bluuebunny/crossref_metadata_2025_split huggingface dataset:
A likelihood approach for uncovering selective sweep signatures from haplotype data
Authors: Harris Alexandre M. , DeGiorgio Michael 
Published: June 2019

AbstractSelective sweeps are frequent and varied signatures in the genomes of natural populations, and detecting them is consequently important in understanding mechanisms of adaptation by natural selection. Following a selective sweep, haplotypic diversity surrounding the site under selection decreases, and this deviation from the background pattern of variation can be applied to identify sweeps. Multiple methods exist to locate selective sweeps in the genome from haplotype data, but none leverage the power of a model-based approach to make their inference. Here, we propose a likelihood ratio test statisticTto probe whole genome polymorphism datasets for selective sweep signatures. Our framework uses a simple but powerful model of haplotype frequency spectrum distortion to find sweeps and additionally make an inference on the number of presently sweeping haplotypes in a population. We found that theTstatistic is suitable for detecting both hard and soft sweeps across a variety of demographic models, selection strengths, and ages of the beneficial allele. Accordingly, we applied theTstatistic to variant calls from European and sub-Saharan African human populations, yielding primarily literature-supported candidates, includingLCT, RSPH3, andZNF211in CEU,SYT1, RGS18, andNNTin YRI, andHLAgenes in both populations. We also searched for sweep signatures inDrosophila melanogaster, finding expected candidates at Ace,Uhg1, andPimet. Finally, we provide open-source software to compute theTstatistic and the inferred number of presently sweeping haplotypes from whole-genome data.
Compositional heterogeneity confers selective advantage to protocellular membranes during the origins of cellular life
Authors: Sarkar Susovan , Dagar Shikha , Verma Ajay , Rajamani Sudha 
Published: June 2019

AbstractProtocells are primitive cellular entities that are thought to have emerged during the dawn of life on Earth. Their membranes are considered to be made up of mixtures of single chain amphiphiles, such as fatty acids and their derivatives, moieties that would have been part of the complex prebiotic chemical landscape. In addition to their composition, the physico-chemical properties of these prebiological membranes would have been significantly affected and regulated by the physical environment that they were present in. In this study, the physico-chemical properties of two different chain length membrane systems were systematically characterized, under pertinent early Earth conditions. The membrane systems were designed to comprise a fatty acid and its alcohol and/or glycerol monoester derivative, to make a range of binary and tertiary vesicle combinations. Their properties were then evaluated as a function of multiple factors including their composition, stability under varying pH, Mg2+ ion concentrations and dilution regimes, and their permeability to small molecules. Our results demonstrate how these environmental constraints would have acted as important prebiotic selection pressures to shape the evolution of prebiological membranes. This study also illustrates how different fatty acid derivatives confer varying degree of stability when combined with their respective fatty acid moiety. Interestingly, when the membrane systems were subjected to multiple selection pressures in a consecutive manner, only the heterogeneous membrane systems survived the ‘race’. Our results illustrate that compositionally diverse membrane systems are more stable and robust to multiple selection pressures, thereby making them more suitable for supporting protocellular life.Significance statementThe physico-chemical environment would have played an important role in shaping the composition and evolution of primitive membrane systems. This study demonstrates the importance of compositional heterogeneity on the stability of protomembrane systems under pertinent prebiotic selection pressures. Two different fatty acid based systems were mixed with their respective alcohol and/or glycerol monoester derivatives, to generate combinations of binary and tertiary membrane systems. Increasing chain length effected the physical property of the membranes thus affecting their stability. Furthermore, we also demonstrate how the head groups of the derivatives employed in this study (e.g. glycerol monoester and alcohol) contribute differently towards stabilizing the mixed membranes under a given selection condition, by discerning the molecular mechanism underlying this process. Our results illustrate how multiple selection pressures would have preferentially supported the emergence of compositionally heterogeneous membrane systems.
Structure-based drug repositioning explains ibrutinib as VEGFR2 inhibitor
Authors: Adasme Melissa F. , Parisi Daniele , Van Belle Kristien , Salentin Sebastian , Haupt V. Joachim , Jennings Gary S. , Heinrich Jörg-Christian , Herman Jean , Sprangers Ben , Louat Thierry , Moreau Yves , Schroeder Michael 
Published: June 2019

AbstractMany drugs are promiscuous and bind to multiple targets. On the one hand, these targets may be linked to unwanted side effects, but on the other, they may achieve a combined desired effect (polypharmacology) or represent multiple diseases (drug repositioning). With the growth of 3D structures of drug-target complexes, it is today possible to study drug promiscuity at the structural level and to screen vast amounts of drug-target interactions to predict side effects, polypharmacological potential, and repositioning opportunities. Here, we pursue such an approach to identify drugs inactivating B-cells, whose dysregulation can function as a driver of autoimmune diseases. Screening over 500 kinases, we identified 22, whose knock out impeded the activation of B-cells. Among these 22 is the gene KDR, whose gene product VEGFR2 is a prominent cancer target with anti-VEGFR2 drugs on the market for over a decade. The main result of this paper is that structure-based drug repositioning for the identified kinase targets identified the cancer drug ibrutinib as micromolar VEGFR2 inhibitor with a very high therapeutic index in B-cell inactivation. These findings prove that ibrutinib is not only acting on the Bruton’s tyrosine kinase BTK, against which it was designed. Instead, it may be a polypharmacological drug, which additionally targets angiogenesis via inhibition of VEGFR2. Therefore ibrutinib carries potential to treat other VEGFR2 associated disease. Structure-based drug repositioning explains ibrutinib’s anti VEGFR2 action through a specific pattern of interactions shared between BTK and VEGFR2. Overall, structure-based drug repositioning was able to predict these findings at a fraction of the time and cost of a conventional screen.
Evidence supporting a viral origin of the eukaryotic nucleus
Authors: Bell Philip JL 
Published: June 2019

AbstractThe defining feature of the eukaryotic cell is the possession of a nucleus that uncouples transcription from translation. This uncoupling of transcription from translation depends on a complex process employing hundreds of eukaryotic specific genes acting in concert and requires the 7-methylguanylate (m7G) cap to prime eukaryotic mRNA for splicing, nuclear export, and cytoplasmic translation. The origin of this complex system is currently a paradox since it is not found or needed in prokaryotic cells which lack nuclei, yet it was apparently present and fully functional in the Last Eukaryotic Common Ancestor (LECA). According to the Viral Eukaryogenesis (VE) hypothesis the abrupt appearance of the nucleus in the eukaryotic lineage occurred because the nucleus descends from the viral factory of a DNA phage that infected the archaeal ancestor of the eukaryotes. Consequently, the system for uncoupling of transcription from translation in eukaryotes is predicted by the VE hypothesis to be viral in origin. In support of this hypothesis it is shown here that m7G capping apparatus that primes the uncoupling of transcription from translation in eukaryotes is present in viruses of the Mimiviridae but absent from bona-fide archaeal relatives of the eukaryotes such as Lokiarchaeota. Furthermore, phylogenetic analysis of the m7G capping pathway indicates that eukaryotic nuclei and Mimiviridae obtained this pathway from a common ancestral source that predated the origin of LECA. These results support the VE hypothesis and suggest the eukaryotic nucleus and the Mimiviridae descend from a common First Eukaryotic Nuclear Ancestor (FENA).
Reconstructing neural representations of tactile space
Authors: Tamè Luigi , Tucciarelli Raffaele , Sadibolova Renata , Sereno Martin I. , Longo Matthew R. 
Published: June 2019

AbstractPsychophysical experiments have demonstrated large and highly systematic perceptual distortions of tactile space. We investigated the neural basis of tactile space by analyzing activity patterns induced by tactile stimulation of nine points on a 3 × 3 square grid on the hand dorsum using functional magnetic resonance (fMRI). We used a searchlight approach within pre-defined regions of interests (ROIs) to compute the pairwise Euclidean distances between the activity patterns elicited by tactile stimulation. Then, we used multidimensional scaling (MDS) to reconstruct tactile space at the neural level and compare it with skin space at the perceptual level. Our reconstructions of the shape of skin space in contralateral primary somatosensory (SI) and motor (M1) cortices reveal that it is distorted in a way that matches the perceptual shape of skin space. This suggests that early sensorimotor areas are critical to processing tactile space perception.Significant StatementHere, we show that the primary somatosensory (SI) and motor (M1) cortices, rather than higher-level brain areas, are critical to estimating distances between tactile stimuli on the hand dorsum. By combining functional magnetic resonance (fMRI), Procrustes alignment, and multidimensional scaling, we reconstructed the shape of skin space in the brain. Strikingly, the shape of the skin that we reconstructed from neural data matches the distortions we found at the behavioral level, providing strong evidence that early sensorimotor areas are critical for the construction of tactile space. Our work therefore supports the view that tactile distance perception is computed at lower level in the somatosensory system than is usually supposed.
HTT is a repressor of ABL activity required for APP induced axonal growth
Authors: Marquilly Claire , Busto Germain , Leger Brittany S. , Giniger Edward , Walker James A. , Fradkin Lee G. , Dura Jean-Maurice 
Published: June 2019

ABSTRACTABL tyrosine kinase activity controls several aspects of development including axon patterning. Amyloid precursor protein (APP) is linked to Alzheimer’s disease and previous work established that ABL is a downstream effector in anAppl, theDrosophilaApp ortholog, signaling pathway which modulates axon outgrowth in the mushroom bodies (MBs), the fly memory center. Here we show thatAblis required for the MB neuron axonal growth. Importantly, bothAbloverexpression and lack of expression produce a similar phenotype in the MBs indicating the necessity of tightly regulating ABL activity. We find that the fly huntingtin protein (HTT), the homolog of the protein involved in Huntington’s disease, behaves genetically as a repressor of ABL activity. Supporting this, FRET-based measurements ofin vivoABL activity in the MBs reveal a clear increase in its activity when HTT levels are reduced. Thus, in addition to its many other reported roles, HTT acts as a negative regulator of ABL activity, at least in the MBs, to maintain its appropriate physiological levels necessary for axon growth.
Molecular profiling predicts meningioma recurrence and reveals loss of DREAM complex repression in aggressive tumors
Authors: Patel Akash J. , Wan Ying-Wooi , Al-Ouran Rami , Revelli Jean-Pierre , Cardenas Maria F. , Oneissi Mazen , Xi Liu , Jalali Ali , Magnotti John F. , Muzny Donna M. , Doddapaneni HarshaVardhan , Sebastian Sherly , Heck Kent A. , Goodman J. Clay , Gopinath Shankar P. , Liu Zhandong , Rao Ganesh , Plon Sharon E. , Yoshor Daniel , Wheeler David A. , Zoghbi Huda Y. , Klisch Tiemo J. 
Published: June 2019

AbstractMeningiomas account for one-third of all primary brain tumors. Although typically benign, about 20% of meningiomas are aggressive, and despite the rigor of the current histopathological classification system, there remains considerable uncertainty in predicting tumor behavior. Here, we analyzed 160 tumors from all three WHO grades (I-III) using clinical, gene expression and sequencing data. Unsupervised clustering analysis identified three molecular types (A, B, and C) that reliably predicted recurrence. These groups did not directly correlate with the WHO grading system, which would classify more than half of the tumors in the most aggressive molecular type as benign. Transcriptional and biochemical analyses revealed that aggressive meningiomas involve loss of the repressor function of the DREAM complex, which results in cell cycle activation; only tumors in this category tend to recur after full resection. These findings should improve our ability to predict recurrence and develop targeted treatments for these clinically challenging tumors.Significance StatementMeningiomas are the most common primary brain tumors. Although most of these tumors are benign, one-fifth will recur despite apparently complete resection. Several studies have demonstrated that genomic approaches can yield important insights into the biology of these tumors. We performed RNA sequencing and whole-exome sequencing of 160 tumors from 140 patients, which identified three distinct groups of meningioma that correlate with recurrence better than the current WHO grading system. Our analysis also revealed that the most aggressive type was characterized by loss of the repressive DREAM complex. These findings should improve prognostication for patients and lead to viable therapeutic targets.
TRESK K+Channel Activity Regulates Trigeminal Nociception and Headache
Authors: Guo Zhaohua , Qiu Chang-Shen , Jiang Xinhua , Zhang Jintao , Li Fengxian , Liu Qin , Dhaka Ajay , Cao Yu-Qing 
Published: June 2019

AbstractAlthough dominant-negative mutations of TRESK background K+channel have been reported in migraine patients, whether TRESK activity controls the generation of trigeminal pain, especially headache, is not established. We found that loss of TRESK in all trigeminal ganglia (TG) neurons preferentially increased the intrinsic excitability of small-diameter TG nociceptors that express neuropeptide CGRP or TRPM8 channels. Surprisingly, loss of TRESK increased the number of TG neurons expressing TRPV1 channels. In dorsal root ganglia neurons, neither the persistent outward current nor the intrinsic excitability was affected by the loss of TRESK. Compared with wild-type controls, TRESK knockout mice exhibited more robust trigeminal pain, especially headache-like behaviors; but displayed normal body and visceral pain responses. Our findings indicate that endogenous TRESK activity is required for trigeminal pain regulation. A substantial reduction of TRESK activity may selectively affect the functions of TG nociceptors, thereby increasing the susceptibility to migraine headache in humans.
Interactions with presynaptic photoreceptors mediated by the Dpr11 and DIP-γ cell surface proteins control selection and survival of Drosophila amacrine neurons
Authors: Menon Kaushiki P. , Kulkarni Vivek , Takemura Shin-ya , Anaya Michael , Zinn Kai 
Published: June 2019

ABSTRACTDrosophila R7 UV photoreceptors (PRs) are divided into yellow (y) and pale (p) subtypes with different wavelength sensitivities. yR7 PRs express the Dpr11 cell surface protein and are presynaptic to Dm8 amacrine neurons (yDm8) that express Dpr11’s binding partner DIP-γ, while pR7 PRs synapse onto DIP-γ-negative pDm8 neurons. Dpr11 and DIP-γ expression patterns define yellow and pale medulla color vision circuits that project to higher-order areas. DIP- γ and dpr11 mutations affect the morphology of yDm8 arbors in the yellow circuit. yDm8 neurons are generated in excess during development and compete for presynaptic yR7 partners. Transsynaptic interactions between Dpr11 and DIP-γ are required for generation of neurotrophic signals that allow yDm8 neurons to survive. yDm8 and pDm8 neurons do not normally compete for neurotrophic support, but can be forced to do so by manipulating R7 subtype fates. DIP-γ-Dpr11 interactions allow yDm8 neurons to select yR7 PRs as their home column partners.
The ER cholesterol sensor SCAP promotes CARTS biogenesis at ER-Golgi contact sites
Authors: Wakana Yuichi , Hayashi Kaito , Nemoto Takumi , Watanabe Chiaki , Taoka Masato , Campelo Felix , Kumata Hidetoshi , Umemura Tomonari , Inoue Hiroki , Arasaki Kohei , Tagaya Mitsuo 
Published: June 2019

AbstractIn response to cholesterol deprivation, SCAP escorts SREBP transcription factors from the endoplasmic reticulum (ER) to the Golgi complex for their proteolytic activation, leading to gene expression for cholesterol synthesis and uptake. Here we show that in cholesterol-fed cells ER-localized SCAP interacts through Sac1 phosphoinositide 4-phosphate (PI4P) phosphatase with a VAP/OSBP complex, which mediates counter-transport of ER cholesterol and Golgi PI4P at ER-Golgi contact sites. SCAP knockdown inhibited the turnover of PI4P perhaps due to a cholesterol transport defect and altered the subcellular distribution of the VAP/OSBP complex. As in the case of perturbation of lipid transfer complexes at ER-Golgi contact sites, SCAP knockdown inhibited the biogenesis of thetrans-Golgi network-derived transport carriers CARTS, which was reversed by expression of wild-type SCAP but not cholesterol sensing-defective mutants. Altogether, our findings reveal a new role of SCAP under cholesterol-fed conditions in the facilitation of CARTS biogenesis at ER-Golgi contact sites, depending on the ER cholesterol.SummarySCAP is the key regulatory protein in cholesterol metabolism. Wakana et al. describe a new role of SCAP in controlling Golgi PI4P turnover and the biogenesis of the Golgi-derived transport carries CARTS via cholesterol/PI4P exchange machinery at ER-Golgi contact sites.
Quantification of the effect of site-specific histone acetylation on chromatin transcription rate
Authors: Wakamori Masatoshi , Okabe Kohki , Ura Kiyoe , Funatsu Takashi , Takinoue Masahiro , Umehara Takashi 
Published: June 2019

ABSTRACTEukaryotic transcription is epigenetically regulated by chromatin structure and post-translational modifications (PTMs). For example, lysine acetylation in histone H4 is correlated with activation of RNA polymerase I-, II-, and III-driven transcription from chromatin templates, which requires prior chromatin remodeling. However, quantitative understanding of the contribution of particular PTM states to the sequential steps of eukaryotic transcription has been hampered partially because reconstitution of a chromatin template with designed PTMs is difficult. In this study, we reconstituted a di-nucleosome with site-specifically acetylated or unmodified histone H4, which contained two copies of theXenopussomatic 5S rRNA gene with addition of a unique sequence detectable by hybridization-assisted fluorescence correlation spectroscopy. Using aXenopusoocyte nuclear extract, we analyzed the time course of accumulation of nascent 5S rRNA-derived transcripts generated on chromatin templatesin vitro.Our mathematically described kinetic model and fitting analysis revealed that tetra-acetylation of histone H4 at K5/K8/K12/K16 increases the rate of transcriptionally competent chromatin formation ~3-fold in comparison with the absence of acetylation. We provide a kinetic model for quantitative evaluation of the contribution of epigenetic modifications to chromatin transcription.
Elongated horizontal and vertical receivers in three‐dimensional electromagnetic modelling and inversion
Authors: Patzer Cedric , Tietze Kristina , Ritter Oliver 
Published: June 2019

ABSTRACTElectromagnetic geophysical methods often rely on measurements of naturally occurring or artificially impressed electric fields. It is technically impossible, however, to measure the electric field directly. Instead, the electric field is approximated by recording the voltage difference between two electrodes and dividing the obtained voltage by the distance between the electrodes. Typically, modelling and inversion algorithms assume that the electric fields are obtained over infinitely short point‐dipoles and thus measured fields are assigned to a single point between the electrodes. Such procedures imply several assumptions: (1) The electric field between the two electrodes is regarded as constant or being a potential field and (2) the receiver dimensions are negligible compared to the dimensions of the underlying modelling grid. While these conditions are often fulfilled for horizontal electric fields, borehole sensors for recordings of the vertical electric field have dimensions in the order of ≈100 m and span several modelling grid cells. Observations from such elongated borehole sensors can therefore only be interpreted properly if true receiver dimensions and variations of electrical conductivity along the receiver are considered. Here, we introduce a numerical solution to include the true receiver geometry into electromagnetic modelling schemes, which does not rely on such simplifying assumptions. The algorithm is flexible, independent of the chosen numerical method to solve Maxwell's equations and can easily be implemented in other electromagnetic modelling and inversion codes. We present conceptual modelling results for land‐based controlled source electromagnetic scenarios and discuss consideration of true receiver geometries for a series of examples of horizontal and vertical electric field measurements. Comparison with Ez data measured in an observation borehole in a producing oil field shows the importance of both considering the true length of the receiver and also its orientation. We show that misalignment from the vertical axis as small as 0.1° may seriously distort the measured signal, as horizontal electric field components are mapped into the desired vertical component. Adequate inclusion of elongated receivers in modelling and inversion can also help reducing effects of static shift when interpreting (natural source) magnetotelluric data.
Income Smoothing and the Usefulness of Earnings for Monitoring in Debt Contracting
Authors: Demerjian Peter , Donovan John , Lewis‐Western Melissa F. 
Published: June 2019

ABSTRACTWe investigate whether income smoothing affects the usefulness of earnings for contracting through the monitoring role of earnings‐based debt covenants. First, we examine initial contract design and predict that income smoothing will increase (decrease) the use of earnings‐based covenants if income smoothing improves (reduces) the usefulness of earnings to monitor borrowers. We find that private debt contracts to borrowers with greater income smoothing are more likely to include earnings‐based covenants. A structural model that explores the cause of this relationship provides evidence that smoothing improves the ability of earnings to reflect credit risk. Second, we examine technical default following contract inception. We find that income smoothing is associated with a lower likelihood of spurious technical default (when the borrower's economic performance has not declined but the loan nevertheless enters technical default). In contrast, we find no association between income smoothing and performance technical default (when the borrower's economic performance has declined). Collectively, this evidence is consistent with income smoothing improving the effectiveness of earnings‐based information in monitoring borrowers.