bluuebunny/crossref_metadata_2025_split huggingface dataset:
Artificial Recruitment of UAF1-USP Complexes by a PHLPP1-E1 Chimeric Helicase Enhances Human Papillomavirus DNA Replication
Authors: Gagnon David , Lehoux Michaël , Archambault Jacques 
Published: April 2015

ABSTRACT

The E1 helicase from anogenital human papillomavirus (HPV) types interacts with the cellular WD repeat-containing protein UAF1 in complex with the deubiquitinating enzyme USP1, USP12, or USP46. This interaction stimulates viral DNA replication and is required for maintenance of the viral episome in keratinocytes. E1 associates with UAF1 through a short UAF1-binding site (UBS) located within the N-terminal 40 residues of the protein. Here, we investigated if the E1 UBS could be replaced by the analogous domain from an unrelated protein, the pleckstrin homology domain and leucine-rich repeat protein phosphatase 1 (PHLPP1). We found that PHLPP1 and E1 interact with UAF1 in a mutually exclusive manner and mapped the minimal PHLPP1 UBS (PUBS) to a 100-amino-acid region sufficient for assembly into UAF1-USP complexes. Similarly to the E1 UBS, overexpression of PUBS in
trans
inhibited HPV DNA replication, albeit less efficiently. Characterization of a PHLPP1-E1 chimeric helicase revealed that PUBS could partially substitute for the E1 UBS in enhancing viral DNA replication and that the stimulatory effect of PUBS likely involves recruitment of UAF1-USP complexes, as it was abolished by mutations that weaken UAF1-binding and by overexpression of catalytically inactive USPs. Although functionally similar to the E1 UBS, PUBS is larger in size and requires both the WD repeat region and C-terminal ubiquitin-like domain of UAF1 for interaction, in contrast to E1, which does not contact the latter. Overall, this comparison of two heterologous UBSs indicates that these domains function as transferable protein interaction modules and provide further evidence that the association of E1 with UAF1-containing deubiquitinating complexes stimulates HPV DNA replication.

IMPORTANCE
The E1 protein from anogenital HPV types interacts with the UAF1-associated deubiquitinating enzymes USP1, USP12, and USP46 to stimulate replication of the viral genome. Little is known about the molecular nature of the E1-UAF1 interaction and, more generally, how UAF1-USP complexes recognize their substrate proteins. To address this question, we characterized the UAF1-binding site (UBS) of PHLPP1, a protein unrelated to E1. Using a PHLPP1-E1 chimeric helicase, we show that the PHLPP1 UBS (PUBS) can partially substitute for the E1 UBS in stimulating HPV DNA replication. This stimulation required conserved sequences in PUBS that meditate its interaction with UAF1, including a motif common to the E1 UBS. These results indicate that UAF1-binding sequences function as transferable protein interaction modules and provide further evidence that UAF1-USP complexes stimulate HPV DNA replication.
Lymphocytic Choriomeningitis Virus Differentially Affects the Virus-Induced Type I Interferon Response and Mitochondrial Apoptosis Mediated by RIG-I/MAVS
Authors: Pythoud Christelle , Rothenberger Sylvia , Martínez-Sobrido Luis , de la Torre Juan Carlos , Kunz Stefan 
Published: April 2015

ABSTRACT
Arenaviruses are important emerging human pathogens maintained by noncytolytic persistent infection in their rodent reservoir hosts. Despite high levels of viral replication, persistently infected carrier hosts show only mildly elevated levels of type I interferon (IFN-I). Accordingly, the arenavirus nucleoprotein (NP) has been identified as a potent IFN-I antagonist capable of blocking activation of interferon regulatory factor 3 (IRF3) via the retinoic acid inducible gene (RIG)-I/mitochondrial antiviral signaling (MAVS) pathway. Another important mechanism of host innate antiviral defense is represented by virus-induced mitochondrial apoptosis via RIG-I/MAVS and IRF3. In the present study, we investigated the ability of the prototypic Old World arenavirus lymphocytic choriomeningitis virus (LCMV) to interfere with RIG-I/MAVS-dependent apoptosis. We found that LCMV does not induce apoptosis at any time during infection. While LCMV efficiently blocked induction of IFN-I via RIG-I/MAVS in response to superinfection with cytopathic RNA viruses, virus-induced mitochondrial apoptosis remained fully active in LCMV-infected cells. Notably, in LCMV-infected cells, RIG-I was dispensable for virus-induced apoptosis via MAVS. Our study reveals that LCMV infection efficiently suppresses induction of IFN-I but does not interfere with the cell's ability to undergo virus-induced mitochondrial apoptosis as a strategy of innate antiviral defense. The RIG-I independence of mitochondrial apoptosis in LCMV-infected cells provides the first evidence that arenaviruses can reshape apoptotic signaling according to their needs.

IMPORTANCE
Arenaviruses are important emerging human pathogens that are maintained in their rodent hosts by persistent infection. Persistent virus is able to subvert the cellular interferon response, a powerful branch of the innate antiviral defense. Here, we investigated the ability of the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) to interfere with the induction of programmed cell death, or apoptosis, in response to superinfection with cytopathic RNA viruses. Upon viral challenge, persistent LCMV efficiently blocked induction of interferons, whereas virus-induced apoptosis remained fully active in LCMV-infected cells. Our studies reveal that the persistent virus is able to reshape innate apoptotic signaling in order to prevent interferon production while maintaining programmed cell death as a strategy for innate defense. The differential effect of persistent virus on the interferon response versus its effect on apoptosis appears as a subtle strategy to guarantee sufficiently high viral loads for efficient transmission while maintaining apoptosis as a mechanism of defense.
The epidemiology of groin injury in senior football: a systematic review of prospective studies
Authors: Waldén Markus , Hägglund Martin , Ekstrand Jan 
Published: April 2015

BackgroundGroin injuries are troublesome in men's and women's football.AimTo review the literature on the epidemiology of groin injury in senior football and compare injury occurrence between sexes.MethodsStudies were identified through a search of PubMed, EMBASE, CINAHL and Web of Science, in the reference lists of the selected articles and the authors’ bibliographies. The number of injuries, percentage of groin injury from all injuries and rate of groin injury per 1000 h were extracted. Exposure and injury data were aggregated across included studies and the absolute differences in groin injury proportion and rate of groin injury were compared between sexes. Risk of bias was assessed using a 5-item checklist.Results34 articles met the study criteria and were included. The proportion of groin injury in club-seasonal football was 4–19% in men and 2–14% in women. Aggregated data analysis (29 studies) showed a higher relative proportion of groin injury in men than in women (12.8% vs 6.9%, absolute difference 5.9%, 95% CI 4.6% to 7.1%). The rate of groin injury varied from 0.2 to 2.1/1000 h in men and 0.1 to 0.6/1000 h in women's club football, and aggregated analysis (23 studies) showed a more than two-fold higher rate in men (0.83/1000 h vs 0.35/1000 h, rate ratio 2.4, 95% CI 2.0 to 2.9). High risk of bias was identified for participant selection (18 studies), exposure (17 studies) and precision estimate (16 studies).ConclusionsGroin injuries are frequent in senior football and are more common in men than women. Future research needs to be of higher quality.
Risk communication with Arab patients with cancer: a qualitative study of nurses and pharmacists
Authors: Wilbur Kerry , Babiker Alya , Al-Okka Maha , Jumaat Ebaa , Al-Yafei Sumaya M Al Saadi , Nashwan Abdulqadir J 
Published: April 2015

ObjectivesTo explore pharmacist and nurse views and experiences in educating patients regarding their treatment safety and tolerability as well as the roles of other professions in this regard.DesignIn this qualitative study, six focus group discussions were conducted.SettingThe National Center for Cancer Care and Research in Qatar.ParticipantsEleven pharmacists and 22 nurses providing direct patient care.ResultsConcepts related to three key themes were drawn from the seeding questions and included factors for determining the level of risk they communicated: the specific treatment regimen in question; the patient; and their assessment of the patient. Patient-related considerations arose from additional subthemes; both nurses and pharmacists described aspects related to the perceived psychological health status of the patient, as well as anticipated comprehension, as ascertained by demonstrated education and language abilities. In all discussions, it was noted that physician and family non-disclosure of cancer diagnosis to the patient profoundly influenced the nature of information they provided. While a high level of cohesion in safety communication prioritisation among these two health disciplines was found, a number of pharmacists asserted a more formal role compared to informal and repeated teaching by nurses.ConclusionsNurses and pharmacists in this Middle East healthcare environment were not reluctant to discuss treatment side effects with patients and draw on similar professional judgements in prioritising treatment risk information. We found that they did not always recognise each other's informal educational encounters and that there are opportunities to explore increased collaboration in this regard to enhance the patient care experience.
Use of nurse-led telephone follow-up as a sole method of assessing patients after nasal surgery
Authors: Sooby Paul , Kirkland Paul 
Published: April 2015

AbstractPatients undergoing nasal surgery have historically been routinely followed up in consultant led clinics some months after surgery. It has been noted that a significant proportion of these patients either did not attend these appointments or did not require them, impacting on the efficiency of ENT outpatient clinics. A quality improvement project was undertaken to assess this problem and to propose a new patient pathway whereby patients are contacted by ENT nursing staff by telephone three months following surgery. During these telephone conversations only 9.5% of patients requested outpatient follow-up and all of these patients were discharged upon their follow-up. The project demonstrates that nurse-led follow up is an efficient, effective and safe way of managing patient care post-nasal surgery.
The mating game
Authors: Rees Gwen 
Published: April 2015

THIS series gives readers the opportunity to consider and contribute to discussion of some of the ethical dilemmas that can arise in veterinary practice. Each month, a case scenario is presented, followed by discussion of some of the issues involved.In addition, a possible way forward is suggested; however, there is rarely a cut‐and‐dried answer in such cases, and readers may wish to suggest an alternative approach. This month's dilemma, ‘The mating game’, was submitted by Richard Brown and is discussed by Gwen Rees. Readers with comments to contribute are invited to send them as soon as possible, so that they can be considered for publication in the next issue. Discussion of the dilemma ‘Always tell the truth?’, which was published in the March issue of In Practice, appears on page 207.The series is being coordinated by Siobhan Mullan, of the University of Bristol. It is hoped it will provide a framework that will help practices find solutions when facing similar dilemmas.
Characterisation of subpopulations of myeloid cells in infantile haemangioma
Authors: Tan Elysia M S , Chudakova Daria A , Davis Paul F , Brasch Helen D , Itinteang Tinte , Tan Swee T 
Published: April 2015

AimsCells expressing markers of mast cells, macrophages and dendritic cells have previously been demonstrated within the interstitium of infantile haemangioma (IH). This study characterised these myeloid cellular subpopulations within IH.MethodsImmunohistochemical staining was performed on proliferating and involuted IHs for the expression of Nanog, tryptase, CD163, DC-SIGN and CD45. The presence of mRNA corresponding to Nanog, tryptase α/β-1, tryptase β-2, CD163 and DC-SIGN was confirmed by NanoString and RT-PCR in snap-frozen IH tissues.ResultsImmunohistochemical staining showed expression of Nanog by interstitial phenotypical mast cells within proliferating IH, which were separate from the interstitial M2-polarised macrophages that also expressed DC-SIGN, a dendritic cell marker. These two myeloid cellular subpopulations in IH did not express the pan-haematopoietic marker, CD45.ConclusionsThere are two interstitial subpopulations of myeloid cells within IH: phenotypical mast cells which also express Nanog, indicating a primitive phenotype; and M2-polarised macrophages which also express DC-SIGN.
NUAK2 Amplification Coupled with PTEN Deficiency Promotes Melanoma Development via CDK Activation
Authors: Namiki Takeshi , Yaguchi Tomonori , Nakamura Kenta , Valencia Julio C. , Coelho Sergio G. , Yin Lanlan , Kawaguchi Masakazu , Vieira Wilfred D. , Kaneko Yasuhiko , Tanemura Atsushi , Katayama Ichiro , Yokozeki Hiroo , Kawakami Yutaka , Hearing Vincent J. 
Published: April 2015

Abstract
The AMPK-related kinase NUAK2 has been implicated in melanoma growth and survival outcomes, but its therapeutic utility has yet to be confirmed. In this study, we show how its genetic amplification in PTEN-deficient melanomas may rationalize the use of CDK2 inhibitors as a therapeutic strategy. Analysis of array-CGH data revealed that PTEN deficiency is coupled tightly with genomic amplification encompassing the NUAK2 locus, a finding strengthened by immunohistochemical evidence that phospho-Akt overexpression was correlated with NUAK2 expression in clinical specimens of acral melanoma. Functional studies in melanoma cells showed that inactivation of the PI3K pathway upregulated p21 expression and reduced the number of cells in S phase. NUAK2 silencing and inactivation of the PI3K pathway efficiently controlled CDK2 expression, whereas CDK2 inactivation specifically abrogated the growth of NUAK2-amplified and PTEN-deficient melanoma cells. Immunohistochemical analyses confirmed an association of CDK2 expression with NUAK2 amplification and p-Akt expression in melanomas. Finally, pharmacologic inhibition of CDK2 was sufficient to suppress the growth of NUAK2-amplified and PTEN-deficient melanoma cells in vitro and in vivo. Overall, our results show how CDK2 blockade may offer a promising therapy for genetically defined melanomas, where NUAK2 is amplified and PTEN is deleted. Cancer Res; 75(13); 2708–15. ©2015 AACR.
FoxM1 Drives a Feed-Forward STAT3-Activation Signaling Loop That Promotes the Self-Renewal and Tumorigenicity of Glioblastoma Stem-like Cells
Authors: Gong Ai-hua , Wei Ping , Zhang Sicong , Yao Jun , Yuan Ying , Zhou Ai-dong , Lang Frederick F. , Heimberger Amy B. , Rao Ganesh , Huang Suyun 
Published: April 2015

Abstract
The growth factor PDGF controls the development of glioblastoma (GBM), but its contribution to the function of GBM stem-like cells (GSC) has been little studied. Here, we report that the transcription factor FoxM1 promotes PDGFA-STAT3 signaling to drive GSC self-renewal and tumorigenicity. In GBM, we found a positive correlation between expression of FoxM1 and PDGF-A. In GSC and mouse neural stem cells, FoxM1 bound to the PDGF-A promoter to upregulate PDGF-A expression, acting to maintain the stem-like qualities of GSC in part through this mechanism. Analysis of the human cancer genomic database The Cancer Genome Atlas revealed that GBM expresses higher levels of STAT3, a PDGF-A effector signaling molecule, as compared with normal brain. FoxM1 regulated STAT3 transcription through interactions with the β-catenin/TCF4 complex. FoxM1 deficiency inhibited PDGF-A and STAT3 expression in neural stem cells and GSC, abolishing their stem-like and tumorigenic properties. Further mechanistic investigations defined a FoxM1-PDGFA-STAT3 feed-forward pathway that was sufficient to confer stem-like properties to glioma cells. Collectively, our findings showed how FoxM1 activates expression of PDGF-A and STAT3 in a pathway required to maintain the self-renewal and tumorigenicity of glioma stem-like cells. Cancer Res; 75(11); 2337–48. ©2015 AACR.
TR4 Nuclear Receptor Alters the Prostate Cancer CD133+ Stem/Progenitor Cell Invasion via Modulating the EZH2-Related Metastasis Gene Expression
Authors: Zhu Jin , Yang Dong-Rong , Sun Yin , Qiu Xiaofu , Chang Hong-Chiang , Li Gonghui , Shan Yuxi , Chang Chawnshang 
Published: April 2015

Abstract
The testicular nuclear receptor 4 (TR4) is a member of the nuclear receptor superfamily that mediates various biologic functions with key impacts on metabolic disorders and tumor progression. Here, we demonstrate that TR4 may play a positive role in prostate cancer CD133+ stem/progenitor (S/P) cell invasion. Targeting TR4 with lentiviral silencing RNA significantly suppressed prostate cancer CD133+ S/P cell invasion both in vitro and in vivo. Mechanism dissection found that TR4 transcriptionally regulates the oncogene EZH2 via binding to its 5′ promoter region. The consequences of targeting TR4 to suppress EZH2 expression may then suppress the expression of its downstream key metastasis-related genes, including NOTCH1, TGFβ1, SLUG, and MMP9. Rescue approaches via adding the EZH2 reversed the TR4-mediated prostate cancer S/P cell invasion. Together, these results suggest that the TR4→EZH2 signaling may play a critical role in the prostate cancer S/P cell invasion and may allow us to develop a better therapy to battle the prostate cancer metastasis. Mol Cancer Ther; 14(6); 1445–53. ©2015 AACR.
Synergy of Radiotherapy and a Cancer Vaccine for the Treatment of HPV-Associated Head and Neck Cancer
Authors: Mondini Michele , Nizard Mevyn , Tran Thi , Mauge Laetitia , Loi Mauro , Clémenson Céline , Dugue Delphine , Maroun Pierre , Louvet Emilie , Adam Julien , Badoual Cécile , Helley Dominique , Dransart Estelle , Johannes Ludger , Vozenin Marie-Catherine , Perfettini Jean-Luc , Tartour Eric , Deutsch Eric 
Published: April 2015

Abstract
There is growing interest in the association of radiotherapy and immunotherapy for the treatment of solid tumors. Here, we report an extremely effective combination of local irradiation (IR) and Shiga Toxin B (STxB)–based human papillomavirus (HPV) vaccination for the treatment of HPV-associated head and neck squamous cell carcinoma (HNSCC). The efficacy of the irradiation and vaccine association was tested using a model of HNSCC obtained by grafting TC-1/luciferase cells at a submucosal site of the inner lip of immunocompetent mice. Irradiation and the STxB-E7 vaccine acted synergistically with both single and fractionated irradiation schemes, resulting in complete tumor clearance in the majority of the treated mice. A dose threshold of 7.5 Gy was required to elicit the dramatic antitumor response. The combined treatment induced high levels of tumor-infiltrating, antigen-specific CD8+ T cells, which were required to trigger the antitumor activity. Treatment with STxB-E7 and irradiation induced CD8+ T-cell memory, which was sufficient to exert complete antitumor responses in both local recurrences and distant metastases. We also report for the first time that a combination therapy based on local irradiation and vaccination induces an increased pericyte coverage (as shown by αSMA and NG2 staining) and ICAM-1 expression on vessels. This was associated with enhanced intratumor vascular permeability that correlated with the antitumor response, suggesting that the combination therapy could also act through an increased accessibility for immune cells. The combination strategy proposed here offers a promising approach that could potentially be transferred into early-phase clinical trials. Mol Cancer Ther; 14(6); 1336–45. ©2015 AACR.
Leaf constituents of Curcuma spp. suppress Meloidogyne hapla and increase bacterial-feeding nematodes
Authors: Nair Muraleedharan G. , Seenivasan Nagachandrabose , Liu Yunbao , Feick Rebecca M. , Maung Zin-Thu-Zar , Melakeberhan Haddish 
Published: April 2015

Bioactive compounds extracted from agronomical plants have the potential to be ecologically safe and efficient alternatives to restricted broad-spectrum nematicides for managing root pests like Meloidogyne hapla. This study determined the effects of Curcuma longa and C. mangga leaf extracts and constituents on M. hapla infection, beneficial nematodes found in soil, and plant growth under glasshouse conditions over 350-420 degree-days (base 10°C). Incorporation of 60 and 120 g fresh leaves (kg soil)−1 of both Curcuma spp. suppressed the numbers of M. hapla infecting roots of tomato cv. Rutgers but increased beneficial nematodes in soil with minimal negative effect on plant health and growth. Curcuma mangga appears to be more favourable to beneficial nematodes than C. longa. Rhabditis, Acrobeloides and Eucephalobus were the dominant beneficial nematodes isolated from soils amended with Curcuma spp. The safe and selective activities of Curcuma spp. suggest potential for developing biologically integrated M. hapla management strategies.
Small-Scale Precipitation Elements in Midlatitude Cyclones Crossing the California Sierra Nevada
Authors: Medina Socorro , Houze Robert A. 
Published: April 2015

Abstract
Radar data in some frontal systems passing over the Sierra Nevada of California show large variance on scales of ~10 km. The most prominent features are a few kilometers in scale and are similar to small-scale precipitation cells embedded in fronts seen over other mountain ranges. Other frontal systems crossing the Sierras are characterized by more uniform air motions. Updrafts in large-variance storms have characteristics of shear-induced turbulence, although buoyant instability may also contribute. Large-variance storms occur under stronger upstream winds and vertically integrated cross- and along-barrier moisture fluxes. Rain gauges indicate that large-variance storms have precipitation greater than smaller-variance storms. Stronger horizontal moisture fluxes may provide greater mean upslope condensation rates; however, it is hypothesized that accelerated microphysical processes are needed to most efficiently convert the condensate into precipitation that falls out on the lower slopes before being carried downstream. Radar data indicate that the turbulence embodied in the cellular motions of the large-variance cases is consistent with microphysical enhancement resulting from updraft elements producing pockets of liquid water conducive to riming and coalescence. In addition, radar spectrum-width data show that the cells contain strong subcell-scale turbulence conducive to particle collisions and aggregation. Polarimetric radar data just below the 0°C level show large raindrops in the cells, consistent with aggregation occurring in cells just above the melting layer. It is hypothesized that such enhanced microphysical processes in large-variance cases hasten the growth and fallout in the regions of maximum condensation over the windward slopes.