bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interspecies Chimeric Conditions Affect the Developmental Rate of Human Pluripotent Stem Cells
Authors: Brown Jared , Barry Christopher , Schmitz Matthew T. , Argus Cara , Bolin Jennifer M. , Schwartz Michael P. , Van Aartsen Amy , Steill John , Swanson Scott , Stewart Ron , Thomson James A. , Kendziorski Christina 
Published: September 2020

ABSTRACTHuman pluripotent stem cells hold significant promise for regenerative medicine. However, long differentiation protocols and immature characteristics of stem cell-derived cell types remain challenges to the development of many therapeutic applications. In contrast to the slow differentiation of human stem cellsin vitrothat mirrors a nine-month gestation period, mouse stem cells develop according to a much faster three-week gestation timeline. Here, we tested if co-differentiation with mouse pluripotent stem cells could accelerate the differentiation speed of human embryonic stem cells. Following a six-week RNA-sequencing time course of neural differentiation, we identified 929 human genes that were upregulated earlier and 535 genes that exhibited earlier peaked expression profiles in chimeric cell cultures than in human cell cultures alone. Genes with accelerated upregulation were significantly enriched in Gene Ontology terms associated with neurogenesis, neuron differentiation and maturation, and synapse signaling. Moreover, chimeric mixed samples correlated within uterohuman embryonic samples earlier than human cells alone, and acceleration was dose-dependent on human-mouse co-culture ratios. Differences in the timing and expression levels of genes corresponding to neuron cell types and brain region identity under chimeric conditions were also observed. The altered developmental rates and lineage outcomes described in this report have implications for accelerating human stem cell differentiation and the use of interspecies chimeric embryos in developing human organs for transplantation.Author SummaryHuman pluripotent stem cells often require longin vitroprotocols to form mature cell types of clinical relevance for potential regenerative therapies, a ramification of a nine-month developmental clockin uterothat also runsex utero. What controls species-specific developmental time and whether the timer is amenable to acceleration is unknown. Further, interspecies chimeric embryos are increasingly being created to study early human development or explore the potential growth of human organs for transplantation. How the conflicting developmental speeds of cells from different species co-differentiating together affect each other is not understood. Here, using genome-wide transcriptional analysis of RNA-sequencing time courses, we show that 1) co-differentiating human embryonic stem cells intermixed with mouse stem cells accelerated elements of human developmental programs, 2) the acceleration was dose-dependent on the proportion of mouse cells, and 3) human cells in chimeric samples correlated toin uterosamples earlier than human only samples. Our results provide evidence that some components of species-specific developmental clocks may be susceptible to acceleration.
Advanced Retinal Imaging and Ocular Parameters of the Rhesus Macaque Eye
Authors: Lin Kira H. , Tran Tu , Kim Soohyun , Park Sangwan , Stout J. Timothy , Chen Rui , Rogers Jeffrey , Yiu Glenn , Thomasy Sara , Moshiri Ala 
Published: September 2020

AbstractPurposeTo determine the normal ocular biometric and perform advanced retinal imaging and functional assessment of a non-human primate used commonly in scientific research, the rhesus macaque.MethodsWe performed ocular phenotyping on rhesus macaques at the California National Primate Research Center. This consisted of anterior and posterior segment eye examination by ophthalmologists, advanced retinal imaging, and functional retinal electrophysiology.ResultsFull eye exams were performed on 142 animals consisting of pupillary light reflex, tonometry, external exam and photography, anterior slit lamp examination, and posterior segment examination by indirect ophthalmoscopy. Ages of the rhesus macaques ranged from 0.7 to 29 years (mean=16.4 years, stdev=7.5 years). Anterior segment measurements such as intraocular pressure (n=142), corneal thickness (n=84), lens thickness (n=114), and axial length (n=114) were acquired. Advanced retinal imaging in the form of fundus photography (n=78), optical coherence tomography (n=60), and quantitative autofluorescence (n=44) were obtained. Electroretinography (n=75) was used to assay retinal function. Quantitative analyses of macular structure, retinal layer segmentation, and rod and cone photoreceptor electrical responses are reported. Quantitative assessments were made and variations between genders and age groups were analyzed to compare with established sex and age-related changes in human eyes.ConclusionsThe rhesus macaque has ocular structure and function very similar to that of the human eye. Age-related ocular changes between rhesus and humans are similar. In particular, macular structure and function are very similar to humans making this species particularly useful for the study of macular biology and development of therapies for inherited and age-related macular degenerations as well as cone photoreceptor disorders.
A hybrid high-resolution anatomical MRI atlas with sub-parcellation of cortical gyri using resting fMRI
Authors: Joshi Anand A. , Choi Soyoung , Liu Yijun , Chong Minqi , Sonkar Gaurav , Gonzalez-Martinez Jorge , Nair Dileep , Wisnowski Jessica L. , Haldar Justin P. , Shattuck David W. , Damasio Hanna , Leahy Richard M. 
Published: September 2020

AbstractWe present a new high-quality, single-subject atlas with sub-millimeter voxel resolution, high SNR, and excellent grey-white tissue contrast to resolve fine anatomical details. The atlas is labeled into two parcellation schemes: 1) the anatomical BCI-DNI atlas, which is manually labeled based on known morphological and anatomical features, and 2) the hybrid USCBrain atlas, which incorporates functional information to guide the sub-parcellation of cerebral cortex. In both cases, we provide consistent volumetric and cortical surface-based parcellation and labeling. The intended use of the atlas is as a reference template for structural coregistration and labeling of individual brains. A single-subject T1-weighted image was acquired at a resolution of 0.547mm×0.547mm×0.800mm five times and averaged. Images were processed by an expert neuroanatomist using semi-automated methods in BrainSuite to extract the brain, classify tissue-types, and render anatomical surfaces. Sixty-six cortical and 29 noncortical regions were manually labeled to generate the BCI-DNI atlas. The cortical regions were further sub-parcellated into 130 cortical regions based on multi-subject connectivity analysis using resting fMRI (rfMRI) data from the Human Connectome Project (HCP) database to produce the USCBrain atlas. In addition, we provide a delineation between sulcal valleys and gyral crowns, which offer an additional set of 26 sulcal subregions per hemisphere. Lastly, a probabilistic map is provided to give users a quantitative measure of reliability for each gyral subdivision. Utility of the atlas was assessed by computing adjusted Rand indices between individual sub-parcellations obtained through structural-only coregistration to the USCBrain atlas and sub-parcellations obtained directly from each subject’s resting fMRI data. Both atlas parcellations can be used with the BrainSuite, FreeSurfer, and FSL software packages.
RANKL from Bone Marrow Adipose Lineage Cells Promotes Osteoclast Formation and Bone Loss
Authors: Hu Yan , Li Xiaoqun , Zhi Xin , Cong Wei , Huang Biaotong , Chen Huiwen , Wang Yajun , Li Yinghua , Wang Lipeng , Fang Chao , Guo Jiawei , Liu Ying , Cui Jin , Cao Liehu , Weng Weizong , Zhou Qirong , Wang Sicheng , Chen Xiao , Su Jiacan 
Published: September 2020

AbstractReceptor activator of NF-κB ligand (RANKL) is essential for osteoclast formation and bone remodeling. Nevertheless, the cellular source of RANKL for osteoclastogenesis has not been fully uncovered. Different from peripheral adipose tissue, bone marrow (BM) adipose lineage cells originate from bone marrow mesenchymal stromal cells(BMSCs). Here we demonstrate that adiponectin promoter-driven Cre expression (AdipoqCre) can target bone marrow adipose lineage cells. We cross theAdipoqCremice withranklfl/flmice to conditionally delete RANKL from BM adipose lineage cells. Conditional deletion of RANKL increases cancellous bone mass of long bones in mice by reducing the formation of trabecular osteoclasts and inhibiting bone resorption but does not affect cortical bone thickness or resorption of calcified cartilage.AdipoqCre; ranklfl/flmice exhibit resistance to estrogen deficiency and rosiglitazone (ROS) induced trabecular bone loss but show bone loss induced by unloading. BM adipose lineage cells therefore represent an essential source of RANKL for the formation of trabecula osteoclasts and resorption of cancellous bone during remodeling under physiological and pathological conditions. Targeting bone marrow adiposity is a promising way of preventing pathological bone loss.
Idiosyncratic variation in the fitness costs of tetracycline-resistance mutations inEscherichia coli
Authors: Card Kyle J. , Jordan Jalin A. , Lenski Richard E. 
Published: September 2020

AbstractA bacterium’s fitness relative to its competitors, both in the presence and absence of antibiotics, plays a key role in its ecological success and clinical impact. In this study, we examine whether tetracycline-resistant mutants are less fit in the absence of the drug than their sensitive parents, and whether the fitness cost of resistance is constant or variable across independently derived lines. Tetracycline-resistant lines suffered, on average, a reduction in fitness of almost 8%. There was substantial among-line variation in the fitness cost. This variation was not associated with the level of phenotypic resistance conferred by the mutations, nor did it vary significantly across several different genetic backgrounds. The two resistant lines with the most extreme fitness costs involved functionally unrelated mutations on different genetic backgrounds. However, there was also significant variation in the fitness costs for mutations affecting the same pathway and even different alleles of the same gene. Our findings demonstrate that the fitness costs of antibiotic resistance do not always correlate with the phenotypic level of resistance or the underlying genetic changes. Instead, these costs reflect the idiosyncratic effects of particular resistance mutations and the genetic backgrounds in which they occur.
Inferring MHC interacting SARS-CoV-2 epitopes recognized by TCRs towards designing T cell-based vaccines
Authors: Mohseni Amir Hossein , Taghinezhad-S Sedigheh , Su Bing , Wang Feng 
Published: September 2020

AbstractThe coronavirus disease 2019 (COVID-19) is triggered by severe acute respiratory syndrome mediated by coronavirus 2 (SARS-CoV-2) infection and was declared by WHO as a major international public health concern. While worldwide efforts are being advanced towards vaccine development, the structural modeling of TCR-pMHC (T Cell Receptor-peptide-bound Major Histocompatibility Complex) regarding SARS-CoV-2 epitopes and the design of effective T cell vaccine based on these antigens are still unresolved. Here, we present both pMHC and TCR-pMHC interfaces to infer peptide epitopes of the SARS-CoV-2 proteins. Accordingly, significant TCR-pMHC templates (Z-value cutoff > 4) along with interatomic interactions within the SARS-CoV-2-derived hit peptides were clarified. Also, we applied the structural analysis of the hit peptides from different coronaviruses to highlight a feature of evolution in SARS-CoV-2, SARS-CoV, bat-CoV, and MERS-CoV. Peptide-protein flexible docking between each of the hit peptides and their corresponding MHC molecules were performed, and a multi-hit peptides vaccine against the S and N glycoprotein of SARS-CoV-2 was designed. Filtering pipelines including antigenicity, and also physiochemical properties of designed vaccine were then evaluated by different immunoinformatics tools. Finally, vaccine-structure modeling and immune simulation of the desired vaccine were performed aiming to create robust T cell immune responses. We anticipate that our design based on the T cell antigen epitopes and the frame of the immunoinformatics analysis could serve as valuable supports for the development of COVID-19 vaccine.
S494 O-glycosylation site on the SARS-COV-2 RBD Affects the Virus Affinity to ACE2 and its Infectivity; A Molecular Dynamics Study
Authors: Rahnama Shadi , Irani Maryam Azimzadeh , Amininasab Mehriar , Ejtehadi Mohammad Reza 
Published: September 2020

AbstractSARS-COV-2 is a strain of Coronavirus family which caused the extensive pandemic of COVID-19, which is still going on. Several studies showed that the glycosylation of virus spike (S) protein and the Angiotensin-Converting Enzyme 2 (ACE2) receptor on the host cell is critical for the virus infectivity. Molecular Dynamics (MD) simulations were used to explore the role of a novel mutated O-glycosylation site (D494S) on the Receptor Binding Domain (RBD) of S protein. This site was suggested as a key mediator of virus-host interaction. We showed that the decoration of S494 with elongated O-glycans results in stabilized interactions on the direct RBD-ACE2 interface with more favorable binding free energies for longer oligosaccharides. Hence, this crucial factor must be taken into account for any further inhibitory approaches towards RBD-ACE2 interaction.
Some theoretical aspects of reprogramming the standard genetic code
Authors: Nowak Kuba , Błażej Paweł , Wnetrzak Małgorzata , Mackiewicz Dorota , Mackiewicz Paweł 
Published: September 2020

1AbstractReprogramming of the standard genetic code in order to include non-canonical amino acids (ncAAs) opens a new perspective in medicine, industry and biotechnology. There are several methods of engineering the code, which allow us for storing new genetic information in DNA sequences and transmitting it into the protein world. Here, we investigate the problem of optimal genetic code extension from theoretical perspective. We assume that the new coding system should encode both canonical and new ncAAs using 64 classical codons. What is more, the extended genetic code should be robust to point nucleotide mutation and minimize the possibility of reversion from new to old information. In order to do so, we follow graph theory to study the properties of optimal codon sets, which can encode 20 canonical amino acids and stop coding signal. Finally, we describe the set of vacant codons that could be assigned to new amino acids. Moreover, we discuss the optimal number of the newly incorporated ncAAs and also the optimal size of codon blocks that are assigned to ncAAs.
Time and Space in Segmentation
Authors: Clark Erik 
Published: September 2020

AbstractArthropod segmentation and vertebrate somitogenesis are leading fields in the experimental and theoretical interrogation of developmental patterning. However, despite the sophistication of current research, basic conceptual issues remain unresolved. These include (1) the mechanistic origins of spatial organisation within the segment addition zone (SAZ); (2) the mechanistic origins of segment polarisation; (3) the mechanistic origins of axial variation; and (4) the evolutionary origins of simultaneous patterning. Here, I explore these problems using coarse-grained models of cross-regulating dynamical processes. In the morphogenetic framework of a row of cells undergoing axial elongation, I simulate interactions between an “oscillator”, a “switch”, and up to three “timers”, successfully reproducing essential patterning behaviours of segmenting systems. By comparing the output of these largely cell-autonomous models to variants that incorporate positional information, I find that scaling relationships, wave patterns, and patterning dynamics all depend on whether the SAZ is regulated by temporal or spatial information. I also identify three mechanisms for polarising oscillator output, all of which functionally implicate the oscillator frequency profile. Finally, I demonstrate significant dynamical and regulatory continuity between sequential and simultaneous modes of segmentation. I discuss these results in the context of the experimental literature.
Ubc9deletion in adipocytes causes lipoatrophy in mice
Authors: Cox Aaron R. , Chernis Natasha , Kim Kang Ho , Masschelin Peter M. , Saha Pradip K. , Briley Shawn M. , Sharp Robert , Felix Jessica B. , Moore David D. , Pangas Stephanie A. , Hartig Sean M. 
Published: September 2020

ABSTRACTObjectiveWhite adipose tissue (WAT) expansion regulates energy balance and overall metabolic homeostasis. WAT absence or loss occurring through lipodystrophy and lipoatrophy contributes to the development of dyslipidemia, hepatic steatosis, and insulin resistance. We previously demonstrated the sole small ubiquitin-like modifier (SUMO) E2-conjuguating enzyme Ubc9 represses human adipocyte differentiation. Germline and other tissue-specific deletions ofUbc9frequently cause lethality in mice. As a result, the role of Ubc9 during WAT development remains unknown.MethodsTo determine how Ubc9 impacts body composition and energy balance, we generated adipocyte-specificUbc9knockout mice (Ubc9a-KO). CRISPR/Cas9 gene editing inserted loxP sites flanking exons 3 and 4 at theUbc9locus. Subsequent genetic crosses to AdipoQ-Cre transgenic mice allowed deletion ofUbc9in white and brown adipocytes. We measured multiple metabolic endpoints that describe energy balance and carbohydrate metabolism inUbc9a-KOand littermate controls during postnatal growth.ResultsTo our surprise,Ubc9a-KOmice developed hyperinsulinemia and hepatic steatosis. Global energy balance defects emerged from dysfunctional WAT marked by pronounced local inflammation, loss of serum adipokines, hepatomegaly, and near absence of major adipose tissue depots. We observed progressive lipoatrophy that commences in the early adolescent period.ConclusionsOur results demonstrate thatUbc9expression in mature adipocytes is essential for maintaining WAT expansion. Deletion ofUbc9in fat cells compromised and diminished adipocyte function that provoked WAT inflammation and ectopic lipid accumulation in the liver. Our findings reveal an indispensable role forUbc9during white adipocyte expansion and endocrine control of energy balance.
Abl2:cortactin interactions regulate dendritic spine stability via control of a stable filamentous actin pool
Authors: Shaw Juliana E. , Kilander Michaela B. C. , Lin Yu-Chih , Koleske Anthony J. 
Published: September 2020

AbstractDendritic spines are enriched with stable and dynamic actin filaments, which determine their structure and shape. Disruption of the Abl2/Arg nonreceptor tyrosine kinase in mice compromises spine stability and size. We provide evidence that binding to cortactin tethers Abl2 in spines, where Abl2 and cortactin maintain the small pool of stable actin required for dendritic spine stability. Using fluorescence recovery after photobleaching of GFP-actin, we find that disruption of Abl2:cortactin interactions eliminates stable actin filaments in dendritic spines, significantly reducing spine density. A subset of spines remaining after Abl2 depletion retain their stable actin pool and undergo activity-dependent spine enlargement associated with increased cortactin levels. Finally, tonic increases in synaptic activity rescue spine loss upon Abl2 depletion by promoting cortactin enrichment in vulnerable spines. Together, our findings strongly suggest Abl2:cortactin interactions promote spine stability by maintaining pools of stable actin filaments in spines.
Citrullination of proteins as a specific response mechanism in plants
Authors: Marondedze Claudius , Elia Giuliano , Thomas Ludivine , Wong Aloysius , Gehring Chris 
Published: September 2020

ABSTRACTArginine deamination, also referred to as citrullination of proteins by peptidyl-arginine deiminases, is a post-translational modification affecting histone modifications, epigenetic transcriptional regulation and proteolysis in animals, but has not been reported in higher plants. Here we report, firstly, thatArabidopsis thalianaproteome contains proteins with a specific citrullination signature and that many of the citrullinated proteins have nucleotide-binding regulatory functions. Secondly, we show that changes in the citrullinome occur in response to cold stress, and thirdly, we identify anArabidopsis thalianaprotein with calcium-dependent arginine deiminase activity. Taken together, these findings establish this post-translational modification as a hitherto neglected component of cellular reprogramming during stress responses.
Bulk segregant analysis reveals environment × genotype interactions determining malaria parasite growth
Authors: Kumar Sudhir , Li Xue , McDew-White Marina , Reyes Ann , Delgado Elizabeth , Sayeed Abeer , Haile Meseret T. , Abatiyow Biley A. , Kennedy Spencer Y. , Camargo Nelly M. , Checkley Lisa A. , Brenneman Katelyn V. , Button-Simons Katrina A. , Duraisingh Manoj T. , Cheeseman Ian H. , Kappe Stefan H. I. , Nosten François , Ferdig Michael T. , Vaughan Ashley M. , Anderson Tim J. C. 
Published: September 2020

AbstractWhat genes determine growth and nutrient utilization in asexual blood-stage malaria parasites? Competition experiments between a lab-adapted African parasite (NF54), and a recently isolated Asian parasite (NHP4026) reveal contrasting outcomes in different media: NF54 outcompetes NHP4026 in media containing human serum, while NHP4026 outcompetes NF54 in media containing AlbuMAX, a lipid-rich bovine serum formulation. We conducted parasite genetic crosses and compared genome-wide allele frequency changes in progeny populations cultured in media containing serum or AlbuMAX: this bulk segregant analysis (BSA) reveals three quantitative trait loci (QTL) underlying differential growth. The strongest QTL (chromosome 13) containsEBA-140: competition experiments betweenEBA-140-knockout and isogenic wildtype parasites showed fitness reversals in the two media types, validating this locus as the causative gene. These results (i) demonstrate the effectiveness of BSA for dissecting fitness traits inPlasmodium falciparum, and (ii) reveal an intimate link between red blood cell invasion and nutrient composition of growth media.
Measuring expression heterogeneity of single-cell cytoskeletal protein complexes
Authors: Vlassakis Julea , Hansen Louise L. , Higuchi-Sanabria Ryo , Zhou Yun , Tsui C. Kimberly , Dillin Andrew , Huang Haiyan , Herr Amy E. 
Published: September 2020

AbstractMultimeric cytoskeletal protein complexes orchestrate normal cellular function. However, protein-complex distributions in stressed, heterogeneous cell populations remain unknown. Cell staining and proximity-based methods have limited selectivity and/or sensitivity for endogenous multimeric protein-complex quantification from single cells. We introduce micro-arrayed, differential detergent fractionation to simultaneously detect protein complexes in 100s of individual cells. Fractionation occurs by 60 s size-exclusion electrophoresis with protein complex-stabilizing buffer that minimizes depolymerization. Co-detection of cytoskeletal protein complexes in U2OS cells treated with filamentous actin (F-actin) destabilizing LatA detects a subpopulation (~11%) exhibiting downregulated F-actin, but upregulated microtubule and intermediate filament protein complexes. Thus, some cells upregulate other cytoskeletal complexes to counteract the stress of LatA treatment. We also sought to understand the effect of non-chemical stress on cellular heterogeneity of F-actin. We find heat shock dysregulates F- and G-actin correlation. The assay overcomes selectivity limitations to biochemically quantify single-cell protein complexes perturbed with diverse stimuli.