bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized Clinical Trial to Assess the Impact of the Broadly Neutralizing HIV-1 Monoclonal Antibody VRC01 on HIV-1 Persistence in Individuals on Effective ART
Authors: Riddler Sharon A , Zheng Lu , Durand Christine M , Ritz Justin , Koup Richard A , Ledgerwood Julie , Bailer Robert T , Koletar Susan L , Eron Joseph J , Keefer Michael C , Macatangay Bernard J C , Cyktor Joshua C , Mellors John W ,   the AIDS Clinical Trials Group A5342 Protocol Team, Hite Mark , Clark Jan , Currin David , Tipton Mandy , Weinman Renee , Onesi Sara , Hurley Christine , Bunce Catherine A , Storey Sheryl , Dunaway Shelia , Lambert Nina , Berzins Baiba , Gottesman Joan , Leonard Michael , Ray Graham , Kittelson Pat , Benson Connie , Muttera Leticia , Flynn Teri , Sbrolla Amy , Wiggins Ilene , Howard Jamilla , Arduino Roberto C , Villamil Aristoteles E , Kessels Lisa , Spitz Teresa , Campbell Danielle , Kudumu Mwenda , Sise Thucuma , Nair Apsara , Baer Jenifer , Epperson Kim , Perelson Alan , Jennings Cheryl , Tressler Randall , Acosta Ed , Casazza Joseph , Benns Alex 
Published: October 2018

AbstractBackgroundBroadly neutralizing monoclonal antibodies (bnMAbs) may promote clearance of HIV-1-expressing cells through antibody-dependent cell-mediated cytotoxicity. We evaluated the effect of the CD4-binding site bnMAb, VRC01, on measures of HIV-1 persistence in chronically infected individuals.MethodsA5342 was a phase 1, randomized, double-blind, placebo-controlled, parallel-arm study. Participants on effective antiretroviral therapy (ART) were randomized to receive 2 infusions of VRC01 (40 mg/kg) at entry and week 3, and 2 infusions of placebo (saline) at weeks 6 and 9; or 2 infusions of placebo at entry and week 3, and 2 infusions of VRC01 at weeks 6 and 9.ResultsInfusion of VRC01 was safe and well tolerated. The median fold-change in the cell-associated HIV-1 RNA/DNA ratio from baseline to week 6 was 1.12 and 0.83 for the VRC01 and placebo arms, respectively, with no significant difference between arms (P = .16). There were no significant differences in the proportions with residual plasma viremia ≥1 copies/mL or in phorbol 12-myristate 13-acetate/ionomycin-induced virus production from CD4+ T cells between arms (both P &gt; .05).ConclusionsIn individuals with chronic HIV-1 infection on ART, VRC01 infusions were safe and well tolerated but did not affect plasma viremia, cellular HIV-1 RNA/DNA levels, or stimulated virus production from CD4+ T cells.ClinicalTrials.gov IdentifierNCT02411539
Postoperative Repositioning of Inverted Descemet Membrane Endothelial Keratoplasty Grafts
Authors: Dragnea Diana C. , Nobacht Siamak , Gericke Adrian , Parker Jack , Oellerich Silke , Ham Lisanne , Melles Gerrit R.J. 
Published: October 2018

Purpose:
To present 4 cases of postoperative repositioning of inverted grafts after Descemet membrane endothelial keratoplasty (DMEK).

Methods:
Retrospective case reports of 4 patients presenting with subtotal to total graft detachment after DMEK, most probably owing to upside-down graft positioning. Graft repositioning was performed 1 to 14 days after initial DMEK surgery. In 3 cases (cases 1, 3, and 4), repositioning was performed without removing the graft from the anterior chamber (AC), whereas for case 2, the graft had to be removed from the AC to attain correct graft orientation.

Results:
In all 4 cases, the initially upside-down DMEK grafts could be successfully repositioned postoperatively. Three cases showed complete graft attachment after graft repositioning with clear corneas until the last available follow-up. One case manifested a persistent central detachment with central corneal edema, eventually requiring re-DMEK. Endothelial cell density decreased from 2800 cells/mm2 preoperatively to 2373 cells/mm2 at 2 years postoperatively for case 1 and from 2600 to 600 cells/mm2 at 6 months postoperatively for case 2. Case 3 showed a clear cornea until the last available follow-up at 1 year postoperatively.

Conclusions:
In cases of upside-down grafts after DMEK, attempting to reposition the graft, with or without removing the graft from the AC, may be a cost- and tissue-efficient alternative before converting to re-DMEK.
Issues in Recruiting and Retaining Asian American Breast Cancer Survivors in a Technology-Based Intervention Study
Authors: Im Eun-Ok , Kim Sangmi , Xu Shu , Lee Chiyoung , Hamajima Yuko , Inohara Ayako , Chang Kathleen , Chee Eunice , Chee Wonshik 
Published: October 2018

Background
Difficulties in recruiting and retaining Asian Americans in traditional research have been well documented. Despite an increasing number of technology-based cancer studies among racial/ethnic minorities, little is still known about potential issues in recruiting and retaining racial/ethnic minority cancer survivors for technology-based intervention research.

Objective
This discussion article aims to examine issues in recruiting and retaining a group of racial/ethnic minorities—Asian American breast cancer survivors—for a technology-based intervention study.

Methods
The parent study is an ongoing large-scale, national-scope, technology-based intervention study among a target number of 330 Asian American breast cancer survivors. During the recruitment and retention process, research diaries were written by research team members, and the written records of weekly research team meetings were kept. The written records were analyzed using a content analysis. Then, the themes were used to support the discussion points made in the article.

Results
There existed subethnic differences in research participation; it was easier to recruit Chinese participants compared with other subethnic groups. The use of culturally matched research team members and multiple languages was essential. Gatekeepers were also elemental for recruitment and retention. Various motivation strategies were needed to retain the participants. Each subethnic group used different communication apps. Finally, trust building was essential to retain the participants in the intervention.

Conclusions
Researchers need to consider these practical issues in future technology-based intervention research.

Implications for Practice
These issues need to be considered in future program/intervention development and implementation among racial/ethnic minority cancer survivors.
IDH1 and IDH2 mutants identified in cancer lose inhibition by isocitrate because of a change in their binding sites
Authors: Bascur Juan P. , Alegría-Arcos Melissa , Araya-Durán Ingrid , Juritz Ezequiel I. , González-Nilo Fernando D. , Almonacid Daniel E. 
Published: October 2018

AbstractIDH1 and IDH2 are human enzymes that convert isocitrate (ICT) into α-ketoglutarate (AKG). However, mutations in positions R132 of IDH1 and R140 and R172 of IDH2 cause these enzymes to convert AKG into 2-hydroxyglutarate (2HG). Concurrently, accumulation of 2HG in the cell is correlated with the development of cancer. This activity change is mainly due to the loss of the competitive inhibition by ICT of these enzymes, but the molecular mechanism behind this loss of inhibition is currently unknown. In this work we characterized the inhibition and loss of inhibition of IDH1 and IDH2 by means of the binding energies derived from molecular docking calculations. We characterized the substrate binding sites and how they differ among the mutant and wild type enzymes using a Jaccard similarity coefficient based on the residues involved in binding the substrates. We found that molecular docking effectively identifies the inhibition by ICT in the wild type and mutant enzymes that do not appear in tumors, and the loss of inhibition in the mutant enzymes that appear in tumors. Additionally, we found that the binding sites of the mutant enzymes are different among themselves. Finally, we found that the regulatory segment of IDH1 plays a prominent role in the change of binding sites between the mutant enzymes and the wild-type enzymes. Our findings show that the loss of inhibition is related to variations in the enzyme binding sites. Additionally, our findings show that a drug capable of targeting all IDH1 and IDH2 mutations in cancer is unlikely to be found due to significant differences among the binding sites of these paralogs. Moreover, the methodology developed here, which combines molecular docking calculations with binding site similarity estimation, can be useful for engineering enzymes, for instance, when aiming to modify the substrate affinity of an enzyme.
The TMCrys server for supporting crystallization of transmembrane proteins
Authors: Varga Julia K. , Tusnády Gábor E. 
Published: October 2018

AbstractMotivationDue to their special properties, the structures of transmembrane proteins are extremely hard to determine. Several methods exist to predict the propensity of successful completion of the structure determination process. However, available predictors incorporate data of any kind of proteins, hence they can hardly differentiate between crystallizable and non-crystallizable membrane proteins.ResultsWe implemented a web server to simplify running TMCrys prediction method that was developed specifically to separate crystallizable and non-crystallizable proteins.Availabilityhttp://tmcrys.enzim.ttk.mta.huContacttusnady.gabor@ttk.mta.huvarga.julia@ttk.mta.hu
Causal Effects of Blood Lipids on Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study
Authors: Zeng Ping , Zhou Xiang 
Published: October 2018

AbstractAmyotrophic lateral sclerosis (ALS) is a late-onset fatal neurodegenerative disorder that is predicted to increase across the globe by ~70% in the following decades. Understanding the disease causal mechanism underlying ALS and identifying modifiable risks factors for ALS hold the key for the development of effective preventative and treatment strategies. Here, we investigate the causal effects of four blood lipid traits that include high density lipoprotein (HDL), low density lipoprotein (LDL), total cholesterol (TC), and triglycerides (TG) on the risk of ALS. By leveraging instrument variables from multiple large-scale genome-wide association studies in both European and East Asian populations, we carry out one of the largest and most comprehensive Mendelian randomization analyses performed to date on the causal relationship between lipids and ALS. Among the four lipids, we found that only LDL is causally associated with ALS and that higher LDL level increases the risk of ALS in both the European and East Asian populations. Specifically, the odds ratio of ALS per one standard deviation (i.e. 39.0 mg/dL) increase of LDL is estimated to be 1.14 (95% CI 1.05 - 1.24, p = 1.38E-3) in the European and population and 1.06 (95% CI 1.00 - 1.12, p = 0.044) in the East Asian population. The identified causal relationship between LDL and ALS is robust with respect to the choice of statistical methods and is validated through extensive sensitivity analyses that guard against various model assumption violations. Our study provides important evidence supporting the causal role of higher LDL on increasing the risk of ALS, paving ways for the development of preventative strategies for reducing the disease burden of ALS across multiple nations.
Regrowth-delay Body as a Bacterial Subcellular Structure marking multidrug tolerant Persisters
Authors: Yu Jiayu , Liu Yang , Yin Huijia , Chang Zengyi 
Published: October 2018

SummaryBacteria have long been recognized to be capable of entering a phenotypically non-growing persister state, in which the cells exhibit an extended regrowth lag and a multidrug tolerance, thus posing a great challenge in treating infectious diseases. Owing to their non-inheritability, low abundance of existence, lack of metabolic activities, and high heterogeneity, properties of persisters remain poorly understood. Here, we report our accidental discovery of a hitherto unreported subcellular structure that we term the regrowth-delay body, which is formed only in non-growing bacterial cells and sequesters multiple key proteins. As of now, this structure, that dissolves when the cell resumes growth, is the most distinguishable subcellular structure marking persisters. Our studies also indicate that persisters exhibit different depth of persistence, as determined by the status of their regrowth-delay bodies. Our findings imply that suppressing the formation and/or promoting the dissolution of regrowth-delay bodies could be viable strategies for eradicating persisters.
Occurrence of ordered and disordered structural elements in postsynaptic proteins supports optimization for interaction diversity
Authors: Kiss-Tóth Annamária , Dobson Laszlo , Péterfia Bálint , Ángyán Annamária F. , Ligeti Balázs , Lukács Gergely , Gáspári Zoltán 
Published: October 2018

AbstractThe human postsynaptic density is an elaborate network comprising thousands of proteins, playing a vital role in the molecular events of learning and the formation of memory. Despite our growing knowledge of specific proteins and their interactions, atomic-level details of their full three-dimensional structure and their rearrangements are mostly elusive. Advancements in structural bioinformatics enabled us to depict the characteristic features of proteins involved in different processes aiding neurotransmission. We show that postsynaptic protein-protein interactions are mediated through the delicate balance of intrinsically disordered regions and folded domains, and this duality is also imprinted in the amino acid sequence. We introduce Diversity of Potential Interactions (DPI), a structure and regulation based descriptor to assess the diversity of interactions. Our approach reveals that the postsynaptic proteome has its own characteristic features and these properties reliably discriminate them from other proteins of the human proteome. Our results suggest that postsynaptic proteins are especially susceptible to forming diverse interactions with each other, which might be key in the reorganization of the PSD in molecular processes related to learning and memory.
Phoneme-level processing in low-frequency cortical responses to speech explained by acoustic features
Authors: Daube Christoph , Ince Robin A. A. , Gross Joachim 
Published: October 2018

AbstractWhen we listen to speech, we have to make sense of a waveform of sound pressure. Hierarchical models of speech perception assume that before giving rise to its final semantic meaning, the signal is transformed into unknown intermediate neuronal representations. Classically, studies of such intermediate representations are guided by linguistically defined concepts such as phonemes. Here we argue that in order to arrive at an unbiased understanding of the mechanisms of speech comprehension, the focus should instead lie on representations obtained directly from the stimulus. We illustrate our view with a strongly data-driven analysis of a dataset of 24 young, healthy humans who listened to a narrative of one hour duration while their magnetoencephalogram (MEG) was recorded. We find that two recent results, a performance gain of an encoding model based on acoustic and annotated linguistic features over a model based on acoustic features alone as well as the decoding of subgroups of phonemes from phoneme-locked responses, can be explained with an encoding model entirely based on acoustic features. These acoustic features capitalise on acoustic edges and outperform Gabor-filtered spectrograms, features with the potential to describe the spectrotemporal characteristics of individual phonemes. We conclude that models of brain responses based on linguistic features can serve as excellent benchmarks. However, we put forward that linguistic concepts are better used when interpreting models, not when building them. In doing so, we find that the results of our analyses favour syllables over phonemes as candidate intermediate speech representations visible with fast non-invasive neuroimaging.
Comprehensive human cell-type methylation atlas reveals origins of circulating cell-free DNA in health and disease
Authors: Moss Joshua , Magenheim Judith , Neiman Daniel , Zemmour Hai , Loyfer Netanel , Korach Amit , Samet Yaacov , Maoz Myriam , Druid Henrik , Arner Peter , Fu Keng-Yeh , Kiss Endre , Spalding Kirsty L. , Landesberg Giora , Zick Aviad , Grinshpun Albert , Shapiro AM James , Grompe Markus , Wittenberg Avigail Dreazan , Glaser Benjamin , Shemer Ruth , Kaplan Tommy , Dor Yuval 
Published: October 2018

AbstractMethylation patterns of circulating cell-free DNA (cfDNA) contain rich information about recent cell death events in the body. Here, we present an approach for unbiased determination of the tissue origins of cfDNA, using a reference methylation atlas of 25 human tissues and cell types. The method is validated usingin silicosimulations as well asin vitromixes of DNA from different tissue sources at known proportions. We show that plasma cfDNA of healthy donors originates from white blood cells (55%), erythrocyte progenitors (30%), vascular endothelial cells (10%) and hepatocytes (1%). Deconvolution of cfDNA from patients reveals tissue contributions that agree with clinical findings in sepsis, islet transplantation, cancer of the colon, lung, breast and prostate, and cancer of unknown primary. We propose a procedure which can be easily adapted to study the cellular contributors to cfDNA in many settings, opening a broad window into healthy and pathologic human tissue dynamics.
The three dimensional structure of Bovine Salivary Protein 30b (BSP30b) and its interaction with specific rumen bacteria
Authors: Zhang Heng , Burrows Judith , Card Graeme L. , Attwood Graeme , Wheeler Thomas T. , Arcus Vickery L. 
Published: October 2018

AbstractBovine Salivary Protein 30b (BSP30b) is a member of the tubular lipid-binding (TULIP) superfamily that includes the human bactericidal/permeability-increasing proteins (BPI), lipopolysaccharide binding proteins (LBP) and palate, lung, and nasal epithelium carcinoma-21 associated proteins (PLUNC). BSP30b is most closely related to the PLUNC family and is predominantly found in bovine saliva. There are four BSP30 isoforms (BSP30a-d) and collectively, they are the most abundant protein component of bovine saliva. The PLUNC family members are proposed to be lipid binding proteins, although in most cases their lipid ligands are unknown. Here, we present the X-ray crystal structure of BSP30b at 2.0 Å resolution. We used a double methionine mutant and Se-Met SAD phasing to solve the structure. The structure adopts a curved cylindrical form with a hydrophobic channel formed by an α/β wrap, which is consistent with the TULIP superfamily. The structure of BSP30b in complex with oleic acid is also presented where the ligand is accommodated within the hydrophobic channel. The electron density for oleic acid suggests that the ligand is only partially occupied in the binding site implying that oleic acid may not be the preferred ligand. GFP-tagged BSP30b binds to the surface of olive oil droplets, as observed under fluorescent microscopy, and acts as a surfactant consistent with its association with decreased susceptibility to bloat in cattle. Bacteria extracted directly from bovine rumen contents indicate that the GFP_BSP30b fusion protein binds to a small number of selected bacterial speciesin vivo. These results suggest that BSP30b may bind to bacterial lipids from specific species and that this abundant protein may have important biological roles via interacting with rumen bacteria during feeding and rumination.
Enhanced plasticity of programmed DNA elimination boosts adaptive potential in suboptimal environments
Authors: Vitali Valerio , Hagen Rebecca , Catania Francesco 
Published: October 2018

AbstractThe impact of ecological changes on the development of new somatic genomes has thus far been neglected. This oversight yields an incomplete understanding of the mechanisms that underlie environmental adaptation and can be tackled leveraging the biological properties of ciliates. WhenParameciumreproduces sexually, its polyploid somatic genome regenerates from the germline genome via a developmental process, Programmed DNA elimination (PDE), that involves the removal of thousands of ORF-interrupting germline sequences. Here, we demonstrate that exposure to sub-optimal temperatures impacts PDE efficiency, prompting the emergence of hundreds of alternative DNA splicing variants that dually embody cryptic (germline) variation andde novoinduced (somatic) mutations. In contrast to trivial biological errors, many of these alternative DNA isoforms display a patterned genomic topography, are epigenetically controlled, inherited trans-somatically, and under purifying selection. Developmental thermoplasticity inParameciumis a likely source of evolutionary innovation.
Selective advantages favour high genomic AT-contents in intracellular elements
Authors: Dietel Anne-Kathrin , Merker Holger , Kaltenpoth Martin , Kost Christian 
Published: October 2018

AbstractExtrachromosomal genetic elements generally exhibit increased AT-contents relative to their hosts’ DNA. The AT-bias of endosymbiotic genomes is commonly explained by neutral evolutionary processes. Here we show experimentally that an increased AT-content of host-dependent elements can be selectively favoured on the host level. Manipulating the nucleotide composition of bacterial cells by introducing A+T-or G+C-rich plasmids, we demonstrate that cells containing GC-rich plasmids are less fit than cells containing AT-rich plasmids. Moreover, the cost of GC-rich elements could be compensated by providing G+C-, but not A+T-precursors, thus linking the observed fitness effects to the cytoplasmic availability of nucleotides. Our work identifies selection as a strong evolutionary force that drives the genomes of intracellular genetic elements toward higher A+T contents.Author SummaryGenomes of endosymbiotic bacteria are commonly more AT-rich than the ones of their free-living relatives. Interestingly, genomes of other intracellular elements like plasmids or bacteriophages also tend to be richer in AT than the genomes of their hosts. The AT-bias of endosymbiotic genomes is commonly explained by neutral evolutionary processes. However, since A+T nucleotides are both more abundant and energetically less expensive than G+C nucleotides, an alternative explanation is that selective advantages drive the nucleotide composition of intracellular elements. Here we provide strong experimental evidence that intracellular elements, whose genome is more AT-rich than the genome of the host, are selectively favored on the host level. Thus, our results emphasize the importance of selection for shaping the DNA base composition of extrachromosomal genetic elements.
Statistical Considerations in the Design and Analysis of Longitudinal Microbiome Studies
Authors: Silverman Justin D , Shenhav Liat , Halperin Eran , Mukherjee Sayan , David Lawrence A 
Published: October 2018

AbstractLongitudinal studies of microbial communities have emphasized that host-associated microbiota are highly dynamic as well as underscoring the potential biomedical relevance of understanding these dynamics. Despite this increasing appreciation, statistical challenges in the design and analysis of longitudinal microbiome studies such as sequence counting, technical variation, signal aliasing, contamination, sparsity, missing data, and algorithmic scalability remain. In this review we discuss these challenges and highlight current progress in the field. Where possible, we try to provide guidelines for best practices as well as discuss how to tailor design and analysis to the hypothesis and ecosystem under study. Overall, this review is intended to serve as an introduction to longitudinal microbiome studies for both statisticians new to the microbiome field as well as biologists with little prior experience with longitudinal study design and analysis.