bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predictive regression modeling with MEG/EEG: from source power to signals and cognitive states
Authors: Sabbagh David , Ablin Pierre , Varoquaux Gaël , Gramfort Alexandre , Engemann Denis A. 
Published: November 2019

AbstractPredicting biomedical outcomes from Magnetoencephalography and Electroencephalography (M/EEG) is central to applications like decoding, brain-computer-interfaces (BCI) or biomarker development and is facilitated by supervised machine learning. Yet most of the literature is concerned with classification of outcomes defined at the event-level. Here, we focus on predicting continuous outcomes from M/EEG signal defined at the subject-level, and analyze about 600 MEG recordings from Cam-CAN dataset and about 1000 EEG recordings from TUH dataset. Considering different generative mechanisms for M/EEG signals and the biomedical outcome, we propose statistically-consistent predictive models that avoid source-reconstruction based on the covariance as representation. Our mathematical analysis and ground truth simulations demonstrated that consistent function approximation can be obtained with supervised spatial filtering or by embedding with Riemannian geometry. Additional simulations revealed that Riemannian methods were more robust to model violations, in particular geometric distortions induced by individual anatomy. To estimate the relative contribution of brain dynamics and anatomy to prediction performance, we propose a novel model inspection procedure based on biophysical forward modeling. Applied to prediction of outcomes at the subject-level, the analysis revealed that the Riemannian model better exploited anatomical information while sensitivity to brain dynamics was similar across methods. We then probed the robustness of the models across different data cleaning options. Environmental denoising was globally important but Riemannian models were strikingly robust and continued performing well even without preprocessing. Our results suggest each method has its niche: supervised spatial filtering is practical for event-level prediction while the Riemannian model may enable simple end-to-end learning.
ATAC-seq identifies thousands of extrachromosomal circular DNA in cancers and cell lines
Authors: Kumar Pankaj , Kiran Shashi , Saha Shekhar , Su Zhangli , Paulsen Teressa , Chatrath Ajay , Dutta Anindya 
Published: November 2019

AbstractExtrachromosomal circular DNAs (eccDNAs) lack centromeres and are not passed equally into daughter cells and thus provide a source of cell-cell heterogeneity in normal and tumor cells. Previously we and other groups purified circular DNA and linearized them by rolling circle amplification for paired end high throughput sequencing to identify eccDNA in cells and tissues. We hypothesized that many eccDNA will have more open chromatin and so will be susceptible to linearization and sequencing by tagmentation. Indeed, we find that ATAC-seq on cell lines and cancers, without any enrichment of circular DNA, identifies thousands of eccDNAs. The identified eccDNAs in cell lines were validated by inverse PCR on DNA that survives exonuclease digestion of linear DNA and by metaphase FISH. We demonstrate that ATAC-seq data generated in Lower Grade Gliomas (LGG) and Glioblastomas (GBM) identify eccDNAs, including one containing the well-known EGFR gene amplicon from chr7. Many of the eccDNAs are identified even before amplification of the locus is detected by genotyping arrays. Thus, standard ATAC-seq is a sensitive method to detect segments of DNA that are present as eccDNA in a subset of the tumor cells, ready to be further amplified under appropriate selection, as during therapy.
Spreading of a mycobacterial cell surface lipid into host epithelial membranes promotes infectivity
Authors: Cambier C.J. , Banik Steven M. , Buonomo Joseph A. , Bertozzi Carolyn R. 
Published: November 2019

ABSTRACTSeveral virulence lipids populate the outer cell wall of pathogenic mycobacteria (Jackson, 2014). Phthiocerol dimycocerosate (PDIM), one of the most abundant outer membrane lipids (Anderson, 1929), plays important roles in both defending against host antimicrobial programs (Camacho et al., 2001; Cox et al., 1999; Murry et al., 2009) and in evading these programs altogether (Cambier et al., 2014a; Rousseau et al., 2004). Immediately following infection, mycobacteria rely on PDIM to evade toll-like receptor (TLR)-dependent recruitment of bactericidal monocytes which can clear infection (Cambier et al., 2014b). To circumvent the limitations in using genetics to understand virulence lipid function, we developed a chemical approach to introduce a clickable, semi-synthetic PDIM onto the cell wall of Mycobacterium marinum. Upon infection of zebrafish, we found that PDIM rapidly spreads into host epithelial membranes, and that this spreading inhibits TLR activation. PDIM’s ability to spread into epithelial membranes correlated with its enhanced fluidity afforded by its methyl-branched mycocerosic acids. Additionally, PDIM’s affinity for cholesterol promoted its occupation of epithelial membranes; treatment of zebrafish with statins, cholesterol synthesis inhibitors, decreased spreading and provided protection from infection. This work establishes that interactions between host and pathogen lipids influence mycobacterial infectivity and suggests the use of statins as tuberculosis preventive therapy by inhibiting PDIM spread.
Structure based analysis of protein cluster size for super-resolution microscopy in the nervous system
Authors: Wong Chia-En , Lee Cheng-Che , Tsai Kuen-Jer 
Published: November 2019

AbstractTo overcome the diffraction limit and resolve target structures in greater detail, far-field super-resolution techniques such as stochastic optical reconstruction microscopy (STORM) have been developed, and different STORM algorithms have been developed to deal with the various problems that arise. In particular, the effect of local structure is an important issue. For objects with closely correlated distributions, simple Gaussian-based localization algorithms often used in STORM imaging misinterpret overlapping point spread functions (PSFs) as one and this limits the ability of super-resolution imaging to resolve nanoscale local structures and leading to inaccurate length measurements. In the present study, we proposed a novel, structure-based, super-resolution image analysis method: structure-based analysis (SBA), which combines a structural function and a super-resolution localization algorithm. Using SBA, we estimated the size of fluorescent beads, inclusion proteins, and subtle synaptic structures in both wide-field and STORM images. The results showed that SBA has comparable and often superior performance to commonly used full-width-at-half-maximum parameters. We also demonstrated that SBA provides size estimations that corroborate previously published electron microscopy data.
Optimizing the Timing and Composition of Therapeutic Phage Cocktails: A Control-theoretic Approach
Authors: Li Guanlin , Leung Chung Yin , Wardi Yorai , Debarbieux Laurent , Weitz Joshua S. 
Published: November 2019

AbstractViruses that infect bacteria, i.e., bacteriophage or ‘phage’, are increasingly considered as treatment options for the control and clearance of bacterial infections, particularly as compassionate use therapy for multi-drug resistant infections. In practice, clinical use of phage often involves the application of multiple therapeutic phage, either together or sequentially. However, the selection and timing of therapeutic phage delivery remains largely ad hoc. In this study, we evaluate principles underlying why careful application of multiple phage (i.e., a ‘cocktail’) might lead to therapeutic success in contrast to the failure of single-strain phage therapy to control an infection. First, we use a nonlinear dynamics model of within-host interactions to show that a combination of fast intra-host phage decay, evolution of phage resistance amongst bacteria, and/or compromised immune response might limit the effectiveness of single-strain phage therapy. To resolve these problems, we combine dynamical modeling of phage, bacteria, and host immune cell populations with control-theoretic principles (via optimal control theory) to devise evolutionarily robust phage cocktails and delivery schedules to control the bacterial populations. Our numerical results suggest that optimal administration of single-strain phage therapy may be sufficient for curative outcomes in immunocompetent patients, but may fail in immunodeficient hosts due to phage resistance. We show that optimized treatment with a two-phage cocktail that includes a counter-resistant phage can restore therapeutic efficacy in immunodeficient hosts.
Entropy-Based Analysis of Vertebrate Sperm Protamine Sequences: Evidence of Dityrosine and Cysteine-Tyrosine Cross-Linking in Sperm Protamines
Authors: Powell Christian D. , Kirchhoff Daniel C. , DeRouchey Jason E. , Moseley Hunter N.B. 
Published: November 2019

AbstractBackgroundSpermatogenesis is the process by which germ cells develop into spermatozoa in the testis. Sperm protamines are small, arginine-rich nuclear proteins which replace somatic histones during spermatogenesis, allowing a hypercondensed DNA state that leads to a smaller nucleus and facilitating sperm head formation. In eutherian mammals, the protamine-DNA complex is achieved through a combination of intra- and intermolecular cysteine cross-linking and possibly histidine-cysteine zinc ion binding. Most metatherian sperm protamines lack cysteine but perform the same function. This lack of dicysteine cross-linking has made the mechanism behind metatherian protamines folding unclear.ResultsProtamine sequences from UniProt’s databases were pulled down and sorted into homologous groups. Multiple sequence alignments were then generated and a gap weighted relative entropy score calculated for each position. For the eutherian alignments, the cysteine containing positions were the most highly conserved. For the metatherian alignment, the tyrosine containing positions were the most highly conserved and corresponded to the cysteine positions in the eutherian alignment.ConclusionsHigh conservation indicates likely functionally/structurally important residues at these positions in the metatherian protamines and the correspondence with cysteine positions within the eutherian alignment implies a similarity in function. One explanation is that the metatherian protamine structure relies upon dityrosine cross-linking between these highly conserved tyrosines. Also, the human protamine P1 sequence has a tyrosine substitution in a position expecting eutherian dicysteine cross-linking. Similarly, some members of the metatherian Planigales genus contain cysteine substitutions in positions expecting plausible metatherian dityrosine cross-linking. Rare cysteine-tyrosine cross-linking could explain both observations.
An Autonomous Molecular Bioluminescent Reporter (AMBER) for voltage imaging in freely moving animals
Authors: Srinivasan Prasanna , Griffin Nicole M , Joshi Pradeep , Thakur Dhananjay , Nguyen-Le Alex , McCotter Sean , Jain Akshar , Saeidi Mitra , Kulkarni Prajakta , Eisdorfer Jaclyn T. , Rothman Joel , Montell Craig , Theogarajan Luke 
Published: November 2019

1.AbstractGenetically encoded reporters have greatly increased our understanding of biology, especially in neuroscience. While fluorescent reporters have been widely used, photostability and phototoxicity have hindered their use in long-term experiments. Bioluminescence overcomes some of these challenges but requires the addition of an exogenous luciferin limiting its use. Using a modular approach we have engineered Autonomous Molecular BioluminEscent Reporter (AMBER), an indicator of membrane potential. Unlike other luciferase-luciferin bioluminescent systems, AMBER encodes the genes to express both the luciferase and luciferin. AMBER is a voltage-gated luciferase coupling the functionalities of theCionavoltage-sensing domain (VSD) and bacterial luciferase, luxAB. When AMBER is co-expressed with the luciferin producing genes it reversibly switches the bioluminescent intensity as a function of membrane potential. Using biophysical and biochemical methods we show that AMBER modulates its enzymatic activity as a function of the membrane potential. AMBER shows several-fold increase in the luminescent (ΔL/L) signal upon switching from the off to on state when the cell is depolarized.In vivoexpression of AMBER inC. elegansallowed detecting pharyngeal pumping action and mechanosensory neural activity from multiple worms simultaneously. AMBER reports neural activity of multiple animals at the same time and can be used in social behavior assays to elucidate the role of membrane potential underlying behavior.2.Significance StatementThere have been many exciting advances in the development of genetically encoded voltage indicators to monitor intracelluar voltage changes. Most sensors employ fluorescence, which requires external light, potentially causing photobleaching or overheating. Consequently, there has been interest in developing luminescence reporters. However, they require addition of an exogenous substrate to produce light intracellularly. Here, we engineered a genetically encoded bioluminescent voltage indicator, AMBER, which unlike other bioluminescent activity indicators, does not require addition of an exogenous substrate. AMBER allows a large differential signal, a high signal-to-noise ratio, and causes minimal metabolic demand on cells. We used AMBER to record voltage activity in freely-moving C.elegans, demonstrating that AMBER is a important new tool for monitoring neuronal activity during social behavior.
Biodiversity-based innovations fortify agricultural growth in Asia-Pacific economies
Authors: Wyckhuys K.A.G. , Lu Y.H. , Zhou W.W. , Cock M.J.W. , Furlong M.J. 
Published: November 2019

AbstractThe Green Revolution (GR) is widely credited with alleviating famine, mitigating poverty and driving aggregate economic growth over the past 6 decades. In Asia, GR technologies secured a tripling of rice output, with one-off germplasm improvements providing benefits beyond US$ 4.3 billion/year. Here, we unveil the magnitude and macro-economic relevance of parallel biodiversity-induced productivity growth in non-rice crops from 1918 to 2018. We empirically demonstrate how biological control (BC) defused invasive pest threats in multiple agricultural commodities, ensuring annually-accruing (on-farm) benefits of US$ 22.6 billion/year. Scientifically-guided BC permitted 73-100% yield-loss recovery in critical food, feed and fiber crops including cassava, banana, breadfruit and coconut. As such, BC promoted rural growth and prosperity even in marginal, poorly-endowed, non-rice environments. By placing agro-ecological innovations on equal footing with input-intensive measures, our work provides lessons for future efforts to mitigate invasive species, restore ecological resilience and sustainably raise output of global agri-food systems.
Biological and statistical interpretation of size-at-age, mixed-effects models of growth
Authors: Vincenzi Simone , Jesensek Dusan , Crivelli Alain J 
Published: November 2019

AbstractThe differences in life-history traits and processes between organisms living in the same or different populations contribute to determine their ecological and evolutionary dynamics. Recent advances in statistical and computational methods make it easier to investigate individual and group variation in life-history traits.We developed mixed-effect model formulations of the popular size-at-age von Bertalanffy and Gompertz growth functions to estimate individual and group variation in body growth, using as a model system four freshwater fish populations living in Slovenian streams, where tagged individuals were sampled for more than 10 years. We used the software Template Model Builder to estimate the parameters of the mixed-effect growth models.Estimates of asymptotic size from the Gompertz and von Bertalanffy models were not significantly correlated, but their predictions of size-at-age of individuals were strongly correlated (r> 0.99). Tests on data that were not used to estimate model parameters showed that predictions of individual growth trajectories using the random-effects model were accurately predicted (R2> 0.80 for the best models over more than 500 predictions) starting from one single observation of body size early in life. Model results pointed to size ranks that are largely maintained throughout the lifetime of individuals in all populations.
Nova proteins direct synaptic integration of somatostatin interneurons through activity-dependent alternative splicing
Authors: Ibrahim Leena A. , Wamsley Brie , Al-Ghamdi Norah , Yusuf Nusrath , Sevier Elaine , Hairston Ariel , Sherer Mia , Jaglin Xavier Hubert , Xu Qing , Guo Lihua , Khodadadi-Jamayran Alireza , Favuzzi Emilia , Yuan Yuan , Dimidschstein Jordane , Darnell Robert , Fishell Gord 
Published: November 2019

AbstractSomatostatin interneurons are the earliest born population of cortical inhibitory cells. They are crucial to support normal brain development and function; however, the mechanisms underlying their integration into nascent cortical circuitry are not well understood. In this study, we begin by demonstrating that the maturation of somatostatin interneurons is activity dependent. We then investigated the relationship between activity, alternative splicing and synapse formation within this population. Specifically, we discovered that the Nova family of RNA-binding proteins are activity-dependent and are essential for the maturation of somatostatin interneurons, as well as their afferent and efferent connectivity. Within this population, Nova2 preferentially mediates the alternative splicing of genes required for axonal formation and synaptic function independently from its effect on gene expression. Hence, our work demonstrates that the Nova family of proteins through alternative splicing are centrally involved in coupling developmental neuronal activity to cortical circuit formation.
Metabolic switching ofMycobacterium tuberculosisduring hypoxia is controlled by the virulence regulator PhoP
Authors: Singh Prabhat Ranjan , Anil Kumar Vijjamarri , Sarkar Dibyendu 
Published: November 2019

ABSTRACTMycobacterium tuberculosis(Mtb) retains the unique ability to establish an asymptomatic latent infection. A fundamental question in mycobacterial physiology is to understand the mechanisms involved in hypoxic stress, a critical player in persistence. Here, we show that the virulence regulator PhoP responds to hypoxia, the dormancy signal and effectively integrates hypoxia with nitrogen metabolism. We also provide evidence to demonstrate that both under nitrogen limiting conditions and during hypoxia,phoPlocus controls key genes involved in nitrogen metabolism. Consistently, under hypoxiaΔphoPshows growth attenuation even with surplus nitrogen, the alternate electron acceptor, and complementation of the mutant restores bacterial growth. Together, our observations provide new biological insights into the role of PhoP in integrating nitrogen metabolism with hypoxia by the assistance of the hypoxia regulator DosR. The results have significant implications on the mechanism of intracellular survival and growth of the tubercle bacilli under a hypoxic environment within the phagosome.ImportanceMtb retains the unique ability to establish an asymptomatic latent infection. To understand the mechanisms involved in hypoxic stress which plays a critical role in persistence, we show that the virulence regulator PhoP responds to hypoxia, the dormancy signal. In keeping with this,phoPwas shown to play a major role in Mtb growth under hypoxia even in presence of surplus nitrogen, the alternate electron acceptor. Our results showing regulation of hypoxia-responsive genes provide new biological insights into role of the virulence regulator in metabolic switching by sensing hypoxia and integrating nitrogen metabolism with hypoxia by the assistance of the hypoxia regulator DosR.
Pseudorabies Virus Infection Accelerates Degradation of the Kinesin-3 Motor KIF1A
Authors: Huang Hao , Koyuncu Orkide O. , Enquist Lynn W. 
Published: November 2019

AbstractAlphaherpesviruses, including pseudorabies virus (PRV), are neuroinvasive pathogens that establish life-long latency in peripheral ganglia following the initial infection at mucosal surfaces. The establishment of latent infection and the subsequent reactivations during which newly-assembled virions are sorted into and transported anterogradely inside axons to the initial mucosal site of infection, rely on axonal bidirectional transport mediated by microtubule-based motors. Previous studies using cultured peripheral nervous system (PNS) neurons have demonstrated that KIF1A, a kinesin-3 motor, mediates the efficient axonal sorting and transport of newly-assembled PRV virions. In this study, we report that KIF1A, unlike other axonal kinesins, is an intrinsically unstable protein prone to proteasomal degradation. Interestingly, PRV infection of neuronal cells leads not only to a non-specific depletion of KIF1A mRNA, but also to an accelerated proteasomal degradation of KIF1A proteins, leading to a near depletion of KIF1A protein late in infection. Using a series of PRV mutants deficient in axonal sorting and anterograde spread, we identified the PRV US9/gE/gI protein complex as a viral factor facilitating the proteasomal degradation of KIF1A proteins. Moreover, by using compartmented neuronal cultures that fluidically and physically separate axons from cell bodies, we found that the proteasomal degradation of KIF1A occurs in axons during infection. We propose that PRV anterograde sorting complex, gE/gI/US9, recruits KIF1A to viral transport vesicles for axonal sorting and transport, and eventually accelerates the proteasomal degradation of KIF1A in axons.ImportancePseudorabies virus (PRV) is an alphaherpesvirus related to human pathogens herpes simplex virus −1, −2 and varicella zoster virus. Alphaherpesviruses are neuroinvasive pathogens that establish life-long latent infections in the host peripheral nervous system (PNS). Following reactivation from latency, infection spreads from the PNS back via axons to the peripheral mucosal tissues, a process mediated by kinesin motors. Here, we unveil and characterize the underlying mechanisms for a PRV-induced, accelerated degradation of KIF1A, a kinesin-3 motor promoting the sorting and transport of PRV virions in axons. We show that PRV infection disrupts the synthesis of KIF1A, and simultaneously promotes the degradation of intrinsically unstable KIF1A proteins by proteasomes in axons. Our work implies that the timing of motor reduction after reactivation would be critical because progeny particles would have a limited time window for sorting into and transport in axons for further host-to-host spread.