bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interplay between obesity and smoking with regard to RA risk
Authors: Hedström Anna Karin , Klareskog Lars , Alfredsson Lars 
Published: April 2019

ObjectivesPrevious studies on rheumatoid arthritis (RA) and body mass index (BMI) have yielded diverging results. We aimed to clarify the influence of BMI on the risk of developing anticitrullinated peptide antibody (ACPA)-positive and ACPA-negative RA by taking into consideration gender, smoking habits and human leukocyte antigen (HLA-DRB1) shared epitope (SE) status.MethodsThe present report is based on a Swedish population-based, case–control study with incident cases of RA (3572 cases, 5772 matched controls). Using logistic regression models, overweight/obese subjects were compared with normal weight subjects regarding risk of developing RA, by calculating ORs with 95% CIs.ResultsWe observed diverging results for women and men. Among women, the risk of both ACPA-positive and ACPA-negative RA increased with increasing BMI, whereas an inverse association was observed among men for ACPA-positive RA. The results were similar regardless if RA onset before or after the age of 55 years was considered. When the analyses were stratified by smoking habits, the influence of BMI on RA risk was mainly restricted to smokers. Among women, a significant interaction was observed between smoking and overweight/obesity with regard to both subsets of RA. No interaction was observed between HLA-DRB1 SE and overweight/obesity with regard to RA risk.ConclusionsThe interaction between smoking and obesity regarding risk for RA in women warrants efforts to reduce these risk factors in those at risk for RA. The sex differences concerning the influence of obesity on RA risk merit further studies to verify these results and understand underlying mechanisms.
Renin-angiotensin system promotes colonic inflammation by inducing TH17 activation via JAK2/STAT pathway
Authors: He Lei , Du Jie , Chen Yinyin , Liu Chunyan , Zhou Min , Adhikari Sarbani , Rubin David T. , Pekow Joel , Li Yan Chun 
Published: April 2019

Previous studies suggest that the renin-angiotensin system (RAS) is a pathogenic factor for colitis. The goal of this study was to elucidate the molecular mechanism whereby angiotensin II (ANG II) promotes colonic inflammation. We found that renin was highly induced in colonic biopsies from patients with ulcerative colitis or Crohn’s disease, and colonic renin and ANG II levels were markedly increased in a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis model, indicating that the colonic RAS is activated in colitis. Renin transgenic (RenTg) mice exhibited increased phosphorylation in Janus kinase-2 (JAK2) and signal transducer and activator of transcription1/3 (STAT1/3) within colonic mucosa at baseline and following TNBS induction, suggesting that ANG II promotes colonic inflammation via the JAK2/STAT1/3 pathway. Treatment with pan-JAK inhibitor tofacitinib blocked JAK2 and STAT1/3 phosphorylation, attenuated T helper (TH)1 and TH17 responses, alleviated colitis, and prevented death of RenTg mice in TNBS model. ANG II stimulated JAK2/STAT1/3 phosphorylation in both Jurkat T lymphocytes and HCT116 epithelial cells. In vitro polarization assays demonstrated that ANG II directly promoted TH17 polarization, but not TH1 polarization, via JAK2/STAT1/3. ANG II stimulation of transforming growth factor-β1 (TGFβ1), IL-6, myosin light chain kinase, and p53 upregulated modulator of apoptosis in HCT116 cells was also mediated by JAK2/STAT1/3. These observations suggest that ANG II promotes TH17 polarization directly as well as indirectly by inducing production of TH17-polarizing cytokines (e.g., TGFβ1 and IL-6) from colonic epithelial cells, both via the JAK2/STAT pathway. Therefore, colonic RAS promotes colonic inflammation, at least in part, by stimulating TH17 activation. NEW & NOTEWORTHY This study demonstrates that the local renin-angiotensin system in the colon is activated in colitis development, which promotes mucosal T helper cell activation through the JAK2/STAT pathway. These observations provide molecular evidence that the renin-angiotensin system is a pathogenic factor for the development of inflammatory bowel diseases.
Supplemental vibrotactile feedback of real-time limb position enhances precision of goal-directed reaching
Authors: Risi Nicoletta , Shah Valay , Mrotek Leigh A. , Casadio Maura , Scheidt Robert A. 
Published: April 2019

We examined vibrotactile stimulation as a form of supplemental limb state feedback to enhance planning and ongoing control of goal-directed movements. Subjects wore a two-dimensional vibrotactile display on their nondominant arm while performing horizontal planar reaching with the dominant arm. The vibrotactile display provided feedback of hand position such that small hand displacements were more easily discriminable using vibrotactile feedback than with intrinsic proprioceptive feedback. When subjects relied solely on proprioception to capture visuospatial targets, performance was degraded by proprioceptive drift and an expansion of task space. By contrast, reach accuracy was enhanced immediately when subjects were provided vibrotactile feedback and further improved over 2 days of training. Improvements reflected resolution of proprioceptive drift, which occurred only when vibrotactile feedback was active, demonstrating that benefits of vibrotactile feedback are due, in part to its integration into the ongoing control of movement. A partial resolution of task space expansion persisted even when vibrotactile feedback was inactive, demonstrating that training with vibrotactile feedback also induced changes in movement planning. However, the benefits of vibrotactile feedback come at a cognitive cost. All subjects adopted a stereotyped strategy wherein they attempted to capture targets by moving first along one axis of the vibrotactile display and then the other. For most subjects, this inefficient approach did not resolve over two bouts of training performed on separate days, suggesting that additional training is needed to integrate vibrotactile feedback into the planning and online control of goal-directed reaching in a way that promotes smooth and efficient movement. NEW & NOTEWORTHY A two-dimensional vibrotactile display provided state (not error) feedback to enhance control of a moving limb. Subjects learned to use state feedback to perform blind reaches with accuracy and precision exceeding that attained using intrinsic proprioception alone. Feedback utilization incurred substantial cognitive cost: subjects moved first along one axis of the vibrotactile display, then the other. This stereotyped control strategy must be overcome if vibrotactile limb state feedback is to promote naturalistic limb movements.
Visual cortex neurons phase-lock selectively to subsets of LFP oscillations
Authors: Swindale N. V. , Spacek M. A. 
Published: April 2019

It is generally thought that apart from receptive field differences, such as preferred orientation and spatial frequency selectivity, primary visual cortex neurons are functionally similar to each other. However, the genetic diversity of cortical neurons plus the existence of inputs additional to those required to explain known receptive field properties might suggest otherwise. Here we report the existence of desynchronized states in anesthetized cat area 17 lasting up to 45 min, characterized by variable narrow-band local field potential (LFP) oscillations in the range 2–100 Hz and the absence of a synchronized 1/ f frequency spectrum. During these periods, spontaneously active neurons phase-locked to variable subsets of LFP oscillations. Individual neurons often ignored frequencies that others phase-locked to. We suggest that these desynchronized periods may correspond to REM sleep-like episodes occurring under anesthesia. Frequency-selective codes may be used for signaling during these periods. Hence frequency-selective combination and frequency-labeled pathways may represent a previously unsuspected dimension of cortical organization. NEW & NOTEWORTHY We investigated spontaneous neuronal firing during periods of desynchronized local field potential (LFP) activity, resembling REM sleep, in anesthetized cats. During these periods, neurons synchronized their spikes to specific phases of multiple LFP frequency components, with some neurons ignoring frequencies that others were synchronized to. Some neurons fired at phase alignments of frequency pairs, thereby acting as phase coincidence detectors. These results suggest that internal brain signaling may use frequency combination codes to generate temporally structured spike trains.
Activation of the Unfolded Protein Response via Inhibition of Protein Disulfide Isomerase Decreases the Capacity for DNA Repair to Sensitize Glioblastoma to Radiotherapy
Authors: Liu Yajing , Ji Wenbin , Shergalis Andrea , Xu Jiaqi , Delaney Amy M. , Calcaterra Andrew , Pal Anupama , Ljungman Mats , Neamati Nouri , Rehemtulla Alnawaz 
Published: April 2019

Abstract

Patients with glioblastoma multiforme (GBM) survive on average 12 to 14 months after diagnosis despite surgical resection followed by radiotheraphy and temozolomide therapy. Intrinsic or acquired resistance to chemo- and radiotherapy is common and contributes to a high rate of recurrence. To investigate the therapeutic potential of protein disulfide isomerase (PDI) as a target to overcome resistance to chemoradiation, we developed a GBM tumor model wherein conditional genetic ablation of prolyl 4-hydroxylase subunit beta (P4HB), the gene that encodes PDI, can be accomplished. Loss of PDI expression induced the unfolded protein response (UPR) and decreased cell survival in two independent GBM models. Nascent RNA Bru-seq analysis of PDI-depleted cells revealed a decrease in transcription of genes involved in DNA repair and cell-cycle regulation. Activation of the UPR also led to a robust decrease in RAD51 protein expression as a result of its ubiquitination-mediated proteosomal degradation. Clonogenic survival assays demonstrated enhanced killing of GBM cells in response to a combination of PDI knockdown and ionizing radiation (IR) compared with either modality alone, which correlated with a decreased capacity to repair IR-induced DNA damage. Synergistic tumor control was also observed with the combination of PDI inhibition and IR in a mouse xenograft model compared with either single agent alone. These findings provide a strong rationale for the development of PDI inhibitors and their use in combination with DNA damage-inducing, standard-of-care therapies such as IR.

Significance:
These findings identify PDIA1 as a therapeutic target in GBM by demonstrating efficacy of its inhibition in combination with radiotherapy through a novel mechanism involving downregulation of DNA repair genes.
tRNA Fragments Show Intertwining with mRNAs of Specific Repeat Content and Have Links to Disparities
Authors: Telonis Aristeidis G. , Loher Phillipe , Magee Rogan , Pliatsika Venetia , Londin Eric , Kirino Yohei , Rigoutsos Isidore 
Published: April 2019

AbstracttRNA-derived fragments (tRF) are a class of potent regulatory RNAs. We mined the datasets from The Cancer Genome Atlas (TCGA) representing 32 cancer types with a deterministic and exhaustive pipeline for tRNA fragments. We found that mitochondrial tRNAs contribute disproportionally more tRFs than nuclear tRNAs. Through integrative analyses, we uncovered a multitude of statistically significant and context-dependent associations between the identified tRFs and mRNAs. In many of the 32 cancer types, these associations involve mRNAs from developmental processes, receptor tyrosine kinase signaling, the proteasome, and metabolic pathways that include glycolysis, oxidative phosphorylation, and ATP synthesis. Even though the pathways are common to multiple cancers, the association of specific mRNAs with tRFs depends on and differs from cancer to cancer. The associations between tRFs and mRNAs extend to genomic properties as well; specifically, tRFs are positively correlated with shorter genes that have a higher density in repeats, such as ALUs, MIRs, and ERVLs. Conversely, tRFs are negatively correlated with longer genes that have a lower repeat density, suggesting a possible dichotomy between cell proliferation and differentiation. Analyses of bladder, lung, and kidney cancer data indicate that the tRF-mRNA wiring can also depend on a patient's sex. Sex-dependent associations involve cyclin-dependent kinases in bladder cancer, the MAPK signaling pathway in lung cancer, and purine metabolism in kidney cancer. Taken together, these findings suggest diverse and wide-ranging roles for tRFs and highlight the extensive interconnections of tRFs with key cellular processes and human genomic architecture.Significance:Across 32 TCGA cancer contexts, nuclear and mitochondrial tRNA fragments exhibit associations with mRNAs that belong to concrete pathways, encode proteins with particular destinations, have a biased repeat content, and are sex dependent.
Early Infection with Cytomegalovirus and Risk of Childhood Hematologic Malignancies
Authors: Wiemels Joseph L. , Talbäck Mats , Francis Stephen , Feychting Maria 
Published: April 2019

Abstract

Background:
Congenital cytomegalovirus (CMV) infection was recently identified as a risk factor for childhood acute lymphocytic leukemia by detecting the presence of CMV sequences in neonatal blood spots. In this study, we asked whether clinically apparent CMV infection could be identified prior to hematologic malignancy, using high-quality Swedish population-based registries.

Methods:
CMV infection was identified with appropriate ICD-9 or ICD-10 codes in the Patient and Medical Birth Registries, and childhood malignancies below the age of 15 years were identified in the Cancer Registry, among 2,782,507 children born in Sweden 1987 to 2014.

Results:
Observing all CMV infections registered earlier than 6 months prior to malignancy diagnosis, an increased HR of CMV-related infections, adjusting for congenital malformations, deformations, and chromosome abnormalities, was detected for hematologic malignancies [HR, 11.2; 95% confidence interval (CI), 5.8–21.5], but not for central nervous system tumors.

Conclusions:
Higher CMV incidence was detected for children ostensibly exposed through maternal CMV infection during pregnancy with the index child.

Impact:
The data are compatible with a congenital infection of CMV leading to increased risk of childhood hematologic malignancies, but not tumors of the central nervous system, although a cautious interpretation is warranted because of the small numbers.
A Novel Mechanism Driving Poor-Prognosis Prostate Cancer: Overexpression of the DNA Repair Gene, Ribonucleotide Reductase Small Subunit M2 (RRM2)
Authors: Mazzu Ying Z. , Armenia Joshua , Chakraborty Goutam , Yoshikawa Yuki , Coggins Si'Ana A. , Nandakumar Subhiksha , Gerke Travis A. , Pomerantz Mark M. , Qiu Xintao , Zhao Huiyong , Atiq Mohammad , Khan Nabeela , Komura Kazumasa , Lee Gwo-Shu Mary , Fine Samson W. , Bell Connor , O'Connor Edward , Long Henry W. , Freedman Matthew L. , Kim Baek , Kantoff Philip W. 
Published: April 2019

Abstract

Purpose:
Defects in genes in the DNA repair pathways significantly contribute to prostate cancer progression. We hypothesize that overexpression of DNA repair genes may also drive poorer outcomes in prostate cancer. The ribonucleotide reductase small subunit M2 (RRM2) is essential for DNA synthesis and DNA repair by producing dNTPs. It is frequently overexpressed in cancers, but very little is known about its function in prostate cancer.

Experimental Design:
The oncogenic activity of RRM2 in prostate cancer cells was assessed by inhibiting or overexpressing RRM2. The molecular mechanisms of RRM2 function were determined. The clinical significance of RRM2 overexpression was evaluated in 11 prostate cancer clinical cohorts. The efficacy of an RRM2 inhibitor (COH29) was assessed in vitro and in vivo. Finally, the mechanism underlying the transcriptional activation of RRM2 in prostate cancer tissue and cells was determined.

Results:
Knockdown of RRM2 inhibited its oncogenic function, whereas overexpression of RRM2 promoted epithelial mesenchymal transition in prostate cancer cells. The prognostic value of RRM2 RNA levels in prostate cancer was confirmed in 11 clinical cohorts. Integrating the transcriptomic and phosphoproteomic changes induced by RRM2 unraveled multiple oncogenic pathways downstream of RRM2. Targeting RRM2 with COH29 showed excellent efficacy. Thirteen putative RRM2-targeting transcription factors were bioinformatically identified, and FOXM1 was validated to transcriptionally activate RRM2 in prostate cancer.

Conclusions:
We propose that increased expression of RRM2 is a mechanism driving poor patient outcomes in prostate cancer and that its inhibition may be of significant therapeutic value.
Arhgef1 Plays a Vital Role in Platelet Function and Thrombogenesis
Authors: Qasim Hanan , Karim Zubair A. , Hernandez Keziah R. , Lozano Dante , Khasawneh Fadi T. , Alshbool Fatima Z. 
Published: April 2019

Background

Platelets are the cellular mediators of hemostasis and thrombosis, and their function is regulated by a number of molecular mediators, such as small
GTP
ases. These small
GTP
ases are themselves regulated by guanine nucleotide exchange factors such as Arhgefs, several of which are found in platelets, including the highly expressed Arhgef1. However, the role of Arhgef1 in platelets has not yet been investigated.

Methods and Results

We employed mice with genetic deletion of Arhgef1 (ie, Arhgef1
−/−
) and investigated their platelet phenotype by employing a host of in vivo and in vitro platelet assays. Our results indicate that Arhgef1
−/−
mice had prolonged carotid artery occlusion and tail bleeding times. Moreover, platelets from these mice exhibited defective aggregation, dense and α granule secretion, α
II
bβ3 integrin activation, clot retraction and spreading, in comparison to their wild‐type littermates. Finally, we also found that the mechanism by which Arhgef1 regulates platelets is mediated in part by a defect in the activation of the RhoA–Rho‐associated kinase axis, but not Rap1b.

Conclusions
Our data demonstrate, for the first time, that Arhgef1 plays a critical role in platelet function, in vitro and in vivo.
Assessment of potential impact of domestic cats on small mammals in a protected insular area
Authors: Ferreira Giovanne A. , Nakano-Oliveira Eduardo , Andriolo Artur , Genaro Gelson 
Published: April 2019

Abstract
The presence of domestic cats in natural areas is considered one of the main reasons for species loss, especially on islands and among native small non-volant mammals, birds and reptiles. However, in this study, we detected values opposite to those expected for species richness, abundance, and diversity among different areas when considering the presence or absence and density of these felines. We also observed that in the evaluated environments, prey availability did not influence consumption of small mammal species. Our results reinforce the theory of domestic cats’ behaviour as being opportunistic and generalist predators. In addition, we only recorded the presence of exotic species in the faeces of cats; that is, we did not capture exotic species in the traps. The close relationship between these exotic species and anthropogenic environments indicates that felines are likely hunting in areas close to the homes where they live. Assessing the impact of predation by domestic cats on native fauna is important for the development and implementation of strategic resource management and to minimize long-term impacts.
Teuku Panglima Polem’s Purse
Authors: Witkam Jan Just 
Published: April 2019

AbstractThe Dutch colonial wars in Southeast Asia had manuscripts as by-products. The subject of the present article is the content of the purse of Teuku Panglima Polem (d. 1940), an Acehnese leader during the final episode of the colonial war that the Dutch waged in Aceh, a staunch Muslim country in the Northern part of Sumatra. The captured purse was part of war booty in 1899. It contained a number of short Islamic texts, written in anyone of the three languages that at the time were in current use in Aceh: Acehnese, Malay and Arabic. It is, in fact, a small portable library. A full description of the purse’s contents is given and an attempt is made to offer an analysis of the texts that Panglima Polem carried on his person. Such documents were often considered as subversive by the colonial authorities. In an appendix, the author identifies a considerable number Islamic manuscripts in the Leiden collection with similar provenances.
The Role of the External in Local Peacebuilding: Enabling Action—Managing Risk
Authors: Lilja Jannie , Höglund Kristine 
Published: April 2019

Abstract
Local peacebuilding has been embraced in principle by many donors, but the practice of external support to local initiatives needs further systematic study. While previous research has exposed the weaknesses of externally supported peacebuilding, less attention has been given to alternative strategies that can be taken to scale. This article puts the focus on international nongovernmental organizations as key intermediary actors in peacebuilding, and how they deal with dilemmas attached to local peacebuilding support. It contributes to the research on external-local dimensions of peacebuilding practice by identifying constructive functions that can be fulfilled by INGOs in situations where local institutions and actors are not able to address conflict on their own. Specifically, it uncovers the role of INGOs as risk absorbers and enablers of local peacebuilding action through the accompaniment of local partners.
Global Governance and the Interplay of Coordination and Contestation: The Case of Renewable Energies in the South
Authors: Hein Wolfgang , Holstenkamp Lars 
Published: April 2019

Abstract
Developing an adequate sustainable energy supply in developing countries is a major challenge for the global community. Recently, a large number of organizations and enterprises have been supporting technological development, carrying out advocative actions, and offering finance for renewable energy. Concomitantly, there have been strong calls to improve coordination in this field. This article elaborates on the importance of institutional opportunities not only to favor coordination, but also to contest common wisdom shaping energy policies and specific project features at a given time. The result would be a more flexible renewable energy “governance dynamics” to provide the institutional framework for private actors and the interaction with public entities. Thus, three dimensions of global governance are analyzed: coordination, contestation, and the resulting process of collective/interactive regulation.
Il fr. 21 Ross dal De Philosophia e il modello astronomico di Eudosso: un’ipotesi di datazione del dialogo
Authors: Trivellizzi Lara 
Published: April 2019

In this paper I aim to discuss a fragment of Aristotle’s De Philosophia (fr. 21 Ross = Cic. N.D.
ii, 44). After defending Cicero’s reliability as a source for the present fragment, I will focus on its contents, with particular reference to the similarities and differences between fr. 21 Ross and De Caelo A-B: my aim in this comparison is to identify two different astronomical systems underlying, on the one hand, the account of fr. 21 Ross and, on the other hand, that given in the treatise. This shift of model is in my view the actual reason for the inconsistency between these accounts. Such an inconsistency might be explained in chronological terms: the last part of the paper, indeed, develops the hypothesis that De Philosophia Γ was written before 353–350bc, namely before Aristotle got acquainted with Eudoxus’ astronomical system.