bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Nimbolide-Based Kinase Degrader Preferentially Degrades Oncogenic BCR-ABL
Authors: Tong Bingqi , Spradlin Jessica N. , Novaes Luiz F.T. , Zhang Erika , Hu Xirui , Moeller Malte , Brittain Scott M. , McGregor Lynn M. , McKenna Jeffrey M. , Tallarico John A. , Schirle Markus , Maimone Thomas J. , Nomura Daniel K. 
Published: April 2020

AbstractTargeted protein degradation (TPD) and proteolysis-targeting chimeras (PROTACs) have arisen as powerful therapeutic modalities for degrading specific protein targets in a proteasome-dependent manner. However, a major limitation to broader TPD applications is the lack of E3 ligase recruiters. Recently, we discovered the natural product nimbolide as a covalent ligand for the E3 ligase RNF114. When linked to the BET family inhibitor JQ1, the resulting heterobifunctional PROTAC molecule was capable of selectively degrading BRD4 in cancer cells. Here, we show the broader utility of nimbolide as an E3 ligase recruiter for TPD applications. We demonstrate that a PROTAC linking nimbolide to the kinase and BCR-ABL fusion oncogene inhibitor dasatinib, BT1, selectively degrades BCR-ABL over c-ABL in leukemia cancer cells, compared to previously reported cereblon or VHL-recruiting BCR-ABL degraders that show opposite selectivity or in some cases inactivity. Further contrasting from cereblon or VHL-recruiting degradation, we show that BT1 treatment not only leads to BCR-ABL degradation, but also stabilizes the endogenous RNF114 substrate and tumor suppressor substrate p21. This leads to additional anti-proliferative effects in leukemia cancer cells beyond those observed with cereblon or VHL-recruiting BCR-ABL PROTACs. Thus, we further establish nimbolide as an additional general E3 ligase recruiter for PROTACs with unique additional benefits for oncology applications. We also further demonstrate the importance of expanding upon the arsenal of E3 ligase recruiters, as such molecules confer differing and unpredictable selectivity for the degradation of neo-substrate proteins.
Phase alignment of low-frequency neural activity to the amplitude envelope of speech reflects evoked responses to acoustic edges, not oscillatory entrainment
Authors: Oganian Yulia , Kojima Katsuaki , Breska Assaf , Cai Chang , Findlay Anne , Chang Edward , Nagarajan Srikantan 
Published: April 2020

AbstractThe amplitude envelope of speech is crucial for accurate comprehension. Considered a key stage in speech processing, the phase of neural activity in the theta-delta bands (1 - 10 Hz) tracks the phase of the speech amplitude envelope during listening. However, the mechanisms underlying this envelope representation have been heavily debated. A dominant model posits that envelope tracking reflects entrainment of endogenous low-frequency oscillations to the speech envelope. Alternatively, envelope tracking reflects a series of evoked responses to acoustic landmarks within the envelope. It has proven challenging to distinguish these two mechanisms. To address this, we recorded magnetoencephalography while participants listened to natural speech, and compared the neural phase patterns to the predictions of two computational models: An oscillatory entrainment model and a model of evoked responses to peaks in the rate of envelope change. Critically, we also presented speech at slowed rates, where the spectrotemporal predictions of the two models diverge. Our analyses revealed transient theta phase-locking in regular speech, as predicted by both models. However, for slow speech we found transient theta and delta phase-locking, a pattern that was fully compatible with the evoked response model but could not be explained by the oscillatory entrainment model. Furthermore, encoding of acoustic edge magnitudes was invariant to contextual speech rate, demonstrating speech rate normalization of acoustic edge representations. Taken together, our results suggest that neural phase locking to the speech envelope is more likely to reflect discrete representation of transient information rather than oscillatory entrainment.
Transcriptomic entropy benchmarks stem cell-derived cardiomyocyte maturation against endogenous tissue at single cell level
Authors: Kannan Suraj , Farid Michael , Lin Brian L. , Miyamoto Matthew , Kwon Chulan 
Published: April 2020

The immaturity of pluripotent stem cell (PSC)-derived tissues has emerged as a universal problem for their biomedical applications. While efforts have been made to generate adult-like cells from PSCs, direct benchmarking of PSC-derived tissues againstin vivodevelopment has not been established. Thus, maturation status is often assessed on anad-hocbasis. Single cell RNA-sequencing (scRNA-seq) offers a promising solution, though cross-study comparison is limited by dataset-specific batch effects. Here, we developed a novel approach to quantify PSC-derived cardiomyocyte (CM) maturation through transcriptomic entropy. Transcriptomic entropy is robust across datasets regardless of differences in isolation protocols, library preparation, and other potential batch effects. With this new model, we analyzed over 45 scRNA-seq datasets and over 52,000 CMs, and established a cross-study, cross-species CM maturation reference. This reference enabled us to directly compare PSC-CMs with thein vivodevelopmental trajectory and thereby to quantify PSC-CM maturation status. We further found that our entropy-based approach can be used for other cell types, including pancreatic beta cells and hepatocytes. Our study presents a biologically relevant and interpretable metric for quantifying PSC-derived tissue maturation, and is extensible to numerous tissue engineering contexts.Significance StatementThere is significant interest in generating mature cardiomyocytes from pluripotent stem cells. However, there are currently few effective metrics to quantify the maturation status of a single cardiomyocyte. We developed a new metric for measuring cardiomyocyte maturation using single cell RNA-sequencing data. This metric, called entropy score, uses the gene distribution to estimate maturation at the single cell level. Entropy score enables comparing pluripotent stem cell-derived cardiomyocytes directly against endogenously-isolated cardiomyocytes. Thus, entropy score can better assist in development of approaches to improve the maturation of pluripotent stem cell-derived cardiomyocytes.
A Critical Role of Hepatic GABA in The Metabolic Dysfunction and Hyperphagia of Obesity
Authors: Geisler Caroline. E. , Ghimire Susma. , Bruggink Stephanie. M. , Miller Kendra E. , Weninger Savanna. N. , Kronenfeld Jason. M. , Yoshino Jun. , Klein Samuel. , Duca Frank. A. , Renquist Benjamin. J. 
Published: April 2020

AbstractHepatic lipid accumulation is a hallmark of type II diabetes (T2D) and associated with hyperinsulinemia, insulin resistance, and hyperphagia. Hepatic synthesis of GABA, catalyzed by GABA-transaminase (GABA-T), is upregulated in obese mice. To assess the role of hepatic GABA production in obesity-induced metabolic and energy dysregulation, we treated mice with two pharmacologic GABA-T inhibitors and knocked down hepatic GABA-T expression using an antisense oligonucleotide. Hepatic GABA-T inhibition and knockdown decreased basal hyperinsulinemia and hyperglycemia, and improved glucose intolerance. GABA-T knockdown improved insulin sensitivity assessed by hyperinsulinemic-euglycemic clamps in obese mice. Hepatic GABA-T knockdown also decreased food intake and induced weight loss without altering energy expenditure in obese mice. Data from people with obesity support the notion that hepatic GABA production and transport are associated with serum insulin, HOMA-IR, T2D, and BMI. These results support a key role for hepatocyte GABA production in the dysfunctional glucoregulation and feeding behavior associated with obesity.
Gene-level, but not chromosome-wide, divergence between a very young house fly proto-Y chromosome and its homologous proto-X chromosome
Authors: Hak Son Jae , Meisel Richard P. 
Published: April 2020

AbstractX and Y chromosomes are usually derived from a pair of homologous autosomes, which then diverge from each other over time. Although Y-specific features have been characterized in sex chromosomes of various ages, the earliest stages of Y chromosome evolution remain elusive. In particular, we do not know whether early stages of Y chromosome evolution consist of changes to individual genes or happen via chromosome-scale divergence from the X. To address this question, we quantified divergence between young proto-X and proto-Y chromosomes in the house fly,Musca domestica. We compared proto-sex chromosome sequence and gene expression between genotypic (XY) and sex-reversed (XX) males. We find evidence for sequence divergence between genes on the proto-X and proto-Y, including five genes with mitochondrial functions. There is also an excess of genes with divergent expression between the proto-X and proto-Y, but the number of genes is small. This suggests that individual proto-Y genes, but not the entire proto-Y chromosome, have diverged from the proto-X. We identified one gene, encoding an axonemal dynein assembly factor (which functions in sperm motility), that has higher expression in XY males than XX males because of a disproportionate contribution of the proto-Y allele to gene expression. The up-regulation of the proto-Y allele may be favored in males because of this gene’s function in spermatogenesis. The evolutionary divergence between proto-X and proto-Y copies of this gene, as well as the mitochondrial genes, is consistent with selection in males affecting the evolution of individual genes during early Y chromosome evolution.
The Neuroanatomy of Speech Processing: A Large-Scale Lesion Study
Authors: Rogalsky Corianne , Basilakos Alexandra , Rorden Chris , Pillay Sara , LaCroix Arianna N. , Keator Lynsey , Mickelsen Soren , Anderson Steven W. , Love Tracy , Fridriksson Julius , Binder Jeffrey , Hickok Gregory 
Published: April 2020

AbstractThe neural basis of language has been studied for centuries, yet the networks critically involved in simply identifying or understanding a spoken word remain elusive. Several functional-anatomical models of critical neural substrates of receptive speech have been proposed, including (1) auditory-related regions in the leftmid-posteriorsuperior temporal lobe, (2)motor-related regions in the left frontal lobe (in normal and/or noisy conditions), the leftanteriorsuperior temporal lobe, or (4)bilateralmid-posterior superior temporal areas. One difficulty in comparing these models is that they often focus on different aspects of the sound-to-meaning pathway and are supported by different types of stimuli and tasks. Two auditory tasks that are typically used in separate studies—syllable discrimination and word comprehension—often yield different conclusions. We assessed syllable discrimination (words and nonwords) and word comprehension (clear speech and with a noise masker) in 158 individuals with focal brain damage: left (n=113) or right (n=19) hemisphere stroke, left (n=18) or right (n=8) anterior temporal lobectomy, and 26 neurologically-intact controls. Discrimination and comprehension tasks are doubly dissociable both behaviorally and neurologically. In support of a bilateral model, clear speech comprehension was near ceiling in 95% of left stroke cases and right temporal damage impaired syllable discrimination. Lesion-symptom mapping analyses for the syllable discrimination and noisy word comprehension tasks each implicated most of the left superior temporal gyrus (STG). Comprehension but not discrimination tasks also implicated the left pMTG, while discrimination but not comprehension tasks also implicated more dorsal sensorimotor regions in posterior perisylvian cortex.
The QT Interval in Patients with SARS-CoV-2 Infection Treated with Hydroxychloroquine/Azithromycin
Authors: Chorin Ehud , Dai Matthew , Shulman Eric , Wadhwani Lalit , Roi-Bar-Cohen  , Barbhaiya Chirag , Aizer Anthony , Holmes Douglas , Bernstein Scott , Spinelli Michael , Park David S. , Chinitz Larry A. , Jankelson Lior 
Published: April 2020

AbstractWe report the change in the QT interval in 84 adult patients with SARS-CoV-2 infection treated with Hydroxychloroquine/Azithromycin combination. QTc prolonged maximally from baseline between days 3 and 4. in 30% of patients QTc increased by greater than 40ms. In 11% of patients QTc increased to >500 ms, representing high risk group for arrhythmia. The development of acute renal failure but not baseline QTc was a strong predictor of extreme QTc prolongation.
Efficient genome editing in multiple salmonid cell lines using ribonucleoprotein complexes
Authors: Gratacap Remi L. , Jin Ye Hwa , Mantsopoulou Marina , Houston Ross D. 
Published: April 2020

AbstractInfectious and parasitic diseases have major negative economic and animal welfare impacts on aquaculture of salmonid species. Improved knowledge of the functional basis of host response and genetic resistance to these diseases is key to developing preventative and treatment options. Cell lines provide a valuable model to study infectious diseases in salmonids, and genome editing using CRISPR provides an exciting avenue to evaluate the function of specific genes in those systems. While CRISPR/Cas9 has been successfully performed in a Chinook salmon cell line (CHSE-214), there are no reports to date of editing of cell lines derived from the most commercially relevant salmonid species Atlantic salmon and rainbow trout, which are difficult to transduce and therefore edit using lentivirus-mediated methods. In the current study, a method of genome editing of salmonid cell lines using ribonucleoprotein (RNP) complexes was optimised and tested in the most commonly-used salmonid fish cell lines; Atlantic salmon (SHK-1 and ASK cell lines), rainbow trout (RTG-2) and Chinook salmon (CHSE-214). Electroporation of RNP based on either Cas9 or Cas12a was efficient at targeted editing of all the tested lines (typically > 90 % cells edited), and the choice of enzyme expands the number of potential target sites for editing within the genomes of these species. These optimised protocols will facilitate functional genetic studies in salmonid cell lines, which are widely used as model systems for infectious diseases in aquaculture.
Host-parasite dynamics set the ecological theatre for the evolution of state- and context-dependent dispersal in hosts
Authors: Deshpande Jhelam N. , Kaltz Oliver , Fronhofer Emanuel A. 
Published: April 2020

AbstractWhile host-parasite interactions are ubiquitous, the large scale consequences of parasite infections are mainly driven by the spatial context. One trait of pivotal importance for the eco-evolutionary dynamics of such metapopulations is the spatial behaviour of hosts, that is, their dispersal. It is well established that dispersal is not a random process, rather dispersal is informed and may depend on internal and external factors. In host-parasite metapopulations, dispersal may be a function of a host’s infection state, but also of the local context, such as host density or parasite prevalence. Using a dynamical host-parasite metapopulation model, we explore whether host dispersal evolves to be state- and context-dependent and what shapes the evolutionarily stable dispersal reaction norms have. We show that state-dependent dispersal readily evolves in the sense that hosts disperse more when infected. This dispersal bias evolves due to kin selection which is consistent with previous studies. Most importantly, we show that prevalence-dependent dispersal evolves, especially when virulence is high and epidemiological dynamics have predictable signatures. The observed evolutionary outcome, a negatively prevalence-dependent dispersal reaction norm for susceptible hosts, seems counter-intuitive at first. However, our results can be readily explained by the emergent epidemiological dynamics, especially their spatial and temporal correlation patterns. Finally, we show that context-dependency in dispersal may rely on both, prevalence, but also host density cues. Our work provides new insights into the evolution of complex dispersal phenotypes in host-parasite metapopulations as well as on associated feedbacks between ecological dynamics and evolutionary change.
The influence of timing, location and social setting on hedonic and emotional evaluations of past eating experiences
Authors: Nath Elizabeth Cassandra , Cannon Peter Robert , Philipp Michael Carl 
Published: April 2020

PurposeOur hedonic and emotional evaluations of the foods we encounter in daily life are predictive of whether we will choose to consume these foods in the future. Given the context-dependent nature of these evaluations and the rise in studies set in naturalistic and ecologically valid consumption settings, it is crucial that we examine the impact of contextual variables on our current consumer emotion measurement methods.Design/methodology/approachThree important factors that influence meal-evoked emotion – meal time, location and social setting – were explored via online survey of 866 English-speaking adults from all over the world. Respondents were asked to recall three meals they had consumed in the past week and report on their subjective liking and emotional associations. Subjective liking was measured with a labelled affective magnitude scale and emotion was measured using EsSense25.FindingsDinner meals, meals eaten at the home of a family member or friend, and meals eaten with one's spouse or partner were rated highest in subjective liking. Meals eaten at work or alone were associated with the lowest intensities of positive emotion.Originality/valueThe majority of investigations into meal context and emotion have measured consumers' emotional associations in the moment and in the laboratory. The present study characterises the influence of contextual variables on the emotional associations of past eating experiences in naturalistic settings.
Business development through knowledge sharing among members of sectoral committees
Authors: Aljuwaiber Abobakr 
Published: April 2020

PurposeThis paper is an empirical study examining how sectoral committees function as knowledge networks within CCIs in Saudi Arabia. It employs the Madinah Chambers of Commerce and Industry (MCCI) branch as a case study. The research examines the influence of individual factors (taking pleasure in helping others, knowledge of self-efficacy, and outcome expectations), and organisational factors (top management support and knowledge sharing culture) on knowledge sharing, to establish whether knowledge sharing assists in the business development of the members of sectoral committees.Design/methodology/approachThe research uses a quantitative methodology to investigate how knowledge sharing between sectoral committee members can assist in the development of their businesses and industries.FindingsThis research provides valuable information regarding the role of knowledge sharing among sectoral committee members and addresses the challenges facing business owners in sectoral committees. Precisely, the results of the survey showed that knowledge sharing in the CCI was considered crucial.Research limitations/implicationsThe research model was confined to the MCCI and using Saudi Arabia as a context of study, which has a unique organisational culture that influenced the participants' perceptions regarding knowledge sharing, and therefore cannot be generalised to other organisations. Further investigation of knowledge sharing using samples from other countries would give a more robust examination of the studied hypotheses.Practical implicationsThe results provided in this research indicated that the activity of knowledge sharing impacts members' business development. This suggests that enhancing knowledge sharing among members of sectoral committees would support the creation of new ideas that were beneficial to improving their business and investments.Originality/valueTo the best of the author's knowledge, this study is the first to investigate the role of knowledge sharing in business development among sectoral committees, particularly within Saudi Arabian CCIs, and is thus able to offer new insight into existing knowledge sharing in sectoral committees in non-Western contexts.
Market reactions to CSR news in different industries
Authors: Pérez Andrea , García de los Salmones María del Mar , López-Gutiérrez Carlos 
Published: April 2020

PurposeBased on the premises of the institutional theory, in this paper, we explore the effects that the media coverage of positive and negative Corporate Social Responsibility (CSR) news have on the stock market value of companies in diverse industries.Design/methodology/approachUsing a sample of 195 online articles published in the most important Spanish business newspaper, we implement an event study and a regression analysis.FindingsThe findings show that positive and negative CSR news, usually, have significant impacts on the stock market value of companies. Specifically, the market reaction is stronger under the announcement of negative news in all industries (i.e. basic, energy, finance and goods and services), although positive news also cause significant positive stock market reactions in the finance and basic industries.Originality/valueAlthough the media plays an indispensable role in the dialogue around CSR, much of the research focused on the role of the media on the CSR-CFP link does not consider how the industry variable can affect the abnormal stock returns derived from CSR news. This research contributes to this gap in the literature by exploring the differences that exist in the stock market reactions to CSR news based on the industry in which the companies operate.
Women managing women: hierarchical relationships and career impact
Authors: Abalkhail Jouharah M. 
Published: April 2020

PurposeThis paper explores the experiences of women in Saudi Arabia who have been managed by other women, and examines how junior women perceive senior women's role in advancing their career.Design/methodology/approachThe paper is based on qualitative data gathered using in-depth semi-structured interviews undertaken with 30 women working in Saudi public organisations.FindingsThis study's findings shows that the hierarchical relationships between women and their woman manager are complex due to a multifaceted web of contextual factors including sociocultural values, family values, religious beliefs and organisational cultures and structures. These factors shape the quality of relationships between senior women and their women subordinates. Also, this study reveals that there is solidarity and ‘sisterly’ relationship between women in the workplace that plays a role in facilitating women's career development and advancement. In addition, this study shows that despite senior women's having supported other women's career advancement, this support tended to be conditional and limited. This can have an influence on women-to-women work relationships, where such relationships can be described as being disconnected and fragile. Furthermore, the study depict that there is evidence of the existence of ‘Queen Bee’-like senior women who distance themselves from other women and block their career advancement. The Queen Bee phenomena can actually become a form of hierarchy that mimics the patriarchal structure and excludes women from serving at top management levels.Originality/valueThis paper provides an in-depth understanding of the hierarchical relationships between women in the workplace and how these relationships have an influence on women's career advancement. Therefore, the paper makes a valuable contribution to the scarce knowledge that currently exists within the field of management research in relation to women's career development – and the advancement of such research within the Arab Middle Eastern context. Also, the findings of this study could potentially inform practitioners and HR department personnel within organisations about the connections between women's hierarchical workplace relationships and women's career development and advancement.