Large-Scale Structural Changes in the Sarcoplasmic Reticulum ATP-ASE are Essential for Calcium Active Transport

This study examines the relationship that both domestic and foreign institutional net equity flows have with the India stock markets. The motivation behind is the study to examine whether increased net equity investments from domestic institutional investors has reduced the influence of foreign equity flows on the Indian stock market volatility. Our results indicate that only during periods in which domestic equity inflows surpass foreign flows by a significant margin, as seen during 2015–2018, is the Indian stock market volatility not significantly influenced by foreign equity investments. However, during periods of re-emergence of strong foreign net inflows, the Indian market volatility is still being impacted significantly, as has been observed since 2019. Furthermore, we find that both large-scale net buying and net selling by domestic funds increased the stock market volatility as observed during 2015–2018 and COVID-impacted year 2020 respectively. The implications of this study are multi-fold. First, the regulators should discuss with industry bodies before enforcing major structural changes like reconstituting of mutual fund investment mandate in 2017 which forced domestic funds to quickly change portfolio allocation amongst large-cap, mid-cap and small-cap stocks resulting in higher stock market volatility. Second, adequate investor educational and awareness programmes need to be conducted regularly for retail investors to minimize herd behaviour of investing during market rise and heavy redemptions at times of fall. Third, the economic policies should be stable and forward-looking to ensure foreign investors remain attracted to the Indian stock markets at all times.

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Structural Changes in Thalamic Nuclei Across Prodromal and Clinical Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-201583 ◽

2021 ◽

pp. 1-11

Author(s):

Adam S. Bernstein ◽

Steven Z. Rapcsak ◽

Michael Hornberger ◽

Manojkumar Saranathan ◽

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Large Scale ◽

Structural Changes ◽

Thalamic Nuclei ◽

Medial Temporal Lobes ◽

Cognitive Changes ◽

Temporal Lobes ◽

Medial Geniculate ◽

Healthy Control

Background: Increasing evidence suggests that thalamic nuclei may atrophy in Alzheimer’s disease (AD). We hypothesized that there will be significant atrophy of limbic thalamic nuclei associated with declining memory and cognition across the AD continuum. Objective: The objective of this work was to characterize volume differences in thalamic nuclei in subjects with early and late mild cognitive impairment (MCI) as well as AD when compared to healthy control (HC) subjects using a novel MRI-based thalamic segmentation technique (THOMAS). Methods: MPRAGE data from the ADNI database were used in this study (n = 540). Healthy control (n = 125), early MCI (n = 212), late MCI (n = 114), and AD subjects (n = 89) were selected, and their MRI data were parcellated to determine the volumes of 11 thalamic nuclei for each subject. Volumes across the different clinical subgroups were compared using ANCOVA. Results: There were significant differences in thalamic nuclei volumes between HC, late MCI, and AD subjects. The anteroventral, mediodorsal, pulvinar, medial geniculate, and centromedian nuclei were significantly smaller in subjects with late MCI and AD when compared to HC subjects. Furthermore, the mediodorsal, pulvinar, and medial geniculate nuclei were significantly smaller in early MCI when compared to HC subjects. Conclusion: This work highlights nucleus specific atrophy within the thalamus in subjects with early and late MCI and AD. This is consistent with the hypothesis that memory and cognitive changes in AD are mediated by damage to a large-scale integrated neural network that extends beyond the medial temporal lobes.

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Metastable Intermediates as Stepping Stones on the Maturation Pathways of Viral Capsids

mBio ◽

10.1128/mbio.02067-14 ◽

2014 ◽

Vol 5 (6) ◽

Cited By ~ 10

Author(s):

Giovanni Cardone ◽

Robert L. Duda ◽

Naiqian Cheng ◽

Lili You ◽

James F. Conway ◽

...

Keyword(s):

Conformational Changes ◽

Large Scale ◽

Structural Changes ◽

Energy Landscape ◽

Potential Hazard ◽

Stepping Stones ◽

Scanning Calorimetry ◽

Conformational Effects ◽

Capsid Maturation ◽

Capsid Integrity

ABSTRACT As they mature, many capsids undergo massive conformational changes that transform their stability, reactivity, and capacity for DNA. In some cases, maturation proceeds via one or more intermediate states. These structures represent local minima in a rich energy landscape that combines contributions from subunit folding, association of subunits into capsomers, and intercapsomer interactions. We have used scanning calorimetry and cryo-electron microscopy to explore the range of capsid conformations accessible to bacteriophage HK97. To separate conformational effects from those associated with covalent cross-linking (a stabilization mechanism of HK97), a cross-link-incompetent mutant was used. The mature capsid Head I undergoes an endothermic phase transition at 60°C in which it shrinks by 7%, primarily through changes in its hexamer conformation. The transition is reversible, with a half-life of ~3 min; however, >50% of reverted capsids are severely distorted or ruptured. This observation implies that such damage is a potential hazard of large-scale structural changes such as those involved in maturation. Assuming that the risk is lower for smaller changes, this suggests a rationalization for the existence of metastable intermediates: that they serve as stepping stones that preserve capsid integrity as it switches between the radically different conformations of its precursor and mature states. IMPORTANCE Large-scale conformational changes are widespread in virus maturation and infection processes. These changes are accompanied by the release of conformational free energy as the virion (or fusogenic glycoprotein) switches from a precursor state to its mature state. Each state corresponds to a local minimum in an energy landscape. The conformational changes in capsid maturation are so radical that the question arises of how maturing capsids avoid being torn apart. Offering proof of principle, severe damage is inflicted when a bacteriophage HK97 capsid reverts from the (nonphysiological) state that it enters when heated past 60°C. We suggest that capsid proteins have been selected in part by the criterion of being able to avoid sustaining collateral damage as they mature. One way of achieving this—as with the HK97 capsid—involves breaking the overall transition down into several smaller steps in which the risk of damage is reduced.

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Type 1 Diabetic Neuropathy and C-peptide

Experimental Diabesity Research ◽

10.1080/15438600490424541 ◽

2004 ◽

Vol 5 (1) ◽

pp. 65-77 ◽

Cited By ~ 29

Author(s):

Anders A. F. Sima ◽

Weixian Zhang ◽

George Grunberger

Keyword(s):

Clinical Trials ◽

Animal Studies ◽

Large Scale ◽

Structural Changes ◽

Diabetic Complication ◽

Diabetic Patients ◽

C Peptide ◽

Beneficial Effects ◽

Regulatory Effects

The most common microvascular diabetic complication, diabetic peripheral polyneuropathy (DPN), affects type 1 diabetic patients more often and more severely. In recent decades, it has become increasingly clear that perpetuating pathogenetic mechanisms, molecular, functional, and structural changes and ultimately the clinical expression of DPN differ between the two major types of diabetes. Impaired insulin/C-peptide action has emerged as a crucial factor to account for the disproportionate burden affecting type 1 patients. C-peptide was long believed to be biologically inactive. However, it has now been shown to have a number of insulin-like glucoseindependent effects. Preclinical studies have demonstrated dose-dependent effects onNa+,K+-ATPase activity, endothelial nitric oxide synthase (eNOS), and endoneurial blood flow. Furthermore, it has regulatory effects on neurotrophic factors and molecules pivotal to the integrity of the nodal and paranodal apparatus and modulatory effects on apoptotic phenomena affecting the diabetic nervous system. In animal studies, C-peptide improves nerve conduction abnormalities, prevents nodal degenerative changes, characteristic of type 1 DPN, promotes nerve fiber regeneration, and prevents apoptosis of central and peripheral nerve cell constituents. Limited clinical trials have confirmed the beneficial effects of C-peptide on autonomic and somatic nerve function in patients with type 1 DPN. Therefore, evidence accumulates that replacement of C-peptide in type 1 diabetes prevents and even improves DPN. Large-scale food and drug administration (FDA)-approved clinical trials are necessary to make this natural substance available to the globally increasing type 1 diabetic population.

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Modelling sarcoplasmic reticulum calcium ATPase and its regulation in cardiac myocytes

Philosophical Transactions of The Royal Society A Mathematical Physical and Engineering Sciences ◽

10.1098/rsta.2008.0304 ◽

2009 ◽

Vol 367 (1896) ◽

pp. 2181-2202 ◽

Cited By ~ 19

Author(s):

Jussi T. Koivumäki ◽

Jouni Takalo ◽

Topi Korhonen ◽

Pasi Tavi ◽

Matti Weckström

Keyword(s):

Sarcoplasmic Reticulum ◽

Large Scale ◽

Cardiac Myocyte ◽

Model Complexity ◽

Transport Mechanisms ◽

Physiological Properties ◽

Theoretical Considerations ◽

Sarcoplasmic Reticulum Calcium ◽

Modelling Approach

When developing large-scale mathematical models of physiology, some reduction in complexity is necessarily required to maintain computational efficiency. A prime example of such an intricate cell is the cardiac myocyte. For the predictive power of the cardiomyocyte models, it is vital to accurately describe the calcium transport mechanisms, since they essentially link the electrical activation to contractility. The removal of calcium from the cytoplasm takes place mainly by the Na + /Ca 2+ exchanger, and the sarcoplasmic reticulum Ca 2+ ATPase (SERCA). In the present study, we review the properties of SERCA, its frequency-dependent and β -adrenergic regulation, and the approaches of mathematical modelling that have been used to investigate its function. Furthermore, we present novel theoretical considerations that might prove useful for the elucidation of the role of SERCA in cardiac function, achieving a reduction in model complexity, but at the same time retaining the central aspects of its function. Our results indicate that to faithfully predict the physiological properties of SERCA, we should take into account the calcium-buffering effect and reversible function of the pump. This ‘uncomplicated’ modelling approach could be useful to other similar transport mechanisms as well.

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Diabetes Induced Renal Complications by Leukocyte Activation of Nuclear Factor κ-B and its Regulated Genes Expression

10.20944/preprints202009.0038.v1 ◽

2020 ◽

Author(s):

Noura Darwish ◽

Yousif Elnahas ◽

Fatmah AlQahtany

Keyword(s):

Gene Expression ◽

Large Scale ◽

Structural Changes ◽

Kidney Injury ◽

Leukocyte Activation ◽

Disease Biomarkers ◽

Genes Expression ◽

Nuclear Factor Κ B ◽

Adhesion Process

Type 2 diabetes mellitus (T2D) is a metabolic disorder characterized by inappropriate insulin function. Despite wide progress in genome studies, defects in gene expression for diabetes prognosis still incompletely identified. Prolonged hyperglycemia activates NF-κB, which is a main player in vascular dysfunctions of diabetes. Activated NF-κB, triggers expression of various genes that promote inflammation and cell adhesion process. Alteration of pro-inflammatory and profibrotic gene expression contribute to the irreversible functional and structural changes in the kidney resulting in diabetic nephropathy (DN). To identify the effect of some important NF-κB related genes on mediation of DN progression, we divided our candidate genes on the basis of their function exerted in bloodstream into three categories (Proinflammatory; NF-κB, IL-1B, IL-6, TNF-α and VEGF); (Profibrotic; FN, ICAM-1, VCAM-1) and (Proliferative; MAPK-1 and EGF). We analyzed their expression profile in leukocytes of patients and explored their correlation to diabetic kidney injury features. Our data revealed the overexpression of both proinflammatory and profibrotic genes in DN group when compared to T2D group and were associated positively with each other in DN group indicating their possible role in DN progression. In DN patients, increased expression of proinflammatory genes correlated positively with glycemic control and inflammatory markers indicating their role in DN progression. Our data revealed that the persistent activation NF-κB and its related genes observed in hyperglycemia might contribute to DN progression and might be a good diagnostic and therapeutic target for DN progression. Large-scale studies are needed to evaluate the potential of these molecules to serve as disease biomarkers.

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An experimental investigation of the effects of compressibility on a turbulent reacting mixing layer

Journal of Fluid Mechanics ◽

10.1017/s002211209700791x ◽

1998 ◽

Vol 356 ◽

pp. 25-64 ◽

Cited By ~ 26

Author(s):

M. F. MILLER ◽

C. T. BOWMAN ◽

M. G. MUNGAL

Keyword(s):

High Speed ◽

Large Scale ◽

Structural Changes ◽

Density Ratio ◽

Mixing Layer ◽

Mixing Layers ◽

Unexpected Result ◽

Entrainment Ratio ◽

Plan View ◽

Compressible Mixing Layer

Experiments were conducted to investigate the effect of compressibility on turbulent reacting mixing layers with moderate heat release. Side- and plan-view visualizations of the reacting mixing layers, which were formed between a high-speed high-temperature vitiated-air stream and a low-speed ambient-temperature hydrogen stream, were obtained using a combined OH/acetone planar laser-induced fluorescence imaging technique. The instantaneous images of OH provide two-dimensional maps of the regions of combustion, and similar images of acetone, which was seeded into the fuel stream, provide maps of the regions of unburned fuel. Two low-compressibility (Mc=0.32, 0.35) reacting mixing layers with differing density ratios and one high-compressibility (Mc=0.70) reacting mixing layer were studied. Higher average acetone signals were measured in the compressible mixing layer than in its low-compressibility counterpart (i.e. same density ratio), indicating a lower entrainment ratio. Additionally, the compressible mixing layer had slightly wider regions of OH and 50% higher OH signals, which was an unexpected result since lowering the entrainment ratio had the opposite effect at low compressibilities. The large-scale structural changes induced by compressibility are believed to be primarily responsible for the difference in the behaviour of the high- and low-compressibility reacting mixing layers. It is proposed that the coexistence of broad regions of OH and high acetone signals is a manifestation of a more biased distribution of mixture compositions in the compressible mixing layer. Other mechanisms through which compressibility can affect the combustion are discussed.

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EVALUATION OF SOCIO-ECONOMIC RESULTS OF UKRAINIAN ECONOMY MANAGEMENT

HERALD of Khmelnytskyi national university ◽

10.31891/2307-5740-2021-298-5(1)-5 ◽

2021 ◽

Vol 298 (5 Part 1) ◽

pp. 28-35

Author(s):

Nila Tiurina ◽

Nataliia Karvatska ◽

Tatiana Nazarchuk ◽

Keyword(s):

Purchasing Power Parity ◽

Capital Investment ◽

Large Scale ◽

Structural Changes ◽

Power Parity ◽

Business Elite ◽

The Social ◽

Macroeconomic Indicators ◽

Extensive Growth ◽

Economic Imbalances

The paper was focused on researching the evolution and the reasons for the crisis in the economy of Ukraine for the period of independence. It was determined that the changes in the social and economic nature of the country’s development were followed by discrepancy in power and resources relations as well as in opposition between political forces and business elite. We analyzed the dynamics of changes in the main macroeconomic indicators in the development of the Ukrainian economy. The results showed that large-scale changes had different effects on the development of the national economy, which was characterized by long periods of crisis and short periods of extensive growth. Three main crises in the economical development have been characterized and the reasons for this were identified. We performed an assessment of the multiple indicators dynamics that characterise the outcomes of the economical governance. Specifically, the level of GDP per capita using purchasing power parity, the dynamics of export, import and balance of foreign trade as well as the dynamics of changes in the index of capital investment and the index of economic freedom. It has been established that the presence of effective structural changes in the economy of the country has caused the accumulation of internal and external economic imbalances. The results of the analysis of the rating assessment of the economy of Ukraine by international organizations showed consistently low positions of the country. We concluded that ineffective economic development became one of the main reasons for the deterioration of the social development of the country. Negative indicators of such development were a sharp decline in population, life expectancy, low wages and social security compared to other European countries.

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Dynamics Redesign of Marine Structures

Journal of Ship Research ◽

10.5957/jsr.1985.29.4.285 ◽

1985 ◽

Vol 29 (04) ◽

pp. 285-295 ◽

Cited By ~ 1

Author(s):

Curtis J. Hoff ◽

Michael M. Bernitsas

Keyword(s):

Large Scale ◽

Structural Changes ◽

Dynamic Equilibrium ◽

Degree Of Freedom ◽

Attractive Alternative ◽

Equilibrium Equations ◽

Element Analysis ◽

Solution Methods ◽

Tower Model ◽

Energy Equations

The dynamic response of a marine structure depends upon the exciting forces and the modal characteristics of the structure. Excessive vibratory response requires reduction of the exciting loads or redesign of the structure or both. In this paper the general redesign problem is formulated. It applies to large-scale structures and allows for large structural changes. Solution of the redesign problem is achieved through perturbation methods which are an attractive alternative to traditional trial-and-error methods. Perturbation solution methods are based on dynamic equilibrium equations or energy equations or both. A new method based on the energy equations which enforces the mode orthogonality conditions is developed and evaluated against all existing methods. Two test cases, a 191-degree-of-freedom two-dimensional ship model and a 810-degree-of-freedom offshore light tower model are used to compare the methods numerically. It is shown that the method developed in this paper can produce, with a single finite element analysis of the baseline system, a structure which satisfies within acceptable limits all nonconflicting design objectives.

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