bluuebunny/crossref_metadata_2025 huggingface dataset:
Revisiting the Fisher–Kolmogorov–Petrovsky–Piskunov equation to interpret the spreading–extinction dichotomy
Authors: El-Hachem Maud , McCue Scott W. , Jin Wang , Du Yihong , Simpson Matthew J.
Published: September 2019

The Fisher–Kolmogorov–Petrovsky–Piskunov model, also known as the Fisher–KPP model, supports travelling wave solutions that are successfully used to model numerous invasive phenomena with applications in biology, ecology and combustion theory. However, there are certain phenomena that the Fisher–KPP model cannot replicate, such as the extinction of invasive populations. The Fisher–Stefan model is an adaptation of the Fisher–KPP model to include a moving boundary whose evolution is governed by a Stefan condition. The Fisher–Stefan model also supports travelling wave solutions; however, a key additional feature of the Fisher–Stefan model is that it is able to simulate population extinction, giving rise to a
spreading–extinction dichotomy
. In this work, we revisit travelling wave solutions of the Fisher–KPP model and show that these results provide new insight into travelling wave solutions of the Fisher–Stefan model and the spreading–extinction dichotomy. Using a combination of phase plane analysis, perturbation analysis and linearization, we establish a concrete relationship between travelling wave solutions of the Fisher–Stefan model and often-neglected travelling wave solutions of the Fisher–KPP model. Furthermore, we give closed-form approximate expressions for the shape of the travelling wave solutions of the Fisher–Stefan model in the limit of slow travelling wave speeds,
c
≪1.
Does testosterone impair men's cognitive empathy? Evidence from two large-scale randomized controlled trials
Authors: Nadler Amos , Camerer Colin F. , Zava David T. , Ortiz Triana L. , Watson Neil V. , Carré Justin M. , Nave Gideon
Published: September 2019

The capacity to infer others' mental states (known as ‘mind reading’ and ‘cognitive empathy’) is essential for social interactions across species, and its impairment characterizes psychopathological conditions such as autism spectrum disorder and schizophrenia. Previous studies reported that testosterone administration impaired cognitive empathy in healthy humans, and that a putative biomarker of prenatal testosterone exposure (finger digit ratios) moderated the effect. However, empirical support for the relationship has relied on small sample studies with mixed evidence. We investigate the reliability and generalizability of the relationship in two large-scale double-blind placebo-controlled experiments in young men (
n
= 243 and
n
= 400), using two different testosterone administration protocols. We find no evidence that cognitive empathy is impaired by testosterone administration or associated with digit ratios. With an unprecedented combined sample size, these results counter current theories and previous high-profile reports, and demonstrate that previous investigations of this topic have been statistically underpowered.
Early integration of pastoralism and millet cultivation in Bronze Age Eurasia
Authors: Hermes Taylor R. , Frachetti Michael D. , Doumani Dupuy Paula N. , Mar'yashev Alexei , Nebel Almut , Makarewicz Cheryl A.
Published: September 2019

Mobile pastoralists are thought to have facilitated the first trans-Eurasian dispersals of domesticated plants during the Early Bronze Age (ca2500–2300 BC). Problematically, the earliest seeds of wheat, barley and millet in Inner Asia were recovered from human mortuary contexts and do not inform on local cultivation or subsistence use, while contemporaneous evidence for the use and management of domesticated livestock in the region remains ambiguous. We analysed mitochondrial DNA and multi-stable isotopic ratios (δ13C, δ15N and δ18O) of faunal remains from key pastoralist sites in the Dzhungar Mountains of southeastern Kazakhstan. Atca2700 BC, Near Eastern domesticated sheep and goat were present at the settlement of Dali, which were also winter foddered with the region's earliest cultivated millet spreading from its centre of domestication in northern China. In the following centuries, millet cultivation and caprine management became increasingly intertwined at the nearby site of Begash. Cattle, on the other hand, received low levels of millet fodder at the sites for millennia. By primarily examining livestock dietary intake, this study reveals that the initial transmission of millet across the mountains of Inner Asia coincided with a substantial connection between pastoralism and plant cultivation, suggesting that pastoralist livestock herding was integral for the westward dispersal of millet from farming societies in China.
Identifying 31 novel breast cancer susceptibility loci using data from genome-wide association studies conducted in Asian and European women
Authors: Shu Xiang , Long Jirong , Cai Qiuyin , Kweon Sun-Seog , Choi Ji-Yeob , Kubo Michiaki , ParK Sue K. , Bolla Manjeet K. , Dennis Joe , Wang Qin , Yang Yaohua , Shi Jiajun , Guo Xingyi , Li Bingshan , Tao Ran , Aronson Kristan J. , Chan Kelvin Y.K. , Chan Tsun L. , Gao Yu-Tang , Hartman Mikael , Ho Weang Kee , Ito Hidemi , Iwasaki Motoki , Iwata Hiroji , John Esther M. , Kasuga Yoshio , Khoo Ui Soon , Kim Mi-Kyung , Kurian Allison W. , Kwong Ava , Li Jingmei , Lophatananon Artitaya , Low Siew-Kee , Mariapun Shivaani , Matsuda Koichi , Matsuo Keitaro , Muir Kenneth , Noh Dong-Young , Park Boyoung , Park Min-Ho , Shen Chen-Yang , Shin Min-Ho , Spinelli John J. , Takahashi Atsushi , Tseng Chiuchen , Tsugane Shoichiro , Wu Anna H. , Xiang Yong-Bing , Yamaji Taiki , Zheng Ying , Milne Roger L. , Dunning Alison M. , Pharoah Paul D.P. , García-Closas Montserrat , Teo Soo-Hwang , Shu Xiao-ou , Kang Daehee , Easton Douglas F. , Simard Jacques , Zheng Wei
Published: September 2019

Common genetic variants in 183 loci have been identified in relation to breast cancer risk in genome-wide association studies (GWAS). These risk variants combined explain only a relatively small proportion of breast cancer heritability, particularly in Asian populations. To search for additional genetic susceptibility loci for breast cancer, we performed a meta-analysis of data from GWAS conducted in Asians (24,206 cases and 24,775 controls). Variants showing an association with breast cancer risk at P < 0.01 were evaluated in GWAS conducted in European women including 122,977 cases and 105,974 controls. In the combined analysis of data from both Asian and European women, the lead variant in 28 loci not previously reported showed an association with breast cancer risk at P < 5 ×10−8. In the meta-analysis of all GWAS data from Asian and European descendants, we identified SNPs in three additional loci in association with breast cancer risk at P < 5 ×10−8. The associations for 10 of these loci were replicated in an independent sample of 16,787 cases and 16,680 controls of Asian women (P < 0.05). Expression quantitative trait locus (eQTL) and gene-based analyses provided evidence for the possible involvement of the YBEY, MAN2C1, SNUPN, TBX1, SEMA4A, STC1, MUTYH, LOXL2, and LINC00886 genes underlying the associations observed in eight of these 28 newly identified risk loci. In addition, we replicated the association for 78 of the 166 previously reported risk variants at P < 0.05 in women of Asian descent using GWAS data. These findings improve our understanding of breast cancer genetics and etiology and extend to Asian populations previous findings from studies of European women.
Comprehensive Spatiotemporal Analysis of Opioid Poisoning Mortality in Ohio from 2010 to 2016
Authors: Park Chihyun , Clemenceau Jean R. , Seballos Anna , Crawford Sara , Lopez Rocio , Coy Tyler , Atluri Gowtham , Hwang Tae Hyun
Published: September 2019

Objective

We aimed to identify (1) differences in opioid poisoning mortality among population groups, (2) geographic clusters of opioid-related deaths over time, and (3) health conditions co-occurring with opioid-related death in Ohio by computational analysis.

Materials and Methods

We used a large-scale Ohio vital statistic dataset from the Ohio Department of Health (ODH) and U.S. Census data from 2010-2016. We surveyed population differences with demographic profiling and use of relative proportions, conducted spatiotemporal pattern analysis with spatial autocorrelation via Moran statistics at the census tract level, and performed comorbidity analysis using frequent itemset mining and association rule mining.

Results

Our analyses found higher rates of opioid-related death in people aged 25-54, whites, and males. We also found that opioid-related deaths in Ohio became more spatially concentrated during 2010-2016, and tended to be most clustered around Cleveland, Columbus and Cincinnati. Drug abuse, anxiety and cardiovascular disease were found to predict opioid-related death.

Discussion

Comprehensive data-driven spatiotemporal analysis of opioid-related deaths provides essential identification of demographic, geographic and health factors related to opioid abuse. Future research should access personal health information for more detailed comorbidity analysis, as well as expand spatiotemporal models for real-time use.

Conclusion

Computational analyses revealed demographic differences in opioid poisoning, changing regional patterns of opioid-related deaths, and health conditions co-occurring with opioid overdose for Ohio from 2010-2016, providing essential knowledge for both government officials and caregivers to establish policies and strategies to best combat the opioid epidemic.
Fluoxetine improves behavioural deficits induced by chronic alcohol addiction by alleviating RNA editing of 5-HT2C receptors in astrocytes
Authors: Li Zexiong , Liang Shanshan , Li Shuai , Chen Beina , Zhang Manman , Xia Maosheng , Guan Dawei , Verkhratsky Alexei , Li Baoman
Published: September 2019

The alcoholism and major depressive disorder are common comorbidity, with alcohol-induced depressive symptoms being eased by selective serotonin re-uptake inhibitors (SSRIs), although the mechanisms underlying pathology and therapy are poorly understood. Chronic alcohol consumption affects the activity of serotonin 2C receptors (5-HT2CR) by regulating adenosine deaminases acting on RNA (ADARs) in neurones. Astrogliopathic changes contribute to alcohol addiction, while decreased release of ATP from astrocytes can trigger depressive-like behaviours in mice. In this study, we discovered that chronic alcohol addiction increased editing of RNA of 5-HT2CR via up-regulating the expression of ADAR2, consequnetly reducing the release of ATP from astrocytes induced by 5-HT2CR agonist, MK212. At the same time SSRI antidepressant fluoxetine decreased the expression of ADAR2 through the transactivation of EGFR/PI3K/AKT/cFos signalling pathway. Reduction in ADAR2 activity eliminated the RNA editing of 5-HT2CR in vivo and increased release of astroglial ATP which was suppressed by chronic alcohol consumption. Meanwhile, fluoxetine improved the behavioural and motor symptoms induced by alcohol addiction and decreased the alcohol intake. Our study suggests that the astrocytic 5-HT2CR contribute to alcohol addiction; fluoxetine thus can be used to alleviate depression, treat alcohol addiction and improve motor coordination.
Solving the transcription start site identification problem with ADAPT-CAGE: a Machine Learning algorithm for analysis of CAGE data
Authors: Georgakilas Georgios K , Perdikopanis Nikos , Hatzigeorgiou Artemis
Published: September 2019

Cap Analysis of Gene Expression (CAGE) experimental protocol has emerged as a powerful experimental technique for assisting in the identification of transcription start sites (TSSs). There is strong evidence that CAGE also identifies capping sites along various other locations of transcribed loci such as splicing byproducts, alternative isoforms and capped molecules overlapping introns and exons. We present ADAPT-CAGE, a Machine Learning framework which is trained to distinguish between CAGE signal derived from TSSs and transcriptional noise. ADAPT-CAGE provides annotation-agnostic, highly accurate and single-nucleotide resolution experimentally derived TSSs on a genome-wide scale. It has been specifically designed aiming for flexibility and ease-of-use by only requiring aligned CAGE data and the underlying genomic sequence. When compared to existing algorithms, ADAPT-CAGE exhibits improved performance on every benchmark that we designed based on both annotation- and experimentally-driven strategies. This performance boost brings ADAPT-CAGE in the spotlight as a computational framework that is able to assist in the refinement of gene regulatory networks, the incorporation of accurate information of gene expression regulators and alternative promoter usage in both physiological and pathological conditions.
LTD at amygdalocortical synapses as a novel mechanism for hedonic learning
Authors: Haley Melissa S. , Bruno Stephen , Fontanini Alfredo , Maffei Arianna
Published: September 2019

A novel, pleasant taste stimulus becomes aversive if associated with gastric malaise, a form of learning known as conditioned taste aversion (CTA). CTA is common to vertebrates and invertebrates and is an important survival response: eating the wrong food may be deadly. CTA depends on the gustatory portion of the insular cortex (GC) and the basolateral nucleus of the amygdala (BLA) however, its synaptic underpinnings are unknown. Here we report that CTA was associated with decreased expression of immediate early genes in rat GC of both sexes, and with reduced amplitude of BLA-GC synaptic responses, pointing to long term depression (LTD) as a mechanism for learning. Indeed, association of a novel tastant with induction of LTD at the BLA-GC input in vivo was sufficient to change the hedonic value of a taste stimulus. Our results demonstrate a direct role for amygdalocortical LTD in taste aversion learning.
Single-cell transcriptomics identifies an effectorness gradient shaping the response of CD4+ T cells to cytokines
Authors: Cano-Gamez Eddie , Soskic Blagoje , Roumeliotis Theodoros I. , So Ernest , Smyth Deborah J. , Baldrighi Marta , Willé David , Nakic Nikolina , Esparza-Gordillo Jorge , Larminie Christopher G. C. , Bronson Paola G. , Tough David F. , Rowan Wendy C. , Choudhary Jyoti S. , Trynka Gosia
Published: September 2019

Naïve CD4+ T cells coordinate the immune response by acquiring an effector phenotype in response to cytokines. However, the cytokine responses in memory T cells remain largely understudied. We used quantitative proteomics, bulk RNA-seq and single-cell RNA-seq of over 40,000 human naïve and memory CD4+ T cells to generate a detailed map of cytokine-regulated gene expression programs. We demonstrated that cytokine response differs substantially between naïve and memory T cells and showed that memory cells are unable to differentiate into the Th2 phenotype. Moreover, memory T cells acquire a Th17-like phenotype in response to iTreg polarization. At the single-cell level, we demonstrated that T cells form a continuum which progresses from naïve to effector memory T cells. This continuum is accompanied by a gradual increase in the expression levels of chemokines and cytokines and thus represents an effectorness gradient. Finally, we found that T cell cytokine responses are determined by where the cells lie in the effectorness gradient and identified genes whose expression is controlled by cytokines in an effectorness-dependent manner. Our results shed light on the heterogeneity of T cells and their responses to cytokines, provide insight into immune disease inflammation and could inform drug development.
Male song sparrows modulate their aggressive signaling in response to plumage signals: experiments with 3-D printed models
Authors: Beck Michelle L. , Akҫay Ҫağlar , Sewall Kendra B.
Published: September 2019

Competitive interactions among conspecifics are often resolved by assessing signals that honestly indicate individual fighting ability or dominance. In territorial species, signals of competitive ability are thought to function primarily during the early stages of territory establishment, but recent evidence suggests that these signals continue to influence interactions with floaters and neighbors well after territory establishment. Here, we examine the influence of the extent of chest spotting displayed by an intruding male on the response of territorial male song sparrows. We exposed males to 3-D printed models with large or small spotting area coupled with conspecific playback and recorded their behavior. We also assessed the response of a subset of males to both the 3-D printed models and a traditional, taxidermic mount to ensure the 3-D models were a realistic stimulus. We found no differences in the number of attacks or proximity to the model due to spotting area. However, territorial males produced more soft songs and tended to sing fewer loud songs, both of which predict attack in our population, in response to the model with less chest spotting. One possibility is that males with less chest spotting elicit a stronger response because they are seen as a greater threat. Based on our previous findings in this system, we think it is more likely that models with less chest spotting are perceived as subordinate and therefore easier to defeat, leading to a stronger response by territory holders. We found males were equally likely to attack 3-D printed models and a taxidermic mount but signaled more aggressively during trials with the taxidermic mount than the 3-D printed models. This suggests that birds recognized the 3-D models as meaningful stimuli but that the use of 3-D printed models should be validated through comparison to a traditional taxidermic mount when possible.
Identification of the Repressive Domain of the Negative Circadian Clock Component CHRONO
Authors: Yang Yu , Li Ning , Qiu Jiameng , Ge Honghua , Qin Ximing
Published: September 2019

Circadian rhythm is an endogenous, self-sustainable oscillation that participates in regulating organisms’ physiological activities. Key to this oscillation is a negative feedback by main clock components Periods and Cryptochromes that repress transcriptional activity of BMAL1/CLOCK complexes. In addition, a novel repressor, CHRONO, has been identified recently, but details of CHRONO’s function during repressing the circadian cycle remain unclear. Here we report that a domain of CHRONO mainly composed of α-helixes is critical to repression through the exploitation of protein-protein interactions according to luciferase reporter assays, co-immunoprecipitation, immunofluorescence, genome editing and structural information analysis via circular dichroism spectroscopy. This repression is fulfilled by interactions between CHRONO with a region on the BMAL1 C-terminus where Cryptochrome and CBP bind. Our results indicate that CHRONO and PER differentially function as BMALA/CLOCK-dependent repressors. We further suggest a repression model of how PER, CRY and CHRONO proteins associate with BMAL1, respectively.
The cyanobacterial saxitoxin exacerbates neural cell death and brain malformations induced by Zika virus
Authors: Pedrosa Carolina da S. G. , Souza Leticia R. Q. , de Lima Caroline V. F. , Ledur Pitia F. , Karmirian Karina , Gomes Tiago A. , Barbeito-Andres Jimena , Costa Marcelo do N. , Higa Luiza M. , Bellio Maria , Lara Flavio A. , Tanuri Amilcar , Garcez Patricia P. , Prata-Barbosa Arnaldo , Tovar-Moll Fernanda , Molica Renato J. R. , Rehen Stevens K.
Published: September 2019

The northeast (NE) region of Brazil commonly goes through drought periods, which favor cyanobacterial blooms, capable of producing neurotoxins with implications for human and animal health. The most severe dry spell in the history of Brazil occurred between 2012 and 2016. Coincidently, the highest incidence of microcephaly associated with the Zika virus (ZIKV) outbreak was described in the NE region of Brazil during the same years. In this work, we tested the hypothesis that saxitoxin (STX), a neurotoxin produced in South America by the freshwater cyanobacteria Raphidiopsis raciborskii, could have contributed to the most severe Congenital Zika Syndrome (CZS) profile described worldwide. Quality surveillance showed higher cyanobacteria amounts and STX occurrence in human drinking water supplies of NE compared to other regions of Brazil. Experimentally, we described that STX doubled the amount of ZIKV-induced neural cell death in progenitor areas of human brain organoids, while the chronic ingestion of water contaminated with STX before and during gestation caused brain abnormalities in offspring of ZIKV-infected immunocompetent C57BL/6J mice. Our data indicate that saxitoxin-producing cyanobacteria is overspread in water reservoirs of the NE and might have acted as a co-insult to ZIKV infection in Brazil. These results raise a public health concern regarding the consequences of arbovirus outbreaks happening in areas with droughts and/or frequent freshwater cyanobacterial blooms.

Author summary

The uncontrolled spreading of cyanobacteria in drinking water reservoirs has been the cause of serious public health problems worldwide. Toxin-producing cyanobacterial blooms commonly occur during drought periods in the northeast (NE) region of Brazil. During Zika Virus (ZIKV) outbreak in 2015-16, Brazilian NE showed disproportionately higher microcephaly incidence. Here, we test the hypothesis that the cyanotoxin saxitoxin (STX) may act as a co-insult for ZIKV. Water quality surveillance data showed increased cyanobacteria population and higher STX amount in NE region during 2014-2018. In vitro, we observed that neural progenitor cell death was doubled after STX exposure to ZIKV-infected brain organoids. In vivo, chronic ingestion of STX during gestational period potentiated ZIKV-derived brain abnormalities in newborn mice. Our study provides new insights that may explain the discrepancies among Brazilian regions regarding CZS severity. Moreover, the data highlight the importance of cyanobacteria and cyanotoxin freshwater monitoring for future arbovirus outbreaks.
Molecular mechanism of translational stalling by inhibitory codon combinations and poly(A) tracts
Authors: Tesina Petr , Lessen Laura N. , Buschauer Robert , Cheng Jingdong , Wu Colin Chih-Chien , Berninghausen Otto , Buskirk Allen R. , Becker Thomas , Beckmann Roland , Green Rachel
Published: September 2019

Inhibitory codon pairs and poly(A) tracts within the translated mRNA cause ribosome stalling and reduce protein output. The molecular mechanisms that drive these stalling events, however, are still unknown. Here, we use a combination ofin vitrobiochemistry, ribosome profiling, and cryo-EM to define molecular mechanisms that lead to these ribosome stalls. First, we use anin vitroreconstituted yeast translation system to demonstrate that inhibitory codon pairs slow elongation rates which are partially rescued by increased tRNA concentration or by an artificial tRNA not dependent on wobble base pairing. Ribosome profiling data extend these observations by revealing that paused ribosomes with empty A sites are enriched on these sequences. Cryo-EM structures of stalled ribosomes provide a structural explanation for the observed effects by showing decoding-incompatible conformations of mRNA in the A sites of all studied stall-inducing sequences. Interestingly, in the case of poly(A) tracts, the inhibitory conformation of the mRNA in the A site involves a nucleotide stacking array. Together, these data demonstrate novel mRNA-induced mechanisms of translational stalling in eukaryotic ribosomes.
Single cell and single nucleus RNA-Seq reveal cellular heterogeneity and homeostatic regulatory networks in adult mouse stria vascularis
Authors: Korrapati Soumya , Taukulis Ian , Olszewski Rafal , Pyle Madeline , Gu Shoujun , Singh Riya , Griffiths Carla , Izquierdo Daniel Martin , Boger Erich , Morell Robert J. , Hoa Michael
Published: September 2019

The stria vascularis (SV) generates the endocochlear potential (EP) in the inner ear and is necessary for proper hair cell mechanotransduction and hearing. While channels belonging to SV cell types are known to play crucial roles in EP generation, relatively little is known about gene regulatory networks that underlie the ability of the SV to generate and maintain the EP. Using single cell and single nucleus RNA-sequencing, we identify and validate known and rare cell populations in the SV. Furthermore, we establish a basis for understanding molecular mechanisms underlying SV function by identifying potential gene regulatory networks as well as druggable gene targets. Finally, we associate known deafness genes with adult SV cell types. This work establishes a basis for dissecting the genetic mechanisms underlying the role of the SV in hearing and will serve as a basis for designing therapeutic approaches to hearing loss related to SV dysfunction.
A novel polyubiquitin chain linkage formed by viral Ubiquitin prevents cleavage by deubiquitinating enzymes
Authors: Negi Hitendra , Reddy Pothula Puroshotham , Patole Chhaya , Das Ranabir
Published: September 2019

TheBaculoviridaefamily of viruses encode a viral Ubiquitin gene. Although the viral Ubiquitin is homologous to eukaryotic Ubiquitin (Ub), preservation of this gene in the viral genome indicates a unique function that is absent in the host eukaryotic Ub. We report the structural, biophysical, and biochemical properties of the viral Ubiquitin fromAutographa Californica Multiple Nucleo-Polyhedrosis Virus(AcMNPV). The structure of viral Ubiquitin (vUb) differs from Ub in the packing of the central helix α1 to the beta-sheet of the β-grasp fold. Consequently, the stability of the fold is lower in vUb compared to Ub. However, the surface properties, ubiquitination activity, and the interaction with Ubiquitin binding domains are similar between vUb and Ub. Interestingly, vUb forms atypical polyubiquitin chain linked by lysine at the 54thposition (K54). The K54-linked polyubiquitin chains are neither effectively cleaved by deubiquitinating enzymes, nor are they targeted by proteasomal degradation. We propose that modification of proteins with the viral Ubiquitin is a mechanism to counter the host antiviral responses.
Uncovering active modulators of native macroautophagy through novel high-content screens
Authors: Safren N , Tank EM , Santoro N , Barmada SJ
Published: September 2019

Autophagy is an evolutionarily conserved pathway mediating the breakdown of cellular proteins and organelles. Emphasizing its pivotal nature, autophagy dysfunction contributes to many diseases; nevertheless, development of effective autophagy modulating drugs is hampered by fundamental deficiencies in available methods for measuring autophagic activity, or flux. To overcome these limitations, we introduced the photoconvertible protein Dendra2 into the MAP1LC3B locus of human cells via CRISPR/Cas9 genome editing, enabling accurate and sensitive assessments of autophagy in living cells by optical pulse labeling. High-content screening of 1,500 tool compounds provided construct validity for the assay and uncovered many new autophagy modulators. In an expanded screen of 24,000 diverse compounds, we identified additional hits with profound effects on autophagy. Further, the autophagy activator NVP-BEZ235 exhibited significant neuroprotective properties in a neurodegenerative disease model. These studies confirm the utility of the Dendra2-LC3 assay, while simultaneously highlighting new autophagy-modulating compounds that display promising therapeutic effects.
Impaired carotid body hypoxic sensing in mice deficient in olfactory receptor 78
Authors: Peng Ying-Jie , Gridina Anna , Nanduri Jayasri , Fox Aaron P. , Prabhakar Nanduri R.
Published: September 2019

Carotid bodies are the sensory organs for detecting hypoxemia (decreased arterial blood oxygen levels) and ensuing chemo reflex is a major regulator of breathing and blood pressure. Chang et al (2015) proposed that olfactory receptor 78 (Olfr78) plays a major role in hypoxic sensing by the carotid body. However, such a possibility was questioned by a subsequent study ((Torres-Torrelo et al. 2018). The discrepancy between the two reports prompted the present study to re-examine the role of Olfr78 in hypoxic sensing by the carotid body (CB). Studies were performed on age and gender matched Olfr78 knock out mice generated on BL6 and JAX backgrounds and corresponding wild type mice. Breathing was monitored by plethysmography in un-sedated and efferent phrenic nerve activity in anesthetized mice. Carotid body sensory nerve activity was determined ex vivo and [Ca2+]i responses were monitored in isolated glomus cells, the primary O2 sensing cells of the carotid body. Olfr78 null mice on both BL6 and JAX backgrounds exhibited attenuated hypoxic ventilatory response, whereas breathing responses to CO2 were unaffected. The magnitude of hyperoxia-induced depression of breathing (Dejour’s test), which is an indirect measure of carotid body hypoxic sensing, was markedly reduced in Olfr78 mutant mice on both background strains. Furthermore, carotid body sensory nerve and glomus cell [Ca2+]i responses to hypoxia were attenuated in BL6 and JAX Olfr78 null mice. These results suggest that Olfr78 plays an important role in hypoxic sensing by the carotid body.
Transcriptional and post-transcriptional regulation and transcriptional memory of chromatin regulators in response to low temperature
Authors: Vyse K. , Faivre L. , Romich M. , Pagter M. , Schubert D. , Hincha D.K. , Zuther E.
Published: September 2019

Chromatin regulation ensures stable repression of stress-inducible genes under non-stress conditions and transcriptional activation and memory of such an activation of those genes when plants are exposed to stress. However, there is only limited knowledge on how chromatin genes are regulated at the transcriptional and post-transcriptional level upon stress exposure and relief from stress. We have therefore set-up a RT-qPCR-based platform for high-throughput transcriptional profiling of a large set of chromatin genes. We find that the expression of a large fraction of these genes is regulated by cold. In addition, we reveal an induction of several DNA and histone demethylase genes and certain histone variants after plants have been shifted back to ambient temperature (deacclimation), suggesting a role in the memory of cold acclimation. We also re-analyse large scale transcriptomic datasets for transcriptional regulation and alternative splicing (AS) of chromatin genes, uncovering an unexpected level of regulation of these genes, particularly at the splicing level. This includes several vernalization regulating genes whose AS results in cold-regulated protein diversity. Overall, we provide a profiling platform for the analysis of chromatin regulatory genes and integrative analyses of their regulation, suggesting a dynamic regulation of key chromatin genes in response to low temperature stress.
Proteomic analysis of the desmosome identifies novel components required for skin integrity
Authors: Badu-Nkansah Kwabena , Lechler Terry
Published: September 2019

Desmosomes are cell-cell adhesions necessary for the maintenance of tissue integrity in the skin and the heart. While the core components of the desmosome have been identified, peripheral components that modulate canonical desmosome functions or that have noncanonical roles remain largely unexplored. Here we used targeted proximity labeling approaches to elaborate the desmosome proteome in epidermal keratinocytes. Quantitative mass spectrometry analysis identified all core desmosome proteins while uncovering a diverse network of new constituents with broad molecular functions. By individually targeting the inner and outer dense plaques, we additionally define proteins enriched in these subcompartments. We validated a number of these novel desmosome-associated proteins and find that many show a dependence upon the core desmosomal protein, desmoplakin, for their localization. We further explored the mechanism of localization and function of two novel desmosome-associated adaptor proteins that we identified, Crk and Crkl. These proteins interacted with Dsg1 and require both Dsg1 and desmoplakin for robust cortical localization. Epidermal deletion of both Crk and CrkL in mice resulted in perinatal lethality with defects in desmosome morphology and keratin organization, thus demonstrating the utility of this dataset in identifying novel proteins required for desmosome-dependent epidermal integrity.
Miswired enhancer logic drives translocation positive rhabdomyosarcoma
Authors: Gryder Berkley E. , Wachtel Marco , Chang Kenneth , El Demerdash Osama , Aboreden Nicholas G. , Mohammed Wardah , Ewert Winston , Pomella Silvia , Rota Rossella , Wei Jun S. , Song Young , Schaefer Beat , Vakoc Christopher R. , Khan Javed
Published: September 2019

Core regularity transcription factors (CR TFs) define cell identity and lineage through an exquisitely precise and logical order during embryogenesis and development. These CR TFs regulate one another in three-dimensional space via distal enhancers that serve as logic gates embedded in their TF recognition sequences. Aberrant chromatin organization resulting in miswired circuitry of enhancer logic is a newly recognized feature in many cancers. Here, we report that PAX3-FOXO1 expression is driven by a translocated FOXO1 distal super enhancer (SE). Using 4C-seq, a technique detecting all genomic regions that interact with the translocated FOXO1 SE, we demonstrate its physical interaction with the PAX3 promotor only in the presence of the oncogenic translocation. Furthermore, RNA-seq and ChIP-seq in tumors bearing rare PAX translocations implicate enhancer miswiring is a pervasive feature across all FP-RMS tumors. HiChIP of enhancer mark H3K27ac showed extended connectivity between the distal FOXO1 SE and additional intra-domain enhancers and the PAX3 promoter. We show by CRISPR-paired-ChIP-Rx that PAX3-FOXO1 transcription is diminished when this network of enhancers is selectively ablated. Therefore, our data reveal a mechanism of a translocated hijacked enhancer which disrupts the normal CR TF logic during skeletal muscle development (PAX3 to MYOD to MYOG), replacing it with an infinite loop logic that locks rhabdomyosarcoma cells in an undifferentiated proliferating stage.
Suppression of p53 response by targeting p53-Mediator binding with a stapled peptide
Authors: Allen BL , Quach K , Levandowski CB , Rubin JD , Read T , Dowell RD , Schepartz A , Taatjes DJ
Published: September 2019

DNA-binding transcription factors (TFs) remain challenging to target with molecular probes. Many TFs function in part through interaction with Mediator; we sought to block p53 function by disrupting the p53-Mediator interaction. Through rational design and activity-based screening, we characterized a stapled peptide, with functional mimics of both p53 activation domains, that selectively inhibited p53- and Mediator-dependent transcription in vitro. This “bivalent peptide” also suppressed p53 transcriptional response in human cancer cells. Our strategy circumvents the TF and instead targets the TF-Mediator interface, with desired transcriptional outcomes. Different TFs target Mediator through different subunits, suggesting this strategy could be broadly applied.
Control of clathrin-mediated endocytosis by NIMA family kinases
Authors: Joseph Braveen B. , Wang Yu , Edeen Phil , Lažetić Vladimir , Grant Barth D. , Fay David S.
Published: September 2019

Endocytosis, the process by which cells internalize plasma membrane and associated cargo, is regulated extensively by posttranslational modifications. Previous studies suggested the potential involvement of scores of protein kinases in endocytic control, of which only a few have been validated within their native context. Here we show that the conserved NIMA-related kinases NEKL-2/NEK8/9 and NEKL-3/NEK6/7 (the NEKLs) control clathrin-mediated endocytosis inC. elegans. Loss of NEKLs leads to clathrin mislocalization and to a dramatic reduction in clathrin mobility at the apical membrane. Strikingly, reducing the levels of active AP2, the major clathrin adapter complex, rescuesneklmutant defects, whereas increased levels of active AP2 exacerbate nekl defects. Moreover, NEKL inhibition alleviates defects associated with reduced AP2 activity, attesting to the tight link between NEKL and AP2 functions. We also show that NEKLs are required for the clustering and internalization of membrane cargo and that human NEKs rescue defects inneklmutant worms.
Tolerance–reliability analysis of mechanical assemblies for quality control based on Bayesian modeling
Authors: Khodaygan S. , Ghaderi A.
Published: September 2019

Purpose

The purpose of this paper is to present a new efficient method for the tolerance–reliability analysis and quality control of complex nonlinear assemblies where explicit assembly functions are difficult or impossible to extract based on Bayesian modeling.

Design/methodology/approach

In the proposed method, first, tolerances are modelled as the random uncertain variables. Then, based on the assembly data, the explicit assembly function can be expressed by the Bayesian model in terms of manufacturing and assembly tolerances. According to the obtained assembly tolerance, reliability of the mechanical assembly to meet the assembly requirement can be estimated by a proper first-order reliability method.

Findings

The Bayesian modeling leads to an appropriate assembly function for the tolerance and reliability analysis of mechanical assemblies for assessment of the assembly quality, by evaluation of the assembly requirement(s) at the key characteristics in the assembly process. The efficiency of the proposed method by considering a case study has been illustrated and validated by comparison to Monte Carlo simulations.

Practical implications

The method is practically easy to be automated for use within CAD/CAM software for the assembly quality control in industrial applications.

Originality/value

Bayesian modeling for tolerance–reliability analysis of mechanical assemblies, which has not been previously considered in the literature, is a potentially interesting concept that can be extended to other corresponding fields of the tolerance design and the quality control.
The prevention of offending behaviour by people with intellectual disabilities: a case for specialist childhood and adolescent early intervention
Authors: Chester Verity , Wells Harriet , Lovell Mark , Melvin Clare , Tromans Samuel Joseph
Published: September 2019

Purpose

Elucidating where antisocial or violent behaviour arises within the life course of individuals with intellectual disability (ID) could improve outcomes within this population, through informing services and interventions which prevent behaviours reaching a forensic threshold. The paper aims to discuss this issue.

Design/methodology/approach

The Historical Clinical Risk Management-20, Version 3 assessments of a cohort of 84 inpatients within a forensic ID service were analysed for this study, with a particular emphasis on items concerned with the age at which antisocial or violence first emerged.

Findings

For most participants, violent or antisocial behaviour was first observed in childhood or adolescence. The study also highlighted a smaller subgroup, whose problems with violence or antisocial behaviour were first observed in adulthood.

Originality/value

The study findings suggest that targeted services in childhood and adolescence may have a role in reducing the offending behaviour and forensic involvement of people with ID. This has implications for the service models provided for children and adolescents with ID with challenging or offending behaviour.
Hedonism or self-growth? The influence of perceived control on individual product preferences for individuals under self-threat
Authors: Zhao Taiyang , Song Wei , Jin Xiaotong , Cui Hongjing , Li Yang
Published: September 2019

Purpose

The purpose of this paper is to study the influence of perceived control on product preferences of consumers under self-threat.

Design/methodology/approach

By conducting four experiments, this paper manipulated the participants’ self-threat and three sources of perceived control – namely, the controllability of the threat itself, the internal and external locus of control of the individual and priming the existing positive or negative experience of the individuals. After the manipulations, the participants’ product preferences for self-growth goods or hedonic goods were measured.

Findings

The findings of this research indicated that when consumers have a higher perceived control of the threats they are facing, they are more likely to adopt problem-focused coping strategies and show a preference for self-growth goods, which can help them resolve their threats. However, when consumers have a lower perceived control on the threats they are facing, they are more likely to adopt emotion-focused coping strategies and show a preference for hedonic goods, which can help them adjust their emotions.

Originality/value

This paper systematically confirms the interactive effect of perceived control and self-threat on consumers’ product preferences, as well as the meditation role of problem-focused coping and emotion-focused coping. It also provides insights for marketers to know what factors may affect consumers’ preferences for products in self-threat situations, thus contributing to marketing practices.
Regulating mediators of internet piracy: P2P websites and cyberlockers
Authors: Walter Jason M.
Published: September 2019

Purpose

Contemporary copyright infringement has significantly changed in the digital era, and because of the unique attributes of internet piracy and method of exchange, traditional regulatory approaches are ineffective. The characteristics of digital goods enable users to almost costlessly copy and exchange content. Much of the contemporary research fails to incorporate the necessary components of exchange that are central to digital piracy. This paper aims to examine the role of peer-to-peer network hosts and the often-omitted cyberlocker.

Design/methodology/approach

A simple framework is constructed that describes how these entities how these entities facilitate digital piracy and operate financially. This framework illustrates the objectives of piracy mediators, highlighting the avenues by which regulation can craft policy. Additional examination of online piracy highlights the challenges of contemporary policy to combat digital piracy due to the secondary consequences.

Findings

Recent policies, aimed at diminishing piracy, would infringe on consumers’ privacy, hurt business finances or strategically used by rivals to hurt the operations of legal entities. Trying to prevent illegal sources (or facilitators) of pirate goods from providing access to files continues to be challenging. In many instances, the blurry line between a legal platform for file exchange and a piracy haven creates significant regulatory problems. For known piracy promoters (host sites or cyberlockers), location and revenue streams continue to limit direct intervention.

Originality/value

This paper discusses the necessary path for piracy to occur by including previously omitted agents necessary for communication and/or distribution. My analysis incorporates these entities that facilitate piracy and the unique features of digital exchange, which has industrial and regulatory implications. Furthermore, my results highlight why regulators have been ineffective in crafting meaningful anti-piracy policy.
Cultural societies and information needs: Croats in New Zealand
Authors: Krtalić Maja , Hebrang Grgić Ivana
Published: September 2019

Purpose

The purpose of this paper was to explore how small immigrant communities in host countries collect, disseminate and present information about their home country and their community, and the role of formal societies and clubs in it.

Design/methodology/approach

This paper presents the results of a case study of the Croatian community in New Zealand. To illustrate how cultural and technological changes affected information dissemination and communication within the community, the case study presents both historical and current situations. Methods used in this case study included a content analysis of historical newspapers published in New Zealand by the Croatian community, content analysis of current webpages and social networking sites, and interviews with participants who have management roles in Croatian societies and communities in New Zealand. Data were collected from December 2018 to February 2019.

Findings

Formally established clubs and societies, but also informal groups of immigrants and their descendants can play a significant role in providing their members with information about the culture, social life and events of the home country. They also play a significant role in preserving part of the history and heritage which is relevant, not only for a specific community but also for the history and culture of a home country.

Originality/value

The methodology used in the research is based on data from community archives and can be used for studying other small immigrant communities in New Zealand or abroad. The case study presented in the paper illustrates how the information environment of small immigrant communities develops and changes over the years under the influence of diverse political, social and technological changes.
Understanding the building of professional identities with the LEGO® SERIOUS PLAY® method using situational mapping and analysis
Authors: Hayes Catherine , Graham Yitka
Published: September 2019

Purpose

The purpose of this paper is to explore the notion that social constructionist approaches to learning, which a building with the hands provides, is a “technique that leverages the potential of the hand-mind dynamic” as historically reported in the extant published literature.

Design/methodology/approach

The use of the LEGO® SERIOUS PLAY® (LSP) method in the context of transformative learning in Higher Education was used to drive a Situational analysis with sixteen postgraduate nursing students, from African learning contexts. This methodological approach was used to specifically explore their identity as learners and then to facilitate processes of critical introspection on social constructivist learning opportunities.

Findings

Students’ perceived LSP permitted a deeper level of critical introspection on their transformative learning journeys than alternative approaches, such as written discourse or extended narratives, could have provided. They also perceived that a major benefit of using the LSP method was that it enabled them to understand and articulate their stories more easily than if they verbally reported them first.

Research limitations/implications

The sampling the authors used was purposive and reflective of the Nigerian background of our research participants, who study at the University of Sunderland.

Practical implications

LSP was perceived as an effective vehicle for the facilitation of reflection and self-awareness, which consequently contribute to students’ capacities to function at a metacognitive level. This has the potential to contribute to authentic transformative learning. Academic learning at postgraduate level hinged on the capacity of students to develop a pragmatic and working knowledge of what acknowledging their epistemic cognition entailed.

Originality/value

The methodological approach implemented in this paper provides a unique means of harnessing a now common gamification technique in pedagogic practice.