bluuebunny/crossref_metadata_2025_split huggingface dataset:
Histologic predictors of renal outcome in diabetic nephropathy
Authors: Stefan Gabriel , Stancu Simona , Zugravu Adrian , Petre Nicoleta , Mandache Eugen , Mircescu Gabriel 
Published: July 2019

Abstract
The prognostic utility of histologic features in patients with diabetic nephropathy (DN) classified according to the Renal Pathology Society (RPS) classification is controversial. Therefore, we aimed to evaluate the relationship between histologic changes and renal outcome in DN patients.
We examined the renal outcome at November 30, 2017 of 74 adult patients (median age of 54.6 years, 69% male, 81% diabetes mellitus (DM) type 2, estimated GFR (eGFR) 29.6 mL/min) with biopsy proven DN between 2010 and 2015. The primary endpoint was renal replacement therapy (RRT) initiation.
Half of the patients progressed to end stage renal disease (ESRD) during follow-up; they had lower eGFR, increased proteinuria, hematuria and serum cholesterol. Regarding the pathologic features, they were more frequently in class III and IV, had higher interstitial fibrosis and tubular atrophy score (IFTA), increased interstitial inflammation, more frequent arteriolar hyalinosis and higher glomerular basement membrane (GBM) thickness. The mean kidney survival time was 2.7 (95%CI 2.1, 3.3) years. In univariate time-dependent analyses, higher RPS DN class, increased IFTA, the presence of arteriolar hyalinosis and arteriosclerosis were associated with RRT initiation.
In the fully adjusted model, the clinical characteristics associated with poor renal survival were longer duration of DM, lower eGFR, increased proteinuria and higher hematuria and the only pathologic lesions to remain significant were the GBM thickness and the IFTA.
In conclusion, in this European cohort, the severity of glomerular lesions evaluated with the RPS DN classification had limited utility in predicting RRT initiation. However, IFTA and GBM thickness were significantly associated with renal survival.
Optimal cut-off threshold in pulse pressure predicting cardiovascular death among newly diagnosed end-stage renal disease patients
Authors: Wang Zheng , Yu Dahai , Cai Yamei , Zhao Bin , Zhang Xiaoxue , Zhao Zhanzheng 
Published: July 2019

Abstract
Cardiovascular disease (CVD) is the leading cause of death in patients with end-stage renal disease (ESRD) treated by dialysis. Pulse pressure (PP) as an independent prognostic factor of cardiovascular risk might be clinically implicated in predicting the short-term deaths due to cardiovascular diseases in ESRD patients. This study aimed to investigate the dose-response association between PP and risk of cardiovascular mortality in patients initializing peritoneal dialysis (PD). All patients registered with the Henan Peritoneal Dialysis Registry (HPDR) between 2007 and 2014 were incorporated in the current cohort study. PP was assessed by the date of initialisation of PD and cardiovascular mortality in 2 years after the initialisation of PD was defined as the outcome. All accessible clinical measurements were screened as covariables. Further dose–response relationships between PP and risks were explored using spline models. There was a non-linear relationship between PP and the risk of 2-year death for a cardiovascular diseases (P <.001 for linearity test). The PP associated with the lowest risk of cardiovascular mortality was 61 (95% CI 56–64) mmHg. In ESRD patients initializing PD, PP is a good prognostic factor of risk of short-term cardiovascular mortality. The risk is lowest with a PP of 56 to 64 mmHg.
Trisk 95 as a Novel Skin Mirror for Normal and Diabetic Systemic Glucose Level
Authors: Ali Nsrein , Rezvani Hamid Reza , Motei Diana , Suleman Sufyan , Mahfouf Walid , Marty Isabelle , Ronkainen Veli-Pekka , Vainio Seppo J. 
Published: July 2019

AbstractCoping with diabetes requires frequent and even today mostly invasive blood glucose-based monitoring. Partly due to this invasive nature and the associated reduced skin wound healing and increased risk of infection, non-invasive glucose monitoring technologies would represent considerable progress. Edited keratinocytes may enable such a function.To address this hypothesis, we conducted a proteomic screen in the skin by making use of the experimental in vivo mouse model of type I diabetes alongside controls. We identified Trisk 95 as the only protein whose expression is induced in response to high blood glucose. A luciferase reporter assay demonstrated that induction of Trisk 95 expression occurs not only at the protein level but also transcriptionally. This induction was associated with a marked elevation in the Fluo-4 signal, suggesting a role for intracellular calcium changes in the signalling cascade. Strikingly, these changes lead concurrently to fragmentation of the mitochondria. As judged from the knockout findings, both the calcium flux and the mitochondrial phenotype were dependent on Trisk 95 function, since the phenotypes in question were abolished.The data demonstrate that the skin represents an organ that reacts robustly and thus mirrors changes in systemic blood glucose levels. The findings are also consistent with a channelling model of Trisk 95 that serves as an insulin-independent but glucose-responsive biomarker taking part in releasing calcium from the cellular stores in the skin. The skin cells may thus provide a novel mean for glucose monitoring when analysing changes in labelled Trisk 95 and calcium. By that, this study is the first proof of the concept of our registered patent (No. PCT FI2016/050917), which proposes the use of cells as biosensors for developing personalized health-monitoring devices.
Mechanisms of active regulation of biomolecular condensates
Authors: Söding Johannes , Zwicker David , Sohrabi-Jahromi Salma , Boehning Marc , Kirschbaum Jan 
Published: July 2019

AbstractLiquid-liquid phase separation is a key organizational principle in eukaryotic cells, on par with intracellular membranes. It allows cells to concentrate specific proteins into condensates, increasing reaction rates and achieving switch-like regulation. However, it is unclear how cells trigger condensate formation or dissolution and regulate their sizes. We predict from first principles two mechanisms of active regulation by post-translational modifications such as phosphorylation: In enrichment-inhibition, the regulating modifying enzyme enriches in condensates and the modifications of proteins inhibit their interactions. Stress granules, Cajal bodies, P granules, splicing speckles, and synapsin condensates obey this model. In localization-induction, condensates form around an immobilized modifying enzyme, whose modifications strengthen protein interactions. Spatially targeted condensates formed during transmembrane signaling, microtubule assembly, and actin polymerization conform to this model. The two models make testable predictions that can guide studies into the many emerging roles of biomolecular condensates.
Proposed model of the Dictyostelium cAMP receptors bound to cAMP
Authors: Greenhalgh Jack Calum , Chandran Aneesh , Harper Matthew Thomas , Ladds Graham , Rahman Taufiq 
Published: July 2019

Abstract3’,5’-cyclic adenosine monophosphate (cAMP) is well known as a ubiquitous intracellular messenger regulating a diverse array of cellular processes. However, for a group of social amoebae or Dictyostelia undergoing starvation, intracellular cAMP is secreted in a pulsatile manner to their exterior. This then uniquely acts as a first messenger, triggering aggregation of the starving amoebae followed by their developmental progression towards multicellular fruiting bodies formation. Such developmental signalling for extracellularly-acting cAMP is well studied in the popular dictyostelid,Dictyostelium discoideum, and is mediated by a distinct family (‘class E’) of G protein-coupled receptors (GPCRs) collectively designated as the cAMP receptors (cARs). Whilst the biochemical aspects of these receptors are well characterised, little is known about their overall 3D architecture and structural basis for cAMP recognition and subtype-dependent changes in binding affinity. Using a ligand docking-guided homology modelling approach, we hereby present for the first time, plausible models of active forms of the cARs fromD. discoideum. Our models highlight some structural features that may underlie the differential affinities of cAR isoforms for cAMP binding and also suggest few residues that may play important roles for the activation mechanism of this GPCR family.
Spatio-temporal correlations between catastrophe events in a microtubule bundle: a computational study
Authors: Diwe Makarand , Gopalakrishnan Manoj 
Published: July 2019

AbstractWe explore correlations between dynamics of different microtubules in a bundle, via numerical simulations, using a one-dimensional stochastic model of a microtubule. The GTP-bound tubulins undergo diffusion-limited binding to the tip. Random hydrolysis events take place along the filament, and converts GTP-tubulin to GDP-tubulin. The filament starts depolymerising when the monomer at the tip becomes GDP-bound; in this case, detachment of GDP-tubulin ensues and continues until either GTP-bound tubulin is exposed or complete depolymerisation is achieved. In the latter case, the filament is defined to have undergone a “catastrophe”. Our results show that, in general, the dynamics of growth and catastrophe in different filaments are coupled to each other; closer the filaments are, the stronger the coupling. In particular, all filaments grow slower, on average, when brought closer together. The reduction in growth velocity also leads to more frequent catastrophes. More dramatically, catastrophe events in the different filaments forming a bundle are found to be correlated; a catastrophe event in one filament is more likely to be followed by a similar event in the same filament. This propensity of bunching disappears when the filaments move farther apart.
Loop-closure Kinetics Reveal a Stable, Right-handed DNA Intermediate in Cre Recombination
Authors: Shoura Massa J. , Giovan Stefan M. , Vetcher Alexandre V. , Ziraldo Riccardo , Hanke Andreas , Levene Stephen D. 
Published: July 2019

AbstractIn Cre site-specific recombination, the synaptic intermediate is a recombinase homotetramer containing a pair of DNA target sites. The strand-exchange mechanism proceeds via a Holliday-junction (HJ) intermediate; however, the geometry of the DNA segments in the synapse has remained highly controversial. In particular, all crystallographic structures are consistent with an achiral planar Holliday-junction (HJ) structure, whereas topological assays based on Cre-mediated knotting of plasmid DNAs are consistent with a right-handed chiral junction. Here we use the kinetics of loop closure involving closely spaced (131-151 bp), directly repeated loxP sites to investigate thein-aqueoensemble of conformations for the longest-lived looped DNA intermediate. Fitting the experimental site-spacing dependence of the loop-closure probability,J, to a statistical-mechanical theory of DNA looping provides evidence for substantial out-ofplane HJ distortion. This result unequivocally stands in contrast to the square-planar intermediate geometry determined from crystallographic data for the Cre-loxP system and other int-superfamily recombinases.Jmeasurements carried out with an isomerization-deficient Cre mutant suggest that the apparent geometry of the wild-type complex may result from the temporal averaging of diverse right-handed and achiral structures. Applied to Cre recombinase, and other biological systems, our approach bridges the static pictures provided by crystal structures and the natural dynamics of macromoleculesin vivo. This approach thus advances a more comprehensive dynamic analysis of large nucleoprotein structures and their mechanisms.
The role of preadaptation, propagule pressure and competition in the colonization of new habitats
Authors: Alzate Adriana , Onstein Renske E. , Etienne Rampal S. , Bonte Dries 
Published: July 2019

ABSTRACTTo successfully colonize new habitats, organisms not only need to gain access to it, but also need to cope with the selective pressures imposed by the local biotic and abiotic conditions. The number of immigrants, the preadaptation to the local habitat and the presence of competitors are important factors determining the success of colonization. Here, using an experimental set-up, we test the combined effect of propagule pressure, preadaptation and interspecific competition on the colonization success of new habitats using the two-spotted spider mite (Tetranychus urticae) as our model system and the red spider mite (Tetranychus evansi) as a competitor. Our results show that propagule pressure and preadaptation positively affect colonization success. More successful populations reach larger final population sizes either by having higher per capita growth rate (due to preadaptation effect) or by starting a population with a larger number of individuals. Although populations are more successful colonizing non-competitive environments than competitive ones, propagule pressure and preadaptation counteract the negative effects of competition, promoting colonization success. Our results show the importance of propagule pressure and preadaptation to cope both with the exigencies of the new environment and the community context for successful colonization of new habitats.
Excitatory neurons are more disinhibited than inhibitory neurons by chloride dysregulation in the spinal dorsal horn
Authors: Lee Kwan Yeop , Ratté Stéphanie , Prescott Steven A. 
Published: July 2019

ABSTRACTNeuropathic pain is a debilitating condition caused by the abnormal processing of somatosensory input. Synaptic inhibition in the spinal dorsal horn plays a key role in that processing. Mechanical allodynia – the misperception of light touch as painful – occurs when inhibition is compromised. Disinhibition is due primarily to chloride dysregulation caused by hypofunction of the potassium-chloride co-transporter KCC2. Here we show, in rats, that excitatory neurons are disproportionately affected. This is not because chloride is differentially dysregulated in excitatory and inhibitory neurons, but, rather, because excitatory neurons rely more heavily on inhibition to counterbalance strong excitation. Receptive fields in both cell types have a center-surround organization but disinhibition unmasks more excitatory input to excitatory neurons. Differences in intrinsic excitability also affect how chloride dysregulation affects spiking. These results deepen understanding of how excitation and inhibition are normally balanced in the spinal dorsal horn, and how their imbalance disrupts somatosensory processing.
High-content interrogation of human induced pluripotent stem cell-derived cortical organoid platforms
Authors: Durens Madel , Nestor Jonathan , Herold Kevin , Niescier Robert F. , Lunden Jason W. , Phillips Andre W. , Lin Yu-Chih , Nestor Michael W. 
Published: July 2019

AbstractThe need for scalable and high-throughput approaches to screening using 3D human stem cell models remains a central challenge in using stem cell disease models for drug discovery. It is imperative to develop standardized systems for phenotypic screening, yet most researchers screen cells across different platforms using a multitude of assays. In this study, we have developed a workflow centered on a small array of assays that can be employed to screen 3D stem cell cultures across a set of platforms. This workflow can be used as a starting point for a standardized approach to phenotypic screening. In this manuscript we hope to provide a roadmap for groups looking to start high-content screening using 3D organoid systems. To do this, we employ serum-free embryoid bodies (SFEBs) created from human induced pluripotent stem cells (hiPSCs). SFEBs are used in this study because they do not display the same level of heterogeneity observed in other neural organoid systems and they are amenable to high content imaging without cryosectioning. They contain populations of excitatory and inhibitory neurons that form synaptically active networks1 and medium- to high-throughput electrophysiology can be performed using SFEBs via the multielectrode array (MEA). The assays outlined in this study allow SFEBs to be scanned for neurite outgrowth, cell number and electrophysiological activity. SFEBs derived from control and disease hiPSCs can be used in combination with high-throughput screening assays to generate sufficient statistical power to compensate for the biological and experimental variability common in 3D cultures, while significantly decreasing processing speed, thus making this an efficient starting point for phenotypic drug screening.
Astaxanthin extends lifespan via altered biogenesis of the mitochondrial respiratory chain complex III
Authors: Hoffman Ronit , Sultan Laure D. , Saada Ann , Hirschberg Joseph , Osterzetser-Biran Oren , Gruenbaum Yosef 
Published: July 2019

AbstractAstaxanthin is aketo-carotenoid produced in some bacteria and algae, which has very important industrial applications (i.e., in cosmetics, coloring additive in aquaculture and as a dietary supplement for human). Here, we analyzed the molecular basis of Astaxanthin-mediated prolongevity in the model organism,Caenorhabditis elegans. The increased lifespan effects of Astaxanthin are restricted inC. elegansto the adult phase and are uninfluenced by various other carotenoids tested. Genetic analyses indicated that the Astaxanthin-mediated life-extension relies on mitochondria activity, via the Rieske iron-sulfur polypeptide-1 (ISP-1), but is not influenced by the functions of other known longevity-related gene-loci, includingCLK-1, DAF-2,DAT-16,EAT-2,GAS-1 GLP-1orMEV-1. Biochemical analyses of native respiratory complexes showed that Astaxanthin affects the biogenesis of holo-complex III (and likely supercomplex I+III, as well). Effects on holo-CIII assembly and activity were also indicated byin-vitroassays, with mitochondria isolated from worms, rodents, human and plants, which were treated with Astaxanthin. These data indicated a cross-species effect on the oxidative phosphorylation (OXPHOS) machinery by the carotenoid, and provide with further insights into the molecular mechanism of animals longevity extension by Astaxanthin.Significance StatementAstaxanthin is a widely consumed pigment by animals and human. In this study we find that Astaxanthin, but not other tested carotenoids, significantly extends the lifespan of animals by affecting respiratory complex III (CIII) biogenesis of the mitochondria, in plants, C. elegans, rodents and human. We further propose a model to try explaining this effect of astaxanthin on animals’ longevity.
Astrocytic striatal GABA transporter activity governs dopamine release and shows maladaptive downregulation in early parkinsonism
Authors: Roberts Bradley M. , Doig Natalie M. , Brimblecombe Katherine R. , Lopes Emanuel F. , Siddorn Ruth E. , Threlfell Sarah , Connor-Robson Natalie , Bengoa-Vergniory Nora , Pasternack Nicholas , Wade-Martins Richard , Magill Peter J. , Cragg Stephanie J. 
Published: July 2019

SummaryStriatal dopamine (DA) is critical for action and learning. Recent data show DA release is under tonic inhibition by striatal GABA. Ambient striatal GABA tone on striatal projection neurons can be governed by plasma membrane GABA uptake transporters (GATs) on astrocytes. However, whether striatal GATs and astrocytes determine DA output are unknown. We reveal that DA release in mouse dorsolateral striatum, but not nucleus accumbens core, is governed by GAT-1 and GAT-3. These GATs are partly localized to astrocytes, and are enriched in dorsolateral striatum compared to accumbens core. In a mouse model of early parkinsonism, GATs were downregulated and tonic GABAergic inhibition of DA release augmented, with corresponding attenuation of GABA co-release from dopaminergic axons. These data define previously unappreciated and important roles for GATs and astrocytes in determining DA release in striatum, and reveal a maladaptive plasticity in early parkinsonism that impairs DA output in vulnerable striatal regions.HighlightsGABA transporters set the level of GABA inhibition of DA output in dorsal striatumAstrocytes facilitate DA release levels by limiting tonic GABA inhibitionTonic inhibition of DA release is augmented in a mouse model of early parkinsonismDA and GABA co-release are reduced in a mouse model of early parkinsonism
Microclimate, CO2and CH4concentration on Blue tits (Cyanistes caeruleus) nests: effects of brood size, nestling age and on ectoparasites
Authors: Castaño-Vázquez Francisco , Merino Santiago , Cuezva Soledad , Sánchez Sergio 
Published: July 2019

ABSTRACTThe presence of nestlings and other nest dwelling living beings in nests built in cavities could alter the composition of gases inside the cavity. In addition, this different concentration of gases could be used by some parasites as a cue to localize their hosts. Here, we explored the temporal variation in the concentration and isotopic signature of carbon dioxide (CO2) and methane (CH4) inside nest boxes of blue titsCyanistes caeruleusduring the nestling period (days 3, 8, 13, 20 and 21 post-hatching). Concentration of gases and isotopic signature were significantly different inside of nests than outside (forest) during the nestling period. CO2concentration was higher inside nest while CH4was lower than in forest air. The differences in the concentration of CO2between nest boxes and forest were higher on days 8th and 20th of nestling age than in other ages while the CH4was lower on day 20th of nestling age than in other ages. Moreover, CO2variation was positive and significantly related with brood size and negative and significantly with hatching date. The difference of CO2between inside of nests and forest on 8th day of nestling age were negative and significantly related to flea larvae abundance as measured at the end of the nestling period. A significant positive relationship was found between the difference of CH4between nests and forest and the final abundance of flea larvae for the same nestling age. In addition, flea larvae abundance was positive and significantly related with the relative humidity in nests at 8 days of nestling age. Moreover, blowfly pupae abundance was negative and significantly related with the difference of temperature in nests at 3 day of nestling age. The condition of blue tit females was negative and significantly related with the abundance of blowfly pupae.