bluuebunny/crossref_metadata_2025_split huggingface dataset:
A synthetic tubular molecular transport system
Authors: Stömmer Pierre , Kiefer Henrik , Kopperger Enzo , Honemann Maximilian N. , Kube Massimo , Simmel Friedrich C. , Netz Roland R. , Dietz Hendrik 
Published: March 2021

AbstractWe report the bottom-up construction of a macromolecular transport system in which molecular pistons diffusively move through micrometer-long, hollow filaments. The pistons can cover micrometer distances in fractions of seconds. We built the system using multi-layer DNA origami and analyzed the structures of the components using transmission electron microscopy. We studied the motion of the pistons along the tubes using single-molecule fluorescence microscopy and performed Langevin simulations to reveal details of the free energy surface that directs the motions of the pistons. The tubular transport system achieves diffusivities and displacement ranges known so far only from natural molecular motors and realizes mobility improvements over five orders of magnitude compared to previous artificial random walker designs. Electric fields can also be employed to actively pull the pistons along the filaments, thereby realizing a nanoscale electric rail system. Our system presents a platform for artificial motors that move autonomously driven by chemical fuels and for performing nanotribology studies, and it could form a basis for future molecular transportation networks.
Single dose of amphetamine induces delayed subregional attenuation of striatal cholinergic interneuron activity
Authors: Ztaou Samira , Oh Soo Jung , Tepler Sophia , Fleury Sixtine , Matamales Miriam , Bertran-Gonzalez Jesus , Chuhma Nao , Rayport Stephen 
Published: March 2021

AbstractPsychostimulants such as amphetamine target dopamine neuron synapses to engender drug-induced plasticity. While dopamine neurons modulate the activity of striatal cholinergic interneurons (ChIs) with regional heterogeneity, how amphetamine affects ChI activity has not been elucidated. Here, we applied quantitative fluorescence imaging approaches to map the dose-dependent effects of a single dose of amphetamine on ChI activity at 2.5 and 24 hours after injection across the mouse striatum using the activity-dependent marker phosphorylated ribosomal protein S6 (p-rpS6). We found that amphetamine did not induce neurotoxic effects on ChIs, as their distribution and morphology were not affected. While low- or high-dose amphetamine did not affect ChI activity after 2.5 hours, ChI activity was significantly reduced in all striatal subregions after 24 hours, with a dose-dependent effect in the nucleus accumbens. Thus, our findings suggest that a single dose of amphetamine has delayed regionally heterogeneous effects on ChI activity.Significance statementUsing the activity dependent marker phosphorylated ribosomal protein S6 (p-rpS6), we mapped amphetamine effects on the activity of cholinergic interneurons (ChIs) across the striatum. Amphetamine caused a delayed attenuation of ChI activity in all striatal subregions, and a dose-dependent effect in the ventral striatum/nucleus accumbens, a critical site of psychostimulant action.
Modulation of pulsatile GnRH dynamics across the ovarian cycle: the role of glutamatergic transmission in the arcuate kisspeptin network
Authors: Voliotis Margaritis , Li Xiao Feng , De Burgh Ross , Lass Geffen , Ivanova Deyana , McIntyre Caitlin , O’Byrne Kevin T. , Tsaneva-Atanasova Krasimira 
Published: March 2021

AbstractPulsatile GnRH release is essential for normal reproductive function. Kisspeptin secreting neurons found in the arcuate nucleus, known as KNDy neurons for co-expressing neurokinin B, and dynorphin, drive pulsatile GnRH release. Furthermore, gonadal steroids regulate GnRH pulsatile dynamics across the ovarian cycle by altering KNDy neurons’ signalling properties. However, the precise mechanism of regulation remains mostly unknown. To better understand these mechanisms we start by perturbing the KNDy system at different stages of the estrous cycle using optogenetics. We find that optogenetic stimulation of KNDy neurons stimulates pulsatile GnRH/LH secretion in estrous mice but inhibits it in diestrous mice. These in-vivo results in combination with mathematical modelling suggest that the transition between estrus and diestrus is underpinned by well-orchestrated changes in neuropeptide signalling and in the excitability of the KNDy population controlled via glutamate signalling. Guided by model predictions, we show that blocking glutamate signalling in diestrous animals inhibits LH pulses, and that optic stimulation of the KNDy population mitigates this inhibition. In estrous mice, disruption of glutamate signalling inhibits pulses generated via sustained low-frequency optic stimulation of the KNDy population, supporting the idea that the level of network excitability is critical for pulse generation. Our results reconcile previous puzzling findings regarding the estradiol-dependent effect that several neuromodulators have on the GnRH pulse generator dynamics. Therefore, we anticipate our model to be a cornerstone for a more quantitative understanding of the pathways via which gonadal steroids regulate GnRH pulse generator dynamics. Finally, our results could inform useful repurposing of drugs targeting the glutamate system in reproductive therapy.
Thyroid Hormone Dependent Transcriptional Programming by TRβ Requires SWI/SNF Chromatin Remodelers
Authors: Gillis Noelle E. , Boyd Joseph R. , Tomczak Jennifer A. , Frietze Seth , Carr Frances E. 
Published: March 2021

ABSTRACTTranscriptional regulation in response to thyroid hormone (T3) is a dynamic and cell-type specific process that maintains cellular homeostasis and identity in all tissues. However, our understanding of the mechanisms of thyroid hormone receptor (TR) actions at the molecular level are actively being refined. We used an integrated genomics approach to profile and characterize the cistrome of TRβ, map changes in chromatin accessibility, and capture the transcriptomic changes in response to T3in normal thyroid cells. There are significant shifts in TRβ genomic occupancy in response to T3, which are associated with differential chromatin accessibility, and differential recruitment of SWI/SNF chromatin remodelers. We further demonstrate selective recruitment of BAF and PBAF SWI/SNF complexes to TRβ binding sites, revealing novel differential functions in regulating chromatin accessibility and gene expression. Our findings highlight three distinct modes of TRβ interaction with chromatin and coordination of coregulator activity.
Cold Adaptation Leads To Repolarization Gradients Development In The Rainbow Trout Heart
Authors: Vaykshnorayte Marina A. , Vityazev Vladimir A. , Azarov Jan E. 
Published: March 2021

ABSTRACTIntroductionThermal adaptation in fish is accompanied by morphological and electrophysiological changes in the myocardium. Little is known regarding changes of spatiotemporal organization of ventricular excitation and repolarization processes with acclimatization. We aimed to evaluate transmural and apicobasal heterogeneity of depolarization and repolarization characteristics in the in-situ heart of rainbow trout in seasonal acclimatization.MethodsThe experiments were done in the summer-acclimatized (SA, 18°C, n=8) and winter-acclimatized (WA, 3°C, n=8) rainbow trout. 24 unipolar electrograms were recorded with plunge needle electrodes (eight lead terminals each) impaled into the ventricular wall. Activation time (AT), end of repolarization time (RT), and activation-repolarization interval (ARI, a surrogate for action potential duration) were determined as dV/dt min during QRS-complex, dV/dt max during T-wave, and RT-AT difference, respectively.ResultsThe SA fish demonstrated relatively flat apicobasal and transmural AT and especially ARI profiles. In the WA animals, ATs and ARIs were longer as compared to SA animals (p≤0.001), ARIs were shorter in the compact layer than in the spongy layer (p≤0.050), and within the compact layer, the apical region had shorter ATs and longer ARIs as compared to the basal region (p≤0.050). In multiple linear regression analysis, ARI duration was associated with cardiac cycle duration and AT in SA and WA animals. The WA animals demonstrated additionally an independent association of ARIs with spatial localization across the ventricle.ConclusionAdaptation to cold conditions in rainbow trout was associated with a spatial ventricular remodeling leading to the development of repolarization gradients typically observed in mammalian myocardium.SUMMARY STATEMENTThe study gives an example of thermal adaptation in fish realized at the level of spatiotemporal organization of myocardial depolarization and repolarization.
New insights into the allosteric effects of CO2and bicarbonate on crocodilian hemoglobin
Authors: Bautista Naim M. , Malte Hans , Natarajan Chandrasekhar , Wang Tobias , Storz Jay F. , Fago Angela 
Published: March 2021

AbstractCrocodilians are unique among vertebrates in that their hemoglobin (Hb) O2binding is allosterically regulated by bicarbonate, which forms in the red blood cell upon hydration of CO2. Although known for decades, this remarkable mode of allosteric control has not yet been experimentally verified with direct evidence of bicarbonate binding to crocodilian Hb, probably because of confounding CO2-mediated effects. Here we provide the first quantitative analysis of the separate allosteric effects of CO2and bicarbonate on Hb of the spectacled caiman (Caiman crocodilus). Using thin-layer gas diffusion chamber and Tucker chamber techniques, we demonstrate that both CO2and bicarbonate bind to Hb with high affinity and strongly decrease Hb-O2saturation, and propose that both effectors bind to an unidentified positively charged site containing a reactive amino group in the low-O2affinity T conformation of the Hb. These results provide the first experimental evidence that bicarbonate binds directly to crocodilian Hb and promotes O2delivery independently of CO2. Using the gas-diffusion chamber, we observed similar effects in the Hbs of a phylogenetically diverse set of other caiman, alligator, and crocodile species, suggesting that the unique mode of allosteric regulation by CO2and bicarbonate evolved >80-100 million years ago in the common ancestor of crocodilians. Taken together, our results show a tight and unusual linkage between O2and CO2transport in the blood of crocodilians, where build-up of blood CO2and bicarbonate ions during breath-hold diving or digestion facilitates O2delivery, while Hb desaturation facilitates CO2transport as protein-bound CO2and bicarbonate.
Brain Iron Imaging Markers in the Presence of White Matter Hyperintensities
Authors: Murray Kyle D. , Tivarus Madalina E. , Schifitto Giovanni , Uddin Md Nasir , Zhong Jianhui 
Published: March 2021

PurposeTo investigate the relationship between pathological brain iron deposition and white matter hyperintensities (WMHs) in cerebral small vessel disease (CSVD), via Monte Carlo simulations of magnetic susceptibility imaging and a novel imaging marker called the Expected Iron Coefficient (EIC).MethodsA synthetic pathological model of a different number of impenetrable spheres at random locations was employed to represent pathological iron deposition. The diffusion process was simulated with a Monte Carlo method with adjustable parameters to manipulate sphere size, distribution, and extracellular properties. Quantitative susceptibility mapping (QSM) was performed in a clinical dataset to study CSVD to derive and evaluate QSM, R2*, the iron microenvironment coefficient (IMC), and EIC in the presence of WMHs.ResultsThe simulations show that QSM signals increase in the presence of increased tissue iron, confirming that the EIC increases with pathology. Clinical results demonstrate that while QSM, R2*, and the IMC do not show differences in brain iron, the EIC does in the context of CSVD.ConclusionThe EIC is more sensitive to subtle changes in brain iron deposition caused by pathology, even when QSM, R2*, and the IMC do not.
Structural modeling of the SARS-CoV-2 Spike/human ACE2 complex interface can identify high-affinity variants associated with increased transmissibility
Authors: Hark Gan Hin , Twaddle Alan , Marchand Benoit , Gunsalus Kristin C. 
Published: March 2021

AbstractThe COVID-19 pandemic has triggered concerns about the emergence of more infectious and pathogenic viral strains. As a public health measure, efficient screening methods are needed to determine the functional effects of new sequence variants. Here we show that structural modeling of SARS-CoV-2 Spike protein binding to the human ACE2 receptor, the first step in host-cell entry, predicts many novel variant combinations with enhanced binding affinities. By focusing on natural variants at the Spike-hACE2 interface and assessing over 700 mutant complexes, our analysis reveals that high-affinity Spike mutations (including N440K, S443A, G476S, E484R, G502P) tend to cluster near known human ACE2 recognition sites (K31 and K353). These Spike regions are conformationally flexible, allowing certain mutations to optimize interface interaction energies. Although most human ACE2 variants tend to weaken binding affinity, they can interact with Spike mutations to generate high-affinity double mutant complexes, suggesting variation in individual susceptibility to infection. Applying structural analysis to highly transmissible variants, we find that circulating point mutations S447N, E484K and N501Y form high-affinity complexes (~40% more than wild-type). By combining predicted affinities and available antibody escape data, we show that fast-spreading viral variants exploit combinatorial mutations possessing both enhanced affinity and antibody resistance, including S447N/E484K, E484K/N501Y and K417T/E484K/N501Y. Thus, three-dimensional modeling of the Spike/hACE2 complex predicts changes in structure and binding affinity that correlate with transmissibility and therefore can help inform future intervention strategies.
TMPRSS2 inhibitor discovery facilitated through anin silicoand biochemical screening platform
Authors: Peiffer Amanda L. , Garlick Julie M. , Wu Yujin , Soellner Matthew B. , Brooks Charles L. , Mapp Anna K. 
Published: March 2021

AbstractThe COVID-19 pandemic has highlighted the need for new antiviral targets, as many of the currently approved drugs have proven ineffective against mitigating SARS-CoV-2 infections. The host transmembrane serine protease TMPRSS2 is a highly promising antiviral target, as it plays a direct role in priming the spike protein before viral entry occurs. Further, unlike other targets such as ACE2, TMPRSS2 has no known biological role. Here we utilize virtual screening to curate large libraries into a focused collection of potential inhibitors. Optimization of a recombinant expression and purification protocol for the TMPRSS2 peptidase domain facilitates subsequent biochemical screening and characterization of selected compounds from the curated collection in a kinetic assay. In doing so, we demonstrate that serine protease inhibitors camostat, nafamostat, and gabexate inhibit through a covalent mechanism. We further identify new non-covalent compounds as TMPRSS2 protease inhibitors, demonstrating the utility of a combined virtual and experimental screening campaign in rapid drug discovery efforts.
Environmental disclosure and firm efficiency: a study of Pakistani firms
Authors: Rahim Imad 
Published: March 2021

PurposeThe purpose of this paper is to examine the effect of environmental disclosure on firm efficiency of the listed firms in Pakistan.Design/methodology/approachThe study uses secondary sources such as sustainability reports, annual reports and company websites to collect the data. A sample of 46 large firms is selected based on market capitalization and listing on the KSE-100 index.FindingsThe results suggest that environmental disclosure plays a significant positive role in determining the efficiency of the listed firms. The robustness test also confirms these results.Research limitations/implicationsThe study suggests that regulators should take appropriate steps for better and increase the firm's environmental disclosure. The number of sample firms restricts the generalization of results from this study. However, the results are consistent and can be validated using a large sample.Practical implicationsThe study includes implications to develop strict guidelines on environmental disclosure in response to its positive effect on the efficiency of the firm.Originality/valueThe study contributes to the growing environmental and efficiency literature by providing empirical evidence from a developing country where there are no strict guidelines on environmental regulations. This study is one of the first to capture environmental disclosure and measure efficiency by employing the data envelopment analysis (DEA) method in developing markets.
Factors affecting decision-making in land valuation process using AHP: a case in the Philippines
Authors: Bencure Jannet C. , Tripathi Nitin K. , Miyazaki Hiroyuki , Ninsawat Sarawut , Kim Sohee Minsun 
Published: March 2021

Purpose
The research aims to establish importance scheme of geospatial factors for land valuation activities that may serve as an eye-opener and aid the concerned government agencies in drafting land valuation policies and guidelines to achieve a sound land governance and administration. It specifically identifies and weighs geospatial valuation factors to establish their importance.

Design/methodology/approach
The research involves discussions and survey questionnaires given to land experts (i.e. appraisers, environmental planners, land economist, geodetic engineers and assessors) who indicated their opinions on influence of geospatial factors on land value. The analytic hierarchy process (AHP) is then used to weigh the factors in terms of its importance.

Findings
The result was then compared with the multiple regression analysis (MRA) taking into consideration the standardized regression coefficient of the 15 factors. The AHP method found out the major road accessibility and slope direction as the most and least influential factors, respectively, while surprisingly MRA found major road accessibility not significant at p < 0.05 level of significance.

Research limitations/implications
The research generally reflects the sub-urban type of study area; hence, inclusion of other road types such as express ways and subways and performing sensitivity analysis of AHP are suggested in future studies.

Practical implications
The findings of the study will provide information of concerned government agencies in improving valuation activities, as well as to update values regularly based on the geospatial factors.

Originality/value
To the best of the authors’ knowledge, this study is the first effort to rank geospatial factors with analytic hierarchy analytic process that further considered both their negative and positive influences on land value. The approach surmounts the flaw and shortcomings of empirical methods of identifying importance of factors.
The influence of board characteristics on environmental performance: evidence from East Asian manufacturing industries
Authors: Nguyen Linh-TX , Thanh Cuong-Le 
Published: March 2021

PurposeThe purpose of this study is to examine the influence of board characteristics on environmental performance in manufacturing firms of the emerging East Asian markets. The authors adopt a triple perspective of environmental performance that focusses on three major environmental areas including resource reduction, emission reduction and product innovation.Design/methodology/approachThe authors consider three main board characteristics, namely, board size, board independence and board leadership structure, and investigate their impacts on a multidimensional construct of environmental performance. Specifically, both linear and quadratic functions are applied to address a possibility of the non-linear relationship between board size and environmental performance. The authors use fixed-effects estimations on a sample of manufacturing firms in the emerging East Asian countries between 2011 and 2016.FindingsThe study explores an inverse U-shaped relationship between board size and environmental performance. The authors also reveal that manufacturing firms are more likely to have better environmental performance when the proportion of independent directors on board increases. However, the separation of CEO and board chair roles has no impact on environmental performance.Practical implicationsThe findings have important implications by identifying the role of a board of directors in implementing environmental protection strategies and by providing a foundation for corporate efforts to enhance sustainable development.Originality/valueThe study provides complete understanding of environmental performance as a multidimensional construct and sheds light on the influence of board characteristics, especially the inverse U-shaped influence of board size, on environmental performance in the East Asian manufacturing industries.
Job demands-resources model, transformational leadership and organizational performance: a multilevel study
Authors: Katou Anastasia A. , Koupkas Michael , Triantafillidou Eleni 
Published: March 2021

PurposeThe purpose of this paper is to integrate an extended by personal resource job demands-resources (JD-R) model in the relationship between transformational leadership and organizational performance. It is argued that the responsive, supportive and developmental leader's style will reduce employees' levels of burnout and increase their levels of work engagement and ultimately will increase organizational performance expressed by productivity, growth and creativity.Design/methodology/approachThe hypotheses were tested among a national sample of 1,011 employees in 107 Greek public and private organizations operating within an environment of economic and financial crises. The operational model was tested using a multilevel structural equation modelling.FindingsIt appeared that job demands and work burnout and job resources and work engagement, serially and fully mediated the relationship between transformational leadership and organizational performance. Further, it is found that personal resources negatively and fully mediate the relationship between job resources and work burnout and positively and partially mediate the relationship between job resources and work engagement.Research limitations/implicationsData were collected using a cross-sectional design, not allowing dynamic causal inferences.Practical implicationsConsidering that the transformational leadership style reduces employees' levels of burnout and increases their levels of work engagement and accordingly improves organizational performance, organizations are well advised to encourage this leadership style.Social implicationsTransformational leadership by balancing job demands and job resources could have a positive impact on employee well-being.Originality/valueThe study, using multilevel testing, demonstrates that the extended JD-R model can be integrated into the transformational leadership– organizational performance relationship.