bluuebunny/crossref_metadata_2025_split huggingface dataset:
Viruses Infecting a Freshwater Filamentous Cyanobacterium (
Nostoc
sp.) Encode a Functional CRISPR Array and a Proteobacterial DNA Polymerase B
Authors: Chénard Caroline , Wirth Jennifer F. , Suttle Curtis A. 
Published: June 2016

ABSTRACT

Here we present the first genomic characterization of viruses infecting
Nostoc
, a genus of ecologically important cyanobacteria that are widespread in freshwater. Cyanophages A-1 and N-1 were isolated in the 1970s and infect
Nostoc
sp. strain PCC 7210 but remained genomically uncharacterized. Their 68,304- and 64,960-bp genomes are strikingly different from those of other sequenced cyanophages. Many putative genes that code for proteins with known functions are similar to those found in filamentous cyanobacteria, showing a long evolutionary history in their host. Cyanophage N-1 encodes a CRISPR array that is transcribed during infection and is similar to the DR5 family of CRISPRs commonly found in cyanobacteria. The presence of a host-related CRISPR array in a cyanophage suggests that the phage can transfer the CRISPR among related cyanobacteria and thereby provide resistance to infection with competing phages. Both viruses also encode a distinct DNA polymerase B that is closely related to those found in plasmids of
Cyanothece
sp. strain PCC 7424,
Nostoc
sp. strain PCC 7120, and
Anabaena variabilis
ATCC 29413. These polymerases form a distinct evolutionary group that is more closely related to DNA polymerases of proteobacteria than to those of other viruses. This suggests that the polymerase was acquired from a proteobacterium by an ancestral virus and transferred to the cyanobacterial plasmid. Many other open reading frames are similar to a prophage-like element in the genome of
Nostoc
sp. strain PCC 7524. The
Nostoc
cyanophages reveal a history of gene transfers between filamentous cyanobacteria and their viruses that have helped to forge the evolutionary trajectory of this previously unrecognized group of phages.

IMPORTANCE
Filamentous cyanobacteria belonging to the genus
Nostoc
are widespread and ecologically important in freshwater, yet little is known about the genomic content of their viruses. Here we report the first genomic analysis of cyanophages infecting filamentous freshwater cyanobacteria, revealing that their gene content is unlike that of other cyanophages. In addition to sharing many gene homologues with freshwater cyanobacteria, cyanophage N-1 encodes a CRISPR array and expresses it upon infection. Also, both viruses contain a DNA polymerase B-encoding gene with high similarity to genes found in proteobacterial plasmids of filamentous cyanobacteria. The observation that phages can acquire CRISPRs from their hosts suggests that phages can also move them among hosts, thereby conferring resistance to competing phages. The presence in these cyanophages of CRISPR and DNA polymerase B sequences, as well as a suite of other host-related genes, illustrates the long and complex evolutionary history of these viruses and their hosts.
Development and preliminary psychometric properties of the Care Experience Feedback Improvement Tool (CEFIT)
Authors: Beattie Michelle , Shepherd Ashley , Lauder William , Atherton Iain , Cowie Julie , Murphy Douglas J 
Published: June 2016

ObjectiveTo develop a structurally valid and reliable, yet brief measure of patient experience of hospital quality of care, the Care Experience Feedback Improvement Tool (CEFIT). Also, to examine aspects of utility of CEFIT.BackgroundMeasuring quality improvement at the clinical interface has become a necessary component of healthcare measurement and improvement plans, but the effectiveness of measuring such complexity is dependent on the purpose and utility of the instrument used.MethodsCEFIT was designed from a theoretical model, derived from the literature and a content validity index (CVI) procedure. A telephone population surveyed 802 eligible participants (healthcare experience within the previous 12 months) to complete CEFIT. Internal consistency reliability was tested using Cronbach's α. Principal component analysis was conducted to examine the factor structure and determine structural validity. Quality criteria were applied to judge aspects of utility.ResultsCVI found a statistically significant proportion of agreement between patient and practitioner experts for CEFIT construction. 802 eligible participants answered the CEFIT questions. Cronbach's α coefficient for internal consistency indicated high reliability (0.78). Interitem (question) total correlations (0.28–0.73) were used to establish the final instrument. Principal component analysis identified one factor accounting for 57.3% variance. Quality critique rated CEFIT as fair for content validity, excellent for structural validity, good for cost, poor for acceptability and good for educational impact.ConclusionsCEFIT offers a brief yet structurally sound measure of patient experience of quality of care. The briefness of the 5-item instrument arguably offers high utility in practice. Further studies are needed to explore the utility of CEFIT to provide a robust basis for feedback to local clinical teams and drive quality improvement in the provision of care experience for patients. Further development of aspects of utility is also required.
Who actually receives cell phone use while driving citations and how much are these laws enforced among states? A descriptive, cross-sectional study
Authors: Rudisill Toni M , Zhu Motao 
Published: June 2016

ObjectivesWhile numerous cell phone use while driving laws have been passed among states, little information exists regarding who gets cited for these traffic infractions and how much these laws are enforced at the state-level within the USA.DesignCross-sectional, descriptive study.Setting14 states and the District of Columbia.ParticipantsThose receiving cell phone use while driving citations within included states from 2007 to 2013.Primary outcomeDemographic characteristics of cited drivers were assessed. Rates of infractions per 100 000 licensed in-state drivers per year for various cell phone use while driving violations were calculated.ResultsDrivers were cited for hand-held use violations (n=2.5 million) more than texting (n=14 682) or young driver all cell phone bans (n=342). Among states that provided data for all traffic violations, cell phone use while driving citations comprised 1% of all written citations. Regardless of ban type, males (68.2%) were cited more frequently than females. Drivers 25–64 years of age (90.8%) were more likely to be cited for hand-held phone use. The average yearly rate of infractions per 100 000 licensed in-state drivers from 2010–2013 was 5.8 for texting bans, 2607 for hand-held bans, and 9954 for any traffic violation.ConclusionsAmong cited drivers, age and sex differences existed by the type of ban violated. State-level enforcement appeared sparse. Due to the potential serious consequences of cell phone use while driving in the USA, more enforcement and targeted public safety campaigns are likely needed.
Inter- and intra-genetic diversity in the Polish Konik horse: implications for the conservation program
Authors: Szwaczkowski Tomasz , Greguła-Kania Monika , Stachurska Anna , Borowska Alicja , Jaworski Zbigniew , Gruszecki Tomasz M. 
Published: June 2016

The main objective of the study was to determine the genetic diversity in the Polish Konik (PK) population in the context of a currently conducted conservation program. A total of 94 horses of 16 PK dam lines currently distinguished by breeders were considered. Pedigree analyses were carried out for the whole population of PK registered in the studbook. Basic molecular parameters were estimated. The average group linkage clustering method was used based on the Euclidean similarity measurements between the lines. The allele frequency of 17 microsatellites was used to determine Euclidean distances. Inbreeding coefficients were extracted from the additive relationship matrix. Moreover, some pedigree parameters were estimated. The observed heterozygosity ranged from 0.48 to 0.76. The expected heterozygosity estimated for the dam lines was higher. PIC values were higher than 0.6 in all the lines. Fis ranged from –0.19 to 0.28, whereas Fit and Fst varied between 0.12 and 0.41 and 0.12 and 0.29, respectively. Minor dissimilarity distances existed for some dam lines. The inbreeding level was 9.3%. The average number of discrete generation equivalents reached 6.85. The majority of the dam lines are not genetically differentiated. Hence, a revision of the breeding strategy seems to be necessary.
Effect of nitrogen rate and fertilizer nitrogen source on physiology, yield, grain quality, and nitrogen use efficiency in corn
Authors: Biswas Dilip K. , Ma Bao-Luo 
Published: June 2016

A two-year (2010–2011) field experiment was undertaken to examine the effect of nitrogen (N) rate (0, 100, 150, and 200 kg N ha−1) and N source (urea, calcium ammonium nitrate; ammonium sulphate) on canopy reflectance, chlorophyll pigments, photosynthesis, yield, grain quality, and N-use efficiency in corn. However, the physiological observations were made only in 2011. We found that stover biomass was unaffected by higher N rate beyond 150 kg N ha−1 in both years. Higher N rates did not provide a yield advantage as compared to 150 kg N ha−1 in 2010, but the highest grain yield was produced with 200 kg N ha−1 in 2011. The higher grain yield by N application was attributed to a greater kernel size in both years. Corn stover [N] was found to increase with increasing N rates in both years. Kernel [N] only responded to the high N rate in 2010. There was no change in the kernel density as affected by N rate in both years. An increased N addition resulted in a decrease in both N-uptake efficiency and agronomic-N use efficiency in both years. There was an inconsistent effect of N source on yield and N use efficiency indices in the corn over two years.
Ivermectin Induces Cytostatic Autophagy by Blocking the PAK1/Akt Axis in Breast Cancer
Authors: Dou Qianhui , Chen Hai-Ning , Wang Kui , Yuan Kefei , Lei Yunlong , Li Kai , Lan Jiang , Chen Yan , Huang Zhao , Xie Na , Zhang Lu , Xiang Rong , Nice Edouard C. , Wei Yuquan , Huang Canhua 
Published: June 2016

AbstractBreast cancer is the most common cancer among women worldwide, yet successful treatment remains a clinical challenge. Ivermectin, a broad-spectrum antiparasitic drug, has recently been characterized as a potential anticancer agent due to observed antitumor effects. However, the molecular mechanisms involved remain poorly understood. Here, we report a role for ivermectin in breast cancer suppression by activating cytostatic autophagy both in vitro and in vivo. Mechanistically, ivermectin-induced autophagy in breast cancer cells is associated with decreased P21-activated kinase 1 (PAK1) expression via the ubiquitination-mediated degradation pathway. The inhibition of PAK1 decreases the phosphorylation level of Akt, resulting in the blockade of the Akt/mTOR signaling pathway. In breast cancer xenografts, the ivermectin-induced cytostatic autophagy leads to suppression of tumor growth. Together, our results provide a molecular basis for the use of ivermectin to inhibit the proliferation of breast cancer cells and indicate that ivermectin is a potential option for the treatment of breast cancer. Cancer Res; 76(15); 4457–69. ©2016 AACR.
Genetic Disruption of the Multifunctional CD98/LAT1 Complex Demonstrates the Key Role of Essential Amino Acid Transport in the Control of mTORC1 and Tumor Growth
Authors: Cormerais Yann , Giuliano Sandy , LeFloch Renaud , Front Benoît , Durivault Jerome , Tambutté Eric , Massard Pierre-André , de la Ballina Laura Rodriguez , Endou Hitoshi , Wempe Michael F. , Palacin Manuel , Parks Scott K. , Pouyssegur Jacques 
Published: June 2016

Abstract
The CD98/LAT1 complex is overexpressed in aggressive human cancers and is thereby described as a potential therapeutic target. This complex promotes tumorigenesis with CD98 (4F2hc) engaging β-integrin signaling while LAT1 (SLC7A5) imports essential amino acids (EAA) and promotes mTORC1 activity. However, it is unclear as to which member of the heterodimer carries the most prevalent protumoral action. To answer this question, we explored the tumoral potential of each member by gene disruption of CD98, LAT1, or both and by inhibition of LAT1 with the selective inhibitor (JPH203) in six human cancer cell lines from colon, lung, and kidney. Each knockout respectively ablated 90% (CD98KO) and 100% (LAT1KO) of Na+-independent leucine transport activity. LAT1KO or JPH203-treated cells presented an amino acid stress response with ATF4, GCN2 activation, mTORC1 inhibition, and severe in vitro and in vivo tumor growth arrest. We show that this severe growth phenotype is independent of the level of expression of CD98 in the six tumor cell lines. Surprisingly, CD98KO cells with only 10% EAA transport activity displayed a normal growth phenotype, with mTORC1 activity and tumor growth rate undistinguishable from wild-type cells. However, CD98KO cells became extremely sensitive to inhibition or genetic disruption of LAT1 (CD98KO/LAT1KO). This finding demonstrates that the tumoral potential of CD98KO cells is due to residual LAT1 transport activity. Therefore, these findings clearly establish that LAT1 transport activity is the key growth-limiting step of the heterodimer and advocate the pharmacology development of LAT1 transporter inhibitors as a very promising anticancer target. Cancer Res; 76(15); 4481–92. ©2016 AACR.
Checkpoint Antibodies but not T Cell–Recruiting Diabodies Effectively Synergize with TIL-Inducing γ-Irradiation
Authors: Hettich Michael , Lahoti Jayashree , Prasad Shruthi , Niedermann Gabriele 
Published: June 2016

Abstract
T cell–recruiting bispecific antibodies (bsAb) show promise in hematologic malignancies and are also being evaluated in solid tumors. In this study, we investigated whether T cell–recruiting bsAbs synergize with hypofractionated tumor radiotherapy (hRT) and/or blockade of the programmed death-1 (PD-1) immune checkpoint, both of which can increase tumor-infiltrating lymphocyte (TIL) numbers. Unexpectedly, large melanomas treated with hRT plus bsAb (AC133×CD3) relapsed faster than those treated with hRT alone, accompanied by massive TIL apoptosis. This fast relapse was delayed by the further addition of anti-PD-1. Mechanistic investigations revealed restimulation-induced cell death mediated by BIM and FAS as an additional cause of bsAb-mediated TIL depletion. In contrast, the double combination of hRT and anti-PD-1 strongly increased TIL numbers, and even very large tumors were completely eradicated. Our study reveals the risk that CD3-engaging bsAbs can induce apoptotic TIL depletion followed by rapid tumor regrowth, reminiscent of tolerance induction by CD3 mAb-mediated T-cell depletion, warranting caution in their use for the treatment of solid tumors. Our findings also argue that combining radiotherapy and anti-PD-1 can be quite potent, including against very large tumors. Cancer Res; 76(16); 4673–83. ©2016 AACR.
HOXC10 Expression Supports the Development of Chemotherapy Resistance by Fine Tuning DNA Repair in Breast Cancer Cells
Authors: Sadik Helen , Korangath Preethi , Nguyen Nguyen K. , Gyorffy Balazs , Kumar Rakesh , Hedayati Mohammad , Teo Wei Wen , Park Sunju , Panday Hardik , Munoz Teresa Gonzalez , Menyhart Otilia , Shah Nilay , Pandita Raj K. , Chang Jenny C. , DeWeese Theodore , Chang Howard Y. , Pandita Tej K. , Sukumar Saraswati 
Published: June 2016

Abstract
Development of drug resistance is a major factor limiting the continued success of cancer chemotherapy. To overcome drug resistance, understanding the underlying mechanism(s) is essential. We found that HOXC10 is overexpressed in primary carcinomas of the breast, and even more significantly in distant metastasis arising after failed chemotherapy. High HOXC10 expression correlates with shorter recurrence-free and overall survival in patients with estrogen receptor–negative breast cancer undergoing chemotherapy. We found that HOXC10 promotes survival in cells treated with doxorubicin, paclitaxel, or carboplatin by suppressing apoptosis and upregulating NF-κB. Overexpressed HOXC10 increases S-phase–specific DNA damage repair by homologous recombination (HR) and checkpoint recovery in cells at three important phases. For double-strand break repair, HOXC10 recruits HR proteins at sites of DNA damage. It enhances resection and lastly, it resolves stalled replication forks, leading to initiation of DNA replication following DNA damage. We show that HOXC10 facilitates, but is not directly involved in DNA damage repair mediated by HR. HOXC10 achieves integration of these functions by binding to, and activating cyclin-dependent kinase, CDK7, which regulates transcription by phosphorylating the carboxy-terminal domain of RNA polymerase II. Consistent with these findings, inhibitors of CDK7 reverse HOXC10-mediated drug resistance in cultured cells. Blocking HOXC10 function, therefore, presents a promising new strategy to overcome chemotherapy resistance in breast cancer. Cancer Res; 76(15); 4443–56. ©2016 AACR.
Expression of CDK7, Cyclin H, and MAT1 Is Elevated in Breast Cancer and Is Prognostic in Estrogen Receptor–Positive Breast Cancer
Authors: Patel Hetal , Abduljabbar Rezvan , Lai Chun-Fui , Periyasamy Manikandan , Harrod Alison , Gemma Carolina , Steel Jennifer H. , Patel Naina , Busonero Claudia , Jerjees Dena , Remenyi Judit , Smith Sally , Gomm Jennifer J. , Magnani Luca , Győrffy Balázs , Jones Louise J. , Fuller-Pace Frances , Shousha Sami , Buluwela Laki , Rakha Emad A. , Ellis Ian O. , Coombes R. Charles , Ali Simak 
Published: June 2016

Abstract
Purpose: CDK-activating kinase (CAK) is required for the regulation of the cell cycle and is a trimeric complex consisting of cyclin-dependent kinase 7 (CDK7), Cyclin H, and the accessory protein, MAT1. CDK7 also plays a critical role in regulating transcription, primarily by phosphorylating RNA polymerase II, as well as transcription factors such as estrogen receptor-α (ER). Deregulation of cell cycle and transcriptional control are general features of tumor cells, highlighting the potential for the use of CDK7 inhibitors as novel cancer therapeutics.
Experimental Design: mRNA and protein expression of CDK7 and its essential cofactors cyclin H and MAT1 were evaluated in breast cancer samples to determine if their levels are altered in cancer. Immunohistochemical staining of &gt;900 breast cancers was used to determine the association with clinicopathologic features and patient outcome.
Results: We show that expressions of CDK7, cyclin H, and MAT1 are all closely linked at the mRNA and protein level, and their expression is elevated in breast cancer compared with the normal breast tissue. Intriguingly, CDK7 expression was inversely proportional to tumor grade and size, and outcome analysis showed an association between CAK levels and better outcome. Moreover, CDK7 expression was positively associated with ER expression and in particular with phosphorylation of ER at serine 118, a site important for ER transcriptional activity.
Conclusions: Expressions of components of the CAK complex, CDK7, MAT1, and Cyclin H are elevated in breast cancer and correlate with ER. Like ER, CDK7 expression is inversely proportional to poor prognostic factors and survival. Clin Cancer Res; 22(23); 5929–38. ©2016 AACR.
Molecular Pathways: Emergence of Protein Kinase CK2 (CSNK2) as a Potential Target to Inhibit Survival and DNA Damage Response and Repair Pathways in Cancer Cells
Authors: Rabalski Adam J. , Gyenis Laszlo , Litchfield David W. 
Published: June 2016

Abstract
Protein kinase CK2 (designated CSNK2) is a constitutively active protein kinase with a vast repertoire of putative substrates that has been implicated in several human cancers, including cancer of the breast, lung, colon, and prostate, as well as hematologic malignancies. On the basis of these observations, CSNK2 has emerged as a candidate for targeted therapy, with two CSNK2 inhibitors in ongoing clinical trials. CX-4945 is a bioavailable small-molecule ATP-competitive inhibitor targeting its active site, and CIGB-300 is a cell-permeable cyclic peptide that prevents phosphorylation of the E7 protein of HPV16 by CSNK2. In preclinical models, either of these inhibitors exhibit antitumor efficacy. Furthermore, in combinations with chemotherapeutics such as cisplatin or gemcitabine, either CX-4945 or CIGB-300 promote synergistic induction of apoptosis. While CSNK2 is a regulatory participant in many processes related to cancer, its potential to modulate caspase action may be particularly pertinent to its emergence as a therapeutic target. Because the substrate recognition motifs for CSNK2 and caspases are remarkably similar, CSNK2 can block the cleavage of many caspase substrates through the phosphorylation of sites adjacent to cleavage sites. Phosphoproteomic strategies have also revealed previously underappreciated roles for CSNK2 in the phosphorylation of several key constituents of DNA damage and DNA repair pathways. Going forward, applications of proteomic strategies to interrogate responses to CSNK2 inhibitors are expected to reveal signatures for CSNK2 inhibition and molecular insights to guide new strategies to interfere with its potential to inhibit caspase action or enhance the susceptibility of cancer cells to DNA damage. Clin Cancer Res; 22(12); 2840–7. ©2016 AACR.
Time Course and Factors Correlating With Ventricular Tachyarrhythmias After Introduction of Steroid Therapy in Cardiac Sarcoidosis
Authors: Segawa Masato , Fukuda Koji , Nakano Makoto , Kondo Masateru , Satake Hiroyuki , Hirano Michinori , Shimokawa Hiroaki 
Published: June 2016

Background—
The time course and factors correlating with ventricular tachyarrhythmias (VTs) after introduction of corticosteroid therapy in patients with cardiac sarcoidosis remain to be elucidated.

Methods and Results—

We examined 68 consecutive patients with cardiac sarcoidosis in the Tohoku University Hospital from October 1998 to September 2014 (age: 57±11 years old; male:female 18:50) and evaluated VTs after initiation of steroid therapy. VTs were defined as documented ventricular tachycardia or ventricular fibrillation lasting for more than 30 seconds or resulting in cardiovascular collapse, or appropriate implantable cardioverter defibrillator therapy. During a mean follow-up of 5.5 years, 20 out of 68 patients (29%) experienced VTs after initiation of corticosteroid therapy, especially in the first 12 months in 14 patients (70%). A multivariable analysis revealed that positive gallium scintigraphy had a significant correlation with VTs (hazard ratio, 11.33; 95% confidence interval, 3.22–39.92;
P
<0.001), in addition to reduced left ventricular ejection fraction (hazard ratio, 0.94; 95% confidence interval, 0.90–0.97;
P
=0.001). Furthermore, electrical storm was noted in 10 patients (14.7%), 8 within the first 12 months of treatment, whereas the recurrence of electric storm was relatively less.

Conclusions—
These results indicate that VTs and electric storm frequently occur in the first 12 months after initiation of corticosteroid therapy, presumably because of inflammatory conditions, and that the positive gallium scintigraphy is a significant and independent predictor of VTs. The present findings may be useful to further improve the management of VTs in patients with cardiac sarcoidosis.