bluuebunny/crossref_metadata_2025_split huggingface dataset:
Some recent trends regarding Lake Baikal phytoplankton and zooplankton
Authors: Silow Eugene A. , Krashchuk Lyudmila S. , Onuchin Konstantin A. , Pislegina Helen V. , Rusanovskaya Olga O. , Shimaraeva Svetlana V. 
Published: April 2016

AbstractPlankton sampling data from the period of 1951–2010 for Lake Baikal were used in this study. Data have been collected at least monthly, generally every 7–10 days, in depth profiles from the surface to 250 m at a single offshore sampling site in the southern basin, where the water depth is approximately 800 m. Measurements of abiotic variables and phytoplankton sampling were made at discrete water depths. The data for the top 50 m of the lake were averaged for temperature and biological characteristics, noting this is the water layer in the lake exhibiting most of the lake's photosynthetic production, as well as containing the most plankton organisms. Zooplankton samples were collected with a closing plankton net and enumerated at the species level and also identified by age class. Under‐ice phytoplankton demonstrated the presence of some succession in spring phytoplankton, including a decreased proportion of endemic algal species. The open‐water complex of the alga species demonstrated that some non‐endemic species exhibited positive trends. The zooplankton analyses demonstrated a noticeable increasing trend for total zooplankton, the main zooplankton components being Epischura baicalensis, as well as increased Cladoceran numbers. These trends can be hypothetically explained by the following: (i) global climate change (although Lake Baikal also exhibits long‐term temperature oscillations); (ii) regional warming (due to construction of reservoir systems during the 1950s–1970s period); (iii) local chemical pollution attributable to increased industrial and agricultural activity in the lake's watershed and airshed basins; and/or (iv) the natural oscillating behaviour of the lake's plankton components.
Strategy and software for the statistical spatial analysis of 3D intracellular distributions
Authors: Biot Eric , Crowell Elizabeth , Burguet Jasmine , Höfte Herman , Vernhettes Samantha , Andrey Philippe 
Published: April 2016

SummaryThe localization of proteins in specific domains or compartments in the 3D cellular space is essential for many fundamental processes in eukaryotic cells. Deciphering spatial organization principles within cells is a challenging task, in particular because of the large morphological variations between individual cells. We present here an approach for normalizing variations in cell morphology and for statistically analyzing spatial distributions of intracellular compartments from collections of 3D images. The method relies on the processing and analysis of 3D geometrical models that are generated from image stacks and that are used to build representations at progressively increasing levels of integration, ultimately revealing statistical significant traits of spatial distributions. To make this methodology widely available to end‐users, we implemented our algorithmic pipeline into a user‐friendly, multi‐platform, and freely available software. To validate our approach, we generated 3D statistical maps of endomembrane compartments at subcellular resolution within an average epidermal root cell from collections of image stacks. This revealed unsuspected polar distribution patterns of organelles that were not detectable in individual images. By reversing the classical ‘measure‐then‐average’ paradigm, one major benefit of the proposed strategy is the production and display of statistical 3D representations of spatial organizations, thus fully preserving the spatial dimension of image data and at the same time allowing their integration over individual observations. The approach and software are generic and should be of general interest for experimental and modeling studies of spatial organizations at multiple scales (subcellular, cellular, tissular) in biological systems.
Using physiologically based models for clinical translation: predictive modelling, data interpretation or something in‐between?
Authors: Niederer Steven A. , Smith Nic P. 
Published: April 2016

AbstractHeart disease continues to be a significant clinical problem in Western society. Predictive models and simulations that integrate physiological understanding with patient information derived from clinical data have huge potential to contribute to improving our understanding of both the progression and treatment of heart disease. In particular they provide the potential to improve patient selection and optimisation of cardiovascular interventions across a range of pathologies. Currently a significant proportion of this potential is still to be realised. In this paper we discuss the opportunities and challenges associated with this realisation. Reviewing the successful elements of model translation for biophysically based models and the emerging supporting technologies, we propose three distinct modes of clinical translation. Finally we outline the challenges ahead that will be fundamental to overcome if the ultimate goal of fully personalised clinical cardiac care is to be achieved.
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Population-level analysis of gut microbiome variation
Authors: Falony Gwen , Joossens Marie , Vieira-Silva Sara , Wang Jun , Darzi Youssef , Faust Karoline , Kurilshikov Alexander , Bonder Marc Jan , Valles-Colomer Mireia , Vandeputte Doris , Tito Raul Y. , Chaffron Samuel , Rymenans Leen , Verspecht Chloë , De Sutter Lise , Lima-Mendez Gipsi , D’hoe Kevin , Jonckheere Karl , Homola Daniel , Garcia Roberto , Tigchelaar Ettje F. , Eeckhaudt Linda , Fu Jingyuan , Henckaerts Liesbet , Zhernakova Alexandra , Wijmenga Cisca , Raes Jeroen 
Published: April 2016

“Normal” for the gut microbiotaFor the benefit of future clinical studies, it is critical to establish what constitutes a “normal” gut microbiome, if it exists at all. Through fecal samples and questionnaires, Falonyet al.and Zhernakovaet al.targeted general populations in Belgium and the Netherlands, respectively. Gut microbiota composition correlated with a range of factors including diet, use of medication, red blood cell counts, fecal chromogranin A, and stool consistency. The data give some hints for possible biomarkers of normal gut communities.Science, this issue pp.560and565
NSs Virulence Factor of Rift Valley Fever Virus Engages the F-Box Proteins FBXW11 and β-TRCP1 To Degrade the Antiviral Protein Kinase PKR
Authors: Kainulainen Markus , Lau Simone , Samuel Charles E. , Hornung Veit , Weber Friedemann 
Published: April 2016

ABSTRACT

Rift Valley fever virus (RVFV, family
Bunyaviridae
, genus
Phlebovirus
) is a relevant pathogen of both humans and livestock in Africa. The nonstructural protein NSs is a major virulence factor known to suppress the type I interferon (IFN) response by inhibiting host cell transcription and by proteasomal degradation of a major antiviral IFN effector, the translation-inhibiting protein kinase PKR. Here, we identified components of the modular SCF (Skp1, Cul1, F-box protein)-type E3 ubiquitin ligases as mediators of PKR destruction by NSs. Small interfering RNAs (siRNAs) against the conserved SCF subunit Skp1 protected PKR from NSs-mediated degradation. Consequently, RVFV replication was severely reduced in Skp1-depleted cells when PKR was present. SCF complexes have a variable F-box protein subunit that determines substrate specificity for ubiquitination. We performed an siRNA screen for all (about 70) human F-box proteins and found FBXW11 to be involved in PKR degradation. The partial stabilization of PKR by FBXW11 depletion upregulated PKR autophosphorylation and phosphorylation of the PKR substrate eIF2α and caused a shutoff of host cell protein synthesis in RVFV-infected cells. To maximally protect PKR from the action of NSs, knockdown of structurally and functionally related FBXW1 (also known as β-TRCP1), in addition to FBXW11 deletion, was necessary. Consequently, NSs was found to interact with both FBXW11 and β-TRCP1. Thus, NSs eliminates the antiviral kinase PKR by recruitment of SCF-type E3 ubiquitin ligases containing FBXW11 and β-TRCP1 as substrate recognition subunits. This antagonism of PKR by NSs is essential for efficient RVFV replication in mammalian cells.

IMPORTANCE
Rift Valley fever virus is a pathogen of humans and animals that has the potential to spread from Africa and the Arabian Peninsula to other regions. A major virulence mechanism is the proteasomal degradation of the antiviral kinase PKR by the viral protein NSs. Here, we demonstrate that NSs requires E3 ubiquitin ligase complexes of the SCF (Skp1, Cul1, F-box protein) type to destroy PKR. SCF-type complexes can engage variant ubiquitination substrate recognition subunits, and we found the F-box proteins FBXW11 and β-TRCP1 to be relevant for the action of NSs against PKR. Thus, we identified the host cell factors that are critically needed by Rift Valley fever virus to uphold its replication against the potent antiviral kinase PKR.
Calcium-Dependent Rubella Virus Fusion Occurs in Early Endosomes
Authors: Dubé Mathieu , Etienne Loïc , Fels Maximilian , Kielian Margaret 
Published: April 2016

ABSTRACT
The E1 membrane protein of rubella virus (RuV) is a class II membrane fusion protein structurally related to the fusion proteins of the alphaviruses, flaviviruses, and phleboviruses. Virus entry is mediated by a low pH-dependent fusion reaction through E1's insertion into the cell membrane and refolding to a stable homotrimer. Unlike the other described class II proteins, RuV E1 contains 2 fusion loops, which complex a metal ion between them by interactions with residues N88 and D136. Insertion of the E1 protein into the target membrane, fusion, and infection require calcium and are blocked by alanine substitution of N88 or D136. Here we addressed the requirements of E1 for calcium binding and the intracellular location of the calcium requirement during virus entry. Our results demonstrated that N88 and D136 are optimally configured to support RuV fusion and are strongly selected for during the virus life cycle. While E1 has some similarities with cellular proteins that bind calcium and anionic lipids, RuV binding to the membrane was independent of anionic lipids. Virus fusion occurred within early endosomes, and chelation of intracellular calcium showed that calcium within the early endosome was required for virus fusion and infection. Calcium triggered the reversible insertion of E1 into the target membrane at neutral pH, but E1 homotrimer formation and fusion required a low pH. Thus, RuV E1, unlike other known class II fusion proteins, has distinct triggers for membrane insertion and fusion protein refolding mediated, respectively, by endosomal calcium and low pH.

IMPORTANCE
Rubella virus causes a mild disease of childhood, but infection of pregnant women frequently results in miscarriage or severe birth defects. In spite of an effective vaccine, RuV disease remains a serious problem in many developing countries. RuV infection of host cells involves endocytic uptake and low pH-triggered membrane fusion and is unusual in its requirement for calcium binding by the membrane fusion protein. Here we addressed the mechanism of the calcium requirement and the required location of calcium during virus entry. Both calcium and low pH were essential during the virus fusion reaction, which was shown to occur in the early endosome compartment.
How information about the time requirements and legacy effects of treatments influence decision-making in patients with diabetes and hypertension
Authors: Laiteerapong Neda , Fairchild Paige C , Nathan Aviva G , Quinn Michael T , Huang Elbert S 
Published: April 2016

ObjectiveWhen deciding about diabetes treatments, patients are typically uninformed about how much time is required before (time requirements), or for how long treatments change outcomes (legacy effects). However, patients may be motivated to adopt treatments with time-related treatment information. We explored whether this information alters a patients' likelihood of starting medications.Research design and methodsWe conducted semistructured interviews with 60 adults with type 2 diabetes for <10 years and hypertension on oral medications. We measured change in likelihood of starting medications after receiving time requirement (diabetes, 10 years; hypertension, 3 years) and legacy effect (diabetes, 10 additional years; hypertension, none) information. Responses were analyzed for themes about time-related treatment information.ResultsAt baseline, 70% of participants reported being very likely to start a recommended medication. Nearly half (40%) were less likely to start a diabetes medication after being informed of time requirements; but after being informed of legacy effects, 32% reported being more likely. Fewer participants changed likelihoods of starting antihypertensives with time-related information. Many participants expressed that medications' benefits were important to them regardless of time-related information. Participants considered time requirements for diabetes medications too long and compared them to their life expectancy. Many participants were interested in legacy effects of diabetes medications because they looked forward to discontinuing medications, although some expressed doubt that benefits could persist after stopping medications.ConclusionsWhile prolonged time requirements may dissuade patients from adopting treatments, the promise of legacy effects may motivate patients to commit to diabetes treatments.
A Randomized Controlled Trial of Progressively Reduced Nicotine Content Cigarettes on Smoking Behaviors, Biomarkers of Exposure, and Subjective Ratings
Authors: Mercincavage Melissa , Souprountchouk Valentina , Tang Kathy Z. , Dumont Rachel L. , Wileyto E. Paul , Carmella Steven G. , Hecht Stephen S. , Strasser Andrew A. 
Published: April 2016

AbstractBackground: The U.S. FDA has the authority to reduce cigarette nicotine content if found to benefit public health. Reduced nicotine content (RNC) cigarette use does not appear to increase harm exposure, but studies have not rigorously assessed smoking behavior or used a comprehensive panel of biomarkers. This study examined the effects of progressively decreasing RNC cigarettes on smoking behaviors, biomarkers of exposure, and subjective ratings.Methods: One hundred and fifty-eight daily, non–treatment-seeking smokers participated in a 35-day randomized, unblinded, parallel study. After a 5-day baseline period, participants were randomly assigned to an experimental group (n = 80) that smoked progressively decreasing RNC cigarettes during three 10-day periods, or control group (n = 78) that smoked their own brand throughout the study.Results: Daily cigarette consumption significantly increased for the intermediate RNCs (P's &lt; 0.001) but approached baseline rate for the lowest RNC (P = 0.686); in contrast, puffing behavior significantly decreased at intermediate levels and increased for the lowest RNC (P's &lt; 0.001). Cotinine and NNAL significantly decreased by RNC period (P's ≤ 0.001–0.02), whereas CO boost initially increased (P's = 0.001–0.005). 1-HOP did not change by period (P = 0.109).Conclusions: Smoking behaviors changed by RNC period via CPD and puffing behavior. Biomarkers of exposure generally decreased with nicotine content.Impact: Findings suggest that RNC use does not ubiquitously reduce smoking behaviors or biomarkers, yet the lowest RNC level tested may reduce harm exposure. This emphasizes the importance of using multiple behavioral and biologic measures to address the impact of RNC cigarette smoking. Cancer Epidemiol Biomarkers Prev; 25(7); 1125–33. ©2016 AACR.
WRN Promoter CpG Island Hypermethylation Does Not Predict More Favorable Outcomes for Patients with Metastatic Colorectal Cancer Treated with Irinotecan-Based Therapy
Authors: Bosch Linda J.W. , Luo Yanxin , Lao Victoria V. , Snaebjornsson Petur , Trooskens Geert , Vlassenbroeck Ilse , Mongera Sandra , Tang Weiliang , Welcsh Piri , Herman James G. , Koopman Miriam , Nagtegaal Iris D. , Punt Cornelis J.A. , van Criekinge Wim , Meijer Gerrit A. , Monnat Raymond J. , Carvalho Beatriz , Grady William M. 
Published: April 2016

Abstract
Purpose: WRN promoter CpG island hypermethylation in colorectal cancer has been reported to increase sensitivity to irinotecan-based therapies. We aimed to characterize methylation of the WRN promoter, determine the effect of WRN promoter hypermethylation upon expression, and validate a previous report that WRN promoter hypermethylation predicts improved outcomes for patients with metastatic colorectal cancer (mCRC) treated with irinotecan-based therapy.
Experimental Design: WRN methylation status was assessed using methylation-specific PCR and bisulfite sequencing assays. WRN expression was determined using qRT-PCR and Western blotting. WRN methylation status was correlated with overall survival (OS) and progression-free survival (PFS) in 183 patients with mCRC. Among these patients, 90 received capecitabine monotherapy as first-line therapy, and 93 received capecitabine plus irinotecan (CAPIRI) therapy as part of the CAIRO phase III clinical trial.
Results: WRN mRNA and WRN protein expression levels were low in colorectal cancer cell lines and in primary colorectal cancer and were largely independent of WRN methylation status. Patients with methylated WRN colorectal cancer had a shorter OS compared with patients who had unmethylated WRN colorectal cancer (HR = 1.6; 95% confidence interval [CI], 1.2–2.2; P = 0.003). Patients with unmethylated WRN showed a significantly longer PFS when treated with CAPIRI compared with capecitabine alone (HR = 0.48; 95% CI, 0.32–0.70; P = 0.0001). In contrast, patients did not benefit from adding irinotecan to capecitabine when WRN was methylated (HR = 1.1; 95% CI, 0.69–1.77; P = 0.7).
Conclusions: WRN expression is largely independent of WRN promoter hypermethylation in colorectal cancer. Moreover, we could not validate the previous finding that WRN promoter hypermethylation predicts improved clinical outcomes of mCRC treated with irinotecan-based therapy and found instead the opposite result. Clin Cancer Res; 22(18); 4612–22. ©2016 AACR.
An expanded pharmacogenomics warfarin dosing table with utility in generalised dosing guidance
Authors: Shahabi Payman , Scheinfeldt Laura , Lynch Daniel , Schmidlen Tara , Perreault Sylvie , Keller Margaret , Kasper Rachel , Wawak Lisa , Jarvis Joseph , Gerry Norman , Gordon Erynn , Christman Michael , Dubé Marie-Pierre , Gharani Neda 
Published: April 2016

SummaryPharmacogenomics (PGx) guided warfarin dosing, using a comprehensive dosing algorithm, is expected to improve dose optimisation and lower the risk of adverse drug reactions. As a complementary tool, a simple genotype-dosing table, such as in the US Food and Drug Administration (FDA) Coumadin drug label, may be utilised for general risk assessment of likely over- or under-anticoagulation on a standard dose of warfarin. This tool may be used as part of the clinical decision support for the interpretation of genetic data, serving as a first step in the anticoagulation therapy decision making process. Here we used a publicly available warfarin dosing calculator (www.warfarindosing.org) to create an expanded gene-based warfarin dosing table, the CPMC-WD table that includes nine genetic variants in CYP2C9, VKORC1, and CYP4F2. Using two datasets, a European American cohort (EUA, n=73) and the Quebec Warfarin Cohort (QWC, n=769), we show that the CPMC-WD table more accurately predicts therapeutic dose than the FDA table (51 % vs 33 %, respectively, in the EUA, McNemar’s two-sided p=0.02; 52 % vs 37 % in the QWC, p<1×10−6). It also outperforms both the standard of care 5 mg/day dosing (51 % vs 34 % in the EUA, p=0.04; 52 % vs 31 % in the QWC, p<1×10−6) as well as a clinical-only algorithm (51 % vs 38 % in the EUA, trend p=0.11; 52 % vs 45 % in the QWC, p=0.003). This table offers a valuable update to the PGx dosing guideline in the drug label.Supplementary Material to this article is available at www.thrombosis-online.com.
Low Systolic Blood Pressure and Vascular Mortality Among More Than 1 Million Korean Adults
Authors: Yi Sang-Wook , Mok Yejin , Ohrr Heechoul , Yi Jee-Jeon , Yun Young Duk , Park Jihwan , Jee Sun Ha 
Published: April 2016

Background—
The association between low systolic blood pressure (SBP) and vascular disease is unclear, especially in nonclinical populations.

Methods and Results—
We studied 1 235 246 individuals who participated in routine medical examinations between 1992 and 1995. The hazard ratios (HRs) were adjusted for potential confounders. During 22.7 million person-years of follow-up, 34 816 individuals died of atherosclerotic vascular diseases. An increase in SBP was directly related to an increase in vascular mortality at SBP above ≈100 mmHg. The group with the lowest SBP (<90 mm Hg) had a higher HR for mortality from atherosclerotic vascular disease (HR, 1.53; 95% confidence interval, 1.15–2.03) in comparison with those with an SBP of 90 to 99 mm Hg. The HR associated with the lowest SBP was 2.54 (95% confidence interval, 1.51–4.29) for ischemic heart disease and 1.21 (95% confidence interval, 0.79–1.85) for stroke. Regarding stroke subtype, mortality from hemorrhagic stroke (HR per 10 mm Hg increase, 0.53; 95% confidence interval, 0.29–0.96), rather than mortality from ischemic stroke (HR per 10 mm Hg increase, 1.00; 95% confidence interval, 0.51–1.97), was inversely associated with SBP when SBP fell to <100 mm Hg. Even when excluding the first 5 years of follow-up, the HRs associated with the lowest SBP did not decrease. The inverse association between SBP and vascular mortality in the range <100 mm Hg tended to be apparent in people aged 60 to 95 years in comparison with individuals aged 30 to 59 years.

Conclusions—
J-curve associations exist between SBP and vascular mortality, which reach a nadir at ≈100 mm Hg. SBP of <90 mm Hg may portend death from vascular disease, particularly from ischemic heart disease.
Promoter methylation status of tumor suppressor genes and inhibition of expression of DNA methyltransferase 1 in non-small cell lung cancer
Authors: Liu Bangqing , Song Jianfei , Luan Jiaqiang , Sun Xiaolin , Bai Jian , Wang Haiyong , Li Angui , Zhang Lifei , Feng Xiaoyan , Du Zhenzong 
Published: April 2016

DNA methylation is an epigenetic DNA modification catalyzed by DNA methyltransferase 1 (DNMT1). The purpose of this study was to investigate DNMT1 gene and protein expression and the effects of methylation status on tumor suppressor genes in human non-small cell lung cancer (NSCLC) cell lines grown in vitro and in vivo. Human lung adenocarcinoma cell lines, A549 and H838, were grown in vitro and inoculated subcutaneously into nude mice to form tumors and were then treated with the DNA methylation inhibitor, 5-aza-2′-deoxycytidine, with and without treatment with the benzamide histone deacetylase inhibitor, entinostat (MS-275). DNMT1 protein expression was quantified by Western blot. Promoter methylation status of tumor suppressor genes ( RASSF1A, ASC, APC, MGMT, CDH13, DAPK, ECAD, P16, and GATA4) was evaluated by methylation-specific polymerase chain reaction. Methylation status of the tumor suppressor genes was regulated by the DNMT1 gene, with the decrease of DNMT1 expression following DNA methylation treatment. Demethylation of tumor suppressor genes ( APC, ASC, and RASSF1A) restored tumor growth in nude mice. The results of this study support a role for methylation of DNA as a potential epigenetic clinical biomarker of prognosis or response to therapy and for DNMT1 as a potential therapeutic target in NSCLC.