bluuebunny/crossref_metadata_2025_split huggingface dataset:
Disruption of the Opal Stop Codon Attenuates Chikungunya Virus-Induced Arthritis and Pathology
Authors: Jones Jennifer E. , Long Kristin M. , Whitmore Alan C. , Sanders Wes , Thurlow Lance R. , Brown Julia A. , Morrison Clayton R. , Vincent Heather , Peck Kayla M. , Browning Christian , Moorman Nathaniel , Lim Jean K. , Heise Mark T. 
Published: November 2017

ABSTRACT

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus responsible for several significant outbreaks of debilitating acute and chronic arthritis and arthralgia over the past decade. These include a recent outbreak in the Caribbean islands and the Americas that caused more than 1 million cases of viral arthralgia. Despite the major impact of CHIKV on global health, viral determinants that promote CHIKV-induced disease are incompletely understood. Most CHIKV strains contain a conserved opal stop codon at the end of the viral nsP3 gene. However, CHIKV strains that encode an arginine codon in place of the opal stop codon have been described, and deep-sequencing analysis of a CHIKV isolate from the Caribbean identified both arginine and opal variants within this strain. Therefore, we hypothesized that the introduction of the arginine mutation in place of the opal termination codon may influence CHIKV virulence. We tested this by introducing the arginine mutation into a well-characterized infectious clone of a CHIKV strain from Sri Lanka and designated this virus Opal524R. This mutation did not impair viral replication kinetics
in vitro
or
in vivo
. Despite this, the Opal524R virus induced significantly less swelling, inflammation, and damage within the feet and ankles of infected mice. Further, we observed delayed induction of proinflammatory cytokines and chemokines, as well as reduced CD4
+
T cell and NK cell recruitment compared to those in the parental strain. Therefore, the opal termination codon plays an important role in CHIKV pathogenesis, independently of effects on viral replication.

IMPORTANCE
Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes significant outbreaks of viral arthralgia. Studies with CHIKV and other alphaviruses demonstrated that the opal termination codon within nsP3 is highly conserved. However, some strains of CHIKV and other alphaviruses contain mutations in the opal termination codon. These mutations alter the virulence of related alphaviruses in mammalian and mosquito hosts. Here, we report that a clinical isolate of a CHIKV strain from the recent outbreak in the Caribbean islands contains a mixture of viruses encoding either the opal termination codon or an arginine mutation. Mutating the opal stop codon to an arginine residue attenuates CHIKV-induced disease in a mouse model. Compared to infection with the opal-containing parental virus, infection with the arginine mutant causes limited swelling and inflammation, as well as dampened recruitment of immune mediators of pathology, including CD4
+
T cells and NK cells. We propose that the opal termination codon plays an essential role in the induction of severe CHIKV disease.
Microdiversity of an Abundant Terrestrial Bacterium Encompasses Extensive Variation in Ecologically Relevant Traits
Authors: Chase Alexander B. , Karaoz Ulas , Brodie Eoin L. , Gomez-Lunar Zulema , Martiny Adam C. , Martiny Jennifer B. H. 
Published: November 2017

ABSTRACT

Much genetic diversity within a bacterial community is likely obscured by microdiversity within operational taxonomic units (OTUs) defined by 16S rRNA gene sequences. However, it is unclear how variation within this microdiversity influences ecologically relevant traits. Here, we employ a multifaceted approach to investigate microdiversity within the dominant leaf litter bacterium,
Curtobacterium
, which comprises 7.8% of the bacterial community at a grassland site undergoing global change manipulations. We use cultured bacterial isolates to interpret metagenomic data, collected
in situ
over 2 years, together with lab-based physiological assays to determine the extent of trait variation within this abundant OTU. The response of
Curtobacterium
to seasonal variability and the global change manipulations, specifically an increase in relative abundance under decreased water availability, appeared to be conserved across six
Curtobacterium
lineages identified at this site. Genomic and physiological analyses in the lab revealed that degradation of abundant polymeric carbohydrates within leaf litter, cellulose and xylan, is nearly universal across the genus, which may contribute to its high abundance in grassland leaf litter. However, the degree of carbohydrate utilization and temperature preference for this degradation varied greatly among clades. Overall, we find that traits within
Curtobacterium
are conserved at different phylogenetic depths. We speculate that similar to bacteria in marine systems, diverse microbes within this taxon may be structured in distinct ecotypes that are key to understanding
Curtobacterium
abundance and distribution in the environment.

IMPORTANCE
Despite the plummeting costs of sequencing, characterizing the fine-scale genetic diversity of a microbial community—and interpreting its functional importance—remains a challenge. Indeed, most studies, particularly studies of soil, assess community composition at a broad genetic level by classifying diversity into taxa (OTUs) defined by 16S rRNA sequence similarity. However, these classifications potentially obscure variation in traits that result in fine-scale ecological differentiation among closely related strains. Here, we investigated “microdiversity” in a highly diverse and poorly characterized soil system (leaf litter in a southern Californian grassland). We focused on the most abundant bacterium,
Curtobacterium
, which by standard methods is grouped into only one OTU. We find that the degree of carbohydrate usage and temperature preference vary within the OTU, whereas its responses to changes in precipitation are relatively uniform. These results suggest that microdiversity may be key to understanding how soil bacterial diversity is linked to ecosystem functioning.
Retractable Compact Directed Complete Poset (Acts)
Authors: Ebrahimi M. Mehdi , Mahmoudi Mojgan , Yavari Mahdieh 
Published: November 2017

Taking domains in the one hand and actions of a semigroup (automaton) on the other, as two crucial notions in mathematics as well as in computer science, we consider the notion of compact directed complete poset (acts), and investigate the interesting notion of absolute retractness for such ordered structures. As monomorphisms and embeddings for domain acts are different notions, we study absolute retractness with respect to both the class of monomorphisms and that of embeddings for compact directed complete poset (acts). We characterize the absolutely retract compact dcpos as complete compact chains. Also, we give some examples of compact directed complete poset acts which are (ε-)absolutely retract (with respect to embeddings) and show that completeness is not a sufficient condition for (ε-)absolute retractness.
Type II Diabetes and Incidence of Estrogen Receptor Negative Breast Cancer in African American Women
Authors: Palmer Julie R. , Castro-Webb Nelsy , Bertrand Kimberly , Bethea Traci N. , Denis Gerald V. 
Published: November 2017

Abstract
White women with type II diabetes (T2D) have an estimated 20% increased risk of developing breast cancer. Little is known about associations by breast cancer subtype or among African American (AA) women, who are disproportionately affected by T2D and estrogen receptor negative (ER−) breast cancer. We assessed the relation of T2D to incidence of ER− and ER+ breast cancer in data from the Black Women's Health Study, a prospective cohort of AA women enrolled in 1995 and followed biennially. During 847,934 person-years of follow-up, there were 1,851 incident invasive breast cancers, including 914 ER+ and 468 ER− cases. Multivariable Cox proportional hazards models were used to compute HRs for breast cancer incidence associated with T2D relative to no T2D, controlling for body mass index (BMI) and other potential confounders. The HR for T2D relative to no T2D was 1.18 [95% confidence interval (CI) 1.00–1.40] for overall breast cancer incidence, with the increase accounted for by ER− cancer: HRs were 1.02 (95% CI, 0.80–1.31) for ER+ and 1.43 (95% CI, 1.03–2.00) for ER− cancer. The HR for T2D and ER− breast cancer was highest among nonobese women (1.92; 95% CI, 1.22–3.04). The findings suggest that AA women with T2D are at increased risk of developing ER− breast cancer and that poor metabolic health may be more important than obesity for this subtype. Given the high prevalence of T2D in AA women, the observed association could, in part, explain racial disparities in incidence of ER− breast cancer. Cancer Res; 77(22); 6462–9. ©2017 AACR.
Collagen Alignment as a Predictor of Recurrence after Ductal Carcinoma In Situ
Authors: Conklin Matthew W. , Gangnon Ronald E. , Sprague Brian L. , Van Gemert Lisa , Hampton John M. , Eliceiri Kevin W. , Bredfeldt Jeremy S. , Liu Yuming , Surachaicharn Nuntida , Newcomb Polly A. , Friedl Andreas , Keely Patricia J. , Trentham-Dietz Amy 
Published: November 2017

Abstract
Background: Collagen fibers surrounding breast ducts may influence breast cancer progression. Syndecan-1 interacts with constituents in the extracellular matrix, including collagen fibers, and may contribute to cancer cell migration. Thus, the orientation of collagen fibers surrounding ductal carcinoma in situ (DCIS) lesions and stromal syndecan-1 expression may predict recurrence.
Methods: We evaluated collagen fiber alignment and syndecan-1 expression in 227 women diagnosed with DCIS in 1995 to 2006 followed through 2014 (median, 14.5 years; range, 0.7–17.6). Stromal collagen alignment was evaluated from diagnostic tissue slides using second harmonic generation microscopy and fiber analysis software. Univariate analysis was conducted using χ2 tests and ANOVA. The association between collagen alignment z-scores, syndecan-1 staining intensity, and time to recurrence was evaluated using HRs and 95% confidence intervals (CIs).
Results: Greater fiber angles surrounding DCIS lesions, but not syndecan-1 staining intensity, were related to positive HER2 (P = 0.002) status, comedo necrosis (P = 0.03), and negative estrogen receptor (P = 0.002) and progesterone receptor (P = 0.02) status. Fiber angle distributions surrounding lesions included more angles closer to 90 degrees than normal ducts (P = 0.06). Collagen alignment z-scores for DCIS lesions were positively related to recurrence (HR = 1.25; 95% CI, 0.84–1.87 for an interquartile range increase in average fiber angles).
Conclusions: Although collagen alignment and stromal syndecan-1 expression did not predict recurrence, collagen fibers perpendicular to the duct perimeter were more frequent in DCIS lesions with features typical of poor prognosis.
Impact: Follow-up studies are warranted to examine whether additional features of the collagen matrix may more strongly predict patient outcomes. Cancer Epidemiol Biomarkers Prev; 27(2); 138–45. ©2017 AACR.
Targeted Delivery of STAT-3 Modulator to Breast Cancer Stem-Like Cells Downregulates a Series of Stemness Genes
Authors: Misra Santosh K. , De Arun , Pan Dipanjan 
Published: November 2017

Abstract
Cancer stem cells are known to be controlled by pathways that are dormant in normal adult cells, for example, PTEN, which is a negative regulator of transcription factor STAT3. STAT3 regulates genes that are involved in stem cell self-renewal and thus represents a novel therapeutic target of enormous clinical significance. Studies on breast cancer stem cells (BCSC) have been also significantly correlated with STATs. We describe here for the first time a novel strategy to selectively target CSCs and to induce downregulation of STAT3 downstream target genes reducing expression of series of “stem-ness genes” in treated tumors. In vitro and in vivo experiments were performed to evaluate functional activity with gene and protein expression studies. The results of the study indicate that this targeted delivery approach deactivates STAT3 causing a reduction of CD44+/CD24− CSC populations with aptly tracked gene and protein regulations of “stemness” characteristics. Mol Cancer Ther; 17(1); 119–29. ©2017 AACR.
Clinical Impact of Diabetes Mellitus on Outcomes After Transcatheter Aortic Valve Replacement
Authors: Abramowitz Yigal , Vemulapalli Sreekanth , Chakravarty Tarun , Li Zhuokai , Kapadia Samir , Holmes David , Matsouaka Roland A. , Wang Alice , Cheng Wen , Forrester James S. , Smalling Richard , Thourani Vinod , Mack Michael , Leon Martin , Makkar Raj R. 
Published: November 2017

Background—
Diabetes mellitus (DM) adversely affects morbidity and mortality for cardiovascular diseases and procedures. Data evaluating the outcomes of transcatheter aortic valve replacement (TAVR) in diabetic patients are limited by small sample size and contradictory results. We aimed to establish the magnitude of risk and the incremental influence of insulin dependency by examining short- and long-term adverse outcomes according to DM status and therapy in the world’s largest TAVR registry.

Methods and Results—

We analyzed data from the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry. In-hospital mortality, 30-day mortality, and 1-year mortality after TAVR in patients with and without DM were evaluated using multivariate modeling. Among 47 643 patients treated with TAVR from November 2011 through September 2015 at 394 US hospitals, there were 17 849 (37.5%) patients with DM. Overall, 6600 of the diabetic patients were insulin treated (IT). Thirty-day mortality was 5.0% in patients with DM (6.1% in IT DM and 4.4% in non-IT DM;
P
<0.001) versus 5.9% in patients without DM (
P
<0.001). Overall, 1-year mortality was 21.8% in patients with DM (24.8% in IT DM and 20.1% in non-IT DM;
P
<0.001) versus 21.2% in patients without DM (
P
=0.274). In a multivariable model, DM was associated with increased 1-year mortality (hazard ratio, 1.30; 95% confidence interval, 1.13–1.49;
P
<0.001). Subgroup multivariable analysis showed stronger mortality association in IT diabetics (hazard ratio, 1.57; 95% confidence interval, 1.28–1.91;
P
<0.001) than in non-IT diabetics (hazard ratio, 1.17; 95% confidence interval, 1.00–1.38;
P
=0.052).

Conclusions—
Our data establish the magnitude of short- and long-term risk conferred by DM and the incremental risk conferred by insulin dependency in the performance of TAVR.

Clinical Trial Registration—

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT01737528.
Value of Progression of Coronary Artery Calcification for Risk Prediction of Coronary and Cardiovascular Events
Authors: Lehmann Nils , Erbel Raimund , Mahabadi Amir A. , Rauwolf Michael , Möhlenkamp Stefan , Moebus Susanne , Kälsch Hagen , Budde Thomas , Schmermund Axel , Stang Andreas , Führer-Sakel Dagmar , Weimar Christian , Roggenbuck Ulla , Dragano Nico , Jöckel Karl-Heinz , Meinertz T. , Bode C. , de Feyter P.J. , Güntert B. , Gutzwiller F. , Heinen H. , Hess O. , Klein B. , Löwel H. , Reiser M. , Schmidt G. , Schwaiger M. , Steinmüller C. , Theorell T. , Willich S.N. , Bode C. , Berger K. , Figulla H.R. , Hamm C. , Hanrath P. , Köpcke W. , Ringelstein B. , Dichgans M. , Zeiher A. 
Published: November 2017

Background:
Computed tomography (CT) allows estimation of coronary artery calcium (CAC) progression. We evaluated several progression algorithms in our unselected, population-based cohort for risk prediction of coronary and cardiovascular events.

Methods:
In 3281 participants (45–74 years of age), free from cardiovascular disease until the second visit, risk factors, and CTs at baseline (b) and after a mean of 5.1 years (5y) were measured. Hard coronary and cardiovascular events, and total cardiovascular events including revascularization, as well, were recorded during a follow-up time of 7.8±2.2 years after the second CT. The added predictive value of 10 CAC progression algorithms on top of risk factors including baseline CAC was evaluated by using survival analysis, C-statistics, net reclassification improvement, and integrated discrimination index. A subgroup analysis of risk in CAC categories was performed.

Results:

We observed 85 (2.6%) hard coronary, 161 (4.9%) hard cardiovascular, and 241 (7.3%) total cardiovascular events. Absolute CAC progression was higher with versus without subsequent coronary events (median, 115 [Q1–Q3, 23–360] versus 8 [0–83],
P
<0.0001; similar for hard/total cardiovascular events). Some progression algorithms added to the predictive value of baseline CT and risk assessment in terms of C-statistic or integrated discrimination index, especially for total cardiovascular events. However, CAC progression did not improve models including CAC
5y
and 5-year risk factors. An excellent prognosis was found for 921 participants with double-zero CAC
b
=CAC
5y
=0 (10-year coronary and hard/total cardiovascular risk: 1.4%, 2.0%, and 2.8%), which was for participants with incident CAC 1.8%, 3.8%, and 6.6%, respectively. When CAC
b
progressed from 1 to 399 to CAC
5y
≥400, coronary and total cardiovascular risk were nearly 2-fold in comparison with subjects who remained below CAC
5y
=400. Participants with CAC
b
≥400 had high rates of hard coronary and hard/total cardiovascular events (10-year risk: 12.0%, 13.5%, and 30.9%, respectively).

Conclusions:
CAC progression is associated with coronary and cardiovascular event rates, but adds only weakly to risk prediction. What counts is the most recent CAC value and risk factor assessment. Therefore, a repeat scan >5 years after the first scan may be of additional value, except when a double-zero CT scan is present or when the subjects are already at high risk.
Transcatheter Interatrial Shunt Device for the Treatment of Heart Failure With Preserved Ejection Fraction (REDUCE LAP-HF I [Reduce Elevated Left Atrial Pressure in Patients With Heart Failure])
Authors: Feldman Ted , Mauri Laura , Kahwash Rami , Litwin Sheldon , Ricciardi Mark J. , van der Harst Pim , Penicka Martin , Fail Peter S. , Kaye David M. , Petrie Mark C. , Basuray Anupam , Hummel Scott L. , Forde-McLean Rhondalyn , Nielsen Christopher D. , Lilly Scott , Massaro Joseph M. , Burkhoff Daniel , Shah Sanjiv J. 
Published: November 2017

Background:
In nonrandomized, open-label studies, a transcatheter interatrial shunt device (IASD, Corvia Medical) was associated with lower pulmonary capillary wedge pressure (PCWP), fewer symptoms, and greater quality of life and exercise capacity in patients with heart failure (HF) and midrange or preserved ejection fraction (EF ≥40%). We conducted the first randomized sham-controlled trial to evaluate the IASD in HF with EF ≥40%.

Methods:
REDUCE LAP-HF I (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure) was a phase 2, randomized, parallel-group, blinded multicenter trial in patients with New York Heart Association class III or ambulatory class IV HF, EF ≥40%, exercise PCWP ≥25 mm Hg, and PCWP-right atrial pressure gradient ≥5 mm Hg. Participants were randomized (1:1) to the IASD versus a sham procedure (femoral venous access with intracardiac echocardiography but no IASD placement). The participants and investigators assessing the participants during follow-up were blinded to treatment assignment. The primary effectiveness end point was exercise PCWP at 1 month. The primary safety end point was major adverse cardiac, cerebrovascular, and renal events at 1 month. PCWP during exercise was compared between treatment groups using a mixed-effects repeated measures model analysis of covariance that included data from all available stages of exercise.

Results:

A total of 94 patients were enrolled, of whom 44 met inclusion/exclusion criteria and were randomized to the IASD (n=22) and control (n=22) groups. Mean age was 70±9 years, and 50% were female. At 1 month, the IASD resulted in a greater reduction in PCWP compared with sham control (
P
=0.028 accounting for all stages of exercise). Peak PCWP decreased by 3.5±6.4 mm Hg in the treatment group versus 0.5±5.0 mm Hg in the control group (
P
=0.14). There were no peri-procedural or 1-month major adverse cardiac, cerebrovascular, and renal events in the IASD group and 1 event (worsening renal function) in the control group (
P
=1.0).

Conclusions:
In patients with HF and EF ≥40%, IASD treatment reduces PCWP during exercise. Whether this mechanistic effect will translate into sustained improvements in symptoms and outcomes requires further evaluation.

Clinical Trial Registration:

URL:
https://clinicaltrials.gov
. Unique identifier: NCT02600234.
The Dead Sea Scrolls in Their Hellenistic Context
Authors: Hartog Pieter B. , Jokiranta Jutta 
Published: November 2017

Abstract
This introduction aims at situating the contributions of the Thematic Issue into wider debates on Hellenism and Hellenisation and changes taking place in scholarship. Essentialist notions of Hellenism are strongly rejected, but how then to study the Dead Sea Scrolls and the Qumran site during the Hellenistic period? Each contextualisation depends on the (comparative) material selected, and themes here vary from literary genres, textual practices, and forms of producing knowledge, to material culture, networks, and social organizations. All contributors see some embeddedness in ideas and practices attested elsewhere in the Hellenistic empires or taking place because of changes during the Hellenistic period. In this framework, similarities are overemphasized, but some differences are also suggested. Most importantly, the question of Hellenism is a question of relocating Jewish and Judaean evidence in the study of ancient history.
Temple Ideology and Hellenistic Private Associations
Authors: Eckhardt Benedikt 
Published: November 2017

Abstract
Soon after the discovery of 1QS, comparisons with private associations from the Hellenistic and Roman world were suggested. There are clearly some parallels in internal organization. However, scholars using this comparison to explain features of the yaḥad have rarely taken the environment that made associations in the Hellenistic world possible into account. By way of a comparison of attitudes towards temples, this article seeks to reintroduce the social context of private associations into the debate. While Hellenistic associations can be said to have developed temple ideologies not dissimilar to certain features of the yaḥad, the conditions, aims and implications of those respective ideologies were fundamentally different. This has obvious implications for understanding the social identity of members, and should caution against decontextualized comparisons.
Anxious Mobilities in Accra and Beyond
Authors: Toivanen Anna-Leena 
Published: November 2017

Abstract
In Aidoo’s Changes: A Love Story (1991), the characters are constantly on the move: tropes of mobility recur throughout the novel. Cars, hotels, business and leisure travel, modern technologies and the figure of what can be referred to as the Afropolitan avant la lettre play a pivotal role in embodying meanings that pertain to class, gender, globalization, and consumerism marking the postcolonial African condition, and give the novel an articulate contemporary character. This article adopts a wholesale understanding of mobility in order to explore the ways in which Aidoo’s characters employ different forms of mobility in their processes of self-fashioning as modern African subjects. The article draws attention to the anxiety that informs processes of self-fashioning among urban African elites, caught as they are between the tensions of the traditional and the modern.