bluuebunny/crossref_metadata_2025_split huggingface dataset:
Atomic Resolution Mechanism of Ligand Binding to a Solvent Inaccessible Cavity in T4 Lysozyme
Authors: Mondal Jagannath , Ahalawat Navjeet , Pandit Subhendu , Kay Lewis E , Vallurupalli Pramodh 
Published: February 2018

AbstractLigand binding sites in proteins are often localized to deeply buried cavities, inaccessible to bulk solvent. Yet, in many cases binding of cognate ligands occurs rapidly. An intriguing system is presented by the L99A cavity mutant of T4 Lysozyme (L99A T4L) that rapidly binds benzene (~106 M−1 s−1). Although the protein has long served as a model system for protein thermodynamics and crystal structures of both free and benzene-bound L99A T4L are available, the kinetic pathways by which benzene reaches its solvent-inaccessible binding cavity remain elusive. The current work, using extensive molecular dynamics simulation, achieves this by capturing the complete process of spontaneous recognition of benzene by L99A T4L at atomistic resolution. A series of multi-microsecond unbiased molecular dynamics simulation trajectories unequivocally reveal how benzene, starting in bulk solvent, diffuses to the protein and spontaneously reaches the solvent inaccessible cavity of L99A T4L. The simulated and high-resolution X-ray derived bound structures are in excellent agreement. A robust four-state Markov model, developed using cumulative 60 µs trajectories, identifies and quantifies multiple ligand binding pathways with low activation barriers. Interestingly, none of these identified binding pathways required large conformational changes for ligand access to the buried cavity. Rather, these involve transient but crucial opening of a channel to the cavity via subtle displacements in the positions of key helices (helix4/helix6, helix7/helix9) leading to rapid binding. Free energy simulations further elucidate that these channel-opening events would have been unfavorable in otherwise ligand-inactive wild type T4L. Taken together, by integrating experiments, these simulations provide unprecedented mechanistic insights into complete ligand recognition process in a buried cavity. By illustrating the power of subtle helix movements in opening up multiple pathways for ligand access, this work offers an alternate view of ligand recognition mechanism in a solvent-inaccessible cavity, contrary to common perception of single dominant pathway for ligand binding.
Template switching causes artificial junction formation and false identification of circular RNAs
Authors: Tang Chong , Yu Tian , Xie Yeming , Wang Zhuqing , McSwiggin Hayden , Zhang Ying , Zheng Huili , Yan Wei 
Published: February 2018

AbstractHundreds of thousands of putative circular RNAs have been identified through deep sequencing and bioinformatic analyses. However, the circularity of these putative RNA circles has not been experimentally validated due to limited methodologies currently available. We reported here that the template-switching capability of commonly used reverse transcriptases (e.g., SuperScript II) leads to the formation of artificial junction sequences, and consequently misclassification of large linear RNAs as RNA circles. Use of reverse transcriptases without terminal transferase activity (e.g., MonsterScript) for cDNA synthesis is critical for the identification of physiological circular RNAs. We also report two methods, MonsterScript junction PCR and high-resolution melting curve analyses, which can reliably distinguish circular RNAs from their linear forms and thus, can be used to discover and validate true circular RNAs.Significance StatementThe vast majority of circular RNAs were identified through computational detection of junction sequences in the deep sequencing reads because these unique fusion sequences represent back-splicing events. We found that artificial junction sequences could be formed through template switching (TS) when MMLV-derived reverse transcriptases, e.g., SuperScript II, are used to synthesize cDNAs. Thus, many of the reported circular RNAs may not be RNA circles, but rather experimental artifacts. Fake circular RNAs can be avoided by using reverse transcriptases without terminal transferase activity (e.g., MonsterScript) for cDNA synthesis. We developed two novel methods, MonsterScript junction PCR and high-resolution melting curve analyses, for distinguishing circular RNAs from their linear form.
LonGP: an additive Gaussian process regression model for longitudinal study designs
Authors: Cheng Lu , Ramchandran Siddharth , Vatanen Tommi , Lietzen Niina , Lahesmaa Riitta , Vehtari Aki , Lähdesmäki Harri 
Published: February 2018

AbstractMotivationBiomedical research typically involves longitudinal study designs where samples from individuals are measured repeatedly over time and the goal is to identify risk factors (covariates) that are associated with an outcome value. General linear mixed effect models have become the standard workhorse for statistical analysis of data from longitudinal study designs. However, analysis of longitudinal data can be complicated for both practical and theoretical reasons, including difficulties in modelling, correlated outcome values, functional (time-varying) covariates, nonlinear effects, and model inference.ResultsWe present LonGP, an additive Gaussian process regression model for analysis of experimental data from longitudinal study designs. LonGP implements a flexible, non-parametric modelling framework that solves commonly faced challenges in longitudinal data analysis. In addition to inheriting all standard features of Gaussian processes, LonGP can model time-varying random effects and non-stationary signals, incorporate multiple kernel learning, and provide interpretable results for the effects of individual covariates and their interactions. We develop an accurate Bayesian inference and model selection method, and implement an efficient model search algorithm for our additive Gaussian process model. We demonstrate LonGP’s performance and accuracy by analysing various simulated and real longitudinal -omics datasets. Our work is accompanied by a versatile software implementation.AvailabilityLonGP software tool is available athttp://research.cs.aalto.fi/csb/software/longp/.Contactlu.cheng.ac@gmail.com,harri.lahdesmaki@aalto.fi
Crystallizing the Parkinson’s Disease Protein LRRK2 Under Microgravity Conditions
Authors: Mathea Sebastian , Baptista Marco , Reichert Paul , Spinale April , Wu Jian , Allaire Marc , Fiske Brian , Knapp Stefan 
Published: February 2018

AbstractMutations in the gene coding for leucine-rich repeat kinase 2 (LRRK2) are a considerable cause for Parkinson’s disease (PD). However, the high- resolution 3D structure of the protein is still lacking. This structure will not only help to understand PD etiology but will also enable rational drug design. We have established a reliable method to produce LRRK2 crystals for the first time. However, the limited resolution of the diffraction data prevented structure determination using crystallographic methods. Herein we describe our efforts to improve the crystal quality by crystallizing under microgravity conditions aboard the International Space Station (ISS). Our method features diffusive sample mixing in capillaries and controlled crystal formation by transporting the samples in a frozen state. The crystallisation was successfully repeated under microgravity conditions. However, comparison of earth-grown and microgravity-grown LRRK2 crystals did not reveal any differences in diffraction quality. Here we present the established protocol and our experience adapting crystallization condition to the requirements necessary for successful crystallization of large and sensitive biomolecules under microgravity.
Two case studies detailing Bayesian parameter inference for dynamic energy budget models
Authors: Boersch-Supan Philipp H. , Johnson Leah R. 
Published: February 2018

AbstractMechanistic representations of individual life-history trajectories are powerful tools for the prediction of organismal growth, reproduction and survival under novel environmental conditions. Dynamic energy budget (DEB) theory provides compact models to describe the acquisition and allocation of energy by organisms over their full life cycle. However, estimating DEB model parameters, and their associated uncertainties and covariances, is not trivial. Bayesian inference provides a coherent way to estimate parameter uncertainty, and propagate it through the model, while also making use of prior information to constrain the parameter space. We outline a Bayesian inference approach for energy budget models and provide two case studies – based on a simplified DEBkiss model, and the standard DEB model – detailing the implementation of such inference procedures using the open-source software package deBInfer. We demonstrate how DEB and DEBkiss parameters can be estimated in a Bayesian framework, but our results also highlight the difficulty of identifying DEB model parameters which serves as a reminder that fitting these models requires statistical caution.
Adaptive and Wireless Recordings of Electrophysiological Signals during Concurrent Magnetic Resonance Imaging
Authors: Mandal Ranajay , Babaria Nishant , Cao Jiayue , Liu Zhongming ,   Senior Member IEEE
Published: February 2018

AbstractStrong electromagnetic fields that occur during functional magnetic resonance imaging (fMRI) presents a challenging environment for concurrent electrophysiological recordings. Here, we present a miniaturized, wireless platform – “MR-Link” (Multimodal Recording Link) that provides a hardware solution for simultaneous electrophysiological and fMRI signal acquisition. The device detects the changes in the electromagnetic field during fMRI to synchronize amplification and sampling of electrophysiological signals with minimal artifacts. It wirelessly transmits the recorded data at a frequency detectable by the MR-receiver coil. The transmitted data is readily separable from MRI in the frequency domain. To demonstrate its efficacy, we used this device to record electrocardiograms and somatosensory evoked potential during concurrent fMRI scans. The device minimized the fMRI-induced artifacts in electrophysiological data and wirelessly transmitted the data back to the receiver coil without compromising fMRI signal quality. The device is compact (22 mm dia., 2gms) and can be placed within the MR-bore to precisely synchronize with fMRI. Therefore, MR-Link offers an inexpensive system by eliminating the need for amplifiers with a high dynamic range, high-speed sampling, additional storage or synchronization hardware for electrophysiological signal acquisition. It is expected to enable a broader range of applications of simultaneous fMRI and electrophysiology in animals and humans.
No Evidence for Systematic White Matter Correlates of Dyslexia and Dyscalculia
Authors: Moreau David , Wilson Anna J. , McKay Nicole S. , Nihill Kasey , Waldie Karen E. 
Published: February 2018

AbstractLearning disabilities such as dyslexia, dyscalculia and their comorbid manifestation are prevalent, affecting as much as fifteen percent of the population. Structural neuroimaging studies have indicated that these disorders can be related to differences in white matter integrity, although findings remain disparate. In this study, we used a unique design composed of individuals with dyslexia, dyscalculia, both disorders and controls, to systematically explore differences in fractional anisotropy across groups using diffusion tensor imaging. Specifically, we focused on the corona radiata and the arcuate fasciculus, two tracts associated with reading and mathematics in a number of previous studies. Using Bayesian hypothesis testing, we show that the present data favor the null model of no differences between groups for these particular tracts—a finding that seems to go against the current view but might be representative of the disparities within this field of research. Together, these findings suggest that structural differences associated with dyslexia and dyscalculia might not be as reliable as previously thought, with potential ramifications in terms of remediation.
Effect of cytochrome CYP2C19 metabolizing activity on antidepressant response and side effects: meta-analysis of data from genome-wide association studies
Authors: Fabbri Chiara , Tansey Katherine E. , Perlis Roy H. , Hauser Joanna , Henigsberg Neven , Maier Wolfgang , Mors Ole , Placentino Anna , Rietschel Marcella , Souery Daniel , Breen Gerome , Curtis Charles , Lee Sang-Hyuk , Newhouse Stephen , Patel Hamel , O’Donovan Michael , Lewis Glyn , Jenkins Gregory , Weinshilboum Richard M. , Farmer Anne , Aitchison Katherine J. , Craig Ian , McGuffin Peter , Schruers Koen , Biernacka Joanna M. , Uher Rudolf , Lewis Cathryn M. 
Published: February 2018

AbstractCytochrome (CYP) P450 enzymes have a primary role in antidepressant metabolism and variants in these polymorphic genes are targets for pharmacogenetic investigation. This is the first meta-analysis to investigate how CYP2C19 polymorphisms predict citalopram/escitalopram efficacy and side effects.CYP2C19 phenotypes comprise poor metabolizers (PM), intermediate and intermediate+ metabolizers (IM; IM+), extensive and extensive+ metabolizers (EM [wild type]; EM+) and ultra-rapid metabolizers (UM) defined by the two most common CYP2C19 functional polymorphisms (rs4244285 and rs12248560) in Caucasians. These polymorphisms were genotyped or imputed from genome-wide data in four samples treated with citalopram or escitalopram (GENDEP, STAR*D, GenPod, PGRN-AMPS). Treatment efficacy was percentage symptom improvement and remission. Side effect data were available at weeks 2–4, 6 and 9 in three of the investigated samples. A fixed-effects meta-analysis was performed using EM as the reference group.Analysis of 2558 patients for efficacy and 2037 patients for side effects showed that PMs had higher symptom improvement (SMD=0.43, CI=0.19–0.66) and higher remission rates (OR=1.55, CI=1.23–1.96) compared to EMs. At weeks 2–4, PMs showed higher risk of gastro-intestinal (OR=1.26, CI=1.08–1.47), neurological (OR=1.28, CI=1.07–1.53) and sexual side effects (OR=1.52, CI=1.23–1.87; week 6 values similar). No difference was seen at week 9 or in total side effect burden. PMs did not have higher risk of dropout at week 4 compared to EMs. Antidepressant dose was not different among CYP2C19 groups.CYP2C19 polymorphisms may provide helpful information for guiding citalopram/escitalopram treatment, despite PMs are relatively rare among Caucasians (~2%).
Decoding of selective attention to continuous speech from the human auditory brainstem response
Authors: Etard Octave , Kegler Mikolaj , Braiman Chananel , Forte Antonio Elia , Reichenbach Tobias 
Published: February 2018

AbstractHumans are highly skilled at analysing complex acoustic scenes. The segregation of different acoustic streams and the formation of corresponding neural representations is mostly attributed to the auditory cortex. Decoding of selective attention from neuroimaging has therefore focussed on cortical responses to sound. However, the auditory brainstem response to speech is modulated by selective attention as well, as recently shown through measuring the brainstem’s response to running speech. Although the response of the auditory brainstem has a smaller magnitude than that of the auditory cortex, it occurs at much higher frequencies and therefore has a higher information rate. Here we develop statistical models for extracting the brainstem response from multi-channel scalp recordings and for analysing the attentional modulation according to the focus of attention. We demonstrate that the attentional modulation of the brainstem response to speech can be employed to decode the attentional focus of a listener from short measurements of ten seconds or less in duration. The decoding remains accurate when obtained from three EEG channels only. We further show how out-of-the-box decoding that employs subject-independent models, as well as decoding that is independent of the specific attended speaker is capable of achieving similar accuracy. These results open up new avenues for investigating the neural mechanisms for selective attention in the brainstem and for developing efficient auditory brain-computer interfaces.
Mosaic representations of odors in the input and output layers of the mouse olfactory bulb
Authors: Chae Honggoo , Kepple Daniel , Bast Walter G. , Murthy Venkatesh N. , Koulakov Alexei , Albeanu Dinu F. 
Published: February 2018

AbstractThe elementary stimulus features encoded by the olfactory system remain poorly understood. We examined the relationship between 1,666 physical-chemical descriptors of odors and the activity of olfactory bulb inputs as well as outputs in awake mice. Glomerular and M/T cell responses were sparse and locally heterogeneous, with only a coarse dependence of glomerular positions on physical-chemical properties. Odor features represented by ensembles of M/T cells were overlapping, but distinct from those represented in glomeruli, consistent with extensive interplay between feedforward and feedback inputs to the bulb. This reformatting was well-described as a rotation in odor space. The descriptors accounted for a small fraction in response variance, and the similarity of odors in physical-chemical space was a poor predictor of similarity in neuronal representations. Our results suggest that commonly used physical-chemical properties are not systematically represented in bulbar activity and encourage further search for better descriptors of odor space.
Genome-wide epigenetic profiling of 5-hydroxymethylcytosine by long-read optical mapping
Authors: Gabrieli Tslil , Sharim Hila , Nifker Gil , Jeffet Jonathan , Shahal Tamar , Arielly Rani , Levi-Sakin Michal , Hoch Lily , Arbib Nissim , Michaeli Yael , Ebenstein Yuval 
Published: February 2018

AbstractThe epigenetic mark 5-hydroxymethylcytosine (5-hmC) is a distinct product of active enzymatic demethylation that is linked to gene regulation, development and disease. Genome-wide 5-hmC profiles generated by short-read next-generation sequencing are limited in providing long-range epigenetic information relevant to highly variable genomic regions, such as the 3.7 Mbp disease-related Human Leukocyte Antigen (HLA) region. We present a long-read, single-molecule mapping technology that generates hybrid genetic/epigenetic profiles of native chromosomal DNA. The genome-wide distribution of 5- hmC in human peripheral blood cells correlates well with 5-hmC DNA immunoprecipitation (hMeDIP) sequencing. However, the long read length of 100 kbp-1Mbp produces 5-hmC profiles across variable genomic regions that failed to showup in the sequencing data. In addition, optical 5-hmC mapping shows strong correlation between the 5-hmC density in gene bodies and the corresponding level of gene expression. The single molecule concept provides information on the distribution and coexistence of 5-hmC signals at multiple genomic loci on the same genomic DNA molecule, revealing long-range correlations and cell-to-cell epigenetic variation.
Conservation of conformational dynamics across prokaryotic actins
Authors: Ng Natalie , Shi Handuo , Colavin Alexandre , Casey Huang Kerwyn 
Published: February 2018

AbstractThe actin family of cytoskeletal proteins is essential to the physiology of virtually all archaea, bacteria, and eukaryotes. While X-ray crystallography and electron microscopy have revealed structural homologies among actin-family proteins, these techniques cannot probe molecular-scale conformational dynamics. Here, we use all-atom molecular dynamic simulations to reveal conserved dynamical behaviors in four prokaryotic actin homologs: MreB, FtsA, ParM, and crenactin. We demonstrate that the majority of the conformational dynamics of prokaryotic actins can be explained by treating the four subdomains as rigid bodies. MreB, ParM, and FtsA monomers exhibited nucleotide-dependent dihedral and opening angles, while crenactin monomer dynamics were nucleotide-independent. We further determine that the opening angle of ParM is sensitive to a specific interaction between subdomains. Steered molecular dynamics simulations of MreB, FtsA, and crenactin dimers revealed that changes in subunit dihedral angle lead to intersubunit bending or twist, suggesting a conserved mechanism for regulating filament structure. Taken together, our results provide molecular-scale insights into the nucleotide and polymerization dependencies of the structure of prokaryotic actins, suggesting mechanisms for how these structural features are linked to their diverse functions.Significance StatementSimulations are a critical tool for uncovering the molecular mechanisms underlying biological form and function. Here, we use molecular-dynamics simulations to identify common and specific dynamical behaviors in four prokaryotic homologs of actin, a cytoskeletal protein that plays important roles in cellular structure and division in eukaryotes. Dihedral angles and opening angles in monomers of bacterial MreB, FtsA, and ParM were all sensitive to whether the subunit was bound to ATP or ADP, unlike in the archaeal homolog crenactin. In simulations of MreB, FtsA, and crenactin dimers, changes in subunit dihedral angle led to bending or twisting in filaments of these proteins, suggesting a mechanism for regulating the properties of large filaments. Taken together, our simulations set the stage for understanding and exploiting structure- function relationships of bacterial cytoskeletons.
New insights on human essential genes based on integrated analysis
Authors: Chen Hebing , Zhang Zhuo , Jiang Shuai , Li Ruijiang , Li Wanying , Zhao Chenghui , Hong Hao , Huang Xin , Li Hao , Bo Xiaochen 
Published: February 2018

AbstractEssential genes are those whose functions govern critical processes that sustain life in the organism. Recent gene-editing technologies have provided new opportunities to characterize essential genes. Here, we present an integrated analysis for comprehensively and systematically elucidating the genetic and regulatory characteristics of human essential genes. First, essential genes act as “hubs” in protein-protein interactions networks, in chromatin structure, and in epigenetic modifications, thus are essential for cell growth. Second, essential genes represent the conserved biological processes across species although gene essentiality changes itself. Third, essential genes are import for cell development due to its discriminate transcription activity in both embryo development and oncogenesis. In addition, we develop an interactive web server, the Human Essential Genes Interactive Analysis Platform (HEGIAP) (http://sysomics.com/HEGIAP/), which integrates abundant analytical tools to give a global, multidimensional interpretation of gene essentiality. Our study provides a new view for understanding human essential genes.
Development of photoactivatable drugs enables nicotinic optopharmacology
Authors: Banala Sambashiva , Arvin Matthew C. , Bannon Nicolas M. , Jin Xiao-Tao , Wang Yong , Zhao Guiqing , Marshall John J. , Gee Kyle R. , Wokosin David L. , Contractor Anis , Lester Henry A. , Kozorovitskiy Yevgenia , Drenan Ryan M. , Lavis Luke D. 
Published: February 2018

AbstractPhotoactivatable (‘caged’) pharmacological agents have revolutionized neuroscience but the palette of available ligands is limited. We describe a general method for caging tertiary amines using an unconventional quaternary ammonium linkage that is chemically stable and elicits a desirable red-shift in activation wavelength. A photoactivatable nicotine (PA-Nic) prepared using this strategy could be uncaged via 1- or 2-photon excitation, making it useful for optopharmacology experiments to study nicotinic acetylcholine receptors (nAChRs) in different experimental preparations and spatiotemporal scales.