bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spatial summation of pain increases logarithmically
Authors: Adamczyk Wacław M. , Manthey Linn , Domeier Christin , Szikszay Tibor M. , Luedtke Kerstin 
Published: July 2020

ABSTRACTPain intensity is difficult to predict. Mostly, because of modulatory processes underlying its formation. For example, when nociceptive stimulation occupies a larger body area, pain increases disproportionally. This modulation is called spatial summation of pain (SSp) and is responsible for coding pain intensity. To predict pain based on spatial variables, a profound understanding of the SSp effect is crucial. The aim of this study was i) to describe the SSp effect as a function of the size (or distance) of a stimulated area(s), ii) to investigate the effect of pain intensity on SSp and iii) to evaluate the influence of the SS type on the magnitude of SSp. Thirty-one healthy participants took part in a within-subject experiment. Participants were exposed to area- and distanced based SSp. In the former, electrocutaneous noxious stimuli were applied by up to 5 electrodes (5 areas) forming a line-like pattern at the ulnar side of the hand, while in the latter the same position and lengths of stimuli were used but only two electrodes were stimulated (5 separations). Each paradigm was repeated using pain of low, moderate and high intensity in a random and counterbalanced order. Each stimulus was assessed on a 0-100 scale. It was found that the pattern of increase in pain followed a logarithmic rather than a linear function. The dynamics of the pain increase were statistically different across pain intensities, with more summation occurring, if stimuli were calibrated to eliciting “high” pain. SSp was resistant to saturation in the area-based but not in the distance- based SSp, where 0.8cm separation between two electrodes produced a similar pain intensity as 1.6cm and 2.4cm. Results indicate that area-based SSp is more painful than distance-based SSp when low and moderate but not when high pain intensity is induced. Presented findings have important implications for all studies, in which the spatial dimension of pain is measured. When the area or separation between nociceptive stimulation increases, pain does not increase linearly. Furthermore, the pattern of the pain increase depends on i) intensity and ii) the number of sites of nociception. In conclusion, a logarithmic function should be considered when predicting the size of a nociceptive source. This pattern is indicative for inhibitory processes underlying SSp.
Transcriptomic and morphological response of SIM-A9 mouse microglia to carbon nanotube neuro-sensors
Authors: Yang Darwin , Yang Sarah J. , Del Bonis-O’Donnell Jackson Travis , Pinals Rebecca L. , Landry Markita P. 
Published: July 2020

AbstractSingle-walled carbon nanotubes (SWCNT) are used in neuroscience for deep-brain imaging, neuron activity recording, measuring brain morphology, and imaging neuromodulation. However, the extent to which SWCNT-based probes impact brain tissue is not well understood. Here, we study the impact of (GT)6-SWCNT dopamine nanosensors on SIM-A9 mouse microglial cells and show SWCNT-induced morphological and transcriptomic changes in these brain immune cells. Next, we introduce a strategy to passivate (GT)6-SWCNT nanosensors with PEGylated phospholipids to improve both biocompatibility and dopamine imaging quality. We apply these passivated dopamine nanosensors to image electrically stimulated striatal dopamine release in acute mouse brain slices, and show that slices labeled with passivated nanosensor exhibit higher fluorescence response to dopamine and measure more putative dopamine release sites. Hence, this facile modification to SWCNT-based dopamine probes provides immediate improvements to both biocompatibility and dopamine imaging functionality with an approach that is readily translatable to other SWCNT-based neurotechnologies.
Theory-guided development of fertility care implementation strategies for adolescents and young adult cancer survivors
Authors: Dornish Anna , Yang Emily M. , Gruspe Jamie , Roesch Erin R. , Aristizabal Paula , Aarons Greg A. , Romero Sally A.D. , Takemoto Michelle B. , Kaiser Bonnie N. , Su H. Irene 
Published: July 2020

AbstractBackgroundOncofertility care remains under-implemented across oncology and fertility care settings, with limited tools to scale up effective implementation strategies. Guided by the Consolidated Framework for Implementation Research (CFIR), we aimed to systematically assess factors that influence implementation of oncofertility care and map strategies, particularly electronic health record (EHR)-enabled ones, that fit adult and pediatric oncology care contexts.MethodsUsing purposeful sampling, we recruited healthcare providers and female adolescent and young adult (AYA) cancer survivors from a comprehensive cancer center and a freestanding children’s hospital. Participants underwent semi-structured interviews and focus groups. Using thematic analysis combining inductive codes with CFIR-based deductive codes, we characterized barriers and facilitators to oncofertility care and implementation strategies. Two coders independently coded each transcript, with a third coder resolving discrepancies by consensus.ResultsWe recruited 19 oncology and fertility providers and 9 AYA survivors. We identified barriers and facilitators to fertility care in the CFIR domains of individual, inner setting, outer setting, and process, allowing us to conceptualize oncofertility care in three necessary stages: screening, referral, and fertility preservation counseling. To fit an adult and a children’s context, five implementation strategies were mapped: needs screen using a best practice advisory, referral order, telehealth fertility counseling, provider audit and feedback, and a provider educational session. All but provider education are facilitated by the EHR system.ConclusionsAn implementation science approach enabled systematic assessment of oncofertility care and co-design of implementation strategies with stakeholders, providing a theory-based approach and scalable EHR tools to support wider dissemination.
High affinity binding of SARS-CoV-2 spike protein enhances ACE2 carboxypeptidase activity
Authors: Lu Jinghua , Sun Peter D. 
Published: July 2020

AbstractA novel coronavirus (SARS-CoV-2) has emerged to a global pandemic and caused significant damages to public health. Human angiotensin-converting enzyme 2(ACE2) was identified as the entry receptor for SARS-CoV-2. As a carboxypeptidase, ACE2 cleaves many biological substrates besides Ang II to control vasodilatation and permeability. Given the nanomolar high affinity between ACE2 and SARS-CoV-2 spike protein, we wonder how this interaction would affect the enzymatic activity of ACE2. Surprisingly, SARS-CoV-2 trimeric spike protein increased ACE2 proteolytic activity ~3-10 fold when fluorogenic caspase-1 substrate and Bradykinin-analog peptides were used to characterize ACE2 activity. In addition, the enhancement was mediated by ACE2 binding of RBD domain of SARS-CoV-2 spike. These results highlighted the altered activity of ACE2 during SARS-CoV-2 infection and would shed new lights on the pathogenesis of COVID-19 and its complications for better treatments.
The UPRmtPreserves Mitochondrial Import to Extend Lifespan
Authors: Xin Nan , Durieux Jenni , Yang Chunxia , Wolff Suzanne , Kim Hyun-Eui , Dillin Andrew 
Published: July 2020

SummaryThe mitochondrial unfolded protein response (UPRmt) is dedicated to promote mitochondrial proteostasis and is linked to extreme longevity in worms, flies, and mice. The key regulator of this process is the transcription factor, ATFS-1. In the absence of mitochondrial stress, ATFS-1 is transported to the mitochondria and degraded. During conditions of mitochondrial stress, ATFS-1 is excluded from the mitochondria and enters the nucleus to regulate the expression of UPRmtgenes. However, there exists a dichotomy in regards to induction of the UPRmtand mitochondrial import. The repair proteins synthesized as a direct result of UPRmtactivation must be transported into damaged mitochondria that had previously excluded ATFS-1 due to reduced import efficiency. To address this conundrum, we analyzed the role of the import machinery under conditions where the UPRmtwas induced. Usingin vitrobiochemical assays of mitochondrial import andin vivoanalysis of mitochondrial proteins, we surprisingly find that the efficiency of mitochondrial import increases when the UPRmtis activated in an ATFS-1 dependent manner, even though membrane potential is reduced. The import machinery is upregulated at the transcription and translation level, and intact import machinery is essential for UPRmt-mediated increase and lifespan extension. With age, import capacity decreases, and activation of the UPRmtdelays this decline and increases longevity. Finally, we find that ATFS-1 has a significantly weaker mitochondrial targeting sequence (MTS), allowing for dynamic subcellular localization during the initial stages of UPRmtactivation.
A simple and highly efficient method for multi-allelic CRISPR-Cas9 editing in primary cell cultures
Authors: Hoellerbauer Pia , Kufeld Megan , Arora Sonali , Wu Hua-Jun , Feldman Heather M. , Paddison Patrick J. 
Published: July 2020

ABSTRACTBackgroundCRISPR-Cas9-based technologies have revolutionized experimental manipulation of mammalian genomes. None-the-less, limitations of the delivery and efficacy of these technologies restrict their application in primary cells.AimsTo create an optimized protocol for penetrant, reproducible, and fast targeted insertiondeletion mutation (indel) formation in cell cultures derived from primary cells, using patient-derived glioblastoma (GBM) stem-like cells (GSCs) and human neural stem/progenitor cells (NSCs) for proof-of-concept experiments.MethodsWe employed transient nucleofection of Cas9:sgRNA ribonucleoprotein complexes using chemically synthesized 2’-O-methyl 3’phosphorothioate-modified sgRNAs and purified Cas9 protein. Indel frequency and size distribution were measured via computational deconvolution of Sanger sequencing trace data. Western blotting was used to evaluate protein loss. RNA-seq in edited NSCs was used to assess gene expression changes resulting from knockout of tumor suppressors commonly altered in GBM.ResultsWe found that with this optimized technique, we can routinely achieve >90% indel formation in only 3 days, without the need to create clonal lines for simple loss-of-function experiments. We observed near-total protein loss of target genes in cell pools. Additionally, we found that this approach allows for the creation of targeted genomic deletions. We also demonstrated the utility of this method for quickly creating a series of gene knockouts that allow for the study of oncogenic activities.ConclusionOur data suggest that this relatively simple method can be used for highly efficient and fast gene knockout, as well as for targeted genomic deletions, even in hyperdiploid cells (such as GSCs). This represents an extremely useful tool for the cancer research community when wishing to inactivate not only coding genes, but also non-coding RNAs, UTRs, enhancers, and promoters. This method can be readily applied to diverse cell types by varying the nucleofection conditions.
Broad phenotypic alterations and potential dysfunctions of lymphocytes in COVID-19 recovered individuals
Authors: Yang Jingyi , Zhong Maohua , Zhang Ejuan , Hong Ke , Yang Qingyu , Zhou Dihan , Xia Jianbo , Chen Yao-Qing , Sun Mingbo , Zhao Bali , Xiang Jie , Liu Ying , Han Yang , Zhou Xi , Huang Chaolin , Shang You , Yan Huimin 
Published: July 2020

SummaryBackgroundLymphopenia is a typical symptom in the COVID-19 patients. While millions of patients are clinical recovered, little is known about the immune status of lymphocytes in these individuals.MethodsA clinical recovered cohort (CR) of 55 COVID-19 individuals (discharged from hospital 4 to 11 weeks), and 55 age and sex matched healthy donors cohort (HD) were recruited. Detailed analysis on phenotype of the lymphocytes in peripheral blood mononuclear cells (PBMCs) was performed by flow cytometry.FindingsCompared with cohort HD, the CD8+T cells in cohort CR had higher Teff and Tem, but lower Tc1 (IFN-γ+), Tc2 (IL-4+) and Tc17 (IL-17A+) frequencies. The CD4+T cells of CR had decreased frequency, especially on the Tcm subset. Moreover, CD4+T cells of CR expressed lower PD-1 and had lower frequencies of Th1 (IFN-γ+), Th2 (IL-4+), Th17 (IL-17A+) as well as circulating Tfh (CXCR5+PD-1+). Accordingly, isotype-switched memory B cell (IgM-CD20hi) in CR had significantly lower proportion in B cells, though level of activation marker CD71 elevated. For CD3-HLA-DRlolymphocytes of CR, besides levels of IFN-γ, Granzyme B and T-bet were lower, the correlation between T-bet and IFN-γ became irrelevant. In addition, taken into account of discharged days, all the lowered function associated phenotypes showed no recovery tendency within whole observation period.InterpretationThe CR COVID-19 individuals still showed remarkable phenotypic alterations in lymphocytes after clinical recovery 4 to 11 weeks. This suggests SARS-CoV-2 infection imprints profoundly on lymphocytes and results in long-lasting potential dysfunctions.FundingKunming Science and Technology Department (2020-1-N-037)
Temporary Immunity and Multiple Waves of COVID-19
Authors: Shayak B , Sharma Mohit M , Misra Anoop 
Published: July 2020

ABSTRACTIn this work we use mathematical modeling to describe the potential phenomena which may occur if immunity to COVID-19 lasts for a finite time instead of being permanent, i.e. if a recovered COVID-19 patient may again become susceptible to the virus after a given time interval following his/her recovery. Whether this really happens or not is unknown at the current time. If it does happen, then we find that for certain combinations of parameter values (social mobility, contact tracing, immunity threshold duration etc), the disease can keep recurring in wave after wave of outbreaks, with a periodicity approximately equal to twice the immunity threshold. Such cyclical attacks can be prevented trivially if public health interventions are strong enough to contain the disease outright. Of greater interest is the finding that should such effective interventions not prove possible, then also the second and subsequent waves can be forestalled by a consciously relaxed intervention level which finishes off the first wave before the immunity threshold is breached. Such an approach leads to higher case counts in the immediate term but significantly lower counts in the long term as well as a drastically shortened overall course of the epidemic.As we write this, there are more than 1,00,00,000 cases (at least, detected cases) and more than 5,00,000 deaths due to COVID-19 all over the globe. The unknowns surrounding this disease outnumber the knowns by orders of magnitude. One of these unknowns is how long does immunity last i.e., once a person recovers from COVID-19 infection, how long does s/he remain insusceptible to a fresh infection. Most modeling studies assume lifetime immunity, or at least sufficiently prolonged immunity as to last until the outbreak is completely over. Among the exceptions are Giordano et. al. [1] and Bjornstad et. al. [2] who account for the possibility of re-infection – while the former find no special behaviour on account of this, the latter find an oscillatory approach towards the eventual equilibrium. In an article which appeared today, Kosinski [3] has found multiple waves of COVID-19 if the immunity threshold is finite. The question of whether COVID-19 re-infection can occur is completely open as of now. A study [4] has found that for benign coronaviruses (NOT the COVID-19 pathogen!), antibodies become significantly weaker six months after the original infection, and re-infection is common from one year onwards. Although it is currently unknown whether COVID-19 re-infections can occur, the mere possibility is sufficiently frightening as to warrant a discussion of what might happen if it is true. In this Article, we use mathematical modeling to present such a discussion. Before starting off, let us declare in the clearest possible terms that this entire Article is a what-if analysis, predicated on an assumption whose veracity is not known at the current time. The contents of this Article are therefore hypothetical – as of now they are neither factual nor counter-factual.
The impact of contact tracing and household bubbles on deconfinement strategies for COVID-19: an individual-based modelling study
Authors: Willem Lander , Abrams Steven , Petrof Oana , Coletti Pietro , Kuylen Elise , Libin Pieter , Møgelmose Signe , Wambua James , Herzog Sereina A. , Faes Christel ,   SIMID COVID19 team, Beutels Philippe , Hens Niel 
Published: July 2020

AbstractBackgroundThe rising COVID-19 pandemic caused many governments to impose policies restricting social interactions. These policies have slowed down the spread of the SARS-CoV-2 virus to the extent that restrictions can be gradually lifted. Models can be useful to assess the consequences of deconfinement strategies with respect to business, school and leisure activities.MethodsWe adapted the individual-based model “STRIDE” to simulate interactions between the 11 million inhabitants of Belgium at the levels of households, workplaces, schools and communities. We calibrated our model to observed hospital incidence and seroprevalence data. STRIDE can explore contact tracing options and account for repetitive leisure contacts in extended household settings (so called “household bubbles”) with varying levels of connectivity.FindingsHousehold bubbles have the potential to reduce the number of COVID-19 hospital admissions by up to 90%. The effectiveness of contact tracing depends on its timing, as it becomes futile more than 4 days after the index case developed symptoms. Assuming that children have a lower level of susceptibility and lower probability to experience symptomatic SARS-CoV-2 infection, (partial) school closure options have relatively little impact on COVID-19 burden.InterpretationNot only the absolute number and intensity of physical contacts drive the transmission dynamics and COVID-19 burden, also their repetitiveness is influential. Contact tracing seems essential for a controlled and persistent release of lockdown measures, but requires timely compliance to testing, reporting and self-isolation. Rapid tracing and testing, and communication ensuring continued involvement of the population are therefore essential.
Corporate governance practices and capital structure decisions: the moderating effect of gender diversity
Authors: A.A Zaid Mohammad , Wang Man , T.F. Abuhijleh Sara , Issa Ayman , W.A. Saleh Mohammed , Ali Farman 
Published: July 2020

PurposeMotivated by the agency theory, this study aims to empirically examine the nexus between board attributes and a firm’s financing decisions of non-financial listed firms in Palestine and how the previous relationship is moderated and shaped by the level of gender diversity.Design/methodology/approachMultiple regression analysis on a panel data was used. Further, we applied three different approaches of static panel data “pooled OLS, fixed effect and random effect.” Fixed-effects estimator was selected as the optimal and most appropriate model. In addition, to control for the potential endogeneity problem and to profoundly analyze the study data, the authors perform the one-step system generalized method of moments (GMM) estimator. Dynamic panel GMM specification was superior in generating robust findings.FindingsThe findings clearly unveil that all explanatory variables in the study model have a significant influence on the firm’s financing decisions. Moreover, the results report that the impact of board size and board independence are more positive under conditions of a high level of gender diversity, whereas the influence of CEO duality on the firm’s leverage level turned from negative to positive. In a nutshell, gender diversity moderates the effect of board structure on a firm’s financing decisions.Research limitations/implicationsThis study was restricted to one institutional context (Palestine); therefore, the results reflect the attributes of the Palestinian business environment. In this vein, it is possible to generate different findings in other countries, particularly in developed markets.Practical implicationsThe findings of this study can draw responsible parties and policymakers’ attention in developing countries to introduce and contextualize new mechanisms that can lead to better monitoring process and help firms in attracting better resources and establishing an optimal capital structure. For instance, entities should mandate a minimum quota for the proportion of women incorporation in boardrooms.Originality/valueThis study provides empirical evidence on the moderating role of gender diversity on the effect of board structure on firm’s financing decisions, something that was predominantly neglected by the earlier studies and has not yet examined by ancestors. Thereby, to protrude nuanced understanding of this novel and unprecedented idea, this study thoroughly bridges this research gap and contributes practically and theoretically to the existing corporate governance–capital structure literature.
Legislative approaches to nondiscrimination at work: a comparative analysis across 13 groups in 193 countries
Authors: Heymann Jody , Bose Bijetri , Waisath Willetta , Raub Amy , McCormack Michael 
Published: July 2020

PurposeThere is substantial evidence of discrimination at work across countries and powerful evidence that antidiscrimination laws can make a difference. This study examines the extent of protections from discrimination at work in countries around the world and which groups were best covered.Design/methodology/approachThis study assesses legal protections in hiring, pay, promotions/demotions, terminations and harassment for 13 different groups across 193 countries using a database the authors created based on analysis of labor codes, antidiscrimination legislation, equal opportunity legislation and penal codes. Differences in levels of protection were examined across social groups and areas of work, as well as by country income level using Chi-square tests.FindingsProtection from gender and racial/ethnic discrimination at work was the most common, and protection across migrant status, foreign national origin, sexual orientation and gender identity was among the least. For all groups, discrimination was more often prohibited in hiring than in promotion/demotion. There was inconsistent protection from harassment and retaliation.Research limitations/implicationsAddressing discrimination at work will require a broad range of synergistic approaches including guaranteeing equal legal rights, implementation and enforcement of laws and norm change. This study highlights where legislative progress has been made and where major gaps remain.Originality/valueThis article presents findings from an original database containing the first data on laws to prevent discrimination in the workplace in all 193 countries around the world. The study analyzes legal protections for a wide range of groups and considers a full range of workplace protections.