bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relativity and Three Four‐dimensionalisms
Authors: Gilmore Cody , Costa Damiano , Calosi Claudio 
Published: February 2016

AbstractRelativity theory is often said to support something called ‘the four‐dimensional view of reality’. But there are at least three different views that sometimes go by this name. One is ‘spacetime unitism’ (as we call it), according to which there is a spacetime manifold, and if there are such things as points of space or instants of time, these are just spacetime regions of different sorts: thus space and time are not separate manifolds. A second is the B‐theory of time, according to which the past, present, and future are all equally real and there is nothing metaphysically special about the present. A third is perdurantism, according to which persisting material objects (rocks, trees, and human beings) are made up of different temporal parts located at different times. We sketch routes from relativity to unitism and to the B‐theory. We then discuss some routes to perdurantism, via the B‐theory and via unitism.
Novel Human Three‐Domain Antibody Fragments Against sTNFα as Well as tmTNFα with High Affinity Generated by the Combination of Ribosome Display and E. coli Expression System
Authors: Zhao X.‐L. , Tian L.‐F. , Zhang S.‐J. , Li J.‐M. , Feng H. , Wang L.‐M. , Wang S. , Wang J. , Wang T. , Chen W.‐Q. 
Published: February 2016

AbstractHuman tumour necrosis factor α (hTNFα) has been proved to be a validated therapeutic target in a number of immune‐mediated inflammatory diseases (IMIDs). Fully human monoclonal antibodies (mAbs) that can neutralize soluble hTNFα (sTNFα) as well as transmembrane hTNFα (tmTNFα) are more desirable hTNFα antagonists. Here, we report that novel anti‐hTNFα human low‐molecular‐weight MAbs have been selected and identified using both sTNFα and tmTNFα as target antigens by the combination of ribosome display and E. coli expression system for the first time. As a newly born engineering small molecular antibody, three‐domain antibody fragment (VH/κ) provides an alternative promising molecular principle to generate biological agents for TNFα‐dependent IMIDs. In this study, a panel of novel human VH/κs (F09, F21, F49 and F409) with high affinity (10−10–10−9 mol/l) to neutralize sTNFα as well as tmTNFα was generated by the combination of ribosome display and E. coli expression system. Among the four clones, F21 and F409 could reduce cytotoxicity on L929 cells induced by sTNFα as well as tmTNFα effectively, and both of them had great potential to inhibit hTNFα‐mediated NF‐κB activation. Soluble F21 and F409 were also able to inhibit the binding of hTNFα to TNFR1 and TNFR2. The new human antibodies described here have desirable capability to neutralize sTNFα as well as tmTNFα effectively with high affinity and reasonable stability; this may provide an alternative approach for patients who are not responding adequately to currently available anti‐TNFα agents.
Identification and Modelling of Translational and Axial Symmetries and their Hierarchical Structures in Building Footprints by Formal Grammars
Authors: Dehbi Youness , Gröger Gerhard , Plümer Lutz 
Published: February 2016

AbstractBuildings and other man‐made objects, for many reasons such as economical or aesthetic, are often characterized by their symmetry. The latter predominates in the design of building footprints and building parts such as façades. Thus the identification and modeling of this valuable information facilitates the reconstruction of these buildings and their parts. This article presents a novel approach for the automatic identification and modelling of symmetries and their hierarchical structures in building footprints, providing an important prior for façade and roof reconstruction. The uncertainty of symmetries is explicitly addressed using supervised machine learning methods, in particular Support Vector Machines (SVMs). Unlike classical statistical methods, for SVMs assumptions on the a priori distribution of the data are not required. Both axial and translational symmetries are detected. The quality of the identified major and minor symmetry axes is assessed by a least squares based adjustment. Context‐free formal grammar rules are used to model the hierarchical and repetitive structure of the underlying footprints. We present an algorithm which derives grammar rules based on the previously acquired symmetry information and using lexical analysis describing regular patterns and palindrome‐like structures. This offers insights into the latent structures of building footprints and therefore describes the associated façade in a relational and compact way.
Emerging roles for vascular smooth muscle cell exosomes in calcification and coagulation
Authors: Kapustin A. N. , Shanahan C. M. 
Published: February 2016

AbstractVascular smooth muscle cell (VSMC) phenotypic conversion from a contractile to ‘synthetic’ state contributes to vascular pathologies including restenosis, atherosclerosis and vascular calcification. We have recently found that the secretion of exosomes is a feature of ‘synthetic’ VSMCs and that exosomes are novel players in vascular repair processes as well as pathological vascular thrombosis and calcification. Pro‐inflammatory cytokines and growth factors as well as mineral imbalance stimulate exosome secretion by VSMCs, most likely by the activation of sphingomyelin phosphodiesterase 3 (SMPD3) and cytoskeletal remodelling. Calcium stress induces dramatic changes in VSMC exosome composition and accumulation of phosphatidylserine (PS), annexin A6 and matrix metalloproteinase‐2, which converts exosomes into a nidus for calcification. In addition, by presenting PS, VSMC exosomes can also provide the catalytic surface for the activation of coagulation factors. Recent data showing that VSMC exosomes are loaded with proteins and miRNA regulating cell adhesion and migration highlight VSMC exosomes as potentially important communication messengers in vascular repair. Thus, the identification of signalling pathways regulating VSMC exosome secretion, including activation of SMPD3 and cytoskeletal rearrangements, opens up novel avenues for a deeper understanding of vascular remodelling processes.
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Unveiling Protein Kinase A Targets in Cryptococcus neoformans Capsule Formation
Authors: Alspaugh J. Andrew 
Published: February 2016

ABSTRACT

The protein kinase A (PKA) signal transduction pathway has been associated with pathogenesis in many fungal species. Geddes and colleagues [mBio 7(1):e01862-15, 2016, doi:10.1128/mBio.01862-15] used quantitative proteomics approaches to define proteins with altered abundance during protein kinase A (PKA) activation and repression in the opportunistic human fungal pathogen
Cryptococcus neoformans
. They observed an association between microbial PKA signaling and ubiquitin-proteasome regulation of protein homeostasis. Additionally, they correlated these processes with expression of polysaccharide capsule on the fungal cell surface, the main virulence-associated phenotype in this organism. Not only are their findings important for microbial pathogenesis, but they also support similar associations between human PKA signaling and ubiquitinated protein accumulation in neurodegenerative diseases.
The Membrane Protein of Severe Acute Respiratory Syndrome Coronavirus Functions as a Novel Cytosolic Pathogen-Associated Molecular Pattern To Promote Beta Interferon Induction via a Toll-Like-Receptor-Related TRAF3-Independent Mechanism
Authors: Wang Yi , Liu Li 
Published: February 2016

ABSTRACT
Most of the intracellular pattern recognition receptors (PRRs) reside in either the endolysosome or the cytoplasm to sense pathogen-derived RNAs, DNAs, or synthetic analogs of double-stranded RNA (dsRNA), such as poly(I:C). However, it remains elusive whether or not a pathogen-derived protein can function as a cytosolic pathogen-associated molecular pattern (PAMP). In this study, we demonstrate that delivering the membrane gene of severe acute respiratory syndrome coronavirus (SARS-CoV) into HEK293T, HEK293ET, and immobilized murine bone marrow-derived macrophage (J2-Mφ) cells significantly upregulates beta interferon (IFN-β) production. Both NF-κB and TBK1-IRF3 signaling cascades are activated by M gene products. M protein rather than M mRNA is responsible for M-mediated IFN-β induction that is preferentially associated with the activation of the Toll-like receptor (TLR) adaptor proteins MyD88, TIRAP, and TICAM2 but not the RIG-I signaling cascade. Blocking the secretion of M protein by brefeldin A (BFA) failed to reverse the M-mediated IFN-β induction. The antagonist of both TLR2 and TLR4 did not impede M-mediated IFN-β induction, indicating that the driving force for the activation of IFN-β production was generated from inside the cells. Inhibition of TRAF3 expression by specific small interfering RNA (siRNA) did not prevent M-mediated IFN-β induction. SARS-CoV pseudovirus could induce IFN-β production in an M rather than M(V68A) dependent manner, since the valine-to-alanine alteration at residue 68 in M protein markedly inhibited IFN-β production. Overall, our study indicates for the first time that a pathogen-derived protein is able to function as a cytosolic PAMP to stimulate type I interferon production by activating a noncanonical TLR signaling cascade in a TRAF3-independent manner.

IMPORTANCE
Viral protein can serve as a pathogen-associated molecular pattern (PAMP) that is usually recognized by certain pathogen recognition receptors (PRRs) on the cell surface, such as Toll-like receptor 2 (TLR2) and TLR4. In this study, we demonstrate that the membrane (M) protein of SARS-CoV can directly promote the activation of both beta interferon (IFN-β) and NF-κB through a TLR-related signaling pathway independent of TRAF3. The driving force for M-mediated IFN-β production is most likely generated from inside the cells. M-mediated IFN-β induction was confirmed at the viral infection level since a point mutation at the V68 residue of M markedly inhibited SARS-CoV pseudovirally induced IFN-β production. Thus, the results indicate for the first time that SARS-CoV M protein may function as a cytosolic PAMP to stimulate IFN-β production by activating a TLR-related TRAF3-independent signaling cascade.
Lambda Interferon Restructures the Nasal Microbiome and Increases Susceptibility to Staphylococcus aureus Superinfection
Authors: Planet Paul J. , Parker Dane , Cohen Taylor S. , Smith Hannah , Leon Justinne D. , Ryan Chanelle , Hammer Tobin J. , Fierer Noah , Chen Emily I. , Prince Alice S. 
Published: February 2016

ABSTRACT

Much of the morbidity and mortality associated with influenza virus respiratory infection is due to bacterial coinfection with pathogens that colonize the upper respiratory tract such as methicillin-resistant
Staphylococcus aureus
(MRSA) and
Streptococcus pneumoniae
. A major component of the immune response to influenza virus is the production of type I and III interferons. Here we show that the immune response to infection with influenza virus causes an increase and restructuring of the upper respiratory microbiota in wild-type (WT) mice but not in

Il28r
−/−

mutant mice lacking the receptor for type III interferon. Mice lacking the IL-28 receptor fail to induce STAT1 phosphorylation and expression of its regulator, SOCS1.

Il28r
−/−

mutant mice have increased expression of interleukin-22 (IL-22), as well as Ngal and RegIIIγ, in the nasal cavity, the source of organisms that would be aspirated to cause pneumonia. Proteomic analysis reveals changes in several cytoskeletal proteins that contribute to barrier function in the nasal epithelium that may contribute to the effects of IL-28 signaling on the microbiota. The importance of the effects of IL-28 signaling in the pathogenesis of MRSA pneumonia after influenza virus infection was confirmed by showing that WT mice nasally colonized before or after influenza virus infection had significantly higher levels of infection in the upper airways, as well as significantly greater susceptibility to MRSA pneumonia than
Il28r
−/−
mutant mice did. Our results suggest that activation of the type III interferon in response to influenza virus infection has a major effect in expanding the upper airway microbiome and increasing susceptibility to lower respiratory tract infection.

IMPORTANCE
S. aureus
and influenza virus are important respiratory pathogens, and coinfection with these organisms is associated with significant morbidity and mortality. The ability of influenza virus to increase susceptibility to
S. aureus
infection is less well understood. We show here that influenza virus leads to a change in the upper airway microbiome in a type III interferon-dependent manner. Mice lacking the type III interferon receptor have altered STAT1 and IL-22 signaling. In coinfection studies, mice without the type III interferon receptor had significantly less nasal
S. aureus
colonization and subsequent pneumonia than infected WT mice did. This work demonstrates that type III interferons induced by influenza virus contribute to nasal colonization and pneumonia due to
S. aureus
superinfection.
Immigrant mothers and access to prenatal care: evidence from a regional population study in Italy
Authors: Chiavarini Manuela , Lanari Donatella , Minelli Liliana , Pieroni Luca , Salmasi Luca 
Published: February 2016

ObjectivesWe addressed the question of whether use of adequate prenatal care differs between foreign-born and Italian mothers and estimated the extent to which unobservable characteristics bias results.SettingThis study is on primary care and especially on adequate access to prenatal healthcare services by immigrant mothers.ParticipantsApproximately 37 000 mothers of both Italian and foreign nationality were studied. Data were obtained from the Standard Certificate of Live Birth between 2005 and 2010 in Umbria.ResultsEstimates from the bivariate probit model indicate that immigrant mothers are three times more likely to make fewer than four prenatal visits (OR=3.35) and 1.66 times more likely to make a late first visit (OR=1.66). The effect is found to be strongest for Asian women.ConclusionsStandard probit models lead to underestimation of the probability of inadequate use of prenatal care services by immigrant women, whereas bivariate probit models, which allow us to consider immigrant status as an endogenous variable, estimated ORs to be three times larger than those obtained with univariate models.
Exploring provision of Innovative Community Education Placements (ICEPs) for junior doctors in training: a qualitative study
Authors: Griffin Ann , Jones Melvyn M , Khan Nada , Park Sophie , Rosenthal Joe , Chrysikou Vasiliki 
Published: February 2016

ObjectiveMedical education in community settings is an essential ingredient of doctors’ training and a key factor in recruiting general practitioners (GP). Health Education England's report ‘Broadening the Foundation’ recommends foundation doctors complete 4-month community placements. While Foundation GP schemes exist; other community settings, are not yet used for postgraduate training. The objective of this study was to explore how community-based training of junior doctors might be expanded into possible ‘innovative community education placements’ (ICEPs), examining opportunities and barriers to these developments.DesignA qualitative study where semistructured interviews were undertaken and themes were generated deductively from the research questions, and iteratively from transcripts.SettingUK community healthcare.ParticipantsStakeholders from UK Community healthcare providers and undergraduate GP and community educators.ResultsNine participants were interviewed; those experienced in delivering community-based undergraduate education, and others working in community settings that had not previously trained doctors. Themes identified were practicalities such as ‘finance and governance’, ‘communication and interaction’, ‘delivery of training’ and ‘perceptions of community’. ICEPs were willing to train Foundation doctors. However, concerns were raised that large numbers and inadequate resources could undermine the quality of educational opportunities, and even cause reputational damage. Organisation was seen as a challenge, which might be best met by placing some responsibility with trainees to manage their placements. ICEP providers agreed that defined service contribution by trainees was required to make placements sustainable, and enhance learning. ICEPs stated the need for positive articulation of the learning value of placements to learners and stakeholders.ConclusionsThis study highlighted the opportunities for foundation doctors to gain specialist and generalist knowledge in ICEPs from diverse clinical teams and patients. We recommend in conclusion ways of dealing with some of the perceived barriers to training.
CD10-positive myoepithelial cells are usually prominent around in situ lobular neoplasia of the breast and much less prominent or absent in DCIS
Authors: Shousha Sami , Forbes Georgina , Hopkins Ilona , Wright Josephine Anne 
Published: February 2016

AimsTo study the relationship between the neoplastic cells of in situ lobular neoplasia (ILN) and ductal carcinoma in situ (DCIS) and the surrounding CD10-positive myoepithelial cells.Materials and methodsTwenty consecutive cases of ILN and 51 of DCIS were stained for CD10 using the immunoperoxidase technique. The presence of CD10-positive cells was assessed semiquantitatively on a scale of 0–3 where 0 indicates their absence and 3 indicates the presence of multiple layers, which can be focal.ResultsNinety per cent of ILN cases scored 3, compared with none of DCIS (p=0.0001). There was a significant relationship between DCIS grade and CD10 score, with the mean scores being 1.43, 0.82 and 0.5 for low, intermediate and high grade, respectively. CD10-positive cells were always present around low-grade DCIS, but absent in 27% of high-grade cases. CD10-positive cells were more frequent in ER-positive than in ER-negative DCIS, and in HER2-negative than in HER2-positive cases, but the difference was not statistically significant.ConclusionsThere is a distinct relationship between the type and grade of in situ neoplasia of the breast and the surrounding CD10-positive myoepithelial cells, suggesting the presence of a ‘cross talk’ between the two elements.
The role of distributed education in recruitment and retention of family physicians
Authors: Lee Joseph , Walus Andrzej , Billing Rajeev , Hillier Loretta M 
Published: February 2016

AbstractBackgroundDistributed medical education (DME) programmes, in which training occurs in underserviced areas, have been established as a strategy to increase recruitment and retention of new physicians following graduation to these areas. Little is known about what makes physicians remain in the area in which they train.ObjectivesTo explore the factors that contributed to family physician's decisions to practice in an underserviced area following graduation from a DME programme.MethodsSemistructured inperson interviews were conducted with 19 family physicians who graduated from a DME residency training programme. Programme records were reviewed to identify practice location of DME programme graduates.ResultsOf the 32 graduates to date from this DME programme, 66% (N=21) and all of the interview participants established their practices in this region after completing their residency training. Five key themes were identified from the interview analysis as impacting physicians' decisions to establish their practice in an underserviced area following graduation: familial ties to the region, practice opportunities, positive clerkship and residency experiences, established relationships with specialists and services in the area and lifestyle opportunities afforded by the location.ConclusionsThis study suggests that DME programmes can be an effective strategy for equalising the distribution of family physicians and highlights the ways in which these programmes can facilitate recruitment and retention in underserviced areas, including being responsive to residents' personal preferences and objectives for learning and shaping their residency experiences to meet to these objectives.
Hypoxic Signaling and the Cellular Redox Tumor Environment Determine Sensitivity to MTH1 Inhibition
Authors: Bräutigam Lars , Pudelko Linda , Jemth Ann-Sofie , Gad Helge , Narwal Mohit , Gustafsson Robert , Karsten Stella , Carreras Puigvert Jordi , Homan Evert , Berndt Carsten , Berglund Ulrika Warpman , Stenmark Pål , Helleday Thomas 
Published: February 2016

Abstract
Cancer cells are commonly in a state of redox imbalance that drives their growth and survival. To compensate for oxidative stress induced by the tumor redox environment, cancer cells upregulate specific nononcogenic addiction enzymes, such as MTH1 (NUDT1), which detoxifies oxidized nucleotides. Here, we show that increasing oxidative stress in nonmalignant cells induced their sensitization to the effects of MTH1 inhibition, whereas decreasing oxidative pressure in cancer cells protected against inhibition. Furthermore, we purified zebrafish MTH1 and solved the crystal structure of MTH1 bound to its inhibitor, highlighting the zebrafish as a relevant tool to study MTH1 biology. Delivery of 8-oxo-dGTP and 2-OH-dATP to zebrafish embryos was highly toxic in the absence of MTH1 activity. Moreover, chemically or genetically mimicking activated hypoxia signaling in zebrafish revealed that pathologic upregulation of the HIF1α response, often observed in cancer and linked to poor prognosis, sensitized embryos to MTH1 inhibition. Using a transgenic zebrafish line, in which the cellular redox status can be monitored in vivo, we detected an increase in oxidative pressure upon activation of hypoxic signaling. Pretreatment with the antioxidant N-acetyl-L-cysteine protected embryos with activated hypoxia signaling against MTH1 inhibition, suggesting that the aberrant redox environment likely causes sensitization. In summary, MTH1 inhibition may offer a general approach to treat cancers characterized by deregulated hypoxia signaling or redox imbalance. Cancer Res; 76(8); 2366–75. ©2016 AACR.
SIRT6 Overexpression Potentiates Apoptosis Evasion in Hepatocellular Carcinoma via BCL2-Associated X Protein–Dependent Apoptotic Pathway
Authors: Ran Long-Kuan , Chen Yong , Zhang Zhen-Zhen , Tao Na-Na , Ren Ji-Hua , Zhou Li , Tang Hua , Chen Xiang , Chen Ke , Li Wan-Yu , Huang Ai-Long , Chen Juan 
Published: February 2016

Abstract
Purpose: To characterize the functional role of SIRT6 in hepatocellular carcinoma (HCC).
Experimental Design: The expression of SIRT6 in 60 paired paraffin-embedded HCC tissues and adjacent nontumoral liver tissues was examined by immunohistochemistry. The expression of SIRT6 in 101 paired frozen HCC tissues and adjacent nontumoral liver tissues was analyzed by Western blotting analysis and qPCR. The biologic consequences of overexpression and knockdown of SIRT6 in HCC cell lines were studied in vitro and in vivo.
Results: SIRT6 expression was frequently upregulated in clinical HCC samples, and its expression was highly associated with tumor grade (P = 0.02), tumor size (P = 0.02), vascular invasion (P = 0.004), and shorter survival (P = 0.024). Depletion of SIRT6 from multiple liver cancer cell lines inhibited their growth and induced apoptosis in vitro. At the molecular level, we observed that the activation of the BCL2-associated X protein (Bax) signaling pathway, a major pathway that determines cancer cell apoptosis, is regulated by SIRT6 via its deacetylase activity. SIRT6 was recruited to the promoter of Bax, where it deacetylated histone 3 lysine 9 and suppressed its promoter activity. Binding of transcription factors (p53 and E2F-1) to Bax promoter was also generally increased in SIRT6-depleted cells. In mouse xenografts, SIRT6 suppression inhibited tumor growth and induced apoptosis. Finally, there is a negative correlation between SIRT6 and Bax mRNA expressions in human HCC samples.
Conclusions: SIRT6 is an important protumorigenic factor in liver carcinogenesis. Thus, the therapeutic targeting of SIRT6 may offer options for HCC treatment. Clin Cancer Res; 22(13); 3372–82. ©2016 AACR.