bluuebunny/crossref_metadata_2025_split huggingface dataset:
Creating an Artificial Tail Anchor as a Novel Strategy To Enhance the Potency of Peptide-Based HIV Fusion Inhibitors
Authors: Su Shan , Zhu Yun , Ye Sheng , Qi Qianqian , Xia Shuai , Ma Zhenxuan , Yu Fei , Wang Qian , Zhang Rongguang , Jiang Shibo , Lu Lu 
Published: October 2016

ABSTRACT
20 (enfuvirtide) and other peptides derived from the human immunodeficiency virus type 1 (HIV-1) gp41 C-terminal heptad repeat (CHR) region inhibit HIV fusion by binding to the hydrophobic grooves on the N-terminal heptad repeat (NHR) trimer and blocking six-helix-bundle (6-HB) formation. Several strategies focusing on the binding grooves of the NHR trimer have been adopted to increase the antiviral activity of the CHR peptides. Here, we developed a novel and simple strategy to greatly enhance the potency of the existing peptide-based HIV fusion inhibitors. First, we identified a shallow pocket adjacent to the groove in the N-terminal region of NHR trimer as a new drug target, and then we designed several short artificial peptides to fit this target. After the addition of IDL (Ile-Asp-Leu) to the C terminus of CHR peptide WQ or MT-WQ, the conjugated peptides, WQ-IDL and MT-WQ-IDL, showed much more potent activities than WQ and T20, respectively, in inhibiting HIV-1 IIIB infection. WQ-IDL and MT-WQ-IDL were also more effective than WQ in blocking HIV-1 Env-mediated membrane fusion and had higher levels of binding affinity with NHR peptide N46. We solved the crystal structure of the 6-HB formed by MT-WQ-IDL and N46 and found that, besides the N-terminal MT hook tail, the IDL tail anchor of MT-WQ-IDL also binds with the shallow hydrophobic pocket outside the groove of the NHR trimer, resulting in enhanced inhibition of HIV-1 fusion with the target cell. It is expected that this novel approach can be widely used to improve the potency of peptidic fusion inhibitors against other enveloped viruses with class I fusion proteins.

IMPORTANCE
The hydrophobic groove of the human immunodeficiency virus type 1 (HIV-1) gp41 NHR trimer has been known as the classic drug target to develop fusion inhibitors derived from the gp41 CHR. Here, we developed a novel and simple strategy to improve the existing peptide-based HIV fusion inhibitors. We identified a shallow pocket adjacent to the groove in the NHR trimer and added a short artificial peptide consisting of three amino acids (IDL) to the C terminus of a fusion inhibitor to fit this new target. The inhibition activity of this new conjugated peptide was significantly enhanced, by 77-fold, making it much more potent than T20 (enfuvirtide) and suggesting that the IDL tail can be adopted for optimizing existing HIV-1 CHR peptide fusion inhibitors. This new approach of identifying a potential binding pocket outside the traditional target and creating an artificial tail anchor can be widely applied to design novel fusion inhibitors against other class I enveloped viruses, such as Middle East respiratory syndrome coronavirus (MERS-CoV).
Interleukin-17A Promotes CD8+T Cell Cytotoxicity To Facilitate West Nile Virus Clearance
Authors: Acharya Dhiraj , Wang Penghua , Paul Amber M. , Dai Jianfeng , Gate David , Lowery Jordan E. , Stokic Dobrivoje S. , Leis A. Arturo , Flavell Richard A. , Town Terrence , Fikrig Erol , Bai Fengwei 
Published: October 2016

ABSTRACTCD8+T cells are crucial components of immunity and play a vital role in recovery from West Nile virus (WNV) infection. Here, we identify a previously unrecognized function of interleukin-17A (IL-17A) in inducing cytotoxic-mediator gene expression and promoting CD8+T cell cytotoxicity against WNV infection in mice. We find that IL-17A-deficient (Il17a−/−) mice are more susceptible to WNV infection and develop a higher viral burden than wild-type (WT) mice. Interestingly, the CD8+T cells isolated fromIl17a−/−mice are less cytotoxic and express lower levels of cytotoxic-mediator genes, which can be restored by supplying recombinant IL-17Ain vitroandin vivo. Importantly, treatment of WNV-infected mice with recombinant IL-17A, as late as day 6 postinfection, significantly reduces the viral burden and increases survival, suggesting a therapeutic potential for IL-17A. In conclusion, we report a novel function of IL-17A in promoting CD8+T cell cytotoxicity, which may have broad implications in other microbial infections and cancers.IMPORTANCEInterleukin-17A (IL-17A) and CD8+T cells regulate diverse immune functions in microbial infections, malignancies, and autoimmune diseases. IL-17A is a proinflammatory cytokine produced by diverse cell types, while CD8+T cells (known as cytotoxic T cells) are major cells that provide immunity against intracellular pathogens. Previous studies have demonstrated a crucial role of CD8+T cells in recovery from West Nile virus (WNV) infection. However, the role of IL-17A during WNV infection remains unclear. Here, we demonstrate that IL-17A protects mice from lethal WNV infection by promoting CD8+T cell-mediated clearance of WNV. In addition, treatment of WNV-infected mice with recombinant IL-17A reduces the viral burden and increases survival of mice, suggesting a potential therapeutic. This novel IL-17A–CD8+T cell axis may also have broad implications for immunity to other microbial infections and cancers, where CD8+T cell functions are crucial.
A Helical Short-Peptide Fusion Inhibitor with Highly Potent Activity against Human Immunodeficiency Virus Type 1 (HIV-1), HIV-2, and Simian Immunodeficiency Virus
Authors: Xiong Shengwen , Borrego Pedro , Ding Xiaohui , Zhu Yuanmei , Martins Andreia , Chong Huihui , Taveira Nuno , He Yuxian 
Published: October 2016

ABSTRACTHuman immunodeficiency virus type 2 (HIV-2) has already spread to different regions worldwide, and currently about 1 to 2 million people have been infected, calling for new antiviral agents that are effective on both HIV-1 and HIV-2 isolates. T20 (enfuvirtide), a 36-mer peptide derived from the C-terminal heptad repeat region (CHR) of gp41, is the only clinically approved HIV-1 fusion inhibitor, but it easily induces drug resistance and is not active on HIV-2. In this study, we first demonstrated that the M-T hook structure was also vital to enhancing the binding stability and inhibitory activity of diverse CHR-based peptide inhibitors. We then designed a novel short peptide (23-mer), termed 2P23, by introducing the M-T hook structure, HIV-2 sequences, and salt bridge-forming residues. Promisingly, 2P23 was a highly stable helical peptide with high binding to the surrogate targets derived from HIV-1, HIV-2, and simian immunodeficiency virus (SIV). Consistent with this, 2P23 exhibited potent activity in inhibiting diverse subtypes of HIV-1 isolates, T20-resistant HIV-1 mutants, and a panel of primary HIV-2 isolates, HIV-2 mutants, and SIV isolates. Therefore, we conclude that 2P23 has high potential to be further developed for clinical use, and it is also an ideal tool for exploring the mechanisms of HIV-1/2- and SIV-mediated membrane fusion.IMPORTANCEThe peptide drug T20 is the only approved HIV-1 fusion inhibitor, but it is not active on HIV-2 isolates, which have currently infected 1 to 2 million people and continue to spread worldwide. Recent studies have demonstrated that the M-T hook structure can greatly enhance the binding and antiviral activities of gp41 CHR-derived inhibitors, especially for short peptides that are otherwise inactive. By combining the hook structure, HIV-2 sequence, and salt bridge-based strategies, the short peptide 2P23 has been successfully designed. 2P23 exhibits prominent advantages over many other peptide fusion inhibitors, including its potent and broad activity on HIV-1, HIV-2, and even SIV isolates, its stability as a helical, oligomeric peptide, and its high binding to diverse targets. The small size of 2P23 would benefit its synthesis and significantly reduce production cost. Therefore, 2P23 is an ideal candidate for further development, and it also provides a novel tool for studying HIV-1/2- and SIV-mediated cell fusion.
Cytokines and Chemokines inMycobacterium tuberculosisInfection
Authors: Domingo-Gonzalez Racquel , Prince Oliver , Cooper Andrea , Khader Shabaana A. 
Published: October 2016

ABSTRACTChemokines and cytokines are critical for initiating and coordinating the organized and sequential recruitment and activation of cells intoMycobacterium tuberculosis-infected lungs. Correct mononuclear cellular recruitment and localization are essential to ensure control of bacterial growth without the development of diffuse and damaging granulocytic inflammation. An important block to our understanding of TB pathogenesis lies in dissecting the critical aspects of the cytokine/chemokine interplay in light of the conditional role these molecules play throughout infection and disease development. Much of the data highlighted in this review appears at first glance to be contradictory, but it is the balance between the cytokines and chemokines that is critical, and the “goldilocks” (not too much and not too little) phenomenon is paramount in any discussion of the role of these molecules in TB. Determination of how the key chemokines/cytokines and their receptors are balanced and how the loss of that balance can promote disease is vital to understanding TB pathogenesis and to identifying novel therapies for effective eradication of this disease.
Predictors of severe psychological distress trajectory after nuclear disaster: evidence from the Fukushima Health Management Survey
Authors: Oe Misari , Maeda Masaharu , Nagai Masato , Yasumura Seiji , Yabe Hirooki , Suzuki Yuriko , Harigane Mayumi , Ohira Tetsuya , Abe Masafumi 
Published: October 2016

ObjectivesThe Fukushima Daiichi Nuclear Power Plant accident, which occurred after the Great East Japan Earthquake and Tsunami in March 2011, may have a considerable long-term impact on the lives of area residents. The aims of this study were to determine the trajectories of psychological distress using 3-year consecutive data, and to find predictive factors of severe distress that may also prove useful for public health intervention.MethodsData were obtained on 12 371 residents who were registered in the municipalities categorised as complete evacuation areas for 3 years after the disaster and who completed an assessment in each of the 3 years.ResultsUsing group-based trajectory modelling, we identified four trajectory patterns distinguished by the levels of psychological distress, which gradually improved over time in all trajectories. Subjective sleep insufficiency, problem drinking, poor social support and perception of radiation risk 3 years after the accident were associated with the severity of psychological distress, according to the multivariate analysis.ConclusionsThe identified factors may be useful for community-based mental healthcare over the long term following a nuclear disaster.
Do rocker-sole shoes influence postural stability in chronic low back pain? A randomised trial
Authors: MacRae C Sian , Critchley Duncan , Morrissey Matthew , Shortland Adam , Lewis Jeremy S 
Published: October 2016

BackgroundPeople with chronic low back pain (CLBP) demonstrate greater postural instability compared with asymptomatic individuals. Rocker-sole shoes are inherently unstable and may serve as an effective balance training device. This study hypothesised that wearing rocker-sole shoes would result in long-term improvement in barefoot postural stability in people with CLBP.Methods20 participants with CLBP were randomised to wear rocker-sole or flat-sole shoes for a minimum of 2 hours each day. Participants were assessed barefoot and shod, over three 40 s trials, under 4 posture challenging standing conditions. The primary outcome was postural stability assessed by root mean squared error of centre of pressure (CoP) displacement (CoPRMSE AP) and mean CoP velocity (CoPVELAP), both in the anteroposterior direction, using force plates. Participants' were assessed without knowledge of group allocation at baseline, 6 weeks and 6 months (main outcome point). Analyses were by intention-to-treat.ResultsAt 6 months, data from 11 of 13 (84.6%) of the rocker-sole and 5 of 7 (71.4%) of the flat-sole group were available for analysis. At baseline, there was a mean increase in CoPRMSE AP(6.41 (2.97) mm, p<0.01) and CoPVELAP(4.10 (2.97) mm, p<0.01) in the rocker-sole group when shod compared with barefoot; there was no difference in the flat-sole group. There were no within-group or between-group differences in change in CoP parameters at any time point compared with baseline (1) for any barefoot standing condition (2) when assessed shod eyes-open on firm ground.ConclusionsAlthough wearing rocker-sole shoes results in greater postural instability than flat-sole shoes, long-term use of rocker-sole shoes did not appear to influence postural stability in people with CLBP.
Testing Higgs coupling precision and new physics scales at lepton colliders
Authors: Ge Shao-Feng , He Hong-Jian , Xiao Rui-Qing 
Published: October 2016

The next-generation lepton colliders, such as CEPC, FCC-ee, and ILC will make precision measurement of the Higgs boson properties. We first extract the Higgs coupling precision from Higgs observables at CEPC to illustrate the potential of future lepton colliders. Depending on the related event rates, the precision can reach percentage level for most couplings. Then, we try to estimate the new physics scales that can be indirectly probed with Higgs and electroweak precision observables. The Higgs observables, together with the existing electroweak precision observables, can probe new physics up to 10 TeV (40 TeV for the gluon-related operator [Formula: see text]) at 95% C.L. Including the [Formula: see text] mass measurements and [Formula: see text]-pole observables at CEPC further pushes the limit up to 35 TeV. Although [Formula: see text]-pole running is originally for the purpose of machine calibration, it can be as important as the Higgs observables for probing the new physics scales indirectly. The indirect probe of new physics scales at lepton colliders can mainly cover the energy range to be explored by the following hadron colliders of [Formula: see text] (50–100 TeV), such as SPPC and FCC-hh.
Probe Higgs potential via multi-Higgs boson final states at hadron colliders
Authors: Yan Qi-Shu 
Published: October 2016

I summarize some results related with the determination of the Higgs potential, including a hadron-level Monte Carlo study of the sensitivity of Higgs boson pair production via the [Formula: see text] channel with the final state [Formula: see text] and the sensitivity study on the triple Higgs boson final state via [Formula: see text] in a 100 TeV collider.
Enhanced Oncolytic Activities of the Telomerase-Specific Replication-Competent Adenovirus Expressing Short-Hairpin RNA against Dicer
Authors: Machitani Mitsuhiro , Sakurai Fuminori , Wakabayashi Keisaku , Tachibana Masashi , Fujiwara Toshiyoshi , Mizuguchi Hiroyuki 
Published: October 2016

Abstract
Oncolytic viruses have been receiving much attention as potential agents for cancer treatment. Among the various types of oncolytic viruses, the telomerase-specific replication-competent adenovirus (TRAD), which carries the tumor-specific promoter-driven E1 gene expression cassette, exhibits efficient antitumor effects. The development of a novel TRAD that shows higher replication efficiency and antitumor activity would be highly beneficial for safer and more efficient cancer therapy. We recently demonstrated that the endoribonuclease Dicer significantly inhibits the replication of wild-type adenovirus (Ad) via the processing of viral-associated (VA)-RNAs, which are Ad-encoded small noncoding RNAs, and that the knockdown of Dicer leads to enhanced VA-RNA expression and Ad replication after infection with wild-type Ad. Based on these findings, we herein developed a novel TRAD expressing short-hairpin RNA against Dicer (shDicer; TRAD-shDicer). After infection, TRAD-shDicer efficiently induced the knockdown of Dicer. TRAD-shDicer showed significantly higher replication efficiency and tumor cell lysis activity compared with the conventional TRAD in tumor cells. The Dicer expression levels and viabilities of normal cells were not altered by infection with TRAD-shDicer. These results indicate that TRAD-shDicer is a potent antitumor reagent by virtue of its enhanced oncolytic activity. Mol Cancer Ther; 16(1); 251–9. ©2016 AACR.
Decreased platelet reactivity in patients with cancer is associated with high risk of venous thromboembolism and poor prognosis
Authors: Riedl Julia , Kaider Alexandra , Marosi Christine , Prager Gerald W. , Eichelberger Beate , Assinger Alice , Pabinger Ingrid , Panzer Simon , Ay Cihan 
Published: October 2016

SummaryPlatelets are suggested to play a crucial role in cancer progression and the prothrombotic state of cancer patients. Here, we aimed to examine the activation status of platelets in cancer patients and investigate their association with risk of death and occurrence of venous thromboembolism (VTE) in a prospective observational cohort study. We measured platelet surface P-selectin, activated glycoprotein (GP) IIb/IIIa and monocyte-platelet aggregate (MPA) formation in vivo and platelet response to ex vivo stimulation with agonists of protease-activated receptor (PAR) −1, −4, and GPVI, by whole blood flow cytometry, before beginning of chemotherapy and repeatedly during the first six months thereafter (total number of samples analysed: 230). Endpoints of the study were occurrence of death or VTE during a two-year follow-up, respectively. Of 62 patients (median age [interquartile range, IQR]: 63 [54–70] years, 48 % female), 32 (51.6 %) died and nine (14.5 %) developed VTE. Association with a higher risk of death was found for lower platelet surface expression of P-selectin and activated GPIIb/IIIa in vivo and in response to PAR-1, −4 and GPVI activation, but not for MPA formation. Furthermore, reduced platelet responsiveness to PAR-1 and GPVI agonists was associated with higher risk of VTE (hazard ratio per decile increase of percentage P-selectin positive platelets: 0.73 [0.56–0.92, p=0.007] and 0.77 [0.59–0.98, p=0.034], respectively). In conclusion, cancer patients with a poor prognosis showed decreased platelet reactivity, presumably as a consequence of continuous activation. Our data suggest that decreased platelet reactivity is associated with increased mortality and VTE in cancer.Supplementary Material to this article is available online at www.thrombosis-online.com.
Using 3D Laser Scanning Technology to Create Digital Models of Hailstones
Authors: Giammanco Ian M. , Maiden Benjamin R. , Estes Heather E. , Brown-Giammanco Tanya M. 
Published: October 2016

Abstract
The emergence of 3D scanning technologies has provided a new opportunity to explore the shape characteristics of hailstones in great detail. The ability to effectively map the shape of hailstones will improve assessments of hailstone aerodynamic properties, how their density relates to their strength, and how radar energy is scattered. Ultimately, 3D scanning of hailstones will contribute toward research in hail detection, forecasting, and damage mitigation of severe hail, which accounts for well over $1 billion in annual insured losses.
The use of a handheld 3D laser scanner in a field setting was explored during field campaigns in 2015 and 2016. Hailstones were collected following thunderstorm passages and were measured, weighed, and scanned. The system was successful in capturing 3D models of more than 40 hailstones. A full scan takes approximately 3 minutes to complete, and data can be captured at a resolution of 0.008 cm. It is believed this is the first time such a system has been used to produce 3D digital hailstone models. Analysis of the model data has shown that hailstones depart from spherical shapes as they increase in diameter, and that bulk density and strength show little correlation. While the dataset presented here is small, the use of 3D scanners in the field is a practical method to obtain detailed datasets on hailstone characteristics. In addition, these data could be used to 3D-print hailstones to explore their aerodynamics, to produce cavity molds for ice impact tests, and for modeling radar scattering properties of natural hailstone shapes.
Faster Arctic Sea Ice Retreat in CMIP5 than in CMIP3 due to Volcanoes
Authors: Rosenblum Erica , Eisenman Ian 
Published: October 2016

Abstract
The downward trend in Arctic sea ice extent is one of the most dramatic signals of climate change during recent decades. Comprehensive climate models have struggled to reproduce this trend, typically simulating a slower rate of sea ice retreat than has been observed. However, this bias has been widely noted to have decreased in models participating in phase 5 of the Coupled Model Intercomparison Project (CMIP5) compared with the previous generation of models (CMIP3). Here simulations are examined from both CMIP3 and CMIP5. It is found that simulated historical sea ice trends are influenced by volcanic forcing, which was included in all of the CMIP5 models but in only about half of the CMIP3 models. The volcanic forcing causes temporary simulated cooling in the 1980s and 1990s, which contributes to raising the simulated 1979–2013 global-mean surface temperature trends to values substantially larger than observed. It is shown that this warming bias is accompanied by an enhanced rate of Arctic sea ice retreat and hence a simulated sea ice trend that is closer to the observed value, which is consistent with previous findings of an approximately linear relationship between sea ice extent and global-mean surface temperature. Both generations of climate models are found to simulate Arctic sea ice that is substantially less sensitive to global warming than has been observed. The results imply that much of the difference in Arctic sea ice trends between CMIP3 and CMIP5 occurred because of the inclusion of volcanic forcing, rather than improved sea ice physics or model resolution.
Observed and Simulated Fingerprints of Multidecadal Climate Variability and Their Contributions to Periods of Global SST Stagnation
Authors: Barcikowska Monika J. , Knutson Thomas R. , Zhang Rong 
Published: October 2016

AbstractThis study investigates spatiotemporal features of multidecadal climate variability using observations and climate model simulation. Aside from a long-term warming trend, observational SST and atmospheric circulation records are dominated by an almost 65-yr variability component. Although its center of action is over the North Atlantic, it manifests also over the Pacific and Indian Oceans, suggesting a tropical interbasin teleconnection maintained through an atmospheric bridge. An analysis shows that simulated internal climate variability in a coupled climate model (CSIRO Mk3.6.0) reproduces the main spatiotemporal features of the observed component. Model-based multidecadal variability includes a coupled ocean–atmosphere teleconnection, established through a zonally oriented atmospheric overturning circulation between the tropical North Atlantic and eastern tropical Pacific. During the warm SST phase in the North Atlantic, increasing SSTs over the tropical North Atlantic strengthen locally ascending air motion and intensify subsidence and low-level divergence in the eastern tropical Pacific. This corresponds with a strengthening of trade winds and cooling in the tropical central Pacific. The model’s derived component substantially shapes its global climate variability and is tightly linked to multidecadal variability of the Atlantic meridional overturning circulation (AMOC). This suggests potential predictive utility and underscores the importance of correctly representing North Atlantic variability in simulations of global and regional climate. If the observations-based component of variability originates from internal climate processes, as found in the model, the recently observed (1970s–2000s) North Atlantic warming and eastern tropical Pacific cooling might presage an ongoing transition to a cold North Atlantic phase with possible implications for near-term global temperature evolution.