bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comprehensive analysis of structural and sequencing data reveals almost unconstrained chain pairing in TCRαβ complex
Authors: Shcherbinin Dmitrii S , Belousov Vlad A , Shugay Mikhail 
Published: July 2019

AbstractAntigen recognition by T-cells is guided by the T-cell receptor (TCR) heterodimer formed by α and β chains. A huge diversity of TCR sequences should be maintained by the immune system in order to be able to mount an effective response towards foreign pathogens, so, due to cooperative binding of α and β chains to the pathogen, any constraints on chain pairing can have a profound effect on immune repertoire structure, diversity and antigen specificity. By integrating available structural data and paired chain sequencing results we were able to show that there are almost no constraints on pairing in TCRαβ complexes, allowing naive T-cell repertoire to reach the highest possible diversity. Additional analysis reveals that the specific choice of contacting amino acids can still have a profound effect on complex conformation. Moreover, antigen-driven selection can distort the uniform landscape of chain pairing, while small, yet significant, differences in the pairing can be attributed to various specialized T-cell subsets such as MAIT and iNKT T-cells, as well as other putative invariant TCRs.
Spider lures exploit insect preferences for floral colour and symmetry
Authors: White Thomas E. , Kemp Darrell J. 
Published: July 2019

AbstractSensory systems can capture only a fraction of available information, which creates opportunities for deceptive signalling. The sensory traps and sensory bias models have proven valuable for explaining how visual systems and environments shape the design of sexual signals, but their application to deceptive signals is largely untapped. Here we use the ‘jewelled’ orb-web spiderGasteracantha fornicatato experimentally test two longstanding hypotheses for the function of deceptive visual lures. Namely, that they: (1) exploit generalised preferences for conspicuous colouration (sensory bias), or (2) co-opt the otherwise-adaptive foraging response of prey toward flowers (sensory traps). In a field-based study we manipulated the conspicuous dorsal signal of female spiders along two axes —– colour pattern and symmetry — to generate a gradient of floral resemblance, and monitored the per-individual consequences for prey interception. As predicted by the traps model, the most attractive phenotypes were those with flower-like radial symmetry and solid colour patterns, and their attractiveness equaled that of wild-type models. These results demonstrate that deceptive orb-web spider lures function, in part, as inter-kingdom sensory traps via floral mimicry, and support the broader extension of sensory-based models to deceptive signalling contexts.
Seroprevalence of anti-microbial antibodies in the normal healthy population with implications in chronic diseases
Authors: Zhang Peilin , Minardi Lawrence M. , Kuenstner J. Todd , Zekan Steve M. , Kruzelock Rusty 
Published: July 2019

AbstractWe have previously discovered a panel of anti-microbial antibodies from patients with Crohn’s disease (CD) and Sjogren’s syndrome (Sjo). We have also demonstrated the increase of these anti-microbial antibodies in other autoimmune disease such as rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis in a small number of cases. The seroprevalence of these antibodies in the normal healthy population is unknown. We set to survey the normal population for these anti-microbial antibodies. We collected 288 blood samples from the donor units of the leukocyte-reduced red blood cells from the American Red Cross, and examined the presence of the anti-microbial antibodies in these blood samples using direct ELISA assays established in our laboratory using the recombinant microbial protein antigens. Our results showed that the prevalence of RPOB antibody in the normal blood donor population is 2.4% (7 positive of 288 samples). The prevalence of EF-G antibody is 4.2% (12 positive of 288 samples), ATP5a 5.2% (15 positive), Hsp65 2.8% (8 positive), EF-Tu 5.6% (16 positive), and NMPC 4.2% (12 positive). Meanwhile, in 109 patients with Crohn’s disease and 28 patients with Sjogren’s syndrome, these anti-bacterial antibodies are significantly increased (p<0.001). These results indicate that the specific anti-microbial antibodies within the normal general population are uncommon, but frequent in chronic disease states. The presence of increased anti-microbial antibodies in the blood of patients but not in normal controls can serve as biomarkers for chronic diseases such as Crohn’s disease and Sjogren’s, and their presence indicates abnormal B-cell/plasma cell function in response to the commensal/pathogenic microbes. Since the antigens were derived from the common microbes present on the surface of the normal population, the antimicrobial antibodies in patients with diseases but not in the normal population suggest a deficient clearance of the microbes from the circulation by the innate immunity system in chronic diseases. These results also raise questions of bacterial vaccination using whole bacterial extracts as these anti-bacterial antibodies appear pathogenic rather than protective, offering fresh thinking in designing bacterial vaccines as preventive or therapeutic measures in chronic diseases such as Crohn’s disease and Sjogren’s Disease.
Mechanism of preferential complex formation by Apoptosis Signal-regulating Kinases
Authors: Trevelyan Sarah J. , Brewster Jodi L. , Burgess Abigail E. , Crowther Jennifer M. , Cadell Antonia L. , Parker Benjamin L. , Croucher David R. , Dobson Renwick C.J. , Murphy James M. , Mace Peter D. 
Published: July 2019

AbstractApoptosis signal-regulating kinases (ASK1–3) are activators of the P38 and JNK MAP kinase pathways. ASK1–3 form oligomeric complexes known as ASK signalosomes that initiate signalling cascades in response to diverse stress stimuli. Here we demonstrate that oligomerization of ASK proteins is driven by previously uncharacterised sterile-alpha motif (SAM) domains that reside at the C-terminus of each ASK protein. SAM domains from ASK1–3 have distinct behaviours: ASK1 forms unstable oligomers, ASK2 is predominantly monomeric, and the ASK3 SAM domain forms a stable oligomer even at low concentration. In contrast to their isolated behaviour, the ASK1 and ASK2 SAM domains preferentially form a stable heterocomplex. The crystal structure of the ASK3 SAM domain, small-angle X-ray scattering, and mutagenesis suggests that ASK3 oligomers and ASK1-ASK2 complexes form discrete quasi-helical rings, via the mid-loop–end-helix interface. Preferential ASK1-ASK2 binding is consistent with mass spectrometry showing that full-length ASK1 forms heterooligomeric complexes incorporating high levels of ASK2. Accordingly, disruption of SAM domain-association impairs ASK activity in the context of electrophilic stress induced by 4-hydroxy-2-nonenal. These findings provide a structural template for how ASK proteins assemble foci to drive inflammatory signalling, and reinforce that strategies targeting ASK kinases should consider the concerted actions of multiple ASK family members.
ARPP19 promotes MYC expression and associates with patient relapse in acute myeloid leukemia
Authors: Mäkelä Eleonora , Löyttyniemi Eliisa , Salmenniemi Urpu , Kauko Otto , Varila Taru , Kairisto Veli , Itälä-Remes Maija , Westermarck Jukka 
Published: July 2019

AbstractDespite of extensive genetic analysis of acute myeloid leukemia (AML), we still do not understand comprehensively mechanism that promote disease relapse from standard chemotherapy. Based on recent indications for non-genomic inhibition of tumor suppressor protein phosphatase 2A (PP2A) in AML, we examined mRNA expression of PP2A inhibitor proteins in AML patient samples. Notably, out of examined PP2A inhibitor proteins, overexpression of ARPP19 mRNA was found independent of current AML risk classification. Functionally, ARPP19 promoted AML cell viability and expression of oncoproteins MYC, CDK1, and another PP2A inhibitor CIP2A. Clinically, ARPP19 mRNA expression was significantly lower at diagnosis (p=0.035) in patients whose disease did not relapse after standard chemotherapy. ARPP19 was an independent predictor for relapse both in univariable (p=0.007) and in multivariable analyses (p=0.0001); and gave additive information to EVI1 expression and risk group status (additive effect, p=0.005). Low ARPP19 expression also associated with better patient outcome in TCGA LAML cohort (p=0.019). In addition, in matched patient samples from diagnosis, remission and relapse phases, ARPP19 expression associated with disease activity (p=0.034).Together, these data identify ARPP19 as a novel oncogenic PP2A inhibitor protein in AML, and demonstrate its risk group independent role in predicting AML patient relapse tendency.
Prediction of microscopic metastases in patients with metachronous oligo-metastases after curative treatment of Non-Small Cell Lung Cancer
Authors: Wolff H.B. , Alberts L. , Kastelijn E.A. , Verstegen N.E. , El Sharouni S.Y. , Schramel F.M.N.H. , Vos R. , Coupe V.M.H. 
Published: July 2019

AbstractMetachronous oligo-metastatic disease is variably defined as one to five metastases detected after a disease-free interval and treatment of the primary tumour with curative intent. Oligo-metastases in non-small cell lung cancer (NSCLC) are often treated with curative intent. However additional metastases are often detected later in time, and 5-year survival is low. Burdensome surgical treatment in patients with undetected metastases may be avoided if patients with high versus low-risk of undetected metastases can be separated.Because there is no clinical data on undetected metastases available, a microsimulation-model of the development and detection of metastases in 100.000 stage I NSCLC patients with a controlled primary tumour was constructed. The model uses data from the literature as well as patient-level data. Calibration was used for unobservable model parameters. Metastases can be detected by a scheduled scan, or an unplanned scan when the patient develops symptoms. The observable information at time of detection is used to identify subgroups of patients with different risk of undetectable metastases. We identified size and number of detected oligo-metastases, as well as presence of symptoms to be the most important risk predictors. Based on these predictors, patients could be divided into a low-risk and a high-risk group having a model-based predicted probability of 8.1% and 89.3% to have undetected metastases, respectively.Currently, the model is based on a synthesis of literature data and individual patient-level data that was not collected for the purpose of this study. Optimisation and validation of the model is necessary to allow clinical usability. We describe the type of data that needs to be collected to update our model, as well as the design of such validation study.
To mate, or not to mate: The evolution of reproductive diapause facilitates insect radiation into African savannahs in the Late Miocene
Authors: Halali Sridhar , Brakefield Paul M. , Collins Steve C. , Brattström Oskar 
Published: July 2019

AbstractMany tropical environments experience cyclical seasonal changes, frequently with pronounced wet and dry seasons, leading to a highly uneven temporal distribution of resources. Short-lived animals inhabiting such environments often show season-specific adaptations to cope with alternating selection pressures.African Bicyclus butterflies show strong seasonal polyphenism in a suite of phenotypic and life-history traits, and their adults are thought to undergo reproductive diapause associated with the lack of available larval host plants during the dry season.Using three years of longitudinal field data for three species in Malawi, dissections demonstrated that one forest species reproduces continuously whereas two savannah species undergo reproductive diapause in the dry season, either with or without pre-diapause mating. Using additional data from field-collected and museum samples, we then documented the same three mating strategies for a further 37 species.Phylogenetic analyses indicated that the ancestral state was a non-diapausing forest species, and that habitat preference and mating strategy evolved in a correlated fashion.Bicyclus butterflies underwent rapid diversification during the Late Miocene, coinciding with expansions into more open savannah habitat. We conclude that the ability to undergo reproductive diapause was a key trait that facilitated colonization and eventual radiation into savannahs in the Late Miocene.
Insights into the bacterial profiles and resistome structures following severe 2018 flood in Kerala, South India
Authors: Divakaran Soumya Jaya , Philip Jamiema Sara , Chereddy Padma , Nori Sai Ravi Chandra , Ganesh Akshay Jaya , John Jiffy , Nelson-Sathi Shijulal 
Published: July 2019

AbstractExtreme flooding is one of the major risk factors for human health, and it can significantly influence the microbial communities and enhance the mobility of infectious disease agents within its affected areas. The flood crisis in 2018 was one of the severe natural calamities recorded in the southern state of India (Kerala) that significantly affected its economy and ecological habitat. We utilized a combination of shotgun metagenomics and bioinformatics approaches for understanding microbiome disruption and the dissemination of pathogenic and antibiotic-resistant bacteria on flooded sites. Here we report, altered bacterial profiles at the flooded sites having 77 significantly different bacterial genera in comparison with non-flooded mangrove settings. The flooded regions were heavily contaminated with faecal contamination indicators such asEscherichia coliandEnterococcus faecalisand resistant strains ofPseudomonas aeruginosa, SalmonellaTyphi/Typhimurium, Klebsiella pneumoniae, Vibrio choleraeandStaphylococcus aureus. The resistome of the flooded sites contains 103 resistant genes, of which 38% are encoded in plasmids, where most of them are associated with pathogens. The presence of 6 pathogenic bacteria and its susceptibility to multiple antibiotics including ampicillin, chloramphenicol, kanamycin and tetracycline hydrochloride were confirmed in flooded and post-flooded sites using traditional culture-based analysis followed by 16S rRNA sequencing. Our results reveal altered bacterial profile following a devastating flood event with elevated levels of both faecal contamination indicators and resistant strains of pathogenic bacteria. The circulation of raw sewage from waste treatment settings and urban area might facilitate the spreading of pathogenic bacteria and resistant genes.
Learning spatiotemporal signals using a recurrent spiking network that discretizes time
Authors: Maes Amadeus , Barahona Mauricio , Clopath Claudia 
Published: July 2019

AbstractLearning to produce spatiotemporal sequences is a common task the brain has to solve. The same neural substrate may be used by the brain to produce different sequential behaviours. The way the brain learns and encodes such tasks remains unknown as current computational models do not typically use realistic biologically-plausible learning. Here, we propose a model where a spiking recurrent network of excitatory and inhibitory biophysical neurons drives a read-out layer: the dynamics of the recurrent network is constrained to encode time while the read-out neurons encode space. Space is then linked with time through plastic synapses that follow common Hebbian learning rules. We demonstrate that the model is able to learn spatiotemporal dynamics on a timescale that is behaviourally relevant. Learned sequences are robustly replayed during a regime of spontaneous activity.Author summaryThe brain has the ability to learn flexible behaviours on a wide range of time scales. Previous studies have successfully build spiking network models that learn a variety of computational tasks. However, often the learning involved is not local. Here, we investigate a model using biological-plausible plasticity rules for a specific computational task: spatiotemporal sequence learning. The architecture separates time and space into two different parts and this allows learning to bind space to time. Importantly, the time component is encoded into a recurrent network which exhibits sequential dynamics on a behavioural time scale. This network is then used as an engine to drive spatial read-out neurons. We demonstrate that the model can learn complicated spatiotemporal spiking dynamics, such as the song of a bird, and replay the song robustly.
Juxta-membrane S-acylation of plant receptor-like kinases – fortuitous or functional?
Authors: Hurst Charlotte H. , Wright Kathryn M. , Turnbull Dionne , Leslie Kerry , Jones Susan , Hemsley Piers A. 
Published: July 2019

AbstractS-acylation is a common post-translational modification of membrane protein cysteine residues with many regulatory roles. S-acylation adjacent to transmembrane domains has been described in the literature as affecting diverse protein properties including turnover, trafficking and microdomain partitioning. However, all of these data are derived from mammalian and yeast systems. Here we examine the role of S-acylation adjacent to the transmembrane domain of the plant pathogen perceiving receptor-like kinase FLS2. Surprisingly, S-acylation of FLS2 adjacent to the transmembrane domain is not required for either FLS2 trafficking or signalling function. Expanding this analysis to the wider plant receptor-like kinase superfamily we find that S-acylation adjacent to receptor-like kinase domains is common but poorly conserved between orthologues through evolution. This suggests that S-acylation of receptor-like kinases at this site is likely the result of chance mutation leading to cysteine occurrence. As transmembrane domains followed by cysteine residues are common motifs for S-acylation to occur, and many S-acyl transferases appear to have lax substrate specificity, we propose that many receptor-like kinases are fortuitously S-acylated once chance mutation has introduced a cysteine at this site. Interestingly some receptor-like kinases show conservation of S-acylation sites between orthologues suggesting that S-acylation has come to play a role and has been positively selected for during evolution. The most notable example of this is in the ERECTA-like family where S-acylation of ERECTA adjacent to the transmembrane domain occurs in all ERECTA orthologues but not in the parental ERECTA-like clade. This suggests that ERECTA S-acylation occurred when ERECTA emerged during the evolution of angiosperms and may have contributed to the neo-functionalisation of ERECTA from ERECTA-like proteins.
Differences in strategic abilities but not associative processes explain memory development
Authors: Müller N.C.J. , Kohn N. , van Buuren M. , Klijn N. , Emmen H. , Berkers R.M.W.J. , Dresler M. , Janzen G. , Fernández G. 
Published: July 2019

AbstractChildren’s learning capabilities change while growing up. One framework that describes the cognitive and neural development of children’s growing learning abilities is the two-component model. It distinguishes processes that integrate separate features into a coherent memory representation (associative component) and executive abilities, such as elaboration, evaluation and monitoring, that support memory processing (strategic component). In an fMRI study using an object-location association paradigm, we investigated how the two components influence memory performance across development. We tested children (10-12 yrs., n=31), late adolescents (18 yrs., n=29) and adults (25+ yrs., n=30) of either sex. For studying the associative component, we also probed how the utilisation of prior knowledge (schemas) facilitates memory across age groups. Children had overall lower retrieval performance, while adolescents and adults did not differ from each other. All groups benefitted from schemas, but this effect did not differ between groups. Performance differences between groups were associated with deactivation of the dorsal medial prefrontal cortex (dmPFC), which in turn was linked to executive functioning. These patterns were stronger in adolescents and adults and seemed absent in children. This pattern of results suggests the children’s executive system, the strategic component, is not as mature and thus cannot facilitate memory performance in the same way as in adolescents/adults. In contrast, we did not find age-related differences in the associative component; with activity in the angular gyrus predicting memory performance systematically across groups. Overall our results suggest that differences of executive rather than associative abilities explain memory differences between children, adolescents and adults.
The human-specific BOLA2 duplication modifies iron homeostasis and anemia predisposition in chromosome 16p11.2 autism patients
Authors: Giannuzzi Giuliana , Schmidt Paul J. , Porcu Eleonora , Willemin Gilles , Munson Katherine M. , Nuttle Xander , Earl Rachel , Chrast Jacqueline , Hoekzema Kendra , Risso Davide , Männik Katrin , De Nittis Pasquelena , Baratz Ethan D. ,   16p11.2 Consortium, Herault Yann , Gao Xiang , Philpott Caroline C. , Bernier Raphael A. , Kutalik Zoltan , Fleming Mark D. , Eichler Evan E. , Reymond Alexandre 
Published: July 2019

AbstractHuman-specific duplications at chromosome 16p11.2 mediate recurrent pathogenic 600 kbp BP4-BP5 copy number variations, one of the most common genetic causes of autism. These copy number polymorphic duplications are under positive selection and include 3–8 copies of BOLA2, a gene involved in the maturation of cytosolic iron-sulfur proteins. To investigate the potential advantage provided by the rapid expansion of BOLA2, we assessed hematological traits and anemia prevalence in 379,385 controls and individuals who have lost or gained copies of BOLA2: 89 chromosome 16p11.2 BP4-BP5 deletion and 56 reciprocal duplication carriers in the UK Biobank. We found that the 16p11.2 deletion is associated with anemia (18/89 carriers, 20%, P=4e-7, OR=5), particularly iron-deficiency anemia. We observed similar enrichments in two clinical 16p11.2 deletion cohorts, with 6/63 (10%) and 7/20 (35%) unrelated individuals with anemia, microcytosis, low serum iron, or low blood hemoglobin. Upon stratification by BOLA2 copy number, we found an association between low BOLA2 dosage and the above phenotypes (8/15 individuals with three copies, 53%, P=1e-4). In parallel, we analyzed hematological traits in mice carrying the 16p11.2 orthologous deletion or duplication, as well as Bola2+/- and Bola2-/- animals. The deletion and Bola2-deficient mice showed early evidence of iron deficiency, including a mild decrease in hemoglobin, lower plasma iron, microcytosis, and an increased red blood cell zinc protoporphyrin to heme ratio. Our results indicate that BOLA2 participates in iron homeostasis in vivo and its expansion has a potential adaptive role in protecting against iron deficiency.