bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spinal TNF-α impedes Fbxo45-dependent Munc13-1 ubiquitination to mediate neuropathic allodynia in rats
Authors: Hsieh Ming-Chun , Ho Yu-Cheng , Lai Cheng-Yuan , Chou Dylan , Chen Gin-Den , Lin Tzer-Bin , Peng Hsien-Yu 
Published: July 2018

AbstractPresynaptic active zone proteins play a crucial role in regulating synaptic plasticity. Although the ubiquitin–proteasome system underlying the degradation of the presynaptic active zone protein is well established, the contribution of this machinery to regulating spinal plasticity during neuropathic pain development remains unclear. Here, using male Sprague Dawley rats, we demonstrated along with behavioral allodynia, neuropathic injury induced a marked elevation in the expression levels of an active zone protein Munc13-1 in the homogenate and synaptic plasma membrane of the ipsilateral dorsal horn. Moreover, nerve injury-increased Munc13-1 expression was associated with an increase in the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) in ipsilateral dorsal horn neurons. This neuropathic injury-induced accumulation of Munc13-1 colocalized with synaptophysin but not homer1 in the dorsal horn. Focal knockdown of spinal Munc13-1 expression attenuated behavioral allodynia and the increased frequency, not the amplitude, of mEPSCs in neuropathic rats. Remarkably, neuropathic injury decreased spinal Fbxo45 expression, Fbxo45-Munc13-1 co-precipitation, and Munc13-1 ubiquitination in the ipsilateral dorsal horn. Conversely, focal knockdown of spinal Fbxo45 expression in naive animals resulted in behavioral allodynia in association with similar protein expression and ubiquitination in the dorsal horn as observed with neuropathic injury rats. Furthermore, both neuropathic insults and intrathecal injection of tumor necrosis factor-α (TNF-α) impeded spinal Fbxo45-dependent Munc13-1 ubiquitination, which was reversed by intrathecal TNF-α-neutralizing antibody. Our data revealed that spinal TNF-α impedes Fbxo45-dependent Munc13-1 ubiquitination that accumulates Munc13-1 in the presynaptic area and hence facilitates the synaptic excitability of nociceptive neurotransmission underlying neuropathic pain.
Overexpression of endophilin A1 exacerbates synaptic alterations in a mouse model of Alzheimer’s disease
Authors: Yu Qing , Wang Yongfu , Du Fang , Yan Shijun , Hu Gang , Origlia Nicola , Rutigliano Grazia , Sun Qinru , Yu Haiyang , Ainge James , Yan Shi Fang , Gunn-Moore Frank , Yan Shirley ShiDu 
Published: July 2018

AbstractEndophilin A1 (EP) is a protein enriched in synaptic terminals that has been linked to Alzheimer’s disease (AD). Previous in vitro studies have shown that EP can bind to a variety of proteins, which elicit changes in synaptic transmission of neurotransmitters and spine formation. Additionally, we previously showed that EP protein levels are elevated in AD patients and AD transgenic animal models. Here, we establish the in vivo consequences of upregulation of EP expression in amyloid-β peptide (Aβ)-rich environments, leading to changes in both long-term potentiation and learning and memory of transgenic animals. Specifically, increasing EP augmented cerebral Aβ accumulation. EP-mediated signal transduction via reactive oxygen species (ROS)/p38 mitogen-activated protein (MAP) kinase contributes to Aβ-induced mitochondrial dysfunction, synaptic injury, and cognitive decline, which could be rescued by blocking either ROS or p38 MAP kinase activity.
Statistical mechanics for metabolic networks during steady state growth
Authors: De Martino Daniele , MC Andersson Anna , Bergmiller Tobias , Guet Călin C. , Tkačik Gašper 
Published: July 2018

AbstractWhich properties of metabolic networks can be derived solely from stoichiometry? Predictive results have been obtained by flux balance analysis (FBA), by postulating that cells set metabolic fluxes to maximize growth rate. Here we consider a generalization of FBA to single-cell level using maximum entropy modeling, which we extend and test experimentally. Specifically, we define for Escherichia coli metabolism a flux distribution that yields the experimental growth rate: the model, containing FBA as a limit, provides a better match to measured fluxes and it makes a wide range of predictions: on flux variability, regulation, and correlations; on the relative importance of stoichiometry vs. optimization; on scaling relations for growth rate distributions. We validate the latter here with single-cell data at different sub-inhibitory antibiotic concentrations. The model quantifies growth optimization as emerging from the interplay of competitive dynamics in the population and regulation of metabolism at the level of single cells.
Asymmetric migration decreases stability but increases resilience in a heterogeneous metapopulation
Authors: Limdi Anurag , Pérez-Escudero Alfonso , Li Aming , Gore Jeff 
Published: July 2018

AbstractMany natural populations are spatially distributed, forming a network of subpopulations linked by migration. Migration patterns are often asymmetric and heterogeneous, with important consequences on the ecology and evolution of the species. Here we investigate experimentally how asymmetric migration and heterogeneous structure affect a simple metapopulation of budding yeast, formed by one strain that produces a public good and a non-producer strain that benefits from it. We study metapopulations with star topology and asymmetric migration, finding that all their subpopulations have a higher fraction of producers than isolated populations. Furthermore, the metapopulations have lower tolerance to challenging environments but higher resilience to transient perturbations. This apparent paradox occurs because tolerance to a constant challenge depends on the weakest subpopulations of the network, while resilience to a transient perturbation depends on the strongest ones.
A critical view on transgenerational epigenetic inheritance in humans
Authors: Horsthemke Bernhard 
Published: July 2018

AbstractTransgenerational epigenetic inheritance refers to the transmission of epigenetic information through the germline. While it has been observed in plants, nematodes and fruit flies, its occurrence in mammals—and humans in particular—is the matter of controversial debate, mostly because the study of transgenerational epigenetic inheritance is confounded by genetic, ecological and cultural inheritance. In this comment, I discuss the phenomenon of transgenerational epigenetic inheritance and the difficulty of providing conclusive proof for it in experimental and observational studies.
Proteasome-targeted nanobodies alleviate pathology and functional decline in an α-synuclein-based Parkinson’s disease model
Authors: Chatterjee Diptaman , Bhatt Mansi , Butler David , De Genst Erwin , Dobson Christopher M. , Messer Anne , Kordower Jeffrey H. 
Published: July 2018

AbstractTherapeutics designed to target α-synuclein (α-syn) aggregation may be critical in halting the progression of pathology in Parkinson’s disease (PD) patients. Nanobodies are single-domain antibody fragments that bind with antibody specificity, but allow readier genetic engineering and delivery. When expressed intracellularly as intrabodies, anti-α-syn nanobodies fused to a proteasome-targeting proline, aspartate or glutamate, serine, and threonine (PEST) motif can modulate monomeric concentrations of target proteins. Here we aimed to validate and compare the in vivo therapeutic potential of gene therapy delivery of two proteasome-directed nanobodies selectively targeting α-syn in a synuclein overexpression-based PD model: VH14*PEST (non-amyloid component region) and NbSyn87*PEST (C-terminal region). Stereotaxic injections of adeno-associated viral 5-α-syn (AAV5-α-syn) into the substantia nigra (SN) were performed in Sprague–Dawley rats that were sorted into three cohorts based on pre-operative behavioral testing. Rats were treated with unilateral SN injections of vectors for VH14*PEST, NbSyn87*PEST, or injected with saline 3 weeks post lesion. Post-mortem assessments of the SN showed that both nanobodies markedly reduced the level of phosphorylated Serine-129 α-syn labeling relative to saline-treated animals. VH14*PEST showed considerable maintenance of striatal dopaminergic tone in comparison to saline-treated and NbSyn87*PEST-treated animals as measured by tyrosine hydroxylase immunoreactivity (optical density), DAT immunoreactivity (optical density), and dopamine concentration (high-performance liquid chromatography). Microglial accumulation and inflammatory response, assessed by stereological counts of Iba-1-labeled cells, was modestly increased in NbSyn87*PEST-injected rats but not in VH14*PEST-treated or saline-treated animals. Modest behavioral rescue was also observed, although there was pronounced variability among individual animals. These data validate in vivo therapeutic efficacy of vector-delivered intracellular nanobodies targeting α-syn misfolding and aggregation in synucleinopathies such as PD.
Use of phosphate-binders and risk of infection-related and all-cause mortality in patients undergoing hemodialysis: The Q-Cohort Study
Authors: Yamada Shunsuke , Tokumoto Masanori , Taniguchi Masatomo , Yoshida Hisako , Arase Hokuto , Tatsumoto Narihito , Hirakata Hideki , Kitazono Takanari , Tsuruya Kazuhiko 
Published: July 2018

AbstractThe use of phosphate (P)-binders allows hemodialysis patients to take in more protein and thus may maintain a good nutritional status. Protein-energy-malnutrition increases the risk of infection-related death. The association between use of P-binders and the relative risks of infection-related death remains unknown in hemodialysis patients. A total of 2926 hemodialysis patients registered to the Q-Cohort Study was followed up for 4-years. The association between use of P-binders and the risks for infection-related and all-cause mortality were estimated by Cox proportional hazards risk model with multiple adjustments by conventional and propensity-score based approaches. During the follow-up period, 106 patients and 492 patients died of infection and any cause, respectively. Cox proportional hazards models with multivariable adjustments including nutritional confounders showed that the incidence of infection-related death was significantly lower in patients with P-binders use compared with those without (hazard ratio [95% confidence interval] for infection-related mortality 0.63 [0.40–0.99]). The results remained significant even after applying four different propensity score-based analyses. Notably, use of P-binders was associated with a lower risk of all-cause mortality. Further studies including randomized controlled clinical trials and observational studies analyzed by an instrumental variable model will provide more robust evidences for the associations observed in our study.
Selection analyses of paired HIV-1 gag and gp41 sequences obtained before and after antiretroviral therapy
Authors: Tzou Philip L. , Rhee Soo-Yon , Pond Sergei L. Kosakovsky , Manasa Justen , Shafer Robert W. 
Published: July 2018

AbstractMost HIV-1-infected individuals with virological failure on a pharmacologically-boosted protease inhibitor (PI) regimen do not develop PI-resistance protease mutations. One proposed explanation is that HIV-1 gag or gp41 cytoplasmic domain mutations might also reduce PI susceptibility. In a recent study of paired gag and gp41 sequences from individuals with virological failure on a PI regimen, we did not identify PI-selected mutations and concluded that if such mutations existed, larger numbers of paired sequences from multiple studies would be needed for their identification. In this study, we generated site-specific amino acid profiles using gag and gp41 published sequences from 5,338 and 4,242 ART-naïve individuals, respectively, to assist researchers identify unusual mutations arising during therapy and to provide scripts for performing established and novel maximal likelihood estimates of dN/dS substitution rates in paired sequences. The pipelines used to generate the curated sequences, amino acid profiles, and dN/dS analyses will facilitate the application of consistent methods to paired gag and gp41 sequence datasets and expedite the identification of potential sites under PI-selection pressure.
Schreien und Rufen von Menschen mit Demenz
Authors: Urselmann Hans-Werner 
Published: July 2018

ZusammenfassungWenn Menschen mit Demenz laut schreien oder rufen, ist für Pflegende häufig schwer einzuschätzen, was sie damit ausdrücken wollen. Wie es gelingt, das oft
herausfordernde und manchmal unerträgliche Verhalten zu interpretieren und welche Interventionen angewendet werden können, schildert unser Autor. Denn eins
steht fest: Es gibt weder sinnlose Schreie oder Rufe von Menschen mit Demenz noch Patentrezepte für den Umgang damit.
Körperliche Wunden lassen sich leichter versorgen als seelische
Authors: Lang Friederike 
Published: July 2018

ZusammenfassungIm zweiten Teil ihres sehr persönlichen Berichts schildert unsere Autorin, welche Erfahrungen sie mit selbstverletzendem Verhalten, Suizidalität und während
ihrer Klinikaufenthalte gemacht hat.
Synergistic Bimetallic Catalysis for Carboboration of Unsaturated Hydrocarbons
Authors: Fañanás-Mastral Martín , Rivera-Chao Eva , Fra Laura 
Published: July 2018

Synergistic bimetallic catalysis has become a very efficient tool for the selective carboboration of unsaturated hydrocarbons. This synthetic approach is based on the use of a catalytically generated boron-substituted organocopper nucleophile in a cross-coupling reaction catalyzed by a second transition metal. This way, hydrocarbons can be used as pro-nucleophiles in this type of transformations thus rendering a clean and operationally simple alternative to the traditional cross-coupling methodologies. This review provides a summary of the developments on this topic and discusses both the synthetic utility and mechanisms of these reactions.1	Introduction2	Carboboration of Alkenes via Synergistic Catalysis3	Carboboration of 1,3-Dienes via Synergistic Catalysis4	Carboboration of Alkynes via Synergistic Catalysis5	Conclusions
R 68 070: Thromboxane A2 Synthetase Inhibition and Thromboxane A2/Prostaglandin Endoperoxide Receptor Blockade Combined in One Molecule - I. Biochemical Profile In Vitro
Authors: Clerck F De , Beetens J , Courcelles D de Chaffoy de , Freyne E , Janssen P A J 
Published: July 2018

SummaryR 68 070 or (E)-5-[[[(3-pyridinyl)[3-(trifluoromethyl)phenyl]- methylen]amino]oxy] pentanoic acid (Janssen Research Foundation, Belgium) combines specific thromboxane A2 (TXA2) synthetase inhibition with TXA2/prostaglandin endoperoxide receptor blockade in one molecule.In vitro, the compound specifically inhibits the production of TXB2 from [14C] arachidonic acid by washed human platelets (IC50 = 8.2 × 10-9 M) and by platelet microsomes (IC50 = 3.6 × 10-9 M), of MDA (IC50 = 1.91 × 10-8 M) and of TXB2 (IC50 = 1.47 × 10-8 M) by thrombin-coagulated human platelet-rich plasma (P.R.P.) and whole blood respectively and increases the levels of PGD2, PGE2, PGF2α and 6-keto-PGF1α. The activity of cyclo-oxygenase-, prostacyclin synthetase-, 5-, 12- and 15-lipoxygenase-enzymes are not affected. Additionally, R 68 070 inhibits human platelet aggregation in P.R.P. induced by U 46619 3 × 10-7 M to 2 × 10-6 M (IC50 = 2.08 × 10-6 M to 2.66 × 10-5 M), collagen 0.5 to 2 μg/ml (IC50 = 2.85 × 10-6 M to 4.81 × 10-5 M), arachidonic acid 7.5 × 10-4 M to 2 × 10- M (IC50 = 2.1 × 10-8 M to 3.3 × 10-8 M) and the U 46619 (1 × 10-7 M)-induced accumulation of [32P] phosphatidic acid (IC50 = 5.24 × 10-7 M) in washed human platelets. Collagen (0.75 μg/ml)-induced ATP release (IC50 = 4.1 × 10-6 M), ADP (1 to 2.5 × 10-6 M)-induced second wave aggregation (IC50 = 3.19 × 10-6 M) in P.R.P. as well as the collagen (1 μg/ml)-induced adhesion/aggregation reaction in human whole blood (IC50 = 1.02 × 10-5 M) are reduced as well by the compoun.Primary platelet reactions induced by serotonin, ADP, PAF, or A 23187, platelet adenylate cyclase- and cAMP phosphodiesterase-activity, and platelet inhibitory activities of PGD2, PGI2, PGE2, PGE1 are not modified by R 68 070.This biochemical profile is compatible with a dual mechanism of action of R 68 070, namely TXA2 synthetase inhibition at low concentrations, plus additionally TXA2/prostaglandin endoperoxide receptor blockade at higher concentrations
Influence of Nicotine and Cotinine on the Expression of Plasminogen Activator Activity in Bovine Aortic Endothelial Cells
Authors: Kuo Be-Sheng , Dryjski Maciej , Bjornsson Thorir D 
Published: July 2018

SummaryThe effects of nicotine and its major metabolite, cotinine, were evaluated on the secretion of plasminogen activator (PA) and plasminogen activator inhibitor (PAI) in cultured bovine aortic endothelial cells. Both compounds increased PA secretion, determined by 125I-fibrin plate assay, in a time- and dose-dependent manner. Maximum effects after 24 hr incubation were observed for nicotine at 10-8 M and for cotinine at 10-7 M, which corresponded to about 2.6-fold increases over control for both compounds. The pharmacological PA stimulation required both RNA and protein syntheses, as evidenced by inhibition by acfinomycin D and cycloheximide. Both control and treated cells produced multiple forms of PA, as evaluated by SDS-PAGE zymography, and a single form of PAI, as evidenced by reverse fibrin autography. Although activities of all species of PA were enhanced by nicotine and cotinine, these compounds had no significant effects on the release of PAI. These results thus suggest that nicotine and cotinine may have fibrinolytic activity in vivo.
Anticardiolipin Antibodies Are Elevated in HIV-1 Infected Haemophiliacs but Do Not Predict for Disease Progression
Authors: Panzer Simon , Stain Christoph , Hartl Hubert , Dudczak Robert , Lechner Klaus 
Published: July 2018

SummaryLevels of anticardiolipin antibodies (ACA) were measured in 55 patients with haemophilia A in serum samples obtained in 1983 and in 1987. Twenty-one patients were negative for anti HIV-1 antibodies in 1983 and remained negative in 1987; 34 patients had anti HIV-1 antibodies in 1983; 17 of these latter patients remained asymptomatic, whereas 17 patients developed ARC or AIDS during the 4 years follow-up. Thirteen anti HIV-1 negative patients had elevated ACA levels in 1983; subsequently, a significant decrease was observed in all these subjects (p <0.001). All anti HIV-1 positive patients had elevated ACA levels in 1983; normal values were found in 9 patients in 1987. Yet, these changes were not significant (p >0.05). ACA levels were significantly higher in HIV-1 infected patients than in those without anti HIV-1 antibodies (p <0.05). There was no difference of ACA levels between the two anti HIV-1 positive patient groups, be it in 1983 or be it in 1987 (p >0.05). There was no correlation of ACA levels with serum IgG concentrations, CD4+ lymphocytes, or the consumption of factor VIII concentrates.
Thrombin Stimulates Inositol Phosphate Accumulation and Prostacyclin Synthesis in Human Endothelial Cells from Umbilical Vein but Not from Omentum
Authors: Carter A J , Eisert W G , Müller T H 
Published: July 2018

SummaryWe have compared the effects of thrombin on the accumulation of inositol phosphates and the synthesis of prostacyclin in cultured human endothelial cells from umbilical vein and the microvasculature of omentum. Active human thrombin induced a dose-dependent accumulation of inositol phosphates and a concomitant synthesis of prostacyclin in endothelial cells from human umbilical vein. However, thrombin at all concentrations tested was unable to stimulate inositol phosphate accumulation and prostacyclin synthesis in microvascular endothelial cells from human omentum. Bradykinin was able to stimulate these effects in both types of cell. These results demonstrate that although inositol phosphate turnover is an initial event associated with prostacyclin synthesis in endothelial cells, there are differences in the way microvascular endothelial cells respond to thrombin.
Spontaneous Whole Blood Platelet Aggregation in Insulin-Dependent Diabetes Mellitus: An Evaluation in an Epidemiologic Study
Authors: Cho Nam H , Becker Dorothy , Dorman Janice S , Wolfson Sidney , Kuller Lewis H , Drash Allan L , Follansbee William F , Kelsey Sherryl F , Orchard Trevor J 
Published: July 2018

SummarySpontaneous whole blood platelet aggregation (SWBPA) was examined in a case-control study, comparing a consecutive series of IDDM subjects (n = 30) to age, and sex matched controls. Subjects were free of platelet altering medications. Platelet aggregation was measured by the percent fall in single platelet count after 15 minutes of both shaking (SK) and magnetic stirring (ST). IDDM subjects showed a significantly greater percent fall in SK (x = 12.1) and ST (x = 34.0) compared to controls (SK x = 8.4, p <0.01; ST x = 24.3, p <0.05). Long-term repeat testing on 15 subjects (diabetics and non-diabetics) up to 4 months apart showed a correlation of 0.7 for SK, p <0.01 but only 0.4 for ST. In a further series of IDDM subjects (n = 176) those with macrovascular disease (n = 27) showed significantly greater percent fall in SK (p<0.05), and ST (p<0.05).We conclude that SWBPA is a simple useful epidemiological technique (shaking being more repeatable than stirring) which relates to both diabetes and macrovascular disease.
Severe Arterial Cerebral Thrombosis in a Patient with Protein S Deficiency (Moderately Reduced Total and Markedly Reduced Free Protein S): A Family Study
Authors: Girolami A , Simioni P , Lazzaro A R , Cordiano I 
Published: July 2018

SummaryDeficiency of protein S has been associated with an increased risk of thrombotic disease as already shown for protein C deficiency. Deficiencies of any of these two proteins predispose to venous thrombosis but have been only rarely associated with arterial thrombosis.In this study we describe a case of severe cerebral arterial thrombosis in a 44-year old woman with protein S deficiency. The defect was characterized by moderately reduced levels of total and markedly reduced levels of free protein S. C4b-bp level was normal. Protein C, AT III and routine coagulation tests were within the normal limits.In her family two other members showed the same defect. All the affected members had venous thrombotic manifestations, two of them at a relatively young age. No other risk factors for thrombotic episodes were present in the family members. The patient reported was treated with ASA and dipyridamole and so far there were no relapses.