bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanism of HIV-1 Neutralization by Antibodies Targeting a Membrane-Proximal Region of gp41
Authors: Chen Jia , Frey Gary , Peng Hanqin , Rits-Volloch Sophia , Garrity Jetta , Seaman Michael S. , Chen Bing 
Published: November 2013

ABSTRACT
Induction of broadly neutralizing antibodies (bNAbs) is an important goal for HIV-1 vaccine development. Two autoreactive bNAbs, 2F5 and 4E10, recognize a conserved region on the HIV-1 envelope glycoprotein gp41 adjacent to the viral membrane known as the membrane-proximal external region (MPER). They block viral infection by targeting a fusion-intermediate conformation of gp41, assisted by an additional interaction with the viral membrane. Another MPER-specific antibody, 10E8, has recently been reported to neutralize HIV-1 with potency and breadth much greater than those of 2F5 or 4E10, but it appeared not to bind phospholipids and might target the untriggered envelope spikes, raising the hope that the MPER could be harnessed for vaccine design without major immunological concerns. Here, we show by three independent approaches that 10E8 indeed binds lipid bilayers through two hydrophobic residues in its CDR H3 (third heavy-chain complementarity-determining region). Its weak affinity for membranes in general and preference for cholesterol-rich membranes may account for its great neutralization potency, as it is less likely than other MPER-specific antibodies to bind cellular membranes nonspecifically. 10E8 binds with high affinity to a construct mimicking the fusion intermediate of gp41 but fails to recognize the envelope trimers representing the untriggered conformation. Moreover, we can improve the potency of 4E10 without affecting its binding to gp41 by a modification of its lipid-interacting CDR H3. These results reveal a general mechanism of HIV-1 neutralization by MPER-specific antibodies that involves interactions with viral lipids.
Characterization of the Noncoding Regions of the 1918 Influenza A H1N1 Virus
Authors: Wang Ruixue , Taubenberger Jeffery K. 
Published: November 2013

ABSTRACTThe terminal noncoding region (NCR) sequences of the eight gene segments of the influenza A/Brevig Mission/1/1918 (H1N1) virus were determined by rapid amplification of cDNA ends (RACE). Chimeric viruses encoding the open reading frames of the 1918 virus but flanked by either the wild-type 1918 NCR sequences or the NCR sequences of two other H1N1 virus strains, A/WSN/1933 and A/New York/312/2001, were produced. No growth differences between the NCR variant 1918 influenza viruses were noted.
Feasibility, acceptability and outcomes at a 12-month follow-up of a novel community-based intervention to prevent type 2 diabetes in adults at high risk: mixed methods pilot study
Authors: Penn Linda , Ryan Vicky , White Martin 
Published: November 2013

Objectives and designLifestyle interventions can prevent type 2 diabetes (T2D) in adults with impaired glucose tolerance. In a mixed methods pilot study, we aimed to assess the feasibility, acceptability and outcomes at a 12-month follow-up of a behavioural intervention for adults at risk of T2D.ParticipantsAdults aged 45–65 years with a Finnish Diabetes Risk Score (FINDRISC) ≥11.SettingThe intervention was delivered in leisure and community settings in a local authority that ranks in the 10 most socioeconomically deprived in England.InterventionA 10-week supported programme to promote increased physical activity (PA), healthy eating and weight loss was delivered by fitness trainers as twice-weekly group PA or cookery sessions, each followed by behavioural counselling with support to 12 months.Outcome measuresWe assessed feasibility and acceptability of the intervention, and change in behavioural and health-related outcomes at 6 and 12 months.ResultsFrom 367 registers of interest, 218 participants were recruited to the programme with baseline mean (SD): age 53.6 (6) years, FINDRISC 13.9 (3.1), body mass index 33.5 (5.9) kg/m2, waist circumference 108.1 (13.7) cm, PA levels (self-report): daily total 49.1 (5.9) metabolic-equivalent (MET) h/day. Follow-up at 12 months was completed by 134 (61%) participants, with an estimated mean (95% CI) change from baseline in weight −5.7 (−7.8 to −2.8); −2.8 (−3.8 to −1.9) kg, waist circumference −7.2 (−9.2 to −5.2); −6.0 (−7.1 to −5.0) cm, and PA level 7.9 (5.8 to 10.1); 6.7 (5.2 to 8.2) MET h/day equivalent, for men and women, respectively (from covariance pattern mixed models). Participants reported an enjoyable, sociable and supportive intervention experience.ConclusionsParticipants’ views indicated a high level of intervention acceptability. High retention and positive outcomes at 12 months provide encouraging indications of the feasibility and potential effectiveness of the intervention. A definitive trial of this intervention is warranted.
Long-term prediction of major coronary or ischaemic stroke event in a low-incidence Southern European population: model development and evaluation of clinical utility
Authors: Veronesi Giovanni , Gianfagna Francesco , Chambless Lloyd E , Giampaoli Simona , Mancia Giuseppe , Cesana Giancarlo , Ferrario Marco M 
Published: November 2013

ObjectiveTo develop a long-term prediction model of first major cardiovascular event and to assess its clinical utility in a low-incidence European population.SettingFour independent population-based cohorts enrolled between 1986 and 1993 in Northern Italy.Participants and methodsN=5247 35-year-old to 69-year-old men and women free of cardiovascular disease at baseline. Absolute 20-year risk of first fatal or non-fatal coronary or ischaemic stroke event (monitoring trends and determinants in cardiovascular disease (MONICA) validated) was estimated from gender-specific Cox models.Main outcome measuresModel discrimination (area under the receiver operating characteristic (ROC)-curve, AUC). ‘High-risk’ subjects were identified based on several threshold values for the 20-year predicted risk. Clinical utility was defined in terms of fraction of missed events (events among those considered at low-risk) and unnecessary treatment (false:true positive ratio). A net benefit curve was also provided.ResultsKaplan-Meier 20-year risk was 16.1% in men (315 events) and 6.1% in women (123 events). Model discrimination (AUC=0.737 in men, 0.801 in women) did not change significantly as compared to 10-year prediction time interval. In men, with respect to risk stratification based on the number of risk factors, a 20% predicted risk cut-off would miss less events (36% vs 50%) and reduce unnecessary treatment (false:true positive ratio 2.2 vs 3.0); the net benefit was higher over the whole range of threshold values. Similar considerations hold for women.ConclusionsLong-term prediction has good discrimination ability and is clinically useful for risk stratification in primary prevention. A clinical utility analysis is recommended to identify the optimal stratification according to different public health goals.
Prevalence and characteristics in coding, classification and diagnosis of diabetes in primary care
Authors: Seidu Samuel , Davies Melanie J , Mostafa Samiul , de Lusignan Simon , Khunti Kamlesh 
Published: November 2013

Abstract

Introduction
Approximately 366 million people worldwide live with diabetes and this figure is expected to rise. Among the correct diagnosis, there will be errors in the diagnosis, classification and coding, resulting in adverse health and financial implications.

Aim
To determine the prevalence and characteristics of diagnostic errors in people with diabetes managed in primary care settings.

Methods
We conducted a cross-sectional study in nine general practices in Leicester, UK, from May to August 2011, using a validated electronic toolkit. Searches identified cases with potential errors which were manually checked for accuracy.

Results
There were 54 088 patients and 2434 (4.5%) diagnosed with diabetes. Out of 316 people identified with potential errors with the toolkit, 180 (57%) had confirmed errors after manually reviewing the records, resulting in an error prevalence of 7.4%. Correctly coded people on registers had significantly greater glycated haemoglobin (HbA1c) reductions. There were no significant differences between patients with and without errors in their HbA1C, body mass index, age and size of practice. There was also no significant association of the errors with pay-for-performance initiatives; however, those patients not on disease register had worse glycaemic control.

Conclusions
A high prevalence of diabetic diagnostic errors was confirmed using medication, biochemical and demographic data. Larger studies are needed to more accurately assess the scale of this problem. Automation of these processes might be possible, which would allow searches to be even more user friendly.
Ultrasound‐guided atlanto‐occipital puncture for cerebrospinal fluid analysis on the standing horse
Authors: Depecker M. , Bizon‐Mercier C. , Couroucé‐Malblanc A. 
Published: November 2013

The atlanto‐occipital site (AO) is convenient for retrieving an adequate volume and quality of cerebrospinal fluid (CSF) in the diagnosis of neurological disease in horses. However, general anaesthesia is not always possible for horses displaying severe neurological signs, or for economical reasons. The objectives of the present work were to determine the feasibility and safety of ultrasound‐guided CSF puncture at the AO site on the standing horse. Seven horses (six healthy and one mildly ataxic) were sedated with acepromazine (0.02 mg/kg bodyweight intravenously or 0.04 mg/kg bodyweight intramuscularly) and detomidine (0.01 mg/kg bodyweight intravenously), and placed in stocks or in a recovery stall with the head kept on a headstand. Puncture was performed by ultrasonographic guidance with a parasagittal technique, as previously described, using a 20 g, 3.5 inch spinal needle. In all horses, no adverse reaction was observed when crossing the dura mater and 20 ml of CSF was rapidly retrieved without any blood contamination. Ultrasound‐guided CSF puncture can be performed easily at the AO site on a healthy standing horse. Regarding the potential risk of this procedure, safety measures and close observation are essential. Further studies on a larger amount of ataxic horses are also required before considering this technique as an alternative option for CSF puncture.
Superior Antitumor Activity of a Novel Bispecific Antibody Cotargeting Human Epidermal Growth Factor Receptor 2 and Type I Insulin-like Growth Factor Receptor
Authors: Chen Chao , Zhang Yanyu , Zhang Yu , Li Jingjing , Tsao Sai Wah , Zhang Mei-Yun 
Published: November 2013

Abstract
The humanized anti-HER2 monoclonal antibody (mAb) trastuzumab (Herceptin; Genentech) effectively inhibits human epidermal growth factor receptor 2 (HER2)-positive breast tumors. However, many patients responding to treatment often develop resistance. Cross-talk between type I insulin–like growth factor receptor (IGF-IR) and HER2 and elevated IGF-IR signaling have been implicated in tumor cell resistance to trastuzumab therapy. Previously, we reported that the anti-IGF-IR mAb m590 inhibits proliferation and migration of breast cancer MCF-7 cells in vitro. Here, we generated a “knobs-into-holes” bispecific antibody (Bi-Ab) against HER2 and IGF-IR by engineering trastuzumab and m590. We compared the effects of Bi-Ab treatment in vitro and in SKOV-3 HER2- and IGF-IR–overexpressing cancer xenograft mouse model with those of m590 and trastuzumab treatment alone or in combination. Bi-Ab effectively inhibited proliferation of HER2- and IGF-IR–overexpressing ovarian cancer SKOV-3 cells in vitro by ablating receptor phosphorylation and downstream PI3K/Akt and mitogen-activated protein kinase signaling. Bi-Ab more effectively inhibited cancer growth in SKOV-3 HER2- and IGF-IR–overexpressing cancer xenograft mouse model than m590 and trastuzumab alone or in combination. Mice bearing SKOV-3 HER2- and IGF-IR–overexpressing xenografts showed extensive and sustainable tumor regression when treated with Bi-Ab. Our results suggest that Bi-Ab has superior antitumor activity compared with monospecific antibodies, and cotargeting HER2 and IGF-IR may be clinically beneficial in minimizing the acquired resistance to trastuzumab therapy. Mol Cancer Ther; 13(1); 90–100. ©2013 AACR.
Protein-Tyrosine Phosphatase H1 Increases Breast Cancer Sensitivity to Antiestrogens by Dephosphorylating Estrogen Receptor at Tyr537
Authors: Suresh Padmanaban S. , Ma Shao , Migliaccio Antimo , Chen Guan 
Published: November 2013

Abstract
Estrogen receptor α (ERα or ER) is the only target of breast cancer therapy using antiestrogens. However, about 50% of ER-expressing breast cancer is intrinsically refractory to the antihormone therapy and strategies to improve the therapeutic response are urgently needed. Dynamic ER phosphorylation and dephosphorylation play an important role in ER activity and antihormone response. Although more than 10 kinases participate in phosphorylating ER protein, phosphatases involved remain mostly unidentified. Here, we tested the hypothesis that the protein-tyrosine phosphatase H1 (PTPH1) may regulate ER tyrosine phosphorylation and thereby impact breast cancer antihormone sensitivity. Our results showed that PTPH1 dephosphorylates ER at Tyr537 in vitro and in breast cancer cells. Moreover, PTPH1 stimulates ER nuclear accumulation and increases breast cancer sensitivity to tamoxifen (TAM) and/or fulvestrant in cell culture and in a xenograft model. Further analysis revealed that PTPH1 depends on its catalytic activity to stimulate ER nuclear accumulation and to enhance breast cancer antihormone sensitivity. These studies thus identified PTPH1 as a novel ER phosphatase and further demonstrate a therapeutic potential of enhancing breast cancer sensitivity to antiestrogens through dephosphorylating ER by PTPH1. Mol Cancer Ther; 13(1); 230–8. ©2013 AACR.
Vitamin K antagonists in heart disease: Current status and perspectives (Section III)
Authors: Husted Steen , Wallentin Lars , Andreotti Felicita , Arnesen Harald , Bachmann Fedor , Baigent Colin , Huber Kurt , Jespersen Jørgen , Kristensen Steen Dalby , Lip Gregory Y. H. , Morais Joaõ , Rasmussen Lars Hvilsted , Siegbahn Agneta , Verheugt Freek W. A. , Weitz Jeffrey I. , Caterina Raffaele De 
Published: November 2013

SummaryOral anticoagulants are a mainstay of cardiovascular therapy, and for over 60 years vitamin K antagonists (VKAs) were the only available agents for long-term use. VKAs interfere with the cyclic inter-conversion of vitamin K and its 2,3 epoxide, thus inhibiting γ-carboxylation of glutamate residues at the amino-termini of vitamin K-dependent proteins, including the coagulation factors (F) II (prothrombin), VII, IX and X, as well as of the anticoagulant proteins C, S and Z. The overall effect of such interference is a dose-dependent anticoagulant effect, which has been therapeutically exploited in heart disease since the early 1950s. In this position paper, we review the mechanisms of action, pharmacological properties and side effects of VKAs, which are used in the management of cardiovascular diseases, including coronary heart disease (where their use is limited), stroke prevention in atrial fibrillation, heart valves and/or chronic heart failure. Using an evidence-based approach, we describe the results of completed clinical trials, highlight areas of uncertainty, and recommend therapeutic options for specific disorders. Although VKAs are being increasingly replaced in most patients with non-valvular atrial fibrillation by the new oral anticoagulants, which target either thrombin or FXa, the VKAs remain the agents of choice for patients with atrial fibrillation in the setting of rheumatic valvular disease and for those with mechanical heart valves.
High-Sensitivity Troponin I for Risk Assessment in Patients With Atrial Fibrillation
Authors: Hijazi Ziad , Siegbahn Agneta , Andersson Ulrika , Granger Christopher B. , Alexander John H. , Atar Dan , Gersh Bernard J. , Mohan Puneet , Harjola Veli-Pekka , Horowitz John , Husted Steen , Hylek Elaine M. , Lopes Renato D. , McMurray John J.V. , Wallentin Lars 
Published: November 2013

Background—
High-sensitivity troponin-I (hs-TnI) measurement improves risk assessment for cardiovascular events in many clinical settings, but the added value in atrial fibrillation patients has not been described.

Methods and Results—

At randomization, hs-TnI was analyzed in 14 821 atrial fibrillation patients in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial comparing apixaban with warfarin. The associations between hs-TnI concentrations and clinical outcomes were evaluated by using adjusted Cox analysis. The hs-TnI assay detected troponin (≥1.3 ng/L) in 98.5% patients, 50% had levels >5.4, 25% had levels >10.1, and 9.2% had levels ≥23 ng/L (the 99th percentile in healthy individuals). During a median of 1.9 years follow-up, annual rates of stroke or systemic embolism ranged from 0.76% in the lowest hs-TnI quartile to 2.26% in the highest quartile (>10.1 ng/L). In multivariable analysis, hs-TnI was significantly associated with stroke or systemic embolism, adjusted hazard ratio 1.98 (1.42–2.78),
P
=0.0007. hs-TnI was also significantly associated with cardiac death; annual rates ranged from 0.40% to 4.24%, hazard ratio 4.52 (3.05–6.70),
P
<0.0001, in the corresponding groups, and for major bleeding hazard ratio 1.44 (1.11–1.86),
P
=0.0250. Adding hs-TnI levels to the CHA
2
DS
2
VASc score improved c-statistics from 0.629 to 0.653 for stroke or systemic embolism, and from 0.591 to 0.731 for cardiac death. There were no significant interactions with study treatment.

Conclusions—

Troponin-I is detected in 98.5% and elevated in 9.2% of atrial fibrillation patients. The hs-TnI level is independently associated with a raised risk of stroke, cardiac death, and major bleeding and improves risk stratification beyond the CHA
2
DS
2
VASc score. The benefits of apixaban in comparison with warfarin are consistent regardless of hs-TnI levels.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00412984.
Comment on “Bias Correction, Quantile Mapping, and Downscaling: Revisiting the Inflation Issue”
Authors: Bürger Gerd 
Published: November 2013

Abstract
In a recent paper, Maraun describes the adverse effects of quantile mapping on downscaling. He argues that when large-scale GCM variables are rescaled directly to small-scale fields or even station data, genuine small-scale covariability is lost and replaced by uniform variability inherited from the larger scales. This leads to a misrepresentation mainly of areal means and long-term trends. This comment acknowledges the former point, although the argument is relatively old, but disagrees with the latter, showing that grid-size long-term trends can be different from local trends. Finally, because it is partly incorrectly addressed, some clarification is added regarding the inflation issue, stressing that neither randomization nor inflation is free of unverified assumptions.
Analysis of the Thermodynamic Properties of Developing and Nondeveloping Tropical Disturbances Using a Comprehensive Dropsonde Dataset
Authors: Zawislak Jonathan , Zipser Edward J. 
Published: November 2013

Abstract
A dropsonde dataset is analyzed to quantify the necessary thermodynamic conditions for tropical cyclogenesis by evaluating the properties that distinguish developing tropical disturbances from nondeveloping disturbances, and by describing the temporal evolution of the developing inner core. The dataset consists of 2204 dropsonde observations from 12 developing disturbances and 245 from four nondeveloping disturbances. These disturbances are the cases with the best pregenesis sampling from field programs between 2005 and 2010, and include those investigated by three coincident field programs during 2010: the NASA Genesis and Rapid Intensification Processes (GRIP) and NCAR/NSF Pre-Depression Investigation of Cloud Systems in the Tropics (PREDICT) experiments, as well as NOAA’s Intensity Forecast Experiment (IFEX). Composite analyses indicate clear differences between developing and nondeveloping disturbances: developing disturbances exhibit greater moisture and a higher humidity at midlevels (above 800 hPa) than nondeveloping, and while the developing inner core experiences some midlevel moistening and stabilization as genesis nears, nondeveloping disturbances become progressively drier and more convectively unstable. Developing disturbances also exhibit some important characteristics in their inner core within 2 days of genesis: the low to midtroposphere (below 500 hPa) approaches near-saturation, a mid- to upper-level warm temperature anomaly develops and progressively deepens toward the low levels, and a low-level (below 900 hPa) cool, dry anomaly develops and is removed by the day of genesis. Overall the results support one proposed pathway to tropical cyclone formation in which an initially stronger midlevel vortex, in a moist, humid environment, precedes primarily low-level intensification within a day of genesis.
CONUS-Wide Evaluation of National Weather Service Flash Flood Guidance Products
Authors: Clark Robert A. , Gourley Jonathan J. , Flamig Zachary L. , Hong Yang , Clark Edward 
Published: November 2013

Abstract
This study quantifies the skill of the National Weather Service’s (NWS) flash flood guidance (FFG) product. Generated by River Forecast Centers (RFCs) across the United States, local NWS Weather Forecast Offices compare estimated and forecast rainfall to FFG to monitor and assess flash flooding potential. A national flash flood observation database consisting of reports in the NWS publication Storm Data and U.S. Geological Survey (USGS) stream gauge measurements are used to determine the skill of FFG over a 4-yr period. FFG skill is calculated at several different precipitation-to-FFG ratios for both observation datasets. Although a ratio of 1.0 nominally indicates a potential flash flooding event, this study finds that FFG can be more skillful when ratios other than 1.0 are considered. When the entire continental United States is considered, the highest observed critical success index (CSI) with 1-h FFG is 0.20 for the USGS dataset, which should be considered a benchmark for future research that seeks to improve, modify, or replace the current FFG system. Regional benchmarks of FFG skill are also determined on an RFC-by-RFC basis. When evaluated against Storm Data reports, the regional skill of FFG ranges from 0.00 to 0.19. When evaluated against USGS stream gauge measurements, the regional skill of FFG ranges from 0.00 to 0.44.