bluuebunny/crossref_metadata_2025_split huggingface dataset:
The molecular basis, genetic control and pleiotropic effects of local gene co-expression
Authors: Ribeiro Diogo M. , Rubinacci Simone , Ramisch Anna , Hofmeister Robin J. , Dermitzakis Emmanouil T. , Delaneau Olivier 
Published: December 2020

AbstractNearby genes are often expressed as a group. Yet, the prevalence, molecular mechanisms and genetic control of local gene co-expression are far from being understood. Here, by leveraging gene expression measurements across 49 human tissues and hundreds of individuals, we found that local gene co-expression occurs in 13% to 53% genes per tissue. By integrating various molecular assays (e.g. ChIP-seq and Hi-C), we estimated the ability of several mechanisms, such as enhancer-gene targeting, in distinguishing gene pairs that are co-expressed from those that are not. Notably, we identified 32,636 expression quantitative trait loci (eQTLs) which associate to co-expressed gene pairs and often overlap enhancer regions. Due to affecting several genes, these eQTLs are more often associated with multiple human traits than other eQTLs. Our extensive search for local gene co-expression opens the way to comprehend trait pleiotropy and comorbidity and provide functional interpretation of QTL and GWAS findings.
Annexin A1 tripeptide mimetic increases sirtuin-3 to augment mitochondrial function and limit ischemic kidney injury
Authors: Suliman Hagir , Ma Qing , Zhang Zhiquan , Ren Jiafa , Morris Benjamin T. , Crowley Steven D. , Ulloa Luis , Privratsky Jamie R. 
Published: December 2020

AbstractBackgroundAcute kidney injury (AKI) is one of the most common organ failures following surgery. We have developed a tripeptide mimetic (ANXA1sp) of the parent annexin A1 molecule that shows promise as an organ protectant limiting cellular stress; however, its potential as a kidney protective agent remains unexplored, and its mechanism of action is poorly understood. Our hypothesis was that ANXA1sp would limit kidney injury and improve mitochondrial function following surgical ischemic kidney injury.MethodsIn blinded fashion, wildtype mice were assigned to receive vehicle control or experimental drug (ANXA1sp) 1 hour prior to and 1 hour after kidney vascular clamping. Our primary outcome was assessment of kidney injury and function by measurement of serum creatinine and blood urea nitrogen (BUN) and histologic injury scoring of kidney tissue sections. Immunofluorescence microscopy, real-time PCR and western blot were used to assess cell death, oxidative stress, and mitochondrial biomarkers. An in vitro model of oxygen-glucose deprivation in immortalized kidney tubule cells was used.ResultsANXA1sp given prior to and after ischemic kidney injury abrogated ischemic AKI. ANXA1sp further limited kidney cell death and oxidative stress following ischemia. ANXA1sp significantly improved markers associated with mitochondrial DNA repair and mitochondrial biogenesis. ANXA1sp upregulated expression of the mitochondrial protectant sirtuin-3 (SIRT3) in the mitochondria of kidney tubular cells. Silencing of SIRT3 limited ANXA1sp-mediated protection against hypoxic cell death.ConclusionsANXA1sp limits kidney injury through upregulation of SIRT3 and consequent preservation of mitochondrial function. ANXA1sp holds considerable promise as a perioperative kidney protectant prior to ischemia inducing surgery and/or kidney transplantation.
Sea urchins, parrotfish and coral reefs in Grand Cayman, BWI: exemplar or outlier?
Authors: Sherman Elizabeth 
Published: December 2020

ABSTRACTThe change in state of Caribbean coral reefs over the last 40 years has been characterized by phase shifts from scleractinian coral cover to macroalgal cover, the loss of structural complexity and a decline in biodiversity. Not only do scientists want to understand these changes, but also predict the future of coral reefs and their capacity for resilience. In particular, the loss of herbivory, due to declines in parrotfish and the sea urchinDiadema antillarum, has been implicated in many studies as a proximate cause of the coral to macroalgal phase shift. However, reports of the particular role of these putative herbivores have varied, with some studies claiming a causal role for parrotfish, others forDiademaand still others suggesting no such relationships. Often these studies just examined one response measure of coral reef biodiversity. In this paper, I report the relationship between parrotfish andDiademato many metrics of reef organization surveyed simultaneously in the same transects in reefs outside and within the Marine Protected Area (MPA) of Grand Cayman, an island that has been affected by increasing tourism over the last 30 years. The magnitudes of the various measures of reef diversity reported here are consistent with those reported elsewhere. The relationships among those measures are consistent with those reported in some prior studies and inconsistent with others, reflecting the variation in responses documented in prior studies. The presence of sea urchins was associated with survey sites having higher levels of coral cover, lower levels of macroalgae cover, and lower densities of parrotfish than survey sites without sea urchins. Moreover, parrotfish abundance was associated with a decrease in coral cover and little relationship to macroalgae cover. Neither coral cover nor macroalgae cover was different in sites within the MPA compared to sites outside the MPA. I argue that the combination of site-specific local stressors and their interaction with global stressors makes it unlikely that any one island or even regional reef system could serve as an exemplar for Caribbean-wide reef degradation. Moreover, it is difficult to assess the potential for reef resilience in the face of the ongoing assaults from increasing tourism pressures and global climate change.
Propagating patterns of intrinsic activity along macroscale gradients coordinate functional connections across the whole brain
Authors: Yousefi Behnaz , Keilholz Shella 
Published: December 2020

AbstractThe intrinsic activity of the human brain, observed with resting-state fMRI (rsfMRI) and functional connectivity, exhibits macroscale spatial organization such as resting-state networks (RSNs) and functional connectivity gradients (FCGs). Dynamic analysis techniques have shown that the time-averaged maps captured by functional connectivity are mere summaries of time-varying patterns with distinct spatial and temporal characteristics. A better understanding of these patterns might provide insight into aspects of the brain’s intrinsic activity that cannot be inferred by functional connectivity, RSNs or FCGs. Here, we describe three spatiotemporal patterns of coordinated activity across the whole brain obtained by averaging similar ~20-second-long segments of rsfMRI timeseries. In each of these patterns, activity propagates along a particular macroscale FCG, simultaneously across the cortical sheet and in most other brain regions. In some areas, like the thalamus, the propagation suggests previously-undescribed FCGs. The coordinated activity across areas is consistent with known tract-based connections, and nuanced differences in the timing of peak activity between brain regions point to plausible driving mechanisms. The magnitude of correlation within and particularly between RSNs is remarkably diminished when these patterns are regressed from the rsfMRI timeseries, a quantitative demonstration of their significant role in functional connectivity. Taken together, our results suggest that a few recurring patterns of propagating intrinsic activity along macroscale gradients give rise to and coordinate functional connections across the whole brain.
A new method based on the von Mises-Fisher distribution shows that a minority of liver-localized CD8 T cells display hard-to-detect attraction toPlasmodium-infected hepatocytes
Authors: Zenkov Viktor S. , O’Connor James , Cockburn Ian , Ganusov Vitaly V. 
Published: December 2020

AbstractMalaria is a disease caused byPlasmodiumparasites, resulting in over 200 million infections and 400,000 deaths every year. A critical step of malaria infection is when sporozoites, injected by mosquitoes, travel to the liver and form liver stages. Malaria vaccine candidates which induce large numbers of malaria-specific CD8 T cells in mice are able to eliminate all liver stages, preventing fulminant malaria. However, how CD8 T cells find all parasites in 48 hours of the liver stage lifespan is not well understood. Using intravital microscopy of murine livers, we generated unique data on T cell search for malaria liver stages within a few hours after infection. To detect attraction of T cells to an infection site, we used the von Mises-Fisher distribution in 3D, similar to the 2D von Mises distribution previously used in ecology. Our results suggest that the vast majority (70-95%) of malaria-specific and non-specific liver-localized CD8 T cells did not display attraction towards the infection site, suggesting that the search for malaria liver stages occurs randomly. However, a small fraction (15-20%) displayed weak but detectable attraction towards parasites which already had been surrounded by several T cells. We found that speeds and turning angles correlated with attraction, suggesting that understanding mechanisms that determine the speed of T cell movement in the liver may improve the efficacy of future T cell-based vaccines. Stochastic simulations suggest that a small movement bias towards the parasite dramatically reduces the number of CD8 T cells needed to eliminate all malaria liver stages, but to detect such attraction by individual cells requires data from long imaging experiments which are not currently feasible. Importantly, as far as we know this is the first demonstration of how activated/memory CD8 T cells might search for the pathogen in nonlymphoid tissues a few hours after infection. We have also established a framework for how attraction of individual T cells towards a location in 3D can be rigorously evaluated.
Cancer-Associated Mutations Perturb the Structure and Interactions of the Intrinsically Disordered p53 Transactivation Domain
Authors: Schrag Lynn G. , Thevarajan Indhujah , Liu Xiaorong , Prakash Om , Zolkiewski Michal , Chen Jianhan 
Published: December 2020

AbstractIntrinsically disordered proteins (IDPs) are key components of regulatory networks that control crucial aspects of cell decision making. The intrinsically disordered transactivation domain (TAD) of tumor suppressor p53 mediates its interactions with multiple regulatory pathways to control the p53 homeostasis during the cellular response to genotoxic stress. Many cancer-associated mutations have been discovered in p53-TAD, but their structural and functional consequences are poorly understood. Here, by combining atomistic simulations, NMR spectroscopy, and binding assays, we demonstrate that cancer-associated mutations can significantly perturb the balance of p53 interactions with key activation and degradation regulators. Importantly, mutations do not all directly disrupt the known interaction interfaces. Instead, some mutations likely modulate the disordered state of p53-TAD, which affects the interactions. Our work suggests that the disordered conformational ensemble of p53-TAD can serve as a central conduit in regulating the response to various cellular stimuli at the protein-protein interaction level. Understanding how the disordered state of IDPs may be modulated by regulatory signals and/or disease associated perturbations will be essential in the studies on the role of IDPs in biology and diseases.
Widespread decrease of cerebral vimentin-immunoreactive astrocytes in depressed suicides
Authors: O’Leary Liam Anuj , Belliveau Claudia , Davoli Maria Antonietta , Ma Jie Christopher , Tanti Arnaud , Turecki Gustavo , Mechawar Naguib 
Published: December 2020

1AbstractPostmortem investigations have implicated cerebral astrocytes immunoreactive (-IR) for glial fibrillary acidic protein (GFAP) in the etiopathology of depression and suicide. However, it remains unclear whether astrocytic subpopulations IR for other astrocytic markers are similarly affected. Astrocytes IR to vimentin (VIM) display different regional densities than GFAP-IR astrocytes in the healthy brain, and so may be differently altered in depression and suicide. To investigate this, we compared the densities of GFAP-IR astrocytes and VIM-IR astrocytes in postmortem brain samples from depressed suicides and matched non-psychiatric controls in three brain regions (dorsomedial prefrontal cortex, dorsal caudate nucleus and mediodorsal thalamus). A quantitative comparison of the fine morphology of VIM-IR astrocytes was also performed in the same regions and subjects. Finally, given the close association between astrocytes and blood vessels, we also assessed densities of CD31-IR blood vessels. Like for GFAP-IR astrocytes, VIM-IR astrocyte densities were found to be globally reduced in depressed suicide relative to controls. By contrast, CD31-IR blood vessel density and VIM-IR astrocyte morphometric features in these regions were similar between groups, except in prefrontal white matter, in which vascularization was increased and astrocytes displayed fewer primary processes. By revealing a widespread reduction of cerebral VIM-IR astrocytes in cases vs. controls, these findings further implicate astrocytic dysfunctions in depression and suicide.
Deep Linear Modeling of Hierarchical Functional Connectivity in the Human Brain
Authors: Zhang Wei , Palacios Eva , Mukherjee Pratik 
Published: December 2020

AbstractThe human brain exhibits hierarchical modular organization, which is not depicted by conventional fMRI functional connectivity reconstruction methods such as independent component analysis (ICA). To map hierarchical brain connectivity networks (BCNs), we propose a novel class of deep (multilayer) linear models that are constructed such that each successive layer decomposes the features of the preceding layer. Three of these are multilayer variants of Sparse Dictionary Learning (SDL), Non-Negative Matrix Factorization (NMF) and Fast ICA (FICA). We present a fourth deep linear model, Deep Matrix Fitting (MF), which incorporates both rank reduction for data-driven hyperparameter determination as well as a distributed optimization function. We also introduce a novel framework for theoretical comparison of these deep linear models based on their combination of mathematical operators, the predictions of which are tested using simulated resting state fMRI data with known ground truth BCNs. Consistent with the theoretical predictions, Deep MF and Deep SDL performed best for connectivity estimation of 1stlayer networks, whereas Deep FICA and Deep NMF were modestly better for spatial mapping. Deep MF provided the best overall performance, including computational speed. These deep linear models can efficiently map hierarchical BCNs without requiring the manual hyperparameter tuning, extensive fMRI training data or high-performance computing infrastructure needed by deep nonlinear models, such as convolutional neural networks (CNNs) or deep belief networks (DBNs), and their results are also more explainable from their mathematical structure. These benefits gain in importance as continual improvements in the spatial and temporal resolution of fMRI reveal more of the hierarchy of spatiotemporal brain architecture. These new models of hierarchical BCNs may also advance the development of fMRI diagnostic and prognostic biomarkers, given the recent recognition of disparities between low-level vs high-level network connectivity across a wide range of neurological and psychiatric disorders.
Frequency-selective oscillatory control of working memory robustness to distractors
Authors: Novikov Nikita , Gutkin Boris 
Published: December 2020

AbstractWorking memory (WM) is the brain’s ability to retain information that is not directly available from the sensory systems. WM retention is accompanied by sustained firing rate modulation and changes of the large-scale oscillatory profile. Among other changes, beta-band activity elevates in task-related regions, presumably stabilizing WM retention. Alpha-band activity, in turn, is stronger in task-irrelevant regions, serving to protect WM trace from distracting information. Although a large body of experimental evidence links neural oscillations to WM functions, theoretical understanding of their interrelations is still incomplete.In this study, we used a computational approach to explore a potential role of beta and alpha oscillations in control of WM stability. First, we examined a single bistable module that served as a discrete object representation and was resonant in the beta-band in the active state. We demonstrated that beta-band input produced differentially stronger excitatory effect on the module in the active state compared to the background state, while this difference decreased with the input frequency. We then considered a system of two competing modules, selective for a stimulus and for a distractor, respectively. We simulated a task, in which a stimulus was loaded into the first module, then an identical oscillatory input to both modules was turned on, after which a distractor was presented to the second module. We showed that beta-band input prevented loading of high-amplitude distractors and erasure of the stimulus from WM. On the contrary, alpha-band input promoted loading of low-amplitude distractors and the stimulus erasure.In summary, we demonstrated that stability of WM trace could be controlled by global oscillatory input in a frequency-dependent manner via controlling the level of competition between stimulus-encoding and distractor-encoding circuits. Such control is possible due to difference in the resonant and non-linear properties between the background and the active states.
Effects of working memory load and CS-US intervals on delay eyeblink conditioning
Authors: Etemadi Leila , Jirenhed Dan-Anders , Rasmussen Anders 
Published: December 2020

AbstractBackgroundEyeblink conditioning is used in many different species to study motor learning and make inferences about cerebellar function. However, considerable discrepancies in performance between different species combined with evidence that awareness of stimulus contingencies affects performance indicates that eyeblink conditioning in part reflects activity in non-cerebellar regions. This questions whether eyeblink conditioning can be used as a pure measure of cerebellar function in humans.MethodsHere we explored two ways to reduce non-cerebellar influences on performance in eyeblink conditioning: (1) using a short interstimulus interval, and (2) having participants do working memory tasks during the conditioning. Data were analyzed, and the influence of the interstimulus interval and working memory tasks was assessed using a linear mixed effects model.ResultsOur results show that subjects trained with a short interstimulus interval (150ms and 250ms) produce few conditioned responses after 100 trials. For subjects trained with a longer interstimulus interval (500ms), those who did working memory tasks produced fewer conditioned responses and had a more gradual learning curve – more akin to those reported in the animal literature.ConclusionsOur results suggest that having subjects perform working memory tasks during eyeblink conditioning can be a viable strategy to reduce non-cerebellar interference in the learning.
Ion mechanism and parameter analysis of anodal-first waveforms for selective stimulation of C-fiber nerves
Authors: He Siyu , Tripanpitak Kornkanok , Yoshida Yu , Takamatsu Shozo , Huang Shao Ying , Yu Wenwei 
Published: December 2020

AbstractFew investigations have been conducted on selective stimulation of small-radius unmyelinated C nerves (C), which is critical to both recoveries of damaged nerves and pain suppressions. The purpose of this study is to understand how an anodal pulse in an anodal-first stimulation could improveC-selectivity over myelinated nociceptive Aδ nerves (Aδ), and further clarify the landscape of the solution space. The Hodgkin-Huxley (HH) model and the Mclntyre-Richardson-Grill (MRG) model were used for modellingCandAδ,respectively to analyze the underlying ion dynamics and the influence of relevant stimulation waveforms, including monopolar, polarity-symmetric, and asymmetric pulses. Results showed that polarity-asymmetric waveforms with preceding anodal stimulations benefitC-selectivity most, underlain by the decrease of the potassium ion current ofC. The optimal parameters forC-selectivity have been identified in the low frequency band, which will benefit remarkably the designs of nociceptive nerve selective stimulation.
Independence from the perspective of the Shari'ah committee
Authors: Zainal Abidin Nor Hafizah , Mat Yasin Fatimah , Zainal Abidin Ahmad 
Published: December 2020

PurposeThe purpose of this study is to gather the perceptions of the Shari'ah committee members on what and how they safeguard and strengthen their independence in fact and independence in appearance during the discharge of their duties.Design/methodology/approachData were gathered through semi-structured interviews with 13 Shari'ah committee members from 13 different Islamic financial institutions (IFIs).FindingsBased on the Islamic worldview and agency theory, the findings suggest that safeguard measures within the context of the Shari'ah committee are strengthened by the following factors: presence of competencies, personal characteristics of the Shari'ah committee members, board engagement, role of the chairman in the Shari'ah committee and accountability to God. Based on the agency theory, it can be suggested that the characteristics of the Shari'ah committee and the presence of an effective governance structure are able to minimise threats to the independence of the Shari'ah committee and enhance its effectiveness.Practical implicationsThe insights from this study highlight that proper and fit criteria need to be enhanced to ensure the independence of the Shari'ah committee members when performing their roles for IFIs. Moreover, it shows that board engagement and chairman involvement in overseeing the Shari'ah committee in the discharge of its duties is able to improve the independence of the Shari'ah committee both in fact and in appearance.Originality/valueThis study contributes to the evidence on safeguard measures in the Malaysian context, which is highly regulated in relation to the Shari'ah governance practices in IFIs. This evidence could be considered by other Shari'ah committees in different contexts.
Nexus between intellectual capital and business performance: evidence from India
Authors: Weqar Faizi , Sofi Zubair Ahmad , Haque S.M. Imamul 
Published: December 2020

PurposeThe prime intention of this study is to examine the influence of intellectual capital (IC) on the financial performance of Indian companies listed on Standard and Poor Bombay Stock Exchange Sensitive Index (BSE SENSEX).Design/methodology/approachThe study employs the data of 30 most significant and most prominent companies of India listed on BSE SENSEX for 10 years from 2009–2010 to 2018–2019. Value Added Intellectual Coefficient (VAICTM) methodology developed by Pulic (2000) was employed for measuring the efficiency of the IC.FindingsThe efficiency of IC is substantially and positively associated with the financial performance of the Indian companies as measured by return on assets (ROA), market-to-book (MB) ratio and return on equity (ROE). Amongst the three dimensions of VAIC, capital employed efficiency (CEE) was the most vital element in contributing to the firm financial performance, followed by human capital efficiency (HCE). Structural capital efficiency (SCE) only helps in enhancing the ROA of Indian firms.Research limitations/implicationsThe study results are only restricted to the 30 companies of India listed on S&P BSE SENSEX Index. Thus generalization of the result needs especial caution.Originality/valueThe study fills the void in the current literature of IC and business performance and extends the understanding of their relationship by providing empirical evidence.