bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multivalent interaction of ESCO2 with the replication machinery is required for cohesion
Authors: Bender Dawn , Da Silva Eulália Maria Lima , Chen Jingrong , Poss Annelise , Gawey Lauren , Rulon Zane , Rankin Susannah 
Published: June 2019

AbstractThe tethering together of sister chromatids by the cohesin complex ensures their accurate alignment and segregation during cell division. In vertebrates, the establishment of cohesion between sister chromatids requires the activity of the ESCO2 acetyltransferase, which modifies the Smc3 subunit of cohesin. It was shown recently that ESCO2 promotes cohesion through interaction with the MCM replicative helicase. However, ESCO2 does not significantly colocalize with the MCM helicase, suggesting there may be additional interactions that are important for ESCO2 function. Here we show that ESCO2 is recruited to replication factories, the sites of DNA replication. We show that ESCO2 contains multiple conserved PCNA-interaction motifs in its N-terminus, and that each of these motifs are essential to ESCO2’s ability to establish sister chromatid cohesion. We propose that multiple PCNA interaction motifs embedded in a largely flexible and disordered region of the protein underlie the ability of ESCO2 to establish cohesion between sister chromatids precisely as they are born during DNA replication.SummaryCohesin modification by the ESCO2 acetyltransferase is required for cohesion between sister chromatids. Here we identify multiple motifs in ESCO2 that mediate its interaction with the replication processivity factor PCNA, and show that their mutation abrogates the ability of ESCO2 to ensure cohesion.
Cryo-EM structures capturing the entire transport cycle of the P4-ATPase flippase
Authors: Hiraizumi Masahiro , Yamashita Keitaro , Nishizawa Tomohiro , Nureki Osamu 
Published: June 2019

AbstractIn eukaryotic membranes, P4-ATPases mediate the translocation of phospholipids from the outer to inner leaflet and maintain lipid asymmetry, which is critical for protein trafficking and signaling pathways. Here we report the cryo-EM structures of six distinct intermediates of the human ATP8A1-CDC50a hetero-complex, at 2.6–3.3 Å resolutions, revealing the entire lipid translocation cycle of this P4-ATPase. ATP-dependent phosphorylation induces a large rotational movement of the actuator domain around the phosphorylation site, accompanied by lateral shifts of the first and second transmembrane helices, thereby allowing phosphatidylserine binding. The phospholipid head group passes through the hydrophilic cleft, while the acyl chain is exposed toward the lipid environment. These findings advance our understanding of the flippase mechanism and the disease-associated mutants of P4-ATPases.One Sentence SummaryCryo-EM reveals lipid translocation by P4-type flippase.
Benefits of higher resistance-training volume depends on ribosome biogenesis
Authors: Hammarström Daniel , Øfsteng Sjur , Koll Lise , Hanestadhaugen Marita , Hollan Ivana , Apro William , Whist Jon Elling , Blomstrand Eva , Rønnestad Bent R. , Ellefsen Stian 
Published: June 2019

AbstractResistance-exercise volume is a determinant of training outcomes. However not all individuals respond in a dose-dependent fashion. In this study, 34 healthy individuals (males n = 16, age 23.6 (4.1) years; females n = 18, 22.0 (1.3) years) performed moderate- (3 sets per exercise, MOD) and low-volume (1 set, LOW) resistance training contralateral fashion for 12 weeks (2-3 sessions × week−1) enabling intra-individual comparisons of effects of training modalities. Muscle cross-sectional area (CSA) and muscle strength was assessed at weeks 0 and 12, along with biopsy sampling (m. Vastus lateralis). Muscle biopsies were also sampled before and one hour after the fifth session (Week 2). MOD resulted in larger increases in muscle CSA (5.2 (3.8)% versus 3.7 (3.7)%, P < 0.001) and strength (3.4-7.7% difference, all P < 0.05). In muscle, this coincided with greater reductions in type IIX fibres from week 0 to week 12 (MOD, −4.6 vs. LOW - 3.2%-point), greater post-exercise (Week 2) phosphorylation of mTOR (12%), S6-kinase 1 (19%) and ribosomal protein S6 (28%, Week 2), greater rested-state total RNA (8.8%, Week 2) and greater exercise-induced elevation of c-Myc mRNA expression (25%, Week 2; all P < 0.05). Fifteen participants displayed robust benefits of MOD on muscle hypertrophy. This was associated with greater accumulation of total RNA at Week 2 in MOD vs. LOW as every 1% difference increased the odds of MOD benefit by 5.4% (P = 0.010). In conclusion, MOD led to on average greater adaptations to resistance training and dose-dependent hypertrophy was associated with volume-dependent regulation of total RNA at week 2. This suggests that ribosomal biogenesis regulates the dose-response relationship between training volume and muscle hypertrophy.Key pointsFor individuals showing suboptimal adaptations to resistance training, manipulation of training volume is a potential measure to facilitate responses. This remains unexplored in previous research.Here, 34 untrained individuals performed contralateral resistance training with moderate and low volume for 12 weeks. Overall, moderate volume led to larger increases in muscle cross-sectional area, strength and type II fibre-type transitions.These changes coincided with greater activation of signaling pathways controlling muscle growth and greater induction of ribosome synthesis.Fifteen individuals displayed clear benefit of moderate-volume training on muscle hypertrophy. This coincided with greater total RNA accumulation in the early-phase of the training period, suggesting that ribosomal biogenesis regulates the dose-response relationship between training volume and muscle hypertrophy.These results demonstrate that there is a dose-dependent relationship between training volume and muscle hypertrophy. On the individual level, benefits of higher training volume was associated with increased ribosomal biogenesis.
Design of biochemical pattern forming systems from minimal motifs
Authors: Glock Philipp , Brauns Fridtjof , Halatek Jacob , Frey Erwin , Schwille Petra 
Published: June 2019

AbstractAlthough molecular self-organization and pattern formation are key features of life, only very few pattern-forming biochemical systems have been identified that can be reconstituted and studied in vitro under defined conditions. A systematic understanding of the underlying mechanisms is often hampered by multiple interactions, conformational flexibility and other complex features of the pattern forming proteins. Because of its compositional simplicity of only two proteins and a membrane, the MinDE system from Escherichia coli has in the past years been invaluable for deciphering the mechanisms of spatiotemporal self-organization in cells. Here we explored the potential of reducing the complexity of this system even further, by identifying key functional motifs in the effector MinE that could be used to design pattern formation from scratch. In a combined approach of experiment and quantitative modeling, we show that starting from a minimal MinE-MinD interaction motif, pattern formation can be obtained by adding either dimerization or membrane-binding motifs. Moreover, we show that the pathways underlying pattern formation are recruitment-driven cytosolic cycling of MinE and recombination of membrane-bound MinE, and that these differ in their in vivo phenomenology.
Neural correlates of exceptional memory ability in SuperAgers: A multimodal approach using FDG-PET, PIB-PET, and MRI
Authors: Borelli Wyllians Vendramini , Leal-Conceição Eduardo , Andrade Michele Alberton , Esper Nathalia Bianchini , Feltes Paula Kopschina , Soder Ricardo Bernardi , Matushita Cristina Sebastião , Hartmann Louise Mross , Radaelli Graciane , Schilling Lucas Porcello , Moriguchi-Jeckel Cristina , da Silva Ana Maria Marques , Portuguez Mirna Wetters , Franco Alexandre Rosa , da Costa Jaderson Costa 
Published: June 2019

AbstractIndividuals at 80 years of age or above with exceptional memory are considered SuperAgers (SA). A multimodal brain analysis of SA may provide biomarkers of successful cognitive aging. Herein, a molecular (PET-FDG, PET-PIB), functional (fMRI) and structural analysis (MRI) of SA was conducted. Ten SA, ten age-matched older adults (C80) and ten cognitively normal middle-aged adults underwent cognitive testing and neuroimaging examinations. The relationship between cognitive scores and cingulate areas and hippocampus were examined. The SA group showed increased FDG SUVr in the left subgenual Anterior Cingulate Cortex (sACC, p<0.005) as compared to that in the C80 group. Amyloid deposition was similar between SA and C80 in the described regions or overall areas (p>0.05). The SA group also presented decreased connectivity between left sACC and posterior cingulate (p<0.005) as compared to that of C80 group. These results support the key role of ACC in SA, even in the presence of amyloid deposition. It also suggests that sACC can be used as a potential memory biomarker in older adults.AbbreviationsBCa – Bias corrected accelerated: SA – SuperAgers: C50 – Middle-aged controls: C80 – Age-matched controls
Synonymous codon substitutions perturb co-translational protein foldingin vivoand impair cell fitness
Authors: Walsh Ian M. , Bowman Micayla A. , Soto Iker F. , Rodriguez Anabel , Clark Patricia L. 
Published: June 2019

AbstractIn the cell, proteins are synthesized from N- to C-terminus and begin to fold during translation. Co-translational folding mechanisms are therefore linked to elongation rate, which varies as a function of synonymous codon usage. However, synonymous codon substitutions can affect many distinct cellular processes, which has complicated attempts to deconvolve the extent to which synonymous codon usage can promote or frustrate proper protein foldingin vivo. Although previous studies have shown that some synonymous changes can lead to different final structures, other substitutions will likely be more subtle, perturbing predominantly the protein folding pathway without radically altering the final structure. Here we show that synonymous codon substitutions encoding a single essential enzyme lead to dramatically slower cell growth. These mutations do not prevent active enzyme formation; instead, they predominantly alter the protein folding mechanism, leading to enhanced degradationin vivo. These results support a model where synonymous codon substitutions can impair cell fitness by significantly perturbing co-translational protein folding mechanisms, despite the chaperoning provided by the cellular protein homeostasis network.SignificanceMany proteins that are incapable of refoldingin vitronevertheless fold efficiently to their native state in the cell. This suggests that more information than the amino acid sequence is required to properly fold these proteins. Here we show that synonymous mRNA mutations can alter a protein folding mechanismin vivo, leading to changes in cellular fitness. This work demonstrates that synonymous codon selection can play an important role in supporting efficient protein productionin vivo.
Spatiotemporal analysis reveals significant overlap of key proepicardial markers in the developing murine heart
Authors: Lupu Irina-Elena , Redpath Andia N. , Smart Nicola 
Published: June 2019

AbstractDuring embryonic development, the epicardium provides a source of multipotent progenitors for cardiac lineages, including pericytes, fibroblasts and coronary smooth muscle cells. The epicardium originates from a region of splanchnopleural mesoderm known as the proepicardial organ (PEO). The potential of the epicardium to contribute to coronary endothelium has been disputed, due to conflicting lineage tracing results with different PEO Cre lines. Controversy also surrounds when epicardial cell fate becomes restricted. Using single-cell RNA-sequencing, microscopy and flow cytometry-based single molecule RNA in situ hybridisation techniques, we systematically investigated the expression of five widely used epicardial markers, Wt1, Tcf21, Tbx18, Sema3d and Scx, over the course of development. We show co-expression of all markers in the PEO and epicardial layer until E13.5, then sequential downregulation as it undergoes quiescence. Markers also decrease in invading epicardium-derived progenitors, with the exception of Tcf21, lost only in epicardium-derived mural cells. Moreover, we demonstrate that the epicardium does not significantly contribute coronary endothelium. Our findings clarify a number of prevailing discrepancies in the field and support the notion that epicardial fate is not pre-determined within the PEO.Summary statementAssessing expression of five principal (pro)epicardial markers reveals their complete overlap during early embryonic development, challenging previous dogma regarding the existence of sub-compartments and the pre-committed fate model.
Teaching R in the undergraduate ecology classroom: approaches, lessons learned, and recommendations
Authors: Auker Linda A. , Barthelmess Erika L. 
Published: June 2019

AbstractEcology requires training in data management and analysis. In this paper, we present data from the last 10 years demonstrating the increase in the use of R, an open-source programming environment, in ecology and its prevalence as a required skill in job descriptions. Because of its transparent and flexible nature, R is increasingly used for data management and analysis in the field of ecology. Consequently, job postings targeting candidates with a bachelor’s degree and a required knowledge of R have increased over the past ten years. We discuss our experiences teaching undergraduates R in two advanced ecology classes using different approaches. One approach, in a course with a field lab, focused on collecting, cleaning, and preparing data for analysis. The other approach, in a course without a field lab, focused on analyzing existing data sets and applying the results to content discussed in the lecture portion of the course. Our experiences determined that each approach had strengths and weaknesses. We recommend that above all, instructors of ecology and related subjects should be encouraged to include R in their coursework. Furthermore, instructors should be aware of the following: learning R is a separate skill from learning statistics; writing R assignments is a significant time sink for course preparation; and, there is a tradeoff between teaching R and teaching content. Determining how one’s course fits into the curriculum and identifying resources outside of the classroom for students’ continued practice will ensure that R training is successful and will extend beyond a one-semester course.
Multiple roles of the polycistronic genetarsaless/mille-pattes/polished-riceduring embryogenesis of the kissing bugRhodnius prolixus
Authors: Tobias-Santos Vitória , Guerra-Almeida Diego , Mury Flavia , Ribeiro Lupis , Berni Mateus , Araujo Helena , Logullo Carlos , Feitosa Natália Martins , de Souza-Menezes Jackson , Costa Evenilton Pessoa , Nunes-da-Fonseca Rodrigo 
Published: June 2019

AbstractGenes encoding small open-reading frames (smORFs) have been characterized as essential players of developmental processes. The smORFtarsaless/mille-pattes/polished-ricehas been thoroughly investigated in holometabolous insects, such as the fruit flyDrosophila melanogasterand the red flour beetleTribolium castaneum, while its function in hemimetabolous insects remains unknown. Thus, we analyzed the function of thetal/pri/mlptortholog in a hemimetabolous insect, the kissing bugRhodnius prolixus (Rp). First, sequence analysis shows thatRp-tal/pri/mlptpolycistronic mRNA encodes two small peptides (11 to 14 amino acids) containing a LDPTG motif. Interestingly, a new hemipteran-specific conserved peptide of approximately 80 amino acids was also identified byin silicoanalysis.In silicodocking analysis supports the high-affinity binding of the small LDPTG peptides to the transcription factor Shavenbaby.Rp-tal/pri/mlpt in situhybridization and knockdown via RNA interference showed a conserved role ofRp-tal/pri/mlptduring embryogenesis, with a major role in the regulation of thoracic versus abdominal segmentation, leg development and head formation. Altogether, our study shows thattal/pri/mlptsegmentation role is conserved in the common ancestor of Paraneoptera and suggests that polycistronic genes might generate order specific smORFs.
Genomic Environments and Their Influence on Transposable Element Communities
Authors: Saylor Brent , Kremer Stefan C. , Gregory T. Ryan , Cottenie Karl 
Published: June 2019

AbstractBackgroundDespite decades of research the factors that cause differences in transposable element (TE) distribution and abundance within and between genomes are still unclear. Transposon Ecology is a new field of TE research that promises to aid our understanding of this often-large part of the genome by treating TEs as species within their genomic environment, allowing the use of methods from ecology on genomic TE data. Community ecology methods are particularly well suited for application to TEs as they commonly ask questions about how diversity and abundance of a community of species is determined by the local environment of that community.ResultsUsing a redundancy analysis, we found that ~ 50% of the TEs within a diverse set of genomes are distributed in a predictable pattern along the chromosome, and the specific TE superfamilies that show these patterns are relate to the phylogeny of the host taxa. In a more focused analysis, we found that ~60% of the variation in the TE community within the human genome is explained by its location along the chromosome, and of that variation two thirds (~40% total) was explained by the 3D location of that TE community within the genome (i.e. what other strands of DNA physically close in the nucleus). Of the variation explained by 3D location half (20% total) was explained by the type of regulatory environment (sub compartment) that TE community was located in. Using an analysis to find indicator species, we found that some TEs could be used as predictors of the environment (sub compartment type) in which they were found; however, this relationship did not hold across different chromosomes.ConclusionsThese analyses demonstrated that TEs are non-randomly distributed across many diverse genomes and were able to identify the specific TE superfamilies that were non-randomly distributed in each genome. Furthermore, going beyond the one-dimensional representation of the genome as a linear sequence was important to understand TE patterns within the genome. Additionally, we extended the utility of traditional community ecology methods in analyzing patterns of TE diversity.
SRSF3 confers selective processing of miR-17-92 cluster to promote tumorigenic properties in colorectal cancer
Authors: Ratnadiwakara Madara , Engel Rebekah , Jarde Thierry , McMurrick Paul J , Abud Helen E , Änkö Minna-Liisa 
Published: June 2019

AbstractAlmost a half of microRNAs (miRNAs) in mammalian cells are generated from polycistronic primary transcripts encoding more than one miRNA. Mature miRNAs from polycistronic clusters frequently regulate complementary sets of target mRNAs. How the processing of individual miRNAs within the clusters is controlled to give rise to distinct miRNA levels in vivo is not fully understood. Our investigation of SRSF3 (Serine-Arginine Rich Splicing Factor3) regulated noncoding RNAs in pluripotent cells identified miR-17-92 cluster as a key SRSF3 target, SRSF3 binding to the CNNC motif 17-18nt downstream of the miRNA stem loop. Here we show that SRSF3 binding site context, not merely the distance from the stem loop, within primary transcript is a critical determinant of the processing efficiency of distinct miRNAs derived from the miR-17-92 cluster. SRSF3 specifically enhanced the processing of two paralog miRNAs, miR-17 and miR-20a, targeting overlapping mRNAs including the cell cycle inhibitor CDKN1A/p21. Functional analysis demonstrated that SRSF3 inhibits CDKN1A expression and promotes cell cycle and self-renewal through the miRNA processing pathway both in normal pluripotent stem cells and cancer cells. Strikingly, analysis of colorectal cancer tumour-normal pairs demonstrated that the SRSF3-regulated miRNA processing pathway is present in a large proportion of colorectal cancer patients and distinguishes poorly differentiated high-grade tumours. Our research uncovers a critical role of SRSF3 in selective processing of miR-17-92 miRNAs, which mechanistically and functionally links SRSF3 to hallmark features of cancer.
Fc receptor-like 6 (FCRL6) defines pre-BCR dependent and independent pathways of natural antibody selection
Authors: Honjo Kazuhito , Won Woong-Jai , King Rodney G. , Ianov Lara , Crossman David K. , Easlick Juliet L. , Shakhmatov Mikhail A. , Khass Mohamed , Vale Andre M. , Stephan Robert P. , Li Ran , Davis Randall S. 
Published: June 2019

AbstractB-1a cells produce ‘natural’ antibodies (Abs) to neutralize pathogens and clear neo self-antigens, but the fundamental selection mechanisms that shape their polyreactive repertoires are poorly understood. Here, we identified a B cell progenitor subset defined by Fc receptor-like 6 (FCRL6) expression, harboring innate-like defense, migration, and differentiation properties conducive for natural Ab generation. Compared to FCRL6-pro B cells, the repressed mitotic, DNA damage repair, and signaling activity of FCRL6+progenitors, yielded VHrepertoires with biased distalIghvsegment accessibility, constrained diversity, and hydrophobic and charged CDR-H3 sequences. Beyond nascent autoreactivity, VH11 productivity, which predominates phosphatidylcholine-specific B-1a B cell receptors (BCRs), was higher for FCRL6+cells as was pre-BCR formation, which was required for Myc induction and VH11, but not VH12, B-1a development. Thus, FCRL6 revealed unexpected heterogeneity in the developmental origins, regulation, and selection of natural Abs at the pre-BCR checkpoint with implications for autoimmunity and lymphoproliferative disorders.