bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk Factors of Post-Large Loop Excision of the Transformation Zone Recurrent High-Grade Cervical Intraepithelial Lesion: A Prospective Cohort Study
Authors: Demarquet Emilie , Mancini Julien , Preaubert Lise , Gondry Jean , Chevreau Julien , Lamblin Gery , Lebail Karine , Lavoué Vincent , Pinsard Marion , Baldauf Jean-Jacques , Bryand Angélique , Henno Sebastien , Agostini Aubert , Douvier Serge , Jarniat Adelaïde , Riethmuller Didier , Mendel Anne , Brun Jean-Luc , Rakotomahenina Hajanirina , Carcopino Xavier 
Published: August 2018

Objective
The aim of the study was to identify the risk factors of post-large loop excision of the transformation zone (LLETZ) recurrent disease and the impact of colposcopic guidance at the time of LLETZ on that risk.

Materials and Methods
From December 2013 to July 2014, 204 patients who had undergone LLETZ for the treatment of high-grade intraepithelial lesion with fully visible cervical squamocolumnar junction were included. The use of colposcopy during each procedure was systematically documented. The dimensions and volume of LLETZ specimens were measured at the time of the procedure before formaldehyde fixation. All participants were invited for a follow-up. The primary endpoint was the diagnosis of post-LLETZ recurrent disease defined as the histologic diagnosis of a high-grade cervical intraepithelial lesion.

Results
The median duration of post-LLETZ follow-up was 25.8 months. Recurrent disease was diagnosed in 8 (3.6%) patients. Older than 38 years (adjusted hazard ratio [aHR] = 11.9, 95% CI = 1.6–86.0), history of excisional therapy (aHR = 21.6, 95% CI = 3.5–135.3), and the absence of colposcopy for the guidance of LLETZ (aHR = 6.4, 95% CI = 1.1–37.7) were found to significantly increase the risk of post-LLETZ recurrent disease. The dimensions and volume of the specimen were not found to have any impact. Only positive endocervical margins were identified to significantly increase the risk of post-LLETZ recurrent disease (aHR = 14.4, 95% CI = 2.0–101.1).

Conclusions
Risk factors of post-LLETZ recurrent disease are older than 38 years, history of excisional therapy, positive endocervical margins, and lack of colposcopic guidance at the time of LLETZ.
Brief Report: A Panel Management and Patient Navigation Intervention Is Associated With Earlier PrEP Initiation in a Safety-Net Primary Care Health System
Authors: Spinelli Matthew A. , Scott Hyman M. , Vittinghoff Eric , Liu Albert Y. , Morehead-Gee Alicia , Gonzalez Rafael , Gandhi Monica , Buchbinder Susan P. 
Published: August 2018

Background:
Timely pre-exposure prophylaxis (PrEP) initiation is critical in at-risk populations, given that HIV acquisition risk persists during delays. Time to treatment initiation, a key metric in HIV care, has not been explored among PrEP users. Interventions that reduce time to PrEP initiation could prevent HIV infections.

Setting:
Individuals initiating PrEP in a large primary care health network of 15 clinics, the San Francisco Primary Care Clinics (SFPCC), from July 2012 to July 2017 (N = 411).

Methods:
We examined factors associated with time from first PrEP discussion with a provider to PrEP initiation date using an adjusted Cox proportional-hazards model, with hazard ratios (HRs) >1 indicating earlier initiation. We also examined the relationship between delayed PrEP initiation and PrEP persistence (staying on PrEP) in an adjusted Cox proportional-hazards model.

Results:
PrEP users initiated PrEP after a median of only 7 days. However, there were notable outliers, with 29% waiting >30 days and 12% waiting >90 days. In an adjusted proportional-hazards model, a panel management and patient navigation intervention was associated with earlier PrEP initiation [HR: 1.5; 95% confidence interval (CI): 1.1 to 2.0], whereas only other race/ethnicity compared with white race was associated with delayed PrEP initiation (HR: 0.7; 95% CI: 0.5 to 1.0). Delayed PrEP initiation >30 days was associated with shorter PrEP persistence in an adjusted proportional-hazards model (HR: 1.3; 95% CI: 1.0 to 1.7).

Conclusions:
PrEP initiation within a week is feasible in a primary care safety-net health system. Setting a goal of rapid PrEP initiation, with the support of panel management and patient navigation, could address delays in at-risk groups.
Role of 18F-FDG PET/CT in Restrictive Allograft Syndrome After Lung Transplantation
Authors: Verleden Stijn E. , Gheysens Olivier , Goffin Karolien E , Vanaudenaerde Bart M. , Verbeken Erik K. , Weynand Birgit , Van Raemdonck Dirk E. , Verleden Geert M. , Vos Robin 
Published: August 2018

Background.
Differential diagnosis of phenotypes of chronic lung allograft dysfunction (CLAD) remains troublesome. We hypothesized that 18F-fluorodeoxyglucose positron emission tomography with computed tomography (18F-FDG PET/CT) may help in differential diagnosis of CLAD phenotypes, as it showed promising results regarding diagnosis and prognosis in interstitial lung diseases.

Methods.
A monocentric, retrospective study was performed including all lung transplant recipients suffering from bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS) who underwent 18F-FDG PET/CT scan, in comparison with stable lung transplant recipients. Maximum standardized uptake value (SUVmax) was associated with pulmonary function and survival. Proof-of-concept microCT and glucose transporter-1 staining served as morphologic validation for regions with different SUVmax.

Results.
Maximum standardized uptake value was higher in RAS (median, 2.6; n = 29) compared with BOS (median, 1.0; n = 15) and stable patients (median, 0.59; n = 8) (P < 0.0001). In RAS, high SUVmax was associated with worse survival after 18F-FDG PET/CT (P = 0.0004; hazard ratio, 1.82). Forced vital capacity at 18F-FDG PET/CT inversely correlated with SUVmax (R = −0.40, P = 0.03). MicroCT analysis revealed extensive fibrosis in regions of high SUVmax, with an increased number of glucose transporter-1–positive cells.

Conclusions.

18F-fluorodeoxyglucose positron emission tomography with CT may noninvasively differentiate RAS from BOS. RAS patients with areas of increased lung metabolism have worse outcome, demonstrating the potential use of 18F-FDG PET/CT during follow-up after lung transplantation.
Single-cell transcriptome analysis of human, marmoset and mouse embryos reveals common and divergent features of preimplantation development
Authors: Boroviak Thorsten , Stirparo Giuliano G , Dietmann Sabine , Hernando-Herraez Irene , Mohammed Hisham , Reik Wolf , Smith Austin , Sasaki Erika , Nichols Jennifer , Bertone Paul 
Published: August 2018

AbstractThe mouse embryo is the canonical model for mammalian preimplantation development. Recent advances in single-cell profiling allow detailed analysis of embryogenesis in other eutherian species, including human, to distinguish conserved from divergent regulatory programs and signalling pathways in the rodent paradigm. Here, we identify and compare transcriptional features of human, marmoset and mouse embryos by single-cell RNA-seq. Zygotic genome activation correlates with the presence of Polycomb Repressive Complexes in all three species, while ribosome biogenesis emerges as a predominant attribute in primate embryos, supporting prolonged translation of maternally deposited RNAs. We find that transposable element expression signatures are species-, stage- and lineage-specific. The pluripotency network in the primate epiblast lacks certain regulators operative in mouse, but encompasses WNT components and genes associated with trophoblast specification. Sequential activation of GATA6, SOX17 and GATA4 markers of primitive endoderm identity is conserved in primates. Unexpectedly, OTX2 is also associated with primitive endoderm specification in human and nonhuman primate blastocysts. Our cross-species analysis demarcates both conserved and primate-specific features of preimplantation development and underscores the molecular adaptability of early mammalian embryogenesis.
Nanobody-antigen catch-bond reveals NK cell mechanosensitivity
Authors: Gonzalez Cristina , Chames Patrick , Kerfelec Brigitte , Baty Daniel , Robert Philippe , Limozin Laurent 
Published: August 2018

ABSTRACTAntibodies are key tools in biomedical research and medicine. Their binding properties are classically measured in solution and characterized by an affinity. However, in physiological conditions, antibodies can bridge an immune effector cell and an antigen presenting cell, implying that mechanical forces apply to the bonds. For example, in antibody-dependent cell cytotoxicity, a major mode of action of therapeutic monoclonal antibodies, the Fab domains bind the antigens on the target cell, while the Fc domain binds to the activating receptor CD16 (also known as FcgRIII) of an immune effector cell, in a quasi bi-dimensional environment (2D). Therefore, there is a strong need to investigating antigen/antibody binding under force (2D), to better understand and predict antibody activityin vivo.We used two anti-CD16 nanobodies targeting two different epitopes and laminar flow chamber assay to measure the association and dissociation of single bonds formed between microsphere-bound CD16 antigens and surface-bound anti-CD16 nanobodies (or single domain antibodies), simulating 2D encounters. The two nanobodies exhibit similar 2D association kinetics, characterized by a strong dependence on the molecular encounter duration. However, their 2D dissociation kinetics strongly differ as a function of applied force: one exhibits a slip bond behaviour where off-rate increases with force; the other exhibits a catch bond behaviour with off-rate decreasing with force. This is the first time, to our knowledge, that catch bond behaviour was reported for antigen-antibody bond. We further exploit this property to show how Natural Killer cells spread differentially on surfaces coated with these molecules, revealing NK cells mechanosensitivity. Our results may also have strong implications for the design of efficient bispecific antibodies for therapeutic applications.
Development of plant regeneration andAgrobacterium tumefaciens-mediated transformation methodology forPhysalis pruinosa
Authors: Swartwood Kerry , Eck Joyce Van 
Published: August 2018

AbstractPhysalis pruinosa, also known as groundcherry, produces a small, yellow, highly nutritious edible fruit that is enveloped by a papery husk. In order for the potential of large-scale production ofP. pruinosafruit to be realized, undesirable characteristics, such as an unmanageable, sprawling growth habit and extensive fruit drop, need to be improved by exploiting approaches available through plant breeding, genetic engineering, and gene editing. In this study, we established plant regeneration andAgrobacterium tumefaciens-mediated methods to allow application of genetic engineering and gene editing ofP. pruinosa. Cotyledon and hypocotyl explants from 7 – 8-day-oldin vitro-grown seedlings were assessed for plant regeneration. Explants were cultured for 2 weeks on a Murashige and Skoog salts-based medium that contained 2 mg/L zeatin followed by transfer to medium containing 1 mg/L zeatin. Only hypocotyl explants regenerated shoots. Hypocotyl explants were infected withAgrobacterium tumefaciensstrain AGL1 containing the pJL33 binary vector that has the green fluorescent protein (GFP) reporter and neomycin phosphotransferase II (nptII) selectable marker genes. After cocultivation, explants were cultured on selective plant regeneration medium that contained 50, 100, 200, 250, and 300 mg/L kanamycin to determine the most effective level for efficient recovery of transgenic lines. Based on rooting of regenerated shoots on selective medium, GFP visualization, and PCR analysis for the presence of thenptIIgene, medium containing 200 mg/L kanamycin resulted in the highest transformation efficiency at 24%. This study sets the foundation for future genetic engineering and gene editing approaches for improvement ofP. pruinosa.
Strand Orientation Bias Detector (SOBDetector) to remove FFPE sequencing artifacts
Authors: Diossy Miklos , Sztupinszki Zsofia , Krzystanek Marcin , Borcsok Judit , Eklund Aron C. , Csabai István , Pedersen Anders Gorm , Szallasi Zoltan 
Published: August 2018

ABSTRACTFormalin-fixed paraffin-embedded (FFPE) tissue, the most common tissue specimen stored in clinical practice, presents challenges in the analysis due to formalin-induced artifacts. Here we present SOBDetector, that is designed to remove these artifacts from a list of variants, which were extracted from next-generation sequencing data, using the posterior predictive distribution of a Bayesian logistic regression model trained on TCGA whole exomes. Based on a concordance analysis, SOBDetector outperforms the currently publicly available FFPE-filtration techniques (Accuracy: 0.9 ± 0.015, AUC = 0.96). SOBDetector is implemented in Java 1.8 and is freely available online.
Knock-in rats expressing Cre and Flp recombinases at the Parvalbumin locus
Authors: Yu Jai Y. , Pettibone Jeffrey R. , Guo Caiying , Zhang Shuqin , Saunders Thomas L. , Hughes Elizabeth D. , Filipiak Wanda E. , Zeidler Michael G. , Bender Kevin J. , Hopf Frederic , Smyth Clay N. , Kharazia Viktor , Kiseleva Anna , Davidson Thomas J. , Frank Loren M. , Berke Joshua D. 
Published: August 2018

AbstractRats have the ability to learn and perform sophisticated behavioral tasks, making them very useful for investigating neural circuit functions. In contrast to the extensive mouse genetic toolkit, the paucity of recombinase-expressing rat models has limited the ability to monitor and manipulate molecularly-defined neural populations in this species. Here we report the generation and validation of two knock-in rat strains expressing either Cre or Flp recombinase under the control of Parvalbumin (Pvalb), a gene expressed in the critical “fast-spiking” subset of inhibitory interneurons (FSIs). These strains were generated with CRISPR-Cas9 gene editing and show highly specific and penetrant labeling of Pvalb-expressing neurons, as demonstrated by in situ hybridization and immunohistochemistry. We validated these models in both prefrontal cortex and striatum using both ex vivo and in vivo approaches, including whole-cell recording, optogenetics, extracellular physiology and photometry. Our results demonstrate the utility of these new transgenic models for a wide range of neuroscience experiments.
A negative role for the interleukin-2-inducible T-cell kinase (ITK) in human Foxp3+ TREG differentiation
Authors: Mamontov Polina , Eberwine Ryan A. , Perrigoue Jackie , Das Anuk , Friedman Joshua R. , Mora J. Rodrigo 
Published: August 2018

ABSTRACTThe Tec kinases ITK (interleukin-2-inducible T-cell kinase) and RLK (resting lymphocyte kinase) are critical components of the proximal TCR/CD3 signal transduction machinery, and data in mice suggest that ITK negatively regulates TREG differentiation. However, whether Tec kinases modulate TREG development and/or function in human T cells remains unknown. Using a novel self-delivery siRNA platform (sdRNA), we found that ITK knockdown in primary human naïve peripheral blood CD4 T cells increased Foxp3+ TREG differentiation under both TREG and T effector (Teff) cell priming conditions. ITK knockdown also enhanced the expression of the co-inhibitory receptor PD-1 on FoxP3+ T cells. TREGS differentiated in vitro (iTREG) after ITK knockdown displayed suppressive capacity against effector CD4+ T cell proliferation. ITK knockdown decreased IL-17A production in T cells primed under Th17 conditions and increased Th1 differentiation. Finally, a dual ITK/RLK Tec kinase inhibitor blocked TREG differentiation and T cell activation in general. Our data suggest that targeting ITK in human T cells may be an effective approach to boost TREG in the context of autoimmune diseases, but non-specific inhibition of other Tec family kinases may broadly inhibit T cell activation.
ELYS coordinates NF-κB pathway dynamics during development inDrosophila
Authors: Mehta Saurabh Jayesh Kumar , Kumar Vimlesh , Mishra Ram Kumar 
Published: August 2018

Summary StatementELYS, a nucleoporin spatiotemporally regulates NF-κB pathway dynamics during development inDrosophilaand its misregulation in post-embryonic stages leads to apoptosis mediated abnormalities.AbstractNuclear pores are the exclusive conduit to facilitate the nucleocytoplasmic transport in a precisely regulated manner. ELYS, a constituent protein of nuclear pores, initiates assembly of nuclear pore complexes (NPCs) into functional nuclear pores towards the end of mitosis. Using cellular, molecular and genetic tools, here, we report that ELYS orthologue (dElys) plays critical roles duringDrosophiladevelopment. Throughin silicoanalyses, we find all conserved structural features indElys except for the presence of non-canonical AT-hook motif strongly binding with DNA.dElys localized to nuclear rim in interphase cells, but during mitosis, it was present on chromatin. RNAi mediated depletion ofdElys leads to aberrant development and defects in the nuclear lamina and NPCs assembly at the cellular level. Furthermore, we demonstrate that indElys depletion NF-κB is activated and accumulates inside the nucleus which results in illimed expression of critical molecules.dElys depletion sustains NF-κB into the nucleus in post-embryonic stages. Prolonged NF-κB inside nucleus induces apoptosis in response to hitherto unknown quality check mechanism and highlights on the under-appreciated apoptotic paradigm of NF-κB pathway.
eQTL of KCNK2 regionally influences the brain sulcal widening: evidence from 15,597 UK Biobank participants with neuroimaging data
Authors: Guen Yann Le , Philippe Cathy , Riviere Denis , Lemaitre Hervé , Grigis Antoine , Fischer Clara , Dehaene-Lambertz Ghislaine , Mangin Jean-François , Frouin Vincent 
Published: August 2018

AbstractThe grey and white matter volumes are known to reduce with age. This cortical shrinkage is visible on magnetic resonance images and is conveniently identified by the increased volume of cerebrospinal fluid in the sulci between two gyri. Here, we replicated this finding using the UK Biobank dataset and studied the genetic influence on these cortical features of aging. We divided all individuals genetically confirmed of British ancestry into two sub-cohorts (12,162 and 3,435 subjects for discovery and replication samples, respectively). We found that the heritability of the sulcal opening ranges from 15 to 45% (s.e.= 4.8%). We identified 4 new loci that contribute to this opening, including one that also affects the sulci grey matter thickness. We identified the most significant variant (rs864736) on this locus as being an expression quantitative trait locus (eQTL) for the KCNK2 gene. This gene regulates the immune-cell into the central nervous system (CNS) and controls the CNS inflammation, which is implicated in cortical atrophy and cognitive decline. These results expand our knowledge of the genetic contribution to cortical shrinking and promote further investigation into these variants and genes in pathological context such as Alzheimer’s disease in which brain shrinkage is a key biomarker.
Quantitative synapse analysis for cell-type specific connectomics
Authors: Kuljis Dika A. , Zemoura Khaled , Telmer Cheryl A. , Lee Jiseok , Park Eunsol , Ackerman Daniel S. , Xu Weifeng , Watkins Simon C. , Arnold Don B. , Bruchez Marcel P. , Barth Alison L. 
Published: August 2018

AbstractAnatomical methods for determining cell-type specific connectivity are essential to inspire and constrain our understanding of neural circuit function. We developed new genetically-encoded reagents for fluorescence-synapse labeling and connectivity analysis in brain tissue, using a fluorogen-activating protein (FAP)-or YFP-coupled, postsynaptically-localized neuroligin-1 targeting sequence (FAP/YFPpost). Sparse viral expression of FAP/YFPpost with the cell-filling, red fluorophore dTomato (dTom) enabled high-throughput, compartment-specific localization of synapses across diverse neuron types in mouse somatosensory cortex. High-resolution confocal image stacks of virally-transduced neurons were used for 3D reconstructions of postsynaptic cells and automated detection of synaptic puncta. We took advantage of the bright, far-red emission of FAPpost puncta for multichannel fluorescence alignment of dendrites, synapses, and presynaptic neurites to assess subtype-specific inhibitory connectivity onto L2 neocortical pyramidal (Pyr) neurons. Quantitative and compartment-specific comparisons show that PV inputs are the dominant source of inhibition at both the soma and across all dendritic branches examined and were particularly concentrated at the primary apical dendrite, a previously unrecognized compartment of L2 Pyr neurons. Our fluorescence-based synapse labeling reagents will facilitate large-scale and cell-type specific quantitation of changes in synaptic connectivity across development, learning, and disease states.
Individual differences in reading comprehension and off-task thought relate to perceptually-coupled and decoupled cognition
Authors: Zhang Meichao , Savill Nicola , Margulies Daniel S. , Smallwood Jonathan , Jefferies Elizabeth 
Published: August 2018

AbstractAlthough the default mode network (DMN) is associated with off-task states, recent evidence shows it can support tasks. This raises the question of how DMN activity can be both beneficial and detrimental to task performance. The decoupling hypothesis proposes that these opposing states occur because DMN supports modes of cognition driven by external input, as well as retrieval states unrelated to input. To test this account, we capitalised on the fact that during reading, regions in DMN are thought to represent the meaning of words through their coupling with visual cortex; the absence of visual coupling should occur when the attention drifts off from the text. We examined individual differences in reading comprehension and off-task thought while participants read an expository text in the laboratory, and related variation in these measures to (i) the neural response during reading in the scanner (Experiment 1), and (ii) patterns of intrinsic connectivity measured in the absence of a task (Experiment 2). The responsiveness of a region of DMN in middle temporal gyrus (MTG) to orthographic inputs during reading predicted good comprehension, while intrinsic decoupling of the same site from visual cortex at rest predicted more frequent off-task thought. In addition, good comprehension was associated with greater intrinsic connectivity between MTG and medial prefrontal regions also within DMN, demonstrating that DMN coupling can support task performance, not only off-task states. These findings indicate that the opposing roles of DMN in cognition reflect its capacity to support both perceptually-coupled and decoupled cognition.