bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of Herpes Simplex Virus 1 γ34.5 in the Regulation of IRF3 Signaling
Authors: Manivanh Richard , Mehrbach Jesse , Knipe David M. , Leib David A. 
Published: September 2017

ABSTRACT

During viral infection, pattern recognition receptors (PRRs) and their associated adaptors recruit TANK-binding kinase 1 (TBK1) to activate interferon regulatory factor 3 (IRF3), resulting in production of type I interferons (IFNs). ICP0 and ICP34.5 are among the proteins encoded by herpes simplex virus 1 (HSV-1) that modulate type I IFN signaling. We constructed a recombinant virus (ΔXX) that lacks amino acids 87 to 106, a portion of the previously described TBK1-binding domain of the γ34.5 gene (D. Verpooten, Y. Ma, S. Hou, Z. Yan, and B. He, J Biol Chem 284:1097–1105, 2009,
https://doi.org/10.1074/JBC.M805905200
). These 20 residues are outside the γ34.5 beclin1-binding domain (BBD) that interacts with beclin1 and regulates autophagy. Unexpectedly, ΔXX showed no deficit in replication
in vivo
in a variety of tissues and showed virulence comparable to that of wild-type and marker-rescued viruses following intracerebral infection. ΔXX was fully capable of mediating the dephosphorylation of eIF2α, and the virus was capable of controlling the phosphorylation of IRF3. In contrast, a null mutant in γ34.5 failed to control IRF3 phosphorylation due to an inability of the mutant to sustain expression of ICP0. Our data show that while γ34.5 regulates IRF3 phosphorylation, the TBK1-binding domain itself has no impact on IRF3 phosphorylation or on replication and pathogenesis in mice.

IMPORTANCE
Interferons (IFNs) are potent activators of a variety of host responses that serve to control virus infections. The
Herpesviridae
have evolved countermeasures to IFN responses. Herpes simplex virus 1 (HSV-1) encodes the multifunctional neurovirulence protein ICP34.5. In this study, we investigated the biological relevance of the interaction between ICP34.5 and TANK-binding kinase 1 (TBK1), an activator of IFN responses. Here, we establish that although ICP34.5 binds TBK1 under certain conditions through a TBK1-binding domain (TBD), there was no direct impact of the TBD on viral replication or virulence in mice. Furthermore, we showed that activation of IRF3, a substrate of TBK1, was independent of the TBD. Instead, we provided evidence that the ability of ICP34.5 to control IRF3 activation is through its ability to reverse translational shutoff and sustain the expression of other IFN inhibitors encoded by the virus. This work provides new insights into the immunomodulatory functions of ICP34.5.
Calcitonin Gene-Related Peptide Induces HIV-1 Proteasomal Degradation in Mucosal Langerhans Cells
Authors: Bomsel Morgane , Ganor Yonatan 
Published: September 2017

ABSTRACT

The neuroimmune dialogue between peripheral neurons and Langerhans cells (LCs) within mucosal epithelia protects against incoming pathogens. LCs rapidly internalize human immunodeficiency virus type 1 (HIV-1) upon its sexual transmission and then
trans
-infect CD4
+
T cells. We recently found that the neuropeptide calcitonin gene-related peptide (CGRP), secreted mucosally from peripheral neurons, inhibits LC-mediated HIV-1
trans
-infection. In this study, we investigated the mechanism of CGRP-induced inhibition, focusing on HIV-1 degradation in LCs and its interplay with
trans
-infection. We first show that HIV-1 degradation occurs in endolysosomes in untreated LCs, and functionally blocking such degradation with lysosomotropic agents results in increased
trans
-infection. We demonstrate that CGRP acts via its cognate receptor and at a viral postentry step to induce faster HIV-1 degradation, but without affecting the kinetics of endolysosomal degradation. We reveal that unexpectedly, CGRP shifts HIV-1 degradation from endolysosomes toward the proteasome, providing the first evidence for functional HIV-1 proteasomal degradation in LCs. Such efficient proteasomal degradation significantly inhibits the first phase of
trans
-infection, and proteasomal, but not endolysosomal, inhibitors abrogate CGRP-induced inhibition. Together, our results establish that CGRP controls the HIV-1 degradation mode in LCs. The presence of endogenous CGRP within innervated mucosal tissues, especially during the sexual response, to which CGRP contributes, suggests that HIV-1 proteasomal degradation predominates
in vivo
. Hence, proteasomal, rather than endolysosomal, HIV-1 degradation in LCs should be enhanced clinically to effectively restrict HIV-1
trans
-infection.

IMPORTANCE
During sexual transmission, HIV-1 is internalized and degraded in LCs, the resident antigen-presenting cells in mucosal epithelia. Yet during
trans
-infection, infectious virions escaping degradation are transferred to CD4
+
T cells, the principal HIV-1 targets. We previously found that the neuroimmune dialogue between LCs and peripheral neurons, innervating mucosal epithelia, significantly inhibits
trans
-infection via the action of the secreted neuropeptide CGRP on LCs. In this study, we investigated whether CGRP-induced inhibition of
trans
-infection is linked to CGRP-controlled HIV-1 degradation in LCs. We show that in untreated LCs, HIV-1 is functionally degraded in endolysosomes. In sharp contrast, we reveal that in CGRP-treated LCs, HIV-1 is diverted toward and degraded via another cytosolic protein degradative pathway, namely, the proteasome. These results establish that CGRP regulates HIV-1 degradation in LCs. As CGRP contributes to the sexual response and present within mucosal epithelia, HIV-1 proteasomal degradation in LCs might predominate
in vivo
and should be enhanced clinically.
Vaccinia Virus Encodes a Novel Inhibitor of Apoptosis That Associates with the Apoptosome
Authors: Ryerson Melissa R. , Richards Monique M. , Kvansakul Marc , Hawkins Christine J. , Shisler Joanna L. 
Published: September 2017

ABSTRACTApoptosis is an important antiviral host defense mechanism. Here we report the identification of a novel apoptosis inhibitor encoded by the vaccinia virus (VACV)M1Lgene.M1Lis absent in the attenuated modified vaccinia virus Ankara (MVA) strain of VACV, a strain that stimulates apoptosis in several types of immune cells. M1 expression increased the viability of MVA-infected THP-1 and Jurkat cells and reduced several biochemical hallmarks of apoptosis, such as PARP-1 and procaspase-3 cleavage. Furthermore, ectopicM1Lexpression decreased staurosporine-induced (intrinsic) apoptosis in HeLa cells. We then identified the molecular basis for M1 inhibitory function. M1 allowed mitochondrial depolarization but blocked procaspase-9 processing, suggesting that M1 targeted the apoptosome. In support of this model, we found that M1 promoted survival inSaccharomyces cerevisiaeoverexpressing human Apaf-1 and procaspase-9, critical components of the apoptosome, or overexpressing only conformationally active caspase-9. In mammalian cells, M1 coimmunoprecipitated with Apaf-1–procaspase-9 complexes. The current model is that M1 associates with and allows the formation of the apoptosome but prevents apoptotic functions of the apoptosome. The M1 protein features 14 predicted ankyrin (ANK) repeat domains, and M1 is the first ANK-containing protein reported to use this inhibitory strategy. Since ANK-containing proteins are encoded by many large DNA viruses and found in all domains of life, studies of M1 may lead to a better understanding of the roles of ANK proteins in virus-host interactions.IMPORTANCEApoptosis selectively eliminates dangerous cells such as virus-infected cells. Poxviruses express apoptosis antagonists to neutralize this antiviral host defense. The vaccinia virus (VACV) M1 ankyrin (ANK) protein, a protein with no previously ascribed function, inhibits apoptosis. M1 interacts with the apoptosome and prevents procaspase-9 processing as well as downstream procaspase-3 cleavage in several cell types and under multiple conditions. M1 is the first poxviral protein reported to associate with and prevent the function of the apoptosome, giving a more detailed picture of the threats VACV encounters during infection. Dysregulation of apoptosis is associated with several human diseases. One potential treatment of apoptosis-related diseases is through the use of designed ANK repeat proteins (DARPins), similar to M1, as caspase inhibitors. Thus, the study of the novel antiapoptosis effects of M1 via apoptosome association will be helpful for understanding how to control apoptosis using either natural or synthetic molecules.
Long-term follow-up of benign positional vertical opsoclonus in infants: retrospective cohort
Authors: Sternfeld Amir , Lobel Daniella , Leiba Hana , Luckman Judith , Michowiz Shalom , Goldenberg-Cohen Nitza 
Published: September 2017

Background/AimsBenign positional vertical opsoclonus in infants, also described as paroxysmal tonic downgaze, is an unsettling phenomenon that leads to extensive work-up, although benign course has been reported in sporadic cases. We describe long-term follow-up of a series of infants with the phenomenon.MethodsThis retrospective cohort included all infants diagnosed with rapid downgaze eye movement in 2012–2015 and followed until 2016. The databases of two medical centres were retrospectively reviewed. Benign positional vertical opsoclonus was diagnosed based on clinical findings of experienced neuro-ophthalmologists. Data were collected on demographics, symptoms and signs, neuro-ophthalmological and neurological evaluations, and outcome. Imaging studies were reviewed. Main outcome measures were long-term outcome and findings of the thorough investigation.ResultsThe cohort included six infants. All infants were born at term. Age at presentation was several days to 12 weeks. Episodes lasted a few seconds and varied in frequency from <10 to dozens per day. In five infants, symptoms occurred in the supine position. There was a wide variability in the work-up without any pathological findings. Follow-up ranged from 1 to 2.5 years. Ocular symptoms gradually decreased until resolution. Infants reached normal developmental milestones.ConclusionsOur identification of six patients in only 3 years suggests benign positional vertical opsoclonus may be more prevalent than previously described. In our experience, it affects otherwise healthy infants and resolves spontaneously. In view of the good long-term outcome, a comprehensive clinical investigation may not be necessary.
Continuation of non-essential medications in actively dying hospitalised patients
Authors: Williams Beverly Rosa , Amos Bailey F , Kvale Elizabeth , Steil Neal , Goode Patricia S , Kennedy Richard E , Burgio Kathryn L 
Published: September 2017

ObjectiveThe objective of this analysis was to examine the use of 11 non-essential medications in actively dying patients.MethodsThis was a planned secondary analysis of data from the Best Practices for End-of-Life Care for Our Nation’s Veterans trial, a multicentre implementation trial of an intervention to improve processes of end-of-life care in inpatient settings. Supported with an electronic comfort care decision support tool, intervention included training hospital staff to identify actively dying patients, communicate the prognosis to patients/families and implement best practices of traditionally home-based hospice care. Data on medication use before and after intervention were derived from electronic medical records of 5476 deceased veterans.ResultsFive non-essential medications, clopidogrel, donepezil, glyburide, metformin and propoxyphene, were ordered in less than 5% of cases. More common were orders for simvastatin (15.8%/15.1%), calcium tablets (8.4%/7.9%), multivitamins (11.6%/10.8%), ferrous sulfate (9.1%/7.6%), diphenhydramine (7.2%/5.1%) and subcutaneous heparin (29.9%/27.5%). Significant decreases were found for donepezil (2.5%/1.3%; p=0.001), propoxyphene (0.8%/0.1%; p=0.001), metformin (0.8%/0.3%; p=0.007) and multivitamins (11.6%/10.8%; p=0.01). Orders for one or more non-essential medications were less likely to occur in association with palliative care consultation (adjusted OR (AOR)=0.64, p<0.001), do-not-resuscitate orders (AOR=0.66, p=0.001) and orders for death rattle medication (AOR=0.35, p<0.001). Patients who died in an intensive care unit were more likely to receive a non-essential medication (AOR=1.60, p=0.009), as were older patients (AOR=1.12 per 10 years, p=0.002).ConclusionsNon-essential medications continue to be administered to actively dying patients. Discontinuation of these medications may be facilitated by interventions that enhance recognition and consideration of patients’ actively dying status.
WHO Mental Health Gap Action Programme (mhGAP) Intervention Guide: a systematic review of evidence from low and middle-income countries
Authors: Keynejad Roxanne C , Dua Tarun , Barbui Corrado , Thornicroft Graham 
Published: September 2017

QuestionDespite mental, neurological and substance use (MNS) disorders being highly prevalent, there is a worldwide gap between service need and provision. WHO launched its Mental Health Gap Action Programme (mhGAP) in 2008, and the Intervention Guide (mhGAP-IG) in 2010. mhGAP-IG provides evidence-based guidance and tools for assessment and integrated management of priority MNS disorders in low and middle-income countries (LMICs), using clinical decision-making protocols. It targets a non-specialised primary healthcare audience, but has also been used by ministries, non-governmental organisations and academics, for mental health service scale-up in 90 countries. This review aimed to identify evidence to date for mhGAP-IG implementation in LMICs.Study selection and analysisWe searched MEDLINE, Embase, PsycINFO, Web of Knowledge/Web of Science, Scopus, CINAHL, LILACS, SciELO/Web of Science, Cochrane, Pubmed databases and Google Scholar for studies reporting evidence, experience or evaluation of mhGAP-IG in LMICs, in any language. Data were extracted from included papers, but heterogeneity prevented meta-analysis.FindingsWe conducted a systematic review of evidence to date, of mhGAP-IG implementation and evaluation in LMICs. Thirty-three included studies reported 15 training courses, 9 clinical implementations, 3 country contextualisations, 3 economic models, 2 uses as control interventions and 1 use to develop a rating scale. Our review identified the importance of detailed reports of contextual challenges in the field, alongside detailed protocols, qualitative studies and randomised controlled trials.ConclusionsThe mhGAP-IG literature is substantial, relative to other published evaluations of clinical practice guidelines: an important contribution to a neglected field.
Graphene on Cu(111) at the nonzero temperatures: Molecular dynamic simulation
Authors: Sidorenkov A. V. , Kolesnikov S. V. , Saletsky A. M. 
Published: September 2017

We present results of molecular dynamic simulation of continuous graphene monolayer on Cu(111). In this paper, we investigate the dependencies of the average binding energy and the average binding distance on the temperature. The interaction between carbon and copper atoms was described by Lennard-Jones potential. It is shown that the binding energy practically remains constant in a wide range of temperatures 0–800 K. However, in the same temperature range, the binding distance of graphene on Cu(111) surface has a linear dependence on temperature. The dependence of the linear thermal expansion coefficient of the binding distance on Lennard-Jones parameters has been calculated. We suggest a simple theoretical model to explain this dependence qualitatively.
Whole-Genome Sequencing Reveals Breast Cancers with Mismatch Repair Deficiency
Authors: Davies Helen , Morganella Sandro , Purdie Colin A. , Jang Se Jin , Borgen Elin , Russnes Hege , Glodzik Dominik , Zou Xueqing , Viari Alain , Richardson Andrea L. , Børresen-Dale Anne-Lise , Thompson Alastair , Eyfjord Jorunn E. , Kong Gu , Stratton Michael R. , Nik-Zainal Serena 
Published: September 2017

Abstract
Mismatch repair (MMR)–deficient cancers have been discovered to be highly responsive to immune therapies such as PD-1 checkpoint blockade, making their definition in patients, where they may be relatively rare, paramount for treatment decisions. In this study, we utilized patterns of mutagenesis known as mutational signatures, which are imprints of the mutagenic processes associated with MMR deficiency, to identify MMR-deficient breast tumors from a whole-genome sequencing dataset comprising a cohort of 640 patients. We identified 11 of 640 tumors as MMR deficient, but only 2 of 11 exhibited germline mutations in MMR genes or Lynch Syndrome. Two additional tumors had a substantially reduced proportion of mutations attributed to MMR deficiency, where the predominant mutational signatures were related to APOBEC enzymatic activity. Overall, 6 of 11 of the MMR-deficient cases in this cohort were confirmed genetically or epigenetically as having abrogation of MMR genes. However, IHC analysis of MMR-related proteins revealed all but one of 10 samples available for testing as MMR deficient. Thus, the mutational signatures more faithfully reported MMR deficiency than sequencing of MMR genes, because they represent a direct pathophysiologic readout of repair pathway abnormalities. As whole-genome sequencing continues to become more affordable, it could be used to expose individually abnormal tumors in tissue types where MMR deficiency has been rarely detected, but also rarely sought. Cancer Res; 77(18); 4755–62. ©2017 AACR.
Structurally Novel Antiestrogens Elicit Differential Responses from Constitutively Active Mutant Estrogen Receptors in Breast Cancer Cells and Tumors
Authors: Zhao Yuechao , Laws Mary J. , Guillen Valeria Sanabria , Ziegler Yvonne , Min Jian , Sharma Abhishek , Kim Sung Hoon , Chu David , Park Ben Ho , Oesterreich Steffi , Mao Chengjian , Shapiro David J. , Nettles Kendall W. , Katzenellenbogen John A. , Katzenellenbogen Benita S. 
Published: September 2017

Abstract
Many estrogen receptor α (ERα)–positive breast cancers develop resistance to endocrine therapy via mutation of ERs whose constitutive activation is associated with shorter patient survival. Because there is now a clinical need for new antiestrogens (AE) against these mutant ERs, we describe here our development and characterization of three chemically novel AEs that effectively suppress proliferation of breast cancer cells and tumors. Our AEs are effective against wild-type and Y537S and D538G ERs, the two most commonly occurring constitutively active ERs. The three new AEs suppressed proliferation and estrogen target gene expression in WT and mutant ER-containing cells and were more effective in D538G than in Y537S cells and tumors. Compared with WT ER, mutants exhibited approximately 10- to 20-fold lower binding affinity for AE and a reduced ability to be blocked in coactivator interaction, likely contributing to their relative resistance to inhibition by AE. Comparisons between mutant ER–containing MCF7 and T47D cells revealed that AE responses were compound, cell-type, and ERα-mutant dependent. These new ligands have favorable pharmacokinetic properties and effectively suppressed growth of WT and mutant ER–expressing tumor xenografts in NOD/SCID-γ mice after oral or subcutaneous administration; D538G tumors were more potently inhibited by AE than Y537S tumors. These studies highlight the differential responsiveness of the mutant ERs to different AEs and make clear the value of having a toolkit of AEs for treatment of endocrine therapy–resistant tumors driven by different constitutively active ERs. Cancer Res; 77(20); 5602–13. ©2017 AACR.
Inhibition of the Receptor Tyrosine Kinase AXL Restores Paclitaxel Chemosensitivity in Uterine Serous Cancer
Authors: Palisoul Marguerite L. , Quinn Jeanne M. , Schepers Emily , Hagemann Ian S. , Guo Lei , Reger Kelsey , Hagemann Andrea R. , McCourt Carolyn K. , Thaker Premal H. , Powell Matthew A. , Mutch David G. , Fuh Katherine C. 
Published: September 2017

Abstract
Uterine serous cancer (USC) is aggressive, and the majority of recurrent cases are chemoresistant. Because the receptor tyrosine kinase AXL promotes invasion and metastasis of USC and is implicated in chemoresistance in other cancers, we assessed the role of AXL in paclitaxel resistance in USC, determined the mechanism of action, and sought to restore chemosensitivity by inhibiting AXL in vitro and in vivo. We used short hairpin RNAs and BGB324 to knock down and inhibit AXL. We assessed sensitivity of USC cell lines to paclitaxel and measured paclitaxel intracellular accumulation in vitro in the presence or absence of AXL. We also examined the role of the epithelial–mesenchymal transition (EMT) in AXL-mediated paclitaxel resistance. Finally, we treated USC xenografts with paclitaxel, BGB324, or paclitaxel plus BGB324 and monitored tumor burden. AXL expression was higher in chemoresistant USC patient tumors and cell lines than in chemosensitive tumors and cell lines. Knockdown or inhibition of AXL increased sensitivity of USC cell lines to paclitaxel in vitro and increased cellular accumulation of paclitaxel. AXL promoted chemoresistance even in cells that underwent the EMT in vitro. Finally, in vivo studies of combination treatment with BGB324 and paclitaxel showed a greater than 51% decrease in tumor volume after 2 weeks of treatment when compared with no treatment or single-agent treatments (P &lt; 0.001). Our results show that AXL expression mediates chemoresistance independent of EMT and prevents accumulation of paclitaxel. This study supports the continued investigation of AXL as a clinical target, particularly in chemoresistant USC. Mol Cancer Ther; 16(12); 2881–91. ©2017 AACR.
Early Exposure to a High Fat/High Sugar Diet Increases the Mammary Stem Cell Compartment and Mammary Tumor Risk in Female Mice
Authors: Lambertz Isabel U. , Luo Linjie , Berton Thomas R. , Schwartz Scott L. , Hursting Stephen D. , Conti Claudio J. , Fuchs-Young Robin 
Published: September 2017

Abstract
Obesity and alterations in metabolic programming from early diet exposures can affect the propensity to disease in later life. Through dietary manipulation, developing mouse pups were exposed to a hyperinsulinemic, hyperglycemic milieu during three developmental phases: gestation, lactation, and postweaning. Analyses showed that a postweaning high fat/high sugar (HF/HS) diet had the main negative effect on adult body weight, glucose tolerance, and insulin resistance. However, dimethylbenz[a]anthracene (DMBA)-induced carcinogenesis revealed that animals born to a mother fed a HF/HS gestation diet, nursed by a mother on a mildly diet-restricted, low fat/low sugar diet (DR) and weaned onto a HF/HS diet (HF/DR/HF) had the highest mammary tumor incidence, while HF/HF/DR had the lowest tumor incidence. Cox proportional hazards analysis showed that a HF/HS postweaning diet doubled mammary cancer risk, and a HF/HS diet during gestation and postweaning increased risk 5.5 times. Exposure to a HF/HS diet during gestation, when combined with a postweaning DR diet, had a protective effect, reducing mammary tumor risk by 86% (HR = 0.142). Serum adipocytokine analysis revealed significant diet-dependent differences in leptin/adiponectin ratio and IGF-1. Flow cytometry analysis of cells isolated from mammary glands from a high tumor incidence group, DR/HF/HF, showed a significant increase in the size of the mammary stem cell compartment compared with a low tumor group, HF/HF/DR. These results indicate that dietary reprogramming induces an expansion of the mammary stem cell compartment during mammary development, increasing likely carcinogen targets and mammary cancer risk. Cancer Prev Res; 10(10); 553–62. ©2017 AACR.
See related editorial by Freedland, p. 551–2.