bluuebunny/crossref_metadata_2025_split huggingface dataset:
GSK-3β regulates the synaptic expression of NMDA receptors via phosphorylation of phosphatidylinositol 4 kinase type IIα
Authors: Amici Mascia , Lee Yeseul , Pope Robert J.P. , Collingridge Graham L. 
Published: November 2019

ABSTRACTUnderstanding the normal functions of GSK-3β in the central nervous system is of major interest because deregulation of this kinase is strongly implicated in a variety of serious brain conditions, such as Alzheimer disease, bipolar disorder and schizophrenia. GSK-3β plays a role in the induction of NMDA receptor-dependent long-term depression (LTD) and several substrates for GSK-3β have been identified in this form of synaptic plasticity, including KLC-2, PSD-95 and tau. Stabilization of NMDA receptors at synapses has also been shown to involve GSK-3β, but the substrates involved are currently unknown. Recent work has identified phosphatidylinositol 4 kinase type IIα (PI4KIIα) as a neuronal GSK-3β substrate that can potentially regulate the surface expression of AMPA receptors. In the present study, we investigated the synaptic role of PI4KIIα in organotypic rat hippocampal slices. We found that knockdown of PI4KIIα had no effect on synaptic AMPA receptors but substantially inhibited synaptic NMDA receptors. Furthermore, the ability of the selective GSK-3 inhibitor, CT99021, to inhibit synaptic NMDA receptors was occluded in shRNA-PI4KIIα transfected neurons. The effects of knocking down PI4KIIα knockdown were fully rescued by a shRNA-resistant wild type construct but could not be rescued by a mutant construct that was unable to be phosphorylated by GSK-3β. The data suggest that GSK-3β phosphorylates PI4KIIα to stabilize the expression of synaptic NMDA receptors.
Abnormal nitration and S-sulfhydration of Sp1-CSE-H2S pathway contribute to the progress of hyperhomocysteinemia: a vicious circle
Authors: Luo Chenghua , Ji Dengyu , Li Yan , Cao Yan , Zhang Shangyue , Yan Wenjing , Xue Ke , Chai Jiayin , Wu Ye , Liu Huirong , Wang Wen 
Published: November 2019

ABSTRACTSp1 (Specificity protein 1)-CSE (cystathionine-γ-lyase)-H2S (hydrogen sulfide) pathway plays an important role in homocysteine-metabolism, whose disorder can result in hyperhomocysteinemia. The deficiency of plasma H2S in patients and animal models with hyperhomocysteinemia has been reported but it is unclear whether this deficiency plays a role in the progress of hyperhomocysteinemia. Furthermore, it remains unknown whether the post-translational modification of Sp1 or CSE mediated by hyperhomocysteinemia itself can in turn affect the development of hyperhomocysteinemia. By both in vivo and in vitro studies, we conducted immunoprecipitation and maleimide assays to detect the post-translational modification of Sp1-CSE-H2S pathway and revealed four major findings: (1) the accumulation of homocysteine augmented the nitration of CSE, thus blunted its bio-activity and caused H2S deficiency. (2) H2S deficiency lowered the S-sulfhydration of Sp1 and inhibited its transcriptional activity, resulted in lower expression of CSE. CSE deficiency decreased the H2S level further, which in turn lowered the S-sulfhydration level of CSE. (3) CSE was S-sulfhydrated at Cys84, Cys109, Cys172, Cys229, Cys252, Cys307 and Cys310 under physiological conditions, mutation of Cys84, Cys109, Cys229, Cys252 and Cys307 decreased its S-sulfhydration level and bio-activity. (4) H2S deficiency could trap hyperhomocysteinemia into a progressive vicious circle and trigger a rapid increase of homocysteine, while blocking nitration or restoring S-sulfhydration could break this circle. In conclusion, this study reveals a novel mechanism involved in the disorder of homocysteine-metabolism, which may provide a candidate therapeutic strategy for hyperhomocysteinemia.
The proteome of small urinary extracellular vesicles after kidney transplantation as an indicator of renal cellular biology and a source for markers predicting outcome
Authors: Braun Fabian , Rinschen Markus , Buchner Denise , Bohl Katrin , Späth Martin , Göbel Heike , Klein Corinna , Kretz Oliver , Puelles Victor G. , Bachurski Daniel , Plagmann Ingo , Wahba Roger , Hallek Michael , Schermer Bernhard , Benzing Thomas , Huber Tobias B. , Beyer Andreas , Stippel Dirk , Kurschat Christine E. , Müller Roman-Ulrich 
Published: November 2019

AbstractKidney transplantation is the preferred renal replacement therapy available. Yet, the biological processes during and after kidney transplantation and how they translate into the overall functional graft outcome are insufficiently understood. Recent developments in the field of extracellular vesicle research allow the deeper exploitation of this non-invasive source. We separated small urinary extracellular vesicles (suEVs) throughout the course of living donor kidney transplantation. SuEVs were collected longitudinally from both the donor and the recipient in 22 living donor kidney transplantations. Unbiased proteomic analysis revealed specific temporal patterns of suEV proteins indicative of the cellular processes involved in the allograft’s response after transplantation with proteins playing a role in complement activation being among the most dynamically regulated components. Using a leave-one-out cross validation model, we identified potential prognostic markers of kidney function at 1 year after transplantation. One of the proteins identified – phosphoenol pyruvate carboxykinase (PCK2) – could be confirmed in an independent validation cohort of another 22 donor-recipient pairs using targeted mass spectrometry. This study sheds the light on early molecular processes during the course of kidney transplantation and shows the future potential of suEVs as a source of biomarkers in this setting. The data set is provided as a unique resource directly accessible through an online tool that allows dynamic interrogation of this first comprising suEV proteome atlas after kidney transplantation.One Sentence SummaryThis study represents the first atlas of the proteomic changes in small urinary extracellular vesicles throughout living donor kidney transplantation identifying PCK2 abundance as a biomarker for renal function 12 months after transplantation
Natural Killer cells dampen the pathogenic features of recall responses to influenza infection
Authors: Mooney Jason P. , Qendro Tedi , Keith Marianne , Philbey Adrian W. , Groves Helen T. , Tregoning John S. , Goodier Martin R. , Riley Eleanor M. 
Published: November 2019

AbstractDespite evidence of augmented Natural Killer (NK) cell responses after influenza vaccination, the role of these cells in vaccine-induced immunity remains unclear. Here, we hypothesized that NK cells might increase viral clearance but possibly at the expense of increased severity of pathology. On the contrary, we found that NK cells serve a homeostatic role during influenza virus infection of vaccinated mice, allowing viral clearance with minimal pathology. Using a diphtheria toxin receptor transgenic mouse model, we were able to specifically deplete NKp46+ NK cells through the administration of diphtheria toxin. Using this model, we assessed the effect of NK cell depletion prior to influenza challenge in vaccinated and unvaccinated mice. NK-depleted, vaccinated animals lost significantly more weight after viral challenge than vaccinated NK intact animals, indicating that NK cells ameliorate disease in vaccinated animals. However, there was also a significant reduction in viral load in NK-depleted, unvaccinated animals indicating that NK cells also constrain viral clearance. Depletion of NK cells after vaccination, but 21 days before infection, did not affect viral clearance or weight loss - indicating that it is the presence of NK cells during the infection itself that promotes homeostasis. Further work is needed to identify the mechanism(s) by which NK cells regulate adaptive immunity in influenza-vaccinated animals to allow efficient and effective virus control whilst simultaneously minimizing inflammation and pathology.
Hubs of long-distance co-alteration in brain pathology
Authors: Cauda Franco , Mancuso Lorenzo , Nani Andrea , Manuello Jordi , Liloia Donato , Gelmini Gabriele , Ficco Linda , Premi Enrico , Duca Sergio , Costa Tommaso 
Published: November 2019

AbstractThe exact mechanisms at the root of pathologic anatomical covariances are still unknown. It is nonetheless becoming clearer that the impact of brain diseases is more convincingly represented in terms of co-alterations rather than in terms of localization of alterations. According to this view, neurological and psychiatric conditions might be seen as whole-brain patterns of modifications. In this context, the physical distance between two co-altered areas may provide insightful information about how pathology develops across the brain, assuming that long-range co-alterations might be relevant features of pathological networks. To demonstrate this hypothesis, we calculated the probability of co-alteration between brain areas across a large database of voxel-based morphometry studies of psychiatric and neurological disorders, and we investigated the physical (Euclidean) distance of the edges of the resulting network. Such analysis produced a series of observations relevant for the understanding of pathology, which range from unanticipated results to the recognition of regions of well-known functional and clinical relevance. For instance, it emphasizes the importance of the anterior and dorsal prefrontal cortices in the distribution of the disease-related alterations, as well as a specular asymmetry of gray matter decreases and increases between the hemispheres. Also, the analyses of schizophrenia and Alzheimer’s disease show that long-distance co-alterations are able to identify areas involved in pathology and symptomatology. Moreover, the good concordance between the measure of the mean physical distance and that of functional degree centrality suggests that co-alterations and connectivity are intimately related. These findings highlight the importance of analyzing the physical distance in pathology, as the areas characterized by a long mean distance may be considered as hubs with a crucial role in the systems of alterations induced by brain diseases.
Transcription-replication conflicts as a source of common fragile site instability caused by BMI1-RNF2 deficiency
Authors: Sanchez Anthony , de Vivo Angelo , Tonzi Peter , Kim Jeonghyeon , Huang Tony T. , Kee Younghoon 
Published: November 2019

AbstractCommon fragile sites (CFSs) are breakage-prone genomic loci, and are considered to be hotspots for genomic rearrangements frequently observed in cancers. Understanding the underlying mechanisms for CFS instability will lead to better insight on cancer etiology. Here we show that Polycomb group proteins BMI1 and RNF2 are suppressors of transcription-replication conflicts (TRCs) and CFS instability. Cells depleted of BMI1 or RNF2 showed slower replication forks and elevated fork stalling. These phenotypes are associated with increase occupancy of RNA Pol II (RNAPII) at CFSs, suggesting that the BMI1-RNF2 complex regulate RNAPII elongation at these fragile regions. Using proximity ligase assays, we showed that depleting BMI1 or RNF2 causes increased associations between RNAPII with EdU-labeled nascent forks and replisomes, suggesting increased TRC incidences. Increased occupancy of a fork protective factor FANCD2 and R-loop resolvase RNH1 at CFSs are observed in RNF2 CRISPR-KO cells, which are consistent with increased transcription-associated replication stress in RNF2-deficient cells. Depleting FANCD2 or FANCI proteins further increased genomic instability and cell death of the RNF2-deficient cells, suggesting that in the absence of RNF2, cells depend on these fork-protective factors for survival. These data suggest that the Polycomb proteins have non-canonical roles in suppressing TRC and preserving genomic integrity.Author summaryIncreasing evidence suggest that instabilities at common fragile sites (CFSs), breakage-prone genomic loci, may be source of genomic aberration seen in cancer cells. Among the proposed mechanisms that can cause CFSs instabilities is the conflict between transcription and replication, and the mechanisms or factors that resolve the possible conflicts are only beginning to be understood. Here we found that deficiency in the Polycomb group proteins BMI1 or RNF2 leads to the CFS instability, and is associated with transcription-associated replication fork stresses. We further found that in the absence of RNF2, cells depend on the Fanconi Anemia fork-protective proteins for genome maintenance and survival. These results underscore that the Polycomb proteins are important for genome maintenance.
A new long-acting GLP-1 derivative 6- KTP ameliorates body weight and lipid metabolism in DIO mice
Authors: Wang Peixiu , Ran Yanhong 
Published: November 2019

AbstractAs a global epidemic, obesity has become the biggest challenge facing global and public health. Glucagon-like peptide-1(GLP-1) has been able to inhibit appetite, slow gastric emptying and reduce body weight. We designed a novel long-acting GLP-1 derivative 6-KTP based on wild-type GLP-1 and performed its pharmacodynamics study on obesity in DIO mice. DIO mice were treated once daily with subcutaneous injections of 6-KTP (1.8 mg/kg body weight), Liraglutide (0.4 mg/kg body weight) or vehicle (phosphate buffered saline (PBS), pH 7.4) for 12 weeks. The results show that 6-KTP decreased food intake, induced anorexia and weight loss, and improved blood lipid and lipid metabolism in DIO mice.
Synapse type-specific proteomic dissection identifies IgSF8 as a hippocampal CA3 microcircuit organizer
Authors: Apóstolo Nuno , Smukowski Samuel N. , Vanderlinden Jeroen , Condomitti Giuseppe , Rybakin Vasily , ten Bos Jolijn , Trobiani Laura , Portegies Sybren , Vennekens Kristel M. , Gounko Natalia V. , Comoletti Davide , Wierda Keimpe D. , Savas Jeffrey N. , de Wit Joris 
Published: November 2019

SummarySynaptic diversity is a key feature of neural circuits. The structural and functional diversity of closely spaced inputs converging on the same neuron suggests that cell-surface interactions are essential in organizing input properties. Here, we analyzed the cell-surface protein (CSP) composition of hippocampal mossy fiber (MF) inputs on CA3 pyramidal neurons to identify regulators of MF-CA3 synapse properties. We uncover a rich cell-surface repertoire that includes adhesion proteins, guidance cue receptors, extracellular matrix (ECM) proteins, and uncharacterized CSPs. Interactome screening reveals multiple ligand-receptor modules and identifies ECM protein Tenascin-R (TenR) as a ligand of the uncharacterized neuronal receptor IgSF8. Presynaptic Igsf8 deletion impairs MF-CA3 synaptic architecture and robustly decreases the density of bouton filopodia that provide feedforward inhibition of CA3 neurons. Consequently, loss of IgSF8 increases CA3 neuron excitability. Our findings identify IgSF8 as a regulator of CA3 microcircuit development and suggest that combinations of CSP modules define input identity.
The transcriptomic response of cells to a drug combination is more than the sum of the responses to the monotherapies
Authors: Diaz Jennifer E. L. , Ahsen Mehmet Eren , Schaffter Thomas , Chen Xintong , Realubit Ronald B. , Karan Charles , Califano Andrea , Losic Bojan , Stolovitzky Gustavo 
Published: November 2019

AbstractOur ability to predict the effects of drug combinations is limited, in part by limited understanding of how the transcriptional response of two monotherapies results in that of their combination. We performed the first analysis of matched time course RNAseq profiling of cells treated with both single drugs and their combinations. The transcriptional signature of the synergistic combination we studied had unique gene expression not seen in either constituent monotherapy. This can be explained mechanistically by the sequential activation of transcription factors in time in the gene regulatory network. The nature of this transcriptional cascade suggests that drug synergy may ensue when the transcriptional responses elicited by two unrelated individual drugs are correlated. We used these results as the basis of a simple prediction algorithm attaining an AUROC of 0.84 in the prediction of synergistic drug combinations in an independent dataset.
Enhanced Cerebral Blood Volume under Normobaric Hyperoxia in the J20-hAPP Mouse Model of Alzheimer’s Disease
Authors: Shabir Osman , Sharp Paul , Rebollar Monica A , Boorman Luke , Howarth Clare , Wharton Stephen B , Francis Sheila E , Berwick Jason 
Published: November 2019

AbstractEarly impairments to neurovascular coupling have been proposed to be a key pathogenic factor in the onset and progression of Alzheimer’s disease (AD). Studies have shown impaired neurovascular function in several mouse models of AD, including the J20-hAPP mouse. In this study, we aimed to investigate early neurovascular changes using wild-type (WT) controls and J20-hAPP mice at 6-9 months of age, by measuring cerebral haemodynamics and neural activity to physiological sensory stimulations. A thinned cranial window was prepared to allow access to cortical vasculature and imaged using 2D-optical imaging spectroscopy (2D-OIS). After chronic imaging sessions where the skull was intact, a terminal acute imaging session was performed where an electrode was inserted into the brain to record simultaneous neural activity. We found that cerebral haemodynamic changes were significantly enhanced in J20-hAPP mice compared with controls in response to physiological stimulations, potentially due to the significantly higher neural activity (hyperexcitability) seen in the J20-hAPP mice. Thus, neurovascular coupling remained preserved under a chronic imaging preparation. Further, under hyperoxia, the baseline blood volume and saturation of all vascular compartments in the brains of J20-hAPP mice were substantially enhanced compared to WT controls, but this effect disappeared under normoxic conditions. This study highlights novel findings not previously seen in the J20-hAPP mouse model, and may point towards a potential therapeutic strategy by driving an increased baseline blood flow to the brain, thereby potentially enhancing the clearance of beta-amyloid.
Entrepreneurial orientation and performance of small and medium-sized enterprises
Authors: Shah Syed Zulfiqar Ali , Ahmad Maqsood 
Published: November 2019

Purpose
This paper aims to investigate the effects of entrepreneurial orientation (EO) on the performance of small and medium-sized enterprises (SMEs) with mediating role of differentiation strategy in Pakistan.

Design/methodology/approach
A theoretical framework has been developed to base the hypotheses, as also to determine the exact approach in this study. To establish the influence of EO on the performance of SME, a five-point Likert scale questionnaire has been used to collect data from middle and senior managers who operate in SMEs in the manufacturing sectors. The sample illustrates 166 incumbents, comprising 68.07 per cent from middle management and 31.93 per cent from senior management operating in manufacturing sector of SMEs, by means of a stratified random sampling technique. The collected data were analyzed using SPSS and Amos graphics software. Hypotheses were tested by using structural equation modeling (SEM) technique.

Findings
EO, as a whole, presents a significant positive effect on the performance of SMEs. Moreover, differentiation strategy partially mediated the relationship between EO and performance of SMEs. Two dimensions of EO, proactiveness and risk-taking propensity, strongly increased firm performance while innovativeness, competitive aggressiveness, autonomy and competitive energy did not cause any significant change. The findings differ from the current view of western enterprises that innovativeness (INO) played a major role by increasing performance of SMEs. The results transpired that innovativeness (INO) tends to reduce performance of SMEs, but the p-value did not reach a high significance value.

Research limitations/implications
The main limitation of this empirical study is comparatively a small size of the sample. The analysis of power suggests that a larger sample could have provided more reliable and extensive results. Regardless of that, the analysis of reliability, using the Cronbach's alpha, exhibited the consistency of outcomes in providing an accurate portrait of the EO influences on the performance of SME.

Practical implications
The study verifies that two dimensions of EO have considerable effects on the performance of SMEs, while the others have not, whereas, the EO, as whole, has significant positive effect on performance of SMEs. These findings should be helpful for researchers looking for appropriate performance measures, and for entrepreneurs aiming at getting support for their decisions and evaluating their performance.

Originality/value
The current study appears to be first of its kind focusing on the link between EOs, as whole, and its dimensions, to performance of SMEs and differentiation strategies within the specific context of Pakistan.
Prioritize the key parameters of Vietnamese coffee industries for sustainability
Authors: Do Thi-Nga , Kumar Vimal , Do Manh-Hoang 
Published: November 2019

Purpose
The purpose of this paper is to identify the critical parameters of the Vietnam coffee industry and develop a comprehensive structural relationship to rank them for effective sustainable development.

Design/methodology/approach
The team of ten experts, having experience of over eight years in the field of various coffee industries in Vietnam, was created to give scores to multiple parameters. Technique for order of preference by similarity to ideal solution (TOPSIS) technique is used to develop the model for fifteen key parameters and then to rank them.

Findings
From the data analysis and results, marketing and brand innovation, product quality, strategic planning and implementation have emerged as top three key parameters while new technology development, supply chain and logistics management, and alliance-joint venture are identified as the bottom three parameters. The findings provide a rank of parameters that help to other coffee industries to identify their key parameters. Besides, the key parameters defined as necessary inputs show the firms more active and well-prepared comprised of ten companies.

Practical implications
The key parameters of the success of any organization are essential contributions. Aiming to improve organizational performance, metrics should be identified as the source of strength to achieve high productivity, profitability and sustainable business performance.

Originality/value
The emphasis of study on key parameters will help organizations to achieve competitive advantage and high productivity for high sustainability in an organizational context.