bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improving Convolutional Network Interpretability with Exponential Activations
Authors: Koo Peter K. , Ploenzke Matt 
Published: May 2019

AbstractDeep convolutional networks trained on regulatory genomic sequences tend to learn distributed representations of sequence motifs across many first layer filters. This makes it challenging to decipher which features are biologically meaningful. Here we introduce the exponential activation that – when applied to first layer filters – leads to more interpretable representations of motifs, both visually and quantitatively, compared to rectified linear units. We demonstrate this on synthetic DNA sequences which have ground truth with various convolutional networks, and then show that this phenomenon holds on in vivo DNA sequences.
Age-Related Changes in Neural Networks Supporting Complex Visual and Social Processing in Adolescence
Authors: Lerner Yulia , Scherf K. Suzanne , Katkov Mikhail , Hasson Uri , Behrmann Marlene 
Published: May 2019

AbstractDespite our differences, there is much about the natural visual world that almost all observers apparently perceive in common. This coherence across observers is evidenced by the finding that, across adults, approximately 30% of the brain is activated in a consistent fashion in response to viewing naturalistic input. The critical question addressed here is how does this consistency emerge and is this pattern of coherence apparent from early in development or does it evolve with time and/or experience? We focused our investigation at a key developmental juncture that might bridge the child and adult patterns, namely, the period of adolescence. We acquired fMRI BOLD data evoked by an 11-minute age-appropriate movie in younger (age 9-14 years) and older adolescents (age 15-19 years) and in adults. Using an intra-subject correlation approach, we characterized the consistency of the neural response within-individual (across two separate runs of the movie), and then, using an inter-subject correlation approach, evaluated the similarity of the response profile within individuals of the same age group and between age-groups. In primary sensory areas (A1+, V1) the response profiles in both groups of adolescents were highly similar to those of the adults, suggesting that these areas are functionally mature at earlier stages of the development. In contrast, some other regions exhibited higher within-age correlations in the adolescent groups than in the adult group. Last, we evaluated the brain responses across the whole cortex and identified the different patterns of maturation as reflected in different inter-subject correlations across the age groups. Together, these findings provide a fine-grained characterization of functional neural development. The approach offers the potential for careful tracking of the development of widespread cortical networks that support the emerging stereotypical responses to naturalistic visual and social stimuli and has important implications for future studies of cortical development.
Castration-mediated IL-8 Promotes Myeloid Infiltration and Prostate Cancer Progression
Authors: Lopez-Bujanda Zoila A. , Haffner Michael C. , Chaimowitz Matthew G. , Chowdhury Nivedita , Venturini Nicholas J. , Obradovic Aleksandar , Hansen Corey S. , Jacków Joanna , Sfanos Karen S. , Bieberich Charles J. , Hurley Paula J. , Selby Mark J. , Korman Alan J. , Christiano Angela M. , De Marzo Angelo M. , Drake Charles G. 
Published: May 2019

SummaryImmunotherapy is a treatment for many types of cancer, primarily due to deep and durable clinical responses mediated by immune checkpoint blockade (ICB)1, 2. Prostate cancer is a notable exception in that it is generally unresponsive to ICB. The standard treatment for advanced prostate cancer is androgen-deprivation therapy (ADT), a form of castration (CTX). ADT is initially effective, but over time patients eventually develop castration-resistant prostate cancer (CRPC). Here, we focused on defining tumor-cell intrinsic factors that contribute to prostate cancer progression and resistance to immunotherapy. We analyzed cancer cells isolated from castration-sensitive and castration-resistant prostate tumors, and discovered that castration resulted in significant secretion of Interleukin-8 (IL-8) and it’s likely murine homolog Cxcl15. These chemokines drove subsequent intra-tumoral infiltration with polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), promoting tumor progression. PMN-MDSC infiltration was abrogated when IL-8 was deleted from prostate cancer epithelial cells using CRISPR/Cas9, or when PMN-MDSC migration was blocked with antibodies against the IL-8 receptor CXCR2. Blocking PMN-MDSC infiltration in combination with anti-CTLA-4 delayed the onset of castration resistance and increased the density of polyfunctional CD8 T cells in tumors. Taken together, our findings establish castration-mediated IL-8 secretion and subsequent PMN-MDSC infiltration as a key suppressive mechanism in the progression of prostate cancer. Targeting of the IL-8/CXCR2 axis around the time of ADT, in combination with ICB, represents a novel therapeutic approach to delay prostate cancer progression to advanced disease.
Single-cell analysis of Non-CG methylation dynamics and gene expression in human oocyte maturation
Authors: Yu Bo , Jayavelu Naresh Doni , Battle Stephanie L. , Smith Thomas H. , Zimmerman Samuel E , Schimmel Timothy , Cohen Jacques , Mar Jessica C. , Hawkins R. David 
Published: May 2019

ABSTRACTOocyte maturation is a coordinated process that is tightly linked to reproductive potential. A better understanding of gene regulation during human oocyte maturation will not only answer an important question in biology, but also facilitate the development of in vitro maturation technology as a fertility treatment. We generated single-cell transcriptome and use previously published single-cell methylome data from human oocytes at different maturation stages to investigate how genes are regulated during oocyte maturation, focusing on the potential regulatory role of non-CG methylation. DNMT3B, a gene encoding a key non-CG methylation enzyme, is one of the 1000 genes upregulated in mature oocytes, which may be at least partially responsible for the increased non-CG methylation as oocytes mature. Non-CG differentially methylated regions (DMRs) between mature and immature oocytes have multiple binding motifs for transcription factors, some of which bind with DNMT3B and may be important regulators of oocyte maturation through non-CG methylation. Over 98% of non-CG DMRs locate in transposable elements, and these DMRs are correlated with expression changes of the nearby genes. Taken together, this data indicates that global non-CG hypermethylation during oocyte maturation may play an active role in gene expression regulation, potentially through the interaction with transcription factors.
Language beyond the language system: dorsal visuospatial pathways support processing of demonstratives and spatial language during naturalistic fast fMRI
Authors: Rocca Roberta , Coventry Kenny R. , Tylén Kristian , Staib Marlene , Lund Torben E. , Wallentin Mikkel 
Published: May 2019

AbstractSpatial demonstratives are powerful linguistic tools used to establish joint attention. Identifying the meaning of semantically underspecified expressions like “this one” hinges on the integration of linguistic and visual cues, attentional orienting and pragmatic inference. This synergy between language and extralinguistic cognition is pivotal to language comprehension in general, but especially prominent in demonstratives.In this study, we aimed to elucidate which neural architectures enable this intertwining between language and extralinguistic cognition using a naturalistic fMRI paradigm. In our experiment, 28 participants listened to a specially crafted dialogical narrative with a controlled number of spatial demonstratives. A fast multiband-EPI acquisition sequence (TR = 388ms) combined with finite impulse response (FIR) modelling of the hemodynamic response was used to capture signal changes at word-level resolution.We found that spatial demonstratives bilaterally engage a network of parietal areas, including the supramarginal gyrus, the angular gyrus, and precuneus, implicated in information integration and visuospatial processing. Moreover, demonstratives recruit frontal regions, including the right FEF, implicated in attentional orienting and reference frames shifts. Finally, using multivariate similarity analyses, we provide evidence for a general involvement of the dorsal (“where”) stream in the processing of spatial expressions, as opposed to ventral pathways encoding object semantics.Overall, our results suggest that language processing relies on a distributed architecture, recruiting neural resources for perception, attention, and extra-linguistic aspects of cognition in a dynamic and context-dependent fashion.
Evaluation of copy number burden in specific epilepsy types from a genome-wide study of 18,564 subjects
Authors: Niestroj Lisa-Marie , Howrigan Daniel P. , Perez-Palma Eduardo , Saarentaus Elmo , Nürnberg Peter , Stevelink Remi , Daly Mark J. , Palotie Aarno , Lal Dennis ,   Epi25 Collaborative
Published: May 2019

AbstractRare and large copy number variants (CNVs) around known genomic ‘hotspots’ are strongly implicated in epilepsy etiology. But it remains unclear whether the observed associations are specific to an epilepsy phenotype, and if additional risk signal can be found outside hotspots. Here, we present the largest CNV burden and first CNV breakpoint level association analysis in epilepsy to date with 11,246 European epilepsy cases and 7,318 ancestry-matched controls. We studied five epilepsy phenotypes: genetic generalized epilepsy, lesional focal epilepsy, non-acquired focal epilepsy, epileptic encephalopathy, and unclassified epilepsy. We discovered novel epilepsy-associated CNV loci and further characterized the CNV burden enrichment among phenotype-specific epilepsies. Finally, we provide evidence for deletion burden outside of known hotspot regions and show that CNVs play a significant role in the genetic architecture of lesional focal epilepsies.
Secondary Structure Motifs Made Searchable to Facilitate the Functional Peptide Design
Authors: Tsai Cheng-Yu , Salawu Emmanuel O , Li Hongchun , Lin Guan-Yu , Kuo Ting-Yu , Voon Liyin , Sharma Adarsh , Hu Kai-Di , Cheng Yi-Yun , Sahoo Sobha , Stuart Lutimba , Chen Chih-Wei , Chang Yuan-Yu , Lu Yu-Lin , Ke Ximai , Wu Chen-Chi , Lan Chung-Yu , Fu Hua-Wen , Yang Lee-Wei 
Published: May 2019

ABSTRACTTo ensure a physicochemically desired sequence motif to adapt a specific type of secondary structures, we compile an α-helix database allowing complicate search patterns to facilitate a data-driven design of therapeutic peptides. Nearly 1.7 million helical peptides in >130 thousand proteins are extracted along with their interacting partners from the protein data bank (PDB). The sequences of the peptides are indexed with patterns and gaps and deposited in our Therapeutic Peptide Design dataBase (TP-DB). We here demonstrate its utility in three medicinal design cases. By our pattern-based search engine but not PHI-BLAST, we can identify a pathogenic protein, Helicobacter pylori neutrophil-activating protein (HP-NAP), a virulence factor of H. pylori, which contains a motif DYKYLE that belongs to the affinity determinant motif DYKXX[DE] of the FLAG-tag and can be recognized by the anti-FLAG M2 antibody. By doing so, the known purification-tag-specific antibody is repurposed into a diagnostic kit for H. pylori. Also by leveraging TP-DB, we discovered a stretch of helical peptide matching the potent membrane-insertion pattern WXXWXXW, elucidated by MD simulations. The newly synthesized peptide has a better minimal inhibitory concentration (MIC) and much lower cytotoxicity against Candida albicans (fungus) than that of previously characterized homologous antimicrobial peptides. In a similar vein, taking the discontinued anchoring residues in the helix-helix interaction interface as the search pattern, TP-DB returns several helical peptides as potential tumor suppressors of hepatocellular carcinoma (HCC) whose helicity and binding affinity were examined by MD simulations. Taken together, we believe that TP-DB and its pattern-based search engine provide a new opportunity for a (secondary-)structure-based design of peptide drugs and diagnostic kits for pathogens without inferring evolutionary homology between sequences sharing the same pattern. TP-DB is made available at http://dyn.life.nthu.edu.tw/design/.
Localization of genetic determinants for pathogenicity of Maize dwarf mosaic virus and Bermudagrass southern mosaic virus
Authors: Mostafavi Neyshabouri Farveh sadat , Yamchi Ahad , Sabbagh Seyed Kazem , Masumi Mahmoud 
Published: May 2019

AbstractMaize dwarf mosaic virus (MDMV) and Bermuda grass southern mosaic virus (BgSMV) are economically important potyviruses of cereals. BgSMV is very similar in genomic sequence to MDMV, but cannot infect Johnsongrass and is not transmitted by Rhopalosiphum maidis. Comparison of their genomes showed an additional stretch of 90 nucleotides in BgSMV coat protein but not in MDMV. Since the 90-nucleotide region is located in the N-terminal of BgSMV coat protein, it seems to have a role in biological properties such as vector transmission and pathogenicity. Recombinant virus constructs were made with and without the 90 nucleotides using SOEing PCR (MDMV (+90) and BgSMV (−90). Johnsongrass plants inoculated with the wild-type MDMV and recombinant BgSMV (−90) showed mosaic symptoms after 16 and 23 days, respectively, whereas plants inoculated with the wild-type BgSMV and recombinant MDMV (+90) didn’t show any symptoms until three months after inoculation. The qRT-PCR results detected significantly higher levels of BgSMV (−90) and MDMV compared to BgSMV and MDMV (+90), respectively. Also, R. maidis was able to transfer only the wild type MDMV and BgSMV (−90) from infected to healthy plants. These results confirmed that the insertion of the 90-nt region into the coat protein of MDMV affects the pathogenicity of the virus.
Velocity coupling of grid cell modules: stable embedding of a low dimensional variable in a high dimensional neural attractor
Authors: Mosheiff Noga , Burak Yoram 
Published: May 2019

AbstractGrid cells in the medial entorhinal cortex (mEC) encode position using a distributed representation across multiple neural populations (modules), each possessing a distinct spatial scale. The modular structure of the representation confers the grid cell neural code with large capacity. Yet, the modularity poses significant challenges for the neural circuitry that maintains the representation, and updates it based on self motion. Small incompatible drifts in different modules, driven by noise, can rapidly lead to large, abrupt shifts in the represented position, resulting in catastrophic readout errors. Here we propose a theoretical model of coupled modules. The coupling suppresses incompatible drifts, allowing for a stable embedding of a two dimensional variable (position) in a higher dimensional neural attractor, while preserving the large capacity. We propose that coupling of this type may be implemented by recurrent synaptic connectivity within the mEC with a relatively simple and biologically plausible structure.
Root morphology and exudate availability is shaped by particle size and chemistry in Brachypodium distachyon
Authors: Sasse Joelle , Jordan Jacob S. , DeRaad Markus , Whiting Katherine , Zhalnina Katherina , Northen Trent 
Published: May 2019

AbstractRoot morphology and exudation define a plants sphere of influence in soils, and are in turn shaped by the physiochemical characteristics of soil. We explored how particle size and chemistry of growth substrates affect root morphology and exudation of the model grass Brachypodium distachyon. Root fresh weight and root lengths were correlated with particle size, whereas root number and shoot weight remained constant. Mass spectrometry imaging suggested that both, root length and number shape root exudation. Exudate metabolite profiles detected with liquid chromatography / mass spectrometry were comparable for plants growing in glass beads or sand with various particles sizes, but distinct for plants growing in clay. However, when exudates of clay-grown plants were collected by removing the plants from the substrate, their exudate profile was similar to sand- or glass beads-grown plants. Clay particles sorbed 20% of compounds exuded by clay-grown plants, and 70% of compounds of a defined exudate medium. The sorbed compounds belonged to a range of chemical classes, among them nucleosides/nucleotides, organic acids, sugars, and amino acids. Some of the sorbed compounds could be de-sorbed by a rhizobacterium (Pseudomonas fluorescens WCS415), supporting its growth. We show that root morphology is affected by substrate size, and that root exudation in contrast is not affected by substrate size or chemistry. The availability of exuded compounds, however, depends on the substrate present. These findings further support the critical importance of the physiochemical properties of soils are crucial to consider when investigating plant morphology, exudation, and plant-microbe interactions.
Echo State Network models for nonlinear Granger causality
Authors: Duggento Andrea , Guerrisi Maria , Toschi Nicola 
Published: May 2019

AbstractWhile Granger Causality (GC) has been often employed in network neuroscience, most GC applications are based on linear multivariate autoregressive (MVAR) models. However, real-life systems like biological networks exhibit notable non-linear behavior, hence undermining the validity of MVAR-based GC (MVAR-GC). Current nonlinear GC estimators only cater for additive nonlinearities or, alternatively, are based on recurrent neural networks (RNN) or Long short-term memory (LSTM) networks, which present considerable training difficulties and tailoring needs. We define a novel approach to estimating nonlinear, directed within-network interactions through a RNN class termed echo-state networks (ESN), where training is replaced by random initialization of an internal basis based on orthonormal matrices. We reformulate the GC framework in terms of ESN-based models, our ESN-based Granger Causality (ES-GC) estimator in a network of noisy Duffing oscillators, showing a net advantage of ES-GC in detecting nonlinear, causal links. We then explore the structure of ES-GC networks in the human brain employing functional MRI data from 1003 healthy subjects drawn from the human connectome project, demonstrating the existence of previously unknown directed within-brain interactions. ES-GC performs better than commonly used and recently developed GC approaches, making it a valuable tool for the analysis of e.g. multivariate biological networks.
MaxQuant software for ion mobility enhanced shotgun proteomics
Authors: Prianichnikov Nikita , Koch Heiner , Koch Scarlet , Lubeck Markus , Heilig Raphael , Brehmer Sven , Fischer Roman , Cox Jürgen 
Published: May 2019

SummaryIon mobility can add a dimension to LC-MS based shotgun proteomics which has the potential to boost proteome coverage, quantification accuracy and dynamic range. Required for this is suitable software that extracts the information contained in the four-dimensional (4D) data space spanned by m/z, retention time, ion mobility and signal intensity. Here we describe the ion mobility enhanced MaxQuant software, which utilizes the added data dimension. It offers an end to end computational workflow for the identification and quantification of peptides, proteins and posttranslational modification sites in LC-IMS-MS/MS shotgun proteomics data. We apply it to trapped ion mobility spectrometry (TIMS) coupled to a quadrupole time-of-flight (QTOF) analyzer. A highly parallelizable 4D feature detection algorithm extracts peaks which are assembled to isotope patterns. Masses are recalibrated with a non-linear m/z, retention time, ion mobility and signal intensity dependent model, based on peptides from the sample. A new matching between runs (MBR) algorithm that utilizes collisional cross section (CCS) values of MS1 features in the matching process significantly gains specificity from the extra dimension. Prerequisite for using CCS values in MBR is a relative alignment of the ion mobility values between the runs. The missing value problem in protein quantification over many samples is greatly reduced by CCS aware MBR.MS1 level label-free quantification is also implemented which proves to be highly precise and accurate on a benchmark dataset with known ground truth. MaxQuant for LC-IMS-MS/MS is part of the basic MaxQuant release and can be downloaded from http://maxquant.org.
Mfn2 requires Hinge 1 integrity for efficient nucleotide-dependent assembly and membrane fusion
Authors: Samanas N.B. , Engelhart E.A. , Hoppins S. 
Published: May 2019

ABSTRACTMitofusins are members of the dynamin-related protein family, large GTPases that harness the energy from nucleotide hydrolysis to remodel membranes. Mitofusins possess four structural domains including two extended helical bundles that are connected by a flexible linker. The role of this linker (Hinge 1) in mitofusin-mediated membrane fusion is not well understood. We have characterized four variants with amino acid substitutions within this region of Mfn2. While a defect was not apparent in cells, a fusion deficiency was observed in vitro, and was rescued by the addition of cytosolic fraction. All four variants had decreased nucleotide-dependent assembly, which was improved by the addition of Bax. Assembly of mitofusins across two membranes was unaffected as formation of the trans complex was similar to wild type for all variants. We further demonstrate that variants with substitutions in both helical bundles are more severely impaired than any single mutant, suggesting that both helical bundles contribute to this function. Our data are consistent with a model where this region contributes to conformational changes that are important for assembly.
Streamlining effects of extra telomeric repeat on telomere folding revealed by fluorescence-force spectroscopy
Authors: Mitra Jaba , Ha Taekjip 
Published: May 2019

AbstractTandem repeats of guanine rich sequences are ubiquitous in the eukaryotic genome. For example, in the human cells, telomeres at the chromosomal ends comprise of kilobases repeats of T2AG3. Four such repeats can form G-quadruplexes (GQs). Biophysical studies have shown that GQs formed from four consecutive repeats possess high diversity both in their structure and in their response to tension. In principle, a GQ can form from any four repeats that may not even be consecutive. In order to investigate the dynamics of GQ possessing such positional multiplicity, we studied five and six repeats human telomeric sequence using single molecule FRET as well as its combination with optical tweezers. Our results suggest preferential formation of GQs at the 3’ end both in K+ and Na+ solutions although minority populations with a 5’ GQ or long-loop GQs were also observed. Using a vectorial folding assay which mimics the directional nature of telomere extension, we found that the 3’ preference holds even when folding is allowed to begin from the 5’ side. Interestingly, the unassociated T2AG3 segment has a streamlining effect in that one or two mechanically distinct species was observed at a single position instead of six or more observed without an unassociated repeat. Location of GQ on a long G-rich telomeric overhang and reduction in diversity of GQ conformations and mechanical responses through adjacent sequences have important implications in processes such as telomerase inhibition, alternative lengthening of telomeres, T-loop formation, telomere end protection and replication.