Inclusion of the glucocorticoid receptor in a hypothalamic pituitary adrenal axis model reveals bistability

BACKGROUND: The body's primary stress management system is the hypothalamic pituitary adrenal (HPA) axis. The HPA axis responds to physical and mental challenge to maintain homeostasis in part by controlling the body's cortisol level. Dysregulation of the HPA axis is implicated in numerous stress-related diseases. RESULTS: We developed a structured model of the HPA axis that includes the glucocorticoid receptor (GR). This model incorporates nonlinear kinetics of pituitary GR synthesis. The nonlinear effect arises from the fact that GR homodimerizes after cortisol activation and induces its own synthesis in the pituitary. This homodimerization makes possible two stable steady states (low and high) and one unstable state of cortisol production resulting in bistability of the HPA axis. In this model, low GR concentration represents the normal steady state, and high GR concentration represents a dysregulated steady state. A short stress in the normal steady state produces a small perturbation in the GR concentration that quickly returns to normal levels. Long, repeated stress produces persistent and high GR concentration that does not return to baseline forcing the HPA axis to an alternate steady state. One consequence of increased steady state GR is reduced steady state cortisol, which has been observed in some stress related disorders such as Chronic Fatigue Syndrome (CFS). CONCLUSION: Inclusion of pituitary GR expression resulted in a biologically plausible model of HPA axis bistability and hypocortisolism. High GR concentration enhanced cortisol negative feedback on the hypothalamus and forced the HPA axis into an alternative, low cortisol state. This model can be used to explore mechanisms underlying disorders of the HPA axis

Effect of non-genetic factors on voluntary and involuntary culling in Holstein Friesian crossbred cattle

The present study focused on analysis of annual disposal pattern and identification of non-genetic factors affecting the incidence of culling in Holstein Friesian crossbred cattle. Data on disposal pattern of 1988 Karan Fries (Holstein Friesian crossbred) cows, spread over a period of 34 years (1978 to 2012), were utilized for the study. Culling was classified into 2 groups viz. voluntary (low milk production) and involuntary culling. Reasons of involuntary culling were categorized into locomotory problem (LP), poor health and weakness (PHW), teat and udder problem (TUP) and reproductive problem (RP). Logistic regression analysis was conducted to assess the effect of various non-genetic factors viz. number of normal lactations completed (NLC), calving type (CT), season of calving (SC) and period of calving (PC) on incidence of culling in various parities. The analysis of annual disposal pattern of the Karan Fries cows, revealed that the average annual replacement index, annual culling rate and annual disposal rate in the herd was 1.46, 24.40 and 29.80% per annum, respectively. Odd ratio estimates indicated that young calvers which did not complete atleast one normal lactation were 1.83 times more prone to culling because of PHW and were 0.95 and 0.33 times lesser prone to culling due to RP and LMP, respectively. Moreover, receiver operating characteristic (ROC) analysis indicated that the role of non-genetic factors in prediction of culling increased with parities and the logistic regression was efficient in predicting the incidence of parity wise culling, due to different involuntary causes, in Karan Fries cattle

Alzheimer's disease-like perturbations in HIV-mediated neuronal dysfunctions: understanding mechanisms and developing therapeutic strategies

Excessive exposure to toxic substances or chemicals in the environment and various pathogens, including viruses and bacteria, is associated with the onset of numerous brain abnormalities. Among them, pathogens, specifically viruses, elicit persistent inflammation that plays a major role in Alzheimer's disease (AD) as well as dementia. AD is the most common brain disorder that affects thought, speech, memory and ability to execute daily routines. It is also manifested by progressive synaptic impairment and neurodegeneration, which eventually leads to dementia following the accumulation of Aβ and hyperphosphorylated Tau. Numerous factors contribute to the pathogenesis of AD, including neuroinflammation associated with pathogens, and specifically viruses. The human immunodeficiency virus (HIV) is often linked with HIV-associated neurocognitive disorders (HAND) following permeation through the blood-brain barrier (BBB) and induction of persistent neuroinflammation. Further, HIV infections also exhibited the ability to modulate numerous AD-associated factors such as BBB regulators, members of stress-related pathways as well as the amyloid and Tau pathways that lead to the formation of amyloid plaques or neurofibrillary tangles accumulation. Studies regarding the role of HIV in HAND and AD are still in infancy, and potential link or mechanism between both is not yet established. Thus, in the present article, we attempt to discuss various molecular mechanisms that contribute to the basic understanding of the role of HIV-associated neuroinflammation in AD and HAND. Further, using numerous growth factors and drugs, we also present possible therapeutic strategies to curb the neuroinflammatory changes and its associated sequels.Peer reviewe

Cellular signalling pathways mediating the pathogenesis of chronic inflammatory respiratory diseases: an update

Respiratory disorders, especially non-communicable, chronic inflammatory diseases, are amongst the leading causes of mortality and morbidity worldwide. Respiratory diseases involve multiple pulmonary components, including airways and lungs that lead to their abnormal physiological functioning. Several signaling pathways have been reported to play an important role in the pathophysiology of respiratory diseases. These pathways, in addition, become the compounding factors contributing to the clinical outcomes in respiratory diseases. A range of signaling components such as Notch, Hedgehog, Wingless/Wnt, bone morphogenetic proteins, epidermal growth factor and fibroblast growth factor is primarily employed by these pathways in the eventual cascade of events. The different aberrations in such cell-signaling processes trigger the onset of respiratory diseases making the conventional therapeutic modalities ineffective. These challenges have prompted us to explore novel and effective approaches for the prevention and/or treatment of respiratory diseases. In this review, we have attempted to deliberate on the current literature describing the role of major cell signaling pathways in the pathogenesis of pulmonary diseases and discuss promising advances in the field of therapeutics that could lead to novel clinical therapies capable of preventing or reversing pulmonary vascular pathology in such patients

An overview of vaccine development for COVID-19

The COVID-19 pandemic continues to endanger world health and the economy. The causative SARS-CoV-2 coronavirus has a unique replication system. The end point of the COVID-19 pandemic is either herd immunity or widespread availability of an effective vaccine. Multiple candidate vaccines - peptide, virus-like particle, viral vectors (replicating and nonreplicating), nucleic acids (DNA or RNA), live attenuated virus, recombinant designed proteins and inactivated virus - are presently under various stages of expansion, and a small number of vaccine candidates have progressed into clinical phases. At the time of writing, three major pharmaceutical companies, namely Pfizer and Moderna, have their vaccines under mass production and administered to the public. This review aims to investigate the most critical vaccines developed for COVID-19 to date

Albumin Nano-Encapsulation of Piceatannol Enhances Its Anticancer Potential in Colon Cancer Via Downregulation of Nuclear p65 and HIF-1 alpha

Piceatannol (PIC) is known to have anticancer activity, which has been attributed to its ability to block the proliferation of cancer cells via suppression of the NF-kB signaling pathway. However, its effect on hypoxia-inducible factor (HIF) is not well known in cancer. In this study, PIC was loaded into bovine serum albumin (BSA) by desolvation method as PIC-BSA nanoparticles (NPs). These PIC-BSA nanoparticles were assessed for in vitro cytotoxicity, migration, invasion, and colony formation studies and levels of p65 and HIF-1α. Our results indicate that PIC-BSA NPs were more effective in downregulating the expression of nuclear p65 and HIF-1α in colon cancer cells as compared to free PIC. We also observed a significant reduction in inflammation induced by chemical colitis in mice by PIC-BSA NPs. Furthermore, a significant reduction in tumor size and number of colon tumors was also observed in the murine model of colitis-associated colorectal cancer, when treated with PIC-BSA NPs as compared to free PIC. The overall results indicate that PIC, when formulated as PIC-BSA NPs, enhances its therpautice potential. Our work could prompt further research in using natural anticancer agents as nanoparticels with possiable human clinical trails. This could lead to the development of a new line of safe and effective therapeutics for cancer patients

Correction: Aljabali, A.A.A.; et al. Albumin Nano-Encapsulation of Piceatannol Enhances Its Anticancer Potential in Colon Cancer via down Regulation of Nuclear p65 and HIF-1α. Cancers 2020, 12, 113

The authors wish to make the following corrections to this paper [...]

Targeting eosinophils in respiratory diseases: Biological axis, emerging therapeutics and treatment modalities

Eosinophils are bi-lobed, multi-functional innate immune cells with diverse cell surface receptors that regulate local immune and inflammatory responses. Several inflammatory and infectious diseases are triggered with their build up in the blood and tissues. The mobilization of eosinophils into the lungs is regulated by a cascade of processes guided by Th2 cytokine generating T-cells. Recruitment of eosinophils essentially leads to a characteristic immune response followed by airway hyperresponsiveness and remodeling, which are hallmarks of chronic respiratory diseases. By analysing the dynamic interactions of eosinophils with their extracellular environment, which also involve signaling molecules and tissues, various therapies have been invented and developed to target respiratory diseases. Having entered clinical testing, several eosinophil targeting therapeutic agents have shown much promise and have further bridged the gap between theory and practice. Moreover, researchers now have a clearer understanding of the roles and mechanisms of eosinophils. These factors have successfully assisted molecular biologists to block specific pathways in the growth, migration and activation of eosinophils. The primary purpose of this review is to provide an overview of the eosinophil biology with a special emphasis on potential pharmacotherapeutic targets. The review also summarizes promising eosinophil-targeting agents, along with their mechanisms and rationale for use, including those in developmental pipeline, in clinical trials, or approved for other respiratory disorders

Rotation-Induced Geometrical Stiffening of a Tapered, Pretwisted Blade

A linear geometrical stiffening model is developed for a rotating beam with an asymmetric cross section undergoing coupled stretch–bending–torsion motion. The model is verified for a twisted and tapered Timoshenko beam mounted on a rotating hub with a presetting angle. The floating frame of reference formulation is adopted where the configuration of the deformable beam is described by using different coordinate systems. Three coordinate systems, viz., inertial reference frame attached to the center of the rigid hub, local reference frame attached to an arbitrary point on the elastic axis of the undeformed beam, and body reference frame attached to the point on the elastic axis of the deformed beam, are defined. The global position vector of an arbitrary point on the beam is specified using a coupled set of reference and elastic coordinates. Reference coordinates define the location and orientation of a body reference frame, and elastic coordinates describe the beam deformation about the body reference frame. For a rotating beam problem, reference and elastic coordinates give the angular displacements of the hub and elastic deformations of the beam, respectively. The expressions for the kinetic and strain energy of the deformable beam are derived. The inertial coupling between the reference and elastic coordinates in the kinetic energy expression is identified as a gyroscopic coupling term. Further, the inertial mass matrix, spin softening matrix, and centrifugal stiffening matrix are obtained from kinetic energy expression. The elastic stiffness matrices, which are independent of elastic coordinates, are derived from strain energy expression. According to the Rayleigh–Ritz method, the elastic coordinates are expressed using a series of admissible functions that satisfy the geometric boundary conditions of a fixed-free beam. The ordinary differential equations of motion are then derived using Lagrange’s equations. A set of dimensionless parameters is identified after the nondimensionalization of the equations of motion. Due to the skewsymmetric nature of the gyroscopic coupling matrix, the eigenvalue problem is not amenable to classical modal analysis. Therefore, a complex modal analysis method is used to determine the modal characteristics. The results from the present model are verified with those available in the literature. The results are also compared with those obtained from the three-dimensional finite element method using ANSYS. The effect of these dimensionless parameters on the modal characteristics of a rotating blade is studied. © 2022 by the American Institute of Aeronautics and Astronautics, Inc. All rights reserved