bluuebunny/crossref_metadata_2025 huggingface dataset:
An analysis of avian vocal performance at the note and song levels
Authors: Logue David M. , Sheppard Jacob A. , Walton Bailey , Brinkman Benjamin E. , Medina Orlando J.
Published: June 2019

Sexual displays that require extreme feats of physiological performance have the potential to reliably indicate the signaller’s skill. The hypothesis that the structure of bird song is physiologically constrained remains controversial. We tested for evidence of performance constraints in Adelaide’s warblers (Setophaga adelaidae) songs. At the note level, we identified three trade-offs with well-defined limits. At the song level, we identified two trade-offs, but their limits were less well-defined than the note-level limits. Trade-offs at both levels suggest that song structure is constrained by limits to the speed of both frequency modulation (while vocalizing and between notes) and respiration. Individual males experience the same trade-offs that characterize the population, but the intensity of those trade-offs varies among individuals. Performance metrics derived from the observed limits to performance varied moderately among individuals and strongly among song types. Note-level performance metrics were positively skewed, as predicted by the hypothesis that this population has experienced positive selection for constrained performance. We conclude that physiological limits on frequency modulation and respiration constrain song structure in male Adelaide’s warblers. Further work is needed to determine whether receivers respond to natural levels of variation in performance, and whether performance correlates with singer quality.
Revisiting the Origin of the Octoploid Strawberry
Authors: Liston Aaron , Wei Na , Tennessen Jacob , Li Junmin , Dong Ming , Ashman Tia-Lynn
Published: June 2019

The cultivated strawberry, Fragaria ×ananassa, originated in France approximately 270 years ago via hybridization between two wild species introduced from North and South America. Both the cultivated strawberry and its parental species are octoploids with 2n=8x=56 chromosomes. In the recent publication of the genome of the cultivated strawberry, the authors present a novel phylogenetic hypothesis, proposing that each of the four subgenomes originated from a different 2n=2x=14 diploid progenitor. They further suggest that the hexaploid species Fragaria moschata was a direct ancestor of the strawberries. We reanalyzed the four octoploid subgenomes in a phylogenomic context, and found that only two extant diploids were progenitors, a result that is consistent with several previous studies. We also conducted a phylogenetic analysis of genetic linkage-mapped loci in the hexaploid F. moschata, and resolved its origin as independent of the octoploids. We identified assumptions in their tree-searching algorithm that prevented it from accepting extinct or unsampled progenitors, and we argue that this is a critical weakness of their approach. Correctly identifying their diploid progenitors is important for understanding and predicting the responses of polyploid plants to climate change and associated environmental stress.
Targeting the oncogene LSF with either the small molecule inhibitor FQI1 or siRNA causes mitotic delays with unaligned chromosomes, resulting in cell death or senescence
Authors: Willoughby Jennifer L.S. , George Kelly , Roberto Mark P. , Chin Hang Gyeong , Stoiber Patrick , Shin Hyunjin , Pedamallu Chandra Sekhar , Schaus Scott E. , Fitzgerald Kevin , Shah Jagesh , Hansen Ulla
Published: June 2019

Background

The oncogene LSF (encoded byTFCP2) has been proposed as a novel therapeutic target for multiple cancers. LSF overexpression in patient tumors correlates with poor prognosis in particular for both hepatocellular carcinoma and colorectal cancer. The limited treatment outcomes for these diseases underscore the need for molecularly targeting novel mechanisms. LSF small molecule inhibitors, Factor Quinolinone Inhibitors (FQIs), have exhibited robust anti-tumor activity in multiple mouse models, with no observable toxicity.

Methods

Cell proliferation and cell cycle progression were analyzed after loss of LSF activity, using HeLa cells as a model cancer cell line responsive to FQI1. In addition, results were compared after treatment with either FQI1 or siRNA targeting LSF to test for biological specificity of targeting LSF by FQI1.

Results

Cellular phenotypes observed upon FQI1 treatment were due specifically to the loss of LSF activity, as siRNA targeting LSF produced highly similar phenotypes. Inhibition of LSF activity by either mechanism induced a strong delay prior to metaphase during progression through mitosis, with condensed, but unaligned, chromosomes. This mitotic disruption resulted in improper cellular division leading to multiple outcomes: multi-nucleation, apoptosis, and cellular senescence.

Conclusions

Specific inhibition of LSF by small molecules or siRNA results in mitotic defects, leading to cell death or senescence - consequences that are desirable in combating cancer. Taken together, these findings not only confirm that LSF is a promising target for cancer treatment, but also that FQIs are promising compounds for obtaining therapeutic effects for multiple LSF-driven cancers with unmet medical need.
Characterizing the temporal dynamics of gene expression in single cells with sci-fate
Authors: Cao Junyue , Zhou Wei , Steemers Frank , Trapnell Cole , Shendure Jay
Published: June 2019

Gene expression programs are dynamic, e.g. the cell cycle, response to stimuli, normal differentiation and development, etc. However, nearly all techniques for profiling gene expression in single cells fail to directly capture the dynamics of transcriptional programs, which limits the scope of biology that can be effectively investigated. Towards addressing this, we developed sci-fate, a new technique that combines S4U labeling of newly synthesized mRNA with single cell combinatorial indexing (sci-), in order to concurrently profile the whole and newly synthesized transcriptome in each of many single cells. As a proof-of-concept, we applied sci-fate to a model system of cortisol response and characterized expression dynamics in over 6,000 single cells. From these data, we quantify the dynamics of the cell cycle and glucocorticoid receptor activation, while also exploring their intersection. We furthermore use these data to develop a framework for inferring the distribution of cell state transitions. We anticipate sci-fate will be broadly applicable to quantitatively characterize transcriptional dynamics in diverse systems.
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

The 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.

Cohesin 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

In 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 Summary

Cryo-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

Resistance-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 points

For 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

Although 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

Individuals 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.

Abbreviations

BCa – 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

In 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.

Significance

Many 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.
Biased Signaling: Distinct Ligand-directed Plasma Membrane Signalosomes Using a Common RGS/G protein Core
Authors: Ross-Elliott Timothy J. , Watkins Justin , Shan Xiaoyi , Lou Fei , Dreyer Bernd , Tunc-Ozdemir Meral , Jia Haiyan , Yang Jing , Wu Luguang , Trusov Yuri , Krysan Patrick , Jones Alan M.
Published: June 2019

Biased signaling occurs when different ligands that are directed at the same receptor launch different cellular outcomes. Because of their pharmacological importance, we know the most about biased ligands and little is known about other mechanisms to achieve signaling bias. In the canonical animal G protein system, endocytosis of a 7-transmembrane GPCR is mediated by arrestins to propagate or arrest cytoplasmic signaling depending on the bias. In Arabidopsis, GPCRs are not required for G protein coupled signaling because the heterotrimeric G protein complex spontaneously exchanges nucleotide. Instead, the prototype 7-transmembrane Regulator of G Signaling 1 protein AtRGS1 modulates G signaling and through ligand-dependent endocytosis, de-repression of signaling is initiated but canonical arrestins are not involved. Endocytosis initiates from two separate pools of plasma membrane: sterol-dependent domains, possibly lipid rafts, and a clathrin-accessible neighborhood, each with a select set of discriminators, activators, and newly-discovered arrestin-like adaptors. Different trafficking origins and trajectories lead to different cellular outcomes. Thus, compartmentation with its attendant signalosome architecture is a previously unknown mechanism to drive biased signaling.
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

During 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 statement

Assessing 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

Ecology 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

Genes 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

Background

Despite 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.

Results

Using 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.

Conclusions

These 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

Almost 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

B-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.
Identification of positive chemotaxis in the protozoan pathogenTrypanosoma brucei
Authors: DeMarco Stephanie F. , Saada Edwin A. , Lopez Miguel A. , Hill Kent L.
Published: June 2019

To complete its infectious cycle, the protozoan parasite,Trypanosoma brucei, must navigate through diverse tissue environments in both its tsetse fly and mammalian hosts. This is hypothesized to be driven by yet unidentified chemotactic cues. Prior work has shown that parasites engaging in social motilityin vitroalter their trajectory to avoid other groups of parasites, an example of negative chemotaxis. However, movement ofT. bruceitoward a stimulus, positive chemotaxis, has so far not been reported. Here we show that upon encounteringE. coli,socially behavingT. bruceiparasites exhibit positive chemotaxis, redirecting group movement toward the neighboring bacterial colony. This response occurs at a distance from the bacteria and involves active changes in parasite motility. By developing a quantitative chemotaxis assay, we show that the attractant is a soluble, diffusible signal dependent on actively growingE. coli. Time-lapse and live video microscopy revealed thatT. bruceichemotaxis involves changes in both group and single cell motility. Groups of parasites change direction of group movement and accelerate as they approach the source of attractant, and this correlates with increasingly constrained movement of individual cells within the group. Identification of positive chemotaxis inT. bruceiopens new opportunities to study mechanisms of chemotaxis in these medically and economically important pathogens. This will lead to deeper insights into how these parasites interact with and navigate through their host environments.

Importance

Almost all living things need to be able to move, whether it is toward desirable environments or away from danger. For vector-borne parasites, successful transmission and infection require that these organisms be able to sense where they are and use signals from their environment to direct where they go next, a process known as chemotaxis. Here we show thatTrypanosoma brucei, the deadly protozoan parasite that causes African sleeping sickness, can sense and move toward an attractive cue. To our knowledge, this is the first report of positive chemotaxis in these organisms. In addition to describing a new behavior inT. brucei, our findings enable future studies of how chemotaxis works in these pathogens, which will lead to deeper understanding of how they move through their hosts and may lead to new therapeutic or transmission-blocking strategies.
High-throughput proteomic analysis of FFPE tissue samples facilitates tumor stratification
Authors: Zhu Yi , Weiss Tobias , Zhang Qiushi , Sun Rui , Wang Bo , Wu Zhicheng , Zhong Qing , Yi Xiao , Gao Huanhuan , Cai Xue , Ruan Guan , Zhu Tiansheng , Xu Chao , Lou Sai , Yu Xiaoyan , Gillet Ludovic , Blattmann Peter , Saba Karim , Fankhauser Christian D. , Schmid Michael B. , Rutishauser Dorothea , Ljubicic Jelena , Christiansen Ailsa , Fritz Christine , Rupp Niels J. , Poyet Cedric , Rushing Elisabeth , Weller Michael , Roth Patrick , Haralambieva Eugenia , Hofer Silvia , Chen Chen , Jochum Wolfram , Gao Xiaofei , Teng Xiaodong , Chen Lirong , Wild Peter J. , Aebersold Ruedi , Guo Tiannan
Published: June 2019

Formalin-fixed, paraffin-embedded (FFPE), biobanked tissue samples offer an invaluable resource for clinical and biomarker research. Here we developed a pressure cycling technology (PCT)-SWATH mass spectrometry workflow to analyze FFPE tissue proteomes and applied it to the stratification of prostate cancer (PCa) and diffuse large B-cell lymphoma (DLBCL) samples. We show that the proteome patterns of FFPE PCa tissue samples and their analogous fresh frozen (FF) counterparts have a high degree of similarity and we confirmed multiple proteins consistently regulated in PCa tissues in an independent sample cohort. We further demonstrate temporal stability of proteome patterns from FFPE samples that were stored between one to 15 years in a biobank and show a high degree of the proteome pattern similarity between two types histological region of small FFPE samples, i.e. punched tissue biopsies and thin tissue sections of micrometer thickness, despite the existence of certain degree of biological variations. Applying the method to two independent DLBCL cohorts we identified myeloperoxidase (MPO), a peroxidase enzyme, as a novel prognostic marker. In summary, this study presents a robust proteomic method to analyze bulk and biopsy FFPE tissues and reports the first systematic comparison of proteome maps generated from FFPE and FF samples. Our data demonstrate the practicality and superiority of FFPE over FF samples for proteome in biomarker discovery. Promising biomarker candidates for PCa and DLBCL have been discovered.
PRC1 catalytic activity is central to Polycomb system function
Authors: Blackledge Neil P. , Fursova Nadezda A. , Kelley Jessica R. , Huseyin Miles K. , Feldmann Angelika , Klose Robert J.
Published: June 2019

The Polycomb repressive system is an essential chromatin-based regulator of gene expression. Despite being extensively studied, how its target genes are selected and whether its histone modifying activities are required for transcriptional repression remains controversial. Here, we directly test the requirement for PRC1 catalytic activity in Polycomb system function. We demonstrate that a mutation widely used to disrupt PRC1 catalysis is hypomorphic, complicating the interpretation of previous studies. To overcome this, we develop a new inducible mutation system in embryonic stem cells that completely ablates PRC1 catalytic activity, revealing that catalysis by PRC1 drives Polycomb chromatin domain formation and higher-order chromatin interactions. In the absence of catalysis, we uncover the primary DNA-based targeting determinants that direct Polycomb target site selection. Finally, we discover that Polycomb-mediated gene repression requires PRC1 catalytic activity. Together these discoveries provide compelling new evidence supporting a PRC1-initiated pathway for Polycomb system function in gene regulation.
Allele-specific single-cell RNA sequencing reveals different architectures of intrinsic and extrinsic gene expression noises
Authors: Sun Mengyi , Zhang Jianzhi
Published: June 2019

Gene expression noise refers to the variation of the expression level of a gene among isogenic cells in the same environment, and has two sources: extrinsic noise arising from the disparity of the cell state and intrinsic noise arising from the stochastic process of gene expression in the same cell state. Due to the low throughput of the existing method for measuring the two noise components, the architectures of intrinsic and extrinsic expression noises remain elusive. Using allele-specific single-cell RNA sequencing, we here estimate the two noise components of 3975 genes in mouse fibroblast cells. Our analyses verify predicted influences of several factors such as the TATA-box and microRNA targeting on intrinsic and extrinsic noises and reveal gene function-associated noise trends implicating the action of natural selection. These findings unravel differential regulations, optimizations, and biological consequences of intrinsic and extrinsic noises and can aid the construction of desired synthetic circuits.
How neural circuits achieve and use stable dynamics
Authors: Kozachkov Leo , Lundqvist Mikael , Slotine Jean-Jacques , Miller Earl K.
Published: June 2019

1

The brain consists of many interconnected networks with time-varying activity. There are multiple sources of noise and variation yet activity has to eventually converge to a stable state for its computations to make sense. We approached this from a control-theory perspective by applying contraction analysis to recurrent neural networks. This allowed us to find mechanisms for achieving stability in multiple connected networks with biologically realistic dynamics, including synaptic plasticity and time-varying inputs. These mechanisms included anti-Hebbian plasticity, synaptic sparsity and excitatory-inhibitory balance. We leveraged these findings to construct networks that could perform functionally relevant computations in the presence of noise and disturbance. Our work provides a blueprint for how to construct stable plastic and distributed networks.
Structural variants identified by Oxford Nanopore PromethION sequencing of the human genome
Authors: De Coster Wouter , De Rijk Peter , De Roeck Arne , De Pooter Tim , D'Hert Svenn , Strazisar Mojca , Sleegers Kristel , Van Broeckhoven Christine
Published: June 2019

We sequenced the genome of the Yoruban reference individual NA19240 on the long-read sequencing platform Oxford Nanopore PromethION for evaluation and benchmarking of recently published aligners and germline structural variant calling tools, as well as a comparison with the performance of structural variant calling from short-read sequencing data. The structural variant caller Sniffles after NGMLR or minimap2 alignment provides the most accurate results, but additional confidence or sensitivity can be obtained by a combination of multiple variant callers. Sensitive and fast results can be obtained by minimap2 for alignment and a combination of Sniffles and SVIM for variant identification. We describe a scalable workflow for identification, annotation, and characterization of tens of thousands of structural variants from long-read genome sequencing of an individual or population. By discussing the results of this well-characterized reference individual, we provide an approximation of what can be expected in future long-read sequencing studies aiming for structural variant identification.
Reversible rearrangement of magnetic nanoparticles in solution studied using time-resolved SAXS method
Authors: Huang Lanqing , Mai Jingeng , Zhu Qihui , Guo Zhen , Qin Siying , Yang Peilin , Li Xuanxuan , Shi Yingchen , Wang Xiaotian , Wang Qining , Li Na , Xie Can , Liu Haiguang
Published: June 2019

Superparamagnetic nanoparticles have broad applications in biology and medicines. Quantitative measurements of magnetic beads in solution are essential in gaining comprehensive understanding of their dynamics and developing applications. Here, using synchrotron X-ray sources combined with well controlled magnetic fields, the results from small-angle X-ray scattering (SAXS) experiments on superparamagnetic particles in solution under the influence of external magnetic fields are reported. The particles mostly remain in monodispersed states and the linear aggregates tend to be aligned with the external magnetic field. After removing the magnetic fields, the superparamagnetic nanoparticles quickly recover to their original states indicating high reversibility of the rearrangement under the control of a magnetic field. The external magnetic field instrument composed of paired permanent magnets is integrated into the SAXS beamline at the Shanghai Synchrotron Radiation Facility providing a platform for studying time-resolved dynamics induced by magnetic fields.
Carbon management framework for sustainable manufacturing using life cycle assessment, IoT and carbon sequestration
Authors: Mishra Shraddha , Singh Surya Prakash
Published: June 2019

Purpose

Emission reduction methodologies alone are not sufficient to mitigate the climatic catastrophes caused due to ongoing carbon emissions. Rather, a bidirectional approach is required to decarbonize the excess carbon in the atmosphere through carbon sequestration along with carbon reduction. Since the manufacturing sector contributes heavily to the ongoing carbon emissions, the purpose of this paper is to propose a framework for carbon emission reduction and carbon sequestration in the context of the manufacturing industry.

Design/methodology/approach

In this paper, life cycle assessment (LCA) is employed to track the carbon emission at each stage of the product development life cycle. The pre-requisite for this is the accurate evaluation of the carbon emissions. Therefore, IoT technologies have been employed for collecting real-time data with high credibility to perceive environmental impact caused during the entire life cycle of the product. The total carbon emission calculation is based on the bill of material (BOM)-based LCA of the product to realize the multi-structure (from parts and components to product) as well as multi-stage (from cradle to gate) carbon emission evaluation. Carbon sequestration due to plantation is evaluated using root-shoot ratio and total biomass.

Findings

A five interwoven layered structure is proposed in the paper to facilitate the real-time data collection and carbon emission evaluation using BOM-based LCA of products. Further, a carbon neutral coefficient (CNC) is proposed to indicate the state of a firm’s carbon sink and carbon emissions. CNC=1 indicates that the firm is carbon neutral. CNC >1 implies that the firm’s carbon sequestration is more than carbon emissions. CNC <1 indicates that the firm’s carbon emission is more than the carbon sink.

Originality/value

The paper provides a novel framework which integrates the real-time data collection and evaluation of carbon emissions with the carbon sequestration.
Bank institutional setting and risk-taking: the missing role of directors’ education and turnover
Authors: D’Amato Antonio , Gallo Angela
Published: June 2019

Purpose

This paper aims to analyze the relationship between bank institutional setting and risk-taking by exploring whether board education and turnover are drivers of the risk propensity of cooperative banks compared to joint-stock banks.

Design/methodology/approach

Based on a comprehensive data set of Italian banks over the 2011-2017 period, this paper examines whether these board characteristics affect the risk propensity of cooperative and joint-stock banks. Bank risk is measured by the Z-index, profit volatility and the ratio of non-performing loans to total gross loans.

Findings

The findings show that cooperatives take less risk than joint-stock banks and have lower board turnover and education. Furthermore, this study finds that while board education mediates the relationship between the cooperative model and bank risk-taking, there is no evidence for board turnover. Thus, the lower educational level of cooperative directors contributes to explaining the lower risk-taking of cooperative banks.

Implications

The findings have several implications. In terms of the more general policy debate, the results point to the need to strengthen the governance model for both joint-stock and cooperative banks while supporting the view that a moread hocperspective on the best models and practices for each type of institutional setting would be preferable. In particular, the study reveals how board education’s effects on bank risk-taking should be carefully monitored.

Originality/value

Through a mediation framework, this study provides empirical evidence on the relationship between bank institutional setting (by distinguishing between cooperative and joint-stock banks) and risk-taking behavior by exploring the underlying mechanisms at the board level, which is novel in the literature.
Factors and determinants of value- and business-driven sustainability initiatives in health care organizations: intrinsic differences and extrinsic similarities
Authors: Rodriguez Rocio , Svensson Göran , Høgevold Nils M. , Eriksson David
Published: June 2019

Purpose

The purpose of this paper is to compare the similarities and differences relating to sustainability initiatives between health-care organizations. The aim is to provide a framework of factors and their determinants to enable a profiling of organizational sustainability initiatives.

Design/methodology/approach

Based on an inductive approach, judgmental sampling was applied to select relevant health-care organizations. Informants were identified according to their knowledge of their organizations’ sustainability initiatives.

Findings

Several factors and their determinants for characterizing differences and similarities were found. The results also reveal that organizational sustainability initiatives are either value-driven or business-driven.

Research limitations/implications

The reported framework of factors and their determinants serves the purpose of profiling organizational sustainability initiatives. Opportunities for further research are provided.

Practical implications

This paper provides managerial guidance for characterizing the differences and similarities with respect to organizational sustainability initiatives in relation to other organizations.

Originality/value

This study establishes a framework for characterizing organizational sustainability initiatives. It also contributes to reveal whether organizational sustainability initiatives are value – or business-driven and considers intrinsic-oriented differences and extrinsic-oriented similarities.