bluuebunny/crossref_metadata_2025_split huggingface dataset:
An engineered Abcb4 expressing model reveals the central role of NF-κB in the regulation of drug resistance in zebrafish
Authors: Sun Cong-Jie , Hu Rong-Yin , Li Zhi-Cao , Jin Lu , Ye Chuan , Lu He , Zhou Yan-Hua , Zhou Ting , He Zhi-Xu , Shu Li-Ping 
Published: April 2020

AbstractMultidrug resistance (MDR) represents the major cause of unsatisfaction in the application of chemotherapy for cancer treatment. So far, anin vivorobust high-throughput screening system for anti-tumor drug MDR is still lacking and the molecular mechanisms for MDR still remain elusive. Given a myriad of merits of zebrafish relative to other animal models, we aimed to establish MDR system in zebrafish stably expressing ATP-binding cassette (ATP-cassette) superfamily transporters and study the potential regulatory mechanism. We first constructed aTg(abcb4:EGFP)transgenic zebrafish stably expressing both Abcb4 and EGFP using Tol2-mediated approach. The expression level of Abcb4 and EGFP was significantly induced whenTg(abcb4:EGFP)transgenic zebrafish embryos were exposed to doxorubicin (DOX) or vincristine (VCR), accompany with a marked decrease in rhodamine B (RhB) accumulation in embryos, which indicates a remarkable increase in drug efflux upon the exposure to DOX or VCR. Mechanistically, AKT and ERK signaling were activated when treated with DOX or VCR. With the application of AKT and ERK inhibitors, the drug resistance phenomena could be reversed with differential responsive effects. Of note, downstream NF-κB played a central role in the regulation of Abcb4-mediated drug resistance. Taken together, the engineeredTg(abcb4:EGFP)transgenic zebrafish model provides a new platform for drug resistance screeningin vivo, which could facilitate and accelerate the process of drug development.
Deletion of Murine Gammaherpesvirus GeneM2in AID-Expressing B Cells Impairs Host Colonization and Viral Reactivation
Authors: Owens Shana M. , Oldenburg Darby G. , White Douglas W. , Forrest J. Craig 
Published: April 2020

ABSTRACTGammaherpesviruses (GHVs) are DNA tumor viruses that establish life-long, chronic infections in lymphocytes of humans and other mammals. GHV infections are associated with numerous cancers, especially in immune compromised hosts. While it is known that GHVs utilize host germinal center (GC) B cell responses during latency establishment, an understanding of how viral gene products function in specific B cell subsets to regulate this process is incomplete. Using murine gammaherpesvirus 68 (MHV68) as a small-animal model to define mechanisms of GHV pathogenesisin vivo, we generated a virus in which theM2gene was flanked byloxPsites (M2.loxP), enabling the use of Cre-lox technology to define M2 function in specific cell types in infection and disease. TheM2gene encodes a protein that is highly expressed in GC B cells that promotes plasma cell differentiation and viral reactivation.M2was efficiently deleted in Cre-expressing cells, and the presence ofloxPsites flankingM2did not alter viral replication or latency in mice that do not express Cre. In contrast, M2.loxP MHV68 exhibited a deficit in latency establishment and reactivation that resembled M2-null virus, following intranasal (IN) infection of mice that express Cre in all B cells (CD19-Cre). Nearly identical phenotypes were observed for M2.loxP MHV68 in mice that express Cre in germinal center (GC) B cells (AID-Cre). However, neither colonization of draining lymph nodes after IN infection nor the spleen after intraperitoneal (IP) infection required M2, although the reactivation defect was retained. Together, these data confirm that M2 function is B cell-specific and demonstrate that M2 primarily functions in AID-expressing cells to facilitate MHV68 dissemination to distal latency reservoirs within the host and reactivation from latency. Our study reveals that a viral latency gene functions within a distinct subset of cells to facilitate host colonization.IMPORTANCEGammaherpesviruses establish life-long chronic infections in cells of the immune system that can lead to lymphomas and other diseases. To facilitate colonization of a host, gammaherpesviruses encode gene products that manipulate processes involved in cellular proliferation and differentiation. Whether and how these viral gene products function in specific cells of the immune system is poorly defined. We report here the use of a viral genetic system that allows for deletion of specific viral genes in discrete populations of cells. We employ this system in anin vivomodel to demonstrate cell-type-specific requirements for a particular viral gene. Our findings reveal that a viral gene product can function in distinct cellular subsets to direct gammaherpesvirus pathogenesis.
A mechanical cusp catastrophe imposes a universal developmental constraint on the shapes of tip-growing cells
Authors: Dumais Jacques , Rojas Enrique R. 
Published: April 2020

AbstractUnderstanding the mechanistic basis for cell morphology is a central problem in biology. Evolution has converged on tip growth many times, yielding filamentous cells, yet tip-growing cells display a range of apical morphologies. To understand this variability, we measured the spatial profiles of cell-wall expansion for three species that spanned the phylogeny and morphology of tip-growth. Profiles were consistent with a mechanical model whereby the wall was stratified and stretched by turgor pressure during cell growth. We calculated the spatial profiles of wall mechanical properties, which could be accurately fit with an empirical two-parameter function. Combined with the mechanical model, this function yielded a “morphospace” that accounted for the shapes of diverse tip-growing species. However, natural shapes were bounded by a cusp bifurcation in the morphospace that separated thin, fast-growing cells from (nonexistent) wide, slow-growing cells. This constraint has important implications for our understanding of the evolution of tip-growing cells.
Analysis of insertion mutants in distal α9 portion of C-terminal heptad repeat (CHR) of HIV-1 gp41 subunit
Authors: Wang Hongyun , Song Jiping , Kawaguchi Yasushi , Inoue Jun-ichiro , Matsuda Zene 
Published: April 2020

AbstractWe have made insertion mutants in α9 of HXB2 gp41 and observed similar phenotypes like recent JRFL mutants: insertion of alanine (653+A), but not glutamine (653+Q), severely attenuated membrane fusion. To understand the underlying mechanism, we performed the fusion inhibition assay by corresponding mutant C34 peptides. Both mutant C34 peptides added at the beginning of the coculture of the effector and target cells showed less efficient inhibition of membrane fusion, which was similar to wildtype C34 added after 30 min of coculture, indicating slow association of mutant C34 peptides with the N-terminal heptad region of gp41. Due to uninterpretable CD profiles of C34 and N36, we tested the longer peptide pairs (N46 and C42) and observed CD profiles indicative of weak α-helix formation. The melting temperatures for N46-C42 pairs of 653+A, 653+Q, and wild type were 56.8 °C, 59.8°C, and 96°C, respectively. Taken together, our data suggested that the phenotypic difference in membrane fusion between 653+A and 653+Q (or wild type) was not based on the stability of the six-helix bundle (6HB), but due to differences in the kinetics of 6HB formation. Further, we examined additional insertions (E, R, I, and L) at position 653, for which only I and L showed fusion recovery similar to Q, suggesting that the polar nature of glutamine was not a phenotypic determinant.
Fragmentation of Small-cell Lung Cancer Regulatory States in Heterotypic Microenvironments
Authors: Schaff Dylan L. , Singh Shambhavi , Kim Kee-Beom , Sutcliffe Matthew D. , Park Kwon-Sik , Janes Kevin A. 
Published: April 2020

AbstractSmall-cell lung cancers derive from pulmonary neuroendocrine cells, which have stemlike properties to reprogram into other cell types upon lung injury. It is difficult to uncouple transcriptional plasticity of these transformed cells from genetic changes that evolve in primary tumors or secondary metastases. Profiling of single cells also problematic if the required sample dissociation activates injury-like signaling and reprogramming. Here, we defined cell-state heterogeneities in situ through laser capture microdissection-based 10-cell transcriptomics coupled with stochastic-profiling fluctuation analysis. Using labeled cells from a small-cell lung cancer mouse model initiated by neuroendocrine deletion ofRb1–Trp53, we profiled variations in transcript abundance to identify cell-to-cell differences in regulatory state in vitro and in vivo. Fluctuating transcripts in spheroid culture were partly shared amongRb1–Trp53-null models, and heterogeneities increased considerably when cells were delivered intravenously to colonize the liver. Colonization of immunocompromised animals drove fractional appearance of alveolar type II-like markers and poised cells for paracrine stimulation from immune cells and hepatocytes. Immunocompetency further exaggerated the fragmentation of tumor states in the liver, yielding mixed stromal signatures evident in bulk sequencing from autochthonous tumors and metastases. Dozens of transcript heterogeneities recur irrespective of biological context; their mapped orthologs brought together observations of murine and human small-cell lung cancer. Candidate heterogeneities recurrent in the liver also stratified primary human tumors into discrete groups not readily explained by molecular subtype but with prognostic relevance. We conclude that heterotypic interactions in the liver and lung are an accelerant for intratumor heterogeneity in small-cell lung cancer.Statement of significanceThe single-cell regulatory heterogeneity of small-cell lung cancer becomes increasingly elaborate in the liver, a common metastatic site for the disease.
Lipoprotein(a) and cardiovascular disease: prediction, attributable risk fraction and estimating benefits from novel interventions
Authors: Welsh Paul , Welsh Claire , Celis-Morales Carlos A , Brown Rosemary , Ferguson Lyn D , Mark Patrick B , Lewsey James , Gray Stuart R , Lyall Donald M , Gill Jason MR , Pell Jill P , de Lemos James A , Willeit Peter , Sattar Naveed 
Published: April 2020

AbstractBackgroundLipoprotein (a) (Lp(a)) is a CVD risk factor amenable to intervention and might help guide risk prediction.ObjectivesTo investigate the population attributable fraction due to elevated Lp(a) and its utility in risk prediction.MethodsUsing a prospective cohort study, 413,724 participants from UK Biobank, associations of serum Lp(a) with composite fatal/nonfatal CVD (n=10,065 events), fatal CVD (n=3247), coronary heart disease (n=16,649), ischaemic stroke (n=3191), and peripheral vascular disease (n=2716) were compared using Cox models. Predictive utility was determined by C-index changes. The population attributable fraction was estimated.ResultsMedian Lp(a) was 19.7nmol/L (interquartile interval 7.6-75.3nmol/L). 20.8% had Lp(a) values >100nmol/L; 9.2% had values >175nmol/L. After adjustment for classical risk factors, in participants with no baseline CVD and not taking a statin, 1 standard deviation increment in log Lp(a) was associated with a HR for fatal/nonfatal CVD of 1.09 (95%CI 1.07-1.11). Associations were similar for fatal CVD, coronary heart disease, and peripheral vascular disease. Adding Lp(a) to a prediction model containing traditional CVD risk factors improved the C-index by +0.0017 (95% CI 0.0009, 0.0026). We estimated that having Lp(a) values >100nmol/L accounts for 5.7% of CVD events in the whole cohort. We modelled that an ongoing trial to lower Lp(a) in patients with CVD and Lp(a) above ∼175nmol/L may reduce CVD risk by 20.3%, assuming causality, and an achieved Lp(a) reduction of 80%.ConclusionsPopulation screening for elevated Lp(a) may help to predict CVD and target Lp(a) lowering drugs, if such drugs prove efficacious, to those with markedly elevated levels.
Optimal timing for social distancing during an epidemic
Authors: Patterson-Lomba Oscar 
Published: April 2020

AbstractSocial distancing is an effective way to contain the spread of a contagious disease, particularly when facing a novel pathogen and no pharmacological interventions are available. In such cases, conventional wisdom suggests that social distancing measures should be introduced as soon as possible after the beginning of an outbreak to more effectively mitigate the spread of the disease. Using a simple epidemiological model we show that, however, there is in fact an optimal time to initiate a temporal social distancing intervention if the goal is to reduce the final epidemic size or “flatten” the epidemic curve. The optimal timing depends strongly on the effective reproduction number (R0) of the disease, such that as the R0 increases, the optimal time decreases non-linearly. Additionally, if pharmacological interventions (e.g., a vaccine) become available at some point during the epidemic, the sooner these interventions become available the sooner social distancing should be initiated to maximize its effectiveness. Although based on a simple model, we hope that these insights inspire further investigations within the context of more complex and data-driven epidemiological models, and can ultimately help decision makers to improve temporal social distancing policies to mitigate the spread of epidemics.
Electronic Health Record Documentation of Psychiatric Assessments in Massachusetts Emergency Department and Outpatient Settings During the COVID-19 Pandemic
Authors: Castro Victor M. , Perlis Roy H. 
Published: April 2020

Key PointsQuestionHow did documentation of psychiatric symptoms in outpatient and emergency room settings change with onset of COVID-19 infection in Eastern Massachusetts?FindingsIn this cohort study spanning 2 academic medical centers and 3 community hospitals, prevalence of narrative notes referencing depression or anxiety decreased 75-81% in outpatient settings following onset of coronavirus in March 2019, and by 44–45% in emergency departments.MeaningThe observation that documentation of psychiatric symptoms declined sharply with increasing coronavirus infection in Massachusetts, even as prevalence of such symptoms is anticipated to increase, suggests additional efforts may be required to address these symptoms in the context of COVID-19.
Estimating the risk of COVID-19 death during the course of the outbreak in Korea, February- May, 2020
Authors: Shim Eunha , Mizumoto Kenji , Choi Wongyeong , Chowell Gerardo 
Published: April 2020

AbstractBackground: In Korea, a total of 10,840 confirmed cases of COVID-19 including 256 deaths have been recorded as of May 9, 2020. The time-delay adjusted case fatality risk (CFR) of COVID-19 in Korea is yet to be estimated. Methods: We obtained the daily series of confirmed cases and deaths in Korea reported prior to May 9, 2020. Using statistical methods, we estimated the time-delay adjusted risk for death from COVID-19 in Daegu, Gyeongsangbuk-do, other regions in Korea, as well as the entire country. Results: Our model-based crude CFR fitted the observed data well throughout the course of the epidemic except for the very early stage in Gyeongsangbuk-do; this was partially due to the reporting delay. Our estimates of the risk of death in Gyeongsangbuk-do reached 25.9% (95% CrI: 19.6%-33.6%), 20.8% (95% CrI: 18.1%-24.0%) in Daegu and 1.7% (95% CrI: 1.1%-2.5%) in other regions, whereas the national estimate was 10.2% (95% CrI: 9.0%-11.5%). Conclusions: The latest estimates of CFR of COVID-19 in Korea are considerably high, even with the early implementation of public health interventions including widespread testing, social distancing, and delayed school openings. Geographic differences in the CFR are likely influenced by clusters tied to hospitals and nursing homes.
Whole-chromosome fusions in the karyotype evolution ofSceloporus(Iguania, Reptilia) are more intense in sex chromosomes than autosomes
Authors: Lisachov Artem P. , Tishakova Katerina V. , Romanenko Svetlana A. , Molodtseva Anna S. , Prokopov Dmitry Yu. , Pereira Jorge C. , Ferguson-Smith Malcolm A. , Borodin Pavel M. , Trifonov Vladimir A. 
Published: April 2020

AbstractThere is a growing body of evidence that the common ancestor of vertebrates had a bimodal karyotype, i.e. consisting of large macrochromosomes and small microchromosomes. This type of karyotype organization is preserved in most reptiles. However, certain species independently experience microchromosome fusions. The evolutionary forces behind this are unclear. We investigated the karyotype of the green spiny lizard,Sceloporus malachiticus,an iguana species which has 2n=22, whereas the ancestral karyotype of iguanas had 2n=36. We obtained and sequenced flow-sorted chromosome-specific DNA samples and found that most of the microchromosome fusions in this species involved sex chromosomes. We found that certain ancestral squamate chromosomes, such as the homologue of theAnolis carolinensischromosome 11, are repeatedly involved in sex chromosome formation in different species. To test the hypothesis that the karyotypic shift could be associated with changes in recombination patterns, and to study sex chromosome synapsis and recombination in meiosis, we performed synaptonemal complex analysis in this species and inS. variabilis,a related species with 2n=34. We found that in the species studied the recombination patterns correlate more with phylogeny than with the structure of the karyotype. The sex chromosomes had two distal pseudoautosomal regions and a medial differentiated region.
Algal Neurotoxin Biosynthesis Repurposes the Terpene Cyclase Structural Fold Into anN-prenyltransferase
Authors: Chekan Jonathan R. , McKinnie Shaun M. K. , Noel Joseph P. , Moore Bradley S. 
Published: April 2020

AbstractPrenylation is a common biological reaction in all domains of life whereupon prenyl diphosphate donors transfer prenyl groups onto small molecules as well as large proteins. The enzymes that catalyze these biotransformations are structurally distinct from ubiquitous terpene cyclases that instead assemble terpene molecules via intramolecular rearrangements. Herein we report the structure and molecular details of a new family of prenyltransferases from marine algae that repurposes the terpene cyclase structural fold for theN-prenylation of glutamic acid during the biosynthesis of the potent neurochemicals domoic acid and kainic acid. We solved the X-ray crystal structure of the prenyltransferase found in domoic acid biosynthesis, DabA, and show distinct active site binding modifications that remodel the canonical Mg2+-binding motif. We then applied our structural knowledge of DabA and a homologous enzyme from the kainic acid biosynthetic pathway, KabA, to alter their isoprene donor specificities (geranyl versus dimethylallyl diphosphate) by a single amino acid switch. While the diatom DabA and seaweed KabA enzymes share a common evolutionary lineage, they are distinct from all other terpene cyclases, suggesting a very distant ancestor.SignificanceDomoic acid is a neurotoxin produced by marine algae that readily bioaccumulates in shellfish and significantly impacts both human and animal life. The first committed step of the biosynthesis of domoic acid is theN-prenylation of L-glutamic acid by the enzyme DabA. By solving the crystal structure of DabA, we demonstrate that this enzyme has repurposed the common terpene cyclase fold to catalyze an extremely unusual reaction,N-prenylation of an unactivated primary amine. Application of these structural insights enabled rational engineering of twoN-prenyltransferase enzymes to accept alternative prenyl donors. Ultimately, these results not only expand the scope of reactions catalyzed by a terpene cyclase family member, but will help inform future domoic acid environmental monitoring efforts.
Exogenous and endogenous HDAC inhibitor effects in Rubinstein-Taybi syndrome models
Authors: Di Fede Elisabetta , Ottaviano Emerenziana , Grazioli Paolo , Ceccarani Camilla , Parodi Chiara , Colombo Elisa Adele , Bassanini Giulia , Severgnini Marco , Milani Donatella , Verduci Elvira , Vaccari Thomas , Massa Valentina , Borghi Elisa , Gervasini Cristina 
Published: April 2020

ABSTRACTRubinstein-Taybi syndrome (RSTS) is an autosomal dominant disorder with specific clinical signs and neurodevelopmental impairment. The two known proteins altered in the majority of RSTS patients are the histone acetylation regulators CBP and p300. For assessing possible ameliorative effects of exogenous and endogenous HDAC inhibitors (HDACi), we exploitedin vivoandin vitroRSTS models. First, HDACi effects were tested onDrosophila melanogaster, showing molecular rescue. In the same model, we observed a shift in gut microbiota composition. We then studied HDACi effects in RSTS cell lines compared to healthy donor cells. We observed patients-specific molecular rescue of acetylation defects at subtoxic concentrations. Finally, we assessed commensal gut microbiota composition in a cohort of RSTS patients compared to healthy siblings. Intriguingly, we observed a significant depletion in butyrate-producing bacteria in RSTS patients. In conclusion, this study reports the possibility of modulating acetylation equilibrium by HDACi treatments and the importance of microbiota composition in a chromatinopathy.
Phylogenetic, geographic and habitat distribution of the green-brown polymorphism in European orthopterans
Authors: Schielzeth Holger 
Published: April 2020

AbstractThe green-brown polymorphism among polyneopteran insects represents one of the most penetrant color polymorphisms in any group of organisms. Yet systematic overviews are lacking. I here present analyses of the phylogenetic, geographic and habitat distribution of the green-brown polymorphism across the complete European orthopteran fauna. Overall, 30% of European orthopterans are green-brown polymorphic. Polymorphic species are scattered across the entire phylogenetic tree, including roughly equal proportions of Ensifera and Caelifera. A few taxonomic groups, however, include only brown species. Polymorphic species occur more frequently in clades that contain monomorphic green species than in those without green species. The relative abundance of color morphs in polymorphic species is skewed towards green, and in particular rare/exceptional brown morphs are more common in predominantly green species than rare/exceptional green morphs in predominantly brown species. The patterns of abundances support the hypothesis that loss-of-function mutations play a role in creating polymorphic populations from green species. Polymorphic species are particularly common in moist to mesic grasslands, alpine and arboreal habitats. Dry, open, rocky and cave habitats as well as nocturnal lifestyles are dominated by monomorphic brown species. The proportion of polymorphic species increases from southern to northern latitudes. These marked habitat-dependencies also show that coloration is affected by natural selection and/or environmental filtering. Overall, the results illustrate that the occurrence of the polymorphism is phylogenetically, geographically and ecologically widespread and they suggest that polymorphism is thus potentially in mutation-selection balance across a large number of species.