications of adult neurogenesis in humans, based on what we know so far, including its potential use as a drug target in the development of pharmacological treatments for various neuropsychiatric disorders., Competing Interests: FUNDING: No funding was provided. DISCLOSURES: The authors have no conflicts of interest relevant to the content of this article. more...

Glaucoma, the world's leading cause of irreversible blindness, is a condition for which elevated intraocular pressure is currently the only modifiable risk factor. However, the disorder can continue to progress even at reduced intraocular pressure. This indicates additional key factors that contribute to the etiopathogenesis. There has been a growing amount of literature suggesting glaucoma as a neurodegenerative disease of the visual system. However, it remains debatable whether the observed pathophysiological conditions are causes or consequences. This review summarizes recent in vivo imaging studies that helped advance the understanding of early glaucoma involvements and disease progression in the brains of humans and experimental animal models. In particular, we focused on the non-invasive detection of early structural and functional brain changes before substantial clinical visual field loss in glaucoma patients; the eye-brain interactions across disease severity; the metabolic changes occurring in the brain's visual system in glaucoma; and, the widespread brain involvements beyond the visual pathway as well as the potential behavioral relevance. If the mechanisms of glaucomatous brain changes are reliably identified, novel neurotherapeutics that target parameters beyond intraocular pressure lowering can be the promise of the near future, which would lead to reduced prevalence of this irreversible but preventable disease., Competing Interests: None more...

Background: Conventional experimental approaches to understand glaucoma etiology and pathogenesis and, consequently, predict its course of progression have not seen much success due to the involvement of numerous molecular, cellular, and other moieties. An overwhelming number of these moieties at different levels combined with numerous environmental factors further complicate the intricacy. Interaction patterns between these factors are important to understand yet difficult to probe with conservative experimental approaches., Methods: We performed a system-level analysis with mathematical modeling by developing and analyzing rate equations with respect to the cellular events in glaucoma pathogenesis. Twenty-two events were enlisted from the literature survey and were analyzed in terms of the sensitivity coefficient of retinal ganglion cells. A separate rate equation was developed for cellular stress also. The results were analyzed with respect to time, and the time course of the events with respect to various cellular moieties was analyzed., Results: Our results suggest that microglia activation is among the earliest events in glaucoma pathogenesis. This modeling method yields a wealth of useful information which may serve as an important guide to better understand glaucoma pathogenesis and design experimental approaches and also identify useful diagnostic/predictive methods and important therapeutic targets., Conclusion: We here report the first mathematical model for glaucoma pathogenesis which provides important insight into the sensitivity coefficient and glia-mediated pathology of glaucoma., How to Cite This Article: Faiq MA, Sidhu T, et al. A Novel Mathematical Model of Glaucoma Pathogenesis. J Curr Glaucoma Pract 2019; 13(1):3-8., Competing Interests: Source of support: Nil Conflict of interest: None more...

Glaucoma is the most common cause of irreversible blindness worldwide, with >65 million sufferers. It is incurable and the only therapeutic approach accepted till now is the lowering of intraocular pressure (IOP) medically and/or surgically. These known interventions might have many side effects and complications. Yoga-based interventions are now well accepted as alternative therapy in many chronic diseases. The effects of yoga in glaucoma, however, have not been studied adequately. Accommodation (the process of adjustment of optical power to maintain clear vision) of eyes leads to instant lowering of IOP. Therefore, we hypothesize that one of the yoga-based interventions, Tratak kriya , which includes ocular exercises might lead to lowering of IOP in glaucoma patients. The proposed Tratak kriya leads to contraction and relaxation of ciliary muscles which might increase outflow of aqueous humor. In addition, this yoga-based intervention might decrease stress and improve quality of life in glaucoma patients., Competing Interests: There are no conflicts of interest. more...

Introduction: There is a significant difference in the Reactive Oxygen Species (ROS) levels of Chronic Myeloid Leukaemia (CML) patients before and during treatment with Tyrosine Kinase Inhibitors (TKIs). This is because high ROS levels support oncogenic phenotype of CML by inducing proliferation pathway and accumulation of further genetic mutations. Often the measurement is done on WBC or serum for ascertaining one type of ROS species, but measurement of global ROS in fresh whole blood will give more accurate estimation of ROS., Aim: To measure global ROS in peripheral blood of CML patients., Materials and Methods: A case control study was undertaken to measure ROS in peripheral blood of CML patients from Northern India. CML patients on TKIs (n=40 on imatinib herein called treated) and untreated (n=17, who were not on any TKIs or alternative medicine, called as treatment naive) and 52 healthy controls were also enrolled. Chemiluminescent assay was carried out using luminol as signal enhancer in 400 µl of blood to measure ROS. The chemiluminescence was measured as Relative Light Units (RLU)/sec/104 WBC. Data was presented in terms of mean±SE or geometric mean (95% Confidence Interval) for continuous variables and percentage for categorical variables. Groups were compared using two sample t-test for continuous variables and chi-square test for categorical variables., Results: The WBC profile and ROS levels of patients taking TKIs were quite similar and showed no significant difference (p<0.999) compared to healthy controls. In contrast, significant increase was observed in the ROS levels of CML patients not on TKIs (untreated) compared to patients under treatment (p<0.029) and healthy controls (p<0.007). We also observed that the absolute ROS values and WBC counts were higher in untreated patients compared to patients on TKIs and healthy controls, even though mean ROS value was less., Conclusion: To ascertain the alterations in ROS levels of CML patients before and during treatment with TKIs, it is better to measure global ROS in fresh whole blood by chemiluminescent method using luminol. Luminol assay is a quick, easy and inexpensive method to measure global ROS. Patient under treatment with TKIs show significant decrease in ROS levels almost similar to the levels measured in healthy controls yet the mechanisms by which this decrease occurs needs to be elucidated. more...

Owing to the reports of microcephaly as a consistent outcome in the fetuses of pregnant women infected with ZIKV in Brazil, Zika virus (ZIKV)-microcephaly etiomechanistic relationship has recently been implicated. Researchers, however, are still struggling to establish an embryological basis for this interesting causal handcuff. The present study reveals robust evidence in favor of a plausible ZIKV-microcephaly cause-effect liaison. The rationale is based on: (1) sequence homology between ZIKV genome and the response element of an early neural tube developmental marker "retinoic acid" in human DNA and (2) comprehensive similarities between the details of brain defects in ZIKV-microcephaly and retinoic acid embryopathy. Retinoic acid is considered as the earliest factor for regulating anteroposterior axis of neural tube and positioning of structures in developing brain through retinoic acid response elements (RARE) consensus sequence (5'-AGGTCA-3') in promoter regions of retinoic acid-dependent genes. We screened genomic sequences of already reported virulent ZIKV strains (including those linked to microcephaly) and other viruses available in National Institute of Health genetic sequence database (GenBank) for the RARE consensus repeats and obtained results strongly bolstering our hypothesis that ZIKV strains associated with microcephaly may act through precipitation of dysregulation in retinoic acid-dependent genes by introducing extra stretches of RARE consensus sequence repeats in the genome of developing brain cells. Additional support to our hypothesis comes from our findings that screening of other viruses for RARE consensus sequence repeats is positive only for those known to display neurotropism and cause fetal brain defects (for which maternal-fetal transmission during developing stage may be required). The numbers of RARE sequence repeats appeared to match with the virulence of screened positive viruses. Although, bioinformatic evidence and embryological features are in favor of our hypothesis, additional studies including animal models are warranted to validate our proposition. Such studies are likely to unfold ZIKV-microcephaly association and may help in devising methods to combat it. more...

CYP1B1 is a dioxin-inducible enzyme belonging to the cytochrome P450 superfamily. It has been observed to be important in a variety of developmental processes including in utero development of ocular structures. Owing to its role in the developmental biology of eye, its dysfunction can lead to ocular developmental defects. This has been found to be true and CYP1B1 mutations have been observed in a majority of primary congenital glaucoma (PCG) patients from all over the globe. Primary congenital glaucoma is an irreversibly blinding childhood disorder (onset at birth or early infancy) typified by anomalous development of trabecular meshwork (TM). How CYP1B1 causes PCG is not known; however, some basic investigations have been reported. Understanding the CYP1B1 mediated etiopathomechanism of PCG is very important to identify targets for therapy and preventive management. In this perspective, we will make an effort to reconstruct the pathomechanism of PCG in the light of already reported information about the disease and the CYP1B1 gene. How to cite this article: Faiq MA, Dada R, Qadri R, Dada T. CYP1 B1-mediated Pathobiology of Primary Congenital Glaucoma. J Curr Glaucoma Pract 2015;9(3):77-80. more...

Cytochrome P450 1B1 (CYP1B1) is a universal cancer marker and is implicated in many other disorders. Mutations in CYP1B1 are also associated with childhood blindness due to primary congenital glaucoma (PCG). To understand the CYP1B1 mediated etiopathology of PCG and pathomechanism of various cancers, it is important to carry out its functional studies. Heterologous expression of CYP1B1 in prokaryotes is imperative because bacteria yield a higher amount of heterologous proteins in lesser time and so the expressed protein is ideal for functional studies. In such expression system there is no interference by other eukaryotic proteins. But the story is not that simple as expression of heterologous CYP1B1 poses many technical difficulties. Investigators have employed various modifications/deletions of CYP N-terminus to improve CYP1B1 expression. However, the drawback of these studies is that it changes the original protein and, as a result, invalidates functional studies. The present study examines the role of various conditions and reagents in successful and consistent expression of sufficient quantities of unmodified/native human CYP1B1 in E. coli. We aimed at expressing CYP1B1 in various strains of E. coli and in the course developed a protocol that results in high expression of unmodified protein sufficient for functional/biophysical studies. We examined CYP1B1 expression with respect to different expression vectors, bacterial strains, types of culture media, time, Isopropyl β-D-1-thiogalactopyranoside concentrations, temperatures, rotations per minute, conditioning reagents and the efficacy of a newly described technique called double colony selection. We report a protocol that is simple, easy and can be carried out in any laboratory without the requirement of a fermentor. Though employed for CYP1B1 expression, this protocol can ideally be used to express any eukaryotic membrane protein. more...

Purpose: Primary congenital glaucoma (PCG) is the second most common cause of blindness, accounting for 0.01%-0.04% of total blindness worldwide. Most congenital glaucoma cases are mapped to the GLC3A locus, and many aspects of PCG are still unknown. Recent studies have reported an increased frequency of mitochondrial DNA (mtDNA) sequence changes in primary open-angle glaucoma, primary angle-closure glaucoma, and pseudoexfoliation glaucoma compared to controls. Thus, this study was planned with the aim of detecting mitochondrial DNA variations in PCG cases., Methods: Twenty primary congenital glaucoma cases were selected from Dr. R. P. Centre for Ophthalmic Sciences of All India Institute of Medical Sciences (AIIMS), New Delhi, India. DNA was isolated from whole blood samples. The entire coding region of the mitochondrial genome was amplified by PCR in 20 patients and 20 controls. The full mtDNA genome was sequenced and analyzed against mitochondrial reference sequence NC&#95;012920., Results: MtDNA sequencing revealed a total of 195 nucleotide variations in PCG patients and 58 in controls. Of the 195 changes, 43 (22.05%) were nonsynonymous, 82 (42.05%) were synonymous, and 30 were in RNA genes. A total of 39/195 (20.00%) variations were observed in the D-loop (hypervariable region), 19/195 (9.74%) in different ribosomal RNA (rRNAs), 11/195 (5.64%) in transfer RNA (tRNAs), 66/195 (33.84%) in complex I, 17/195 (8.71%) in complex III, 27/195 (13.84%) in complex IV, and 15/195 (7.69%) in complex V. Of 58 variations in the controls, 14 were nonsynonymous changes. The Sorting Intolerant from Tolerant and Polymorphism Phenotyping analyses of all nonsynonymous changes from patients revealed two pathogenic changes in NADH-ubiquinone oxidoreductase chain 2 (ND2) and cytochrome oxidase subunit III (COXIII) subunits. In one of the patients, the insertion of cytosine introduced a frame shift change (p.Ile104AsnfsX26) in the cytochrome b (CYB) subunit of the electron transport chain. In another patient, a variation (G8572A) in ATP synthase 8 (ATpase8) led to the introduction of a stop codon or termination at amino acid position 69. Haplogroup/phylogenetic analysis of mtDNA showed that primary congenital glaucoma patients belong to three macrohaplogroups: M (4), N (15), and L (1). Fifty percent of the patients belonged to the H2a2a lineage of the N-derived haplogroup., Conclusions: Although several mutations were found at a higher frequency among our population, there is a need to complement this study with functional studies and to analyze a large number of samples in different populations of different haplogroups, as penetrance varies among haplogroups. more...