bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sensing of Bacterial Type IV Secretion via the Unfolded Protein Response
Authors: de Jong Maarten F. , Starr Tregei , Winter Maria G. , den Hartigh Andreas B. , Child Robert , Knodler Leigh A. , van Dijl Jan Maarten , Celli Jean , Tsolis Renée M. 
Published: February 2013

ABSTRACT

Host cytokine responses to
Brucella abortus
infection are elicited predominantly by the deployment of a type IV secretion system (T4SS). However, the mechanism by which the T4SS elicits inflammation remains unknown. Here we show that translocation of the T4SS substrate VceC into host cells induces proinflammatory responses. Ectopically expressed VceC interacted with the endoplasmic reticulum (ER) chaperone BiP/Grp78 and localized to the ER of HeLa cells. ER localization of VceC required a transmembrane domain in its N terminus. Notably, the expression of VceC resulted in reorganization of ER structures. In macrophages, VceC was required for
B. abortus
-induced inflammation by induction of the unfolded protein response by a process requiring inositol-requiring transmembrane kinase/endonuclease 1. Altogether, these findings suggest that translocation of the T4SS effector VceC induces ER stress, which results in the induction of proinflammatory host cell responses during
B. abortus
infection.

IMPORTANCE
Brucella
species are pathogens that require a type IV secretion system (T4SS) to survive in host cells and to maintain chronic infection. By as-yet-unknown pathways, the T4SS also elicits inflammatory responses in infected cells. Here we show that inflammation caused by the T4SS results in part from the sensing of a T4SS substrate, VceC, that localizes to the endoplasmic reticulum (ER), an intracellular site of
Brucella
replication. Possibly via binding of the ER chaperone BiP, VceC causes ER stress with concomitant expression of proinflammatory cytokines. Thus, induction of the unfolded protein response may represent a novel pathway by which host cells can detect pathogens deploying a T4SS.
Efficient Replication of the Novel Human Betacoronavirus EMC on Primary Human Epithelium Highlights Its Zoonotic Potential
Authors: Kindler Eveline , Jónsdóttir Hulda R. , Muth Doreen , Hamming Ole J. , Hartmann Rune , Rodriguez Regulo , Geffers Robert , Fouchier Ron A. M. , Drosten Christian , Müller Marcel A. , Dijkman Ronald , Thiel Volker 
Published: February 2013

ABSTRACT
The recent emergence of a novel human coronavirus (HCoV-EMC) in the Middle East raised considerable concerns, as it is associated with severe acute pneumonia, renal failure, and fatal outcome and thus resembles the clinical presentation of severe acute respiratory syndrome (SARS) observed in 2002 and 2003. Like SARS-CoV, HCoV-EMC is of zoonotic origin and closely related to bat coronaviruses. The human airway epithelium (HAE) represents the entry point and primary target tissue for respiratory viruses and is highly relevant for assessing the zoonotic potential of emerging respiratory viruses, such as HCoV-EMC. Here, we show that pseudostratified HAE cultures derived from different donors are highly permissive to HCoV-EMC infection, and by using reverse transcription (RT)-PCR and RNAseq data, we experimentally determined the identity of seven HCoV-EMC subgenomic mRNAs. Although the HAE cells were readily responsive to type I and type III interferon (IFN), we observed neither a pronounced inflammatory cytokine nor any detectable IFN responses following HCoV-EMC, SARS-CoV, or HCoV-229E infection, suggesting that innate immune evasion mechanisms and putative IFN antagonists of HCoV-EMC are operational in the new host. Importantly, however, we demonstrate that both type I and type III IFN can efficiently reduce HCoV-EMC replication in HAE cultures, providing a possible treatment option in cases of suspected HCoV-EMC infection.

IMPORTANCE
A novel human coronavirus, HCoV-EMC, has recently been described to be associated with severe respiratory tract infection and fatalities, similar to severe acute respiratory syndrome (SARS) observed during the 2002-2003 epidemic. Closely related coronaviruses replicate in bats, suggesting that, like SARS-CoV, HCoV-EMC is of zoonotic origin. Since the animal reservoir and circumstances of zoonotic transmission are yet elusive, it is critically important to assess potential species barriers of HCoV-EMC infection. An important first barrier against invading respiratory pathogens is the epithelium, representing the entry point and primary target tissue of respiratory viruses. We show that human bronchial epithelia are highly susceptible to HCoV-EMC infection. Furthermore, HCoV-EMC, like other coronaviruses, evades innate immune recognition, reflected by the lack of interferon and minimal inflammatory cytokine expression following infection. Importantly, type I and type III interferon treatment can efficiently reduce HCoV-EMC replication in the human airway epithelium, providing a possible avenue for treatment of emerging virus infections.
Physiological states and functional relation between thyrotropin and free thyroxine in thyroid health and disease: in vivo and in silico data suggest a hierarchical model
Authors: Midgley John E M , Hoermann Rudolf , Larisch Rolf , Dietrich Johannes W 
Published: February 2013

AimsUnderstanding the exact relationship between serum thyrotropin/thyroid stimulating hormone (TSH) and free thyroxine (FT4) is a prerequisite for improving diagnostic reliability and clinical decision making.MethodsWe (1) retrospectively studied the relationship between TSH and FT4in a large unselected clinical sample (n=6641) of primary hypothyroid, euthyroid and hyperthyroid subjects, and (2) applied a mathematical model of thyroid hormone feedback control to assess the relation between structural parameters and TSH levels in the different functional states.ResultsWhen separately analysing total sample and untreated subjects, the correlation slope for logTSH versus FT4for hypothyroid subjects was significantly different from that of the euthyroid panel and hyperthyroid subjects (the latter being compromised by reaching the TSH assay's lower detection limit). As trends between functional states changed, each functional segment appeared to become differently regulated. Theoretical modelling and sensitivity analysis revealed that the influence of various structural parameters on TSH levels also depends on the overall function of the feedback loop.ConclusionsOur data suggest that the states of hypothyroidism, euthyroidism and hyperthyroidism can be regarded as differently regulated entities. The apparent complexity could be replicated by mathematical modelling suggesting a hierarchical type of feedback regulation involving patterns of operative mechanisms unique to each condition. For clinical purposes and assay evaluation, neither the standard model relating logTSH with FT4, nor an alternative model based on non-competitive inhibition can be reliably represented by a single correlation comparing all samples for both hormones in one all-inclusive group.
Notch1-Hes1 signalling axis in the tumourigenesis of biliary neuroendocrine tumours
Authors: Harada Kenichi , Sato Yasunori , Ikeda Hiroko , Hsu Maylee , Igarashi Saya , Nakanuma Yasuni 
Published: February 2013

AimsBiliary neuroendocrine tumours (NETs) are rare and mostly exist as a component of mixed adenoneuroendocrine carcinomas (MANECs). Although the NET component in biliary MANECs is generally more malignant and clinically more important to the prognosis than the ordinary adenocarcinomatous component, the histogenesis of biliary NET has not been clarified. In this study, the role of the Notch1-Hes1 signalling axis in the histogenesis of biliary NETs was examined.MethodsImmunohistochemistry for Notch1, its ligand Jagged1 and Hes1 was performed using surgical specimens from 11 patients with biliary MANEC. Moreover, after the knock-down of Notch1 mRNA expression in a cholangiocarcinoma cell line, the expression of chromogranin A (a neuroendocrine marker) and Ascl1 (a neuroendocrine-inducing molecule inhibited by activated Hes1) was examined by quantitative PCR.ResultsHistological examination revealed that the adenocarcinomatous components were predominately located at the luminal surface of the MANEC and the majority of stromal invasion involved NET components. Ordinary adenocarcinomas and non-neoplastic biliary epithelium constantly expressed Notch1, Jagged1 and Hes1, but the expression of Notch1 and Hes1 was decreased or absent in NET components, suggesting interference with the Notch1-Hes1 signalling axis in biliary NET. Moreover, in the cholangiocarcinoma cell line in which the expression of Notch1 mRNA was knocked down, the mRNA expression of Ascl1 and chromogranin A was increased.ConclusionsThe Notch1-Hes1 signalling axis suppresses neuroendocrine differentiation and maintains tubular/acinar features in adenocarcinoma and non-neoplastic epithelium in the biliary tree. Moreover, a disruption of this signalling axis may be associated with the tumourigenesis of NETs in biliary MANEC.
Automated Tracking of Nanoparticle-labeled Melanoma Cells Improves the Predictive Power of a Brain Metastasis Model
Authors: Sundstrøm Terje , Daphu Inderjit , Wendelbo Ingvild , Hodneland Erlend , Lundervold Arvid , Immervoll Heike , Skaftnesmo Kai Ove , Babic Michal , Jendelova Pavla , Sykova Eva , Lund-Johansen Morten , Bjerkvig Rolf , Thorsen Frits 
Published: February 2013

Abstract
Biologic and therapeutic advances in melanoma brain metastasis are hampered by the paucity of reproducible and predictive animal models. In this work, we developed a robust model of brain metastasis that empowers quantitative tracking of cellular dissemination and tumor progression. Human melanoma cells labeled with superparamagnetic iron oxide nanoparticles (SPION) were injected into the left cardiac ventricle of mice and visualized by MRI. We showed that SPION exposure did not affect viability, growth, or migration in multiple cell lines across several in vitro assays. Moreover, labeling did not impose changes in cell-cycle distribution or apoptosis. In vivo, several SPION-positive cell lines displayed similar cerebral imaging and histologic features. MRI-based automated quantification of labeled cells in the brain showed a sigmoid association between metastasis frequency and doses of inoculated cells. Validation of this fully automated quantification showed a strong correlation with manual signal registration (r2 = 0.921, P &lt; 0.001) and incidence of brain metastases (r2 = 0.708, P &lt; 0.001). Metastasis formation resembled the pattern seen in humans and was unaffected by SPION labeling (histology; tumor count, P = 0.686; survival, P = 0.547). In summary, we present here a highly reproducible animal model that can improve the predictive value of mechanistic and therapeutic studies of melanoma brain metastasis. Cancer Res; 73(8); 2445–56. ©2013 AACR.
The Emerging “Hallmarks” of Metabolic Reprogramming and Immune Evasion: Distinct or Linked?
Authors: Kareva Irina , Hahnfeldt Philip 
Published: February 2013

AbstractThe role of the immune system in tumor elimination has been shown to be increasingly ambiguous, as many tumors not only escape recognition by the adaptive immune response but also even prime the immune cells to promote tumor growth. This effect is achieved through a number of mechanisms, which include both direct interference with the cells of the adaptive immune response and indirect immunosuppression achieved through modification of the tumor microenvironment. We propose that through upregulation of glycolysis and the consequent lowering of pH in the tumor microenvironment, tumors can take advantage of a pH control system, already exploited by specific immune cell subpopulations, to gain control of the immune system and suppress both cytotoxic and antigen-presenting cells. This is accomplished through the direct competition of tumor cells with actively proliferating glycolytic immune cells for glucose and indirectly through the creation by the tumor of a microenvironment that interferes with maturation and activation of antigen-presenting cells and naïve cytotoxic T cells. Immunosuppressive properties of an acidic microenvironment in the vicinity of the tumor can thus provide additional benefits for upregulation of glycolysis by tumor cells, suggesting that the two emerging “hallmarks of cancer,” altered glucose metabolism and immune suppression, are in fact fundamentally linked. Cancer Res; 73(9); 2737–42. ©2013 AACR.
Challenges and Key Considerations of the Enhanced Permeability and Retention Effect for Nanomedicine Drug Delivery in Oncology
Authors: Prabhakar Uma , Maeda Hiroshi , Jain Rakesh K. , Sevick-Muraca Eva M. , Zamboni William , Farokhzad Omid C. , Barry Simon T. , Gabizon Alberto , Grodzinski Piotr , Blakey David C. 
Published: February 2013

Abstract
Enhanced permeability of the tumor vasculature allows macromolecules to enter the tumor interstitial space, whereas the suppressed lymphatic filtration allows them to stay there. This phenomenon, enhanced permeability and retention (EPR), has been the basis of nanotechnology platforms to deliver drugs to tumors. However, progress in developing effective drugs using this approach has been hampered by heterogeneity of EPR effect in different tumors and limited experimental data from patients on effectiveness of this mechanism as related to enhanced drug accumulation. This report summarizes the workshop discussions on key issues of the EPR effect and major gaps that need to be addressed to effectively advance nanoparticle-based drug delivery. Cancer Res; 73(8); 2412–7. ©2013 AACR.
Inhibition of 15-Hydroxyprostaglandin Dehydrogenase by Helicobacter pylori in Human Gastric Carcinogenesis
Authors: Ryu Yeon-Mi , Myung Seung-Jae , Park Young Soo , Yang Dong-Hoon , Song Ho June , Jeong Jin-Yong , Lee Sun Mi , Song Miyeoun , Kim Do Hoon , Lee Hyo-Jeong , Park Soo-Kyung , Fink Stephen P. , Markowitz Sandy D. , Jung Kee Wook , Kim Kyung-Jo , Ye Byong Duk , Byeon Jeong-Sik , Jung Hwoon-Yong , Yang Suk-Kyun , Kim Jin-Ho 
Published: February 2013

Abstract
Helicobacter pylori (H. pylori) infection induces a chronic inflammatory response, which promotes gastric carcinogenesis. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) plays a key role as a tumor suppressor in gastrointestinal cancers. The aim of this study was to elucidate the role of 15-PGDH in gastric carcinogenesis associated with H. pylori. 15-PGDH expression in gastric biopsies from H. pylori–infected (n = 25) and noninfected (n = 15) subjects was analyzed by quantitative real-time PCR, Western blot analysis, and immunohistochemistry. 15-PGDH DNA methylation was evaluated by methylation-specific PCR and pyrosequencing. The expression of 15-PGDH, Snail, extracellular signal–regulated kinase (ERK)1/2, TLR4, and MyD88 in response to H. pylori infection was assessed by immunoblot analysis. Compared with negative specimens, H. pylori–positive specimens had 2-fold lower 15-PGDH mRNA levels and significantly less 15-PGDH protein. In four H. pylori–infected subjects with longitudinal follow-up, the suppression of 15-PGDH expression was reversed by H. pylori eradication therapy. In parallel with suppressing 15-PGDH expression, H. pylori infection activated expression of TLR4 and MyD88 expression, increased levels of phospho-ERK1/2, and increased expression of EGF receptor (EGFR)-Snail. Inhibition of Snail and MyD88 reversed suppression of 15-PGDH expression, and siMyD88 reduced phosphorylated ERK1/2. Similarly, treatment with an ERK1/2 and EGFR inhibitor also restored 15-PGDH expression. H. pylori appeared to promote gastric carcinogenesis by suppressing15-PGDH. This process is mediated by the TLR4/MyD88 pathway via ERK1/2 or EGFR-Snail transcriptional regulation. 15-PGDH may be a useful marker and a potential therapeutic target in H. pylori–induced gastric carcinogenesis. Cancer Prev Res; 6(4); 349–59. ©2013 AACR.
Effects of Minocycline Plus Tissue Plasminogen Activator Combination Therapy After Focal Embolic Stroke in Type 1 Diabetic Rats
Authors: Fan Xiang , Lo Eng H. , Wang Xiaoying 
Published: February 2013

Background and Purpose—
Poststroke hyperglycemia is associated with resistance to tissue plasminogen activator (tPA) reperfusion, higher risk of intracerebral hemorrhage, and worse neurological outcomes. In this study, we asked whether minocycline combined with intravenous tPA may ameliorate inflammation and brain injury after focal embolic stroke in type 1 diabetic rats.

Methods—
Type 1 diabetic rats were subjected to a focal embolic stroke. Three treatment groups were used: (1) saline at 1.5 hours after stroke; (2) tPA alone at 1.5 hours after stroke; (3) combined minocycline (intravenously) at 1 hour plus tPA at 1.5 hours, and second treatment of minocycline (intraperitoneally) at 12 hours after stroke. Acute brain tissue damages were assessed at 24 hours after stroke. Inflammatory biomarkers interleukin-1β and matrix metalloproteinases 2 and 9 were examined in plasma. Neutrophil infiltration, microglia activation, matrix metalloproteinase activation, and degradation of the tight junction protein claudin-5 were examined in the brain.

Results—
Compared with saline or tPA alone treatments, minocycline plus tPA combination therapy significantly reduced brain infarction, intracerebral hemorrhage, and hemispheric swelling at 24 hours after stroke. The combination also significantly suppressed the elevated plasma levels of matrix metalloproteinase-9 and interleukin-1β up to 24 hours after stroke. At 16 hours after stroke, neutrophil infiltration, microglia activation, matrix metalloproteinase-9, and tight junction protein claudin-5 degradation in the peri-infarct brain tissues were also significantly attenuated by the combination therapy.

Conclusions—
Combination therapy with minocycline plus tPA may be beneficial in ameliorating inflammation and reducing infarction, brain swelling, and hemorrhage after ischemic stroke with diabetes mellitus/hyperglycemia.
The Making of Meaning: Churches, Development Projects and Violence in Eastern Uganda
Authors: Jones Ben 
Published: February 2013

Abstract
Churches and development projects are a shared feature of the landscape of much of rural Africa. In this article I look at these two very different sorts of institution in a village in the Teso region of eastern Uganda, exploring the ways in which people do, or do not, make meaning through their participation in churches and development projects. In this context recently-formed Pentecostal churches have become a significant part of the local landscape, while the community structures built up by NGOs struggle to keep going once the funding ends. In explaining this difference I make an argument about how institutions are made sense of by people living in a particular place. The Teso region experienced a violent insurgency in the late 1980s and early 1990s and the idea of becoming born again has had particular resonance against this history. By contrast the work of NGOs is at a distance from what matters to people. This is evidenced not only in the rusted road signs that mark the failure of past projects, or in the new aluminium-roofed village churches, but also in the way people talk about churches and NGOs. Discussions about NGOs were dry and matter-of-fact, whereas conversations on new churches were rich and wide-ranging linking to other aspects of village life. It can be argued that development projects and Pentecostal churches are interpreted differently, and this differential explains the durability of churches and the brief after-lives of development interventions.
Weather Forecasting as a Learning Tool in a Large Service Course: Does Practice Make Perfect?
Authors: Suess Elizabeth J. , Cervato Cinzia , Gallus William A. , Hobbs Jonathon M. 
Published: February 2013

Abstract
Each spring roughly 200 students, mostly nonmajors, enroll in the Introduction to Meteorology course at Iowa State University and are required to make at least 25 forecasts throughout the semester. The Dynamic Weather Forecaster (DWF) forecasting platform requires students to forecast more than just simple “numeric” forecasts and includes questions on advection, cloudiness, and precipitation factors that are not included in forecast contests often used in meteorology courses. The present study examines the evolution of forecasting skill for students enrolled in the class in spring 2010 and 2011 and compares student performance with that of an “expert forecaster.” The expert forecasters were chosen from meteorology students in an advanced forecasting course who showed exemplary forecasting skill throughout the previous semester. It is shown that these introductory students improve in forecast skill over only the first 10–15 days that they forecast, a number smaller than the 25 days found in an earlier study examining meteorology majors in an upper-level course. The skill of both groups plateaus after that time. An analysis of two types of questions in the DWF reveals that students do have skill slightly better than that of a persistence forecast when predicting parameters traditionally used in forecasting contests, but fail to outperform persistence when predicting more complex atmospheric processes like temperature advection and factors influencing precipitation such as moisture content and instability. The introduction of a contest “with prizes” halfway through the semester in 2011 was found to have at best mixed impacts on forecast skill.
Integrating mHealth mobile applications to reduce high risk drinking among underage students
Authors: Kazemi Donna M , Cochran Allyson R , Kelly John F , Cornelius Judith B , Belk Catherine 
Published: February 2013

Objective: College students embrace mobile cell phones (MCPs) as a primary communication and entertainment device. The aim of this study was to investigate college students’ perceptions toward using mHealth technology to deliver interventions to prevent high-risk drinking and associated consequences. Design/setting: Four focus group interviews were conducted during the spring and fall of 2011 at a large public university in the southeastern United States of America (USA) to collect data on the applicability of mHealth technology to alcohol-prevention programmes. The participants were students currently enrolled in a face-to-face alcohol-prevention programme. Method: Thematic analysis of the content in the transcriptions was used to analyse the focus group responses using a codebook. Results: Four major themes emerged which were: (1) education and usability; (2) Skype capabilities; (3) enhanced social networking; and (4) use for tracking and feedback. All of the participants said they would join an alcohol-intervention programme that incorporated mHealth mobile technology as a primary mode of communication. Conclusions: The positive responses to the use of mobile applications indicate that use of interactive, real-time technology would be valuable to college students. Given the cost of face-to-face delivery of interventions, the findings are encouraging and support further exploration of the application of mHealth technology. Mobile technologies (mHealth) could provide a more effective delivery of alcohol-intervention programmes and increase the accessibility, relevance, and value of alcohol-intervention programmes.