bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel Small Molecules Targeting the Intrinsically Disordered Structural Ensemble of α-Synuclein Protect Against Diverse α-Synuclein Mediated Dysfunctions
Authors: Tóth Gergely , Neumann Thomas , Berthet Amandine , Masliah Eliezer , Spencer Brian , Tao Jiahui , Jobling Michael F. , Gardai Shyra J. , Bertoncini Carlos W. , Cremades Nunilo , Bova Michael , Ballaron Stephen , Chen Xiao-Hua , Mao Wenxian , Nguyen Phuong , Tabios Mariano C. , Tambe Mitali A. , Rochet Jean-Christophe , Junker Hans-Dieter , Schwizer Daniel , Sekul Renate , Ott Inge , Anderson John P. , Szoke Balazs , Hoffman Wherly , Christodoulou John , Yednock Ted , Agard David A. , Schenk Dale , McConlogue Lisa 
Published: May 2019

AbstractThe over-expression and aggregation of α-synuclein (αSyn) are linked to the onset and pathology of Parkinson’s disease. Native monomeric αSyn exists in an intrinsically disordered ensemble of interconverting conformations, which has made its therapeutic targeting by small molecules highly challenging. Nonetheless, here we successfully target the monomeric structural ensemble of αSyn and thereby identify novel drug-like small molecules that impact multiple pathogenic processes. Using a surface plasmon resonance high-throughput screen, in which monomeric αSyn is incubated with microchips arrayed with tethered compounds, we identified novel αSyn interacting drug-like compounds. Because these small molecules could impact a variety of αSyn forms present in the ensemble, we tested representative hits for impact on multiple αSyn malfunctions in vitro and in cells including aggregation and perturbation of vesicular dynamics. We thereby identified a compound that inhibits αSyn misfolding and is neuroprotective, multiple compounds that restore phagocytosis impaired by αSyn overexpression, and a compound blocking cellular transmission of αSyn. Our studies demonstrate that drug-like small molecules that interact with native αSyn can impact a variety of its pathological processes. Thus, targeting the intrinsically disordered ensemble of αSyn offers a unique approach to the development of small molecule research tools and therapeutics for Parkinson’s disease.
ClassifyMe: a field-scouting software for the identification of wildlife in camera trap images
Authors: Falzon G , Lawson C , Cheung K-W , Vernes K , Ballard GA , Fleming PJS , Glen AS , Milne H , Mather-Zardain AT , Meek PD 
Published: May 2019

AbstractWe presentClassifyMea software tool for the automated identification of animal species from camera trap images.ClassifyMeis intended to be used by ecologists both in the field and in the office. Users can download a pre-trained model specific to their location of interest and then upload the images from a camera trap to a laptop or workstation.ClassifyMewill identify animals and other objects (e.g. vehicles) in images, provide a report file with the most likely species detections and automatically sort the images into sub-folders corresponding to these species categories. False Triggers (no visible object present) will also be filtered and sorted. Importantly, theClassifyMesoftware operates on the user’s local machine (own laptop or workstation) not via internet connection. This allows users access to state-of-the-art camera trap computer vision softwarein situ, rather than only in the office. The software also incurs minimal cost on the end-user as there is no need for expensive data uploads to cloud services. Furthermore, processing the images locally on the users’ end-device allows them data control and resolves privacy issues surrounding transfer and third-party access to users’ datasets.
Transcript degradation and codon usage regulate gene expression in a lytic phage
Authors: Jack Benjamin R. , Boutz Daniel R. , Paff Matthew L. , Smith Bartram L. , Wilke Claus O. 
Published: May 2019

AbstractMany viral genomes are small, containing only single- or double-digit numbers of genes and relatively few regulatory elements. Yet viruses successfully execute complex regulatory programs as they take over their host cells. Here, we propose that some viruses regulate gene expression via a carefully balanced interplay between transcription, translation, and transcript degradation. As our model system, we employ bacteriophage T7, whose genome of approximately 60 genes is well annotated and for which there is a long history of computational models of gene regulation. We expand upon prior modeling work by implementing a stochastic gene expression simulator that tracks individual transcripts, polymerases, ribosomes, and RNases participating in the transcription, translation, and transcript-degradation processes occurring during a T7 infection. By combining this detailed mechanistic modeling of a phage infection with high throughput gene expression measurements of several strains of bacteriophage T7, evolved and engineered, we can show that both the dynamic interplay between transcription and transcript degradation, and between these two processes and translation, appear to be critical components of T7 gene regulation. Our results point to a generic gene regulation strategy that may have evolved in many other viruses. Further, our results suggest that detailed mechanistic modeling may uncover the biological mechanisms at work in both evolved and engineered virus variants.
Design of a genetic layered feedback controller in synthetic biological circuitry
Authors: Hu Chelsea Y. , Murray Richard M. 
Published: May 2019

AbstractFeedback control is the key to achieve robust performances for many engineered systems. However, its application in biological contexts is still largely unexplored. In this work, we designed, analyzed and simulated a layered controller functioning at both molecular and populational levels. First, we used a minimal model of three states to represent a system where state A activates state B; state R is a by-product of state B that acts as a negative feedback regulating both state A, B, and sequentially R. We call the feedback applied to state B acisfeedback and the one applied to state A atransfeedback. Through stability analysis via linearization at equilibrium and sensitivity analysis at transient state, we found that thecisfeedback attenuates disturbances better but recovers slower; thetransfeedback recovers faster but has more dramatic responses to fluctuations; the layered feedback demonstrates both advantageous traits of the two single layers. Then we designed two versions of synthetic genetic circuits to implement the layered controller in living cells. One version with an sRNA as regulator R, the other with a transcription factor protein as the regulator R. The analysis and dynamical simulation of the models confirmed the analytical results from the minimal model. At the same time, we found that the protein regulated feedback controls have faster recovery speed but the RNA version has a stronger disturbance attenuation effect.
Rapid phenotypic and metabolomic domestication of wildPenicilliummolds on cheese
Authors: Bodinaku Ina , Shaffer Jason , Connors Allison B. , Steenwyk Jacob L. , Kastman Erik , Rokas Antonis , Robbat Albert , Wolfe Benjamin 
Published: May 2019

ABSTRACTFermented foods provide novel ecological opportunities for natural populations of microbes to evolve through successive recolonization of resource-rich substrates. Comparative genomic data have reconstructed the evolutionary histories of microbes adapted to food environments, but experimental studies directly demonstrating the process of domestication are lacking for most fermented food microbes. Here we show that during the repeated colonization of cheese, phenotypic and metabolomic traits of wildPenicilliummolds rapidly change to produce mutants with properties similar to industrial cultures used to make Camembert and other bloomy rind cheeses. Over a period of just a few weeks, populations of wildPenicilliumstrains serially passaged on cheese resulted in the reduction or complete loss of pigment, spore, and mycotoxin production. Mutants also had a striking change in volatile metabolite production, shifting from production of earthy or musty volatile compounds (e.g. geosmin) to fatty and cheesy volatiles (e.g. 2-nonanone, 2-undecanone). RNA-sequencing demonstrated a significant decrease in expression of 356 genes in domesticated mutants, with an enrichment of many secondary metabolite production pathways in these downregulated genes. By manipulating the presence of neighboring microbial species and overall resource availability, we demonstrate that the limited competition and high nutrient availability of the cheese environment promote rapid trait evolution ofPenicilliummolds.IMPORTANCEIndustrial cultures of filamentous fungi are used to add unique aesthetics and flavors to cheeses and other microbial foods. How these microbes adapted to live in food environments is generally unknown as most microbial domestication is unintentional. Our work demonstrates that wild molds closely related to the starter culturePenicillium camembertican readily lose undesirable traits and quickly shift toward producing desirable aroma compounds. In addition to experimentally demonstrating a putative domestication pathway forP. camemberti, our work suggests that wildPenicilliumisolates could be rapidly domesticated to produce new flavors and aesthetics in fermented foods.
Polylactic acid, a sustainable, biocompatible, transparent substrate material for Organ-On-Chip, and Microfluidic applications
Authors: Ongaro Alfredo E. , Giuseppe Davide Di , Kermanizadeh Ali , Crespo Allende Miguelez , Mencatti Arianna , Ghibelli Lina , Mancini Vanessa , Wlodarczyk Krystian L. , Hand Duncan P. , Martinelli Eugenio , Stone Vicki , Howarth Nicola , Carrubba Vincenzo La , Pensabene Virginia , Kersaudy-Kerhoas Maïwenn 
Published: May 2019

AbstractOrgan-on-chips are miniaturised devices aiming at replacing animal models for drug discovery, toxicology and studies of complex biological phenomena. The field of Organ-On-Chip has grown exponentially, and has led to the formation of companies providing commercial Organ-On-Chip devices. Yet, it may be surprising to learn that the majority of these commercial devices are made from Polydimethylsiloxane (PDMS), a silicone elastomer that is widely used in microfluidic prototyping, but which has been proven difficult to use in industrial settings and poses a number of challenges to experimentalists, including leaching of uncured oligomers and uncontrolled adsorption of small compounds. To alleviate these problems, we propose a new substrate for organ-on-chip devices: Polylactic Acid (PLA). PLA is a material derived from renewable resources, and compatible with high volume production technologies, such as microinjection moulding. PLA can be formed into sheets and prototyped into desired devices in the research lab. In this article we uncover the suitability of Polylactic acid as a substrate material for Microfluidic cell culture and Organ-on-a-chip applications. Surface properties, biocompatibility, small molecule adsorption and optical properties of PLA are investigated and compared with PDMS and other reference polymers.SignificanceOrgan-On-Chip (OOC) technology is a powerful and emerging tool that allows the culture of cells constituting an organ and enables scientists, researchers and clinicians to conduct more physiologically relevant experiments without using expensive animal models. Since the emergence of the first OOC devices 10 years ago, the translation from research to market has happened relatively fast. To date, at least 28 companies are proposing body and tissue on-a chip devices. The material of choice in most commercial organ-on-chip platforms is an elastomer, Polydymethyloxane (PDMS), commonly used in microfluidic R&D. PDMS is however subject to poor reproducibility, and absorbs small molecule compounds unless treated. In this study we show that PLA overcomes all the drawbacks related to PDMS: PLA can be prototyped in less than 45 minutes from design to test, is transparent, not autofluorescent, and biocompatible. PLA-based microfluidic platforms have the potential to transform the OOC industry as well as to provide a sustainable alternative for future Lab-On-Chip and point-of-care devices.
Co-Stimulation–Induced AP-1 Activity is Required for Chromatin Opening During T Cell Activation
Authors: Yukawa Masashi , Jagannathan Sajjeev , Kartashov Andrey V. , Chen Xiaoting , Weirauch Matthew T. , Barski Artem 
Published: May 2019

AbstractActivation of T cells is dependent on organized and timely opening and closing of chromatin. Herein, we identify AP-1 as the transcription factor that directs most of this remodeling. Chromatin accessibility profiling showed quick opening of closed chromatin in naïve T cells within 5 hours of activation. These newly open regions were strongly enriched for the AP-1 motif, and indeed, ChIP-seq demonstrated AP-1 binding at more than 70% of them. Broad inhibition of AP-1 activity prevented chromatin opening at AP-1 sites and reduced expression of nearby genes. Similarly, induction of anergy in the absence of co-stimulation during activation, was associated with reduced induction of AP-1 and a failure of proper chromatin remodeling. The translational relevance of these findings was highlighted by the substantial overlap of AP-1–dependent elements with risk loci for multiple immune diseases, including multiple sclerosis, inflammatory bowel disease and allergic disease. Our findings define AP-1 as the key link between T cell activation and chromatin remodeling.
Molecular organization of soluble type III secretion system sorting platform complexes
Authors: Bernal Ivonne , Börnicke Jonathan , Heidemann Johannes , Svergun Dmitri , Tuukkanen Anne , Uetrecht Charlotte , Kolbe Michael 
Published: May 2019

AbstractMany medically relevant Gram-negative bacteria use the type III secretion system (T3SS) to translocate effector proteins into the host for their invasion and intracellular survival. A multi-protein complex located at the cytosolic interface of the T3SS is proposed to act as a sorting platform by selecting and targeting substrates for secretion through the system. However, the precise stoichiometry and 3D organization of the sorting platform components is unknown. Here we reconstitute soluble complexes of theSalmonellaTyphimurium sorting platform proteins including the ATPase InvC, the regulator OrgB, the protein SpaO and a recently identified subunit SpaOC, which we show to be essential for the solubility of SpaO. We establish domain-domain interactions, determine for the first time the stoichiometry of each subunit within the complexes by native mass spectrometry and gain insight into their organization using small-angle X-ray scattering. Importantly, we find that in solution the assembly of SpaO/SpaOC/OrgB/InvC adopts an extended L-shaped conformation resembling the sorting platform pods seen inin situcryo-electron tomography, proposing that this complex is the core building block that can be conceivably assembled into higher oligomers to form the T3SS sorting platform. The determined molecular arrangements of the soluble complexes of the sorting platform provide important insights into its architecture and assembly.
Altered Nucleoprotein Binding to Influenza Virus RNA Impacts Packaging Efficiency and Replication
Authors: Le Sage Valerie , Kanarek Jack P. , Nturibi Eric , Nanni Adalena V. , Snyder Dan J. , Cooper Vaughn S. , Lakdawala Seema S. , Lee Nara 
Published: May 2019

AbstractThe genome of Influenza A viruses consists of eight negative-sense RNA segments that are bound by viral nucleoprotein (NP). We recently showed that NP binding is not uniform along the segments but exhibits regions of enrichment as well as depletion. Furthermore, genome-wide NP binding profiles are distinct even in strains with high sequence similarity, such as the two H1N1 strains A/WSN/1933 and A/California/07/2009. Here, we performed interstrain segment swapping experiments with segments of either high or low congruency in NP binding, which suggested that a segment with a similar overall NP binding profile preserved replication fitness of the resulting virus. Further sub-segmental swapping experiments demonstrated that NP binding is affected by changes to the underlying nucleotide sequence, as NP peaks can either become lost or appearde novoat mutated regions. Unexpectedly, these local nucleotide changes in one segment not only affect NP bindingin cis, but also impact the genome-wide NP binding profile on other segments in a vRNA sequence-independent manner, suggesting that primary sequence alone is not the sole determinant for NP association to vRNA. Moreover, we observed that sub-segmental mutations that affect NP binding profiles can result in reduced replication fitness, which is caused by defects in vRNA packaging efficiency and an increase in semi-infectious particle production. Taken together, our results indicate that the pattern of NP binding to vRNA is important for efficient virus replication.Author SummaryEach viral RNA (vRNA) segment is bound by the polymerase complex at the 5′ and 3′ ends, while the remainder of the vRNA is coated non-uniformly and non-randomly by nucleoprotein (NP). To explore the constraints of NP binding to vRNA, we used high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP) of mutant H1N1 strains with exchanged vRNA sequences and observed that NP binding can be changed based on vRNA sequence. The most striking observation of our study is that nucleotide changes in one segment can have genome-wide effects on the NP binding profile of other segments. We refer to this phenomenon as the ‘butterfly effect’ of influenza packaging. Our results provide an important context in which to consider future studies regarding influenza packaging and assembly.
Time-Resolved Integrative Optical Imaging of Diffusion during Spreading Depression
Authors: Hrabe J. , Hrabetova S. 
Published: May 2019

ABSTRACTAn improved version of Integrative Optical Imaging method has been developed which substantially increases the time resolution of diffusion measurements. We present a theory for Time-Resolved Integrative Optical Imaging (TR-IOI) that incorporates time-dependent effective diffusion coefficient in homogeneous anisotropic media and time-dependent nonspecific linear clearance. The method was applied to measure the very fast changes in extracellular diffusion that occur during spreading depression in rat hippocampal slices. We were able to achieve time resolution of approximately one second, an improvement of at least ten times compared to the standard methods for extracellular diffusion measurement. We have found that diffusion of a small fluorescent extracellular marker (MW 3000) completely stopped during the maximum DC shift associated with the spreading depression wave, then gradually resumed over several minutes afterward. The effect of spreading depression on extracellular space is much larger than previously estimated by other methods with lower time resolution.
Determinants of hotel guests’ satisfaction from the perspective of online hotel reviewers
Authors: Alrawadieh Zaid , Law Rob 
Published: May 2019

PurposeWith the proliferation of Web 2.0 and the travel-related user-generated content platforms, researchers can obtain abundant unsolicited data to examine guests’ perceptions, preferences and behaviors. Drawing on online reviews, this study aims to identify the key factors that determine guest satisfaction in lodging businesses.Design/methodology/approachA total of 400 English-language reviews posted about the best-rated hotels in Istanbul, Turkey, according to TripAdvisor’s ranking system, were selected and content-analyzed. A hybrid approach of inductive and deductive content analysis was adopted in this study.FindingsThe findings suggested that the quality and size of rooms, along with the service quality from staff, mainly determine guest satisfaction. The findings also reveal that relatively young European male travelers who stay in couple and with family are more likely to share their accommodation experiences in cyberspace.Originality/valueThe study adds to the literature on the determinants of guest satisfaction by examining online reviews. Unlike research using conventional research methods, the present study contributes to the existing literature of guest satisfaction in the hotel industry by harnessing the power of the word of mouse.
A multi-level analysis of mixed gender couple’s food decisions in a tourism context
Authors: Coskun Guliz , Jodice Laura W. , Moore DeWayne 
Published: May 2019

Purpose
Through application of multi-level structural equation modeling as the data analysis technique, the purpose of this paper is to analyze the group-level impacts on a couple’s food choices during travel at a coastal destination.

Design/methodology/approach
Researchers obtained 380 individual questionnaires from 190 mixed gender couples (who eat oysters) in Charleston and Beaufort County, South Carolina, USA. Data were collected from both members of the couple during their vacation. Due to missing data and normality issues 5 couples and 30 individuals were eliminated. The remaining data were analyzed with SPSS 21 and EQS 6.2 with advanced confirmatory factor analysis and multi-level (ML) regression techniques.

Findings
The study results indicated that while women have a more negative attitude than men toward oysters, their intention to eat oysters during vacation is not different from their partner. By detecting the interdependency of responses of individuals within a couple, this study revealed that a ML approach is a more powerful way to understand the decision-making process of couples. Additionally the difference in the results of single- and ML models showed that the latter approach lowers the chance of Type 2 error and provides more accurate results.

Originality/value
In tourism decision-making literature, the focus has been mostly on the individual despite the collectivistic nature of tourism activity. The current study is the first to analyze a couple’s decision-making process at the group level. Furthermore by collecting data from both members of the group during their vacation, this study has distinguished itself from previous studies.