bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of stromal genes differentially expressed in lobular breast cancer highlights role for pregnancy-associated-plasma protein-A
Authors: Gómez-Cuadrado Laura , Zhao Hong , Souleimanova Margarita , Noer Pernille Rimmer , Turnbull Arran K , Oxvig Claus , Bertos Nicholas , Dixon J Michael , Park Morag , Sims Andrew H , Brunton Valerie G 
Published: April 2020

AbstractBackgroundInvasive lobular carcinoma (ILC) is the second most common histological subtype of breast cancer and exhibits a number of clinico-pathological characteristics that are distinct from the more common invasive ductal carcinoma (IDC). Despite these differences, ILC is treated in the same way as IDC. We set out to identify alterations in the tumor microenvironment (TME) of ILC with potential clinical significance.MethodsWe used laser-capture microdissection (LCM) to separate tumor epithelium from stroma in 23 ER+ ILC samples. Gene expression analysis was used to identify genes that are enriched in the stroma of ILC, but not IDC or normal breast.Results45 genes involved in regulation of the extracellular matrix (ECM) were enriched in the stroma of ILC, but not stroma from ER+ IDC or normal breast. Of these, 10 were expressed in cancer-associated fibroblasts (CAFs) and were increased in ILC compared to IDC in bulk gene expression datasets.PAPPAwas the most enriched in the stroma compared to the tumor epithelial compartment in ILC.PAPPAencodes pregnancy-associated plasma protein-A (PAPP-A), a metalloproteinase that cleaves insulin-like binding protein-4 (IGFBP-4) increasing IGF-1 bioavailability and subsequent downstream signaling. Analysis ofPAPPAandIGF1associated genes identified a paracrine signaling pathway and active PAPP-A was shown to be secreted from primary CAFs. Comprehensive survival analysis across 3000 breast cancers identifiedPAPPAas a potential ILC-specific prognostic marker.ConclusionsThis is the first study to demonstrate molecular differences in the TME between ILC and IDC and identifies PAPP-A, a CAF-derived proteinase, as a potential prognostic marker.
Repeat DNA-PAINT suppresses background and non-specific signals in optical nanoscopy
Authors: Clowsley Alexander H. , Kaufhold William T. , Lutz Tobias , Meletiou Anna , Di Michele Lorenzo , Soeller Christian 
Published: April 2020

AbstractDNA-PAINT is a versatile optical super-resolution technique relying on the transient binding of fluorescent DNA ‘imagers’ to target epitopes. Its performance in biological samples is often constrained by strong background signals and non-specific binding events, both exacerbated by high imager concentrations. Here we describe Repeat DNA-PAINT, a method that enables a substantial reduction in imager concentration, thus suppressing spurious signals. Additionally, Repeat DNA-PAINT reduces photoinduced target-site loss and can accelerate sampling, all without affecting spatial resolution.
An adjunctive therapy administered with an antibiotic prevents enrichment of antibiotic-resistant clones of a colonizing opportunistic pathogen
Authors: Morley Valerie J. , Kinnear Clare L. , Sim Derek G. , Olson Samantha N. , Jackson Lindsey M. , Hansen Elsa , Usher Grace A. , Showalter Scott A. , Pai Manjunath P. , Woods Robert J. , Read Andrew F. 
Published: April 2020

AbstractA key challenge in antibiotic stewardship is figuring out how to use antibiotics therapeutically without promoting the evolution of antibiotic resistance. Here, we demonstrate proof of concept for an adjunctive therapy that allows intravenous antibiotic treatment without driving the evolution and onward transmission of resistance. We repurposed the FDA-approved bile sequestrant cholestyramine, which we show binds the antibiotic daptomycin, as an ‘anti-antibiotic’ to disable systemically-administered daptomycin reaching the gut. We hypothesized that adjunctive cholestyramine could enable therapeutic daptomycin treatment in the bloodstream, while preventing transmissible resistance emergence in opportunistic pathogens colonizing the gastrointestinal tract. We tested this idea in a mouse model ofEnterococcus faeciumgastrointestinal tract colonization. In mice treated with daptomycin, adjunctive cholestyramine therapy reduced the fecal shedding of daptomycin-resistantE. faeciumby up to 80-fold. These results provide proof of concept for an approach that could reduce the spread of antibiotic resistance for important hospital pathogens.
Fractal analysis of muscle activity patterns during locomotion: pitfalls and how to avoid them
Authors: Santuz Alessandro , Akay Turgay 
Published: April 2020

AbstractTime-dependent physiological data, such as electromyogram (EMG) recordings from multiple muscles, is often difficult to interpret objectively. Here, we used EMG data gathered during mouse locomotion to investigate the effects of calculation parameters and data quality on two metrics for fractal analysis: the Higuchi’s fractal dimension (HFD) and the Hurst exponent (H). A curve is fractal if it repeats itself at every scale or, in other words, if its shape remains unchanged when zooming in the curve at every zoom level. Many linear and nonlinear analysis methods are available, each of them aiming at the explanation of different data features. In recent years, fractal analysis has become a powerful nonlinear tool to extract information from physiological data not visible to the naked eye. It can present, however, some dangerous pitfalls that can lead to misleading interpretations. To calculate the HFD and the H, we have extracted muscle synergies from normal and mechanically perturbed treadmill locomotion from the hindlimb of adult mice. Then, we used one set per condition (normal and perturbed walking) of the obtained time-dependent coefficients to create surrogate data with different fluctuations over the original mean signal. Our analysis shows that HFD and H are exceptionally sensitive to the presence or absence of perturbations to locomotion. However, both metrics suffer from variations in their value depending on the parameters used for calculations and the presence of quasi-periodic elements in the time series. We discuss those issues giving some simple suggestions to reduce the chance of misinterpreting the outcomes.New & NoteworthyDespite the lack of consensus on how to perform fractal analysis of physiological time series, many studies rely on this technique. Here, we shed light on the potential pitfalls of using the Higuchi’s fractal dimension and the Hurst exponent. We expose and suggest how to solve the drawbacks of such methods when applied to data from normal and perturbed locomotion by combiningin vivorecordings and computational approaches.
InLyl1-/-mice, adipose stem cell vascular niche impairment leads to premature development of fat tissues
Authors: Hussain Abid , Kebriti Leila El , Deleuze Virginie , Glasson Yaël , Pirot Nelly , Mathieu Danièle , Pinet Valérie 
Published: April 2020

ABSTRACTLymphoblastic leukemia-derived sequence 1(Lyl1)encodes a hematopoietic- and endothelial-specific transcriptional factor.Lyl1-deficient mice are viable, but they display mild hematopoietic and vascular defects. Here, we report that youngLyl1-/-mice exhibit transient obesity associated with general expansion of adipose tissues and unrelated to food intake. The increased fat tissue development inLyl1-/-mice resulted from an earlier adipocyte differentiation of adipose stem cells (ASCs) through non-cell autonomous mechanisms. Specifically, we found that inLyl1-/-mice, the vascular structures of adipose tissues are unstable, more prone to angiogenesis and, consequently, cannot maintain adipose progenitors in the niche vessel wall. Together, our data show that inLyl1-/-mice, the impaired vascular compartment of the adipose niche promotes uncontrolled ASC activation and differentiation, leading to early adipocyte expansion and premature depletion of ASCs. Our study highlights the major structural role of the adipose tissue vascular niche in coordinating stem cell self-renewal and differentiation into adipocytes.
Dissociable Effects of Emotional Stimuli on Perception and Decision-Making for Time
Authors: Gladhill Keri , Mioni Giovanna , Wiener Martin 
Published: April 2020

AbstractPrevious research has demonstrated that negative emotional faces dilate time perception, however, the mechanisms underlying this phenomenon are not fully understood. Previous attempts focus on the pacemaker-accumulator model of time perception, which includes a clock, memory, and decision-making stage, wherein emotion affects one of these stages; possibly by increasing pacemaker rate via arousal, increasing accumulation rate via attention, or by biasing decision-making. To further investigate the stage(s) that emotion is affecting time perception we conducted a visual temporal bisection task with sub-second intervals while recording 64-channel electroencephalogram (EEG). To separate the influence of face and timing responses the temporal stimulus was preceded and followed by a face stimulus displaying a neutral or negative expression creating three trial-types: Neg→Neut, Neut→Neg, or Neut→Neut. The data revealed a leftward shift in bisection point (BP) in Neg→Neut and Neut→Neg suggesting an overestimation of time. Neurally, we found the face-responsive N170 component was larger for negative faces and the N1 and contingent negative variation (CNV) were larger when preceded by a negative face. We also found an interaction effect between condition and response for the late positive component of timing (LPCt) and a significant difference between response (short/long) in the neutral condition. We conclude that a preceding negative face affects the clock stage leading to more pulses being accumulated, either through attention or arousal, as indexed by a larger N1, CNV, and N170; whereas viewing the negative face second biased decision-making leading to “short” responses being less likely, as evidenced by the LPCt.
On the robustness of graph-based clustering to random network alterations
Authors: Stacey R. Greg , Skinnider Michael A. , Foster Leonard J. 
Published: April 2020

ABSTRACTBiological functions emerge from complex and dynamic networks of protein-protein interactions. Because these protein-protein interaction networks, or interactomes, represent pairwise connections within a hierarchically organized system, it is often useful to identify higher-order associations embedded within them, such as multi-member protein-complexes. Graph-based clustering techniques are widely used to accomplish this goal, and dozens of field-specific and general clustering algorithms exist. However, interactomes can be prone to errors, especially interactomes that infer interactions using high-throughput biochemical assays. Therefore, robustness to network-level variability is an important criterion for any clustering algorithm that aims to generate robust, reproducible clusters. Here, we tested the robustness of a range of graph-based clustering algorithms in the presence of network-level noise, including algorithms common across domains and those specific to protein networks. We found that the results of all clustering algorithms measured were profoundly sensitive to injected network noise.Randomly rewiring 1% of network edges yielded up to a 57% change in clustering results, indicating that clustering markedly amplified network-level noise. However, the impact of network noise on individual clusters was not uniform. We found that some clusters were consistently robust to injected network noise while others were not. Therefore, we developed theclust.perturbR package and Shiny web application, which measures the reproducibility of clusters by randomly perturbing the network. We show thatclust.perturbresults are predictive of real-world cluster stability: poorly reproducible clusters as identified byclust.perturbare significantly less likely to be reclustered across experiments. We conclude that quantifying the robustness of a cluster to network noise, as implemented inclust.perturb, provides a powerful tool for ranking the reproducibility of clusters, and separating stable protein complexes from spurious associations.
A splicing isoform of GPR56 mediates microglial synaptic refinement via phosphatidylserine binding
Authors: Li Tao , Chiou Brian , Gilman Casey K , Luo Rong , Koshi Tatsuhiro , Yu Diankun , Oak Hayeon C , Giera Stefanie , Johnson-Venkatesh Erin , Muthukumar Allie K. , Stevens Beth , Umemori Hisashi , Piao Xianhua 
Published: April 2020

AbstractDevelopmental synaptic remodeling is important for the formation of precise neural circuitry and its disruption has been linked to neurodevelopmental disorders such as autism and schizophrenia. Microglia prune synapses, but integration of this synapse pruning with overlapping and concurrent neurodevelopmental processes remains elusive. Adhesion G protein-coupled receptor ADGRG1/GPR56 controls multiple aspects of brain development in a cell type-specific manner: in neural progenitor cells, GPR56 regulates cortical lamination, whereas in oligodendrocyte progenitor cells, GPR56 controls developmental myelination and myelin repair. Here, we show that microglial GPR56 maintains appropriate synaptic numbers in several brain regions in a time- and circuit-dependent fashion. Phosphatidylserine (PS) on pre-synaptic elements binds GPR56 in a domain-specific manner, and microglia-specific deletion ofGpr56leads to increased synapses as a result of reduced microglial engulfment of PS+pre-synaptic inputs. Remarkably, a particular alternatively spliced isoform of GPR56 is selectively required for microglia-mediated synaptic pruning. Our present data provide a ligand- and isoform-specific mechanism underlying microglial GPR56-mediated synapse pruning in the context of complex neurodevelopmental processes.
Multi-modal characterization and simulation of human epileptic circuitry
Authors: Buchin Anatoly , de Frates Rebecca , Nandi Anirban , Mann Rusty , Chong Peter , Ng Lindsay , Miller Jeremy , Hodge Rebecca , Kalmbach Brian , Bose Soumita , Rutishauser Ueli , McConoughey Stephen , Lein Ed , Berg Jim , Sorensen Staci , Gwinn Ryder , Koch Christof , Ting Jonathan , Anastassiou Costas A. 
Published: April 2020

AbstractTemporal lobe epilepsy is the fourth most common neurological disorder with about 40% of patients not responding to pharmacological treatment. Increased cellular loss in the hippocampus is linked to disease severity and pathological phenotypes such as heightened seizure propensity. While the hippocampus is the target of therapeutic interventions such as temporal lobe resection, the impact of the disease at the cellular level remains unclear in humans. Here we show that properties of hippocampal granule cells change with disease progression as measured in living, resected hippocampal tissue excised from epilepsy patients. We show that granule cells increase excitability and shorten response latency while also enlarging in cellular volume, surface area and spine density. Single-cell RNA sequencing combined with simulations ascribe the observed electrophysiological changes to gradual modification in three key ion channel conductances: BK, Cav2.2 and Kir2.1. In a bio-realistic computational network model, we show that the changes related to disease progression bring the circuit into a more excitable state. In turn, we observe that by reversing these changes in the three key conductances produces a less excitable, “early disease-like” state. These results provide mechanistic understanding of epilepsy in humans and will inform future therapies such as viral gene delivery to reverse the course of the disorder.
“Comparative Analysis of Gut Microbiome in Individuals of the Old Civilization of Caral-Supe Based on Data from 16S rRNA and ITS region”
Authors: Vásquez-Domínguez Andrés , Jaramillo-Valverde Luis , Levano Kelly S. , Novoa-Bellota Pedro , Machaguay-Romero Marco , Garcia-de-la-Guarda Ruth , Cano Raul J. , Solis Ruth Shady , Guio Heinner 
Published: April 2020

ABSTRACTGenetic and microbiome studies of ancient Caral-Supe civilization have not yet been published. For this reason, the objective of this work is to identify the microorganisms and possible diseases that existed in this ancient civilization using coprolites samples. To do this, two coprolites samples were analyzing through high-throughput sequencing data of 16S rRNA gene and an intergenic region (ITS).
Simultaneous determination of87Sr/86Sr and trace-element data in otoliths and other sclerochronological hard structures
Authors: Hegg Jens C. , Fisher Christopher M. , Vervoort Jeffrey 
Published: April 2020

AbstractChronological data from hard structures have been instrumental in reconstructing information about the past across numerous disciplines. Isotopic and trace elemental chronologies from the depositional layers of speleothems, corals, bivalve shells, fish otoliths and other structures are routinely used to reconstruct climate, growth, temperature, geological, archeological and migratory histories. Recentin situanalytical advances have revolutionized the use of these structures. This is particularly true of fish, in which detailed origin, life-history, and migration history can be reconstructed from their otoliths. Specifically, improvements in laser ablation-inductively coupled plasma mass spectrometry (LA-ICPMS) have allowed increases in temporal resolution, precision, and sample throughput. Many studies now combine multiple chemical and isotopic tracers, taking advantage of multivariate statistical methods and multiple trace-elements and isotope systems to glean further information from individual samples. This paper describes a novel laser ablation split-stream (LASS) methodology which allows simultaneous collection of the Sr isotope composition (87Sr/86Sr) and trace-elemental data from chronologically deposited carbonate samples. The study investigates the accuracy and precision of varying laser spot sizes on a marine shell standard and fish otoliths using LASS and presents a comparison to traditional “single stream methods” using pre-existing otolith data on the same samples. Our results indicate that LASS techniques can be used to provide accurate and precise data at the same laser spot sizes as previous otolith studies, thereby doubling analytical throughput, while also providing improved spatially and temporally-matched data reduction using newly developed features for the Iolite data reduction platform.
SARS-CoV-2 Productively Infects Human Gut Enterocytes
Authors: Lamers Mart M. , Beumer Joep , van der Vaart Jelte , Knoops Kèvin , Puschhof Jens , Breugem Tim I. , Ravelli Raimond B.G. , van Schayck J. Paul , Mykytyn Anna Z. , Duimel Hans Q. , van Donselaar Elly , Riesebosch Samra , Kuijpers Helma J.H. , Schipper Debby , van de Wetering Willine J. , de Graaf Miranda , Koopmans Marion , Cuppen Edwin , Peters Peter J. , Haagmans Bart L. , Clevers Hans 
Published: April 2020

AbstractCOVID-19, caused by SARS-CoV-2, is an influenza-like disease with a respiratory route of transmission, yet clinical evidence suggests that the intestine may present another viral target organ. Indeed, the SARS-CoV-2 receptor angiotensin converting enzyme 2 (ACE2) is highly expressed on differentiated enterocytes. In human small intestinal organoids, enterocytes were readily infected by SARS-CoV and SARS-CoV-2 as demonstrated by confocal- and electron-microscopy. Consequently, significant titers of infectious viral particles were measured. mRNA expression analysis revealed strong induction of a generic viral response program. We conclude that intestinal epithelium supports SARS-CoV-2 replication.One Sentence SummarySARS-CoV-2 infection of enterocytes in human small intestinal organoids
MMEJ-based Precision Gene Editing for applications in Gene Therapy and Functional Genomics
Authors: Martínez-Gálvez Gabriel , Manduca Armando , Ekker Stephen C. 
Published: April 2020

ABSTRACTExperiments in gene editing commonly elicit error-prone non-homologous end joining for DNA double-strand break (DSB) repair. Microhomology-mediated end joining (MMEJ) can generate more predictable outcomes for functional genomic and somatic therapeutic applications. MENTHU is a computational tool that predicts nuclease-targetable sites likely to result in MMEJ-repaired, homogeneous genotypes (PreMAs) in zebrafish. We deployed MENTHU on 5,885 distinct Cas9-mediated DSBs in mouse embryonic stem cells, and compared the predictions to those by inDelphi, another DSB repair predictive algorithm. MENTHU correctly identified 46% of all PreMAs available, doubling the sensitivity of inDelphi. We also introduce MENTHU@4, an MENTHU update trained on this large dataset. We trained two MENTHU-based algorithms on this larger dataset and validated them against each other, MENTHU, and inDelphi. Finally, we estimated the frequency and distribution of SpCas9-targetable PreMAs in vertebrate coding regions to evaluate MMEJ-based targeting for gene discovery. 44 out of 54 genes (81%) contained at least one early out-of-frame PreMA and 48 out of 54 (89%) did so when also considering Cas12a. We suggest that MMEJ can be deployed at scale for reverse genetics screenings and with sufficient intra-gene density rates to be viable for nearly all loss-of-function based gene editing therapeutic applications.
Genetic inactivation of the translin/trax microRNA-degrading enzyme phenocopies the robust adiposity induced byTranslin(Tsn) deletion
Authors: Fu Xiuping , Shah Aparna P. , Li Zhi , Li Mengni , Tamashiro Kellie L. , Baraban Jay M. 
Published: April 2020

AbstractObjectiveDeletion ofTranslin(Tsn) from mice induces an unusual metabolic profile characterized by robust adiposity, normal body weight and glucose tolerance. Translin (TN) protein and its partner, trax (TX), form the TN/TX microRNA-degrading enzyme. Since the microRNA system plays a prominent role in regulating metabolism, we reasoned that the metabolic profile displayed byTsnKO mice might reflect dysregulation of microRNA signaling.MethodsTo test this hypothesis, we inserted a mutation, E126A, inTsnax, the gene encoding TX, that abolishes the microRNA-degrading enzymatic activity of the TN/TX complex. In addition, to help define the cell types that drive the adiposity phenotype, we have also generated mice with floxed alleles of Tsn or Tsnax.ResultsIntroduction of the E126A mutation inTsnaxdoes not impair expression of TN or TX proteins or their co-precipitation. Furthermore, these mice display selective increases in microRNAs that match those induced byTsndeletion, confirming that this mutation inTsnaxinactivates the microRNA-degrading activity of the TN/TX complex. Mice homozygous for theTsnax(E126A) mutation display a metabolic profile that closely mimics that ofTsnKO mice.Selective deletion ofTsnorTsnaxfrom either adipocytes or hepatocytes, two candidate cell types, does not phenocopy the elevated adiposity displayed by mice with constitutiveTsndeletion or theTsnax(E126A) mutation. Furthermore, global, conditional deletion ofTsnin adulthood does not elicit increased adiposity.ConclusionTaken together, these findings indicate that inactivation of the TN/TX microRNA-degrading enzyme during development is necessary to drive the robust adiposity displayed byTsnKO mice.