bluuebunny/crossref_metadata_2025_split huggingface dataset:
Axogenic mechanism enhances retinal ganglion cell excitability during early progression in glaucoma
Authors: Risner Michael L. , Pasini Silvia , Cooper Melissa L. , Lambert Wendi S. , Calkins David J. 
Published: February 2018

Significance
Identifying new therapies for neurodegenerative disease requires understanding how neurons respond to stress and whether this response includes adaptation to slow progression. Because neurodegeneration affects both axons and dendrites, with their synaptic contacts, adaptation could involve both compartments. We investigated this question in experimental glaucoma, the world’s leading cause of irreversible vision loss. Glaucoma attacks retinal ganglion cell neurons and their axons, which comprise the optic nerve. We found that elevations in ocular pressure, a prominent risk factor for glaucoma, caused a paradoxical increase in ganglion cell excitability, including response to light, even in cells with substantial dendritic pruning. This adaptation arose from voltage-dependent mechanisms in the axon and may help maintain signaling to the brain to preserve vision.
A comprehensive model for the proliferation–quiescence decision in response to endogenous DNA damage in human cells
Authors: Heldt Frank S. , Barr Alexis R. , Cooper Sam , Bakal Chris , Novák Béla 
Published: February 2018

Significance
Controlled transitions of human cells between proliferating and nonproliferating states are essential for normal development and tissue homeostasis. To understand how the decision to proliferate is made in response to positive input from growth factors and negative input from the DNA damage response, we have built a mathematical model of the underlying molecular network, based on data from live cell-imaging experiments. Our model suggests that two major cell-cycle transitions are crucial for decision making: the restriction point, which integrates pro- and antiproliferative signals, and the G1/S transition, which temporarily insulates cells from some aspects of the DNA damage response. Together, our model gives mechanistic insight into how cells maintain both sensitivity and robustness to external signals.
Crop intensification, land use, and on-farm energy-use efficiency during the worldwide spread of the green revolution
Authors: Pellegrini Pedro , Fernández Roberto J. 
Published: February 2018

SignificanceGlobal crop production tripled during the last 50 years, mainly by an increase in yield (production/area). We show that the energy embedded in the main oil-based inputs (machinery, fuel, and fertilizers) increased worldwide at a rate at first larger, but in the last decades slower, than crop production, resulting in a recent overall improved energy-use efficiency (EUE). This was explained by advances in the nitrogen fertilizer industry, irrigation, and other technologies and perhaps some environmental changes. Our results fit the “Jevons paradox”: Efficiency gains, both for EUE and land (yield), did not lead to resource savings. Just as increasing production does not guarantee alleviating hunger, technologies make land (and biodiversity) savings possible, but realizing them depends on bold political decisions.
Translational control in the tumor microenvironment promotes lung metastasis: Phosphorylation of eIF4E in neutrophils
Authors: Robichaud Nathaniel , Hsu Brian E. , Istomine Roman , Alvarez Fernando , Blagih Julianna , Ma Eric H. , Morales Sebastian V. , Dai David L. , Li Glenn , Souleimanova Margarita , Guo Qianyu , del Rincon Sonia V. , Miller Wilson H. , Ramón y Cajal Santiago , Park Morag , Jones Russell G. , Piccirillo Ciriaco A. , Siegel Peter M. , Sonenberg Nahum 
Published: February 2018

Significance
Our findings document mRNA translation in cells of the tumor microenvironment (TME) as a crucial factor in metastatic progression. The results underscore the importance of understanding how translation-targeting therapies affect different cell types within the TME. We provide a rationale for targeting eIF4E phosphorylation in both cancer cells and cells that comprise the TME to halt metastasis and demonstrate the efficacy of this strategy using merestinib, a small molecule targeting the mitogen-activated protein kinase integrating kinases (MNKs). Our findings raise the possibility that a combination of MNK inhibitors with immunotherapy represents a therapeutic opportunity worthy of further investigation for treating cancer metastasis.
Robo and Ror function in a common receptor complex to regulate Wnt-mediated neurite outgrowth in
Caenorhabditis elegans
Authors: Wang Jiaming , Ding Mei 
Published: February 2018

Significance
How a limited repertoire of secreted molecules pattern a large number of axon trajectories is an enduring mystery. Both Slit-Robo and Wnt-Ror pathways are involved in proper neurite extension, but whether and how these two signaling pathways are interacted is largely unknown. Here, we found that instead of mediating Slit signaling, Robo could bind and respond to Wnt ligand. By forming a complex with the Ror receptor and Dsh effector, the Robo receptor promotes signal transduction from Wnt to Dsh. The mechanistic link between the Robo receptor and Wnt-Ror-Dsh signaling revealed here will markedly advance our understanding of how guidance molecules interact in space and time to orchestrate the dynamic process of growth cone navigation through a complex cellular environment.
Functional and physical interaction between yeast Hsp90 and Hsp70
Authors: Kravats Andrea N. , Hoskins Joel R. , Reidy Michael , Johnson Jill L. , Doyle Shannon M. , Genest Olivier , Masison Daniel C. , Wickner Sue 
Published: February 2018

Significance
The Hsp90 molecular chaperone remodels and activates a large variety of client proteins. Its activity requires collaboration with the more than 25 Hsp90 cochaperone proteins, including the Hsp70 chaperone. In higher eukaryotes, Hsp90 collaborates with Hsp70 through a bridging protein, the Hop cochaperone. We show that yeast Hsp90 (Hsp82) and Hsp70 (Ssa1) directly interact in vitro in the absence of yeast Hop (Sti1) and identify a region in the middle domain of yeast Hsp90 that is important for interaction with Hsp70. This region of Hsp90 is also important for interactions with several cochaperones and client proteins, suggesting that collaboration between Hsp70 and Hsp90 in protein remodeling may be modulated through competition between Hsp70 and Hsp90 cochaperones for the interaction surface.
MHC-mismatched mixed chimerism restores peripheral tolerance of noncross-reactive autoreactive T cells in NOD mice
Authors: Zhang Mingfeng , Racine Jeremy J. , Lin Qing , Liu Yuqing , Tang Shanshan , Qin Qi , Qi Tong , Riggs Arthur D. , Zeng Defu 
Published: February 2018

SignificanceMixed chimerism has shown good potential to cure some autoimmune diseases and prevent tissue rejection. It is known that MHC-mismatched but not -matched mixed chimerism effectively tolerizes autoreactive T cells, even those noncross-reactive T cells that do not directly recognize donor-type antigen presenting cells [i.e., dendritic cells (DCs)]. How this is accomplished remains unknown. These studies have shown that tolerizing peripheral residual host-type noncross-reactive autoreactive T cells requires engraftment of donor-type DCs and involves a host-type DC-mediated increase in donor-type Treg cells, which associates with restoration of tolerogenic features of host-type plasmacytoid DCs and expansion of host-type Treg cells. This study suggests a previously unrecognized tolerance network among donor- and host-type DCs and Treg cells in MHC-mismatched mixed chimeras.
Gibberellin DELLA signaling targets the retromer complex to redirect protein trafficking to the plasma membrane
Authors: Salanenka Yuliya , Verstraeten Inge , Löfke Christian , Tabata Kaori , Naramoto Satoshi , Glanc Matouš , Friml Jiří 
Published: February 2018

Significance
This study identifies and outlines a nontranscriptional branch of the canonical GA signaling pathway that redirects protein traffic from the vacuolar degradation route to the plasma membrane. As a result, the amount of receptors and transporters, such as PIN transporters for the plant hormone auxin, is functionally regulated at the cell surface. The identified branching occurs at the level of DELLA proteins that, besides transcriptional regulation, also target the microtubule (MT) network and protein trafficking. In this work, we provide multiple lines of evidence that DELLA proteins act via their interacting partners Prefoldins and that a downstream MT/CLASP1 module regulates the activity of the retromer complex that directs protein trafficking at the intersection of the vacuolar and recycling pathways.
Gi- and Gs-coupled GPCRs show different modes of G-protein binding
Authors: Van Eps Ned , Altenbach Christian , Caro Lydia N. , Latorraca Naomi R. , Hollingsworth Scott A. , Dror Ron O. , Ernst Oliver P. , Hubbell Wayne L. 
Published: February 2018

SignificanceActivation of G protein-coupled receptors (GPCRs) initiates conformational shifts that trigger interaction with a specific G-protein subtype from a structurally homologous set. A major unsolved problem is the mechanism by which this selectivity is achieved. Structures of GPCR–G protein complexes so far fail to reveal the origin of selectivity because they all involve one G-protein subtype (Gs). In this work, we report a structural model of the activated GPCR rhodopsin in complex with another G-protein subtype (Gi) derived from intermolecular distance mapping with DEER-EPR and refinement with modeling. Comparison of the model with structures of complexes involving Gsreveals distinct GPCR–G protein-binding modes, the differences of which suggest key features of the structural selectivity filter.
Optically functional isoxanthopterin crystals in the mirrored eyes of decapod crustaceans
Authors: Palmer Benjamin A. , Hirsch Anna , Brumfeld Vlad , Aflalo Eliahu D. , Pinkas Iddo , Sagi Amir , Rosenne Shaked , Oron Dan , Leiserowitz Leslie , Kronik Leeor , Weiner Steve , Addadi Lia 
Published: February 2018

Significance
Some aquatic animals use reflectors in their eyes either to form images or to increase photon capture. Guanine is the most widespread molecular component of these reflectors. Here, we show that crystals of isoxanthopterin, a pteridine analog of guanine, form both the image-forming “distal” mirror and the intensity-enhancing tapetum reflector in the compound eyes of some decapod crustaceans. The crystal structure of isoxanthopterin was determined, providing an explanation for why these crystals are so well suited for efficient reflection. Pteridines were previously known only as pigments, and our discovery raises the question of which other organic molecules may be used to form crystals with superior reflective properties either in organisms or in artificial optical devices.
Signal peptide of HIV envelope protein impacts glycosylation and antigenicity of gp120
Authors: Yolitz Jason , Schwing Catherine , Chang Julia , Van Ryk Donald , Nawaz Fatima , Wei Danlan , Cicala Claudia , Arthos James , Fauci Anthony S. 
Published: February 2018

Significance
Significant heterogeneity exists in the structure and antigenicity of HIV-1 envelope protein (Env) gp120 due, in part, to various posttranslational modifications. Using glycan and antigenic analysis, we show that the signal peptide (SP) of HIV Env can impact the glycan profile of gp120, which in turn impacts antigenicity of the mature protein. Thus, although the SP is not present in the mature gp120 protein, it is likely subject to immune pressure. Moreover, to the extent that glycan content impacts transmission fitness, variation in the SP may influence transmission. These observations potentially help us better understand both the early events in HIV transmission as well as the mechanisms whereby HIV evades humoral immune responses, providing additional information for HIV vaccine design.
Derivative culpability
Authors: Montminy Martin 
Published: February 2018

AbstractI explore the question of when an agent isderivatively, rather thandirectly, culpable for an undesirable outcome. The undesirable outcome might be a harmful incompetent or unwitting act, or it might be a harmful event. By examining various cases, I develop a sophisticated account of indirect culpability that is neutral about controversies regarding normative ethical issues and the condition on direct culpability.
Handgrip Strength and Blood Pressure in Children and Adolescents: Evidence From NHANES 2011 to 2014
Authors: Zhang Rui , Li Changwei , Liu Tingting , Zheng Liqiang , Li Shengxu 
Published: February 2018

Abstract

BACKGROUND
Previous studies have reported that handgrip strength, a measure of muscular fitness, is associated with cardiovascular risk factors. However, the association of handgrip strength with blood pressure (BP) in children has been inconsistent. We tested the association of handgrip strength with systolic and diastolic BP in children and adolescents from the National Health and Nutrition Examination Survey (NHANES) 2011–2014.

METHODS
The study included 3,929 participants aged 8–19 years who underwent a handgrip test. The sum of the maximum handgrip strength from both hands was used. General linear models were used to examine the associations between handgrip strength and the outcome variables.

RESULTS
After adjustment for age, race, sex, body mass index, and physical activities, handgrip strength was significantly and positively associated with systolic (P &lt; 0.0001) and diastolic (P = 0.01) BP. There was an increasing trend in systolic BP as handgrip strength increased from the bottom quartile to the top quartile, with 2.1 mm Hg difference between the top and the bottom quartiles (P for trend &lt;0.0001). Similar results were observed for diastolic BP.

CONCLUSIONS
Muscular fitness is positively associated with BP in children and adolescents. The implications and underlying mechanisms for these results need further examinations.
ViCTree: an automated framework for taxonomic classification from protein sequences
Authors: Modha Sejal , Thanki Anil S , Cotmore Susan F , Davison Andrew J , Hughes Joseph 
Published: February 2018

Abstract

Motivation
The increasing rate of submission of genetic sequences into public databases is providing a growing resource for classifying the organisms that these sequences represent. To aid viral classification, we have developed ViCTree, which automatically integrates the relevant sets of sequences in NCBI GenBank and transforms them into an interactive maximum likelihood phylogenetic tree that can be updated automatically. ViCTree incorporates ViCTreeView, which is a JavaScript-based visualization tool that enables the tree to be explored interactively in the context of pairwise distance data.

Results
To demonstrate utility, ViCTree was applied to subfamily Densovirinae of family Parvoviridae. This led to the identification of six new species of insect virus.

Availability and implementation
ViCTree is open-source and can be run on any Linux- or Unix-based computer or cluster. A tutorial, the documentation and the source code are available under a GPL3 license, and can be accessed at http://bioinformatics.cvr.ac.uk/victree_web/.

Supplementary information
Supplementary data are available at Bioinformatics online.
EPIC-CoGe: managing and analyzing genomic data
Authors: Nelson Andrew D L , Haug-Baltzell Asher K , Davey Sean , Gregory Brian D , Lyons Eric 
Published: February 2018

Abstract

Summary
The EPIC-CoGe browser is a web-based genome visualization utility that integrates the GMOD JBrowse genome browser with the extensive CoGe genome database (currently containing over 30 000 genomes). In addition, the EPIC-CoGe browser boasts many additional features over basic JBrowse, including enhanced search capability and on-the-fly analyses for comparisons and analyses between all types of functional and diversity genomics data. There is no installation required and data (genome, annotation, functional genomic and diversity data) can be loaded by following a simple point and click wizard, or using a REST API, making the browser widely accessible and easy to use by researchers of all computational skill levels. In addition, EPIC-CoGe and data tracks are easily embedded in other websites and JBrowse instances.

Availability and implementation
EPIC-CoGe Browser is freely available for use online through CoGe (https://genomevolution.org). Source code (MIT open source) is available: https://github.com/LyonsLab/coge.

Supplementary information
Supplementary data are available at Bioinformatics online.
Subaru High-z Exploration of Low-Luminosity Quasars (SHELLQs). III. Star formation properties of the host galaxies at z ≳ 6 studied with ALMA
Authors: Izumi Takuma , Onoue Masafusa , Shirakata Hikari , Nagao Tohru , Kohno Kotaro , Matsuoka Yoshiki , Imanishi Masatoshi , Strauss Michael A , Kashikawa Nobunari , Schulze Andreas , Silverman John D , Fujimoto Seiji , Harikane Yuichi , Toba Yoshiki , Umehata Hideki , Nakanishi Kouichiro , Greene Jenny E , Tamura Yoichi , Taniguchi Akio , Yamaguchi Yuki , Goto Tomotsugu , Hashimoto Yasuhiro , Ikarashi Soh , Iono Daisuke , Iwasawa Kazushi , Lee Chien-Hsiu , Makiya Ryu , Minezaki Takeo , Tang Ji-Jia 
Published: February 2018

Abstract
We present our ALMA Cycle 4 measurements of the [C ii] emission line and the underlying far-infrared (FIR) continuum emission from four optically low-luminosity (M1450 &gt; −25) quasars at z ≳ 6 discovered by the Subaru Hyper Suprime Cam (HSC) survey. The [C ii] line and FIR continuum luminosities lie in the ranges $L_{\rm [C\,{\small {II}}]} = (3.8\mbox{--}10.2)\times 10^{8}\,L_{\odot }$ and LFIR = (1.2–2.0) × 1011 L$_{\odot}$, which are at least one order of magnitude smaller than those of optically-luminous quasars at z ≳ 6. We estimate the star formation rates (SFRs) of our targets as ≃ 23–40 M$_{\odot}$ yr−1. Their line and continuum-emitting regions are marginally resolved, and found to be comparable in size to those of optically-luminous quasars, indicating that their SFR or likely gas mass surface densities (key controlling parameter of mass accretion) are accordingly different. The $L_{\rm [C\,{\small {II}}]}/L_{\rm FIR}$ ratios of the hosts, ≃ (2.2–8.7) × 10−3, are fully consistent with local star-forming galaxies. Using the [C ii] dynamics, we derived their dynamical masses within a radius of 1.5–2.5 kpc as ≃ (1.4–8.2) × 1010 M$_{\odot}$. By interpreting these masses as stellar ones, we suggest that these faint quasar hosts are on or even below the star-forming main sequence at z ∼ 6, i.e., they appear to be transforming into quiescent galaxies. This is in contrast to the optically-luminous quasars at those redshifts, which show starburst-like properties. Finally, we find that the ratios of black hole mass to host galaxy dynamical mass of most of the low-luminosity quasars, including the HSC ones, are consistent with the local value. The mass ratios of the HSC quasars can be reproduced by a semi-analytical model that assumes merger-induced black hole host galaxy evolution.
A genome-wide miRNA screen identifies regulators of tetraploid cell proliferation
Authors: Vittoria Marc A. , Shenk Elizabeth M. , O’Rourke Kevin P. , Bolgioni Amanda F. , Lim Sanghee , Kacprzak Victoria , Quinton Ryan J. , Ganem Neil J. 
Published: February 2018

AbstractTetraploid cells, which are most commonly generated by errors in cell division, are genomically unstable and have been shown to promote tumorigenesis. Recent genomic studies have estimated that ∼40% of all solid tumors have undergone a genome-doubling event during their evolution, suggesting a significant role for tetraploidy in driving the development of human cancers. To safeguard against the deleterious effects of tetraploidy, non-transformed cells that fail mitosis and become tetraploid activate both the Hippo and p53 tumor suppressor pathways to restrain further proliferation. Tetraploid cells must therefore overcome these anti-proliferative barriers to ultimately drive tumor development. However, the genetic routes through which spontaneously arising tetraploid cells adapt to regain proliferative capacity remain poorly characterized. Here, we conducted a comprehensive, gain-of-function genome-wide screen to identify miRNAs that are sufficient to promote the proliferation of tetraploid cells. Our screen identified 23 miRNAs whose overexpression significantly promotes tetraploid proliferation. The vast majority of these miRNAs facilitate tetraploid growth by enhancing mitogenic signaling pathways (e.g. miR-191-3p); however, we also identified several miRNAs that impair the p53/p21 pathway (e.g. miR-523-3p), and a single miRNA (miR-24-3p) that potently inactivates the Hippo pathway via downregulation of the tumor suppressor gene NF2. Collectively, our data reveal several avenues through which tetraploid cells may regain the proliferative capacity necessary to drive tumorigenesis.
Binding of General Anesthetics to Ion Channels
Authors: Stock Letícia , Hosoume Juliana , Cirqueira Leonardo , Treptow Werner 
Published: February 2018

ABSTRACTThe direct-site hypothesis assumes general anesthetics bind ion channels to impact protein equilibrium and function, inducing anesthesia. Despite advancements in the field, a first-principle all-atom demonstration of this structure-function premise misses. We focus on clinically used sevoflurane interaction to anesthetic-sensitive Kv1.2 mammalian channel to resolve if sevoflurane binds the protein’s well-characterized open and closed structures in a conformation-dependent manner to shift channel equilibrium. We employ an innovative approach relying on extensive docking calculations and free-energy perturbation and find sevoflurane binds open and closed structures at multiple sites under complex saturation and concentration effects. Results point to a non-trivial interplay of conformation-dependent modes of action involving distinct binding sites that increase channel open-probability at diluted ligand concentrations. Given the challenge in exploring more complex processes potentially impacting channel-anesthetic interaction, the result is reassuring as demonstrates that the process of multiple binding events alone may account for open-probability shifts recorded in measurements.
Familial hypercholesterolemia: a single-nucleotide variant (SNV) in mosaic at the Low density lipoprotein receptor (LDLR)
Authors: Rodríguez-Nóvoa Sonia , Alonso Concepción , Rodríguez-Jiménez Carmen , Rodriguez-Laguna Lara , Gordo Gema , Martinez-Glez Victor , García Polo Iluminada 
Published: February 2018

AbstractIntroductionFamilial hypercholesterolemia (FH) is most frequently caused by genetic variants in the LDLR gene. Most of LDLR pathogenic variants are missense, followed by splicing and deletion/insertions variants. Mosaicism is a genetic condition in which an individual shows more than one clone of cells with different genotypes.ObjectiveMolecular characterization of a patient with hypercholesterolemia.MethodsGenetic analysis of DNA from peripheral blood and saliva was performed by NGS, sanger sequencing and pyrosequencing technologies.ResultsNGS analysis detected the pathogenic variant LDLR:c.1951G>T:p.(Asp651Tyr) in 9%-12% of reads. The presence of the variant was confirmed by pyrosequencing analysis.ConclusionHerein, we report the first case of a mosaic single nucleotide variant affecting the LDLR gene in a patient with familial hypercholesterolemia. As has been described for other pathologies, mosaicism could be underestimated in FH and its detection will improve with the introduction of NGS technologies in the diagnostic routine.