bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bispecific Antibodies Targeting Different Epitopes on the HIV-1 Envelope Exhibit Broad and Potent Neutralization
Authors: Asokan M. , Rudicell R. S. , Louder M. , McKee K. , O'Dell S. , Stewart-Jones G. , Wang K. , Xu L. , Chen X. , Choe M. , Chuang G. , Georgiev I. S. , Joyce M. G. , Kirys T. , Ko S. , Pegu A. , Shi W. , Todd J. P. , Yang Z. , Bailer R. T. , Rao S. , Kwong P. D. , Nabel G. J. , Mascola J. R. 
Published: October 2015

ABSTRACT

The potency and breadth of the recently isolated neutralizing human monoclonal antibodies to HIV-1 have stimulated interest in their use to prevent or to treat HIV-1 infection. Due to the antigenically diverse nature of the HIV-1 envelope (Env), no single antibody is highly active against all viral strains. While the physical combination of two broadly neutralizing antibodies (bNAbs) can improve coverage against the majority of viruses, the clinical-grade manufacturing and testing of two independent antibody products are time and resource intensive. In this study, we constructed bispecific immunoglobulins (IgGs) composed of independent antigen-binding fragments with a common Fc region. We developed four different bispecific IgG variants that included antibodies targeting four major sites of HIV-1 neutralization. We show that these bispecific IgGs display features of both antibody specificities and, in some cases, display improved coverage over the individual parental antibodies. All four bispecific IgGs neutralized 94% to 97% of antigenically diverse viruses in a panel of 206 HIV-1 strains. Among the bispecific IgGs tested, VRC07 × PG9-16 displayed the most favorable neutralization profile. It was superior in breadth to either of the individual antibodies, neutralizing 97% of viruses with a median 50% inhibitory concentration (IC
50
) of 0.055 μg/ml. This bispecific IgG also demonstrated
in vivo
pharmacokinetic parameters comparable to those of the parental bNAbs when administered to rhesus macaques. These results suggest that IgG-based bispecific antibodies are promising candidates for the prevention and treatment of HIV-1 infection in humans.

IMPORTANCE
To prevent or treat HIV-1 infection, antibodies must potently neutralize nearly all strains of HIV-1. Thus, the physical combination of two or more antibodies may be needed to broaden neutralization coverage and diminish the possibility of viral resistance. A bispecific antibody that has two different antibody binding arms could potentially display neutralization characteristics better than those of any single parental antibody. Here we show that bispecific antibodies contain the binding specificities of the two parental antibodies and that a single bispecific antibody can neutralize 97% of viral strains with a high overall potency. These findings support the use of bispecific antibodies for the prevention or treatment of HIV-1 infection.
Increased prevalence and rupture status of feeder vessel aneurysms in posterior fossa arteriovenous malformations
Authors: Orning Jennifer , Amin-Hanjani Sepideh , Hamade Youssef , Du Xinjian , Hage Ziad A , Aletich Victor , Charbel Fady , Alaraj Ali 
Published: October 2015

BackgroundPosterior fossa arteriovenous malformations (AVMs) are considered to have a higher risk of poor outcome, as are AVMs with associated aneurysms. We postulated that posterior fossa malformations may be more prone to associated feeder vessel aneurysms, and to aneurysmal source of hemorrhage.ObjectiveTo examine the prevalence and hemorrhagic risk of posterior fossa AVM-associated feeder vessel aneurysms.MethodsA retrospective review of AVMs was performed with attention paid to location and presence of aneurysms. The hemorrhage status and origin of the hemorrhage was also reviewed.Results571 AVMs were analyzed. Of 90 posterior fossa AVMs, 34 (37.8%) had aneurysms (85% feeder vessel, 9% intranidal, 15% with both). Of the 481 supratentorial AVMs, 126 (26.2%) harbored aneurysms (65% feeder vessel, 29% intranidal, 6% both). The overall incidence of feeder aneurysms was higher in posterior fossa AVMs, which were evident in 34.4% of infratentorial AVMs compared to 18.5% of supratentorial malformations (p<0.01). The presence of intranidal aneurysms was similar in both groups (9.2% vs 8.8%). Feeder artery aneurysms were much more likely to be the source of hemorrhage in posterior fossa AVMs than in supratentorial AVMs (30% vs 7.6%, p<0.01).ConclusionsPosterior fossa AVMs are more prone to developing associated aneurysms, specifically feeder vessel aneurysms. Feeder vessel aneurysms are more likely to be the source of hemorrhage in the posterior fossa. As such, they may be the most appropriate targets for initial and prompt control by embolization or surgery due to their elevated threat.
Dynamic Inventory and Pricing Policy in a Periodic-Review Inventory System with Finite Ordering Capacity and Price Adjustment Cost
Authors: Yang Baimei , Gao Chunyan , Liu Na , Xu Liang 
Published: October 2015

We consider a dynamic inventory control and pricing optimization problem in a periodic-review inventory system with price adjustment cost. Each order occurs with a fixed ordering cost; the ordering quantity is capacitated. We consider a sequential decision problem, where the firm first chooses the ordering quantity and then the sale price to maximize the expected total discounted profit over the sale horizon. We show that the optimal inventory control is partially characterized by as, s′, ppolicy in four regions, and the optimal pricing policy is dependent on the inventory level after the replenishment decision. We present some numerical examples to explore the effects of various parameters on the optimal pricing and replenishment policy.
A Composite Gene Expression Signature Optimizes Prediction of Colorectal Cancer Metastasis and Outcome
Authors: Schell Michael J. , Yang Mingli , Missiaglia Edoardo , Delorenzi Mauro , Soneson Charlotte , Yue Binglin , Nebozhyn Michael V. , Loboda Andrey , Bloom Gregory , Yeatman Timothy J. 
Published: October 2015

Abstract
Purpose: We previously found that an epithelial-to-mesenchymal transition (EMT)–based gene expression signature was highly correlated with the first principal component (PC1) of 326 colorectal cancer tumors and was prognostic. This study was designed to improve these signatures for better prediction of metastasis and outcome.
Experimental Design: A total of 468 colorectal cancer tumors including all stages (I–IV) and metastatic lesions were used to develop a new prognostic score (ΔPC1.EMT) by subtracting the EMT signature score from its correlated PC1 signature score. The score was validated on six other independent datasets with a total of 3,697 tumors.
Results: ΔPC1.EMT was found to be far more predictive of metastasis and outcome than its parent scores. It performed well in stages I to III, among microsatellite instability subtypes, and across multiple mutation-based subclasses, demonstrating a refined capacity to predict distant metastatic potential even in tumors with a “good” prognosis. For example, in the PETACC-3 clinical trial dataset, it predicted worse overall survival in an adjusted multivariable model for stage III patients (HR standardized by interquartile range [IQR] = 1.50; 95% confidence interval, 1.25–1.81; P = 0.000016, N = 644). The improved performance of ΔPC1.EMT was related to its propensity to identify epithelial-like subpopulations as well as mesenchymal-like subpopulations. Biologically, the signature was correlated positively with RAS signaling but negatively with mitochondrial metabolism. ΔPC1.EMT was a “best of assessed” prognostic score when compared with 10 other known prognostic signatures.
Conclusions: The study developed a prognostic signature score with a propensity to detect non-EMT features, including epithelial cancer stem cell–related properties, thereby improving its potential to predict metastasis and poorer outcome in stage I–III patients. Clin Cancer Res; 22(3); 734–45. ©2015 AACR.
A Phase II Trial of AZD6244 (Selumetinib, ARRY-142886), an Oral MEK1/2 Inhibitor, in Relapsed/Refractory Multiple Myeloma
Authors: Holkova Beata , Zingone Adriana , Kmieciak Maciej , Bose Prithviraj , Badros Ashraf Z. , Voorhees Peter M. , Baz Rachid , Korde Neha , Lin Hui-Yi , Chen Jin-Qiu , Herrmann Michelle , Xi Liqiang , Raffeld Mark , Zhao Xiuhua , Wan Wen , Tombes Mary Beth , Shrader Ellen , Weir-Wiggins Caryn , Sankala Heidi , Hogan Kevin T. , Doyle Austin , Annunziata Christina M. , Wellons Martha , Roberts John D. , Sullivan Daniel , Landgren Ola , Grant Steven 
Published: October 2015

Abstract
Purpose: AZD6244 is a MEK1/2 inhibitor with significant preclinical activity in multiple myeloma cells. This phase II study used a two-stage Simon design to determine the AZD6244 response rate in patients with relapsed or refractory multiple myeloma.
Experimental Design: AZD6244 (75 mg) was administered orally, twice a day, continuously for 28-day cycles. Response was evaluated after three cycles.
Results: Thirty-six patients received therapy. The median age was 65 years (range: 43–81) and the median number of prior therapies was 5 (range: 2–11). The most common grade 3 and 4 toxicities included anemia, neutropenia, thrombocytopenia, diarrhea, and fatigue. Three deaths occurred possibly related to AZD6244 (2 due to sepsis, 1 due to acute kidney injury). After AZD6244 discontinuation, three additional deaths occurred due to disease progression. The response rate (CR + PR) was 5.6% with a mean duration of response of 4.95 months and median progression-free survival time of 3.52 months. One patient had a very good partial response (VGPR), 1 patient had a partial response, 17 patients had stable disease, 13 patients had progressive disease, and 4 patients could not be assessed for response. Pharmacodynamic studies revealed variable effects on bone marrow CD138+ cell MEK1/2 and ERK1/2 phosphorylation. The best clinical response, a prolonged VGPR, occurred in a patient with an MMSET translocation.
Conclusions: Single-agent AZD6244 was tolerable and had minimal activity in this heavily pretreated population. Clin Cancer Res; 22(5); 1067–75. ©2015 AACR.
A Cross-Species Analysis in Pancreatic Neuroendocrine Tumors Reveals Molecular Subtypes with Distinctive Clinical, Metastatic, Developmental, and Metabolic Characteristics
Authors: Sadanandam Anguraj , Wullschleger Stephan , Lyssiotis Costas A. , Grötzinger Carsten , Barbi Stefano , Bersani Samantha , Körner Jan , Wafy Ismael , Mafficini Andrea , Lawlor Rita T. , Simbolo Michele , Asara John M. , Bläker Hendrik , Cantley Lewis C. , Wiedenmann Bertram , Scarpa Aldo , Hanahan Douglas 
Published: October 2015

Abstract
Seeking to assess the representative and instructive value of an engineered mouse model of pancreatic neuroendocrine tumors (PanNET) for its cognate human cancer, we profiled and compared mRNA and miRNA transcriptomes of tumors from both. Mouse PanNET tumors could be classified into two distinctive subtypes, well-differentiated islet/insulinoma tumors (IT) and poorly differentiated tumors associated with liver metastases, dubbed metastasis-like primary (MLP). Human PanNETs were independently classified into these same two subtypes, along with a third, specific gene mutation–enriched subtype. The MLP subtypes in human and mouse were similar to liver metastases in terms of miRNA and mRNA transcriptome profiles and signature genes. The human/mouse MLP subtypes also similarly expressed genes known to regulate early pancreas development, whereas the IT subtypes expressed genes characteristic of mature islet cells, suggesting different tumorigenesis pathways. In addition, these subtypes exhibit distinct metabolic profiles marked by differential pyruvate metabolism, substantiating the significance of their separate identities.
Significance: This study involves a comprehensive cross-species integrated analysis of multi-omics profiles and histology to stratify PanNETs into subtypes with distinctive characteristics. We provide support for the RIP1-TAG2 mouse model as representative of its cognate human cancer with prospects to better understand PanNET heterogeneity and consider future applications of personalized cancer therapy. Cancer Discov; 5(12); 1296–313. ©2015 AACR.
This article is highlighted in the In This Issue feature, p. 1225
The alternative complement pathway is longitudinally associated with adverse cardiovascular outcomes
Authors: Hertle Elisabeth , Arts Ilja C. W. , Kallen Carla J. H. van der , Feskens Edith J. M. , Schalkwijk Casper G. , Stehouwer Coen D. A. , Greevenbroek Marleen M. J. van 
Published: October 2015

SummaryThe alternative pathway of complement activation is highly reactive and can be activated spontaneously in the vasculature. Activation may contribute to vascular damage and development of cardiovascular disease (CVD). We aimed to investigate functional components of the alternative pathway in cardiovascular risk. We studied 573 individuals who were followed-up for seven years. At baseline, we measured the enhancer properdin; the rate-limiting protease factor D (FD); and a marker of systemic activation, Bb. Using generalised estimating equations, we investigated their longitudinal associations with cardiovascular events (CVE, N=89), CVD (N=159), low-grade inflammation (LGI), endothelial dysfunction (ED) and carotid intima-media thickness (cIMT). Furthermore, we investigated associations with incident CVE (N=39) and CVD (N=73) in 342 participants free of CVD at baseline. CVE included myocardial infarction, stroke, cardiac angioplasty and/or cardiac bypass. CVD additionally included ischaemia on an electrocardiogram and/or ankle-brachial index < 0.9. In adjusted analyses, properdin was positively associated with CVE (per 1SD, longitudinal OR=1.36 [1.07; 1.74], OR for incident CVE=1.53 [1.06; 2.20]), but not with CVD. Properdin was also positively associated with ED (β=0.13 [95 %CI 0.06; 0.20]), but not with LGI or cIMT. FD and Bb were positively associated with LGI (per 1SD, FD: β=0.21 [0.12; 0.29], Bb: β=0.14 [0.07; 0.21]), and ED (FD: β=0.20 [0.11; 0.29], Bb: β=0.10 [0.03; 0.18]), but not with cIMT, CVE or CVD. Taken together, this suggests that the alternative complement pathway contributes to processes of vascular damage, and that in particular a high potential to enhance alternative pathway activation may promote unfavourable cardiovascular outcomes in humans.Supplementary Material to this article is available online at www.thrombosis-online.com.
A Minimum Standard for Publishing Computational Results in the Weather and Climate Sciences
Authors: Irving Damien 
Published: October 2015

Abstract
Weather and climate science has undergone a computational revolution in recent decades, to the point where all modern research relies heavily on software and code. Despite this profound change in the research methods employed by weather and climate scientists, the reporting of computational results has changed very little in relevant academic journals. This lag has led to something of a reproducibility crisis, whereby it is impossible to replicate and verify most of today’s published computational results. While it is tempting to simply decry the slow response of journals and funding agencies in the face of this crisis, there are very few examples of reproducible weather and climate research upon which to base new communication standards. In an attempt to address this deficiency, this essay describes a procedure for reporting computational results that was employed in a recent Journal of Climate paper. The procedure was developed to be consistent with recommended computational best practices and seeks to minimize the time burden on authors, which has been identified as the most important barrier to publishing code. It should provide a starting point for weather and climate scientists looking to publish reproducible research, and it is proposed that journals could adopt the procedure as a minimum standard.
Reconciling Past and Future Rainfall Trends over East Africa
Authors: Rowell David P. , Booth Ben B. B. , Nicholson Sharon E. , Good Peter 
Published: October 2015

Abstract
The “long rains” season of East Africa has recently experienced a series of devastating droughts, whereas the majority of climate models predict increasing rainfall for the coming decades. This has been termed the East African climate paradox and has implications for developing viable adaptation policies. A logical framework is adopted that leads to six key hypotheses that could explain this paradox. The first hypothesis that the recent observed trend is due to poor quality data is promptly rejected. An initial judgment on the second hypothesis that the projected trend is founded on poor modeling is beyond the scope of a single study. Analysis of a natural variability hypothesis suggests this is unlikely to have been the dominant driver of recent droughts, although it may have contributed. The next two hypotheses explore whether the balance between competing forcings could be changing. Regarding the possibility that the past trend could be due to changing anthropogenic aerosol emissions, the results of sensitivity experiments are highly model dependent, but some show a significant impact on the patterns of tropical SST trends, aspects of which likely caused the recent long rains droughts. Further experiments suggest land-use changes are unlikely to have caused the recent droughts. The last hypothesis that the response to CO2 emissions is nonlinear explains no more than 10% of the contrast between recent and projected trends. In conclusion, it is recommended that research priorities now focus on providing a process-based expert judgment of the reliability of East Africa projections, improving the modeling of aerosol impacts on rainfall, and better understanding the relevant natural variability.
Energetics of Bottom Ekman Layers during Buoyancy Arrest
Authors: Umlauf Lars , Smyth William D. , Moum James N. 
Published: October 2015

AbstractTurbulent bottom Ekman layers are among the most important energy conversion sites in the ocean. Their energetics are notoriously complex, in particular near sloping topography, where the feedback between cross-slope Ekman transports, buoyancy forcing, and mixing affects the energy budget in ways that are not well understood. Here, the authors attempt to clarify the energy pathways and different routes to mixing, using a combined theoretical and modeling approach. The analysis is based on a newly developed energy flux diagram for turbulent Ekman layers near sloping topography that allows for an exact definition of the different energy reservoirs and energy pathways. Using a second-moment turbulence model, it is shown that mixing efficiencies increase for increasing slope angle and interior stratification, but do not exceed the threshold of 5% except for very steep slopes, where the canonical value of 20% may be reached. Available potential energy generated by cross-slope advection may equal up to 70% of the energy lost to dissipation for upwelling-favorable flow, and up to 40% for downwelling-favorable flow.
Impact of Coupling an Ocean Model to WRF Nor’easter Simulations
Authors: Nicholls Stephen D. , Decker Steven G. 
Published: October 2015

Abstract
The impact of ocean–atmosphere coupling and its possible seasonal dependence upon Weather Research and Forecasting (WRF) Model simulations of seven, wintertime cyclone events was investigated. Model simulations were identical aside from the degree of ocean model coupling (static SSTs, 1D mixed layer model, full-physics 3D ocean model). Both 1D and 3D ocean model coupling simulations show that SSTs following the passage of a nor’easter did tend to cool more strongly during the early season (October–December) and were more likely to warm late in the season (February–April). Model simulations produce SST differences of up to 1.14 K, but this change did not lead to significant changes in storm track (&lt;100 km), maximum 10-m winds (&lt;2 m s−1), or minimum sea level pressure (≤5 hPa). Simulated precipitation showed little sensitivity to model coupling, but all simulations did tend to overpredict precipitation extent (bias &gt; 1) and have low-to-moderate threat scores (0.31–0.59). Analysis of the storm environment and the overall simulation failed to reveal any statistically significant differences in model error attributable to ocean–atmosphere coupling. Despite this result, ocean model coupling can reduce dynamical field error at a single level by up to 20%, and this was slightly greater (1%–2%) with 3D ocean model coupling as compared to 1D ocean model coupling. Thus, while 3D ocean model coupling tended to generally produce more realistic simulations, its impact would likely be more profound for longer-term simulations.
Predicting Wind Power with Reforecasts
Authors: Dabernig Markus , Mayr Georg J. , Messner Jakob W. 
Published: October 2015

Abstract
Energy traders and decision-makers need accurate wind power forecasts. For this purpose, numerical weather predictions (NWPs) are often statistically postprocessed to correct systematic errors. This requires a dataset of past forecasts and observations that is often limited by frequent NWP model enhancements that change the statistical model properties. Reforecasts that recompute past forecasts with a recent model provide considerably longer datasets but usually have weaker setups than operational models. This study tests the reforecasts from the National Oceanic and Atmospheric Administration (NOAA) and the European Centre for Medium-Range Weather Forecasts (ECMWF) for wind power predictions. The NOAA reforecast clearly performs worse than the ECMWF reforecast, the operational ECMWF deterministic and ensemble forecasts, and a limited-area model of the Austrian weather service [Zentralanstalt für Meteorologie und Geodynamik (ZAMG)]. On the contrary, the ECMWF reforecast has, of all tested models, the smallest squared errors and one of the highest financial values in an energy market.
Tailoring a web-based weight maintenance intervention for Northern Plains American Indian public university students
Authors: Hemmingson Kaitlyn , Lucchesi Roxanne , Droke Elizabeth , Kattelmann Kendra K 
Published: October 2015

Objective: High levels of obesity-related health disparities are common among US American Indian (AI) populations. AI public university students often face unique challenges that may contribute to weight gain and related consequences. Few weight maintenance interventions have been developed that meet the needs of AI public university students. The goal of this study was to determine how to tailor Project Y.E.A.H. (Young Americans Eating and Active for Health), a web-delivered, weight maintenance tool developed for college students to make it culturally relevant for AI public university students. Methods: Three mini focus groups ( N = 15) and five in-depth interviews ( N = 11) were conducted with self-identified AI college students on the campus of South Dakota State University. Participants were recruited with assistance from the American Indian Education and Cultural Center and through campus publicity. Recorded sessions were transcribed and multistep coding was used to assess the aesthetic appeal of the website and determine variations of certain health-related factors. Results: AI public university students have specific and culturally influenced aesthetic, food and physical activity exposures and preferences. AI students may perceive unique stressors compared to non-AI students and practise cultural forms of stress relief. Conclusion: Specific and culturally relevant psychographic information regarding AI college student preferences is needed for the development of effective weight maintenance tools.