bluuebunny/crossref_metadata_2025_split huggingface dataset:
Amyloid Precursor Protein (APP) controls excitatory/inhibitory synaptic inputs by regulating the transcriptional activator Neuronal PAS Domain Protein 4 (NPAS4)
Authors: Opsomer Rémi , Contino Sabrina , Perrin Florian , Tasiaux Bernadette , Doyen Pierre , Vergouts Maxime , Vrancx Céline , Doshina Anna , Pierrot Nathalie , Octave Jean-Noël , Stanga Serena , Kienlen-Campard Pascal 
Published: December 2018

AbstractSequential proteolysis of the amyloid precursor protein (APP) and amyloid-β peptide (Aβ) release is an upstream event in Alzheimer’s disease (AD) pathogenesis. The function of APP in neuronal physiology is still, however, poorly understood. Along with its paralog APP-like Proteins 1 and 2 (APLP1-2), APP is involved in neurite formation and synaptic function by mechanisms that are not elucidated. APP is a single-pass transmembrane protein expressed at high levels in the brain that resembles a cell adhesion molecule or a membrane receptor, suggesting that its function relies on cell interaction processes and/or activation of intracellular pathways of signal transduction. Along this line, the APP intracellular domain (AICD) was reported to act as a transcriptional factor for targeted gene activation that mediates physiological APP functions. Here, we used an unbiased transcriptome-based approach to identify the genes transcriptionally regulated by APP in the rodent embryonic cortex and upon maturation of primary cortical neurons. The transcriptome analysis did not detect any significant differences in expression of previously proposed AICD target genes. The overall transcriptional changes were subtle, but we found that genes clustered in neuronal-activity dependent pathways are dysregulated in the absence of APP. Among these genes, we found the activity-dependent Neuronal PAS domain protein 4 (NPAS4) Immediate Early Gene to be downregulated in the absence of APP. Down-regulation of NPAS4 in APP knock-out (KO) neurons is not related to AICD but to the APP ectodomain. We studied the effect of APP deficiency on GABAergic and glutamatergic transmission, and found an increased production of the inhibitory neurotransmitter GABA in APP KO neurons, along with a reduced expression of the GABA(A) receptors alpha1, suggesting an impaired GABAergic neurotransmission in the absence of APP. CRISPR-Cas-mediated silencing of NPAS4 in neurons led to similar observations. Altogether, our results point out a new role for APP in the regulation of excitatory/inhibitory neurotransmission through the regulation of the activity-dependent NPAS4 gene.
Structural and Biochemical Studies of Dihydrofolate Reductase fromStreptococcus pyogenesas a Target for Antifolate Antibiotics
Authors: Hajian Behnoush , Krucinska Jolanta , Martins Michael , G-Dayanan Narendran , Viswanathan Kishore , Tavakoli Sara , Wright Dennis 
Published: December 2018

ABSTRACTStreptococcus pyogenes, abeta-hemolytic bacterium, causes a wide spectrum of infections in human including pharyngitis, tonsillitis, scarlet fever, rheumatic fever, and necrotizing fasciitis. Streptococcal infections can also exist as co-infection with methicillin resistantStaphylococcus aureus(MRSA). Trimethoprim-sulfamethoxazole (TMP-SMX) combination has been used for treatment ofS. pyogenesand MRSA co-infection. However, resistance to TMP, an inhibitor of dihydrofolate reductase enzyme (DHFR), has challenged the efficacy of TMP-SMX combination. We explored the activity of a series of novel DHFR inhibitors againstS. pyogenes. This study identified potent inhibitors of DHFR enzyme fromS. pyogeneswith excellent inhibitory activity against the growth of the live bacteria. We determined, for the first time, the crystal structure ofS. pyogenesDHFR which provides structural insights into design and development of antifolate agents against this global pathogen.
Design of a Synthetic sRNA-based Feedback Filter Module
Authors: Delalez Nicolas , Sootla Aivar , Wadhams George H. , Papachristodoulou Antonis 
Published: December 2018

SummaryFilters are widely used in engineering to reduce noise and/or the magnitude of a signal of interest. Feedback filters, or adaptive filters, are preferred if the signal noise distribution is unknown. One of the main challenges in Synthetic Biology remains the design of reliable constructs but these often fail to work as intended due, e.g. to their inherent stochasticity and burden on the host. Here we design, implement and test experimentally a biological feedback filter module based on small non-coding RNAs (sRNAs) and self-cleaving ribozymes. Mathematical modelling demonstrates that it attenuates noise for a large range of parameters due to negative feedback introduced by the use of ribozymes and sRNA. Our module modifies the steady-state response of the filtered signal, and hence can be used for tuning the feedback strength while also reducing noise. We demonstrated these properties theoretically on the TetR autorepressor, enhanced with our sRNA module.
Controlling Organization and Forces in Active Matter Through Optically-Defined Boundaries
Authors: Ross Tyler D. , Lee Heun Jin , Qu Zijie , Banks Rachel A. , Phillips Rob , Thomson Matt 
Published: December 2018

AbstractLiving systems are capable of locomotion, reconfiguration, and replication. To perform these tasks, cells spatiotemporally coordinate the interactions of force-generating, “active” molecules that create and manipulate non-equilibrium structures and force fields that span up to millimeter length scales [1–3]. Experimental active matter systems of biological or synthetic molecules are capable of spontaneously organizing into structures [4, 5] and generating global flows [6–9]. However, these experimental systems lack the spatiotemporal control found in cells, limiting their utility for studying non-equilibrium phenomena and bioinspired engineering. Here, we uncover non-equilibrium phenomena and principles by optically controlling structures and fluid flow in an engineered system of active biomolecules. Our engineered system consists of purified microtubules and light-activatable motor proteins that crosslink and organize microtubules into distinct structures upon illumination. We develop basic operations, defined as sets of light patterns, to create, move, and merge microtubule structures. By composing these basic operations, we are able to create microtubule networks that span several hundred microns in length and contract at speeds up to an order of magnitude faster than the speed of an individual motor. We manipulate these contractile networks to generate and sculpt persistent fluid flows. The principles of boundary-mediated control we uncover may be used to study emergent cellular structures and forces and to develop programmable active matter devices.
Megakaryocyte emperipolesis mediates membrane transfer from intracytoplasmic neutrophils to platelets
Authors: Cunin Pierre , Bouslama Rim , Machlus Kellie R. , Martínez-Bonet Marta , Lee Pui Y. , Nelson-Maney Nathan , Morris Allyn , Guo Li , Weyrich Andrew S. , Sola-Visner Martha , Boilard Eric , Italiano Joseph E. , Nigrovic Peter A. 
Published: December 2018

SummaryBone marrow megakaryocytes engulf neutrophils in a phenomenon termed emperipolesis. We show here that emperipolesis is a dynamic process mediated actively by both lineages, in part through the β2-integrin/ICAM-1/ezrin pathway. Tethered neutrophils enter in membrane-bound vesicles before penetrating into the megakaryocyte cytoplasm. Intracytoplasmic neutrophils develop membrane contiguity with the demarcation membrane system, thereby transferring membrane to the megakaryocyte and to daughter platelets. This phenomenon occurs in otherwise unmanipulated marrowin vivo, resulting in circulating platelets that bear membrane from non-megakaryocytic hematopoietic donors. Transit through megakaryocytes can be completed as rapidly as minutes, after which neutrophils egress intact. Emperipolesis is amplified in models of inflammation associated with platelet overproduction, contributing to platelet productionin vitroandin vivo.These findings identify emperipolesis as a new cell-in-cell interaction that enables neutrophils and potentially other cells passing through the megakaryocyte cytoplasm to modulate the production and membrane content of platelets.
Lifespan associated global patterns of coherent neural communication
Authors: Sahoo Bikash , Pathak Anagh , Deco Gustavo , Banerjee Arpan , Roy Dipanjan 
Published: December 2018

AbstractHealthy ageing is accompanied by changes to spontaneous electromagnetic oscillations. At the macroscopic scale, previous studies have quantified the basic features, e.g., power and frequencies in rhythms of interest from the perspective of attention, perception, learning and memory. On the other hand, signatures and modes of neural communication have recently been argued to be identifiable from global measures applied on neuro-electromagnetic data such as global coherence that quantifies the degree of togetherness of distributed neural oscillations and metastability that parametrizes the transient dynamics of the network switching between successive stable states. Here, we demonstrate that global coherence and metastability can be informative measures to track healthy ageing dynamics over lifespan and together with the traditional spectral measures provides an attractive explanation of neuronal information processing. Finding normative patterns of brain rhythms in resting state MEG would naturally pave the way for tracking task relevant metrics that could crucially determine cognitive flexibility and performance. While previously reported observations of a reduction in peak alpha frequency and increased beta power in older adults are reflective of changes at individual sensors (during rest and task), global coherence and metastability truly pinpoint the underlying coordination dynamics over multiple brain areas across the entire lifespan. In addition to replication of the previous observations in a substantially larger lifespan cohort than what was previously reported, we also demonstrate, for the first time to the best of our knowledge, age related changes in coherence and metastability in signals over time scales of neuronal processing. Furthermore, we observed a marked frequency dependence in changes in global coordination dynamics, which, coupled with the long held view of specific frequency bands sub-serving different aspects of cognition, hints at differential functional processing roles for slower and faster brain dynamics.
ComammoxNitrospiraare the dominant ammonia oxidizers in a mainstream low dissolved oxygen nitrification reactor
Authors: Roots Paul , Wang Yubo , Rosenthal Alex F. , Griffin James S. , Sabba Fabrizio , Petrovich Morgan , Yang Fenghua , Kozak Joseph A. , Zhang Heng , Wells George F. 
Published: December 2018

AbstractRecent findings show that a subset of bacteria affiliated withNitrospira, a genus known for its importance in nitrite oxidation for biological nutrient removal applications, are capable ofcompleteammoniaoxidation (comammox) to nitrate. Early reports suggested that they were absent or present in low abundance in most activated sludge processes, and thus likely functionally irrelevant. Here we show the accumulation of comammoxNitrospirain a nitrifying sequencing batch reactor operated at low dissolved oxygen (DO) concentrations. Actual mainstream wastewater was used as influent after primary settling and an upstream pre-treatment process for carbon and phosphorus removal. The ammonia removal rate was stable and exceeded that of the treatment plant’s parallel full-scale high DO nitrifying activated sludge reactor. 16S rRNA sequencing showed a steady accumulation ofNitrospirato 53% total abundance and a decline in conventional ammonia oxidizing bacteria to <1% total abundance over 400+ days of operation. After ruling out other known ammonia oxidizers, qPCR confirmed the accumulation of comammoxNitrospirabeginning around day 200, to eventually comprise 94% of all detectedamoAand 4% of total bacteria by day 407. Quantitative fluorescence in-situ hybridization confirmed the increasing trend and high relative abundance ofNitrospira. These results demonstrate that comammox can be metabolically relevant to nitrogen transformation in wastewater treatment, and can even dominate the ammonia oxidizing community. Our results suggest that comammox may be an important functional group in energy efficient nitrification systems designed to operate at low DO levels.
The neural dynamics of hierarchical Bayesian inference in multisensory perception
Authors: Rohe Tim , Ehlis Ann-Christine , Noppeney Uta 
Published: December 2018

AbstractTransforming the barrage of sensory signals into a coherent multisensory percept relies on solving the binding problem – deciding whether signals come from a common cause and should be integrated, or instead be segregated. Human observers typically arbitrate between integration and segregation consistent with Bayesian Causal Inference, but the neural mechanisms remain poorly understood. We presented observers with audiovisual sequences that varied in the number of flashes and beeps. Combining Bayesian modelling and EEG representational similarity analyses, we show that the brain initially represents the number of flashes and beeps and their numeric disparity mainly independently. Later, it computes them by averaging the forced-fusion and segregation estimates weighted by the probabilities of common and independent cause models (i.e. model averaging). Crucially, prestimulus oscillatory alpha power and phase correlate with observers’ prior beliefs about the world’s causal structure that guide their arbitration between sensory integration and segregation.
scAlign: a tool for alignment, integration and rare cell identification from scRNA-seq data
Authors: Johansen Nelson , Quon Gerald 
Published: December 2018

AbstractscRNA-seq dataset integration occurs in different contexts, such as the identification of cell type-specific differences in gene expression across conditions or species, or batch effect correction. We present scAlign, an unsupervised deep learning method for data integration that can incorporate partial, overlapping or a complete set of cell labels, and estimate per-cell differences in gene expression across datasets. scAlign performance is state-of-the-art and robust to cross-dataset variation in cell type-specific expression and cell type composition. We demonstrate that scAlign identifies a rare cell population likely to drive malaria transmission. Our framework is widely applicable to integration challenges in other domains.
Full Atomistic Model of Prion Structure and Conversion
Authors: Spagnolli Giovanni , Rigoli Marta , Orioli Simone , Sevillano Alejandro M. , Faccioli Pietro , Wille Holger , Biasini Emiliano , Requena Jesùs R. 
Published: December 2018

AbstractPrions are unusual protein assemblies that propagate their conformationally-encoded information in absence of nucleic acids. The first prion identified, the scrapie isoform (PrPSc) of the cellular prion protein (PrPC), is the only one known to cause epidemic and epizootic episodes(1). Most aggregates of other misfolding-prone proteins are amyloids, often arranged in a Parallel-In-Register-β-Sheet (PIRIBS)(2) or β-solenoid conformations(3). Similar folding models have also been proposed for PrPSc, although none of these have been confirmed experimentally. Recent cryo-electron microscopy (cryo-EM) and X-ray fiber-diffraction studies provided evidence that PrPSc is structured as a 4-rung β-solenoid (4RβS)(4, 5). Here, we combined different experimental data and computational techniques to build the first physically-plausible, atomic resolution model of mouse PrPSc, based on the 4RβS architecture. The stability of this new PrPSc model, as assessed by Molecular Dynamics (MD) simulations, was found to be comparable to that of the prion forming domain of Het-s, a naturally-occurring β-solenoid. Importantly, the 4RβS arrangement allowed the first simulation of the sequence of events underlying PrPC conversion into PrPSc. Our results provide the most updated, experimentally-driven and physically-coherent model of PrPSc, together with an unprecedented reconstruction of the mechanism underlying the self-catalytic propagation of prions.SignificanceSince the original hypothesis by Stanley Prusiner, prions have represented enigmatic agents diverging from the classical concept of genetic inheritance. However, the structure of PrPSc, the infectious isoform of the cellular prion protein (PrPC), has so far remained elusive, mostly due to technical challenges posed by its aggregation propensity. Here, we present a new high resolution model of PrPSc derived from the integration of a wide array of recent experimental constraints. By coupling the information of such model with a newly developed computational method, we reconstructed for the first time the conformational transition of PrPC to PrPSc. This study offers a unique workbench for designing therapeutics against prion diseases, and a physically-plausible mechanism explaining how protein conformation could self-propagate.
Bioprinted pluripotent stem cell-derived kidney organoids provide opportunities for high content screening
Authors: Higgins J. William , Chambon Alison , Bishard Kristina , Hartung Anke , Arndt Derek , Brugnano Jamie , Er Pei Xuan , Lawlor Kynan T. , Vanslambrouck Jessica M. , Wilson Sean , Combes Alexander N. , Howden Sara E. , Tan Ker Sin , Kumar Santhosh V. , Hale Lorna J. , Shepherd Benjamin , Pentoney Stephen , Presnell Sharon C. , Chen Alice E. , Little Melissa H. 
Published: December 2018

AbstractRecent advances in the directed differentiation of human pluripotent stem cells to kidney brings with it the prospect of drug screening and disease modelling using patient-derived stem cell lines. Development of such an approach for high content screening will require substantial quality control and improvements in throughput. Here we demonstrate the use of the NovoGen MMX 3D bioprinter for the generation of highly reproducible kidney organoids from as few as 4,000 cells. Histological and immunohistochemical analyses confirmed the presence of renal epithelium, glomeruli, stroma and endothelium, while single cell RNAseq revealed equivalence to the cell clusters present within previously described organoids. The process is highly reproducible, rapid and transferable between cell lines, including genetically engineered reporter lines. We also demonstrate the capacity to bioprint organoids in a 96-well format and screen for response to doxorubicin toxicity as a proof of concept for high content compound screening.
Three‐parameter Radon transform in layered transversely isotropic media
Authors: Abedi Mohammad Mahdi , Riahi Mohammad Ali , Stovas Alexey 
Published: December 2018

ABSTRACTRadon transform is a powerful tool with many applications in different stages of seismic data processing, because of its capability to focus seismic events in the transform domain. Three‐parameter Radon transform can optimally focus and separate different seismic events, if its basis functions accurately match the events. In anisotropic media, the conventional hyperbolic or shifted hyperbolic basis functions lose their accuracy and cannot preserve data fidelity, especially at large offsets. To address this issue, we propose an accurate traveltime approximation for transversely isotropic media with vertical symmetry axis, and derive two versions of Radon basis functions, time‐variant and time‐invariant. A time‐variant basis function can be used in time domain Radon transform algorithms while a time‐invariant version can be used in, generally more efficient, frequency domain algorithms. Comparing the time‐variant and time‐invariant Radon transform by the proposed basis functions, the time‐invariant version can better focus different seismic events; it is also more accurate, especially in presence of vertical heterogeneity. However, the proposed time‐invariant basis functions are suitable for a specific type of layered anisotropic media, known as factorized media. We test the proposed methods and illustrate successful applications of them for trace interpolation and coherent noise attenuation.
House Prices and Consumption in the United States
Authors: Vinson Philip 
Published: December 2018

AbstractI estimate the house price elasticity of consumption using panel data for households in the United States for the years 1999–2013. I find that the average house price elasticity of consumption is positive but modest and varies by age. However, when measuring the elasticity separately for households who are credit constrained, I find that households with a high loan‐to‐value mortgage have a much larger house price elasticity of consumption of about 0.2. I also find that poor hand‐to‐mouth households consume more than others when their house price increases while wealthy hand‐to‐mouth ones do not.
Loss of response to scheduled infliximab therapy for Crohn's disease in adults: A systematic review and meta‐analysis
Authors: Zhang Qi Wei , Shen Jun , Zheng Qing , Ran Zhi Hua 
Published: December 2018

ObjectiveTo determine the potential predictors of loss of response (LOR) to infliximab (IFX) maintenance therapy for adult patients with Crohn's disease (CD).MethodsWe searched for English‐language articles published between 1990 and March 2017 in PubMed, Embase, and the Cochrane Library. After identifying eligible studies, data extraction was performed independently by two reviewers. The potential prognostic variables were identified and dichotomized for meta‐analysis. Based on the heterogeneity among study variables, random‐effects models was used in our meta‐analysis.ResultsTwenty‐six studies met our eligibility criteria and consolidated drug response data were obtained from 3212 patients. The pooled rate of LOR to IFX maintenance therapy with a median follow‐up of 1.1 years was 34%. The incidence of LOR to IFX therapy was increased in CD patients with perianal lesions (odds ratio [OR] 1.69, 95% confidence interval [CI] 1.04‐2.75, P = 0.03), colon involvement (OR 2.56, 95% CI 1.20‐5.50, P = 0.02) and younger age at CD onset (standardized mean difference −0.79, 95% CI −1.41 to −0.18, P = 0.01).ConclusionsThe meta‐analysis estimates the incidence of LOR among adult CD patients undergoing IFX therapy is 34%. The presence of perianal lesions, younger age at CD onset, and involvement of the colon are relative risk factors of LOR in CD patients received scheduled IFX maintenance therapy.
Climatic Controls on Watershed Reference Evapotranspiration Varied during 1961–2012 in Southern China
Authors: Qin Mengsheng , Hao Lu , Sun Lei , Liu Yongqiang , Sun Ge 
Published: December 2018

AbstractReference evapotranspiration (ETo) is an important hydrometeorological term widely used in understanding and projecting the hydrological effects of future climate and land use change. We conducted a case study in the Qinhuai River Basin that is dominated by a humid subtropical climate and mixed land uses in southern China. Long‐term (1961–2012) meteorological data were used to estimate ETo by the FAO‐56 Penman–Monteith model. The individual contribution from each meteorological variable to the trend of ETo was quantified. We found basin‐wide annual ETo decreased significantly (p < 0.05) by 3.82 mm/yr during 1961–1987, due to decreased wind speed, solar radiation, vapor pressure deficit (VPD), and increased relative humidity (RH). However, due to the increased VPD and decreased RH, the ETo increased significantly (p < 0.05) in spring, autumn, and annually at a rate of 2.55, 0.56, and 3.16 mm/yr during 1988–2012, respectively. The aerodynamic term was a dominant factor controlling ETo variation in both two periods. We concluded the key climatic controls on ETo have shifted as a result of global climate change during 1961–2012. The atmospheric demand, instead of air temperature alone, was a major control on ETo. Models for accurately predicting ETo and hydrological change under a changing climate must include VPD in the study region. The shifts of climatic control on the hydrological cycles should be considered in future water resource management in humid regions.