bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased gamma and decreased fast ripple connections of epileptic tissue: A high‐frequency directed network approach
Authors: Zweiphenning Willemiek J. E. M. , Keijzer Hanneke M. , van Diessen Eric , van ‘t Klooster Maryse A. , van Klink Nicole E. C. , Leijten Frans S. S. , van Rijen Peter C. , van Putten Michel J. A. M. , Braun Kees P. J. , Zijlmans Maeike 
Published: July 2019

AbstractObjectiveNew insights into high‐frequency electroencephalographic activity and network analysis provide potential tools to improve delineation of epileptic tissue and increase the chance of postoperative seizure freedom. Based on our observation of high‐frequency oscillations “spreading outward” from the epileptic source, we hypothesize that measures of directed connectivity in the high‐frequency range distinguish epileptic from healthy brain tissue.MethodsWe retrospectively selected refractory epilepsy patients with a malformation of cortical development or tumor World Health Organization grade I/II who underwent epilepsy surgery with intraoperative electrocorticography for tailoring the resection based on spikes. We assessed directed functional connectivity in the theta (4‐8 Hz), gamma (30‐80 Hz), ripple (80‐250 Hz), and fast ripple (FR; 250‐500 Hz) bands using the short‐time direct directed transfer function, and calculated the total, incoming, and outgoing propagation strength for each electrode. We compared network measures of electrodes covering the resected and nonresected areas separately for patients with good and poor outcome, and of electrodes with and without spikes, ripples, and FRs (group level: paired t test; patient level: Mann‐Whitney U test). We selected the measure that could best identify the resected area and channels with epileptic events using the area under the receiver operating characteristic curve, and calculated the positive and negative predictive value, sensitivity, and specificity.ResultsWe found higher total and outstrength in the ripple and gamma bands in resected tissue in patients with good outcome (rippletotal: P = .01; rippleout: P = .04; gammatotal: P = .01; gammaout: P = .01). Channels with events showed lower total and instrength, and higher outstrength in the FR band, and higher total and outstrength in the ripple, gamma, and theta bands (FRtotal: P = .05; FRin: P < .01; FRout: P = .02; gammatotal: P < .01; gammain: P = .01; gammaout: P < .01; thetatotal: P = .01; thetaout: P = .01). The total strength in the gamma band was most distinctive at the channel level (positive predictive value [PPV]good = 74%, PPVpoor = 43%).SignificanceInterictally, epileptic tissue is isolated in the FR band and acts as a driver up to the (fast) ripple frequency range. The gamma band total strength seems promising to delineate epileptic tissue intraoperatively.
NMR and crystallographic structural studies of the extremely stable monomeric variant of human cystatin C with single amino acid substitution
Authors: Maszota‐Zieleniak Martyna , Jurczak Przemyslaw , Orlikowska Marta , Zhukov Igor , Borek Dominika , Otwinowski Zbyszek , Skowron Piotr , Pietralik Zuzanna , Kozak Maciej , Szymańska Aneta , Rodziewicz‐Motowidło Sylwia 
Published: July 2019

Human cystatin C (hCC), a member of the superfamily of papain‐like cysteine protease inhibitors, is the most widespread cystatin in human body fluids. This small protein, in addition to its physiological function, is involved in various diseases, including cerebral amyloid angiopathy, cerebral hemorrhage, stroke, and dementia. Physiologically active hCC is a monomer. However, all structural studies based on crystallization led to the dimeric structure formed as a result of a three‐dimensional exchange of the protein domains (3D domain swapping). The monomeric structure was obtained only for hCC variant V57N and for the protein stabilized by an additional disulfide bridge. With this study, we extend the number of models of monomeric hCC by an additional hCC variant with a single amino acid substitution in the flexible loop L1. The V57G variant was chosen for the X‐ray and NMR structural analysis due to its exceptional conformational stability in solution. In this work, we show for the first time the structural and dynamics studies of human cystatin C variant in solution. We were also able to compare these data with the crystal structure of the hCC V57G and with other cystatins. The overall cystatin fold is retained in the solute form. Additionally, structural information concerning the N terminus was obtained during our studies and presented for the first time.DatabaseCrystallographic structure: structural data are available in PDB databases under the accession number 6ROA. NMR structure: structural data are available in PDB and BMRB databases under the accession numbers 6RPV and 34399, respectively.
Post‐translational modifications in capsid proteins of recombinant adeno‐associated virus (AAV) 1‐rh10 serotypes
Authors: Mary Bertin , Maurya Shubham , Arumugam Sathyathithan , Kumar Vikas , Jayandharan Giridhara R. 
Published: July 2019

Post‐translational modifications in viral capsids are known to fine‐tune and regulate several aspects of the infective life cycle of several viruses in the host. Recombinant viruses that are generated in a specific producer cell line are likely to inherit unique post‐translational modifications during intra‐cellular maturation of its capsid proteins. Data on such post‐translational modifications in the capsid of recombinant adeno‐associated virus serotypes (AAV1‐rh10) is limited. We have employed liquid chromatography and mass spectrometry analysis to characterize post‐translational modifications in AAV1‐rh10 capsid protein. Our analysis revealed a total of 52 post‐translational modifications in AAV2‐AAVrh10 capsids, including ubiquitination (17%), glycosylation (36%), phosphorylation (21%), SUMOylation (13%) and acetylation (11%). While AAV1 had no detectable post‐translational modification, at least four AAV serotypes had >7 post‐translational modifications in their capsid protein. About 82% of these post‐translational modifications are novel. A limited validation of AAV2 capsids by MALDI‐TOF and western blot analysis demonstrated minimal glycosylation and ubiquitination of AAV2 capsids. To further validate this, we disrupted a glycosylation site identified in AAV2 capsid (AAV2‐N253Q), which severely compromised its packaging efficiency (~ 100‐fold vs. AAV2 wild‐type vectors). In order to confirm other post‐translational modifications detected such as SUMOylation, mutagenesis of a SUMOylation site(K258Q) in AAV2 was performed. This mutant vector demonstrated reduced levels of SUMO‐1/2/3 proteins and negligible transduction, 2 weeks after ocular gene transfer. Our study underscores the heterogeneity of post‐translational modifications in AAV vectors. The data presented here, should facilitate further studies to understand the biological relevance of post‐translational modifications in AAV life cycle and the development of novel bioengineered AAV vectors for gene therapy applications.EnzymesTrypsin, EC 3.4.21.4
Farnesylation of human guanylate‐binding protein 1 as safety mechanism preventing structural rearrangements and uninduced dimerization
Authors: Lorenz Charlotte , Ince Semra , Zhang Tao , Cousin Anneliese , Batra‐Safferling Renu , Nagel‐Steger Luitgard , Herrmann Christian , Stadler Andreas M. 
Published: July 2019

Human guanylate‐binding protein 1 (hGBP1) belongs to the family of dynamin‐like proteins and is activated by addition of nucleotides, leading to protein oligomerization and stimulated GTPase activity. In vivo, hGBP1 is post‐translationally modified by attachment of a farnesyl group yielding farn‐hGBP1. In this study, hydrodynamic differences in farn‐hGBP1 and unmodified hGBP1 were investigated using dynamic light scattering (DLS), analytical ultracentrifugation (AUC) and analytical size‐exclusion chromatography (SEC). In addition, we performed small‐angle X‐ray scattering (SAXS) experiments coupled with a SEC setup (SEC‐SAXS) to investigate structural properties of nonmodified hGBP1 and farn‐hGBP1 in solution. SEC‐SAXS measurements revealed that farnesylation keeps hGBP1 in its inactive monomeric and crystal‐like conformation in nucleotide‐free solution, whereas unmodified hGBP1 forms a monomer–dimer equilibrium both in the inactive ground state in nucleotide‐free solution as well as in the activated state that is trapped by addition of the nonhydrolysable GTP analogue GppNHp. Nonmodified hGBP1 is structurally perturbed as compared to farn‐hGBP. In particular, GppNHp binding leads to large structural rearrangements and higher conformational flexibility of the monomer and the dimer. Structural changes observed in the nonmodified protein are prerequisites for further oligomer assemblies of farn‐hGBP1 that occur in the presence of nucleotides.DatabaseAll SEC‐SAXS data, corresponding fits to the data and structural models are deposited in the Small Angle Scattering Biological Data Bank [SASBDB (Nucleic Acids Res, 43, 2015, D357)] with project IDs: SASDEE8, SASDEF8, SASDEG8, SASDEH8, SASDEJ8, SASDEK8, SASDEL8 and SASDEM8.
Diversity decoupled from sulfur isotope fractionation in a sulfate‐reducing microbial community
Authors: Colangelo‐Lillis Jesse , Pelikan Claus , Herbold Craig W. , Altshuler Ianina , Loy Alexander , Whyte Lyle G. , Wing Boswell A. 
Published: July 2019

AbstractThe extent of fractionation of sulfur isotopes by sulfate‐reducing microbes is dictated by genomic and environmental factors. A greater understanding of species‐specific fractionations may better inform interpretation of sulfur isotopes preserved in the rock record. To examine whether gene diversity influences net isotopic fractionation in situ, we assessed environmental chemistry, sulfate reduction rates, diversity of putative sulfur‐metabolizing organisms by 16S rRNA and dissimilatory sulfite reductase (dsrB) gene amplicon sequencing, and net fractionation of sulfur isotopes along a sediment transect of a hypersaline Arctic spring. In situ sulfate reduction rates yielded minimum cell‐specific sulfate reduction rates < 0.3 × 10−15 moles cell−1 day−1. Neither 16S rRNA nor dsrB diversity indices correlated with relatively constant (38‰–45‰) net isotope fractionation (ε34Ssulfide‐sulfate). Measured ε34S values could be reproduced in a mechanistic fractionation model if 1%–2% of the microbial community (10%–60% of Deltaproteobacteria) were engaged in sulfate respiration, indicating heterogeneous respiratory activity within sulfate‐reducing populations. This model indicated enzymatic kinetic diversity of Apr was more likely to correlate with sulfur fractionation than DsrB. We propose that, above a threshold Shannon diversity value of 0.8 for dsrB, the influence of the specific composition of the microbial community responsible for generating an isotope signal is overprinted by the control exerted by environmental variables on microbial physiology.
Origins and organization of the NHLBI State of the Science Workshop: Generating a national blueprint for future research on factor VIII inhibitors
Authors: Sabatino Denise E. , Pipe Steven W. , Nugent Diane J. , Soucie J. Michael , Hooper W. Craig , Hoots W. Keith , DiMichele Donna M. 
Published: July 2019

IntroductionThe major complication of protein replacement therapy for haemophilia A is the development of anti‐FVIII antibodies or inhibitors that occur in 25%‐30% of persons with severe haemophilia A. Alternative therapeutics such as bypassing agents or immune tolerance induction protocols have additional challenges and are not always effective.AimAssemble a National Heart, Lung and Blood Institute (NHLBI) State of the Science (SOS) Workshop to generate a national blueprint for research on inhibitors to solve the problem of FVIII immunogenicity.MethodsAn Executive Steering Committee was formed in October 2017 to establish the scientific focus and Scientific Working Groups for the SOS Workshop in May 2018. Four working groups were assembled to address scientific priorities in basic, translational and clinical research on inhibitors.ResultsWorking Group 1 was charged with determining the scientific priorities for clinical trials to include the integration of non‐intravenous, non‐factor therapeutics including gene therapy into the standard of care for people with haemophilia A with inhibitors. Working Group 2 established the scientific priorities for 21st‐century data science and biospecimen collection for observational inhibitor cohort studies. The scientific priorities for acquiring an actionable understanding of FVIII immunogenicity and the immunology of the host response and FVIII tolerance were developed by Working Group 3. Working Group 4 designed prospective pregnancy/birth cohorts to study FVIII immunogenicity, inhibitor development and eradication.ConclusionThe NHLBI SOS Workshop generated a focused summary of scientific priorities and implementation strategies to overcome the challenges of eradicating and preventing inhibitors in haemophilia A.
The national blueprint for pregnancy/birth longitudinal cohorts to study factor VIII immunogenicity: NHLBI State of the Science (SOS) Workshop on factor VIII inhibitors
Authors: Johnsen Jill M. , Brown Deborah L. ,   the Members of Working Group 4, the NHLBI State of the Science Workshop on Factor VIII Inhibitors: Generating a National Blueprint for Future Research
Published: July 2019

AbstractIntroductionPatients with haemophilia can develop inhibitors to exogenous coagulation factors. Some patients are tolerant to factor, while those who develop inhibitors do so early in life. Genetics and environmental factors are known to contribute to inhibitor risk. However, it is not yet possible to predict inhibitor formation or treatment responsiveness in individuals. We hypothesize that factors in the antenatal/neonatal period inform inhibitor risk development.AimTo consider the design of longitudinal studies beginning in the antenatal/neonatal period and the use of new technologies to better understand haemophilia inhibitors.MethodsA working group was formed for the NHLBI State of the Science Workshop: Factor VIII Inhibitors: Generating a National Blueprint for Future Research to solicit input from the US haemophilia community and international collaborators to consider design of pregnancy/birth longitudinal cohorts that leverage ‐omics, existing phenotypic data, and in silico modelling to study inhibitors.ResultsAn antenatal/neonatal longitudinal cohort should begin with enrolment of pregnant genetic carriers of haemophilia and span the at‐risk period for inhibitor development in the child. Data and samples from the mother, placenta, neonate and young child can be obtained that are amenable to existing assays, genomics and other ‐omics studies. Data can inform in silico prediction and mathematical models.ConclusionA longitudinal study beginning before birth offers the unique opportunity to study factors that influence inhibitor development prior to exposure. Advances in ‐omics and computational biology can study complex phenotypes in this rare disease. This study could be accomplished through interdisciplinary efforts and patient community engagement.
The national blueprint for future basic and translational research to understand factor VIII immunogenicity: NHLBI State of the Science Workshop on factor VIII inhibitors
Authors: Meeks Shannon L. , Herzog Roland W. ,   on behalf of the Members of Working Group 3, the NHLBI State of the Science Workshop on factor VIII inhibitors: Generating a national blueprint for future research
Published: July 2019

IntroductionInhibitor formation against coagulation factor VIII (FVIII) is an unresolved serious problem in replacement therapy for the X‐linked bleeding disorder haemophilia A. Although FVIII inhibitors have been extensively studied, much of the basic mechanism of this immune response remains to be uncovered.AimWithin the NHLBI State of the Science Workshop on Factor VIII Inhibitors, Working Group 3 identified three scientific priorities for basic and translational research on FVIII inhibitor formation.MethodsA larger list of potential areas of research was initially developed as a basis for subsequent prioritization. Each scientific goal was further evaluated based on required effort, potential impact, approach, methods, technologies and models.ResultsThe three priorities include the following: activation signals and immune regulation that shape the response to FVIII (including innate immunity, microbiome, adaptive immunity and regulatory T cell studies in humans); utility of animal models and non‐animal approaches (in silico, genetic, single‐cell/sorted population “omics,” in vitro) to help predict inhibitor formation and identify novel therapeutics; and impact of the source of FVIII, its structure and von Willebrand factor on immunogenicity and tolerance.ConclusionsEarly interactions between FVIII and the immune system, biomarker development and studies in different patient groups (previously treated or untreated, with or without inhibitor formation, patients undergoing immune tolerance induction or gene therapy) deserve particular emphasis. Finally, linking basic to clinical studies, development of a repository for biospecimens and opportunities for interdisciplinary research training are important components to solving the urgent problem of inhibitor formation.
Daily dietary phosphorus intake variability and hemodialysis patient adherence to phosphate binder therapy
Authors: Tao Xingjuan , Zhang Haifen , Yang Yan , Zhang Caihong , Wang Min 
Published: July 2019

AbstractIntroduction: Phosphate balance could be reached only by an optimized combination of dietary restriction and the careful use of phosphate binders for patients receiving standard hemodialysis treatment. Little is known about individual variability of phosphorus intake and phosphate binder use in hemodialysis patients. The purposes of this study were to quantify phosphorus intake and to describe individual phosphate‐binder use in hemodialysis patients.Methods: This was a cross‐sectional study. The dietary phosphorus intake was assessed using a 3‐day duplicate portion sampling method combined with chemical analysis. Patients' adherence to phosphate binders was evaluated by the Morisky Medication Adherence Scale, with a score of <6 being considered as an indicator of inadequate adherence.Findings: A total of 101 food samples from 36 patients were collected and analyzed. The mean daily phosphorus, protein, and energy intake was 15.1 mg/kg/d, 1.0 g/kg/d, and 28.9 kcal/kg/d, respectively. There was a higher consumption of phosphorus on dialysis days (DDs) than on non‐dialysis days (NDDs) (16.2 mg/kg/d vs. 14.0 mg/kg/d, P = 0.035); however, such a trend was not observed for dietary protein and energy intake (1.1 g/kg/d vs. 1.0 g/kg/d, P = 0.706; 30.3 kcal/kg/d vs. 27.6 kcal/kg/d, P = 0.225). A significantly higher percentage of patients on low phosphorus intake (<1000 mg/d) reported inadequate phosphate‐binding adherence than those on high phosphorus intake (60% vs. 18%, P = 0.031).Discussion: Patients receiving hemodialysis had a higher consumption of phosphorus on DDs than on NDDs; such a pattern was not obviously observed for protein and energy intake. For patients achieving phosphorus intake recommendation, medication nonadherence that possibly being attributed to the patient's necessity beliefs may pose extra hurdles for phosphate control.
Selected commensal bacteria change profiles of Helicobacter pylori‐induced T cells via dendritic cell modulation
Authors: Wiese‐Szadkowska Malgorzata , Helmin–Basa Anna , Eljaszewicz Andrzej , Gackowska Lidia , Januszewska Milena , Motyl Ilona , Andryszczyk Marek , Wieczynska Jolanta , Michalkiewicz Jacek 
Published: July 2019

AbstractBackgroundThe mechanisms of downregulation of protective immunity against Helicobacter pylori (Hp) infection strongly depend on dendritic cell (DC)‐induced T‐lymphocyte differentiation pattern. Lactic acid bacteria (LAB) strains can modulate Hp‐induced immunoresponse by changes in DC activation profiles. Here, we want to find out if the LAB‐pulsed DCs will change Hp‐induced T‐cell responsiveness patterns.Materials and MethodsThe naive peripheral CD4+ T cells were co‐cultured with Hp CagA + pulsed monocyte‐derived DCs (DC/CD4+ T cell) in the presence/absence of the feces‐derived probiotics: antagonistic or non‐antagonistic to Hp (Lactobacillus rhamnosus 900, Lr, Lactobacillus paracasei 915, Lp, respectively), as assessed by the agar slab method. The regulatory T‐cell (Treg) population was assessed by flow cytometry, and IFN‐γ, IL‐12p70, IL‐10, and IL‐17A levels were evaluated by ELISA method.ResultsThe Hp‐pulsed DC/CD4+ T‐cell co‐cultures were characterized by high IL‐10, decreased IL‐12p70 and IFN‐γ levels, and elevated Treg population. In contrast, Lr‐pulsed DC/CD4+ T‐cell co‐cultures expressed low IL‐10, high IL‐12p70 and IFN‐γ levels and declined Treg population; this responsiveness pattern was not changed by Hp. The responsiveness pattern of the Lp/Hp‐pulsed DC/CD4+ T‐cell co‐cultures did not differ from those pulsed with Hp alone.ConclusionIn contrast to Lp, Lr probiotic strain overcomes Hp‐mediated immune profile in the DC/T‐cell co‐cultures toward Th1 pattern and limited generation of Tregs in vitro. Lr may therefore be used as a component of anti‐Hp treatment.
Higher immunoglobulin A nephropathy recurrence in related‐donor kidney transplants: The Japan Academic Consortium of Kidney Transplantation study
Authors: Okumi Masayoshi , Okada Daigo , Unagami Kohei , Kakuta Yoichi , Iizuka Junpei , Takagi Toshio , Shirakawa Hiroki , Omoto Kazuya , Ishida Hideki , Tanabe Kazunari ,   the Japan Academic Consortium of Kidney Transplantation (JACK)
Published: July 2019

ObjectiveTo investigate the 10‐year biopsy‐proven recurrence rates and risk factors for immunoglobulin A nephropathy recurrence in kidney transplant recipients.MethodsWe included 299 kidney transplant recipients from 1995 to 2015, who had biopsy‐proven underlying immunoglobulin A nephropathy and underwent zero‐hour biopsy. The primary end‐point was recurrence of immunoglobulin A nephropathy. We compared clinical, treatment and graft failure among those with and without recurrent immunoglobulin A nephropathy. A time‐to‐recurrence analysis was carried out using the competing risk analysis and time‐dependent Cox model.ResultsOf 299 recipients, 80 had recurrent immunoglobulin A nephropathy (66.3% with clinical biopsy and 33.7% with protocol biopsy, post‐transplant biopsy rate: 90.6%). The 10‐year recurrence rate was 34.3% (95% confidence interval 27.6–41.1). Related‐donor transplantation (hazard ratio 2.28, P = 0.009) and post‐transplant increased proteinuria (hazard ratio 1.59, P < 0.001) were identified as potential risk factors for immunoglobulin A nephropathy recurrence. The 10‐year rates were 41.5% in related donor recipients and 16.3% in unrelated donor recipients. There was no conclusive evidence that the calcineurin inhibitor, antimetabolites, basiliximab and rituximab reduce immunoglobulin A nephropathy recurrence. Immunoglobulin A nephropathy recurrence was associated with an increased risk of death‐censored graft failure (hazard ratio 5.29, 95% confidence interval 1.39–20.17, P = 0.015). However, related donor itself was not associated with an increased risk of graft failure.ConclusionsThe present results have clinical implications in that the signs of recurrent immunoglobulin A nephropathy should be evaluated carefully in recipients receiving related‐donor transplants. There is a need for further studies related to genetic and/or familial interactions in kidney transplant recipients with immunoglobulin A nephropathy and related donors.