bluuebunny/crossref_metadata_2025 huggingface dataset:
Primordial black holes and the origin of the matter–antimatter asymmetry
Authors: García-Bellido Juan
Published: November 2019

We review here a new scenario of
hot spot
electroweak baryogenesis where the local energy released in the gravitational collapse to form primordial black holes (PBHs) at the quark-hadron (QCD) epoch drives over-the-barrier sphaleron transitions in a far from equilibrium environment with just the standard model CP violation. Baryons are efficiently produced in relativistic collisions around the black holes and soon redistribute to the rest of the universe, generating the observed matter–antimatter asymmetry well before primordial nucleosynthesis. Therefore, in this scenario there is a common origin of both the dark matter to baryon ratio and the photon to baryon ratio. Moreover, the sudden drop in radiation pressure of relativistic matter at
H
0
/
W
±
/
Z
0
decoupling, the QCD transition and
e
+
e
−
annihilation enhances the probability of PBH formation, inducing a multi-modal broad mass distribution with characteristic peaks at 10
−6
, 1, 30 and 10
6
 
M
⊙
, rapidly falling at smaller and larger masses, which may explain the LIGO–Virgo black hole mergers as well as the OGLE-GAIA microlensing events, while constituting all of the cold dark matter today. We predict the future detection of binary black hole (BBH) mergers in LIGO with masses between 1 and 5 
M
⊙
, as well as above 80 
M
⊙
, with very large mass ratios. Next generation gravitational wave and microlensing experiments will be able to test this scenario thoroughly.

This article is part of a discussion meeting issue ‘Topological avatars of new physics’.
Excavating New Facts from Ancient Hepatitis B Virus Sequences
Authors: Datta Sibnarayan
Published: November 2019

Recently, Muhlemann et al. (2018) and Krause-Kyora et al. (2018) discovered 15 ancient Hepatitis B virus (aHBV) sequences dating back to the Neolithic age (NA) and the Bronze age (BA). Being published simultaneously, neither of these studies could include sequences from the other for analyses. In the present research, aHBV sequences from these studies were collective re-analysed with reference to a comprehensive database comprising extant HBV diversity to understand their relatedness and role in the evolution of extant HBV diversity. Present analyses revealed several interesting findings on distribution, dispersal, phylogenetic and recombinational relatedness of ancient HBV to extant genotypes, which were not recognized previously. Several interesting recombination patterns were observed, which corroborated well with ancient human migration, shown by the human genetic studies. Present analyses suggest that comparable to the replacement of the Neolithic European farmer associated Y chromosome haplogroups by haplogroups associated with the steppe people during Steppe migration, HBV genotype associated with the early Neolithic European farming cultures was also replaced by the ancestral HBV genotype A probably carried by the migrating steppe people, and a variant of this genotype is the prevalent HBV genotype in contemporary European populations. Additionally, based on recent literature, this research also indicates that HBV genotype divergence estimates proposed by Muhlemann et al., and others cannot sufficiently explain distribution of certain extant HBV genotypes. Hence, an alternative possibility to explain long distance and trans-oceanic distribution of phylogenetically related HBV genotypes was reviewed and discussed in the light of currently available knowledge. Through this manuscript, novel and important findings of the present analyses are communicated.
Inter-hemispheric inhibition in stroke survivors is related to fatigue and cortical excitability
Authors: Ondobaka Sasha , Ward Nick , Kuppuswamy Annapoorna
Published: November 2019

Objective

Persistent post-stroke fatigue is a major debilitating condition that has been linked to low corticomotor excitability and aberrant attention, both phenomena that are associated with the inter-hemispheric inhibition balance in the brain. In this study, we examined the relationship between inter-hemispheric inhibitory effective connectivity, motor cortex excitability and chronic persistence of post-stroke fatigue.

Methods

We tested eighteen non-depressed stroke survivors with minimal motoric and cognitive impairments using spectral dynamic causal modelling (spDCM) of ‘resting state’ magnetic resonance imaging (rs-fMRI) and transcranial magnetic stimulation (TMS) measures of cortical excitability. We also assessed the levels of non-exercise induced, persistent fatigue using Fatigue Severity Scale (FSS) - a self-report questionnaire which has been widely applied and validated across different conditions. To understand neural effective connectivity mechanisms involved in fatigue and corticomotor excitability we examined the balance in inhibitory connectivity between homologue regions in M1, anterior insula, caudate and thalamus of the resting brain.

Results

Inter-hemispheric inhibition balance between left and right M1 accounted for 67% of variability in the reported fatigue (R=.82, p<0.001). Inter-hemispheric inhibition balance in M1 also accounted for 54% of variability in the corticomotor excitability characterised by individual resting motor thresholds (R=.74, p<0.001), a measure that has been associated with subjective fatigue reports. Other examined inter-hemispheric connections did not show significant relationships with either fatigue or cortical excitability measures.

Conclusion

Our findings suggest that the balance in inter-hemispheric effective connectivity between primary motor regions is involved in regulation of corticomotor excitability and could explain subjective post-stroke fatigue.
Synthetic gene regulatory networks in the opportunistic human pathogenStreptococcus pneumoniae
Authors: Sorg Robin A. , Gallay Clement , Veening Jan-Willem
Published: November 2019

Streptococcus pneumoniaecan cause disease in various human tissues and organs, including the ear, the brain, the blood and the lung, and thus in highly diverse and dynamic environments. It is challenging to study how pneumococci control virulence factor expression, because cues of natural environments and the presence of an immune system are difficult to simulatein vitro. Here, we apply synthetic biology methods to reverse-engineer gene expression control inS. pneumoniae. A selection platform is described that allows for straightforward identification of transcriptional regulatory elements out of combinatorial libraries. We present TetR- and LacI-regulated promoters that show expression ranges of four orders of magnitude. Based on these promoters, regulatory networks of higher complexity are assembled, such as logic AND and IMPLY gates. Finally, we demonstrate single-copy genome-integrated toggle switches that give rise to bimodal population distributions. The tools described here can be used to mimic complex expression patterns, such as the ones found for pneumococcal virulence factors, paving the way forin vivoinvestigations of the importance of gene expression control on the pathogenicity ofS. pneumoniae.
BceAB-type antibiotic resistance transporters appear to act by target protection of cell wall synthesis
Authors: Kobras Carolin M , Piepenbreier Hannah , Emenegger Jennifer , Sim Andre , Fritz Georg , Gebhard Susanne
Published: November 2019

Resistance against cell wall-active antimicrobial peptides in bacteria is often mediated by transporters. In low GC-content Gram-positive bacteria, a wide-spread type of such transporters are the BceAB-like systems, which frequently provide a high level of resistance against peptide antibiotics that target intermediates of the lipid II cycle of cell wall synthesis. How a transporter can offer protection from drugs that are active on the cell surface, however, has presented researchers with a conundrum. Multiple theories have been discussed, ranging from removal of the peptides from the membrane, internalisation of the drug for degradation, to removal of the cellular target rather than the drug itself. To resolve this much-debated question, we here investigated the mode of action of the transporter BceAB ofBacillus subtilis. We show that it does not inactivate or import its substrate antibiotic bacitracin. Moreover, we present evidence that the critical factor driving transport activity is not the drug itself, but instead the concentration of drug-target complexes in the cell. Our results, together with previously reported findings, lead us to propose that BceAB-type transporters act by transiently freeing lipid II cycle intermediates from the inhibitory grip of antimicrobial peptides, and thus provide resistance through target protection of cell wall synthesis. Target protection has so far only been reported for resistance against antibiotics with intracellular targets, such as the ribosome. However, this mechanism offers a plausible explanation for the use of transporters as resistance determinants against cell wall-active antibiotics in Gram-positive bacteria where cell wall synthesis lacks the additional protection of an outer membrane.
Machine learning reveals adaptive maternal responses to infant distress calls in wild chimpanzees
Authors: Dezecache Guillaume , Zuberbühler Klaus , Davila-Ross Marina , Dahl Christoph D.
Published: November 2019

Distress calls are an acoustically variable group of vocalizations ubiquitous in mammals and other animals. Their presumed function is to recruit help, but it is uncertain whether this is mediated by listeners extracting the nature of the disturbance from calls. To address this, we used machine learning to analyse distress calls produced by wild infant chimpanzees. It enabled us to classify calls and examine them in relation to the external event triggering them and the distance to the intended receiver, the mother. In further steps, we tested whether the acoustic variants produced by infants predicted maternal responses. Our results demonstrated that, although infant chimpanzee distress calls were highly graded, they conveyed information about discrete events, which in turn guided maternal parenting decisions. We discuss these findings in light of one the most vexing problems in communication theory, the evolution of vocal flexibility in the human lineage.
Prominent members of the human gut microbiota express endo-acting O-glycanases to initiate mucin breakdown
Authors: Crouch Lucy I. , Liberato Marcelo V. , Urbanowicz Paulina A. , Baslé Arnaud , Lamb Christopher A. , Stewart Christopher J. , Cooke Katie , Doona Mary , Needham Stephanie , Brady Richard R. , Berrington Janet E. , Madunic Katarina , Wuhrer Manfred , Chater Peter , Pearson Jeffery P. , Glowacki Robert , Martens Eric C. , Zhang Fuming , Linhardt Robert J. , Spencer Daniel I. R. , Bolam David N.
Published: November 2019

The human gut microbiota (HGM) are closely associated with health, development and disease. The thick intestinal mucus layer, especially in the colon, is the key barrier between the contents of the lumen and the epithelial cells, providing protection against infiltration by the microbiota as well potential pathogens. The upper layer of the colonic mucus is a niche for a subset of the microbiota which utilise the mucin glycoproteins as a nutrient source and mucin grazing by the microbiota appears to play a key role in maintaining barrier function as well as community stability. Despite the importance of mucin breakdown for gut health, the mechanisms by which gut bacteria access this complex glycoprotein are not well understood. The current model for mucin degradation involves exclusively exo-acting glycosidases that sequentially trim monosaccharides from the termini of the glycan chains to eventually allow access to the mucin peptide backbone by proteases. However, this model is in direct contrast to the Sus paradigm of glycan breakdown used by the Bacteroidetes which involves extracellular cleavage of glycans by surface located endo-acting enzymes prior to import of the oligosaccharide products. Here we describe the discovery and characterisation of endo-acting family 16 glycoside hydrolases (GH16s) from prominent mucin degrading gut bacteria that specifically target the oligosaccharide side chains of intestinal mucins from both animals and humans. These endo-acting O-glycanases display β1,4-glactosidase activity and in several cases are surface located indicating they are involved in the initial step in mucin breakdown. The data suggest a new paradigm for mucin breakdown by the microbiota and the endo-mucinases provide a potential tool to explore changes that occur in mucin structure in intestinal disorders such as inflammatory bowel disease and colon cancer.
Genome-wide association study for maize leaf cuticular conductance identifies candidate genes involved in the regulation of cuticle development
Authors: Lin Meng , Matschi Susanne , Vasquez Miguel , Chamness James , Kaczmar Nicholas , Baseggio Matheus , Miller Michael , Stewart Ethan L. , Qiao Pengfei , Scanlon Michael J. , Molina Isabel , Smith Laurie G. , Gore Michael A.
Published: November 2019

The cuticle, a hydrophobic layer of cutin and waxes synthesized by plant epidermal cells, is the major barrier to water loss when stomata are closed at night and under water-limited conditions. Elucidating the genetic architecture of natural variation for leaf cuticular conductance (gc) is important for identifying genes relevant to improving crop productivity in drought-prone environments. To this end, we conducted a genome-wide association study ofgcof adult leaves in a maize inbred association panel that was evaluated in four environments (Maricopa, AZ, and San Diego, CA in 2016 and 2017). Five genomic regions significantly associated withgcwere resolved to seven plausible candidate genes (ISTL1, two SEC14 homologs, cyclase-associated protein, a CER7 homolog, GDSL lipase, and β-D-XYLOSIDASE 4). These candidates are potentially involved in cuticle biosynthesis, trafficking and deposition of cuticle lipids, cutin polymerization, and cell wall modification. Laser microdissection RNA sequencing revealed that all these candidate genes, with the exception of the CER7 homolog, were expressed in the zone of the expanding adult maize leaf where cuticle maturation occurs. With direct application to genetic improvement, moderately high average predictive abilities were observed for whole-genome prediction ofgcin locations (0.46 and 0.45) and across all environments (0.52). The findings of this study provide novel insights into the genetic control ofgcand have the potential to help breeders more effectively develop drought-tolerant maize for target environments.

Article summary

The cuticle serves as the major barrier to water loss when stomata are closed at night and under water-limited conditions and potentially relevant to drought tolerance in crops. We performed a genome-wide association study to elucidate the genetic architecture of natural variation for maize leaf cuticular conductance. We identified epidermally expressed candidate genes that are potentially involved in cuticle biosynthesis, trafficking and deposition, cutin polymerization, and cell wall modification. Finally, we observed moderately high predictive abilities for whole-genome prediction of leaf cuticular conductance. Collectively, these findings may help breeders more effectively develop drought-tolerant maize.
Germline and somatic genetic variants in the p53 pathway interact to affect cancer risk, progression and drug response
Authors: Zhang Ping , Kitchen-Smith Isaac , Xiong Lingyun , Stracquadanio Giovanni , Brown Katherine , Richter Philipp , Wallace Marsha , Bond Elisabeth , Sahgal Natasha , Moore Samantha , Nornes Svanhild , De Val Sarah , Surakhy Mirvat , Sims David , Wang Xuting , Bell Douglas A. , Zeron-Medina Jorge , Jiang Yanyan , Ryan Anderson , Selfe Joanna , Shipley Janet , Kar Siddhartha , Pharoah Paul , Loveday Chey , Jansen Rick , Grochola Lukasz F. , Palles Claire , Protheroe Andrew , Millar Val , Ebner Daniel , Pagadala Meghana , Blagden Sarah P. , Maughan Tim , Domingo Enric , Tomlinson Ian , Turnbull Clare , Carter Hannah , Bond Gareth
Published: November 2019

Insights into oncogenesis derived from cancer susceptibility loci could facilitate better cancer management and treatment through precision oncology. However, therapeutic applications have thus far been limited by our current lack of understanding regarding both their interactions with somatic cancer driver mutations and their influence on tumorigenesis. Here, by integrating germline datasets relating to cancer susceptibility with tumour data capturing somatically-acquired genetic variation, we provide evidence that single nucleotide polymorphism (SNPs) and somatic mutations in the p53 tumor suppressor pathway can interact to influence cancer development, progression and treatment response. We go on to provide human genetic evidence of a tumor-promoting role for the pro-survival activities of p53, which supports the development of more effective therapy combinations through their inhibition in cancers retaining wild-type p53.

Significance

We describe significant interactions between heritable and somatic genetic variants in the p53 pathway that affect cancer susceptibility, progression and treatment response. Our results offer evidence of how cancer susceptibility SNPs can interact with cancer driver genes to affect cancer progression and identify novel therapeutic targets.
GNMFLMI: Graph Regularized Nonnegative Matrix Factorization for Predicting LncRNA-MiRNA Interactions
Authors: Wang Mei-Neng , You Zhu-Hong , Li Li-Ping , Wong Leon , Chen Zhan-Heng , Gan Cheng-Zhi
Published: November 2019

Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been involved in various biological processes. Emerging evidence suggests that the interactions between lncRNAs and miRNAs play an important role in regulating of genes and the development of many diseases. Due to the limited scale of known lncRNA-miRNA interactions, and expensive time and labor costs for identifying them by biological experiments, more accurate and efficient lncRNA-miRNA interactions computational prediction approach urgently need to be developed. In this work, we proposed a novel computational method, GNMFLMI, to predict lncRNA-miRNA interactions using graph regularized nonnegative matrix factorization. More specifically, the similarities both lncRNA and miRNA are calculated based on known interaction information and their sequence information. Then, the affinity graphs for lncRNAs and miRNAs are constructed using thep-nearest neighbors, respectively. Finally, a graph regularized nonnegative matrix factorization model is developed to accurately identify potential interactions between lncRNAs and miRNAs. To evaluate the performance of GNMFLMI, five-fold cross validation experiments are carried out. GNMFLMI achieves the AUC value of 0.9769 which outperforms the compared methods NMF and CNMF. In the case studies for lncRNA nonhsat159254.1 and miRNA hsa-mir-544a, 20 and 16 of the top-20 associations predicted by GNMFLMI are confirmed, respectively. Rigorous experimental results demonstrate that GNMFLMI can effectively predict novel lncRNA-miRNA interactions, which can provide guidance for relevant biomedical research.
Unblended Disjoint Tree Merging using GTM improves species tree estimation
Authors: Smirnov Vladimir , Warnow Tandy
Published: November 2019

Phylogeny estimation is an important part of much biological research, but large-scale tree estimation is infeasible using standard methods due to computational issues. Recently, an approach to large-scale phylogeny has been proposed that divides a set of species into disjoint subsets, computes trees on the subsets, and then merges the trees together using a computed matrix of pairwise distances between the species. The novel component of these approaches is the last step: Disjoint Tree Merger (DTM) methods. We present GTM (Guide Tree Merger), a polynomial time DTM method that adds edges to connect the subset trees, so as to provably minimize the topological distance to a computed guide tree. Thus, GTM performs unblended mergers, unlike the previous DTM methods. Yet, despite the potential limitation, our study shows that GTM has excellent accuracy, generally matching or improving on two previous DTMs, and is much faster than both. Thus, the GTM approach to the DTM problem is a useful new tool for large-scale phylogenomic analysis, and shows the surprising potential for unblended DTM methods. The software for GTM is available at https://github.com/vlasmirnov/GTM.
Themacrophage-expressed gene(mpeg)1identifies a subpopulation of B cells in the adult zebrafish
Authors: Ferrero Giuliano , Gomez Etienne , Iyer Sowmya , Rovira Mireia , Miserocchi Magali , Langenau David M. , Bertrand Julien Y. , Wittamer Valérie
Published: November 2019

The mononuclear phagocytic system (MPS) consists of many cells, in particular macrophages, scattered throughout the body. However, there is increasing evidence for the heterogeneity of tissue-resident macrophages, leading to a pressing need for new tools to discriminate MPS subsets from other hematopoietic lineages.Mpeg1.1is an evolutionary conserved gene encodingperforin-2, a pore-forming protein associated with host defense against pathogens. Zebrafishmpeg1.1:GFPandmpeg1.1:mCherryreporters were originally established to specifically label macrophages. Since, more than 100 peer-reviewed publications have made use ofmpeg1.1-driven transgenics forin vivostudies, providing new insights into key aspects of macrophage ontogeny, activation and function. However, while the macrophage-specific expression pattern of thempeg1.1promoter has been firmly established in the zebrafish embryo, it is currently not known whether this specificity is maintained through adulthood. Here we report direct evidence that beside macrophages, a subpopulation of B-lymphocytes is marked bympeg1.1reporters in most adult zebrafish organs. Thesempeg1.1+lymphoid cells endogenously expressmpeg1.1and can be separated frommpeg1.1+macrophages by virtue of their light-scatter characteristics using FACS. Remarkably, our analyses also revealed that B-lymphocytes, rather than mononuclear phagocytes, constitute the mainmpeg1.1-positive population inirf8nullmyeloid-defective mutants, which were previously reported to recover tissue-resident macrophages in adulthood. One notable exception are skin macrophages, whose development and maintenance appear to be independent fromirf8, similar to mammals. Collectively, our findings demonstrate thatirf8functions in myelopoiesis are evolutionary conserved and highlight the need for alternative macrophage-specific markers to study the MPS in adult zebrafish.

SUMMARY SENTENCE

Mpeg1 is not a restricted macrophage marker, but also labels B cells in the adult zebrafish. Therefore, previously identifiedirf8-independent macrophages likely consist of B lymphocytes.

Graphical Abstract
Balancing control: a Bayesian interpretation of habitual and goal-directed behavior
Authors: Schwöbel Sarah , Markovic Dimitrije , Smolka Michael N. , Kiebel Stefan J.
Published: November 2019

In everyday life, our behavior varies on a continuum from automatic and habitual to deliberate and goal-directed. Recent evidence suggests that habit formation and relearning of habits operate in a context-dependent manner: Habit formation is promoted when actions are performed in a specific context, while breaking off habits is facilitated after a context change. It is an open question how one can computationally model the brain’s balancing between context-specific habits and goal-directed actions. Here, we propose a hierarchical Bayesian approach for control of a partially observable Markov decision process that enables conjoint learning of habits and reward structure in a context-specific manner. In this model, habit learning corresponds to an updating of priors over policies and interacts with the learning of the outcome contingencies. Importantly, the model is solely built on probabilistic inference, which effectively provides a simple explanation of how the brain may balance contributions of habitual and goal-directed control. We illustrated the resulting behavior using agent-based simulated experiments, where we replicated several findings of devaluation, extinction, and renewal experiments, as well as the so-called two-step task which is typically used with human participants. In addition, we show how a single parameter, the habitual tendency, can explain individual differences in habit learning and the balancing between habitual and goal-directed control. Finally, we discuss the link of the proposed model to other habit learning models and implications for understanding specific phenomena in substance use disorder.
Functional characterisation of gut microbiota and metabolism in Type 2 diabetes indicates thatClostridialesandEnterococcuscould play a key role in the disease
Authors: Mora-Ortiz Marina , Oregioni Alain , Claus Sandrine P.
Published: November 2019

There is growing evidence indicating that gut microbiota contributes to the development of metabolic syndrome and Type 2 Diabetes (T2D). The most widely-used model for T2D research is the leptin deficientdb/dbmouse model. Yet, a characterisation of the gut microbial composition in this model in relationship with the metabolism is lacking. The objectives of this study were to identify metabolomics and microbial modulations associated with T2D in thedb/dbmouse model. The majority of microbial changes observed included an increase of Enterobacteriaceae and a decrease of Clostridiales in diabetics. The metabolomics interrogation of caecum indicated a lower proteolytic activity in diabetics, who also showed higher Short-Chain Fatty Acid (SCFA) levels. In the case of faeces, the model identified 9 metabolites, the main ones were acetate, butyrate and Branched Chain Amino Acids (BCAAs). Finally, liver was the organ with more metabolic links with gut-microbiota followed by the Gut-Brain Axis (GBA). In conclusion, the interaction between Clostridiales and Enterococcus with caecal metabolism could play a key role in the onset and development of diabetes. Further studies should investigate whether the role of these bacteria is causal or co-occurring.
Spatial and temporal patterns of nitric oxide diffusion and degradation drive emergent cerebrovascular dynamics
Authors: Haselden William , Kedarasetti Ravi Teja , Drew Patrick J.
Published: November 2019

Nitric oxide (NO) is a gaseous signaling molecule that plays an important role in neurovascular coupling. NO produced by neurons diffuses into the smooth muscle surrounding cerebral arterioles, driving vasodilation. However, the rate of NO degradation in hemoglobin is orders of magnitude higher than in brain tissue, though how this might impact NO signaling dynamics is not completely understood. We used simulations to investigate how the spatial and temporal patterns of NO generation and degradation impacted dilation of a penetrating arteriole in cortex. We found that the spatial location of NO production and the size of the vessel both played an important role in determining its responsiveness to NO. The much higher rate of NO degradation and scavenging of NO in the blood relative to the tissue drove emergent vascular dynamics. Large vasodilation events could be followed by post-stimulus constrictions driven by the increased degradation of NO by the blood, and vasomotion-like 0.1-0.3 Hz oscillations could also be generated. We found that these dynamics could be enhanced by elevation of free hemoglobin in the plasma, which occurs in diseases such as malaria and sickle cell anemia, or following blood transfusions. Finally, we show that changes in blood flow during hypoxia or hyperoxia could be explained by altered NO degradation in the parenchyma. Our simulations suggest that many common vascular dynamics may be emergent phenomenon generated by NO degradation by the blood or parenchyma.
Mass spectrometry based immunopeptidomics leads to robust predictions of phosphorylated HLA class I ligands
Authors: Solleder Marthe , Guillaume Philippe , Racle Julien , Michaux Justine , Pak HuiSong , Müller Markus , Coukos George , Bassani-Sternberg Michal , Gfeller David
Published: November 2019

The presentation of peptides on class I human leukocyte antigen (HLA-I) molecules plays a central role in immune recognition of infected or malignant cells. In cancer, non-self HLA-I ligands can arise from many different alterations, including non-synonymous mutations, gene fusion, cancer-specific alternative mRNA splicing or aberrant post-translational modifications. Identifying HLA-I ligands remains a challenging task that requires either heavy experimental work forin-vivoidentification or optimized bioinformatics tools for accurate predictions. To date, no HLA-I ligand predictor includes post-translational modifications. To fill this gap, we curated phosphorylated HLA-I ligands from several immunopeptidomics studies (including six newly measured samples) covering 72 HLA-I alleles, and retrieved a total of 2,066 unique phosphorylated peptides. We then expanded our motif deconvolution tool to identify precise binding motifs of phosphorylated HLA-I ligands. Our results reveal a clear enrichment of phosphorylated peptides among HLA-C ligands and demonstrate a prevalent role of both HLA-I motifs and kinase motifs on the presentation of phosphorylated peptides. This data further enabled us to develop and validate the first predictor of interactions between HLA-I molecules and phosphorylated peptides.
Genome-wide association study of musical beat synchronization demonstrates high polygenicity
Authors: Niarchou Maria , Gustavson Daniel E. , Sathirapongsasuti J. Fah , Anglada-Tort Manuel , Eising Else , Bell Eamonn , McArthur Evonne , Straub Peter ,   The 23andMe Research Team, McAuley J. Devin , Capra John A. , Ullén Fredrik , Creanza Nicole , Mosing Miriam A. , Hinds David , Davis Lea K. , Jacoby Nori , Gordon Reyna L.
Published: November 2019

Moving in synchrony to the beat is a fundamental component of musicality. Here, we conducted a genome-wide association study (GWAS) to identify common genetic variants associated with beat synchronization in 606,825 individuals. Beat synchronization exhibited a highly polygenic architecture, with sixty-nine loci reaching genome-wide significance (p<5×10−8) and SNP-based heritability (on the liability scale) of 13%-16%. Heritability was enriched for genes expressed in brain tissues, and for fetal and adult brain-specific gene regulatory elements, underscoring the role of central nervous system-expressed genes linked to the genetic basis of the trait. We performed validations of the self-report phenotype (through internet-based experiments) and of the GWAS (polygenic scores for beat synchronization were associated with patients algorithmically classified as musicians in medical records of a separate biobank). Genetic correlations with breathing function, motor function, processing speed, and chronotype suggest shared genetic architecture with beat synchronization and provide avenues for new phenotypic and genetic explorations.
Accelerating functional gene discovery in osteoarthritis
Authors: Butterfield Natalie C. , Curry Katherine F. , Steinberg Julia , Dewhurst Hannah , Komla-Ebri Davide , Mannan Naila S. , Adoum Anne-Tounsia , Leitch Victoria D. , Logan John G. , Waung Julian A. , Ghirardello Elena , Southam Lorraine , Youlten Scott E. , Mark Wilkinson J , McAninch Elizabeth A. , Vancollie Valerie E. , Kussy Fiona , White Jacqueline K. , Lelliott Christopher J. , Adams David J. , Jacques Richard , Bianco Antonio C. , Boyde Alan , Zeggini Eleftheria , Croucher Peter I. , Williams Graham R. , Duncan Bassett J. H.
Published: November 2019

Osteoarthritis causes debilitating pain and disability, resulting in a huge socioeconomic burden, yet no drugs are available that prevent disease onset or progression. Here, we develop, validate and use rapid-throughput imaging techniques to identify abnormal joint phenotypes in unselected mutant mice generated by the International Knockout Mouse Consortium. We identify 14 genes with functional involvement in osteoarthritis pathogenesis, including the homeobox genePitx1, and functionally characterize 6 candidate human osteoarthritis genes in mouse models. We demonstrate sensitivity of the methods by identifying age-related degenerative joint damage in wild-type mice. Finally, we generate mutant mice with an osteoarthritis-associated polymorphism in theDio2gene byCrispr/Cas9genome editing and demonstrate a protective role in disease onset with public health implications. This expanding resource of unselected mutant mice will transform the field by accelerating functional gene discovery in osteoarthritis and offering unanticipated drug discovery opportunities for this common and incapacitating chronic disease.
Novel patterns of complex structural variation revealed across thousands of cancer genome graphs
Authors: Hadi Kevin , Yao Xiaotong , Behr Julie M. , Deshpande Aditya , Xanthopoulakis Charalampos , Rosiene Joel , Darmofal Madison , Tian Huasong , DeRose Joseph , Mortensen Rick , Adney Emily M. , Gajic Zoran , Eng Kenneth , Wala Jeremiah A. , Wrzeszczyński Kazimierz O. , Arora Kanika , Shah Minita , Emde Anne-Katrin , Felice Vanessa , Frank Mayu O. , Darnell Robert B. , Ghandi Mahmoud , Huang Franklin , Maciejowski John , De Lange Titia , Setton Jeremy , Riaz Nadeem , Reis-Filho Jorge S. , Powell Simon , Knowles David , Reznik Ed , Mishra Bud , Beroukhim Rameen , Zody Michael C. , Robine Nicolas , Oman Kenji M. , Sanchez Carissa A. , Kuhner Mary K. , Smith Lucian P. , Galipeau Patricia C. , Paulson Thomas G. , Reid Brian J. , Li Xiaohong , Wilkes David , Sboner Andrea , Mosquera Juan Miguel , Elemento Olivier , Imielinski Marcin
Published: November 2019

Cancer genomes often harbor hundreds of somatic DNA rearrangement junctions, many of which cannot be easily classified into simple (e.g. deletion, translocation) or complex (e.g. chromothripsis, chromoplexy) structural variant classes. Applying a novel genome graph computational paradigm to analyze the topology of junction copy number (JCN) across 2,833 tumor whole genome sequences (WGS), we introduce three complex rearrangement phenomena: pyrgo, rigma, and tyfonas. Pyrgo are “towers” of low-JCN duplications associated with early replicating regions and superenhancers, and are enriched in breast and ovarian cancers. Rigma comprise “chasms” of low-JCN deletions at late-replicating fragile sites in esophageal and other gastrointestinal (GI) adenocarcinomas. Tyfonas are “typhoons” of high-JCN junctions and fold back inversions that are enriched in acral but not cutaneous melanoma and associated with a previously uncharacterized mutational process of non-APOBEC kataegis. Clustering of tumors according to genome graph-derived features identifies subgroups associated with DNA repair defects and poor prognosis.
Design of Ceramic Packages for Acoustically Coupled Implantable Medical Devices
Authors: Shen Konlin , Maharbiz Michel M.
Published: November 2019

Objective

Ultrasonic acoustic power transfer is an efficient mechanism for coupling energy to millimeter and sub-millimeter implants in the body. To date, published ultrasonically powered implants have been encapsulated with thin film polymers that are susceptible to well-documented failure modes in vivo, including water penetration and attack by the body. As with all medical implants, packaging with ceramic or metallic materials can reduce water vapor transmission and improve biostability to provide decadal device lifetime. In this paper, we evaluate methods of coupling acoustic energy to the interior of ceramic packages.

Methods

The classic wave approach and modal expansion are used to obtain analytical expressions for acoustic transmission through two different package designs and these approaches are validated experimentally. A candidate package design is demonstrated using alumina packages and titanium lids, designed to be acoustically transparent.

Results

Bulk modes are shown to be more effective at coupling acoustic energy to a piezoelectric receiver than flexural modes. Using bulk modes, packaged motes have an overall link efficiency of roughly 10%, compared to 25% for unpackaged motes. Packaging does not have a significant effect on translational misalignment penalties, but does increase angular misalignment penalties. Passive amplitude-modulated backscatter communication is demonstrated.

Conclusion

Thin lids enable the use of acoustically coupled devices even with package materials of very different acoustic impedance. Significance: This work provides an analysis and method for designing packages that enable acoustic coupling with implantable medical devices, which could facilitate clinical translation.
Temperature predicts the maximum tree-species richness and water and frost shape the residual variation
Authors: Segovia Ricardo
Published: November 2019

The kinetic hypothesis of biodiversity proposes that temperature is the main driver of variation in species richness, given its exponential effect on biological activity and, potentially, on rates of diversification. However, limited support for this hypothesis has been found to date. I tested the fit of this model on the variation of tree-species richness along a continuous latitudinal gradient in the Americas. I found that the kinetic hypothesis accurately predicts the upper bound of the relationship between the inverse of mean annual temperature (1/kK) and the natural logarithm of species richness, at a broad scale. In addition, I found that water availability and the number of days with freezing temperatures organize a part of the residual variation of the upper bound model. The finding of the model fitting on the upper bound rather than on the mean values suggest that the kinetic hypothesis is modeling the variation of the potential maximum species richness per unit of temperature. Likewise, the distribution of the residuals of the upper bound model in function of the number of days with freezing temperatures suggest the importance of environmental thresholds rather than gradual variation driving the observable variation in species richness.
Parameter tuning facilitates the evolution of diverse tunneling patterns in termites
Authors: Mizumoto Nobuaki , Bardunias Paul M. , Pratt Stephen C.
Published: November 2019

The nest structures built by social insects are complex group-level patterns that emerge from interactions among individuals following simple behavioral rules. The theory of complex systems predicts that there is no simple one-to-one relationship between variations in collective patterns and variation in individual behaviors; therefore, it is essential to know how actual behavior evolves to change pattern formation. Here we demonstrate that the evolutionary divergence of termite tunneling patterns is achieved by quantitative tuning of shared behavioral rules, rather than the acquisition of novel behaviors. We compared tunnel formation between two closely related species,Reticulitermes tibialisandHeterotermes aureus, and found thatH. aureusbuilds more highly branched tunnels thanR. tibialis.Our behavioral analysis and data-based modeling revealed that these species share the same behavioral repertoire, but a quantitative difference in the probability of sidewall excavation leads to diverse tunneling patterns. In contrast, we also found thatParaneotermes simplicicornis, which evolved tunneling independently, possesses a distinct behavioral repertoire, but shows convergence of branching patterns withR. tibialis. These results elucidate the complex relationship between individual behavior and group-level patterns; in some cases, distinct behavioral rules can produce similar group-level patterns, but in others, a common rule set can yield distinct patterns via parameter tuning. The evolutionary process of collective behavior is flexible and much more complex than we can infer from group-level patterns alone.
WAVE complex self-organization templates lamellipodial formation
Authors: Pipathsouk Anne , Brunetti Rachel M. , Town Jason P. , Breuer Artù , Pellett Patrina A. , Marchuk Kyle , Tran Ngoc-Han T. , Krummel Matthew F. , Stamou Dimitrios , Weiner Orion D.
Published: November 2019

How local interactions of actin regulators yield large-scale organization of cell shape and movement is not well understood. For example, why does the WAVE complex build lamellipodia, the broad sheet-like protrusions that power cell migration, whereas the homologous actin regulator N-WASP forms spiky finger-like actin networks? N-WASP is known to oligomerize into focal condensates that generate an actin finger. In contrast, the WAVE complex exhibits the linear distribution needed to generate an actin sheet. This linear organization of the WAVE complex could either arise from interactions with the actin cytoskeleton or could represent an ability of the complex to self-organize into a linear template. Using super-resolution microscopy, we find that the WAVE complex forms higher-order linear oligomers that curve into 270 nanometer-wide ring structures in the absence of actin polymer. These rings localize to the necks of membrane invaginations, which display saddle point geometries with positive curvature in one axis and negative curvature in the orthogonal axis. To investigate the molecular mechanism of saddle curvature enrichment, we show that the WAVE complex and IRSp53, a membrane curvature-sensitive protein, collaborate to recognize saddle curvature that IRSp53 cannot sense alone. This saddle preference for the WAVE complex could explain emergent cell behaviors, such as expanding and self-straightening lamellipodia as well as the ability of endothelial cells to recognize and seal transcellular holes. Our work highlights how partnering protein interactions enable complex shape sensing and how feedback between cell shape and actin regulators yields self-organized cell morphogenesis.
Application of Optogenetic Amyloid-β Distinguishes Between Metabolic and Physical Damage in Neurodegeneration
Authors: Hsien Lim Chu , Kaur Prameet , Teo Emelyne , Lam Vanessa , Zhu Fangchen , Kibat Caroline , Mathuru Ajay , Gruber Jan , Tolwinski Nicholas S.
Published: November 2019

The brains of Alzheimer’s Disease patients show a decrease in brain mass and a preponderance of extracellular Amyloid-β plaques. These plaques are formed by aggregation of polypeptides that are derived from Amyloid Precursor Protein (APP). Amyloid-β plaques are thought to play either a direct or an indirect role in disease progression, however the exact role of aggregation and plaque formation in the ethology of Alzheimer’s Disease is subject to debate, not least because the biological effects of soluble and aggregated Amyloid-β peptides are difficult to separatein vivo. To investigate the consequences of formation of Amyloid-β oligomers in living tissues, we developed a fluorescently tagged, optogenetic Amyloid-β peptide that oligomerizes rapidly in the presence of blue light. We applied this system to the crucial question of how intracellular Amyloid-β oligomers underlie the pathologies of Alzheimer’s Disease. We show that, although both expression and induced oligomerization of Amyloid-β were detrimental to lifespan and healthspan, we were able to separate the metabolic and physical damage caused by light-induced Amyloid-β oligomerization from Amyloid-β expression alone. The physical damage caused by Amyloid-β oligomers also recapitulated the catastrophic tissue loss that is a hallmark of late AD. We show that the lifespan deficit induced by Amyloid-β oligomers was reduced with Li+treatment. Our results present the first model to separate different aspects of disease progression.
The effects of age on resting-state BOLD signal variability is explained by cardiovascular and cerebrovascular factors
Authors: Tsvetanov Kamen A. , Henson Richard N.A. , Jones P. Simon , Mutsaerts Henk-Jan , Fuhrmann Delia , Tyler Lorraine K. ,   Cam-CAN, Rowe James B.
Published: November 2019

Accurate identification of brain function is necessary to understand neurocognitive ageing, and thereby promote health and well-being. Many studies of neurocognitive aging have investigated brain function with the blood-oxygen level-dependent (BOLD) signal measured by functional magnetic resonance imaging. However, the BOLD signal is a composite of neural and vascular signals, which are differentially affected by aging. It is therefore essential to distinguish the age effects on vascularversusneural function. The BOLD signal variability at rest (known as resting state fluctuation amplitude, RSFA), is a safe, scalable and robust means to calibrate vascular responsivity, as an alternative to breath-holding and hypercapnia. However, the use of RSFA for normalization of BOLD imaging assumes that age differences in RSFA reflecting only vascular factors, rather than age-related differences in neural function (activity) or neuronal loss (atrophy). Previous studies indicate that two vascular factors, cardiovascular health and cerebrovascular function, are insufficient when used alone to fully explain age-related differences in RSFA. It remains possible that their joint consideration is required to fully capture age differences in RSFA. We tested the hypothesis that RSFA no longer varies with age after adjusting for a combination of cardiovascular and cerebrovascular measures. We also tested the hypothesis that RSFA variation with age is not associated with atrophy. We used data from the population-based, lifespan Cam-CAN cohort. After controlling for cardiovascular and cerebrovascular estimates alone, the residual variance in RSFA across individuals was significantly associated with age. However, when controlling for both cardiovascular and cerebrovascular estimates, the variance in RSFA was no longer associated with age. Grey matter volumes did not explain age-differences in RSFA, after controlling for cardiovascular health. The results were consistent between voxel-level analysis and independent component analysis. Our findings indicate that cardiovascular and cerebrovascular signals are together sufficient predictors of age differences in RSFA. We suggest that RSFA can be used to separate vascular from neuronal factors, to characterise neurocognitive aging. We discuss the implications and make recommendations for the use of RSFA in the research of aging.
Crosslinking of nucleotide binding domains improves the coupling efficiency of an ABC transporter
Authors: Fan Chengcheng , Kaiser Jens T. , Rees Douglas C.
Published: November 2019

ATP Binding Cassette (ABC) transporters often exhibit significant basal ATPase activity in the absence of transported substrates. To investigate the factors that contribute to this inefficient coupling of ATP hydrolysis to transport, we characterized the structures and functions of variants of the bacterial Atm1 homolog fromNovosphingobium aromaticivorans(NaAtm1), including forms with disulfide crosslinks between the nucleotide binding domains. Unexpectedly, disulfide crosslinked variants ofNaAtm1 reconstituted into proteoliposomes not only transported oxidized glutathione, but also exhibited more efficient coupling of ATP hydrolysis to GSSG transport than the native transporter. These observations suggest that enhanced conformational dynamics of reconstitutedNaAtm1 may contribute to the inefficient use of ATP. Understanding the origins of this uncoupled ATPase activity, and reducing the impact through disulfide crosslinking or other protocols, will be critical for the detailed dissection of ABC transporter mechanism to assure that the ATP dependent steps are indeed relevant to substrate translocation.