bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modulation of Nigrofugal and Pallidofugal Pathways in Deep Brain Stimulation for Parkinson Disease
Authors: Avecillas-Chasin Josue M , Honey Christopher R 
Published: November 2019

Abstract

BACKGROUND
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established surgical therapy for patients with Parkinson disease (PD).

OBJECTIVE
To define the role of adjacent white matter stimulation in the effectiveness of STN-DBS.

METHODS
We retrospectively evaluated 43 patients with PD who received bilateral STN-DBS. The volumes of activated tissue were analyzed to obtain significant stimulation clusters predictive of 4 clinical outcomes: improvements in bradykinesia, rigidity, tremor, and reduction of dopaminergic medication. Tractography of the nigrofugal and pallidofugal pathways was performed. The significant clusters were used to calculate the involvement of the nigrofugal and pallidofugal pathways and the STN.

RESULTS
The clusters predictive of rigidity and tremor improvement were dorsal to the STN with most of the clusters outside of the STN. These clusters preferentially involved the pallidofugal pathways. The cluster predictive of bradykinesia improvement was located in the central part of the STN with an extension outside of the STN. The cluster predictive of dopaminergic medication reduction was located ventrolateral and caudal to the STN. These clusters preferentially involved the nigrofugal pathways.

CONCLUSION
Improvements in rigidity and tremor mainly involved the pallidofugal pathways dorsal to the STN. Improvement in bradykinesia mainly involved the central part of the STN and the nigrofugal pathways ventrolateral to the STN. Maximal reduction in dopaminergic medication following STN-DBS was associated with an exclusive involvement of the nigrofugal pathways.
Fiscal Decentralization and Public Investment in Innovation: A Country Panel Analysis
Authors: Colombo Daniel G , Martinez-Vazquez Jorge 
Published: November 2019

AbstractThis article presents a first analysis of the potential link between the level of fiscal decentralization of a country and its public investment in innovation. We present a theoretical model where a “benevolent government” invests in research and development (R&D) aiming at maximizing net income, and R&D results are subject to interregional knowledge spillovers. The model predicts that decentralization leads to a lower level of public spending on innovation, and to a lower share of basic research in the government R&D budget. These hypotheses are empirically tested using country aggregate data. The results provide empirical support to the mentioned hypotheses, as we find evidence that higher levels of both expenditure and revenue decentralization are associated with a lower intensity of basic research in public R&D and with a lower level of R&D spending. The strength of the evidence, however, is weakened by the small sample size and shortcomings of the indicators used in the analysis.
Impact of eHealth technologies on patient outcomes: a meta-analysis of chronic gastrointestinal illness interventions
Authors: Rohde Jacob A , Barker Joshua O , Noar Seth M 
Published: November 2019

Abstract
Gastrointestinal (GI) illness interventions are increasingly utilizing eHealth technologies, yet little is currently known about the extent of their impact on patient outcomes. The purpose of this study was to conduct a meta-analysis of the GI eHealth intervention literature. We used a comprehensive search strategy to locate studies. To be included, studies had to be a randomized controlled trial comparing an eHealth intervention condition against a no-treatment or waitlist control condition. Studies had to report data on at least one of the following patient outcomes: medication adherence, quality of life (QoL), psychological distress, illness-related knowledge, or number of patient visits to the clinic/hospital. Analyses weighted effect sizes (d) by their inverse variance and combined them using random effects meta-analytic procedures. K = 19 studies conducted in eight countries with a cumulative sample size of N = 3,193 were meta-analyzed. Findings indicated that GI eHealth interventions improved patients’ QoL (d = .25, p = .008), psychological distress (d = .24, p = .017), medication adherence (d = .17, p = .014), and illness-related knowledge (d = .19, p = .002). GI eHealth interventions also significantly reduced the number of patient visits to the clinic/hospital (d = .78, p = .005). Our findings suggest that eHealth interventions hold promise in improving patient outcomes for those with GI illnesses. We suggest the next generation of GI interventions continue developing and evaluating the impact of technology using randomized controlled trial designs, and perhaps consider adapting existing efficacious interventions for burgeoning platforms, such as smartphones and tablets.
An integrative resource for investigating genetic model of drug response in cancer
Authors: Guo Yi , Chen Xiang 
Published: November 2019

AbstractBackgroundThe most important goal of pharmacogenetics research is to obtain genetic models closely related to drug efficacyin vivoandin vitro, which can be used to measure individual responses and then to assess the sensitivity and toxicity of anticancer drugs. However, these models are scattered in different pharmacogenetic studies and are difficult to be effectively used and analyzed.ResultsTo this end, we have developed an integrated resource named iGMDR that provides the genetic models of both clinical and preclinical anticancer drugs. iGMDR provides a unique resource for mining the links between anticancer drugs and individual genomes, which will attempt to discover cancer knowledge and unlock the potential value of this data.ConclusionsWe developed iGMDR as a web service whose code was released at GitHub repository of ModelLAB (https://github.com/ModelLAB-ZJU/iGMDR), it also provided online access and application interface (https://igmdr.modellab.cn). MySQL dump for the integrated resources was stored at zenodo.org (DOI: 10.5281/ zencomod.1432561).
The insulin receptor adaptor IRS2 is an APC/C substrate that promotes cell cycle protein expression and a robust spindle assembly checkpoint
Authors: Manohar Sandhya , Yu Qing , Gygi Steven P. , King Randall W. 
Published: November 2019

AbstractInsulin receptor substrate 2 (IRS2) is an essential adaptor that mediates signaling downstream of the insulin receptor and other receptor tyrosine kinases. Transduction through IRS2-dependent pathways is important for coordinating metabolic homeostasis, and dysregulation of IRS2 causes systemic insulin signaling defects. Despite the importance of maintaining proper IRS2 abundance, little is known about what factors mediate its protein stability. We conducted an unbiased proteomic screen to uncover novel substrates of the Anaphase Promoting Complex/Cyclosome (APC/C), a ubiquitin ligase that controls the abundance of key cell cycle regulators. We found that IRS2 levels are regulated by APC/C activity and that IRS2 is a direct APC/C target in G1. Consistent with the APC/C’s role in degrading cell cycle regulators, quantitative proteomic analysis of IRS2-null cells revealed a deficiency in proteins involved in cell cycle progression. We further show that cells lacking IRS2 display a weakened spindle assembly checkpoint in cells treated with microtubule inhibitors. Together, these findings reveal a new pathway for IRS2 turnover and indicate that IRS2 is a component of the cell cycle control system in addition to acting as an essential metabolic regulator.
DNA-BOT: A low-cost, automated DNA assembly platform for synthetic biology
Authors: Storch Marko , Haines Matthew C. , Baldwin Geoff S. 
Published: November 2019

AbstractMulti-part DNA assembly is the physical starting point for many projects in Synthetic and Molecular Biology. The ability to explore a genetic design space by building extensive libraries of DNA constructs is essential for creating programmed biological systems that perform the desired functions. With multiple DNA assembly methods and standards adopted in the Synthetic Biology community, automation of the DNA assembly process has received serious attention in recent years. Importantly, automating DNA assembly enables larger builds using less researcher time, increasing the accessible design space. However, these benefits currently incur high costs for both equipment and consumables. Here, we address this limitation by introducing low-cost DNA assembly with BASIC on OpenTrons (DNA-BOT). For this purpose, we developed an open-source software package dnabot (https://github.com/BASIC-DNA-ASSEMBLY/dnabot). We demonstrate the performance of DNA-BOT by simultaneously assembling 88 constructs composed of 10 genetic parts, exploring the promoter, ribosome binding site (RBS) and gene order design space for a 3-gene operon. All 88 constructs were assembled with high accuracy, at a cost of $1.50 - $5.50 per construct. This illustrates the efficiency, accuracy and affordability of DNA-BOT making it accessible for most labs and democratising automated DNA assembly.
Variation at the Klotho gene locus does not affect cognitive function in up to 335,074 British Caucasians in the UK Biobank
Authors: Amin Hasnat A , Drenos Fotios , Blakemore Alexandra I 
Published: November 2019

AbstractThe proportion of older adults in Western populations is increasing and there is, therefore, a need to define factors affecting maintenance of physical and cognitive health in old age. Variations in the Klotho (KL) gene, and specifically the KL-VS haplotype, have been identified by several authors as potentially influencing cognitive function and decline. We have attempted to verify the reported associations between KL variants, including the KL-VS haplotype, and cognitive function in up to 335,074 British Caucasian participants aged 40-79 years from the UK Biobank. We do not find evidence that KL-VS affects cognitive function or its decline with increasing age. We examined a further 244 KL variants and found that rs117650866 was associated with Prospective Memory, but could not replicate this in follow-up samples. In conclusion, there is insufficient evidence in the UK Biobank to support the concept that KL variants affect cognitive function or its rate of decline.
HIV-1 Envelope and MPER antibody structures in lipid assemblies
Authors: Rantalainen Kimmo , Berndsen Zachary T. , Antanasijevic Aleksandar , Schiffner Torben , Zhang Xi , Lee Wen-Hsin , Torres Jonathan L. , Zhang Lei , Irimia Adriana , Copps Jeffrey , Zhou Kenneth , Kwon Young Do , Law William H. , Schramm Chaim A. , Verardi Raffaello , Krebs Shelly , Kwong Peter D. , Doria-Rose Nicole A. , Wilson Ian A. , Zwick Michael B. , Yates John R. , Schief William R. , Ward Andrew B. 
Published: November 2019

SummaryStructural and functional studies of HIV Env as a transmembrane protein have long been complicated by challenges associated with inherent flexibility of the molecule and the membrane-embedded hydrophobic regions. Thus, most structural studies have utilized soluble forms where the regions C-terminal to the ectodomain are deleted. Here, we present approaches for incorporating full-length, wild-type HIV-1 Env, as well as C-terminally truncated and stabilized versions, into lipid assemblies, providing a modular platform for Env structural studies by single particle electron microscopy. We reconstituted a full-length Env clone into a nanodisc with MSP1D1 scaffold, complexed it with an MPER targeting antibody 10E8, and structurally defined the full quaternary epitope of 10E8 consisting of lipid, MPER and ectodomain contacts. By aligning this and other Env-MPER antibody complex reconstructions with the lipid bilayer, we observe evidence of Env tilting as part of the neutralization mechanism for MPER-targeting antibodies. We also adapted the platform toward vaccine design purposes by introducing stabilizing mutations that allow purification of unliganded Env with peptidisc scaffold.
Can Living with an Alien Invasive Fish, Tilapia, Influence the Shoaling Decision-Making and Exploratory Behaviour of an Air-Breathing Freshwater Fish, the Climbing Perch?
Authors: Binoy V V , Ingle Bhagyasree J , Bhattacharya Aniket , Sinha Anindya 
Published: November 2019

AbstractThe biodiversity of freshwater aquatic ecosystems is threatened by invasive alien species across the world. We studied the impact of the presence of an invasive piscine species, the tilapia Oreochromis mossambicus and acquisition of familiarity with it on the social decision-making and exploratory behaviour of a native, air-breathing, freshwater fish, the climbing perch Anabas testudineus. Our results reveal that the climbing perch did not show any significant preference or aversion to any of the stimulus shoals when unfamiliar monospecific shoals of tilapia, mixed-species shoals of tilapia and climbing perch that were divergent in the composition, or groups comprising only tilapia familiar to the subject fish for a duration of 30, 60, 90 or 120 days, were presented in opposition to a shoal with an equal number of unfamiliar conspecific individuals. No preference for isolated familiar individual tilapia was also observed against its unfamiliar counterpart or a conspecific individual. It is also noteworthy that the propensity of subject climbing perch to initiate exploration of a novel area (a measure of boldness) or exploratory activity and its sociability remained unchanged under different social conditions, including presence of unfamiliar conspecific, familiar conspecific, unfamiliar heterospecific or familiar heterospecific individuals. These results are discussed in the light of ever-increasing levels of invasion by alien fish species and the struggle for survival that currently confront native piscine species in most tropical freshwater ecosystems globally.
Sensorimotor expectations bias motor resonance during observation of object lifting: The causal role of pSTS
Authors: Rens Guy , van Polanen Vonne , Botta Alessandro , Gann Mareike A. , Orban de Xivry Jean-Jacques , Davare Marco 
Published: November 2019

AbstractTranscranial magnetic stimulation (TMS) studies have highlighted that corticospinal excitability (CSE) is increased during observation of object lifting, an effect termed ‘motor resonance’. This facilitation is driven by movement features indicative of object weight, such as object size or observed movement kinematics. Here, we investigated in 35 humans (23 females) how motor resonance is altered when the observer’s weight expectations, based on visual information, do not match the actual object weight as revealed by the observed movement kinematics. Our results highlight that motor resonance is not robustly driven by object weight but easily masked by a suppressive mechanism reflecting the correctness of the weight expectations. Subsequently, we investigated in 24 humans (14 females) whether this suppressive mechanism was driven by higher-order cortical areas. For this, we induced ‘virtual lesions’ to either the posterior superior temporal sulcus (pSTS) or dorsolateral prefrontal cortex (DLPFC) prior to having participants perform the task. Importantly, virtual lesion of pSTS eradicated this suppressive mechanism and restored object weight-driven motor resonance. In addition, DLPFC virtual lesion eradicated any modulation of motor resonance. This indicates that motor resonance is heavily mediated by top-down inputs from both pSTS and DLPFC. Altogether, these findings shed new light on the theorized cortical network driving motor resonance. That is, our findings highlight that motor resonance is not only driven by the putative human mirror neuron network consisting of the primary motor and premotor cortices as well as the anterior intraparietal sulcus, but also by top-down input from pSTS and DLPFC.Significance StatementObservation of object lifting activates the observer’s motor system in a weight-specific fashion: Corticospinal excitability is larger when observing lifts of heavy objects compared to light ones. Interestingly, here we demonstrate that this weight-driven modulation of corticospinal excitability is easily suppressed by the observer’s expectations about object weight and that this suppression is mediated by the posterior superior temporal sulcus. Thus, our findings show that modulation of corticospinal excitability during observed object lifting is not robust but easily altered by top-down cognitive processes. Finally, our results also indicate how cortical inputs, originating remotely from motor pathways and processing action observation, overlap with bottom-up motor resonance effects.
Exploring valence bias as a metric for frontoamygdalar connectivity and depressive symptoms in childhood
Authors: Petro Nathan M. , Tottenham Nim , Neta Maital 
Published: November 2019

AbstractNegativity bias is a core feature of depression that is associated with dysfunctional frontoamygdalar connectivity; this pathway is associated with emotion regulation and sensitive to neurobiological change during puberty. We used a valence bias task (ratings of emotional ambiguity) as a potential early indicator of depression risk and differences in frontoamygdalar connectivity. Previous work using this task demonstrated that children normatively have a negative bias that attenuates with maturation. Here, we test the hypothesis that persistence of this negativity bias as manturation ensues may reveal differences in emotion regulation development, and may be associated with increased risk for depression. Within a restricted age range (6-13 years), we tested the moderating role of puberty on relationships between valence bias, depressive symptoms, and frontoamygdalar connectivity. A negative bias was associated with increased depressive symptoms for those at more advanced pubertal stages (within this sample) and less regulatory frontoamygdalar connectivity, whereas a more positive bias was associated with more regulatory connectivity patterns. These data suggest that with maturation, individual differences in positivity biases and associated emotion regulation circuitry confer a differential risk for depression. Longitudinal work is necessary to determine the directionality of these effects and explore the influence of early life events.
SLAST: Simple Local Alignment Search Tool
Authors: Bermúdez Juanjo 
Published: November 2019

AbstractWe present a local alignment search tool not based on the usual strategy of seed and grow often employed for these tools. Instead, we just find regions in the database sequences having a high density of seed matches and then we perform a Smith-Waterman local alignment of the query sequence into these regions. This approach has some advantages for some use cases.
Affinity-engineered human antibodies detect celiac disease gluten pMHC complexes and inhibit T-cell activation
Authors: Frick Rahel , Høydahl Lene S. , Hodnebrug Ina , Kumari Shraddha , Berntsen Grete , Jeliazkov Jeliazko R. , Gunnarsen Kristin S. , Frigstad Terje , Vik Erik S. , Lundin Knut E.A. , Yaqub Sheraz , Jahnsen Jørgen , Gray Jeffrey J. , Sollid Ludvig M. , Sandlie Inger , Løset Geir Åge 
Published: November 2019

AbstractAntibodies specific for antigenic peptides bound to major histocompatibility complex (MHC) molecules are valuable tools for studies of antigen presentation. Such T-cell receptor (TCR)-like antibodies may also have therapeutic potential in human disease due to their ability to target disease-associated antigens with high specificity. We previously generated celiac disease (CeD) relevant TCR-like antibodies that recognize the prevalent gluten epitope DQ2.5-glia-α1a in complex with HLA-DQ2.5. Here, we report on second-generation high-affinity antibodies towards this epitope as well as a panel of novel TCR-like antibodies to another immunodominant gliadin epitope, DQ2.5-glia-α2. The strategy for affinity engineering was based on Rosetta modeling combined with pIX phage display and is applicable to similar protein engineering efforts. We isolated picomolar affinity binders and validated them in Fab and IgG format. Flow cytometry experiments with CeD biopsy material confirm the unique disease specificity of these TCR-like antibodies and reinforce the notion that B cells and plasma cells have a dominant role in gluten antigen presentation in the inflamed CeD gut. Further, the lead candidate 3.C11 potently inhibited CD4+ T-cell activation and proliferation in vitro in an HLA and epitope specific manner, pointing to a potential for targeted disease interception without compromising systemic immunity.Significance StatementConsumption of gluten-containing food drives celiac disease in genetically predisposed individuals. The underlying disease mechanism is not fully understood, but it is strictly dependent on activation of pathogenic T cells. We have engineered high-affinity human antibodies recognizing the T-cell target HLA-DQ2.5 in complex with gluten epitopes and studied cell-specific antigen presentation in patients, which shows that plasma cells and not dendritic cells dominate the inflamed tissue. The only available treatment is lifelong adherence to a gluten-free diet, which is difficult and not effective in all cases. We show that at least one of our antibodies can specifically inhibit activation of pathogenic T-cells in vitro and therefore shows promise for therapy.
Mapping cellular-scale internal stiffness in 3D tissues with smart material hydrogel probes
Authors: Mok Stephanie , Al Habyan Sara , Ledoux Charles , Lee Wontae , MacDonald Katherine , McCaffrey Luke , Moraes Christopher 
Published: November 2019

AbstractLocal stiffness plays a critical role in cell function, but measuring rigidity at cellular length scales in living 3D tissues presents considerable challenges. Here we present thermoresponsive, smart material microgels that can be dispersed or injected into tissues and optically assayed to measure internal tissue stiffness over several weeks. We first develop the material design principles to measure tissue stiffness across physiological ranges, with spatial resolutions approaching that of individual cells. Using the microfabricated sensors, we demonstrate that mapping internal stiffness profiles of live multicellular spheroids at high resolutions reveal distinct architectural patterns, that vary with subtle differences in spheroid aggregation method. Finally, we determine that small sites of unexpectedly high stiffness (> 250 kPa) develop in invasive breast cancer spheroids, and inin vivomouse model tumors as the cancer progresses towards metastatic disease. These highly focal sites of increased intratumoral stiffness likely form via active cell mechanical behavior, and suggest new possibilities for how early mechanical cues that drive cancer cells towards invasion might arise within the evolving tumor microenvironment.