bluuebunny/crossref_metadata_2025_split huggingface dataset:
The paradoxical effects of K+channel gain-of-function are mediated by GABAergic neuron hypoexcitability and hyperconnectivity
Authors: Shore Amy N. , Colombo Sophie , Tobin William F. , Petri Sabrina , Cullen Erin R. , Dominguez Soledad , Bostick Christopher D. , Beaumont Michael A. , Williams Damian , Khodagholy Dion , Yang Mu , Lutz Cathleen M. , Peng Yueqing , Gelinas Jennifer N. , Goldstein David B. , Boland Michael J. , Frankel Wayne N. , Weston Matthew C. 
Published: March 2020

SUMMARYGain-of-function (GOF) variants in K+channels cause severe childhood epilepsies, but there are no mechanisms to explain how increased K+currents lead to network hyperexcitability. Here, we introduced a human Na+-activated K+(KNa) channel variant (KCNT1-Y796H) into mice and, using a multiplatform approach, found motor cortex hyperexcitability and early-onset seizures, phenotypes strikingly similar to those of human patients. Although the variant increased KNacurrents in cortical excitatory and inhibitory neurons, there was a selective increase in the KNacurrent across subthreshold voltages in inhibitory neurons, particularly in those with non-fast spiking properties, resulting in impaired excitability and AP generation. We further observed evidence of synaptic rewiring associated with hyperexcitable networks, including increases in homotypic synaptic connectivity and the ratio of excitatory-to-inhibitory synaptic input. These findings support inhibitory neuron-specific mechanisms in mediating the epileptogenic effects of K+channel GOF, offering cell-type-specific currents and effects as promising targets for therapeutic intervention.GRAPHICAL ABSTRACT
Mesophilic enzyme function at high temperature: molecular dynamics of hyperthermophilic and mesophilic pyrophosphatases
Authors: Agarwal Rupesh , Shrestha Utsab R. , Chu Xiang-Qiang , Petridis Loukas , Smith Jeremy C. 
Published: March 2020

AbstractThe mesophilic inorganic pyrophosphatase fromEscherichia coli(EcPPase) retains function at 353 K, the physiological temperature of hyperthermophilicThermoccoccus thioreducens, whereas, the homolog protein from the hyperthermophilic organism (TtPPase) cannot function at room temperature. To explain this asymmetric behavior, we examined structural and dynamical properties of the two proteins using molecular dynamics simulations. The global flexibility ofTtPPase is significantly higher than its mesophilic homolog at all tested temperature/pressure conditions. However, at 353 K,EcPPase reduces its solvent-exposed surface area and increases subunit compaction while maintaining flexibility in its catalytic pocket. In contrast,TtPPase lacks this adaptability and has increased rigidity and reduced protein:water interactions in its catalytic pocket at room temperature, providing a plausible explanation for its inactivity near room temperature.
Ancestry adjustment improves genome-wide estimates of regional intolerance
Authors: Hayeck Tristan J. , Stong Nicholas , Baugh Evan , Dhindsa Ryan , Turner Tychele N. , Malakar Ayan , Mosbruger Timothy L. , Duan Yuncheng , Ionita-Laza Iuliana , Goldstein David , Allen Andrew S. 
Published: March 2020

AbstractGenomic regions subject to purifying selection are more likely to carry disease causing mutations. Cross species conservation is often used to identify such regions but has limited resolution to detect selection on short evolutionary timescales such as that occurring in only one species. In contrast, intolerance looks for depletion of variation relative to expectation within a species, allowing species specific features to be identified. When estimating the intolerance of noncoding sequence methods strongly leverage variant frequency distributions. As the expected distributions depend on demography, if not properly controlled for, ancestral population source may obfuscate signals of selection. We demonstrate that properly incorporating demography in intolerance estimation greatly improved variant classification (13% increase in AUC relative to comparison constraint test, CDTS; and 9% relative to conservation). We provide a genome-wide intolerance map that is conditional on demographic history that is likely to be particularly valuable for variant prioritization.
Medial temporal atrophy in preclinical dementia: visual and automated assessment during six year follow-up
Authors: Mårtensson Gustav , Håkansson Claes , Pereira Joana B. , Palmqvist Sebastian , Hansson Oskar , van Westen Danielle , Westman Eric 
Published: March 2020

AbstractMedial temporal lobe (MTL) atrophy is an important morphological marker of many dementias and is closely related to cognitive decline. In this study we aimed to characterize longitudinal progression of MTL atrophy in 93 individuals with subjective cognitive decline and mild cognitive impairment followed up over six years, and to assess if clinical rating scales are able to detect these changes. All MRI images were visually rated according to Scheltens’ scale of medial temporal atrophy (MTA) by two neuroradiologists and AVRA, a software for automated MTA ratings. The images were also segmented using FreeSurfer’s longitudinal pipeline in order to compare the MTA ratings to volumes of the hippocampi and inferior lateral ventricles. We found that MTL atrophy rates increased with CSF biomarker abnormality, used to define preclinical stages of Alzheimer’s Disease. Both AVRA’s and the radiologists’ MTA ratings showed a similar longitudinal trajectory as the subcortical volumes, suggesting that visual rating scales provide a valid alternative to automatic segmentations. While the MTA scores from each radiologist showed strong correlations to subcortical volumes, the inter-rater agreement was low. We conclude that the main limitation of quantifying MTL atrophy with visual ratings in clinics is the subjectiveness of the assessment.
Human TRPA1 is an inherently mechanosensitive bilayer-gated ion channel
Authors: Moparthi Lavanya , Zygmunt Peter M. 
Published: March 2020

AbstractThe Transient Receptor Potential Ankyrin 1 (TRPA1) channel is an intrinsic chemo- and thermo-sensitive ion channel with distinct sensory signaling properties. Although a role of TRPA1 in mammalian mechanosensory transductionin vivoseems likely, it remains to be shown that TRPA1 has the inherent capability to respond to mechanical stimuli. Here we have used the patch-clamp technique to study the response of human purified TRPA1 (hTRPA1), reconstituted into artificial lipid bilayers, to changes in bilayer pressure. We report that hTRPA1 responded with increased single-channel open probability (Po) within the applied pressure interval of 7.5 to 60 mmHg with a half maximum Po(P50) value of 38.0 ± 2.3 mmHg. The Povalue reached a maximum close to 1 (0.87 ± 0.02) at 60 mmHg. Within the same pressure interval, hTRPA1 without its N-terminal ankyrin repeat domain (Δ1-688 hTRPA1) responded fully opened (0.99 ± 0.01) at 60 mmHg and with a P50value of 39.0 ± 1.1 mmHg. The pressure-evoked responses of hTRPA1 and Δ1-688 hTRPA1 at 45 mmHg were inhibited by the TRPA1 antagonist HC030031, and the activity of purified hTRPA1 at 45 mmHg was abolished by the thiol reducing agent tris(2-carboxyethyl)phosphine (TCEP). In conclusion, hTRPA1 is an inherent mechanosensitive ion channel gated by force-from-lipids. The hTRPA1 mechanosensitivity is dependent on the redox environment, and it is suggested that oxidative stress shifts hTRPA1 into a protein conformation sensitive to mechanical stimuli.
EYES ABSENT and TIMELESS integrate photoperiodic and temperature cues to regulate seasonal physiology inDrosophila
Authors: Abrieux Antoine , Xue Yongbo , Cai Yao , Lewald Kyle M. , Nhu Nguyen Hoang , Zhang Yong , Chiu Joanna C. 
Published: March 2020

AbstractOrganisms possess photoperiodic timing mechanisms to anticipate variations in day length and temperature as the seasons progress. The nature of the molecular mechanisms interpreting and signaling these environmental changes to elicit downstream neuroendocrine and physiological responses are just starting to emerge. Here, we demonstrate that inDrosophila melanogaster, EYES ABSENT (EYA) acts as a seasonal sensor by interpreting photoperiodic and temperature changes to trigger appropriate physiological responses. We observed that tissue-specific genetic manipulation ofeyaexpression is sufficient to disrupt the ability of flies to sense seasonal cues, thereby altering the extent of female reproductive dormancy. Specifically we observed that EYA proteins, which peak at night in short photoperiod and accumulate at higher levels in the cold, promote reproductive dormancy in femaleD. melanogaster. Furthermore, we provide evidence indicating that the role of EYA in photoperiodism and temperature sensing is aided by the stabilizing action of the light-sensitive circadian clock protein TIMELESS (TIM). We postulate that increased stability and level of TIM at night under short photoperiod together with the production of cold-induced and light-insensitive TIM isoforms facilitate EYA accumulation in winter conditions. This is supported by our observations thattimnull mutants exhibit reduced incidence of reproductive dormancy in simulated winter conditions, while flies overexpressingtimshow an increased incidence of reproductive dormancy even in long photoperiod.Significance StatementExtracting information on calendar time from seasonal changes in photoperiod and temperature is critical for organisms to maintain circannual cycles in physiology and behavior. Here we found that in flies, EYES ABSENT (EYA) protein act as a seasonal sensor by adjusting its abundance and circadian phase in response to changes in photoperiod and temperature. We show that the manipulation of EYA levels is sufficient to impair the ability of femaleDrosophilato regulate seasonal variation in reproductive dormancy. Finally, our results suggest an important role of the circadian clock protein TIMELESS (TIM) in modulating EYA level through its ability to measure night length, linking the circadian clock to seasonal timing.
Detection of HER2 expression and its structural alterations in gastric cancer tissues infected with cagA+H. pylori
Authors: Srivastava Akhileshwar Kumar , Singh Divya 
Published: March 2020

AbstractBackgroundHelicobacter pylori(HP) cagA is the causing agent for development of gastric cancer (GC).H. pylorialso involves to trigger the EGFR (epidermal growth factor receptor) expression in gastric cancer cells. However, the prognostic relation of cagA with HER2 status in GC was not well understood.ObjectiveThe main aim of this study was to investigate the link of HER2 expression with CagA+H. pyloriin GC tissues.Materials and MethodsThe study was performed on 85 GC tissues of GC patients. The specific primers of 16S rDNA and cagA for PCR amplification were used. For investigation of HER2 status in GC tissues, immunohistochemistry and PCR amplification were performed. In silico study was performed for the investigation of interactive potential of HER2 with CagA protein.ResultsPCR amplified the 54 (63.52 %) of 85 GC tissues for HP that showed 34 (62.96 %) cagA+ HP. Immunohistochemistry of tissues revealed 57 (67.05 %) diffuse and 28 (32.94 %) intestinal type cancer. Of 85 cases, 21 GC tissues scored (2 + or 3 +) for positive HER2 expression and score (0 or 1 +) of 64 (75.29 %) showed negative. Of 21 HER2 + GC tissue, 15 biopsies had cagA+ HP and 2 were negative. PCR amplified single amplicon in 17 (20 %) CagA+ tissues and 3 (5.55 %) in CagA - HP. The molecular interactions of CagA was also showed its efficiency for HER2 expression.ConclusionThe study concluded that CagA+ HP may induce HER2 overexpression in GC tissues.
Dataset Augmentation Allows Deep Learning-Based Virtual Screening To Better Generalize To Unseen Target Classes, And Highlight Important Binding Interactions
Authors: Scantlebury Jack , Brown Nathan , Von Delft Frank , Deane Charlotte M. 
Published: March 2020

AbstractCurrent deep learning methods for structure-based virtual screening take the structures of both the protein and the ligand as input but make little or no use of the protein structure when predicting ligand binding. Here we show how a relatively simple method of dataset augmentation forces such deep learning methods to take into account information from the protein. Models trained in this way are more generalisable (make better predictions on protein-ligand complexes from a different distribution to the training data). They also assign more meaningful importance to the protein and ligand atoms involved in binding. Overall, our results show that dataset augmentation can help deep learning based virtual screening to learn physical interactions rather than dataset biases.Graphical TOC Entry
Choices Change the Temporal Weighting of Decision Evidence
Authors: Talluri Bharath Chandra , Urai Anne E. , Bronfman Zohar Z. , Brezis Noam , Tsetsos Konstantinos , Usher Marius , Donner Tobias H. 
Published: March 2020

ABSTRACTDecisions do not occur in isolation, but are embedded in sequences of other decisions, often pertaining to the same source of evidence. Here, we characterized the impact of intermittent choices on the accumulation of a protracted stream of decision-relevant evidence towards a final decision. Human participants performed two versions, based on perceptual or numerical evidence, of a decision task that required two successive judgments at different times during the evidence stream: an intermittent response consisting of a binary choice, and a continuous estimation at the end of the evidence stream. In a control condition, subjects executed a choice-independent motor response instead of binary choice as the intermittent response. In both, perceptual and numerical tasks, the intermittent choice reduced the sensitivity of subsequent evidence, and flipped the relative temporal weighting of early and late evidence in the final estimation judgment. The individual extent of the choice-induced overall (non-selective) sensitivity reduction predicted the extent of the selective down-weighting of subsequent evidence inconsistent with the initial choice, a form of confirmation bias. In sum, active decisions about a protracted evidence stream profoundly alter the dynamics of evidence accumulation, consistent with an active, modulatory mechanism triggered by the choice.
Alternative paradigms for sustainability: a Relational worldview
Authors: Kennedy Ann-Marie , McGouran Cathy , Kemper Joya A. 
Published: March 2020

PurposeThe authors do not claim that the following represents the views of any one tribe but instead the culmination of the academic literature written on the topic. Marketing’s current Western dominant social paradigm (DSP) is said to perpetuate “green”, yet unsustainable practices. The DSP does not support strictly pro-environmental practices and its proposed alternative, the new environmental paradigm (NEP), lacks in-depth conceptualisation, especially concerning business and marketing activities. However, the two paradigms contrast so much that a shift from one to the other is vehemently argued against and conceptually rife with problems. This paper aims to expand upon the merits of the NEP using indigenous people’s environmental philosophies [1] – as examples of historically supported and successful sustainable philosophies. It conceptualises a Relational view to provide a more practical alternative to the DSP and includes propositions for marketing implementation of this perspective.FindingsBy explicating both the DSP and NEP and reflecting on each through an indigenous Māori view, this paper provides propositions for a broadened paradigm that supports sustainability and its application for sustainable marketing.Research limitations/implicationsThe implications of this research are in the area of paradigm development and in providing an alternative paradigm to that of the DSP. This paper is the first to fully explicate parts of the NEP and considers a solution to the problems of changing the current DSP so drastically by broadening the NEP using a Relational worldview.Practical implicationsThe propositions and examples provided in this work give practical application of the newly presented paradigm for marketers influenced by indigenous belief systems.Originality/valueThis paper is the first to explicate parts of the NEP and broaden its reach by integrating a Relational worldview as an alternative to drastically changing the current DSP. It does so by proposing that marketers embrace a middle ground that is influenced by indigenous belief systems.
An integrated three-layered foresight framework
Authors: van Dorsser Cornelis , Taneja Poonam 
Published: March 2020

Purpose
The paper aims to present an integrated foresight framework and method to support decision-makers who are confronted with today’s complex and rapidly changing world. The method aims at reducing the degree of uncertainty by addressing the inertia or duration of unfolding trends and by placing individual trends in a broader context.

Design/methodology/approach
The paper presents a three-layered framework and method for assessing megatrends based on their inertia or duration. It suggests that if long-term trends and key future uncertainties are studied in conjunction at a meta-level and placed in a broader multi-layered framework of trends, it can result in new insights.

Findings
The application of the proposed foresight method helps to systematically place a wide range of unrelated trends and key uncertainties in the context of a broader framework of trends, thereby improving the ability to understand the inertia, direction and mutual interaction of these trends.

Research limitations/implications
The elaboration of identified trends and key uncertainties is partly case-specific and subject to interpretation. It is aimed at illustrating the potential use of the framework.

Practical implications
The paper presents a new approach that may, by itself or in combination with existing foresight methods, offer new means for anticipating future developments.

Social implications
The use of the proposed framework has potential to provide better insight in the complexity of today’s rapid-changing world and the major transitions taking place. It aims to result in sharper foresight by reducing epistemic uncertainty for decision-makers.

Originality/value
The paper demonstrates how megatrends, Kondratieff waves and century-long trends can be placed in an integrated framework and analysed in conjunction.
Entrepreneurs' behavioural competencies for internationalisation
Authors: Cortellazzo Laura , Bonesso Sara , Gerli Fabrizio 
Published: March 2020

PurposeThe entrepreneur is the main decision-maker in small and medium-sized enterprises and is the principal force in the implementation of a firm's international strategy. Research has paid limited attention to the intangible aspects of human capital, namely behavioural competencies that may have an impact on the entrepreneur's ability to take advantage of international opportunities. This study addresses this gap, identifying the behavioural competencies that distinguish entrepreneurs who pursue a stronger internationalisation expansion beyond the European market.Design/methodology/approachA competency modelling process is implemented for a sample of Italian entrepreneurs. Data on behavioural competencies are obtained through the coding of behavioural event interviews administrated to the entrepreneurs. Export intensity is adopted as a performance criterion to classify the entrepreneurs.FindingsThree behavioural competencies (change catalyst, teamwork and organisational learning orientation) emerged as more significantly activated by entrepreneurs who show a higher export intensity in the global market.Research limitations/implicationsThe exploratory nature of the study, conducted in a small sample and in a specific geographical area, may reduce the generalisability of the findings.Practical implicationsEntrepreneurs can become aware of the behavioural competencies needed for the implementation of internationalisation processes. Additionally, training programmes can be designed to promote the development of these behaviours.Originality/valueBridging the literature on international entrepreneurship, cross-cultural studies and competency-based research, this study highlights the role of behavioural competencies in the internationalisation process from a micro level of analysis. This article proposes a competency framework that can be adopted to assess a broader portfolio of entrepreneurs' behaviours.
The impact of reverse logistics onto green supply chain competitiveness evidence from Serbian consumers
Authors: Aćimović Slobodan , Mijušković Veljko , Rajić Vesna 
Published: March 2020

PurposeThe purpose of this paper is to explain what determines the influence of reverse logistics onto green supply chain competitiveness and to find out if that influence is always uniform.Design/methodology/approachThe paper contains an empirical research conducted using a survey-based study, which encompassed a sample size of 228 participants and final consumers that have experience in buying/using products derived from the reverse logistics process.FindingsThe results indicate that the influence of reverse logistics onto green supply chain competitiveness is dependent on the product return option and is mainly negative with Serbian consumers, since the perceived quality of each of the three return options is considered to be inferior compared to new products.Practical implicationThe study's empirical results show the there is a generally negative perception among consumers regarding the perceived quality of each of the three product return options, thus directly questioning the general justification of using reverse logistics in Serbian business practice. That is a sign for Serbian managers to enhance their efforts to raise future awareness of the green initiatives importance among business partners, but also final consumers.Originality/valueThe study`s contribution is twofold: first, it helps to additionally test the established and known methodology created by Hazenet al.(2011), thus contributing to the practical dimension of international comparability concerning consumer perceptions. Second, the study adds to research by addressing the gap in practical surveys regarding the reverse logistics practices.