bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spontaneous Neuronal Oscillations in the Human Insula are Hierarchically Organized Traveling Waves
Authors: Das Anup , Myers John , Mathura Raissa , Shofty Ben , Metzger Brian , Bijanki Kelly , Wu Chengyuan , Jacobs Joshua , Sheth Sameer A. 
Published: December 2021

AbstractThe insula plays a fundamental role in a wide range of adaptive human behaviors, but its electrophysiological dynamics are poorly understood. Here we used human intracranial electroencephalographic recordings to investigate the electrophysiological properties and hierarchical organization of spontaneous neuronal oscillations within the insula. We analyzed the neuronal oscillations of the insula directly and found that rhythms in the theta and beta frequency oscillations are widespread and spontaneously present. These oscillations are largely organized along the anterior–posterior axis of the insula. Both the left and right insula showed anterior-to-posterior decreasing gradients for the power of oscillations in the beta frequency band. The left insula also showed a posterior-to-anterior decreasing frequency gradient and an anterior-to-posterior decreasing power gradient in the theta frequency band. In addition to measuring the power of these oscillations, we also examined the phase of these signals across simultaneous recording channels and found that the insula oscillations in the theta and beta bands are traveling waves. The strength of the traveling waves in each frequency was positively correlated with the amplitude of each oscillation. However, the theta and beta traveling waves were uncoupled to each other in terms of phase and amplitude, which suggested that insula traveling waves in the theta and beta bands operate independently. Our findings provide new insights into the spatiotemporal dynamics and hierarchical organization of neuronal oscillations within the insula, which, given its rich connectivity with widespread cortical regions, indicates that oscillations and traveling waves have an important role in intra- and inter-insula communication.
A Mathematical Model of Mitochondria in Proximal Tubule and Thick Ascending Limb Cells
Authors: Bell William , Layton Anita T. 
Published: December 2021

AbstractMitochondria are a key player in several kinds of tissue injury, and are even the ultimate cause of certain diseases. In this work we introduce new models of mitochondrial ATP generation in multiple tissues, including liver hepatocytes and the medullary thick ascending limb in the kidney. Using this model, we predict these tissues’ responses to hypoxia, uncoupling, ischemia-reperfusion, and oxidative phosphorylation dysfunction. Our results suggest mechanisms explaining differences in robustness of mitochondrial function across tissues.The medullary thick ascending limb and proximal tubule in the kidney both experience a high metabolic demand, while having lower baseline activity of oxidative phosphorylation relative to the liver. These factors make these tissues susceptible to dysfunction of ComplexIII. A lower baseline oxygen tension observed in the thick ascending limb makes it susceptible to Complex IV. On the other hand, since the liver lacks these risk factors, and has higher baseline rates of glycolysis, it is less susceptible to all kinds of oxidative phosphorylation dysfunction.
Clinical genetics laboratories use divergent demographic frameworks across countries: comparing data structures for ‘race’, ‘ethnicity’, and ‘ancestry’ on test requisition forms
Authors: Popejoy Alice B. , Mayol Julia Gimbernat , Anderson Katherine , Hooker Gillian 
Published: December 2021

ABSTRACTPurposeThe goal of this study is to investigate how population groups are represented on requisition forms for clinical genetic testing in different laboratories.MethodsClinical laboratory test requisition forms (RFs) were obtained from 70 laboratories in the US, Canada, Europe, and Australia. Details about the laboratories and how RFs represent patient demographics were extracted and analyzed for trends between forms in the U.S. (N=213) and other countries (N=203).ResultsClinical genetics laboratories included in the analysis vary widely regarding the format of demographic data collected on test requisition forms. US-based laboratory RFs are more likely than those from other countries to include ‘race’ or ‘ethnicity’. These are most often represented as categorical data, with multiple-choice options. RFs from laboratories in other countries do not include ‘race’, and those that include ‘ethnicity’ most often provide a blank space for open-ended responses.ConclusionsThese results are consistent with existing research on heterogeneity in the nomenclature and number of categories used to describe patient populations across clinical genetics laboratories in the US. It also suggests systemic differences in the way measures of diversity are conceptualized in the US compared to other countries.
A Model of Mitochondria in the Rat Hepatocyte
Authors: Bell William , Layton Anita T. 
Published: December 2021

AbstractMitochondria are a key player in several kinds of tissue injury, and are even the ultimate cause of certain diseases. In this work we introduce a new model of mitochondrial ATP generation in liver hepatocytes of the rat. Ischemia-reperfusion is an intriguing example of a non-equilibrium behaviour driven by a change in tissue oxygen tension. Ischemia involves prolonged hypoxia, followed by the sudden return of oxygen during reperfusion. During reperfusion, we predict that the build up of succinate causes the electron transport chain in the liver to temporarily be in a highly reduced state. This can lead to the production of reactive oxygen species. We accurately predict the timescale on which the electron transport chain is left in a reduced state, and we observe levels of reduction likely to lead to reactive oxygen species production. Aside from the above, we predict thresholds for ATP depletion from hypoxia, and we predict the consequences for oxygen consumption of uncoupling.
Optimizing Dosage-Specific Treatments in a Multi-Scale Model of a Tumor Growth
Authors: Ponce-de-Leon Miguel , Montagud Arnau , Akasiadis Charilaos , Schreiber Janina , Ntiniakou Thaleia , Valencia Alfonso 
Published: December 2021

ABSTRACTThe emergence of cell resistance in cancer treatment is a complex phenomenon that emerges from the interplay of processes that occur at different scales. For instance, molecular mechanisms and population-level dynamics such as competition and cell-cell variability have been described as playing a key role in the emergence and evolution of cell resistances. Multi-scale models are a useful tool to study biology at a very different time and spatial scales, as they can integrate different processes that take place at the molecular, cellular and intercellular levels. In the present work, we use an extended hybrid multi-scale model of 3T3 fibroblast spheroid to perform a deep exploration of the parameter space of effective treatment strategies based on TNF pulses. To explore the parameter space of effective treatments in different scenarios and conditions, we have developed an HPC-optimized model exploration workflow based on EMEWS. We first studied the effect of the cells spatial distribution in the values of the treatment parameters by optimizing the supply strategies in 2D monolayers and 3D spheroids of different sizes. We later study the robustness of the effective treatments when heterogeneous populations of cells are considered. We found that our model exploration workflow can find effective treatments in all the studied conditions. Our results show that cells’ spatial geometry, as well as, population variability should be considered when optimizing treatment strategies in order to find robust parameter sets.
Air Pollution Particles Hijack Peroxidasin to Disrupt Immunosurveillance and Promote Lung Cancer
Authors: Wang Zhenzhen , Zhai Ziyu , Chen Chunyu , Tian Xuejiao , Xing Zhen , Xing Panfei , Yang Yushun , Zhang Junfeng , Wang Chunming , Dong Lei 
Published: December 2021

AbstractAlthough fine particulate matter (FPM) in air pollutants and tobacco smoke is recognized as a strong carcinogen and global threat to public health, its biological mechanism for inducing lung cancer remains unclear. Here, by investigating FPM’s bioactivities in lung carcinoma mice models, we discover that these particles promote lung tumor progression by inducing aberrant thickening of tissue matrix and hampering migration of anti-tumor immunocytes. Upon inhalation into lung tissue, these FPM particles abundantly adsorb peroxidasin (PXDN) – an enzyme mediating type IV collagen (Col IV) crosslinking – onto their surface. The adsorbed PXDN exerts abnormally high activity to crosslink Col IV via increasing the formation of sulfilimine bonds at the NC1 domain, leading to an overly dense matrix in the lung tissue. This disordered structure decreases the mobility of cytotoxic CD8+ T lymphocytes into the lung and consequently impairs the local immune surveillance, enabling the flourish of nascent tumor cells. Meanwhile, inhibiting the activity of PXDN effectively abolishes the tumor-promoting effect of FPM, indicating the key impact of aberrant PXDN activity on tumorigenic process. In summary, our finding elucidates a new mechanism for FPM-induced lung tumorigenesis and identifies PXDN as a potential target for treatment or prevention of the FPM-relevant biological risks.Graphical abstract
Structure prediction of the druggable fragments in SARS-CoV-2 untranslated regions
Authors: Gumna Julita , Antczak Maciej , Adamiak Ryszard W. , Bujnicki Janusz M. , Chen Shi-Jie , Ding Feng , Ghosh Pritha , Li Jun , Mukherjee Sunandan , Nithin Chandran , Pachulska-Wieczorek Katarzyna , Ponce-Salvatierra Almudena , Popenda Mariusz , Sarzynska Joanna , Wirecki Tomasz , Zhang Dong , Zhang Sicheng , Zok Tomasz , Westhof Eric , Szachniuk Marta , Miao Zhichao , Rybarczyk Agnieszka 
Published: December 2021

AbstractThe outbreak of the COVID-19 pandemic has led to intensive studies of both the structure and replication mechanism of SARS-CoV-2. In spite of some secondary structure experiments being carried out, the 3D structure of the key function regions of the viral RNA has not yet been well understood. At the beginning of COVID-19 breakout, RNA-Puzzles community attempted to envisage the three-dimensional structure of 5′- and 3′-Un-Translated Regions (UTRs) of the SARS-CoV-2 genome. Here, we report the results of this prediction challenge, presenting the methodologies developed by six participating groups and discussing 100 RNA 3D models (60 models of 5′-UTR and 40 of 3′-UTR) predicted through applying both human experts and automated server approaches. We describe the original protocol for the reference-free comparative analysis of RNA 3D structures designed especially for this challenge. We elaborate on the deduced consensus structure and the reliability of the predicted structural motifs. All the computationally simulated models, as well as the development and the testing of computational tools dedicated to 3D structure analysis, are available for further study.
Evaluation of the effects of nicotine on the friction of the articular cartilage and the reversion of the estrogen in vitro
Authors: Li Huiqin , Tang Jiaxin , Zhang Ying , Han Yao 
Published: December 2021

AbstractBackgroundOsteoarthritis is a severe disease for menopausal women, especially for those who exposed in the smoking and second hand-smoking. This study investigated the effect of the nicotine and estrogen on the articular cartilage.MethodsThe articular cartilages were treated by nicotine and estrogen in vitro. Then the frictional properties and morphology on the surface were investigated using atomic force microscope. Proteoglycan 4(PRG4), as the key boundary lubricant of articular cartilage was characterized.ResultsNicotine down-regulates the friction coefficient and secretion of PRG4 significantly and then the estrogen increase them again. The adhesion forces also showed the same trend due to the content of anti-adhesive PRG4.DiscussionThis study demonstrated that the present concentration nicotine has a negative effect on the articular cartilage and the estrogen has a better protecting effect. This may provide a potential guide for OA prevention and treatment.
Identification of CDRH3 Loops in the B Cell Receptor Repertoire that Can Be Engaged by Candidate Immunogens
Authors: Swanson Olivia , Beem Joshua S. Martin , Rhodes Brianna , Wang Avivah , Barr Maggie , Chen Haiyan , Parks Robert , Saunders Kevin O. , Haynes Barton F. , Wiehe Kevin , Azoitei Mihai L. 
Published: December 2021

AbstractA major goal for the development of vaccines against rapidly mutating viruses, such as influenza or HIV, is to elicit antibodies with broad neutralization capacity. However, B cell precursors capable of maturing into broadly neutralizing antibodies (bnAbs) can be rare in the immune repertoire. Due to the stochastic nature of B cell receptor (BCR) rearrangement, a limited number of third heavy chain complementary determining region (CDRH3) sequences are identical between different individuals. Thus, in order to successfully engage broadly neutralizing antibody precursors that rely on their CDRH3 loop for antigen recognition, immunogens must be able to tolerate sequence diversity in the B cell receptor repertoire across an entire vaccinated population. Here, we present a combined experimental and computational approach to identify BCRs in the human repertoire with CDRH3 loops predicted to be engaged by a target immunogen. For a given antibody/antigen pair, deep mutational scanning was first used to measure the effect of CDRH3 loop substitution on binding. BCR sequences, isolated experimentally or generatedin silico, were subsequently evaluated to identify CDRH3 loops expected to be bound by the candidate immunogen. We applied this method to characterize two HIV-1 germline-targeting immunogens and found differences in the frequencies with which they are expected to engage target B cells, thus illustrating how this approach can be used to evaluate candidate immunogens towards B cell precursors engagement and to inform immunogen optimization strategies for more effective vaccine design.
A neuronal prospect theory model in the brain reward circuitry
Authors: Imaizumi Yuri , Tymula Agnieszka , Tsubo Yasuhiro , Matsumoto Masayuki , Yamada Hiroshi 
Published: December 2021

SummaryProspect theory, arguably the most prominent theory of choice, is an obvious candidate for neural valuation models. How the activity of individual neurons, a possible computational unit, reflects prospect theory remains unknown. Here, we show with theoretical accuracy equivalent to that of human neuroimaging studies that single-neuron activity in four core reward-related cortical and subcortical regions represents the subjective valuation of risky gambles in monkeys. The activity of individual neurons in monkeys passively viewing a lottery reflects the desirability of probabilistic rewards, parameterized as a multiplicative combination of a utility and probability weighting functions in the prospect theory framework. The diverse patterns of valuation signals were not localized but distributed throughout most parts of the reward circuitry. A network model aggregating these signals reliably reconstructed risk preferences and subjective probability perceptions revealed by the animals’ choices. Thus, distributed neural coding explains the computation of subjective valuations under risk.
Depletion of ALMS1 affects TGF-β signalling pathway and downstream processes such as cell migration and adhesion capacity
Authors: Bea-Mascato Brais , Neira-Goyanes Elena , Iglesias-Rodríguez Antía , Valverde Diana 
Published: December 2021

ABSTRACTBackgroundALMS1 is a ubiquitous gene associated with Alström syndrome (ALMS). The main symptoms of ALMS affect multiple organs and tissues, generating at last, multi-organic fibrosis in the lungs, kidneys and liver. TGF-β is one of the main pathways implicated in fibrosis, controlling the cell cycle, apoptosis, cell migration, cell adhesion and epithelial-mesenchymal transition (EMT). Nevertheless, the role of ALMS1 gene in fibrosis generation and other implicated processes such as cell migration or cell adhesion via the TGF-β pathway has not been elucidated yet.MethodsInitially, we evaluated how depletion of ALMS1 affects different processes like apoptosis, cell cycle and mitochondrial activity in HeLa cells. Then, we performed proteomic profiling with TGF-β stimuli in HeLa ALMS1 −/− cells and validated the results by examining different EMT biomarkers using qPCR. The expression of these EMT biomarkers were also studied in hTERT-BJ-5ta ALMS1 −/−. Finally, we also evaluated the SMAD3 and SMAD2 phosphorylation and cell migration capacity in both models.ResultsDepletion of ALMS1 generated apoptosis resistance to thapsigargin (THAP) and C2-Ceramide (C2-C), and G2/M cell cycle arrest in HeLa cells. For mitochondrial activity, results did not show significant differences between ALMS1 +/+ and ALMS1 −/−. Proteomic results showed inhibition of downstream pathways regulated by TGF-β. The protein-coding genes (PCG) were associated with processes like focal adhesion or cell-substrate adherens junction in HeLa. SNAI1 showed an opposite pattern to what would be expected when activating the EMT in HeLa and BJ-5ta. Finally, in BJ-5ta model a reduced activation of SMAD3 but not SMAD2 were also observed. In HeLa models no alterations in the canonical TGF-β pathway were observed but both cell lines showed a reduction in migration capacity.ConclusionALMS1 has a role in controlling the cell cycle and the apoptosis processes. Moreover, the depletion of ALMS1 affects the signal transduction through the TGF-β and other processes like the cell migration and adhesion capacity.
A widespread family of WYL-domain transcriptional regulators co-localises with diverse phage defence systems and islands
Authors: Picton David M. , Harling-Lee Joshua D. , Duffner Samuel J. , Went Sam C. , Morgan Richard D. , Hinton Jay C. D. , Blower Tim R. 
Published: December 2021

AbstractBacteria are under constant assault by bacteriophages and other mobile genetic elements. As a result, bacteria have evolved a multitude of systems that protect from attack. Genes encoding bacterial defence mechanisms can be clustered into “defence islands”, providing a potentially synergistic level of protection against a wider range of assailants. However, there is a comparative paucity of information on how expression of these defence systems is controlled. Here, we functionally characterise a transcriptional regulator, BrxR, encoded within a recently described phage defence island from a multidrug resistant plasmid of the emerging pathogen Escherichia fergusonii. Using a combination of reporters and electrophoretic mobility shift assays, we discovered that BrxR acts as a repressor. We present the structure of BrxR to 2.15 Å, the first structure of this family of transcription factors, and pinpoint a likely binding site for ligands within the WYL-domain. Bioinformatic analyses demonstrated that BrxR homologues are widespread amongst bacteria. About half (48%) of identified BrxR homologues were co-localised with a diverse array of known phage defence systems, either alone or clustered into defence islands. BrxR is a novel regulator that reveals a common mechanism for controlling the expression of the bacterial phage defence arsenal.
Unconstrained coevolution of bacterial size and the latent period of plastic phage
Authors: Bonachela Juan A. , Choua Melinda , Heath Michael R. 
Published: December 2021

AbstractViruses play critical roles in the dynamics of microbial communities. Lytic viruses, for example, kill significant proportions of autotrophic and heterotrophic microbes. The dynamic interplay between viruses and microbes results from an overlap of physiological, ecological, and evolutionary responses: environmental changes trigger host physiological changes, affecting the ecological interactions of host and virus and, ultimately, the evolutionary pressures influencing the two populations. Recent theoretical work studied how the dependence of viral traits on host physiology (viral plasticity) affects the evolutionarily stable host cell size and viral infection time emerging from coevolution. Here, we broaden the scope of the framework to consider any coevolutionary outcome, including potential evolutionary collapses of the system. We used the case study of Escherichia coli and T-like viruses under chemo-stat conditions, but the framework can be adapted to any microbe-virus system. Oligotrophic conditions led to smaller, lower-quality but more abundant hosts, and infections that were longer but produced a reduced viral offspring. Conversely, eutrophic conditions resulted in fewer but larger higher-quality hosts, and shorter but more productive infections. The virus influenced host evolution decreasing host radius more noticeably for low than for high dilution rates, and for high than for low nutrient input concentration. For low dilution rates, the emergent infection time minimized host need/use, but higher dilution led to an opportunistic strategy that shortened the duration of infections. System collapses driven by evolution resulted from host failure to adapt quickly enough to the evolving virus. Our results contribute to understanding the eco-evolutionary dynamics of microbes and virus, and to improving the predictability of current models for host-virus interactions. The large quantitative and qualitative differences observed with respect to a classic description (in which viral traits are assumed to be constant) highlights the importance of including viral plasticity in theories describing short- and long-term host-virus dynamics.
Free lunch or vital support? Export promotion in The Netherlands
Authors: van den Berg Marcel 
Published: December 2021

Purpose
The purpose of this paper is to add to the debate concerning the merits of export promotion efforts by governments by investigating the effect of export promotion program (EPP) participation on the export performance of Dutch small and medium-sized enterprises (SMEs).

Design/methodology/approach
The authors confront participation data of an EPP targeting SMEs with rich firm-level data and use propensity score matching techniques combined with regression analysis.

Findings
The authors show that exports generated by participants do generally rise in the years after program entry, however, export growth does not outpace that of comparable, but unsupported firms. Nonetheless, there is some evidence suggesting that export shares in sales rise faster among program entrants, particularly in the first and second years after participation. Furthermore, the authors present evidence suggesting that the probability of becoming a permanent exporter is higher for participants relative to beginning exporters that did not receive support from the program.

Originality/value
The analysis contributes to the still relatively small literature dealing with the impact of government export promotion instruments on export performance using firm-level micro-data. The subject of analysis are Dutch small businesses. SMEs, particularly operating in advanced economies, are a group that is not frequently considered separately in this respect.