bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutations in Pdd1 Reveal Distinct Requirements for Its Chromodomain and Chromoshadow Domain in Directing Histone Methylation and Heterochromatin Elimination
Authors: Schwope Rachel M. , Chalker Douglas L. 
Published: December 2013

ABSTRACT

Pdd1, a specialized HP1-like protein, is required for genome-wide DNA rearrangements that restructure a previously silent germ line genome into an active somatic genome during macronuclear differentiation of
Tetrahymena thermophila
. We deleted or otherwise mutated conserved regions of the protein to investigate how its different domains promote the excision of thousands of internal eliminated sequences (IESs). Previous studies revealed that Pdd1 contributes to recognition of IES loci after they are targeted by small-RNA-guided methylation of histone H3 on lysine 27 (H3K27), subsequently aids the establishment of H3K9 methylation, and recruits proteins that lead to excision. The phenotypes we observed for different Pdd1 alleles showed that each of the two chromodomains and the chromoshadow domain (CSD) have distinct contributions during somatic genome differentiation. Chromodomain 1 (CD1) is essential for conjugation as either its deletion or the substitution of two key aromatic amino acid residues (the W97A W100A mutant) is lethal. These mutations caused mislocalization of a cyan fluorescent protein (CFP)-tagged protein, prevented the establishment of histone H3 dimethylated on K9 (H3K9me2), and abolished IES excision. Nevertheless, the requirement for CD1 could be bypassed by recruiting Pdd1 directly to an IES by addition of a specific DNA binding domain. Chromodomain 2 (CD2) was necessary for producing viable progeny, but low levels of H3K9me2 and IES excision still occurred. A mutation in the chromoshadow domain (CSD) prevented Pdd1 focus formation but still permitted ∼17% of conjugants to produce viable progeny. However, this mutant was unable to stimulate excision when recruited to an ectopic IES, indicating that this domain is important for recruitment of excision factors.
Sck1 Negatively Regulates Gpa2-Mediated Glucose Signaling in Schizosaccharomyces pombe
Authors: Mudge Dayna K. , Yang Fan , Currie Brian M. , Kim James M. , Yeda Kelly , Bashyakarla Varoon K. , Ivey F. Douglas , Hoffman Charles S. 
Published: December 2013

ABSTRACT

Schizosaccharomyces pombe
detects extracellular glucose via a G protein-mediated cyclic AMP (cAMP)-signaling pathway activating protein kinase A (PKA) and regulating transcription of genes involved in metabolism and sexual development. In this pathway, Gpa2 Gα binds to and activates adenylyl cyclase in response to glucose detection by the Git3 G protein-coupled receptor. Using a two-hybrid screen to identify extrinsic regulators of Gpa2, we isolated a clone that expresses codons 471 to 696 of the Sck1 kinase, which appears to display a higher affinity for Gpa2
K270E
-activated Gα relative to Gpa2
+
Gα. Deletion of
sck1
+
or mutational inactivation of the Sck1 kinase produces phenotypes reflecting increased PKA activity in strains expressing Gpa2
+
or Gpa2
K270E
, suggesting that Sck1 negatively regulates PKA activation through Gpa2. In contrast to the Gpa2
K270E
GDP-GTP exchange rate mutant, GTPase-defective Gpa2
R176H
weakly binds Sck1 in the two-hybrid screen and a deletion of
sck1
+
in a Gpa2
R176H
strain confers phenotypes consistent with a slight reduction in PKA activity. Finally, deleting
sck1
+
in a
gpa2
Δ strain results in phenotypes consistent with a second role for Sck1 acting in parallel with PKA. In addition to this parallel role with PKA, our data suggest that Sck1 negatively regulates Gpa2, possibly targeting the nucleotide-free form of the protein that may expose the one and only AKT/PKB consensus site in Gpa2 for Sck1 to bind. This dual role for Sck1 may allow
S. pombe
to produce distinct biological responses to glucose and nitrogen starvation signals that both activate the Wis1-Spc1/StyI stress-activated protein kinase (SAPK) pathway.
Hepcidin Induction by Pathogens and Pathogen-Derived Molecules Is Strongly Dependent on Interleukin-6
Authors: Rodriguez Richard , Jung Chun-Ling , Gabayan Victoria , Deng Jane C. , Ganz Tomas , Nemeth Elizabeta , Bulut Yonca 
Published: December 2013

ABSTRACT

Hepcidin, the iron-regulatory hormone, is increased during infection or inflammation, causing hypoferremia. This response is thought to be a host defense mechanism that restricts iron availability to invading pathogens. It is not known if hepcidin is differentially induced by bacterial versus viral infections, whether the stimulation of pattern recognition receptors directly regulates hepcidin transcription, or which of the proposed signaling pathways are essential for hepcidin increase during infection. We analyzed hepcidin induction and its dependence on interleukin-6 (IL-6) in response to common bacterial or viral infections in mice or in response to a panel of pathogen-derived molecules (PAMPs) in mice and human primary hepatocytes. In wild-type (WT) mice, hepcidin mRNA was induced several hundred-fold both by a bacterial (
Streptococcus pneumoniae
) and a viral infection (influenza virus PR8) within 2 to 5 days. Treatment of mice and human primary hepatocytes with most Toll-like receptor ligands increased hepcidin mRNA within 6 h. Hepcidin induction by microbial stimuli was IL-6 dependent. IL-6 knockout mice failed to increase hepcidin in response to
S. pneumoniae
or influenza infection and had greatly diminished hepcidin response to PAMPs.
In vitro
, hepcidin induction by PAMPs in primary human hepatocytes was abolished by the addition of neutralizing IL-6 antibodies. Our results support the key role of IL-6 in hepcidin regulation in response to a variety of infectious and inflammatory stimuli.
Murine Neonates Infected with Yersinia enterocolitica Develop Rapid and Robust Proinflammatory Responses in Intestinal Lymphoid Tissues
Authors: Siefker David T. , Echeverry Andrea , Brambilla Roberta , Fukata Masayuki , Schesser Kurt , Adkins Becky 
Published: December 2013

ABSTRACTNeonatal animals are generally very susceptible to infection with bacterial pathogens. However, we recently reported that neonatal mice are highly resistant to orogastric infection withYersinia enterocolitica. Here, we show that proinflammatory responses greatly exceeding those in adults arise very rapidly in the mesenteric lymph nodes (MLN) of neonates. High-level induction of proinflammatory gene expression occurred in the neonatal MLN as early as 18 h postinfection. Marked innate phagocyte recruitment was subsequently detected at 24 h postinfection. Enzyme-linked immunosorbent spot assay (ELISPOT) analyses indicated that enhanced inflammation in neonatal MLN is contributed to, in part, by an increased frequency of proinflammatory cytokine-secreting cells. Moreover, both CD11b+and CD11b−cell populations appeared to play a role in proinflammatory gene expression. The level of inflammation in neonatal MLN was also dependent on key bacterial components.Y. enterocoliticalacking the virulence plasmid failed to induce innate phagocyte recruitment. In contrast, tumor necrosis factor alpha (TNF-α) protein expression and neutrophil recruitment were strikingly higher in neonatal MLN after infection with ayopP-deficient strain than with wild-typeY. enterocolitica, whereas only modest increases occurred in adults. This hyperinflammatory response was associated with greater colonization of the spleen and higher mortality in neonates, while there was no difference in mortality among adults. This model highlights the dynamic levels of inflammation in the intestinal lymphoid tissues and reveals the protective (wild-type strain) versus harmful (yopP-deficient strain) consequences of inflammation in neonates. Moreover, these results reveal that the neonatal intestinal lymphoid tissues have great potential to rapidly mobilize innate components in response to infection with bacterial enteropathogens.
The Integron Integrase Efficiently Prevents the Melting Effect of Escherichia coli Single-Stranded DNA-Binding Protein on Folded
attC
Sites
Authors: Loot Céline , Parissi Vincent , Escudero José Antonio , Amarir-Bouhram Jihane , Bikard David , Mazel Didier 
Published: December 2013

ABSTRACT

Integrons play a major role in the dissemination of antibiotic resistance genes among bacteria. Rearrangement of gene cassettes occurs by recombination between
attI
and
attC
sites, catalyzed by the integron integrase. Integron recombination uses an unconventional mechanism involving a folded single-stranded
attC
site. This site could be a target for several host factors and more precisely for proteins able to bind single-stranded DNA. One of these,
Escherichia coli
single-stranded DNA-binding protein (SSB), regulates many DNA processes. We studied the influence of this protein on integron recombination. Our results show the ability of SSB to strongly bind folded
attC
sites and to destabilize them. This effect was observed only in the absence of the integrase. Indeed, we provided evidence that the integrase is able to counterbalance the observed effect of SSB on
attC
site folding. We showed that IntI1 possesses an intrinsic property to capture
attC
sites at the moment of their extrusion, stabilizing them and recombining them efficiently. The stability of DNA secondary structures in the chromosome must be restrained to avoid genetic instability (mutations or deletions) and/or toxicity (replication arrest). SSB, which hampers
attC
site folding in the absence of the integrase, likely plays an important role in maintaining the integrity and thus the recombinogenic functionality of the integron
attC
sites. We also tested the RecA host factor and excluded any role of this protein in integron recombination.
Effect of social networks intervention in type 2 diabetes: a partial randomised study
Authors: Shaya Fadia T , Chirikov Viktor V , Howard DeLeonardo , Foster Clyde , Costas Julian , Snitker Soren , Frimpter Jeffrey , Kucharski Kathrin 
Published: December 2013

BackgroundIn this partially randomised intervention study, we assessed the effect of social networks on the improvement of type 2 diabetes management in a largely African–American population in Baltimore.MethodsPatients in the intervention group (n=68) were asked to recruit peers, form small groups, and attend monthly diabetes education sessions, emphasising peer support. Patients in the control group (n=70) were recruited individually to attend standard diabetes education sessions. The primary outcomes were changes in haemoglobin A1C (HbA1c) and blood glucose. Secondary outcomes included blood pressure, weight, functional status, self-efficacy, perceived cohesion, social network connectedness and diabetes knowledge. General linear mixed models were built to assess mean absolute changes in primary and secondary outcomes at 3 and 6 months.ResultsAt 6 months from baseline, the social network intervention group achieved a larger reduction in HbA1cof −0.32% (p<0.0001) and blood glucose of −10.6 mg/dL, (p<0.0001) compared to the control group. In analyses of secondary endpoints, the intervention group had more favourable outcomes over time for weight, quality of life, self-efficacy, social network scores and diabetes knowledge, compared to the control group. While blood pressure decreased, and perceived cohesion increased in both groups over the duration of the study, the difference between groups was not statistically significant.ConclusionsThe social networks intervention showed improved integration of patients within their existing networks leading to a greater reduction in HbA1cand blood glucose, as well as improved behaviour mediating outcomes.
A community-based multilevel intervention for smoking, physical activity and diet: short-term findings from the Community Interventions for Health programme in Hangzhou, China
Authors: Lv Jun , Liu Qing-Min , Ren Yan-Jun , He Ping-Ping , Wang Sheng-Feng , Gao Fang , Li Li-Ming ,   on behalf of the Community Interventions for Health (CIH) collaboration
Published: December 2013

BackgroundTo assess the short-term impact of a comprehensive, community-based multilevel intervention on knowledge, beliefs and practices with respect to smoking, physical activity and diet in Hangzhou, China.MethodsA non-randomised, controlled, before-after quasi-experimental trial was conducted in two intervention areas and one comparison area. The intervention built on a socioecological framework and took place across four settings: neighbourhoods, schools, workplaces and community health centres. Two independent cross-sectional surveys of adults aged 18–64 years at baseline and a subsequent follow-up were conducted in 2008/2009 and 2011 in the intervention and comparison areas. A 2-year intervention programme was begun in mid-2009 and continued until mid-2011.ResultsA total of 2016 adults at baseline and 2016 adults at follow-up completed the survey. Over the 2-year intervention period, the intervention areas showed a statistically significant decline (25.2% vs 18.7%, p<0.001) in the prevalence of smoking compared with the comparison area (18.0% vs 16.4%, p=0.343). The proportion of individuals who had noticed anyone smoking in any of nine locations in the previous 30 days demonstrated a statistically significant decline in the intervention (78.9% vs 66.5%, p<0.001) and comparison (76.3% vs 66.5%, p<0.001) areas. The fruit and vegetable consumption score increased in a statistically significant manner in the intervention (24.84 vs 25.97, p=0.036) and comparison (24.25 vs 26.67, p<0.001) areas. The metabolic equivalent of physical activity increased from 1204 to 1386 (p=0.023) in the intervention areas compared with 918 to 924 in the comparison area (p=0.201).ConclusionsAfter a 2-year intervention, beneficial changes were noted in the intervention areas with respect to smoking and physical activity but not diet. A community-based multilevel intervention programme is feasible in urban China.
A clinical survey on the prevalence and types of cheek teeth disorders present in 400 Zamorano‐Leonés and 400 Mirandês donkeys (Equus asinus)
Authors: Rodrigues J. B. , Dixon P. M. , Bastos E. , San Roman F. , Viegas C. 
Published: December 2013

Dental disease is now recognised as a major but often unrecognised disorder of equids, including horses and donkeys. However, very few large clinical studies have documented the prevalence and type of dental disease present in different equid populations and no dental studies have been reported in Zamorano‐Leonés or Mirandês donkeys, two endangered donkey breeds. Clinical and detailed oral examinations were performed in 400 Mirandês and 400 Zamorano‐Leonés donkeys in Portugal and Spain. It was found that just 4.5 per cent had ever received any previous dental care. Cheek teeth (CT) disorders were present in 82.8 per cent of these donkeys, ranging from a prevalence of 29.6 per cent in the <2.5‐year‐old group to 100 per cent in the >25‐year‐old group. These CT disorders included enamel overgrowths (73.1 per cent prevalence but with just 6.3 per cent having associated soft tissue injuries), focal overgrowths (37.3 per cent), periodontal disease (23.5 per cent) and diastemata (19.9 per cent). Peripheral caries was present in 5.9 per cent of cases, but inexplicably, infundibular caries was very rare (1.3 per cent prevalence); this may have been due to their almost fully foraged diet. The high prevalence of enamel overgrowths in these donkeys, most which never received concentrates, also raises questions about the aetiology of this disorder. This very high prevalence of CT disorders, especially in older donkeys, was of great welfare concern in some cases and emphasises the need for routine dental care in these cases on welfare grounds and in order to help preserve these unique breeds.
HIC1 Silencing in Triple-Negative Breast Cancer Drives Progression through Misregulation of LCN2
Authors: Cheng Guangcun , Sun Xueqing , Wang Jinglong , Xiao Gang , Wang Xiumin , Fan Xuemei , Zu Lidong , Hao Mingang , Qu Qing , Mao Yan , Xue Yunjing , Wang Jianhua 
Published: December 2013

Abstract
The tumor suppressor gene HIC1 is frequently deleted or epigenetically silenced in human cancer, where its restoration may improve cancer prognosis. Here, we report results illuminating how HIC1 silencing alters effect or signals in triple-negative breast cancer (TNBC), which are crucial for its pathogenesis. HIC1 expression was silenced only in TNBC compared with other molecular subtypes of breast cancer. Restoring HIC1 expression in TNBC cells reduced cell migration, invasion, and metastasis, whereas RNAi-mediated silencing of HIC1 in untransformed human breast cells increased their invasive capabilities. Mechanistic investigations identified the small-secreted protein lipocalin-2 (LCN2), as a critical downstream target of HIC1 in TNBC cells. Elevating LCN2 expression in cells expressing HIC1 partially rescued its suppression of cell invasion and metastasis. Notably, autocrine secretion of LCN2 induced by loss of HIC1 activated the AKT pathway through the neutrophil gelatinase–associated lipocalin receptor, which is associated with TNBC progression. Taken together, our findings revealed that the HIC1–LCN2 axis may serve as a subtype-specific prognostic biomarker, providing an appealing candidate target for TNBC therapy. Cancer Res; 74(3); 862–72. ©2013 AACR.
The Diagnostic Value of Adiponectin Multimers in Healthy Men Undergoing Screening for Prostate Cancer
Authors: Medina Edward A. , Shi Xiaoyu , Grayson Marcia H. , Ankerst Donna P. , Livi Carolina B. , Medina Maria V. , Thompson Ian M. , Leach Robin J. 
Published: December 2013

Abstract
Background: Adiponectin has been reported to have a prohibitory effect on prostate cancer. The goal of this study was to evaluate the diagnostic value of adiponectin multimers for prostate cancer.
Methods: Total adiponectin, high- and low-molecular-weight (HMW, LMW), ratios of these measures, and body mass index (BMI) were compared in a prospective prostate cancer–screened cohort. Multivariable logistic regression was used to assess the association between adiponectin measures, their interaction with BMI, and risk of prostate cancer and Gleason score upgrading from biopsy to prostatectomy.
Results: A total of 228 prostate cancer cases and 239 controls were analyzed: 72 (31.6%) of the cancer cases were high grade (Gleason grade ≥7). Only percent HMW had a statistically significant relationship with prostate cancer (P = 0.04). Among normal and overweight men, the risk of prostate cancer increased as percent HMW increased [OR = 1.24 for a doubling of percent HMW, 95% confidence interval (CI), 0.41–3.75 and OR = 1.81; 95% CI, 1.02–3.20, respectively], whereas among obese men, the risk of prostate cancer decreased (OR = 0.62; 95% CI, 0.32–1.18). Among 97 patients who underwent radical prostatectomy, there was no association between Gleason score upgrading and any of the adiponectin multimers.
Conclusion: This study was unable to confirm the utility of total adiponectin as a biomarker for prostate cancer risk. For the adiponectin multimers, only HMW showed increases with prostate cancer but not in all weight classes.
Impact: Although adiponectin may play a role in the pathogenesis of prostate cancer, our results do not support adiponectin multimers as biomarkers of detection. Cancer Epidemiol Biomarkers Prev; 23(2); 309–15. ©2013 AACR.
Access to the Indian Health Service Care System Is Not Associated with Early Enrollment in Medicaid for American Indian and Alaska Natives with Cancer
Authors: Burnett-Hartman Andrea N. , Bensink Mark E. , Berry Kristin , Mummy David G. , Warren-Mears Victoria , Korenbrot Carol , Ramsey Scott D. 
Published: December 2013

Abstract
Background: For uninsured American Indians and Alaskan Natives (AIAN) diagnosed with cancer, prompt enrollment in Medicaid may speed access to treatment and improve survival. We hypothesized that AIANs who were eligible for the Indian Health Service Care System (IHSCS) at cancer diagnosis may be enrolled in Medicaid sooner than other AIANs.
Methods: Using Washington, Oregon, and California State Cancer Registries, we identified AIANs with a primary diagnosis of lung, breast, colorectal, cervical, ovarian, stomach, or prostate cancer between 2001 and 2007. Among AIANs enrolled in Medicaid within 365 days of a cancer diagnosis, we linked cancer registry records with Medicaid enrollment data and used a multivariate logistic regression model to compare the odds of delayed Medicaid enrollment between those with (n = 223) and without (n = 177) IHSCS eligibility.
Results: Among AIANs who enrolled in Medicaid during the year following their cancer diagnosis, approximately 32% enrolled &gt;1 month following diagnosis. Comparing those without IHSCS eligibility to those with IHSCS eligibility, the adjusted odds ratio (OR) for moderately late Medicaid enrollment (between 1 and 6 months after diagnosis) relative to early Medicaid enrollment (≤1 month after diagnosis) was 1.10 [95% confidence interval (CI), 0.62–1.95] and for very late Medicaid enrollment (&gt;6 months to 12 months after diagnosis), OR was 1.14 (CI, 0.54–2.43).
Conclusion: IHSCS eligibility at the time of diagnosis does not seem to facilitate early Medicaid enrollment.
Impact: Because cancer survival rates in AIANs are among the lowest of any racial group, additional research is needed to identify factors that improve access to care in AIANs. Cancer Epidemiol Biomarkers Prev; 23(2); 362–4. ©2013 AACR.
HIF-1α of Bone Marrow Endothelial Cells Implies Relapse and Drug Resistance in Patients with Multiple Myeloma and May Act as a Therapeutic Target
Authors: Ria Roberto , Catacchio Ivana , Berardi Simona , De Luisi Annunziata , Caivano Antonella , Piccoli Claudia , Ruggieri Vitalba , Frassanito Maria Antonia , Ribatti Domenico , Nico Beatrice , Annese Tiziana , Ruggieri Simona , Guarini Attilio , Minoia Carla , Ditonno Paolo , Angelucci Emanuele , Derudas Daniele , Moschetta Michele , Dammacco Franco , Vacca Angelo 
Published: December 2013

Abstract
Purpose: To investigate the role of hypoxia-inducible factor-1α (HIF-1α) in angiogenesis and drug resistance of bone marrow endothelial cells of patients with multiple myeloma.
Experimental Design: HIF-1α mRNA and protein were evaluated in patients with multiple myeloma endothelial cells (MMEC) at diagnosis, at relapse after bortezomib- or lenalidomide-based therapies or on refractory phase to these drugs, at remission; in endothelial cells of patients with monoclonal gammapathies of undetermined significance (MGUS; MGECs), and of those with benign anemia (controls). The effects of HIF-1α inhibition by siRNA or panobinostat (an indirect HIF-1α inhibitor) on the expression of HIF-1α proangiogenic targets, on MMEC angiogenic activities in vitro and in vivo, and on overcoming MMEC resistance to bortezomib and lenalidomide were studied. The overall survival of the patients was also observed.
Results: Compared with the other endothelial cell types, only MMECs from 45% of relapsed/refractory patients showed a normoxic HIF-1α protein stabilization and activation that were induced by reactive oxygen species (ROS). The HIF-1α protein correlated with the expression of its proangiogenic targets. The HIF-1α inhibition by either siRNA or panobinostat impaired the MMECs angiogenesis–related functions both in vitro and in vivo and restored MMEC sensitivity to bortezomib and lenalidomide. Patients with MMECs expressing the HIF-1α protein had shorter overall survival.
Conclusions: The HIF-1α protein in MMECs may induce angiogenesis and resistance to bortezomib and lenalidomide and may be a plausible target for the antiangiogenic management of patients with well-defined relapsed/refractory multiple myeloma. It may also have prognostic significance. Clin Cancer Res; 20(4); 847–58. ©2013 AACR.