bluuebunny/crossref_metadata_2025_split huggingface dataset:
What is Antagonistic Pleiotropy?
Authors: Mitteldorf Josh 
Published: May 2018

AbstractAntagonistic Pleiotropy has been the dominant theory for evolution of aging since it was first proposed 60 years ago. Indeed, examples of pleiotropy have been observed, but there are also many examples of mutations that lead to longer lifespan without apparent cost. This poses a dilemma for the logic of the theory, which depends critically on the assumption that pleiotropy has imposed an inescapable precondition on evolution. Another interpretation is possible for the pleiotropy observed in nature. Natural selection may actually favor pleiotropy as an evolved adaptation. This is because the combination of high fertility and long lifespan is a temptation for individuals, but a danger for the health of populations. Predator populations that grow faster than their prey can recover are at risk of extinction. Once a sustainable mix of fertility and longevity has been established by multilevel natural selection, pleiotropy can help to assure that it is not lost. The population is free to shift from (high fertility/short lifespan) to (lower fertility/longer lifespan) as varying environmental conditions demand, without risking population overshoot and collapse. I describe herein experiments with an individual-based computer simulation in which pleiotropy evolves as a group-selected adaptation under a range of assumptions and in a broad swath of parameter space.
Recent evolution of a TET-controlled and DPPA3/STELLA-driven pathway of passive demethylation in mammals
Authors: Mulholland Christopher B. , Nishiyama Atsuya , Ryan Joel , Nakamura Ryohei , Yiğit Merve , Glück Ivo M. , Trummer Carina , Qin Weihua , Bartoschek Michael D. , Traube Franziska R. , Parsa Edris , Ugur Enes , Modic Miha , Acharya Aishwarya , Stolz Paul , Ziegenhain Christoph , Wierer Michael , Enard Wolfgang , Carell Thomas , Lamb Don C. , Takeda Hiroyuki , Nakanashi Makoto , Bultmann Sebastian , Leonhardt Heinrich 
Published: May 2018

AbstractGenome-wide DNA demethylation is a unique feature of mammalian development and naïve pluripotent stem cells. So far, it was unclear how mammals specifically achieve global DNA hypomethylation, given the high conservation of the DNA (de-)methylation machinery among vertebrates. We found that DNA demethylation requires TET activity but mostly occurs at sites where TET proteins are not bound suggesting a rather indirect mechanism. Among the few specific genes bound and activated by TET proteins was the naïve pluripotency and germline markerDppa3(Pgc7, Stella), which undergoes TDG dependent demethylation. The requirement of TET proteins for genome-wide DNA demethylation could be bypassed by ectopic expression ofDppa3. We show that DPPA3 binds and displaces UHRF1 from chromatin and thereby prevents the recruitment and activation of the maintenance DNA methyltransferase DNMT1. We demonstrate that DPPA3 alone can drive global DNA demethylation when transferred to amphibians (Xenopus) and fish (medaka), both species that naturally do not have aDppa3gene and exhibit no post-fertilization DNA demethylation. Our results show that TET proteins are responsible for active and - indirectly also for - passive DNA demethylation; while TET proteins initiate local and gene-specific demethylation in vertebrates, the recent emergence of DPPA3 introduced a unique means of genome-wide passive demethylation in mammals and contributed to the evolution of epigenetic regulation during early mammalian development.
Lead-DBS v2: Towards a comprehensive pipeline for deep brain stimulation imaging
Authors: Horn Andreas , Li Ningfei , Dembek Till A , Kappel Ari , Boulay Chadwick , Ewert Siobhan , Tietze Anna , Husch Andreas , Perera Thushara , Neumann Wolf-Julian , Reisert Marco , Si Hang , Oostenveld Robert , Rorden Christopher , Yeh Fang-Cheng , Fang Qianqian , Herrington Todd M , Vorwerk Johannes , Kühn Andrea A. 
Published: May 2018

AbstractDeep brain stimulation (DBS) is a highly efficacious treatment option for movement disorders and a growing number of other indications are investigated in clinical trials. To ensure optimal treatment outcome, exact electrode placement is required. Moreover, to analyze the relationship between electrode location and clinical results, a precise reconstruction of electrode placement is required, posing specific challenges to the field of neuroimaging. Since 2014 the open source toolbox Lead-DBS is available, which aims at facilitating this process. The tool has since become a popular platform for DBS imaging. With support of a broad community of researchers worldwide, methods have been continuously updated and complemented by new tools for tasks such as multispectral nonlinear registration, structural / functional connectivity analyses, brain shift correction, reconstruction of microelectrode recordings and orientation detection of segmented DBS leads. The rapid development and emergence of these methods in DBS data analysis require us to revisit and revise the pipelines introduced in the original methods publication. Here we demonstrate the updated DBS and connectome pipelines of Lead-DBS using a single patient example with state-of-the-art high-field imaging as well as a retrospective cohort of patients scanned in a typical clinical setting at 1.5T. Imaging data of the 3T example patient is co-registered using five algorithms and nonlinearly warped into template space using ten approaches for comparative purposes. After reconstruction of DBS electrodes (which is possible using three methods and a specific refinement tool), the volume of tissue activated is calculated for two DBS settings using four distinct models and various parameters. Finally, four whole-brain tractography algorithms are applied to the patient’s preoperative diffusion MRI data and structural as well as functional connectivity between the stimulation volume and other brain areas are estimated using a total of eight approaches and datasets. In addition, we demonstrate impact of selected preprocessing strategies on the retrospective sample of 51 PD patients. We compare the amount of variance in clinical improvement that can be explained by the computer model depending on the method of choice.This work represents a multi-institutional collaborative effort to develop a comprehensive, open source pipeline for DBS imaging and connectomics, which has already empowered several studies, and may facilitate a variety of future studies in the field.
Expression of novel fusion antiviral proteins Ricin A Chain-Pokeweed Antiviral Proteins (RTA-PAPs) in Escherichia coli and their inhibition of protein synthesis and of hepatitis B virus in vitro
Authors: Hassan Yasser , Ogg Sherry , Ge Hui 
Published: May 2018

AbstractRicin A chain (RTA) and Pokeweed antiviral proteins (PAPs) are plant-derived N-glycosidase ribosomal-inactivating proteins (RIPs) isolated from Ricinus communis and Phytolacca Americana respectively. This study was to investigate the potential antiviral value of novel fusion proteins between RTA and PAPs (RTA-PAPs). In brief, RTA-Pokeweed antiviral protein isoform 1 from seeds (RTA-PAPS1) was produced in E. coli in vivo expression system, purified from inclusion bodies using gel filtration chromatography and protein synthesis inhibitory activity assayed by comparison to the production of a control protein Luciferase. The antiviral activity of the RTA-PAPS1 against Hepatitis B virus (HBV) in HepAD38 cells was then determined using a dose response assay by quantifying supernatant HBV DNA compared to control virus infected HepAD38 cells. The cytotoxicity in HepAD38 cells was determined by measuring cell viability using a tetrazolium dye uptake assay. Results showed that RTA-PAPS1 could effectively be recovered and purified from inclusion bodies. The refolded protein was bioactive with 50% protein synthesis inhibitory concentration (IC50) of 0.06nM (3.63ng/ml). The results also showed that RTA-PAPS1 had a synergetic activity against HBV with a half-maximal response concentration value (EC50) of 0.03nM (1.82ng/ml) and a therapeutic index of >21818. The fusion protein was further optimized using in silico tools, produced in E. coli in vivo expression system, purified by three-step process from soluble lysate and protein synthesis inhibition activity assayed. Results showed that the optimized protein RTA mutant-Pokeweed antiviral protein isoform 1 from leaves (RTAM-PAP1) could be recovered and purified from soluble lysates with gain of function activity on protein synthesis inhibition with an IC50 of 0.03nM (1.82ng/ml). Collectively, our results demonstrate that RTA-PAPs are amenable to effective production and purification in native form, possess significant antiviral activity against HBV in vitro with a high therapeutic index and, thus, meriting further development as potential antiviral agents against chronic HBV infection.
Functional connectivity alterations of the temporal lobe and hippocampus in semantic dementia and Alzheimer’s disease
Authors: Schwab Simon , Afyouni Soroosh , Chen Yan , Han Zaizhu , Guo Qihao , Dierks Thomas , Wahlund Lars-Olof , Grieder Matthias 
Published: May 2018

AbstractThe severe semantic memory impairments in semantic dementia have been attributed to a pronounced atrophy and functional disruption of the anterior temporal lobes. In contrast, the medial and posterior temporal lobe damage predominantly found in patients with Alzheimer’s disease has been associated with episodic memory disturbance. However, the two dementia subtypes share hippocampal deterioration, despite a relatively spared episodic memory in semantic dementia. To gain more insight into the mutual and divergent functional alterations seen in Alzheimer’s disease and semantic dementia, we assessed the differences in intrinsic functional connectivity between temporal lobe regions in patients with Alzheimer’s disease (n = 16), semantic dementia patients from two international sites (n = 23), and healthy controls (n = 17). In an exploratory study, we used a functional parcellation of the temporal cortex to extract time series. The Alzheimer’s disease group showed a single connection with reduced functional connectivity as compared to the controls. This connection was located between the right orbitofrontal cortex and the right anterior temporal lobe. In contrast, functional connectivity was decreased in the semantic dementia group in six connections, mainly involving the hippocampus, lingual gyrus, temporal pole, and orbitofrontal cortex. We identified a common pathway with semantic dementia, since the functional connectivity between the right anterior temporal lobe and the right orbitofrontal cortex was reduced in both types of dementia. This might be related to social knowledge deficits as part of semantic memory decline. However, such interpretations are preferably made in the context of all disease-specific semantic impairments and functional connectivity changes. Despite some limitations owed to the two database sites, this study provides a first preliminary picture of the brain’s functional dysconnectivity in Alzheimer’s disease and semantic dementia. Future studies are needed to replicate findings of such a common pathway with matched diagnosis, neuropsychological, and data MRI acquisition procedures.
Modelling palaeoecological time series using generalized additive models
Authors: Simpson Gavin L. 
Published: May 2018

AbstractIn the absence of annual laminations, time series generated from lake sediments or other similar stratigraphic sequences are irregularly spaced in time, which complicates formal analysis using classical statistical time series models. In lieu, statistical analyses of trends in palaeoen-vironmental time series, if done at all, have typically used simpler linear regressions or (non-) parametric correlations with little regard for the violation of assumptions that almost surely occurs due to temporal dependencies in the data or that correlations do not provide estimates of the magnitude of change, just whether or not there is a linear or monotonic trend. Alternative approaches have used Loess-estimated trends to justify data interpretations or test hypotheses as to the causal factors without considering the inherent subjectivity of the choice of parameters used to achieve the Loessfit (e.g. span width, degree of polynomial). Generalized additive models (GAMs) are statistical models that can be used to estimate trends as smooth functions of time. Unlike Loess, GAMs use automatic smoothness selection methods to objectively determine the complexity of the fitted trend, and as formal statistical models, GAMs, allow for potentially complex, non-linear trends, a proper accounting of model uncertainty, and the identification of periods of significant temporal change. Here, I present a consistent and modern approach to the estimation of trends in palaeoenvironmental time series using GAMs, illustrating features of the methodology with two example time series of contrasting complexity; a 150-year bulk organic matterδ15N time series from Small Water, UK, and a 3000-year alkenone record from Braya-Sϕ, Greenland. I discuss the underlying mechanics of GAMs that allow them to learn the shape of the trend from the data themselves and how simultaneous confidence intervals and the first derivatives of the trend are used to properly account for model uncertainty and identify periods of change. It is hoped that by using GAMs greater attention is paid to the statistical estimation of trends in palaeoenvironmental time series leading to more a robust and reproducible palaeoscience.
An average-case sublinear exact Li and Stephens forward algorithm
Authors: Rosen Yohei M. , Paten Benedict J. 
Published: May 2018

AbstractHidden Markov models of haplotype inheritance such as the Li and Stephens model allow for computationally tractable probability calculations using the forward algorithms as long as the representative reference panel used in the model is sufficiently small. Specifically, the monoploid Li and Stephens model and its variants are linear in reference panel size unless heuristic approximations are used. However, sequencing projects numbering in the thousands to hundreds of thousands of individuals are underway, and others numbering in the millions are anticipated.To make the Li and Stephens forward algorithm for these datasets computationally tractable, we have created a numerically exact version of the algorithm with observed average case 𝒪(nk0.35) runtime, avoiding any tradeoff between runtime and model complexity. We demonstrate that our approach also provides a succinct data structure for general purpose haplotype data storage. We discuss generalizations of our algorithmic techniques to other hidden Markov models.2012 ACM Subject ClassificationTheory of computation ⟶ Streaming, sublinear and near linear time algorithms; Applied computing ⟶ BioinformaticsSupplement Materialhttps://github.com/yoheirosen/sublinear-Li-Stephens.FundingThis work was supported by the National Human Genome Research Institute of the National Institutes of Health under Award Number 5U54HG007990, the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number 1U01HL137183-01, and grants from the W.M. Keck foundation and the Simons Foundation.AcknowledgementsWe would like to thank Jordan Eizenga for his helpful discussions throughout the development of this work.
Discovery of a novel stereospecific β-hydroxyacyl-CoA lyase/thioesterase shared by three metabolic pathways inMycobacterium tuberculosis
Authors: Wang Hua , Fedorov Alexander A. , Fedorov Elena V. , Hunt Deborah M. , Rodgers Angela , Garza-Garcia Acely , Bonanno Jeffrey B. , Almo Steven C. , de Carvalho Luiz Pedro S. 
Published: May 2018

AbstractThe vast number of poorly characterised enzymes inMycobacterium tuberculosis(Mtb) is one of the key barriers precluding a better understanding of the biology that underpins pathogenesis. Here, we investigated the Mtb orphan enzyme Rv2498c to delineate its physiological role. Our results fromin vitroenzymatic assays, phylogenetic analysis, X-ray crystallography andin vivoMtb experiments, de-orphan Rv2498c as a multi-functional β-hydroxyacyl-CoA lyase/thioesterase (β-HAClyase/thioesterase) that participates in three different metabolic pathways: L-leucine catabolism, itaconate dissimilation, and glyoxylate shunt. Moreover, the deletion of therv2498cgene from the Mtb genome resulted in attenuation in the mouse model compared to infection with the parent strain. To the best of our knowledge, this is the first report of an (R)-3-hydroxyl-3-methylglutaryl-CoA for leucine catabolism and an itaconate-specific resistance mechanism in Mtb.
Microtubule dynamics is required for rapid coiling of haptonemata in haptophyte algae
Authors: Nomura Mami , Atsuji Kohei , Hirose Keiko , Shiba Kogiku , Nakayama Takeshi , Ishida Ken-ichiro , Inaba Kazuo 
Published: May 2018

ABSTRACTA haptonema is an elongated microtubule-based motile organelle uniquely present in haptophytes. The most notable and rapid movement of a haptonema is “coiling”, which occurs within a few milliseconds following mechanical stimulation in an unknown motor-independent mechanism. Here, we analyzed the coiling process in detail by high-speed filming and showed that haptonema coiling was initiated by left-handed twisting of the haptonema, followed by writhing to form a helix from the distal tip. On recovery from a mechanical stimulus, the helix slowly uncoiled from the proximal region. Electron microscopy showed that the seven microtubules in a haptonema were arranged mostly in parallel but that one of the microtubules often wound around the others in the extended state. The persistence lengths calculated from the curvature of the haptonematal microtubules indicated their unusual flexibility. A microtubule stabilizer, paclitaxel, inhibited coiling and induced right-handed twisting of the haptonema in the absence of Ca2+, suggesting changes in the microtubule surface lattice. Addition of Ca2+caused bend propagation toward the proximal region. These results indicate that switching microtubule conformation with the aid of Ca2+-binding microtubule-associated proteins is responsible for rapid haptonematal coiling.Summary StatementMicroscopy observations and pharmacological experiments revealed that the rapid coiling of a non-motor microtubule-based motile organelle, the haptonema, is explained by conformational changes of microtubules, including twisting and writhing.
Bacterial Glycosyltransferase-mediated Cell-surface Chemoenzymatic Glycan Editing: Methods and Applications
Authors: Hong Senlian , Shi Yujie , Wu Nicholas C. , Grande Geramie , Douthit Lacey , Wilson Ian A. , Xie Jia , Wu Peng 
Published: May 2018

Abstract:Chemoenzymatic glycan editing that modifies glycan structures directly on the cell surface has emerged as a complementary tool to metabolic oligosaccharide engineering. In this article, we report the discovery that three bacterial enzymes—Pasteurella multocidaα2-3-sialyltransferase M144D mutant (Pm2,3ST-M144D),Photobacterium damselα2-6-sialyltransferase (Pd2,6ST) andHelicobacter mustelaeα1-2-fucosyltransferase (Hm1,2FT)—can serve as highly efficient tools for cell-surface glycan editing. Among these three enzymes, the two sialyltransferases were also found to be tolerant to large substituents introduced to the C-5 position of the cytidine monophosphateN-acetylneuraminic acid donor, including biotin and fluorescent dyes. Combining these enzymes with our previously discoveredHelicobacter pyloriα1-3-FT, we developed a live cell-based assay to probe host-cell glycan-mediated influenza A virus (IAV) infection including both wild-type and mutant strains of human H1N1 and H3N2 influenza subtypes. At high SiaNAcα2-6-Gal levels, the ability of a viral strain to induce the host cell death is positively correlated with the SiaNAcα2-6-Gal binding affinity of its haemagglutinin. Surprisingly, the creation of sLeXon the host cell surfacevia in situα1-3-Fuc editing also exacerbated the killing induced by several wild-type IAV strains as well as a mutant known as HK68-MTA. Structural alignment of HAs from the wild-type HK68 and HK68-MTA revealed the formation of a putative hydrogen bond between Trp222 of HA-HK68-MTA and the C-4 hydroxyl group of the α1-3-linked fucose of sLeX. This interaction is likely to be responsible for the better binding affinity of HA-HK68-MTA to sLeXand accordingly the enhanced host-cell killing compared with the wild-type HK68.
Loss-of-function in IRF2BPL is associated with neurological phenotypes
Authors: Marcogliese Paul C. , Shashi Vandana , Spillmann Rebecca C. , Stong Nicholas , Rosenfeld Jill A. , Koenig Mary Kay , Martínez-Agosto Julián A. , Herzog Matthew , Chen Agnes H. , Dickson Patricia I. , Lin Henry J. , Vera Moin U. , Salamon Noriko , Ortiz Damara , Infante Elena , Steyaert Wouter , Dermaut Bart , Poppe Bruce , Chung Hyung-Lok , Zuo Zhongyuan , Lee Pei-Tseng , Kanca Oguz , Xia Fan , Yang Yaping , Smith Edward C. , Jasien Joan , Kansagra Sujay , Spiridigliozzi Gail , El-Dairi Mays , Lark Robert , Riley Kacie , Koeberl Dwight D. , Golden-Grant Katie ,   Program for Undiagnosed Diseases (UD-PrOZA) Undiagnosed Diseases Network, Yamamoto Shinya , Wangler Michael F. , Mirzaa Ghayda , Hemelsoet Dimitri , Lee Brendan , Nelson Stanley F. , Goldstein David B. , Bellen Hugo J. , Pena Loren D.M. 
Published: May 2018

AbstractThe Interferon Regulatory Factor 2 Binding Protein Like (IRF2BPL) gene encodes a member of the IRF2BP family of transcriptional regulators. Currently the biological function of this gene is obscure, and the gene has not been associated with a Mendelian disease. Here we describe seven individuals affected with neurological symptoms who carry damaging heterozygous variants in IRF2BPL. Five cases carrying nonsense variants in IRF2BPL resulting in a premature stop codon display severe neurodevelopmental regression, hypotonia, progressive ataxia, seizures, and a lack of coordination. Two additional individuals, both with missense variants, display global developmental delay and seizures and a relatively milder phenotype than those with nonsense alleles. The bioinformatics signature for IRF2BPL based on population genomics is consistent with a gene that is intolerant to variation. We show that the IRF2BPL ortholog in the fruit fly, called pits (protein interacting with Ttk69 and Sin3A), is broadly expressed including the nervous system. Complete loss of pits is lethal early in development, whereas partial knock-down with RNA interference in neurons leads to neurodegeneration, revealing requirement for this gene in proper neuronal function and maintenance. The nonsense variants in IRF2BPL identified in patients behave as severe loss-of-function alleles in this model organism, while ectopic expression of the missense variants leads to a range of phenotypes. Taken together, IRF2BPL and pits are required in the nervous system in humans and flies, and their loss leads to a range of neurological phenotypes in both species.