bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phenotyping of Klf14 mouse white adipose tissue enabled by whole slide segmentation with deep neural networks
Authors: Casero Ramón , Westerberg Henrik , Horner Neil R , Yon Marianne , Aberdeen Alan , Grau Vicente , Cox Roger D , Rittscher Jens , Mallon Ann-Marie 
Published: June 2021

AbstractWhite adipose tissue (WAT) plays a central role in metabolism, with multiple diseases and genetic mutations causing its remodeling. Quantitative analysis of white adipocyte size is of great interest to understand physiology and disease, but previous studies of H&E histology have been limited to a subsample of whole depot cross-sections. In this paper, we present the deep learning pipeline DeepCytometer, that can segment mouse and human whole slides (≃40,000 cells per mouse slide on average) using an adaptive tiling method, correct for cell overlap and reject non-white adipocytes from the segmentation. Using quantile colour maps we show intra- and inter-depot cell size heterogeneity with local correlation; quantile estimates also suggest significant differences in population estimates from 75 whole slides compared to smaller data sets. We propose three linked levels (body weight BW, depot weight DW and cell area quartiles) for exploratory analysis of mouse Klf14 phenotypes in gonadal and subcutaneous depots. We find a rich set of phenotypes when stratifying by sex, depot and three genotype strata: (1) WTs/Hets with a Het father (Controls), (2) WTs with a Het mother, and (3) Hets with a Het mother (functional KOs or FKOs). Namely, at BW level, mean difference testing suggests that female FKOs are similar to Controls, but WTs with a Het mother are significantly larger. At DW and cell levels, linear models with interaction terms and BW or DW covariates, respectively, reveal phenotypes not shown by difference of means tests. For example, at DW level, gonadal and subcutaneous models are similar, and female FKOs have lower fat percentage than Controls due to both an offset and the DW/BW slope in the linear model. Meanwhile, female WTs with a Het mother have on average similar fat percentage to Controls, but as their slopes are close to zero, their DWs are uncorrelated to BW, suggesting that larger female WTs with a Het mother have lower fat percentage than smaller ones. In contrast to depot level, at cell level female gonadal phenotypes diverge from subcutaneous ones. Furthermore, male Controls and FKOs have similar average area values in subcutaneous depots, but area~DW slope flattening in FKOs suggests that larger DWs could be caused by cell size increase in Controls and by cell count increase in FKOs. Thus, DeepCytometer and associated exploratory analysis reveal new insights into adipocyte heterogeneity and phenotyping.
A novel tubulin binding molecule drives differentiation of acute myeloid leukaemia cells
Authors: Jackson Thomas R. , Vuorinen Aini , Josa-Culleré Laia , Madden Katrina S. , Conole Daniel , Cogswell Thomas J. , Wilkinson Isabel V. L. , Kettyle Laura M. , Zhang Douzi , O’Mahony Alison , Gracias Deanne , McCall Lorna , Westwood Robert , Terstappen Georg C. , Davies Stephen G. , Tate Edward W. , Wynne Graham M. , Vyas Paresh , Russell Angela J. , Milne Thomas A. 
Published: June 2021

AbstractAcute Myeloid Leukaemia (AML) continues to have a poor prognosis, especially in the elderly. One reason for this is that many treatment regimens are not well tolerated by elderly patients. Much current focus is on the development of therapies that can target specific vulnerabilities of AML while having fewer toxic side effects. However, despite much recent progress in developing better drugs, many patients with AML still die within a year of diagnosis, partly due to the fact that it is difficult to identify therapeutic targets that are effective across multiple AML subtypes. One common factor across AML subtypes is the presence of a block in differentiation. Thus screening for compounds that can overcome this block in genetically diverse AML models should allow for the identification of agents that are not dependent on a specific mutation for their efficacy. Here, we used a phenotypic screen to identify novel compounds that stimulate differentiation in several AML cell lines. Lead compounds were shown to decrease tumour burden and to increase survivalin vivo. Using multiple complementary target deconvolution approaches, these compounds were revealed to be anti-mitotic tubulin disruptors that cause differentiation by inducing a G2-M mitotic arrest. Together, these results reveal a novel function for tubulin disruptors in causing differentiation of AML cells.
Western Amazon was a center of Neotropical fish dispersal, as evidenced by the continental-wide time-stratified biogeographic analysis of the hyper-diverseHypostomuscatfish
Authors: de Queiroz Luiz Jardim , Meyer Xavier , Cardoso Yamila P. , Bahechar Ilham A. , Covain Raphaël , Parente Thiago E. , Torrente-Vilara Gislene , Buckup Paulo A. , Montoya-Burgos Juan I. 
Published: June 2021

AbstractThe Amazon is probably the most diverse realm on Earth, and is considered to be the primary source of diversity and a center of dispersal for Neotropical terrestrial organisms. Yet, the assumption that the Amazon basin is a primordial place of fish species origination and dispersal into other drainages still need to be tested. We addressed this issue by inferring a time-stratified biogeographic history and reconstructing the ancestral habitat preference ofHypostomus, a continentally widespread and species-rich Neotropical genus. We found thatHypostomusemerged in the Western Amazon (∼14.7 Ma), when the Western Amazon River was flowing northwards and disconnected from the Eastern Amazon. We show that dispersal events in the first half ofHypostomusevolution occurred from the Western Amazon into adjacent basins, initiating its Neotropical radiation. The ancestral preferred habitat consisted in small rivers with running waters, a predominant habitat in river headwaters. Because of strong niche conservatism in the early evolution ofHypostomus, we suggest that most of the out-of-Western-Amazon dispersal occurred via headwater captures. The radiation ofHypostomuswas further promoted by major reconfigurations of river basins, which opened dispersal opportunities into new drainages. Diversification in habitat preference coincided with colonization of basins already occupied by congenerics, indicative of niche shifts triggered by inter-specific competition and species coexistence. By analyzing the evolutionary history ofHypostomus, we show that Western Amazon was the main center of fish dispersal in the Neotropical Region from Middle Miocene to the present, supporting the cradle hypothesis of fish origination and dispersal.
SmMIP-tools: a computational toolset for processing and analysis of single-molecule molecular inversion probes derived data
Authors: Medeiros Jessie J. F. , Capo-Chichi Jose-Mario , Shlush Liran I. , Dick John E. , Arruda Andrea , Minden Mark D. , Abelson Sagi 
Published: June 2021

AbstractSingle-molecule molecular inversion probes (smMIPs) provides a modular and cost-effective platform for high-multiplex targeted next-generation sequencing (NGS). Nevertheless, translating the raw smMIP-derived sequencing data into accurate and meaningful information currently requires proficient computational skills and a large amount of computational work, prohibiting wide-scale adoption of smMIP-based technologies. To enable easy, efficient, and accurate interrogation of smMIP-derived data, we developed SmMIP-tools, a computational toolset that combines the critical analytic steps for smMIP data interpretation into a single computational pipeline. Here, we describe in detail two of the software’s major components. The first is a read processing tool that performs quality control steps, generates read-smMIP linkages and retrieves molecular tags. The second is an error-aware variant caller capable of detecting single nucleotide variants (SNVs) and short insertions and deletions (indels). Using a cell-line DNA dilution series and a cohort of blood cancer patients, we benchmarked SmMIP-tools and evaluated its performance against clinical sequencing reports. We anticipate that SmMIP-tools will increase accessibility to smMIP-technology, enabling cost-effective genetic research to push personalized medicine forward.
Differential regulation of alternative promoters emerges from unified kinetics of enhancer-promoter interaction
Authors: Wang Jingyao , Zhang Shihe , Lu Hongfang , Xu Heng 
Published: June 2021

AbstractMany eukaryotic genes contain alternative promoters with distinct expression patterns. How these promoters are differentially regulated remains elusive. Here, we apply single-molecule imaging to quantify the transcriptional regulation of two alternative promoters (P1 and P2) of the Bicoid (Bcd) target gene hunchback in syncytial blastoderm Drosophila embryos. Contrary to the previous notion that Bcd only activates P2, we find that Bcd activates both promoters via the same two enhancers. P1 activation is less frequent and requires binding of more Bcd molecules than P2 activation. Using a theoretical model to relate promoter activity to enhancer states, we show that the two promoters follow common transcription kinetics driven by sequential Bcd binding at the two enhancers. Bcd binding at either enhancer primarily activates P2, while P1 activation relies more on Bcd binding at both enhancers. These results provide a quantitative framework for understanding the kinetic mechanisms of complex eukaryotic gene regulation.
Molecular evolution of the Angiotensin II receptors AT1 and AT2: Specificity of the sodium binding site in amniota
Authors: Tiss Asma , Boubaker Rym Ben , Henrion Daniel , Guissouma Hajer , Chabbert Marie 
Published: June 2021

ABSTRACTIn vertebrates, the octopeptide angiotensin II (AngII) is an importantin vivoregulator of the cardiovascular system. It acts mainly through two G protein-coupled receptors, AT1 and AT2. To better understand the interplay between these receptors throughout the evolution of the renin-angiotensin system (RAS), we combined a phylogenetic study to electrostatics computations and molecular dynamics (MD) simulations of AT1 and AT2 receptors from different species. The phylogenetic analysis reveals a mirror evolution of AT1 and AT2 that are both split in two clades, separating fish from terrestrian receptors. It also indicates that the unusual allosteric sodium binding site of human AT1 is specific of amniota. Other AT1 and AT2 receptors display a canonical sodium binding site with a serine at position 7.46 (Ballesteros numbering). Electrostatics computations and MD simulations support maintained sodium binding to human AT1 with ingress from the extracellular side. Comparison of the sodium binding modes in AT1 and AT2 from humans and eels indicates that the allosteric control by sodium in both AT1 and AT2 evolved during the transition from an aqueous to a terrestrial environment. The unusual S7.46N mutation in amniota AT1 is mirrored by a L3.36M mutation in amniota AT2. The S7.46N mutation increases the specificity of AT1 for AngII relative to Ang derivatives, whereas the L3.36M mutation might have the opposite effect on AT2. Both mutations should contribute to the split of the renin-angiotensin system into the classical (AngII/AT1) and counter-regulatory (Ang1-7/AT2, Mas) arms in amniota.AUTHOR SUMMARYThe analysis of protein sequences from different species can reveal interesting trends in the structural and functional evolution of a protein family. Here, we analyze the evolution of two G protein-coupled receptors, AT1 and AT2, which bind the angiotensin II peptide and are important regulators of the cardiovascular system. We show that these receptors underwent a mirror evolution and that specific mutations of the sodium binding pocket in both AT1 and AT2 occurred in amniota. We underwent electrostatics computations and molecular dynamics simulations to decipher the details of the sodium binding mode in eel and human receptors, as prototype of fish and amniota receptors. Our results suggest that evolution favored an increased specificity of AT1 and a decreased specificity of AT2 for angiotensin II as compared to its derivatives. In turn, these data suggest that mutations in the sodium binding pocket of G protein-coupled receptors might be an efficient way to gain functional evolution.
Self-transfecting GMO-PMO and PMO-GMO chimeras enable gene silencingin vitro and in vivozebrafish model and NANOG Inhibition Induce the Apoptosis in Breast and Prostate Cancer Cells
Authors: Kundu Jayanta , Das Ujjal , Bose Chandra , Bhadra Jhuma , Sinha Surajit 
Published: June 2021

AbstractPhosphorodiamidate Morpholino Oligonucleotides (PMOs)-based antisense reagents cannot enter inside cells by itself without the help of any delivery technique which is the last hurdle for their clinical applications. To overcome this limitation, a self-transfecting GMO-PMO or PMO-GMO chimeras has been explored as a gene silencing reagent where GMO stands for guanidinium morpholino oligonucleotides which linked either at the OH- or NH-end of PMOs. GMO not only facilitates cellular internalization of such chimeras but also participates in Watson-Crick base pairing during gene silencing in ShhL2 cells when designed against mGli1and compared with scrambled GMO-PMO where mutations were made only to the GMO part. GMO-PMO-mediated knockdown ofno tailgene resulted no tail-dependent phenotypes in zebrafish and worked even after the delivery at 16-, 32- and 64-cell stages which were previously unachievable by regular PMO. Furthermore, GMO-PMO chimeras has shown the inhibition ofNANOG, a key regulator of self-renewal and pluripotency of both embryonic and cancer stem cells. Its inhibition influences on the expression of other cancer related proteins and the respective phenotypes in breast cancer cells and increases the therapeutic potential of taxol. To the best of our knowledge, this is the first report on the self-transfecting antisense reagents since the discovery of guanidinium linked DNA (DNG) and most effective among the all cell-penetrating PMOs reported till date expected to solve the longstanding problem of PMO delivery. In principle, this technology could be useful for the inhibition of any target gene without using any delivery vehicle and should have applications in the fields of antisense therapy, diagnostic and nanotechnology area.Abstract Figure
Tricalbin proteins regulate plasma membrane phospholipid homeostasis
Authors: Thomas Ffion B. , Omnus Deike J. , Bader Jakob M. , Chung Gary H. C. , Kono Nozomu , Stefan Christopher J. 
Published: June 2021

AbstractThe evolutionarily conserved extended synaptotagmin (E-Syt) proteins are calcium-activated lipid transfer proteins that function at contacts between the endoplasmic reticulum and plasma membrane (ER-PM contacts). However, roles of the E-Syt family members in PM lipid organisation remain unclear. Among the E-Syt family, the yeast tricalbin (Tcb) proteins are essential for PM integrity upon heat stress, but it is not known how they contribute to PM maintenance. Using quantitative lipidomics and microscopy, we find that the Tcb proteins regulate phosphatidylserine homeostasis at the PM. Moreover, upon heat-induced membrane stress, Tcb3 co-localises with the PM protein Sfk1 that is implicated in PM phospholipid asymmetry and integrity. The Tcb proteins also promote the recruitment of Pkh1, a stress-activated protein kinase required for PM integrity. Phosphatidylserine has evolutionarily conserved roles in PM organisation, integrity, and repair. We suggest that phospholipid regulation is an ancient essential function of E-Syt family members in PM integrity.
The impact of audit committee characteristics on internal audit professionalization: empirical evidence from Greece
Authors: Vadasi Christina , Bekiaris Michalis , Koutoupis Andreas G. 
Published: June 2021

PurposeThis paper aims to provide empirical evidence of the association between audit committee characteristics and internal audit quality through internal audit professionalization.Design/methodology/approachThe investigation of the research question was based on 45 usable responses that were received from a survey of chief audit executives from firms listed on the Athens Stock Exchange and combined with publicly available information from annual reports.FindingsThe results indicate that audit committee characteristics (independence, diligence through frequent meetings and interaction with internal audit through valuation) influence internal audit professionalization. In addition, they demonstrate that internal audit professionalization is also influenced by CEO duality and firm’s external auditor.Practical implicationsThe findings of this study have implications for audit committees wishing to improve their overall effectiveness, by identifying areas with substantial impact on internal audit quality. Moreover, regulators of corporate governance bodies can also benefit from the results to strengthen audit committee’s efficiency regarding internal audit function oversight.Originality/valueThe results add to the literature on the discussion of internal audit professionalization and complement the work of other researchers in the field of audit committee’s impact on internal audit quality/effectiveness. This study attempts to fill a gap in the literature on the effect of audit committee characteristics on internal audit professionalization, an element introduced from an institutional theory perspective.
Initial coin offerings: an emergent research area
Authors: Brochado Ana , Troilo Michael Louis 
Published: June 2021

PurposeThe purpose of this paper is to identify the main insights current literature offers regarding initial coin offerings (ICOs) and the avenues for future research.Design/methodology/approachThe approach consists of a systematic literature review of 130 papers from the SCOPUS database published in English between January 2018 and December 2020, with supplemental semantic analysis of the abstracts to obtain key themes and concepts.FindingsRegulation and the determinants of ICO success are the main themes for current research and represent fruitful areas of continued scholarship. The research agenda in ICOs is just beginning and several topics and questions merit future inquiry: the behaviour of issuers and investors, the importance of human capital, the role of intermediaries and infomediaries and the use of signalling.Originality/valueTo the knowledge, this is one of the first systematic studies of current literature in ICOs. It provides a roadmap for future work on a phenomenon that will only grow in significance.
I regret to hide knowledge: a coping strategy model
Authors: Islam Talat , Chaudhary Arooba , Aziz Muhammad Faisal 
Published: June 2021

Purpose
This study aims to examine the effect of knowledge hiding (KH) on organizational citizenship behavior toward individuals (OCBI) through the mediation of self-conscious emotions (SCE), namely, shame and guilt. This paper further considers the supervisor’s Islamic work ethics (IWE) as a conditional variable.

Design/methodology/approach
In this quantity-based research, this paper collected data from 473 employees working in various service and manufacturing organizations through Google form at two-lags.

Findings
The study applied structural equation modeling and identified that employees experience SCE due to KH. More specifically, rationalized hiding was found to have a negative effect, whereas playing dumb and evasive hiding was found to have a positive effect on shame and guilt. The results also revealed SCE (shame and guilt) as mediators between KH and OCBI. Further, the supervisor’s IWE was found to be a conditional variable to strengthen the association between KH and SCE.

Research limitations/implications
The study collected data from a single source. However, the issue of common method variance was tackled through time-lags.

Practical implications
The study suggests that supervisors must communicate with employees about the negative outcomes of KH. They must create such an environment that discourages the engagement of employees in KH and encourages the employees to engage themselves in helping behaviors to maintain a productive and creative work environment.

Originality/value
This study adds to the limited literature on the emotional consequences of KH from knowledge hiders’ perspective and unfolds the behavior-emotion-behavior sequence through the emotional pathway. More specifically, this study examined the negative emotional effect of hiding the knowledge that leads to compensatory strategy (organizational citizenship behavior) through SCE (shame and guilt). Finally, zooming into SCE, this study elucidates the supervisor’s IWE as a conditional variable.
Cyberbullying and cyber-mobbing in developing countries
Authors: Kintonova Aliya , Vasyaev Alexander , Shestak Viktor 
Published: June 2021

Purpose
This paper aims to consider modern internet phenomena such as cyberbullying and cybermobbing. The emphasis in the paper is placed on the problematic issues of the legal practice of combating cyberbullying and cyber-mobbing in developing countries as these phenomena are still insufficiently studied. The subject of this paper is modern internet phenomena such as cyberbullying and cyber-mobbing. The emphasis in the paper is placed on the problematic issues of the legal practice of combating cyberbullying and cyber-mobbing in developing countries as these phenomena are still insufficiently studied.

Design/methodology/approach
The legislation of developing countries is compared with doctrinal and practical developments in the fight against the studied problem in developed countries of the West, as well as countries of the former USSR. Moreover, experiment was conducted to determine the effectiveness of methods to combat cyberbullying using social networks. Thus, 40 random accounts of people (presumably from 18 to 30 years old) were analyzed.

Findings
This paper indicates the concepts of cyber-mobbing and cyberbullying, as well as their varieties that exist in the modern world. This study examines statistical data, programs and measures of different states in the fight against cyberbullying and cyber-mobbing. Results of experiments showed that Instagram users are aware of the availability of built-in extensions of the social network to protect against cyberbullying and use them relatively frequently. With that, female segment of Instagram users is more concerned about the content of the comments under their photos than the male one.

Originality/value
Measures have been developed to prevent and counteract cyberbullying and cyber-mobbing, the introduction of which into the policies of states might help in the fight against these social phenomena.