bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential effects of human TAU isoforms: Somatic retention of 2N-TAU and increased microtubule number induced by 4R-TAU
Authors: Bachmann S. , Bell M. , Klimek J. , Zempel H. 
Published: June 2020

AbstractIn the adult human brain, six isoforms of the microtubule-associated protein TAU are expressed, which result from alternative splicing of exons 2, 3 and 10 of theMAPTgene. These isoforms differ in the number of N-terminal inserts (0N, 1N, 2N) and C-terminal repeat domains (3R or 4R) and are differentially expressed depending on the brain region and developmental stage. Although all TAU isoforms can aggregate and form neurofibrillary tangles, some tauopathies, such as Pick’s Disease and Progressive Supranuclear Palsy, are characterized by the accumulation of specific TAU isoforms. The influence of the individual TAU isoforms in a cellular context, however, is understudied. In this report, we investigated the subcellular localization of the human-specific TAU isoforms in primary neurons, and analyzed TAU isoform-specific effects on cell area and microtubule dynamics in SH-SY5Y neuroblastoma cells. Our results show that 2N-TAU isoforms are particularly retained from axonal sorting and that axonal enrichment is independent from the number of repeat domains, but that the additional repeat domain of 4R-TAU isoform results in a general reduction of cell size and an increase of microtubule counts in cells expressing 4R-TAU isoforms. Our study points out that individual TAU isoforms may influence microtubule dynamics differentially both by different sorting patterns as well as by direct effects on microtubule dynamics.
PyXlinkViewer: a flexible tool for visualisation of protein chemical crosslinking data within the PyMOL molecular graphics system
Authors: Schiffrin Bob , Radford Sheena. E. , Brockwell David. J. , Calabrese Antonio N. 
Published: June 2020

AbstractChemical crosslinking-mass spectrometry (XL-MS) is a valuable technique for gaining insights into protein structure and the organization of macromolecular complexes. XL-MS data yields inter-residue restraints that can be compared with high-resolution structural data. Distances greater than the crosslinker spacer-arm can reveal lowly-populated “excited” states of proteins/protein assemblies, or crosslinks can be used as restraints to generate structural models in the absence of structural data. Despite increasing uptake of XL-MS, there are few tools to enable rapid and facile mapping of XL-MS data onto high-resolution structures or structural models. PyXlinkViewer is a user-friendly plugin for PyMOL v2 that maps intra-protein, inter-protein and dead-end crosslinks onto protein structures/models and automates the calculation of inter-residue distances for the detected crosslinks. This enables rapid visualisation of XL-MS data, assessment of whether a set of detected crosslinks is congruent with structural data, and easy production of high-quality images for publication.
Mast cells participate in the development of diastolic dysfunction in diabetic obese mice
Authors: Guimbal Sarah , Cornuault Lauriane , Hollier Pierre-Louis , Chapouly Candice , Bats Marie-Lise , Gadeau Alain-Pierre , Couffinhal Thierry , Renault Marie-Ange 
Published: June 2020

AbstractRationalHeart failure with preserved ejection fraction (HFpEF) is a growing epidemiologic issue. However, to date, its pathophysiology remains poorly understood.ObjectiveOur goal was to investigate the role of microvessel disease in the pathophysiology of diastolic dysfunction.FindingsTo do so, we used Leptin receptor deficient (Leprdb/db) female mice as a model of diastolic dysfunction. In these mice, the increased end diastolic pressure (EDP) signing diastolic dysfunction is associated with vascular leakage, endothelial cell activation and leucocyte infiltration. Strikingly, a RNA sequencing analysis of the cardiac vascular fraction of both Leprdb/dband control female mice confirmed endothelial dysfunction and systemic inflammation but also revealed a strong increase in several mast cell markers (notably FceR1a, Tryptase and Chymase). We then histologically confirmed an accumulation of activated mast cells in the heart of Leprdb/dbmice. Importantly, mast cell degranulation inhibition reduced EDP, vascular leakage and leucocyte infiltration in Leprdb/dbmice.ConclusionMast cells play a critical role in the development of cardiac microvessel disease and diastolic dysfunction.
Targeting Scavenger Receptor Type B1 In Cholesterol-Addicted Lymphomas Abolishes Glutathione Peroxidase 4 and Results in Ferroptosis
Authors: Rink Jonathan S. , Lin Adam Yuh , McMahon Kaylin M. , Calvert Andrea E. , Yang Shuo , Taxter Tim , Moreira Jonathan , Chadburn Amy , Behdad Amir , Karmali Reem , Thaxton C. Shad , Gordon Leo I. 
Published: June 2020

ABSTRACTNormal human cells can either synthesize or uptake cholesterol from lipoproteins to meet their metabolic requirements. Some malignant cells absolutely require cholesterol uptake from lipoproteins for survival becausede novocholesterol synthesis genes are transcriptionally silent or mutated. Recent data suggest that lymphoma cells dependent upon lipoprotein-mediated cholesterol uptake are also dependent on the expression of the lipid hydroperoxidase enzyme glutathione peroxidase 4 (GPX4) to prevent cell death by ferroptosis. Ferroptosis is an oxygen-and iron-dependent cell death mechanism that results from the accumulation of oxidized lipids in cell membranes. To study mechanisms linking cholesterol uptake with ferroptosis, we employed lymphoma cell lines known to be sensitive to cholesterol uptake depletion and treated them with high-density lipoprotein-like (HDL) nanoparticles (HDL NPs). HDL NPs are a cholesterol-poor ligand of the receptor for cholesterol-rich HDL, scavenger receptor type B-1 (SCARB1). Our data reveal that HDL NP treatment activates a compensatory metabolic response in treated cells favoringde novocholesterol synthesis, which is accompanied by reduced expression of GPX4. As a result, accumulation of oxidized membrane lipids leads to cell death through a mechanism consistent with ferroptosis. Furthermore, ferroptosis was validatedin vivoafter systemic administration of HDL NPs in mouse lymphoma xenografts and in primary samples obtained from patients with lymphoma. In summary, targeting SCARB1 with HDL NPs in cholesterol uptake addicted lymphoma cells abolishes GPX4 and cancer cell death ensues through a mechanism consistent with ferroptosis.
Thermal niches of specialized gut symbionts: the case of social bees
Authors: Hammer Tobin J. , Le Eli , Moran Nancy A. 
Published: June 2020

AbstractResponses to climate change are particularly complicated in species that engage in symbioses, as the niche of one partner may be modified by that of the other. We explored thermal traits in gut symbionts of honeybees and bumblebees, which are vulnerable to rising temperatures.In vitroassays of symbiont strains isolated from 16 host species revealed variation in thermal niches. Strains from bumblebees tended to be less heat-tolerant than those from honeybees, possibly due to bumblebees maintaining cooler nests or inhabiting cooler climates. Overall however, bee symbionts grew at temperatures up to 44 °C and withstood temperatures up to 52 °C, at or above the upper thermal limits of their hosts. While heat-tolerant, most strains of the symbiontSnodgrassellagrew relatively slowly below 35 °C, perhaps because of adaptation to the elevated body temperatures that bees maintain through thermoregulation. In a gnotobiotic bumblebee experiment,Snodgrassellawas unable to consistently colonize bees reared below 35 °C under conditions that limit thermoregulation. Thus, host thermoregulatory behavior appears important in creating a warm microenvironment for symbiont establishment. Bee-microbiome-temperature interactions could affect host health and pollination services, and inform research on the thermal biology of other specialized gut symbionts, such as those of humans.
Postsynaptic serine racemase regulates NMDA receptor function
Authors: Wong Jonathan M. , Folorunso Oluwarotimi , Barragan Eden V. , Berciu Cristina , Harvey Theresa L. , DeChellis-Marks Michael R. , Glausier Jill R. , MacDonald Matthew L. , Coyle Joseph T. , Balu Darrick T. , Gray John A. 
Published: June 2020

AbstractD-serine is the primary NMDA receptor (NMDAR) co-agonist at mature forebrain synapses and is synthesized by the enzyme serine racemase (SR). However, our understanding of the mechanisms regulating the availability of synaptic D-serine remains limited. Though early studies suggested D-serine is synthesized and released from astrocytes, more recent studies have demonstrated a predominantly neuronal localization of SR. More specifically, recent work intriguingly suggests that SR may be found at the postsynaptic density, yet the functional implications of postsynaptic SR on synaptic transmission are not yet known. Here, we show an age-dependent dendritic and postsynaptic localization of SR and D-serine by immunohistochemistry and electron microscopy in mouse CA1 pyramidal neurons, as well as the presence of SR in human hippocampal synaptosomes. In addition, using a single-neuron genetic approach in SR conditional knockout mice, we demonstrate a cell-autonomous role for SR in regulating synaptic NMDAR function at Schaffer collateral (CA3)-CA1 synapses. Importantly, single-neuron genetic deletion of SR resulted in the elimination of LTP at one month of age. Interestingly, there was a restoration of LTP by two months of age that was associated with an upregulation of synaptic GluN2B. Our findings support a cell-autonomous role for postsynaptic neuronal SR in regulating synaptic NMDAR function and suggests a possible autocrine mode of D-serine action.
Differential covariance: A new method to estimate functional connectivity in fMRI
Authors: Lin Tiger W. , Chen Yusi , Bukhari Qasim , Krishnan Giri P. , Bazhenov Maxim , Sejnowski Terrence J. 
Published: June 2020

AbstractMeasuring functional connectivity from fMRI recordings is important in understanding processing in cortical networks. However, because the brain’s connection pattern is complex, currently used methods are prone to producing false functional connections. We introduce differential covariance analysis, a new method that uses derivatives of the signal for estimating functional connectivity. We generated neural activities from Dynamical Causal Modeling and a neural network of Hodgkin-Huxley neurons and then converted them to hemodynamic signals using the forward Balloon model. The simulated fMRI signals together with the ground truth connectivity pattern were used to benchmark our method with other commonly used methods. Differential covariance achieved better results in complex network simulations. This new method opens an alternative way to estimate functional connectivity.
Nucleus accumbens melanin-concentrating hormone signaling promotes feeding in a sex-specific manner
Authors: Terrill Sarah J. , Subramanian Keshav , Lan Rae , Liu Clarissa M. , Cortella Alyssa M. , Noble Emily E. , Kanoski Scott E. 
Published: June 2020

AbstractMelanin-concentrating hormone (MCH) is an orexigenic neuropeptide produced in the lateral hypothalamus and zona incerta that increases food intake. The neuronal pathways and behavioral mechanisms mediating the orexigenic effects of MCH are poorly understood, as is the extent to which MCH-mediated feeding outcomes are sex-dependent. Here we investigate the hypothesis that MCH-producing neurons act in the nucleus accumbens shell (ACBsh) to promote feeding behavior and motivation for palatable food in a sex-dependent manner. We utilized ACBsh MCH receptor (MCH1R)-directed pharmacology as well as a dual virus chemogenetic approach to selectively activate MCH neurons that project to the ACBsh. Results reveal that both ACBsh MCH1R activation and activating ACBsh-projecting MCH neurons increase consumption of standard chow and palatable sucrose in male rats without affecting motivated operant responding for sucrose, general activity levels, or anxiety-like behavior. In contrast, food intake was not affected in female rats by either ACBsh MCH1R activation or ACBsh-projecting MCH neuron activation. To determine a mechanism for this sexual dimorphism, we investigated whether the orexigenic effect of ACBsh MCH1R activation is reduced by endogenous estradiol signaling. In ovariectomized female rats on a cyclic regimen of either estradiol (EB) or oil vehicle, ACBsh MCH1R activation increased feeding only in oil-treated rats, suggesting that EB attenuates the ability of ACBsh MCH signaling to promote food intake. Collective results show that that MCH ACBsh signaling promotes feeding in an estrogen- and sex-dependent manner, thus identifying novel neurobiological mechanisms through which MCH and female sex hormones interact to influence food intake.
Methotrexate carried in lipid core nanoparticles reduces microglial activation and is neuroprotective after ischemic cortical stroke
Authors: Pereira Edmundo L. R. , Dias Michelle N.C. , dos Santos Ijair R. , Ramos Ana Carolina , Hamoy Moisés , Feio Danielle Cristine A. , Tavoni Thauany M. , da Silva Priscila Carvalho M. , Maranhão Raul , Gomes-Leal Walace 
Published: June 2020

AbstractMethotrexate carried in lipid core nanoparticles (LDE-MTX) is a low toxicity compound effective in reducing inflammation and secondary damage in experimental models of arthritis, atherosclerosis, myocardial infarction, cardiac allograft vasculopathy and other pathological conditions. Nevertheless, whether it is neuroprotective after stroke is unknown. Here, we explored whether LDE-MTX could cross blood brain barrier (BBB) to exert anti-inflammatory and neuroprotecive effects after experimental cortical stroke in rats. Tissue uptake was assessed by injecting radioactively labeled-LDE through the caudal vein into both sham (n=18) and adult Wistar rats submitted to endothelin-1 (ET-1)-induced cortical stroke (n=11). To address possible neuroprotective effects of LDE-MTX after stroke, 10 adult male Wistar rats were randomly allocated in two groups: animals treated with LDE-MTX (1 mg/kg,i.v., n=5) or LDE-alone (i.v., n=5) at 4 hours after stroke induction. Animals were perfused with 0.9% saline and 4% paraformaldehyde at 7 days post-injury. Histopathology was assessed by cresyl violet staining. Mature neuronal bodies (anti-NeuN), astrocytes (anti-GFAP) and microglia (anti-Iba1) were immunolabeled by immunohistochemistry. Scintigraphy technique revealed accumulation of tritiated LDE in different brain regions and in non-neural organs without overt toxicity in both sham and ischemic rats. LDE-MTX treatment induced a 10-fold (1000%) reduction in microglial activation in the ischemic cortex and afforded a 319% increase in neuronal preservation in the ischemic periinfarct region compared to LDE-alone group. There was no effect of LDE-MTX treatment on primary infarct area and astrocytosis. The results suggest that LDE-MTX formulation must be considered a very promising neuroprotective agent for ischemic stroke. Future studies using different concentrations and longer survival times are needed before assessing the suitability of LDE-MTX as a neuroprotective agent for human stroke.
Four different mechanisms for switching cell polarity
Authors: Tostevin Filipe , Wigbers Manon , Søgaard-Andersen Lotte , Gerland Ulrich 
Published: June 2020

AbstractThe mechanisms and design principles of regulatory systems establishing stable polarized protein patterns within cells are well studied. However, cells can also dynamically control their cell polarity. Here, we ask how an upstream signaling system can switch the orientation of a polarized pattern. We use a mathematical model of a core polarity system based on three proteins as the basis to study different mechanisms of signal-induced polarity switching. The analysis of this model reveals four general classes of switching mechanisms with qualitatively distinct behaviors: the transient oscillator switch, the reset switch, the prime-release switch, and the push switch. Each of these regulatory mechanisms effectively implements the function of a spatial toggle switch, however with different characteristics in their nonlinear and stochastic dynamics. We identify these characteristics and also discuss experimental signatures of each type of switching mechanism.
Formula 1, city and tourism: a research theme analyzed on the basis of a systematic literature review
Authors: Roult Romain , Auger Denis , Lafond Marie-Pierre 
Published: June 2020

PurposeThis paper aims to draw up the state of scientific knowledge in the field of Formula 1 with relation to tourism and urban studies.Design/methodology/approachThis study is based on a systematic review of the scientific literature regarding this issue. Using targeted keywords and the analysis of various documentary databases, 8,075 references were identified and 40 documents were analyzed in an exhaustive manner.FindingsThis study presents a very nuanced portrait of the urban and tourism impacts of Formula 1 on the host territories. In many of the studies analyzed, a gap may be noted, sometimes flagrant, between the development goals of the promoters of these mega-events and local realities. This study also highlights the fact that Formula 1 has established itself as a sports events industry that can renew and enhance the brand image of certain cities.Originality/valueVery few recent studies have exhaustively reviewed the scientific literature published in English and French with regard to the field of Formula 1 from a tourism and urban perspective. This study makes it possible to identify the main analytical findings and research perspectives resulting from this scientific work while discussing them using a theoretical framework related to the hypermodern character of different societies.
Impact of natural disasters on New Zealand regional family businesses: perspectives of baby boomer family business owners
Authors: Wu Julia Yonghua 
Published: June 2020

PurposeThis paper aims to describe what baby boomer family business owners in New Zealand perceive the implications of earthquakes on their business and succession planning. The current study focuses on how some businesses have survived significant uncontrollable contingencies, for instance, natural disasters. This paper also documents the insight of what baby boomer family business owners value in their succession planning.Design/methodology/approachQualitative method was undertaken, comprising face-to-face in-depth interviews with 18 participants, who are baby boomers family business owners in New Zealand.FindingsDriven by the unique social and political conditions in New Zealand, baby boomer family business owner’s revealed unique mind-sets and motivations that are oriented in their family value and/or the sense of self-fulfillment. As a result, they are able to adapt to uncertainties and reflect on their adaptability. Although approaching their retirement age and survived earthquakes, most interviewees neither have any urgency to establish or execute succession plans nor are they prepared for contingencies. A profitable trade sale has been identified as a preferred exit strategy.Research limitations/implicationsThe current study is aimed to fill in the gap of exploring how some baby boomers’ family businesses in New Zealand survived deadly earthquakes and how they approach their own succession planning.Practical implicationsIt is hoped that this research will contribute to the well-being of family businesses and be of value to practitioners who provide professional advises for family firms and those who aspire to a career in family businesses. This paper also aims to shed light on the implication of aging population and government policies on family businesses. The findings are, therefore, useful for academics, professional consultants, advisors and regulators.Originality/valueHowever, natural disasters, social unrest and many uncontrollable events disrupt business operations and can be viewed as uncontrollable contingencies. Ageing population and generation-based similarities are also common to many countries and communities. Nonetheless, the interdisciplinary research on ageing population is scant in the context of financial planning, management accounting or taxation at the firm level. This paper also calls for more in-depth exploration on the implications of demographical factors on the organisations and their success or demise.
BIM-based integrated solution for analysis and management of mismatches during construction
Authors: Gharouni Jafari Kobra , Ghazi Sharyatpanahi Nozhat Sadat , Noorzai Esmatullah 
Published: June 2020

Purpose
Prompt and effective responses to incompatibilities between as-designed and as-built drawings prevent cost and time overruns and material waste. This paper aims to provide an efficient framework to handle mismatches between these two models with the least negative impact on the whole project.

Design/methodology/approach
First, 11 most frequent mismatches were identified through questionnaires. Also, the respondents were asked to determine the mismatches’ roots and solutions and the impact of applying solutions on the whole project. Afterward, the process to present the optimum solution to one of these mismatches was modeled. After running the application programming interface developed in Navisworks software, decision-makers access a form, showing mismatches, their causes and solutions, as well as the solutions’ effect. To finalize the optimal solution, a platform was provided on whether to accept the system solution or to propose an alternative.

Findings
To empirically validate the reliability of the proposed framework, two projects were investigated. Two different approaches to dealing with the same mismatch occurred in these projects were compared in terms of time, cost and material required. The results showed that addressing the mismatches through the proposed framework can efficiently enhance time, cost and material consumption, in comparison with the traditional approach.

Originality/value
There is currently no building information modeling-based holistic framework for managing mismatches between as-designed and as-built drawings. The results of this research can help contractors to make the best decision, saving project resources, when setting about a mismatch during construction.