bluuebunny/crossref_metadata_2025_split huggingface dataset:
ADS-J1 Disaggregates Semen-derived Amyloid Fibrils
Authors: Li J. , Yang Z. , Liu H. , Lan Y. , Zhang T. , Li W. , Qi T. , Qiu Y. , Li L. , Zhou X , Liu S. , Tan S. 
Published: March 2018

ABSTRACTSemen-derived amyloid fibrils, composing SEVI (semen-derived enhancer of viral infection) fibrils and SEM1 fibrils, could remarkably enhance HIV-1 sexual transmission and thus, are potential targets for the development of an effective microbicide. Previously, we found that ADS-J1, apart from being an HIV-1 entry inhibitor, could also potently inhibit seminal amyloid fibrillization and block fibril-mediated enhancement of viral infection. However, the remodeling effects of ADS-J1 on mature seminal fibrils were unexplored. Herein, we investigated the capacity of ADS-J1 to disassemble seminal fibrils and the potential mode of action by applying several biophysical and biochemical measurements, combined with molecular dynamic (MD) simulations. We found that ADS-J1 effectively remodeled SEVI, SEM186-107 fibrils and endogenous seminal fibrils. Unlike epi-gallocatechin gallate (EGCG), a universal amyloid fibril breaker, ADS-J1 disaggregated SEVI fibrils into monomeric peptides, which was independent of oxidation reaction. MD simulations revealed that ADS-J1 displayed strong binding potency to the full-length PAP248-286 via electrostatic interactions, hydrophobic interactions and hydrogen bonds. ADS-J1 might initially bind to the fibrillar surface and then occupy the amyloid core, which eventually lead to fibril disassembly. Furthermore, the binding of ADS-J1 with PAP248-286 might induce conformational changes of PAP248-286. Disassembled PAP248-286 might not be favor to re-aggregate into fibrils. ADS-J1 also exerts abilities to remodel a panel of amyloid fibrils, including Aβ1-42, hIAPP1-37 and EP2 fibrils. ADS-J1 displays promising potential to be a combination microbicide and an effective lead-product to treat amyloidogenic diseases.
Optical recording of action potential initiation and propagation in mouse skeletal muscle fibers
Authors: Banks Q. , Pratt S.J.P. , Iyer S.R. , Lovering R.M. , Hernández-Ochoa E.O. , Schneider M.F. 
Published: March 2018

ABSTRACTIndividual skeletal muscle fibers have been used to examine a wide variety of cellular functions and pathologies. Among other parameters, skeletal muscle action potential propagation has been measured to assess the integrity and function of skeletal muscle. In this paper, we utilize Di-8-ANEPPS, a potentiometric dye and mag-fluo-4, a low-affinity intracellular calcium indicator to non-invasively and reliably measure action potential conduction velocity in skeletal muscle. We used an extracellular bipolar electrode to generate an electric field that will initiate an action potential at one end of the fiber or the other. Using enzymatically dissociated flexor digitorum brevis (FDB) fibers, we demonstrate the strength and applicability of this technique. Using high-speed line scans, we estimate the conduction velocity to be approximately 0.4 m/s. In addition to measuring the conduction velocity, we can also measure the passive electrotonic potentials elicited by pulses by either applying tetrodotoxin (TTX) or reducing the bath sodium levels. We applied these methodologies to FDB fibers under elevated extracellular potassium conditions, and found that the conduction velocity is significantly reduced compared to our control concentration. Lastly, we have constructed a circuit model of a skeletal muscle in order to predict passive polarization of the fiber by the field stimuli. Our predictions from the model fiber closely resemble the recordings acquired from in vitro assays. With these techniques, we can examine how many different pathologies and mutations affect skeletal muscle action potential propagation. Our work demonstrates the utility of using Di-8-ANEPPS or mag-fluo-4 to non-invasively measure action potential conduction velocity.
Influence of elevated CO2 on development and food utilization of target armyworm Mythimna separata fed on transgenic Bt maize infected by nitrogen-fixing bacteria
Authors: Li Zhuo , Song Yingying , Li Likun , Wang Long , Liu Bin , Parajulee Megha N. , Chen Fajun 
Published: March 2018

AbstractBt crops will face a new ecological risk of reduced effectiveness against target-insect pests owing to the general decrease in exogenous-toxin content in Bt crops grown under elevated CO2. How to deal with this issue may affect the sustainability of transgenic crops as an effective pest management tool especially under future CO2 raising. In this study, azotobacters, as being one potential biological regulator to enhance crops’ nitrogen utilization efficiency, were selected and the effects of Bt maize and non-Bt maize infected by Azospirillum brasilense and Azotobacter chroococcum on development and food utilization of target Mythimna separate were studied under ambient and elevated CO2. The results indicated that azotobacter infection significantly increased larval life-span, pupal duration, RCR and AD of M. separata, and significantly decreased RGR, ECD and ECI of M. separata fed on Bt maize; There were opposite trends in development and food utilization of M. separata fed on non-Bt maize infected with azotobacters compared with the buffer control regardless of CO2 level. Presumably, the application of azotobacter infection could make Bt maize facing lower field hazards from the target pest of M. separate, and finally improve the resistance of Bt maize against target lepidoptera pests especially under elevated CO2.Summary statementElevated CO2 effect on development and food utilization of target armyworm Mythimna separata fed on Bt maize infected by azotobacter, Azospirillum brasilense and Azotobacter chroococcum
Short cracks in knee meniscus tissue cause strain concentrations, but do not reduce ultimate stress, in single-cycle uniaxial tension
Authors: Peloquin John M. , Santare Michael H. , Elliott Dawn M. 
Published: March 2018

AbstractTears are central to knee meniscus pathology and, from a mechanical perspective, are crack-like defects (cracks). In many materials, cracks create stress concentrations that cause progressive local rupture and reduce effective strength. It is currently un-known if cracks in meniscus have these consequences; if they do, this would have repercussions for management of meniscus pathology. The objective of this study was to determine if a short crack in meniscus tissue, which mimics a preclinical meniscus tear, (a) causes crack growth and reduces effective strength, (b) creates a near-tip strain concentration, and (c) creates unloaded regions on either side of the crack. Specimens with and without cracks were tested in uniaxial tension and compared in terms of macroscopic stress–strain curves and digital image correlation strain fields. The strain fields were used as an indicator of stress concentrations and unloaded regions. Effective strength was found to be insensitive to the presence of a crack (potential effect < 0.86 s.d.; β = 0.2), but significant strain concentrations, which have the potential to lead to long-term accumulation of tissue or cell damage, were observed near the crack tip.
Integrating Predicted Transcriptome From Multiple Tissues Improves Association Detection
Authors: Barbeira Alvaro N. , Pividori Milton D. , Zheng Jiamao , Wheeler Heather E. , Nicolae Dan L. , Im Hae Kyung 
Published: March 2018

AbstractIntegration of genome-wide association studies (GWAS) and expression quantitative trait loci (eQTL) studies is needed to improve our understanding of the biological mechanisms underlying GWAS hits, and our ability to identify therapeutic targets. Gene-level association test methods such as PrediXcan can prioritize candidate targets. However, limited eQTL sample sizes and absence of relevant developmental and disease context restricts our ability to detect associations. Here we propose an efficient statistical method that leverages the substantial sharing of eQTLs across tissues and contexts to improve our ability to identify potential target genes: MulTiXcan. MulTiXcan integrates evidence across multiple panels while taking into account their correlation. We apply our method to a broad set of complex traits available from the UK Biobank and show that we can detect a larger set of significantly associated genes than using each panel separately. To improve applicability, we developed an extension to work on summary statistics: S-MulTiXcan, which we show yields highly concordant results with the individual level version. Results from our analysis as well as software and necessary resources to apply our method are publicly available.
Receptor binding and proteolysis do not induce large conformational changes in the SARS-CoV spike
Authors: Kirchdoerfer Robert N. , Wang Nianshuang , Pallesen Jesper , Wrapp Daniel , Turner Hannah L. , Cottrell Christopher A. , Corbett Kizzmekia S. , Graham Barney S. , McLellan Jason S. , Ward Andrew B. 
Published: March 2018

AbstractSevere acute respiratory syndrome coronavirus (SARS-CoV) emerged in 2002 as a highly transmissible pathogenic human betacoronavirus. The viral spike glycoprotein (S) utilizes angiotensin-converting enzyme 2 (ACE2) as a host protein receptor and mediates fusion of the viral and host membranes, making S essential to viral entry into host cells and host species tropism. As SARS-CoV enters host cells, the viral S undergoes two proteolytic cleavages at S1/S2 and S2’ sites necessary for efficient membrane fusion. Here, we present a cryo-EM analysis of the trimeric SARS-CoV S interactions with ACE2 and of the trypsin-cleaved S. Surprisingly, neither binding to ACE2 nor cleavage by trypsin at the S1/S2 cleavage site impart large conformational changes within S or expose the secondary cleavage site, S2’. These observations suggest that S2’ cleavage does not occur in the S prefusion conformation and that additional triggers may be required.
Partial reprogramming induces a steady decline in epigenetic age before loss of somatic identity
Authors: Olova Nelly , Simpson Daniel J , Marioni Riccardo , Chandra Tamir 
Published: March 2018

SummaryInduced pluripotent stem cells (IPSCs), with their unlimited regenerative capacity, carry the promise for tissue replacement to counter age-related decline. However, attempts to realise in vivo iPSC have invariably resulted in the formation of teratomas. Partial reprogramming in prematurely aged mice has shown promising results in alleviating age-related symptoms without teratoma formation. Does partial reprogramming lead to rejuvenation (i.e. “younger” cells), rather than dedifferentiation, which bears the risk of cancer? Here we analyse the dynamics of cellular age during human iPSC reprogramming and find that partial reprogramming leads to a reduction in the epigenetic age of cells. We also find that the loss of somatic gene expression and epigenetic age follow different kinetics, suggesting that they can be uncoupled and there could be a safe window where rejuvenation can be achieved with a minimised risk of cancer.
Small RNA-mediated genomic silencing promotes telomere stability in the absence of telomerase
Authors: Longtine Charlie , Frenk Stephen , Ahmed Shawn 
Published: March 2018

AbstractTelomerase deficiency in human somatic cells results in telomere erosion and senescence. Small RNAs that target telomeres have been observed in diverse organisms but their functions are not well characterized. We define an endogenous small RNA pathway in Caenorhabditis elegans that promotes heterochromatin formation at telomeres via Dicer, the perinuclear Argonaute protein WAGO-1 and the nuclear Argonaute protein HRDE-1. Loss of telomerase induces biogenesis of siRNAs that target the telomeric lncRNA TERRA, whereas loss of both telomerase and small RNA-mediated telomeric silencing induces TERRA expression, DNA damage, and an accelerated sterility phenotype. These phenotypes can be rescued by exogenous telomeric siRNAs or by loss of the DNA damage response protein EXO-1. Thus, endogenous siRNAs interact with TERRA to promote heterochromatin formation in a manner that is critical for the stability of naturally eroding telomeres. We propose that small RNA-mediated genome silencing could be broadly relevant to regulation of proliferative aging.
Predictive control of electrophysiological network architecture using direct, single-node neurostimulation in humans
Authors: Khambhati Ankit N. , Kahn Ari E. , Costantini Julia , Ezzyat Youssef , Solomon Ethan A. , Gross Robert E. , Jobst Barbara C. , Sheth Sameer A. , Zaghloul Kareem A. , Worrell Gregory , Seger Sarah , Lega Bradley C. , Weiss Shennan , Sperling Michael R. , Gorniak Richard , Das Sandhitsu R. , Stein Joel M. , Rizzuto Daniel S. , Kahana Michael J. , Lucas Timothy H. , Davis Kathryn A. , Tracy Joseph I. , Bassett Danielle S. 
Published: March 2018

AbstractChronically implantable neurostimulation devices are becoming a clinically viable option for treating patients with neurological disease and psychiatric disorders. Neurostimulation offers the ability to probe and manipulate distributed networks of interacting brain areas in dysfunctional circuits. Here, we use tools from network control theory to examine the dynamic reconfiguration of functionally interacting neuronal ensembles during targeted neurostimulation of cortical and subcortical brain structures. By integrating multi-modal intracranial recordings and diffusion tensor imaging from patients with drug-resistant epilepsy, we test hypothesized structural and functional rules that predict altered patterns of synchronized local field potentials. We demonstrate the ability to predictably reconfigure functional interactions depending on stimulation strength and location. Stimulation of areas with structurally weak connections largely modulates the functional hubness of downstream areas and concurrently propels the brain towards more difficult-to-reach dynamical states. By using focal perturbations to bridge large-scale structure, function, and markers of behavior, our findings suggest that stimulation may be tuned to influence different scales of network interactions driving cognition.
Protein structure and function analyses to understand the implication of mutually exclusive splicing
Authors: Lam Su Datt , Orengo Christine , Lees Jonathan 
Published: March 2018

ABSTRACTAlternative splicing (AS) has been suggested as one of the major processes expanding the diversity of proteomes in multicellular organisms. Mutually exclusive exons (MXE) provide one form of AS that is less likely to disrupt protein structure and is over-represented in the proteome compared to other forms of AS. We used domain structure information from the CATH classification to perform a systematic structural analysis of the effects of MXE splicing in high quality animal genomes (e.g. human, fly, mouse and 2 fishes) and we were able to annotate approximately 50% of MXE events with structural information. For those MXE events which can be mapped to a structure, we found that although embedded in domains, they were strongly enriched in surface exposed residues. We also demonstrated that the variable residues between splicing events lie close to known and/or predicted functional sites. We present some examples of MXE events in proteins that have important roles in cells. This work presents the first large scale systematic study of the structural/functional effects of MXE splicing using predominantly domain based modelling and functional annotation tools. Our study supports and expands on previous work in this field and helps to build a picture of how MXE events facilitate evolution of new functions.
Optimal feedback mechanisms for regulating cell numbers
Authors: Modi Saurabh , Singh Abhyudai 
Published: March 2018

AbstractHow living cells employ counting mechanisms to regulate their numbers or density is a long-standing problem in developmental biology that ties directly with organism or tissue size. Diverse cells types have been shown to regulate their numbers via secretion of factors in the extracellular space. These factors act as a proxy for the number of cells and function to reduce cellular proliferation rates creating a negative feedback. It is desirable that the production rate of such factors be kept as low as possible to minimize energy costs and detection by predators. Here we formulate a stochastic model of cell proliferation with feedback control via a secreted extracellular factor. Our results show that while low levels of feedback minimizes random fluctuations in cell numbers around a given set point, high levels of feedback amplify Poisson fluctuations in secreted-factor copy numbers. This trade-off results in an optimal feedback strength, and sets a fundamental limit to noise suppression in cell numbers. Intriguingly, this fundamental limit depends additively on two variables: relative half-life of the secreted factor with respect to the cell proliferation rate, and the average number of factors secreted in a cell’s lifespan. We further expand the model to consider external disturbances in key physiological parameters, such as, proliferation and factor synthesis rates. Intriguingly, while negative feedback effectively mitigates disturbances in the proliferation rate, it amplifies disturbances in the synthesis rate. In summary, these results provide unique insights into the functioning of feedback-based counting mechanisms, and apply to organisms ranging from unicellular prokaryotes and eukaryotes to human cells.
Antibody-based vaccine for tuberculosis: validation in horse foals challenged with the TB-related pathogen Rhodococcus equi
Authors: Cywes-Bentley C. , Rocha J. N. , Bordin A. I. , Vinacur M. , Rehman S. , Zaidi T.S. , Meyer M. , Anthony S. , Lambert M. , Vlock D. R. , Giguère S. , Cohen N. D. , Pier G. B. 
Published: March 2018

AbstractImmune correlates for protection against Mycobacterium tuberculosis (Mtb) infection and other intracellular pathogens are largely undetermined. Whether there is a role for antibody-mediated immunity is controversial. Rhodococcus equi is an intracellular pathogen causing severe pneumonia in young horse foals, eliciting a disease with many similarities to TB including intracellular residence, formation of granulomas and induction of severe respiratory distress. No purified vaccine antigens exist for R. equi or Mtb infections. Both express the microbial surface polysaccharide antigen poly-N-acetyl glucosamine (PNAG). In a randomized, controlled, blinded challenge trial, vaccination of pregnant mares with a synthetic PNAG oligosaccharide conjugated to tetanus toxoid elicited antibody that transferred to foals via colostrum and provided nearly complete protection against R. equi pneumonia. Infusion of PNAG-hyperimmune plasma protected 100% of foals against R. equi pneumonia. Vaccination induced opsonic antibodies that killed extracellular and intracellular R. equi and other intracellular pathogens. Killing of intracellular organisms was dependent on antibody recognition of surface expression of PNAG on infected macrophages, complement deposition and PMN-assisted lysis of infected macrophages. Protection also correlated with PBMC release of interferon-γ in response to PNAG. Antibody-mediated opsonic killing and interferon-γ release in response to PNAG may protect against disease caused by intracellular bacterial pathogens.
Tricin inhibits the CCL5 induction required for efficient growth of human cytomegalovirus
Authors: Itoh Akimasa , Sadanari Hidetaka , Takemoto Masaya , Matsubara Keiko , Daikoku Tohru , Murayama Tsugiya 
Published: March 2018

ABSTRACTTreatment of human embryonic lung fibroblast (HEL) cells with tricin (4′, 5, 7‐trihydroxy‐3′, 5′‐dimethoxyflavone) following infection with human cytomegalovirus (HCMV) reportedly significantly suppresses HCMV replication. In the present work, the mechanisms for the anti‐HCMV effects of tricin in HEL cells were examined. It was found that exposure of HEL cells to tricin inhibited HCMV replication, with concomitant decreases in amounts of transcripts of the CC chemokine RANTES (CCL5)‐encoding gene and in expression of the CCL5 protein. It was also found that transcripts of HCMV immediate early 1 (IE1), and HCMV UL54 (encoding DNA polymerase) and replication of HCMV was significantly lower in CCL5 gene‐knockdown cells. These results suggest that the anti‐HCMV activity of tricin differs from that of ganciclovir and that CCL5 is one of the chemokines involved in HCMV replication. In addition, it is possible that chemokine CCL5 is one of the targets of tricin.
Soil microbes promote complementarity effects among co‐existing trees through soil nitrogen partitioning
Authors: Luo Shan , Schmid Bernhard , De Deyn Gerlinde B. , Yu Shixiao 
Published: March 2018

Abstract

Plant resource partitioning is a mechanism promoting species coexistence and ecosystem functioning. Yet, we still have limited understanding of how soil microbes, especially plant symbiotic microbes, influence resource partitioning. We hypothesized that soil‐borne microbes, in particular mycorrhizal fungi, facilitate differential performance of tree species depending on different nitrogen sources and that this leads to a positive plant diversity–community productivity relationship.

We conducted two complementing glasshouse experiments. In a “monoculture experiment,” we supplied nitrogen as ammonium, nitrate or glycine and tested the growth response of three tree species associated with different root symbionts: one associated with ectomycorrhizal fungi, one associated with arbuscular mycorrhizal fungi, and the third associated with both arbuscular mycorrhizal fungi and N‐fixing bacteria. In an “intermixed experiment,” we grew the tree species at three richness levels (one, two or three species) in soil supplied with a mix of the three nitrogen forms or no added nitrogen, and with or without soil microbes.

The monoculture experiment showed that in the presence of soil microbes, the ectomycorrhizal plant species grew best when supplied with glycine and the two arbuscular mycorrhizal plant species grew best with either nitrate or ammonium addition. When the different forms of nitrogen were mixed in the intermixed experiment, plant mixtures produced more biomass than plant monocultures in the presence of soil microbes, with positive complementarity effects indicating microbe‐mediated plant resource partitioning.

Our results suggest that co‐existing tree species can partition soil nitrogen when grown with their particular mycorrhizal symbionts or other soil microbes, resulting in positive biodiversity effects in complex resource environments.

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