bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

SummaryCancer 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

AbstractObjectiveUltrasonic 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.MethodsThe 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.ResultsBulk 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.ConclusionThin 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

ABSTRACTThe 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

AbstractThe 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

ABSTRACTHow 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

AbstractThe 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

SummaryAccurate 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

AbstractATP 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.
A unique conformational escape reaction of HIV-1 against an allosteric integrase inhibitor
Authors: Nakamura Tomofumi , Nakamura Teruya , Amano Masayuki , Miyakawa Toshikazu , Yamagata Yuriko , Matsuoka Masao , Nakata Hirotomo 
Published: November 2019

AbstractHIV-1 integrase (IN) contributes to HIV-1 RNA binding, which is required for viral maturation. Non-catalytic site integrase inhibitors (NCINIs) have been developed as allosteric IN inhibitors, which perform anti-HIV-1 activity by disrupting IN multimerization. Here, we show that IN undergoes a novel conformational alteration to escape from NCINIs. We observed that NCINI-resistant HIV-1 variants have accumulated amino acid (AA) mutations in the IN-encoding region. We employed HPLC and thermal stability assays to show that the AA mutations affect the folding and dimerization interface of the IN catalytic core domains, resulting in severely decreased multimerization of full-length IN proteins (IN under-multimerization). The under-multimerization of IN was finally restored by HIV-1 RNA in the viral particles. Our study demonstrates that HIV-1 countervails NCINIs by IN under-multimerization as a novel escape mechanism. Our findings provide information on the understanding of IN multimerization and influence the development of unique anti-HIV-1 strategies.
The efficacy of obesity polygenic risk scores in an autistic population
Authors: Zhang David Y. , Palmer Nathan P. , Hong Chuan , Zhang Luwan , Finlayson Samuel G. , Avillach Paul , Kohane Isaac S. 
Published: November 2019

AbstractPolygenic risk scores (PRS) bear great promise in understanding complex diseases and improving clinical diagnoses, but the competency of these risk scores in different populations is known to vary significantly, especially between those of European ancestry and those of other ethnic ancestries. Additionally, the applicability of these risk scores across populations different by disease, instead of ethnicity, is poorly understood. A current and largely unexplored population for the accuracy of PRS is that of individuals with autism. Combined with the increased prevalence of obesity in autistic populations, we seek to evaluate the difference in efficacy of PRS for obesity in autistic versus non-autistic populations. We show that genetic variants strongly associated with obesity in non-autistic populations are significantly less representative of the disease in autistic populations. Rather, these cases of obesity phenocopies in patients with autism may follow a different and non-conventional mechanism of action involving the regulation of oxytocin in the brain among other potential behavioral factors. Our findings elucidate the limits of PRS across populations contrasting by disease and suggest that obesity may be regulated differently in individuals with autism as compared to those without autism.
A novel dynamic network imaging analysis method reveals aging-related fragmentation of cortical networks in mouse
Authors: Llano Daniel A , Ma Chihua , Di Fabrizio Umberto , Taheri Aynaz , Stebbings Kevin A. , Yudintsev Georgiy , Xiao Gang , Kenyon Robert V. , Berger-Wolf Tanya Y. 
Published: November 2019

AbstractNetwork analysis of large-scale neuroimaging data has proven to be a particularly challenging computational problem. In this study, we adapt a novel analytical tool, known as the community dynamic inference method (CommDy), which was inspired by social network theory, for the study of brain imaging data from an aging mouse model. CommDy has been successfully used in other domains in biology; this report represents its first use in neuroscience. We used CommDy to investigate aging-related changes in network parameters in the auditory and motor cortices using flavoprotein autofluorescence imaging in brain slices andin vivo. Analysis of spontaneous activations in the auditory cortex of slices taken from young and aged animals demonstrated that cortical networks in aged brains were highly fragmented compared to networks observed in young animals. Specifically, the degree of connectivity of each activated node in the aged brains was significantly lower than those seen in the young brain, and multivariate analyses of all derived network metrics showed distinct clusters of these metrics in young vs. aged brains. CommDy network metrics were then used to build a random-forests classifier based on NMDA-receptor blockade data, which successfully recapitulated the aging findings, suggesting that the excitatory synaptic substructure of the auditory cortex may be altered during aging. A similar aging-related decline in network connectivity was also observed in spontaneous activity obtained from the awake motor cortex, suggesting that the findings in the auditory cortex are reflections of general mechanisms that occur during aging. Therefore, CommDy therefore provides a new dynamic network analytical tool to study the brain and provides links between network-level and synaptic-level dysfunction in the aging brain.
Integrative nascent RNA methods to reveal cell-type specific transcription programs in peripheral blood and its derivative cells
Authors: Kim Samantha Sae-Young , Kim Eunyoo , Kimm Aileen Kang , Kwak Hojoong 
Published: November 2019

AbstractNascent RNA sequencing is a powerful method to measure transcription with high resolution, sensitivity, and directional information, which gives distinctive information about transcription from other methods such as chromatin immunoprecipitation or mRNA sequencing. We present an integrated package of nascent RNA-seq methods - ultrafast Precision Run On (uPRO) combined with computational procedures to discover cell type specific enhancers, promoters, and transcription factor networks. uPRO is composed of adaptor ligation and reverse transcription reactions, which is reduced to a one-day procedure and makes nascent RNA-seq more feasible and flexible for a widespread use. We generated genome-wide profiles of nascent transcription in human blood derived cell lines and clinical samples of ~1 ml of untreated whole blood. We integrated these data into deep learning and hierarchical network analysis to detect enhancers, promoters, and co-expression networks to define cell-type specific transcription programs. We found conservation of position but variation of expression in cell type specific enhancers and transcription start sites. Transcription factors (TFs) such as TCF-3 and OCT1 were pivotally associated with TF-enhancer-gene networks across cell types. Intriguingly, we also discovered that TFs related to cell stress and inflammation - such as SRF, ATF, CHOP, and NF-kB - are associated with inter-individual variation of leukocyte transcription in whole blood. Our integration of experimental and computational nascent RNA methods will provide an efficient strategy to identify specific transcriptional programs, both in cell-type and patient/disease-associated, with minimal sample requirements.