bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of intact proviruses in blood and lymph node from HIV-infected individuals undergoing analytical treatment interruption
Authors: Vibholm Line K. , Lorenzi Julio C.C. , Pai Joy A. , Cohen Yehuda Z. , Oliveira Thiago Y. , Barton John P. , Noceda Marco Garcia , Lu Ching-Lan , Ablanedo-Terrazas Yuria , Del Rio Estrada Perla M. , Teran Gustavo Reyes , Tolstrup Martin , Denton Paul W. , Damsgaard Tine , Søgaard Ole S. , Nussenzweig Michel C. 
Published: November 2018

AbstractThe role of lymphoid tissue as a potential source of HIV-1 rebound following interruption of antiretroviral therapy is uncertain. To address this issue, we compared the latent viruses obtained from CD4+ T cells in peripheral blood and lymph nodes to viruses emerging during treatment interruption. Latent viruses were characterized by sequencing near full-length (NFL) proviral DNA, and env from viral outgrowth cultures (VOAs). 5 HIV-1 infected individuals on antiretroviral therapy (ART) were studied, 4 of whom participated in a clinical trial that included an analytical treatment interruption. Intact or replication competent clonal sequences from blood and lymph node overlapped. In contrast, there was no overlap between 205 latent reservoir and 125 rebound sequences in the 4 individuals who underwent treatment interruption. However, rebound viruses could be accounted for by recombination. The data suggests that CD4+ T cells carrying latent viruses circulate between blood and lymphoid tissues in individuals on ART and support the idea that recombination may play a role in the emergence of rebound viremia.
Predicting time to dementia using a quantitative template of disease progression
Authors: Murat Bilgel , Jedynak Bruno M. 
Published: November 2018

AbstractIntroductionCharacterization of longitudinal trajectories of biomarkers implicated in sporadic Alzheimer’s disease (AD) in decades prior to clinical diagnosis is important for disease prevention and monitoring.MethodsWe used a multivariate Bayesian model to temporally align 1369 AD Neuroimaging Initiative participants based on the similarity of their longitudinal biomarker measures and estimated a quantitative template of the temporal evolution cerebrospinal fluid (CSF) Aβ1-42, p-tau181p, and t-tau, hippocampal volume, brain glucose metabolism, and cognitive measurements. We computed biomarker trajectories as a function of time to AD dementia, and predicted AD dementia onset age in a disjoint sample.ResultsQuantitative template showed early changes in verbal memory, CSF Aβ1-42 and p-tau181p, and hippocampal volume. Mean error in predicted AD dementia onset age was < 1.5 years.DiscussionOur method provides a quantitative approach for characterizing the natural history of AD starting at preclinical stages despite the lack of individual-level longitudinal data spanning the entire disease timeline.
Biomarker-based patient selection improves stroke rehabilitation trial efficiency
Authors: Stinear Cathy M. , Byblow Winston D. , Barber P. Alan , Ackerley Suzanne J. , Smith Marie-Claire , Cramer Steven C. 
Published: November 2018

AbstractBackground and PurposeInter-subject variability complicates trials of novel stroke rehabilitation therapies, particularly in the sub-acute phase after stroke. We tested whether selecting patients using motor evoked potential (MEP) status, a physiological biomarker of motor system function, could improve trial efficiency.MethodsA retrospective analysis of data from 207 patients (103 women, mean (SD) 70.6 (15.1) years) was used to estimate sample sizes and recruitment rates required to detect a 7-point difference between hypothetical control and treatment groups in upper-limb Fugl-Meyer and Action Research Arm Test scores at 90 days post-stroke. Analyses were carried out for the full sample and for subsets defined by motor evoked potential (MEP) status.ResultsSelecting patients according to MEP status reduced the required sample size by 75% compared to an unselected sample. The estimated time needed to recruit the required sample was also reduced by 72% for patients with MEPs, and was increased by 2-3-fold for patients without MEPs.ConclusionsUsing biomarkers to select patients can improve stroke rehabilitation trial efficiency by reducing the sample size and recruitment time needed to detect a clinically meaningful effect of the tested intervention.
Targeting and Vaccine Durability Are Key for Population-level Impact and Cost-Effectiveness of a Pox-Protein HIV Vaccine Regimen in South Africa
Authors: Selinger Christian , Bershteyn Anna , Dimitrov Dobromir T. , Adamson Blythe J.S. , Revill Paul , Hallett Timothy B. , Phillips Andrew N. , Bekker Linda-Gail , Rees Helen , Gray Glenda 
Published: November 2018

AbstractBackgroundRV144 is to date the only HIV vaccine trial to demonstrate efficacy, albeit rapidly waning over time. The HVTN 702 trial is currently evaluating in South Africa a similar vaccine formulation to that of RV144 for subtype C HIV with additional boosters (pox-protein regimen). Using a detailed stochastic individualbased network model of disease transmission calibrated to the HIV epidemic, we investigate population-level impact and maximum cost of an HIV vaccine to remain cost-effective.MethodsConsistent with the original pox-protein regimen, we model a primary series of five vaccinations meeting the goal of 50% cumulative efficacy 24 months after the first dose and include two-yearly boosters that maintain durable efficacy over 10 years. We simulate vaccination programs in South Africa starting in 2027 under various vaccine targeting and HIV treatment and prevention assumptions.ResultsOur analysis shows that this partially effective vaccine could prevent, at catchup vaccination with 60% coverage, up to 941,000 (15.6%) new infections between 2027 and 2047 assuming current trends of antiretroviral treatment. An impact of up to 697,000 (11.5%) infections prevented could be achieved by targeting age cohorts of highest incidence. Economic evaluation indicates that, if treatment scale-up was achieved, vaccination could be cost-effective at a total cost of less than $385 and $62 per 10-year series (cost-effectiveness thresholds of $5,691 and $750).ConclusionsWhile a partially effective, rapidly waning vaccine could help to prevent HIV infections, it will not eliminate HIV as a public health priority in sub-Saharan Africa. Vaccination is expected to be most effective under targeted delivery to age groups of highest HIV incidence. Awaiting results of trial, the introduction of vaccination should go in parallel with continued innovation in HIV prevention, including studies to determine the costs of delivery and feasibility and further research into products with greater efficacy and durability.
Real-Time Selective Sequencing with RUBRIC: Read Until with Basecall and Reference-Informed Criteria
Authors: Edwards Harrison S. , Krishnakumar Raga , Sinha Anupama , Bird Sara W. , Patel Kamlesh D. , Bartsch Michael S. 
Published: November 2018

AbstractThe Oxford MinION, the first commercial nanopore sequencer, is also the first to implement molecule-by-molecule real-time selective sequencing or “Read Until”. As DNA transits a MinION nanopore, real-time pore current data can be accessed and analyzed to provide active feedback to that pore. Fragments of interest are sequenced by default, while DNA deemed non-informative is rejected by reversing the pore bias to eject the strand, providing a novel means of background depletion and/or target enrichment. In contrast to the previously published pattern-matching Read Until approach, our RUBRIC method is the first example of real-time selective sequencing where on-line basecalling enables alignment against conventional nucleic acid references to provide the basis for sequence/reject decisions. We evaluate RUBRIC performance across a range of optimizable parameters, apply it to mixed human/bacteria and CRISPR/Cas9-cut samples, and present a generalized model for estimating real-time selection performance as a function of sample composition and computing configuration.
Paradoxical changes in brain reward status during oxycodone self-administration in a novel test of the negative reinforcement hypothesis
Authors: Nguyen Jacques D. , Grant Yanabel , Taffe Michael A. 
Published: November 2018

ABSTRACTBackground and PurposeThe extra-medical use of, and addiction to, prescription opioid analgesics is a growing health problem. To characterize how prescription opioid abuse develops, this study investigated the affective consequences of escalating prescription opioid use using intracranial self-stimulation (ICSS) reward and oxycodone intravenous self-administration (IVSA) models.Experimental ApproachMale Wistar rats were given access to oxycodone IVSA (0.15 mg/kg/infusion, i.v.) in Short Access (ShA; 1 h) or Long Access (LgA; 12 h) sessions for 5 sessions/week followed by intermittent 60 h discontinuations from drug access, a novel explicit test of the negative reinforcement hypothesis. Separate groups were first trained in the ICSS procedure and then in oxycodone IVSA in 11 h LgA sessions.Key ResultsRats given LgA to oxycodone escalated their responding more than ShA rats, with further significant increases observed following each 60 h discontinuation. Pre-session brain reward thresholds increased with sequential daily LgA IVSA sessions, consistent with a growing negative affective state consequent to successive daily intoxication/abstinence cycles. A 1 h oxycodone IVSA interval was sufficient to normalize these elevated reward thresholds, as was, paradoxically, a 60 h weekend abstinence. The increase in ICSS thresholds was attenuated in a group treated with the long-acting kappa opioid antagonist norBNI prior to IVSA training.Conclusions and ImplicationsChanges in brain reward function during escalation of oxycodone self-administration are driven by an interplay between kappa opioid receptor-mediated negative affective state associated with escalated oxycodone intake and dynamic restoration of brain reward status during longer periods of abstinence.
Low-cost, sub-micron resolution, wide-field computational microscopy using opensource hardware
Authors: Aidukas Tomas , Eckert Regina , Harvey Andrew R. , Waller Laura , Konda Pavan C. 
Published: November 2018

ABSTRACTThe revolution in low-cost consumer photography and computation provides fertile opportunity for a disruptive reduction in the cost of biomedical imaging. Conventional approaches to low-cost microscopy are fundamentally restricted, however, to modest field of view (FOV) and/or resolution. We report a low-cost microscopy technique, implemented with a Raspberry Pi single-board computer and color camera combined with Fourier ptychography (FP), to computationally construct 25-megapixel images with sub-micron resolution. New image-construction techniques were developed to enable the use of the low-cost Bayer color sensor, to compensate for the highly aberrated re-used camera lens and to compensate for misalignments associated with the 3D-printed microscope structure. This high ratio of performance to cost is of particular interest to high-throughput microscopy applications, ranging from drug discovery and digital pathology to health screening in low-income countries. 3D models and assembly instructions of our microscope are made available for open source use.
Tfap2a is a novel gatekeeper of differentiation in renal progenitors during kidney development
Authors: Chambers Brooke E. , Gerlach Gary F. , Chen Karen H. , Clark Eleanor G. , Leshchiner Ignaty , Goessling Wolfram , Wingert Rebecca A. 
Published: November 2018

AbstractRenal functional units known as nephrons undergo patterning events during development that create a segmental array of cellular populations with discrete physiological tasks. Knowledge about the terminal differentiation programs of each nephron segment has central importance for understanding kidney disease and to advance regenerative medicine, as mammalian nephrons grown in organoid cultures from pluripotent cells fail to terminally differentiate. Here, from a novel forward genetic screen using zebrafish we report the discovery thattranscription factor AP-2 alpha(tfap2a)coordinates a gene regulatory network that controls the progression of nephron distal segment progenitors into the differentiated state. Overexpression oftfap2arescued differentiation in mutants and caused ectopic expression of distal segment markers in wild-type nephrons, indicatingtfap2ais sufficient to instigate the distal segment differentiation program.tfap2a/2bdeficiency exacerbated distal nephron segment differentiation defects, revealing functional redundancy wheretfap2ahas a dominant role upstream of its family member. With further genetic studies, we assembled a blueprint of thetfap2agene regulatory network during nephrogenesis. We demonstrate thattfap2aacts downstream ofIroquois homeobox 3b, a conserved distal lineage transcription factor.tfap2acontrols a circuit consisting ofirx1a, tfap2b,and genes encoding solute transporters that dictate the specialized metabolic functions of the distal nephron segments, and we show for the first time that this regulatory node is distinct from the pathway circuits controlling aspects such as apical-basal polarity and ciliogenesis during the differentiation process. Thus, our studies reveal new insights into the genetic control of differentiation, wheretfap2aregulates the suite of segment transporter traits. These findings have relevance for understanding renal birth defects, as well as efforts to recapitulate nephrogenesisin vivoto make functional units that can facilitate organoid applications such as drug discovery and regenerative therapies.Summary StatementHere, we report for the first time thattranscription factor AP-2 alpha(tfap2a) controls the progression from nephron progenitor into the fully differentiated state. This fundamentally deepens our knowledge about the genetic control of kidney development.
Mechanical Interactions between a Cell and an Extracellular Environment Facilitate Durotactic Cell Migration
Authors: Hassan Abdel-Rahman , Biel Thomas , Kim Taeyoon 
Published: November 2018

ABSTRACTCell migration is a fundamental process in biological systems, playing an important role for diverse physiological processes. Cells often exhibit directed migration in a specific direction in response to various types of cues. In particular, cells are able to sense the rigidity of surrounding environments and then migrate towards stiffer regions. To understand this mechanosensitive behavior called durotaxis, several computational models have been developed. However, most of the models made phenomenological assumptions to recapitulate durotactic behaviors, significantly limiting insights provided from these studies. In this study, we developed a computational biomechanical model without any phenomenological assumption to illuminate intrinsic mechanisms of durotactic behaviors of cells migrating on a two-dimensional substrate. The model consists of a simplified cell generating contractile forces and a deformable substrate coarse-grained into an irregular triangulated mesh. Using the model, we demonstrated that durotactic behaviors emerge from purely mechanical interactions between the cell and the underlying substrate. We investigated how durotactic migration is regulated by biophysical properties of the substrate, including elasticity, viscosity, and stiffness profile.
Characterization of Pacific oyster (Crassostrea gigas) proteomic response to natural environmental differences
Authors: Venkataraman Yaamini R. , Timmins-Schiffman Emma , Horwith Micah J. , Lowe Alexander T. , Nunn Brook , Vadopalas Brent , Spencer Laura H. , Roberts Steven B. 
Published: November 2018

AbstractGlobal climate change is rapidly altering coastal marine ecosystems important for food production. A comprehensive understanding of how organisms will respond to these complex environmental changes can come only from observing and studying species within their natural environment. To this end, the effects of environmental drivers — pH, dissolved oxygen content, salinity, and temperature — on Pacific oyster (Crassostrea gigas) physiology were evaluated in an outplant experiment. Sibling juvenile oysters were outplanted to eelgrass and unvegetated habitat at five different estuarine sites within the Acidification Nearshore Monitoring Network in Washington State, USA to evaluate how regional environmental drivers influence molecular physiology. Within each site, we also determined if eelgrass presence that buffered pH conditions changed the oysters’ expressed proteome. A novel, two-step, gel-free proteomic approach was used to identify differences in protein abundance in C. gigas ctenidia tissue after a 29 day outplant by 1) identifying proteins in a data independent acquisition survey step and 2) comparing relative quantities of targeted environmental response proteins using selected reaction monitoring. While there was no difference in protein abundance detected between habitats or among sites within Puget Sound, C. gigas outplanted at Willapa Bay had significantly higher abundances of antioxidant enzymes and molecular chaperones. Environmental factors at Willapa Bay, such as higher average temperature, may have driven this protein abundance pattern. These findings generate a suite of new hypotheses for lab and field experiments to compare the effects of regional conditions on physiological responses of marine invertebrates.
Calcium imaging in freely-moving mice during electrical stimulation of deep brain structures
Authors: Trevathan J. K. , Asp A. J. , Nicolai E. N. , Trevathan J. M. , Kremer N.A. , Kozai T.D. , Cheng D. , Schachter M. , Nassi J. J. , Otte S. L. , Parker J. G. , Lujan J. L. , Ludwig K. A. 
Published: November 2018

AbstractAfter decades of study in humans and animal models, there remains a lack of consensus regarding how the action of electrical stimulation on neuronal and non-neuronal elements – e.g. neuropil, cell bodies, glial cells, etc. – leads to the therapeutic effects of neuromodulation therapies. To further our understanding of neuromodulation therapies, there is a critical need for novel methodological approaches using state-of-the-art neuroscience tools to study neuromodulation therapy in preclinical models of disease. In this manuscript we outline one such approach combining chronic behaving single-photon microendoscope recordings in a pathological mouse model with electrical stimulation of a common deep brain stimulation (DBS) target. We describe in detail the steps necessary to realize this approach, as well as discuss key considerations for extending this experimental paradigm to other DBS targets for different therapeutic indications. Additionally, we make recommendations from our experience on implementing and validating the required combination of procedures that includes: the induction of a pathological model (6-OHDA model of Parkinson’s disease) through an injection procedure, the injection of the viral vector to induce GCaMP expression, the implantation of the GRIN lens and stimulation electrode, and the installation of a baseplate for mounting the microendoscope. We proactively identify unique data analysis confounds occurring due to the combination of electrical stimulation and optical recordings and outline an approach to address these confounds. In order to validate the technical feasibility of this unique combination of experimental methods, we present data to demonstrate that 1) despite the complex multifaceted surgical procedures, chronic optical recordings of hundreds of cells combined with stimulation is achievable over week long periods 2) this approach enables measurement of differences in DBS evoked neural activity between anesthetized and awake conditions and 3) this combination of techniques can be used to measure electrical stimulation induced changes in neural activity during behavior in a pathological mouse model. These findings are presented to underscore the feasibility and potential utility of minimally constrained optical recordings to elucidate the mechanisms of DBS therapies in animal models of disease.
Cantharidin alters GPI-anchored protein sorting by targeting Cdc1 mediated remodeling in Endoplasmic Reticulum
Authors: Kumar Sahu Pushpendra , Singh Tomar Raghuvir 
Published: November 2018

ABSTRACTCantharidin (CTD) is a potent anticancer small molecule produced by several species of blister beetle. It has been a traditional medicine for the treatment of warts and tumors for many decades. CTD suppresses the tumor growth by inducing apoptosis, cell cycle arrest, and DNA damage. It is a known inhibitor of PP2A and PP1. In this study, we identified new molecular targets of CTD usingSaccharomyces cerevisiaeas a model organism which expresses a Cantharidin Resistance Gene (CRG1).CRG1encodes a SAM-dependent methyltransferase that inactivates CTD by methylation. CTD alters lipid homeostasis, cell wall integrity, endocytosis, adhesion, and invasion in yeast cells. We found that CTD specifically affects the phosphatidylethanolamine (PE) associated functions which can be rescued by supplementation of ethanolamine (ETA) in the growth media. CTD also perturbed ER homeostasis and cell wall integrity by altering the GPI-anchored protein sorting. The CTD dependent genetic interaction profile ofCRG1revealed that Cdc1 activity in GPI-anchor remodeling is the key target of CTD, which we found to be independent of PP2A and PP1. Furthermore, our experiments with human cells suggest that CTD functions through a conserved mechanism in higher eukaryotes as well. Altogether, we conclude that CTD induces cytotoxicity by targeting Cdc1 activity in GPI-anchor remodeling in the endoplasmic reticulum (ER).
Combined neural tuning in human ventral temporal cortex resolves the perceptual ambiguity of morphed 2-D images
Authors: Rosenke Mona , Davidenko Nicolas , Grill-Spector Kalanit , Weiner Kevin S. 
Published: November 2018

ABSTRACTWe have an amazing ability to categorize objects in the world around us. Nevertheless, how cortical regions in human ventral temporal cortex (VTC), which is critical for categorization, support this behavioral ability, is largely unknown. Here, we examined the relationship between neural responses and behavioral performance during the categorization of morphed silhouettes of faces and hands, which are animate categories processed in cortically adjacent regions in VTC. Our results reveal that the combination of neural responses from VTC face- and body-selective regions more accurately explains behavioral categorization than neural responses from either region alone. Furthermore, we built a model that predicts a person’s behavioral performance using estimated parameters of brain-behavioral relationships from a different group of people. We further show that this brain-behavioral model generalizes to adjacent face- and body-selective regions in lateral occipito-temporal cortex. Thus, while face- and body-selective regions are located within functionally-distinct domain-specific networks, cortically adjacent regions from both networks likely integrate neural responses to resolve competing and perceptually ambiguous information from both categories.