bluuebunny/crossref_metadata_2025_split huggingface dataset:
Kinetic and thermodynamic analysis defines roles for two metal ions in DNA polymerase specificity and catalysis
Authors: Gong Shanzhong , Kirmizialtin Serdal , Chang Adrienne , Mayfield Joshua E. , Zhang Yan Jessie , Johnson Kenneth A. 
Published: October 2020

AbstractWe examined the roles of Mg2+ions in DNA polymerization by kinetic analysis of single nucleotide incorporation catalyzed by HIV reverse transcriptase and by molecular dynamics simulation of Mg2+binding. Binding of the Mg-nucleotide complex induces a conformational change of the enzyme from open to closed states in a process that is independent of free Mg2+concentration. Subsequently, the second Mg2+binds weakly to the closed state of the enzyme-DNA-Mg.dNTP complex with an apparentKd= 3.7 mM and facilitates the catalytic reaction. This weak binding of the catalytic Mg2+is important to maintain fidelity in that the Mg2+samples the correctly aligned substrate without perturbing the equilibrium at physiological Mg2+concentrations. The binding of the catalytic Mg2+increases nucleotide specificity (kcat/Km) by increasing the rate of the chemistry and decreasing the rate of enzyme opening allowing nucleotide release. Changing the free Mg2+concentration from 0.25 to 10 mM increased nucleotide specificity (kcat/Km) by 12-fold. Mg2+binds very weakly to the open state of the enzyme in the absence of nucleotide (Kd≈ 34 mM) and competes with Mg.dNTP. Analysis based on publish crystal structures showed that HIV RT binds only two metal ions during incorporation of a correct base-pair. MD simulations support the kinetic studies suggesting weak binding of the catalytic Mg2+in open and closed states. They also support the two-metal ion mechanism, although the polymerase may bind a third metal ion in the presence of a mismatched nucleotide.
Mycobacterium abscessus biofilms have viscoelastic properties which may contribute to their recalcitrance in chronic pulmonary infections
Authors: Gloag Erin S. , Wozniak Daniel J. , Stoodley Paul , Hall-Stoodley Luanne 
Published: October 2020

AbstractMycobacterium abscessus is emerging as a cause of recalcitrant chronic pulmonary infections, particularly in people with cystic fibrosis (CF). Biofilm formation has been implicated in the pathology of this organism, however the role of biofilm formation in infection is unclear. Two colony-variants of M. abscessus are routinely isolated from CF samples, smooth (MaSm) and rough (MaRg). These two variants display distinct colony morphologies due to the presence (MaSm) or absence (MaRg) of cell wall glycopeptidolipids (GPLs). We hypothesized that MaSm and MaRg variant biofilms might have different biophysical and mechanical properties, including stiffness, viscosity and elasticity. To test this hypothesis, we performed uniaxial mechanical indentation, and shear rheometry on MaSm and MaRg colony-biofilms. We identified that MaRg biofilms were significantly stiffer than MaSm under a normal force, while MaSm biofilms were more pliant compared to MaRg, under both normal and shear forces. Furthermore, using theoretical indices of mucociliary and cough clearence, we identified that M. abscessus biofilms may be more resistant to mechanical forms of clearance from the lung, compared to other common pulmonary pathogens, such as P. aeruginosa. Thus, the mechanical properties of M. abscessus biofilms may contribute to the persistent nature of pulmonary infections caused by this organism.
Enteric viruses evoke broad host immune responses resembling bacterial microbiome
Authors: Simone Dallari , Thomas Heaney , Adriana Rosas-Villegas , Neil Jessica A. , Serre-Yu Wong , Brown Judy J. , Kelly Urbanek , Dermody Terence S. , Ken Cadwell 
Published: October 2020

SUMMARYContributions of the viral component of the microbiome, the virome, to the development of innate and adaptive immunity are largely unknown. Here, we systematically defined the host response in mice to a panel of eukaryotic enteric viruses representing six different families. Most of these viruses asymptomatically infected the mice, the magnitude and duration of which was dependent on the microbiota. Flow cytometric and transcriptional profiling of mice mono-associated with these viruses unveiled general adaptations by the host, such as lymphocyte differentiation and IL-22 signatures in the intestine as well as numerous viral strain-specific responses that persist. Comparison with a dataset derived from analogous bacterial mono-association mice identified bacterial species that evoke an immune response comparable to the viruses we examined. These results expand an understanding of the immune space occupied by the enteric virome and underscore the importance of viral exposure events.
In vivoimaging of retrovirus infection reveals a role for Siglec-1/CD169 in multiple routes of transmission
Authors: Haugh Kelsey A. , Ladinsky Mark S. , Ullah Irfan , Pi Ruoxi , Gilardet Alexandre , Kumar Priti , Bjorkman Pamela J. , Mothes Walther , Uchil Pradeep D. 
Published: October 2020

AbstractEarly events in retrovirus transmission are determined by interactions between incoming viruses and frontline cells near entry sites. Despite their importance for retroviral pathogenesis, very little is known about these events. We developed a bioluminescence imaging (BLI)-guided multiscale imaging approach to study these eventsin vivo. Engineered murine leukemia reporter viruses allowed us to monitor individual stages of the retrovirus life cycle including virus particle flow, virus entry into cells, infection and spread for retroorbital, subcutaneous and oral routes. BLI permitted temporal tracking of orally administered retroviruses along the gastrointestinal tract as they traversed the lumen through Peyer’s Patch to reach the draining mesenteric sac. Importantly, capture and acquisition of lymph-, blood- and milk-borne retroviruses spanning three routes, was promoted by a common host factor, the I-type lectin CD169, expressed on sentinel macrophages. These results highlight how retroviruses co-opt the immune surveillance function of tissue resident sentinel macrophages for establishing infection.
Targeted modulation of protein liquid-liquid phase separation by evolution of amino-acid sequence
Authors: Lichtinger Simon M. , Garaizar Adiran , Collepardo-Guevara Rosana , Reinhardt Aleks 
Published: October 2020

AbstractRationally and efficiently modifying the amino-acid sequence of proteins to control their ability to undergo liquid-liquid phase separation (LLPS) on demand is not only highly desirable, but can also help to elucidate which protein features are important for LLPS. Here, we propose an innovative computational method that couples a genetic algorithm to a sequence-dependent coarse-grained protein model to evolve the amino-acid sequences of phase-separating intrinsically disordered protein regions (IDRs), and purposely enhance or inhibit their capacity to phase-separate. We apply it to the phase-separating IDRs of three naturally occurring proteins, namely FUS, hnRNPA1 and LAF1, as prototypes of regions that exist in cells and undergo homotypic LLPS driven by different types of intermolecular interaction. We find that the evolution of amino-acid sequences towards enhanced LLPS is driven in these three cases, among other factors, by an increase in the average size of the amino acids. However, the direction of change in the molecular driving forces that enhance LLPS (such as hydrophobicity, aromaticity and charge) depends on the initial amino-acid sequence: the critical temperature can be enhanced by increasing the frequency of hydrophobic and aromatic residues, by changing the charge patterning, or by a combination of both. Finally, we show that the evolution of amino-acid sequences to modulate LLPS is strongly coupled to the composition of the medium (e.g. the presence or absence of RNA), which may have significant implications for our understanding of phase separation within the many-component mixtures of biological systems.
HIF1α inhibition by dual targeting of CDK4/6 and HSP90 reduces cancer cell viability including Rb-deficient cells
Authors: Zhao Shuai , Zhou Lanlan , Dicker David T. , Lev Avital , Zhang Shengliang , El-Deiry Wafik S. 
Published: October 2020

AbstractMost cancers harbor intra-tumoral hypoxia which promotes tumor progression and therapy resistance. Hypoxia-inducible factor 1α (HIF1α) mediates an adaptive response to hypoxia and contributes to multiple cancer hallmarks. We describe cancer therapeutic targeting of HIF1α by combination of CDK4/6 inhibitors (CDK4/6i) and heat-shock protein 90 inhibitors (HSP90i). CDK1 contributes to HSP90-mediated HIF1α stabilization whereas CDK1-knockdown enhances HIF1α reduction by HSP90i. Dual CDK1- and HSP90-inhibition increases apoptosis and synergistically inhibits cancer cell viability. To translate our findings, we use FDA-approved CDK4/6i in combination with HSP90i to reduce HIF1α expression and suppress viability of multiple cancer cell types, including Rb-deficient cancer cells. Overexpression of HIF1α668Epartially rescues the cell viability inhibition by combination CDK4/6i and HSP90i treatment under hypoxia. CDK4/6i and HSP90i suppresses tumor growthin vivo. Thus, combined targeting of CDK4/6 and HSP90, through a drug class effect, inhibits HIF1α and shows preclinical anti-cancer therapeutic efficacy, including with Rb-deficiency.
Interactions with stromal cells promote a more oxidized cancer cell redox state in pancreatic tumors
Authors: Datta Rupsa , Lau Allison N. , Sivanand Sharanya , Florek Logan , Wyckoff Jeffrey , Skala Melissa C. , Vander Heiden Matthew G. 
Published: October 2020

AbstractAccess to electron acceptors supports oxidized biomass synthesis and can be limiting for cancer cell proliferation, but how cancer cells overcome this limitation in tumors is incompletely understood. Non-transformed cells in tumors can help cancer cells overcome metabolic limitations, particularly in pancreatic cancer, where pancreatic stellate cells (PSCs) promote cancer cell proliferation and tumor growth. However, whether PSCs affect the redox state of cancer cells is not known. By taking advantage of the endogenous fluorescence properties of reduced nicotinamide adenine dinucleotide cofactors and oxidized flavin adenine dinucleotide, we use optical imaging to assess the redox state of pancreatic cancer cells and PSCs and find that the redox state of cancer cells is more reduced while the redox state of PSCs is more oxidized. Direct interactions between PSCs and cancer cells promote a more oxidized state in cancer cells, suggesting that metabolic interactions between cancer cells and PSCs is a mechanism to overcome the redox limitations of cell proliferation in pancreatic cancer.
Auditory cortex is susceptible to lexical influence as revealed by informational vs. energetic masking of speech categorization
Authors: Carter Jared A. , Bidelman Gavin M. 
Published: October 2020

ABSTRACTSpeech perception requires the grouping of acoustic information into meaningful phonetic units via the process of categorical perception (CP). Environmental masking influences speech perception and CP. However, it remains unclear at which stage of processing (encoding, decision, or both) masking affects listeners’ categorization of speech signals. The purpose of this study was to determine whether linguistic interference influences the early acoustic-phonetic conversion process inherent to CP. To this end, we measured source level, event related brain potentials (ERPs) from auditory cortex (AC) and inferior frontal gyrus (IFG) as listeners rapidly categorized speech sounds along a /da/ to /ga/ continuum presented in three listening conditions: quiet, and in the presence of forward (informational masker) and time-reversed (energetic masker) 2-talker babble noise. Maskers were matched in overall SNR and spectral content and thus varied only in their degree of linguistic interference (i.e., informational masking). We hypothesized a differential effect of informational versus energetic masking on behavioral and neural categorization responses, where we predicted increased activation of frontal regions when disambiguating speech from noise, especially during lexical-informational maskers. We found (1) informational masking weakens behavioral speech phoneme identification above and beyond energetic masking; (2) low-level AC activity not only codes speech categories but is susceptible to higher-order lexical interference; (3) identifying speech amidst noise recruits a cross hemispheric circuit (ACleft→ IFGright) whose engagement varies according to task difficulty. These findings provide corroborating evidence for top-down influences on the early acoustic-phonetic analysis of speech through a coordinated interplay between frontotemporal brain areas.
Multiple sequential prediction errors during reward processing in the human brain
Authors: Hoy Colin W. , Steiner Sheila C. , Knight Robert T. 
Published: October 2020

SUMMARYRecent developments in reinforcement learning, cognitive control, and systems neuroscience highlight the complimentary roles in learning of valenced reward prediction errors (RPEs) and non-valenced salience prediction errors (PEs) driven by the magnitude of surprise. A core debate in reward learning focuses on whether valenced and non-valenced PEs can be isolated in the human electroencephalogram (EEG). Here, we combine behavioral modeling and single-trial EEG regression revealing a sequence of valenced and non-valenced PEs in an interval timing task dissociating outcome valence, magnitude, and probability. Multiple regression across temporal, spatial, and frequency dimensions revealed a spatio-tempo-spectral cascade from valenced RPE value represented by the feedback related negativity event-related potential (ERP) followed by non-valenced RPE magnitude and outcome probability effects indexed by subsequent P300 and late frontal positivity ERPs. The results show that learning is supported by a sequence of multiple PEs evident in the human EEG.
Helping Behavior in Prairie Voles: A Model of Empathy and the Importance of Oxytocin
Authors: Kitano Kota , Yamagishi Atsuhito , Horie Kengo , Nishimori Katsuhiko , Sato Nobuya 
Published: October 2020

SummarySeveral studies suggest that rodents show empathic responses and helping behavior toward others. We examined whether prairie voles (Microtus ochrogaster) would help conspecifics who were soaked in water by opening a door to a safe area. Door-opening latency decreased as task sessions progressed. When the conspecific was not soaked in water, the latency of the door-opening did not decrease, indicating that the distress of the conspecific is necessary for the learning of the door-opening. These suggest that prairie voles learn helping behavior. We found no sex difference in the door-opening latency or the interest in other voles soaked in water. Additionally, we also examined the helping behavior in prairie voles in which oxytocin receptors were genetically knocked out. Oxytocin receptor knockout voles demonstrated less learning of the door-opening and less interest in other voles soaked in water. This suggests that oxytocin is important for the emergence of helping behavior.
RIT2 reduces LRRK2 kinase activity and protects against alpha-synuclein neuropathology
Authors: Obergasteiger Julia , Castonguay Anne-Marie , Frapporti Giulia , Lobbestael Evy , Baekelandt Veerle , Hicks Andrew A. , Pramstaller Peter P. , Gravel Claude , Corti Corrado , Lévesque Martin , Volta Mattia 
Published: October 2020

AbstractIn Parkinson’s disease (PD) misfolded alpha-synuclein (aSyn) accumulates in the substantia nigra, where dopaminergic neurons are progressively lost. The mechanisms underlying aSyn pathology are still unclear but hypothesized to involve the autophagy-lysosome pathway (ALP). LRRK2 mutations are a major cause of familial and sporadic PD, hyperactivate kinase activity and its pharmacological inhibition reduces pS129-aSyn inclusions. We observed selective downregulation of the novel PD risk factorRIT2in G2019S-LRRK2 expressing cells. Here we studied whether RIT2 could modulate LRRK2 kinase activity. RIT2 overexpression in G2019S-LRRK2 cells rescued ALP abnormalities and diminished aSyn inclusions.In vivo, viral mediated overexpression of RIT2 conferred neuroprotection against AAV-A53T-aSyn. Furthermore, RIT2 overexpression prevented the A53T-aSyn-dependent increase of LRRK2 kinase activityin vivo. Our data indicate that RIT2 inhibits overactive LRRK2 to ameliorate ALP impairment and counteract aSyn aggregation and related deficits. Targeting RIT2 could represent a novel strategy to combat neuropathology in familial and idiopathic PD.
Adoption of artificial intelligence integrated CRM system: an empirical study of Indian organizations
Authors: Chatterjee Sheshadri , Nguyen Bang , Ghosh Soumya Kanti , Bhattacharjee Kalyan Kumar , Chaudhuri Sumana 
Published: October 2020

PurposeThe purpose of this study is to explore the behavioral intention of the employees to adopt artificial intelligence (AI) integrated customer relationship management (CRM) system in Indian organizations.Design/methodology/approachTo identify the factors impacting the behavioral intention of the employees to adopt AI integrated CRM system in Indian organizations helps of literature review and theories have been taken. Thereafter, some hypotheses have been formulated followed by the development of a theoretical model conceptually. The model has been tested statistically for validation using a survey by considering 308 usable respondents.FindingsThe results of this study show that perceived usefulness and perceived ease of use directly impact the behavioral intention of the employees to adopt an AI integrated CRM system in organizations. Also, these two exogenous factors impact the behavioral intention of the employees to adopt an AI integrated CRM system mediating through two intermediate variables such as utilitarian attitude (UTA) and hedonic attitude (HEA). The proposed model has achieved predictive power of 67%.Research limitations/implicationsBy the help of the technology acceptance model and motivational theory, the predictors of behavioral intention to adopt AI integrated CRM systems in organizations were identified. The effectiveness of the model was strengthened by the consideration of two employee-centric attitudinal attributes such as UTA and HEA, which is claimed to have provided contributions to the extant literature. The proposed theoretical model claims a special theoretical contribution as no extant literature considered the effects of leadership support as a moderator for the adoption of an AI integrated CRM system in Indian organizations.Practical implicationsThe model implies that the employees using AI integrated CRM system in organizations must be made aware of the usefulness of the system and the employees must not face any complexity to use the system. For this, the managers of the concerned organizations must create a conducive atmosphere congenial for the employees to use the AI integrated CRM system in the organizations.Originality/valueStudies covering exploration of the adoption of AI integrated CRM systems in Indian organizations are found to be in a rudimentary stage and in that respect, this study claims to have possessed its uniqueness.
Responding to COVID-19 in an African university: the case the National University of Lesotho library
Authors: Mbambo-Thata Buhle 
Published: October 2020

Purpose
The purpose of this paper is to discuss the National University of Lesotho Library’s shift to supporting of contact teaching to e-learning because of COVID-19. The university library increased access to digital content and broadened digital services.

Design/methodology/approach
This case study is based on reflective practice methodology in which practitioners learn from their practice, reflect and adapt to change as they improve on their practice. The library team members were reflective participants in the transformation of library services from on-site to digital services. The main research questions are “How did the digital libraries meet the needs of the digital community?” and “What will be the new normal after COVID-19 experience in digital libraries and their communities?” The literature review juxtaposes reports on transformation of library services to digital services.

Findings
The library transformed from on-site to digital services library. It also reports on observed increase in databases usage during lockdown.

Research limitations/implications
The nature of a case study is limited by time and geography.

Practical implications
This paper has implications and possible applications for other university libraries in African countries that are resources constrained such as Lesotho.

Originality/value
This paper makes a valuable contribution to lessons on how African universities’ libraries respond to pandemics such as COVID-19. It speaks to the need to strengthen existing infrastructure and digital content, while ensuring the library staff and the university community adapts to the new normal.
An algorithm to elicitate ELECTRE II, III and IV parameters
Authors: e Souza Rodrigues Brunno , Martins Floriano Carla , Pereira Valdecy , Costa Roboredo Marcos 
Published: October 2020

PurposeThis paper presents an algorithm that can elicitate all or any combination of parameters for the ELECTRE II, III or IV, methods. The algorithm takes some steps of a machine learning ensemble technique, the random forest, and for that, the authors named the approach as Ranking Trees Algorithm.Design/methodology/approachFirst, for a given method, the authors generate a set of ELECTRE models, where each model solves a random sample of criteria and actions (alternatives). Second, for each generated model, all actions are projected in a 1D space; in general, the best actions have higher values in a 1D space than the worst ones; therefore, they can be used to guide the genetic algorithm in the final step, the optimization phase. Finally, in the optimization phase, each model has its parameters optimized.FindingsThe results can be used in two different ways; the authors can merge all models, to find the elicitated parameters in this way, or the authors can ensemble the models, and the median of all ranks represents the final rank. The numerical examples achieved a Kendall Tau correlation rank over 0.85, and these results could perform as well as the results obtained by a group of specialists.Originality/valueFor the first time, the elicitation of ELECTRE parameters is made by an ensemble technique composed of a set of uncorrelated multicriteria models that can generate robust solutions.