bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Cluster of Four Homologous Small RNAs Modulates C
1
Metabolism and the Pyruvate Dehydrogenase Complex in Rhodobacter sphaeroides under Various Stress Conditions
Authors: Billenkamp Fabian , Peng Tao , Berghoff Bork A. , Klug Gabriele 
Published: March 2015

ABSTRACT

In bacteria, regulatory RNAs play an important role in the regulation and balancing of many cellular processes and stress responses. Among these regulatory RNAs,
trans
-encoded small RNAs (sRNAs) are of particular interest since one sRNA can lead to the regulation of multiple target mRNAs. In the purple bacterium
Rhodobacter sphaeroides
, several sRNAs are induced by oxidative stress. In this study, we focused on the functional characterization of four homologous sRNAs that are cotranscribed with the gene for the conserved hypothetical protein RSP_6037, a genetic arrangement described for only a few sRNAs until now. Each of the four sRNAs is characterized by two stem-loops that carry CCUCCUCCC motifs in their loops. They are induced under oxidative stress, as well as by various other stress conditions, and were therefore renamed here sRNAs CcsR1 to CcsR4 (CcsR1–4) for
c
onserved
C
CUCCUCCC motif
s
tress-induced
R
NAs 1 to 4. Increased CcsR1–4 expression decreases the expression of genes involved in C
1
metabolism or encoding components of the pyruvate dehydrogenase complex either directly by binding to their target mRNAs or indirectly. One of the CcsR1–4 target mRNAs encodes the transcriptional regulator FlhR, an activator of glutathione-dependent methanol/formaldehyde metabolism. Downregulation of this glutathione-dependent pathway increases the pool of glutathione, which helps to counteract oxidative stress. The FlhR-dependent downregulation of the pyruvate dehydrogenase complex reduces a primary target of reactive oxygen species and reduces aerobic electron transport, a main source of reactive oxygen species. Our findings reveal a previously unknown strategy used by bacteria to counteract oxidative stress.

IMPORTANCE
Phototrophic organisms have to cope with photo-oxidative stress due to the function of chlorophylls as photosensitizers for the formation of singlet oxygen. Our study assigns an important role in photo-oxidative stress resistance to a cluster of four homologous sRNAs in the anoxygenic phototrophic bacterium
Rhodobacter sphaeroides
. We reveal a function of these regulatory RNAs in the fine-tuning of C
1
metabolism. A model that relates oxidative stress defense to C
1
metabolism is presented.
Neisseria gonorrhoeae MutS Affects Pilin Antigenic Variation through Mismatch Correction and Not by
pilE
Guanine Quartet Binding
Authors: Rotman Ella , Seifert H. Steven 
Published: March 2015

ABSTRACT

Many pathogens use homologous recombination to vary surface antigens to avoid immune surveillance.
Neisseria gonorrhoeae
achieves this in part by changing the properties of its surface pili in a process called pilin antigenic variation (AV). Pilin AV occurs by high-frequency gene conversion reactions that transfer silent
pilS
sequences into the expressed
pilE
locus and requires the formation of an upstream guanine quartet (G4) DNA structure to initiate this process. The MutS and MutL proteins of the mismatch correction (MMC) system act to correct mismatches after replication and prevent homeologous (i.e., partially homologous) recombination, but MutS orthologs can also bind to G4 structures. A previous study showed that mutation of MutS resulted in a 3-fold increase in pilin AV, which could be due to the loss of MutS antirecombination properties or loss of G4 binding. We tested two site-directed separation-of-function MutS mutants that are both predicted to bind to G4s but are not able to perform MMC. Pilus phase variation assays and DNA sequence analysis of
pilE
variants produced in these mutants showed that all three
mutS
mutants and a
mutL
mutant had similar increased frequencies of pilin AV. Moreover, the
mutS
mutants all showed similar increased levels of pilin AV-dependent synthetic lethality. These results show that antirecombination by MMC is the reason for the effect that MutS has on pilin AV and is not due to
pilE
G4 binding by MutS.

IMPORTANCE
Neisseria gonorrhoeae
continually changes its outer surface proteins to avoid recognition by the immune system.
N. gonorrhoeae
alters the antigenicity of the pilus by directed recombination between partially homologous pilin copies in a process that requires a guanine quartet (G4) structure. The MutS protein of the mismatch correction (MMC) system prevents recombination between partially homologous sequences and can also bind to G4s. We confirmed that loss of MMC increases the frequency of pilin antigenic variation and that two MutS mutants that are predicted to separate the two different functions of MutS inhibit pilin variation similarly to a complete-loss-of-function mutant, suggesting that interaction of MutS with the G4 structure is not a major factor in this process.
Mutations in Pneumococcal
cpsE
Generated via
In Vitro
Serial Passaging Reveal a Potential Mechanism of Reduced Encapsulation Utilized by a Conjunctival Isolate
Authors: Shainheit Mara G. , Valentino Michael D. , Gilmore Michael S. , Camilli Andrew 
Published: March 2015

ABSTRACT

The polysaccharide capsule of
Streptococcus pneumoniae
is required for nasopharyngeal colonization and for invasive disease in the lungs, blood, and meninges. In contrast, the vast majority of conjunctival isolates are acapsular. The first serotype-specific gene in the capsule operon,
cpsE
, encodes the initiating glycosyltransferase and is one of the few serotype-specific genes that can tolerate null mutations. This report characterizes a spontaneously arising TIGR4 mutant exhibiting a reduced capsule, caused by a 6-nucleotide duplication in
cpsE
which results in duplication of Ala and Ile at positions 45 and 46. This strain (AI45dup) possessed more exposed phosphorylcholine and was hypersusceptible to C3 complement deposition compared to the wild type. Accordingly, the mutant was significantly better at forming abiotic biofilms and binding epithelial cells
in vitro
but was avirulent in a sepsis model.
In vitro
serial passaging of the wild-type strain failed to reproduce the AI45dup mutation but instead led to a variety of mutants with reduced capsule harboring single nucleotide polymorphisms (SNPs) in
cpsE
. A single passage in the sepsis model after high-dose inoculation readily yielded revertants of AI45dup with restored wild-type capsule level, but the majority of SNP alleles of
cpsE
could not revert, suppress, or bypass. Analysis of
cpsE
in conjunctival isolates revealed a strain with a single missense mutation at amino acid position 377, which was responsible for reduced encapsulation. This study supports the hypothesis that spontaneous, nonreverting mutations in
cpsE
serve as a form of adaptive mutation by providing a selective advantage to
S. pneumoniae
in niches where expression of capsule is detrimental.

IMPORTANCE
While the capsule of
Streptococcus pneumoniae
is required for colonization and invasive disease, most conjunctival isolates are acapsular by virtue of deletion of the entire capsular operon. We show that spontaneous acapsular mutants isolated
in vitro
harbor mostly nonrevertible single nucleotide polymorphism (SNP) null mutations in
cpsE
, encoding the initiating glycosyltransferase. From a small collection of acapsular conjunctival isolates, we identified one strain with a complete capsular operon but containing a SNP in
cpsE
that we show is responsible for the acapsular phenotype. We propose that acapsular conjunctival isolates may arise initially from such nonreverting SNP null mutations in
cpsE
, which can be followed later by deletion of portions or all of the
cps
operon.
Prevalence, risk factors and associations of primary Raynaud's phenomenon: systematic review and meta-analysis of observational studies
Authors: Garner Rozeena , Kumari Rakesh , Lanyon Peter , Doherty Michael , Zhang Weiya 
Published: March 2015

ObjectiveTo systematically review the literature with regard to the prevalence, incidence, risk factors and associations of primary Raynaud's phenomenon (PRP).MethodA systematic review of the literature of observational studies for PRP was undertaken using five electronic databases. Any studies reporting prevalence, incidence and risk factors of PRP were collected. Relative risk or OR and 95% CI were extracted or calculated to present the association between risk factors and PRP. Random effects model was used to pool the results.Results33 articles assessing a total of 33 733 participants were included in this analysis (2 cohort, 17 cross-sectional and 14 case–control studies). The pooled prevalence of PRP was 4.85% (95% CI 2.08% to 8.71%) in the general population. The pooled annual incidence of PRP was 0.25% (95% CI 0.19% to 0.32%). Risk factors and associations for PRP included female gender (OR=1.65, 95% CI 1.42 to 1.91), family history (OR=16.6, 95% CI 7.44 to 36.8), smoking (OR=1.27, 95% CI 1.06 to 1.53), manual occupation (OR=2.66 95% CI 1.73 to 4.08), migraine (OR=4.02, 95% CI 2.62 to 6.17), cardiovascular disease (OR=1.69, 95% CI 1.22 to 2.34) and marital status (married, OR=0.60, 95% CI 0.43 to 0.83). The definition of PRP varied considerably between studies.ConclusionsThis is the first systematic review of the prevalence, incidence, risk factors and associations of PRP. Further study using uniform strict criteria for the condition is required to confirm these findings, particularly the possible association with cardiovascular disease.
Laboratory characterization and pilot site tests of residual sludge from dimension stones for civil and environmental applications
Authors: Dino Giovanna Antonella , Lasagna Manuela , Clemente Paolo , De Luca Domenico Antonio 
Published: March 2015

Abstract
Residual sludge from dimension-stone working plants, both from gangue saws with abrasive shot and frame saws, is classified as waste and presents a number of problems for the stone industry. These problems include a fine size distribution, heavy metals and total petroleum hydrocarbon (TPH) content, all of which impede recovery and reuse. Residual sludge, management of which is administered in accordance with the Italian Legislative Decree 152/06, can be used in waste form for environmental restoration or for cement plants. However, it is also possible that sludge applications could go beyond these limited uses with incorporation of systematic treatment for the production of secondary raw materials (SRM), for example, filler, or for ‘new products’, for example, artificial loam. Such new products or SRM have to be certified not only on the basis of their technical and physical characteristics but also by means of appropriate chemical analyses to guarantee that the products are not contaminated.

This paper outlines the results from laboratory and
in situ
characterization of residual sludge. In particular, three potential applications of sludge either by itself or mixed with other materials were evaluated: landfill waterproofing material, filler material for civil works and artificial soil for land rehabilitation.
Early Life Body Fatness and Risk of Colorectal Cancer in U.S. Women and Men—Results from Two Large Cohort Studies
Authors: Zhang Xuehong , Wu Kana , Giovannucci Edward L. , Ma Jing , Colditz Graham A. , Fuchs Charles S. , Willett Walter C. , Stampfer Meir J. , Nimptsch Katharina , Ogino Shuji , Wei Esther K. 
Published: March 2015

Abstract
Background: The association between body fatness before adulthood and later risk of colorectal cancer remains unclear. We hypothesized that, independent of adult body fatness, early life body fatness would be associated with a higher risk of developing colorectal cancer.
Methods: We assessed body fatness during childhood and adolescence using a validated 9-level somatotype and inquired body weight in young adulthood in the Nurses' Health Study and Health Professionals Follow-up Study. We used the Cox proportional hazard regression modeling to estimate relative risks [RR, 95% confidence intervals (CI)] adjusting for adult body mass index (BMI) and other known colorectal cancer risk factors.
Results: We identified 2,100 incident colorectal cancer cases (1,292 in women and 808 in men) during 22 years of follow-up. Among women, the RR (95% CI) for childhood body fatness of level 5 or higher versus level 1 was 1.28 (1.04–1.58; Ptrend = 0.08) and for adolescent body fatness, it was 1.27 (1.01–1.60; Ptrend = 0.23). The corresponding RRs for men were 1.04 (0.82–1.31; Ptrend = 0.48) and 0.98 (0.75–1.27; Ptrend = 0.20), respectively. Results were generally similar across anatomic subsites within the colorectum. In addition, the RRs comparing BMI categories ≥27.5 to &lt;19 kg/m2 were 1.44 (1.06–1.95, at age 18; Ptrend = 0.009) for women and 1.18 (0.84–1.65, at age 21; Ptrend = 0.57) for men.
Conclusion: Increased body fatness in early life, independent of adult obesity, might be a risk factor for colorectal cancer in women, but we observed a weaker association in men.
Impact: Our findings support the growing evidence that early life body fatness affects the risk of colorectal cancer many decades later. Cancer Epidemiol Biomarkers Prev; 24(4); 690–7. ©2015 AACR.
Significance of Circulating Tumor Cells in Metastatic Triple-Negative Breast Cancer Patients within a Randomized, Phase II Trial: TBCRC 019
Authors: Paoletti Costanza , Li Yufeng , Muñiz Maria C. , Kidwell Kelley M. , Aung Kimberly , Thomas Dafydd G. , Brown Martha E. , Abramson Vandana G. , Irvin William J. , Lin Nancy U. , Liu Minetta C. , Nanda Rita , Nangia Julie R. , Storniolo Anna M. , Traina Tiffany A. , Vaklavas Christos , Van Poznak Catherine H. , Wolff Antonio C. , Forero-Torres Andres , Hayes Daniel F. 
Published: March 2015

Abstract
Purpose: Circulating tumor cells (CTC) are prognostic in metastatic breast cancer (MBC). We tested whether EpCAM-based capture system (CellSearch) is effective in patients with triple-negative (TN) MBC, and whether CTC apoptosis and clustering enhances the prognostic role of CTC.
Experimental Design: CTC enumeration and apoptosis were determined using the CXC CellSearch kit at baseline and days 15 and 29 in blood drawn from TN MBC patients who participated in a prospective randomized phase II trial of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) with or without tigatuzumab. Association between levels of CTC and patient outcomes was assessed using logistic regression, Kaplan–Meier curves, and Cox proportional hazards modeling.
Results: Nineteen of 52 (36.5%), 14 of 52 (26.9%), and 13 of 49 (26.5%) patients who were evaluable had elevated CTC (≥5 CTC/7.5 mL whole blood) at baseline and at days 15 and 29, respectively. Patients with elevated versus not elevated CTC at each time point had worse progression-free survival (PFS; P = 0.005, 0.0003, 0.0002, respectively). The odds of clinical benefit response for those who had elevated versus low CTC at baseline and days 15 and 29 were 0.25 (95% CI: 0.08–0.84; P = 0.024), 0.19 (95% CI: 0.05–0.17; P = 0.014), and 0.06 (95% CI: 0.01–0.33; P = 0.001), respectively. There was no apparent prognostic effect comparing CTC apoptosis versus non-apoptosis. Presence of CTC cluster at day 15 and day 29 was associated with shorter PFS.
Conclusions: CTC were detected using CellSearch assay in approximately one-third of TN MBC patients. Elevated CTC at baseline and days 15 and 29 were prognostic, and reductions in CTC levels reflected response. Clin Cancer Res; 21(12); 2771–9. ©2015 AACR.
See related article by Forero-Torres et al., p. 2722
Monoclonal Antibodies Targeting LecLex-Related Glycans with Potent Antitumor Activity
Authors: Chua Jia Xin , Vankemmelbeke Mireille , McIntosh Richard S. , Clarke Philip A. , Moss Robert , Parsons Tina , Spendlove Ian , Zaitoun Abid M. , Madhusudan Srinivasan , Durrant Lindy G. 
Published: March 2015

Abstract
Purpose: To produce antitumor monoclonal antibodies (mAbs) targeting glycans as they are aberrantly expressed in tumors and are coaccessory molecules for key survival pathways.
Experimental Design: Two mAbs (FG88.2 and FG88.7) recognizing novel tumor-associated Lewis (Le) glycans were produced by immunizations with plasma membrane lipid extracts of the COLO205 cell line.
Results: Glycan array analysis showed that both mAbs bound LecLex, di-Lea, and LeaLex, as well as Lea-containing glycans. These glycans are expressed on both lipids and proteins. Both mAbs showed strong tumor reactivity, binding to 71% (147 of 208) of colorectal, 81% (155 of 192) of pancreatic, 54% (52 of 96) of gastric, 23% (62 of 274) of non–small cell lung, and 31% (66 of 217) of ovarian tumor tissue in combination with a restricted normal tissue distribution. In colorectal cancer, high FG88 glyco-epitope expression was significantly associated with poor survival. The mAbs demonstrated excellent antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), in addition to direct tumor cell killing via a caspase-independent mechanism. Scanning electron microscopy revealed antibody-induced pore formation. In addition, the mAbs internalized, colocalized with lysosomes, and delivered saporin that killed cells with subnanomolar potency. In vivo, the mAbs demonstrated potent antitumor efficacy in a metastatic colorectal tumor model, leading to significant long-term survival.
Conclusions: The mAbs direct and immune-assisted tumor cell killing, pan-tumor reactivity, and potent in vivo antitumor efficacy indicate their potential as therapeutic agents for the treatment of multiple solid tumors. In addition, internalization of saporin conjugates and associated tumor cell killing suggests their potential as antibody drug carriers. Clin Cancer Res; 21(13); 2963–74. ©2015 AACR.
The Tumor Suppressor NKX3.1 Is Targeted for Degradation by DYRK1B Kinase
Authors: Song Liang-Nian , Silva Jose , Koller Antonius , Rosenthal Andrew , Chen Emily I. , Gelmann Edward P. 
Published: March 2015

Abstract
NKX3.1 is a prostate-specific homeodomain protein and tumor suppressor whose expression is reduced in the earliest phases of prostatic neoplasia. NKX3.1 expression is not only diminished by genetic loss and methylation, but the protein itself is a target for accelerated degradation caused by inflammation that is common in the aging prostate gland. NKX3.1 degradation is activated by phosphorylation at C-terminal serine residues that mediate ubiquitination and protein turnover. Because NKX3.1 is haploinsufficient, strategies to increase its protein stability could lead to new therapies. Here, a high-throughput screen was developed using an siRNA library for kinases that mediate NKX3.1 degradation. This approach identified several candidates, of which DYRK1B, a kinase that is subject to gene amplification and overexpression in other cancers, had the greatest impact on NKX3.1 half-life. Mechanistically, NKX3.1 and DYRK1B were shown to interact via the DYRK1B kinase domain. In addition, an in vitro kinase assay showed that DYRK1B phosphorylated NKX3.1 at serine 185, a residue critical for NKX3.1 steady-state turnover. Lastly, small-molecule inhibitors of DYRK1B prolonged NKX3.1 half-life. Thus, DYRK1B is a target for enzymatic inhibition in order to increase cellular NKX3.1.
Implications: DYRK1B is a promising and novel kinase target for prostate cancer treatment mediated by enhancing NKX3.1 levels. Mol Cancer Res; 13(5); 913–22. ©2015 AACR.
Five-Year Cervical (Pre)Cancer Risk of Women Screened by HPV and Cytology Testing
Authors: Uijterwaal Margot H. , Polman Nicole J. , Van Kemenade Folkert J. , Van Den Haselkamp Sander , Witte Birgit I. , Rijkaart Dorien , Berkhof Johannes , Snijders Peter J.F. , Meijer Chris J.L.M. 
Published: March 2015

AbstractPrimary human papillomavirus (HPV)–based cervical screening will be introduced in the Netherlands in 2016. We assessed the 5-year cervical (pre)cancer risk of women with different combinations of HPV and cytology test results. Special attention was paid to risks for cervical intraepithelial neoplasia grade 3 and 2 or more (CIN3+/2+) of HPV-positive women with a negative triage test, because this determines the safety of a 5-year screening interval for HPV-positive, triage test–negative women. In addition, age-related effects were studied. A total of 25,553 women were screened by HPV testing and cytology in a screening setting. Women were managed on the presence of HPV and/or abnormal cytology. Five-year cumulative incidences for CIN3+/2+ were calculated. Five-year CIN3+(2+) risk was 10.0% (17.7%) among HPV-positive women. When stratified by cytology, the CIN3+(CIN2+) risk was 7.9% (12.9%) for women with normal cytology and 22.2% (45.3%) for women with equivocal or mildly abnormal (i.e., BMD) cytology. For HPV-negative women, the 5-year CIN3+(2+) risk was 0.09% (0.21%). Additional triage of HPV-positive women with normal cytology by repeat cytology at 12 months showed a 5-year CIN3+(2+) risk of 4.1% (7.0%). HPV-non 16/18-positive women with normal cytology at baseline had comparable risks of 3.5% (7.9%). HPV-non 16/18-positive women with normal baseline cytology and normal repeat cytology had a 5-year CIN3+ risk of 0.42%. No age-related effects were detected. In conclusion, HPV-positive women with normal cytology and a negative triage test, either repeat cytology after 12 months or baseline HPV 16/18 genotyping, develop a non-negligible CIN3+ risk over 5 years. Therefore, extension of the screening interval over 5 years only seems possible for HPV screen–negative women. Cancer Prev Res; 8(6); 502–8. ©2015 AACR.
A Dynamically Computed Convective Time Scale for the Kain–Fritsch Convective Parameterization Scheme
Authors: Bullock O. Russell , Alapaty Kiran , Herwehe Jerold A. , Kain John S. 
Published: March 2015

Abstract
Many convective parameterization schemes define a convective adjustment time scale τ as the time allowed for dissipation of convective available potential energy (CAPE). The Kain–Fritsch scheme defines τ based on an estimate of the advective time period for deep convective clouds within a grid cell, with limits of 1800 and 3600 s, based on practical cloud-lifetime considerations. In simulations from the Weather Research and Forecasting (WRF) Model using 12-km grid spacing, the value of τ often defaults to the lower limit, resulting in relatively rapid thermodynamics adjustments and high precipitation rates. Herein, a new computation for τ in the Kain–Fritsch scheme is implemented based on the depth of the buoyant layer and the convective velocity scale. This new τ formulation is applied using 12- and 36-km model grid spacing in conjunction with a previous modification that takes into account the radiation effects of parameterized convective clouds. The dynamically computed convective adjustment time scale is shown to reduce the precipitation bias by approximately 15% while also providing improved simulations of inland rainfall from tropical storms.