bluuebunny/crossref_metadata_2025_split huggingface dataset:
HIV-1 Uncoating Is Facilitated by Dynein and Kinesin 1
Authors: Lukic Zana , Dharan Adarsh , Fricke Thomas , Diaz-Griffero Felipe , Campbell Edward M. 
Published: September 2014

ABSTRACT
Following entry into the target cell, human immunodeficiency virus type 1 (HIV-1) must reverse transcribe its RNA genome to DNA and traffic to the nuclear envelope, where the viral genome is translocated into the nucleus for subsequent integration into the host cell chromosome. During this time, the viral core, which houses the genome, undergoes a poorly understood process of disassembly, known as uncoating. Collectively, many studies suggest that uncoating is tightly regulated to allow nuclear import of the genome while minimizing the exposure of the newly synthesized DNA to cytosolic DNA sensors. However, whether host cellular proteins facilitate this process remains poorly understood. Here we report that intact microtubules facilitate HIV-1 uncoating in target cells. Disruption of microtubules with nocodazole substantially delays HIV-1 uncoating, as revealed with three different assay systems. This defect in uncoating did not correlate with defective reverse transcription at early times postinfection, demonstrating that microtubule-facilitated uncoating is distinct from the previously reported role of viral reverse transcription in the uncoating process. We also find that pharmacological or small interfering RNA (siRNA)-mediated inhibition of cytoplasmic dynein or the kinesin 1 heavy chain KIF5B delays uncoating, providing detailed insight into how microtubules facilitate the uncoating process. These studies reveal a previously unappreciated role for microtubules and microtubule motor function in HIV-1 uncoating, establishing a functional link between viral trafficking and uncoating. Targeted disruption of the capsid motor interaction may reveal novel mechanisms of inhibition of viral infection or provide opportunities to activate cytoplasmic antiviral responses directed against capsid or viral DNA.

IMPORTANCE
During HIV-1 infection, fusion of viral and target cell membranes dispenses the viral ribonucleoprotein complex into the cytoplasm of target cells. During this time, the virus must reverse transcribe its RNA genome, traffic from the location of fusion to the nuclear membrane, and undergo the process of uncoating, whereby the viral capsid core disassembles to allow the subsequent nuclear import of the viral genome. Numerous cellular restriction factors target the viral capsid, suggesting that perturbation of the uncoating process represents an excellent antiviral target. However, this uncoating process, and the cellular factors that facilitate uncoating, remains poorly understood. The main observation of this study is that normal uncoating requires intact microtubules and is facilitated by dynein and kinesin motors. Targeting these factors may either directly inhibit infection or delay it enough to trigger mediators of intrinsic immunity that recognize cytoplasmic capsid or DNA and subsequently induce an antiviral state in these cells.
Vaginal Memory T Cells Induced by Intranasal Vaccination Are Critical for Protective T Cell Recruitment and Prevention of Genital HSV-2 Disease
Authors: Sato Ayuko , Suwanto Aldina , Okabe Manami , Sato Shintaro , Nochi Tomonori , Imai Takahiko , Koyanagi Naoto , Kunisawa Jun , Kawaguchi Yasushi , Kiyono Hiroshi 
Published: September 2014

ABSTRACTProtective immunity against genital pathogens causing chronic infections, such as herpes simplex virus 2 (HSV-2) or human immunodeficiency virus, requires the induction of cell-mediated immune responses locally in the genital tract. Intranasal immunization with a thymidine kinase-deficient (TK−) mutant of HSV-2 effectively induces HSV-2-specific gamma interferon (IFN-γ)-secreting memory T cell production and protective immunity against intravaginal challenge with wild-type HSV-2. However, the precise mechanism by which intranasal immunization induces protective immunity in the distant genital mucosa more effectively than does systemic immunization is unknown. Here, we showed that intranasal immunization with live HSV-2 TK−induced the production of effector T cells and their migration to, and retention in, the vaginal mucosa, whereas systemic vaccination barely established a local effector T cell pool, even when it induced the production of circulating memory T cells in the systemic compartment. The long-lasting HSV-2-specific local effector T cells induced by intranasal vaccination provided superior protection against intravaginal wild-type HSV-2 challenge by starting viral clearance at the entry site earlier than with intraperitoneal immunization. Intranasal immunization is an effective strategy for eliciting high levels of cell-mediated protection of the genital tract by providing long-lasting antigen (Ag)-specific local effector T cells without introducing topical infection or inflammation.IMPORTANCEIntranasal (i.n.) vaccines against sexually transmitted diseases that are caused by viruses such as herpes simplex virus 2 (HSV-2) have long been in development, but no vaccine candidate is currently available. Understanding the cellular mechanisms of immune responses in a distant vaginal mucosa induced by i.n. immunization with HSV-2 will contribute to designing such a vaccine. Our study demonstrated that i.n. immunization with an attenuated strain of HSV-2 generated long-lasting IFN-γ-secreting T cells in vaginal mucosa more effectively than systemic immunization. We found that these vaginal effector memory T cells are critical for the early stage of viral clearance at natural infection sites and prevent severe vaginal inflammation and herpes encephalitis.
Utilization of Pipeline embolization device for treatment of ruptured intracranial aneurysms: US multicenter experience
Authors: Lin Ning , Brouillard Adam M , Keigher Kiffon M , Lopes Demetrius K , Binning Mandy J , Liebman Kenneth M , Veznedaroglu Erol , Magarik Jordan A , Mocco J , Duckworth Edward A , Arthur Adam S , Ringer Andrew J , Snyder Kenneth V , Levy Elad I , Siddiqui Adnan H 
Published: September 2014

ObjectiveUtilization of the Pipeline embolization device (PED) in complex ruptured aneurysms has not been well studied. We evaluated the safety and effectiveness data from five participating US centers.MethodsRecords of patients with ruptured cerebral aneurysms who underwent PED treatment between 2011 and 2013 were retrospectively reviewed.Results26 patients with ruptured aneurysms underwent PED treatment (mean age 51.4±13.2 years;16 women). At presentation, 8 patients (30.8%) had a Hunt–Hess grade of IV or above; 11 required extraventricular drain placement. Aneurysm morphologies were: 8 dissecting, 8 blister-like, 6 fusiform, and 4 saccular. There were 22 anterior circulation and 4 posterior circulation aneurysms. PED deployment was successful in all patients, with adjunctive coiling utilized in 12. Periprocedural complications occurred in 5 (19.2%), including 3 inhospital deaths. 23 patients (88.5%) had postoperative angiography at a mean of 5.9 months: 18 aneurysms (78.3%) were completely occluded, 3 (13.0%) had residual neck filling, and 2 (8.7%) had residual dome filling. All blister-type aneurysms were completely occluded at follow-up. Clinical follow-up was available for an average of 10.1 months (range 2–21 months), with one asymptomatic in-stent stenosis and one asymptomatic thromboembolic stroke noted. Good outcome (modified Rankin Scale (mRS) score of 0–2) was achieved in 20 patients (76.9%), fair (mRS 3–4) in 3 (11.5%), and 3 died (11.5%).ConclusionsThe PED can be utilized for ruptured aneurysms and is a good option for blister-type aneurysms. However, due to periprocedural complications, it should be reserved for lesions that are difficult to treat by conventional clipping or coiling.
Cerebral vasospasm patterns following aneurysmal subarachnoid hemorrhage: an angiographic study comparing coils with clips
Authors: Jones J , Sayre J , Chang R , Tian J , Szeder V , Gonzalez N , Jahan R , Vinuela F , Duckwiler G , Tateshima S 
Published: September 2014

Background and purposeCerebral vasospasm following aneurysmal subarachnoid hemorrhage (aSAH) results in significant morbidity due to ischemia. Subarachnoid hematoma evacuation during aneurysm clipping reduces the incidence of vasospasm. However, studies comparing endovascular coiling with open clipping have reported similar rates of spasm. We addressed the question of how coiling produces similar (if not less) vasospasm without the benefit of clot evacuation by evaluating vasospasm patterns among patients with aSAH. We hypothesize that cerebrospinal fluid (CSF) circulation plays a major role in clearing blood breakdown products, and that coiling may preserve CSF flow in the subarachnoid space.MethodsA retrospective chart review identified 36 (18 coiled/18 clipped) patients with aSAH who developed angiographic vasospasm. The degree of spasm was quantified using an ordinal scale from 0 (none) to 5 (severe) for 26 anatomic vessel segments evaluated on 164 successive angiograms. Statistical analysis was performed using the Fisher exact test for proportions and the Wilcoxon and Student t tests on ordinal/continuous measures. Quadratic regression was also used as a model for spasm activity versus post-bleed days.ResultsIn both the coiling and clipping groups the most severely spastic vessels were located adjacent to aneurysm rupture. Perianeurysmal spasm affected all subjects. However, whereas spasm remained largely confined in patients treated by clipping, those who underwent coiling developed stepwise progression distally over time. The distal vasospasm severity scores were higher among subjects treated by coiling, particularly in the most dependent regions of the subarachnoid space.ConclusionsPatients with aSAH treated by endovascular coiling and surgical clipping demonstrate distinct vasospasm patterns. While both initially exhibit perianeurysmal spasm, patients treated by coiling go on to develop stepwise progression distally over time. This finding may reflect dispersion of blood breakdown products along preserved CSF egress pathways in patients treated by endovascular coiling.
Volcanism and tectonism across the inner solar system: an overview
Authors: Platz T. , Byrne P. K. , Massironi M. , Hiesinger H. 
Published: September 2014

Abstract
Volcanism and tectonism are the dominant endogenic means by which planetary surfaces change. This book, in general, and this overview, in particular, aim to encompass the broad range in character of volcanism, tectonism, faulting and associated interactions observed on planetary bodies across the inner solar system – a region that includes Mercury, Venus, Earth, the Moon, Mars and asteroids. The diversity and breadth of landforms produced by volcanic and tectonic processes are enormous, and vary across the inventory of inner solar system bodies. As a result, the selection of prevailing landforms and their underlying formational processes that are described and highlighted in this review are but a primer to the expansive field of planetary volcanism and tectonism. In addition to this extended introductory contribution, this Special Publication features 21 dedicated research articles about volcanic and tectonic processes manifest across the inner solar system. Those articles are summarized at the end of this review.
Effects of Tumor Microenvironment Heterogeneity on Nanoparticle Disposition and Efficacy in Breast Cancer Tumor Models
Authors: Song Gina , Darr David B. , Santos Charlene M. , Ross Mark , Valdivia Alain , Jordan Jamie L. , Midkiff Bentley R. , Cohen Stephanie , Nikolaishvili-Feinberg Nana , Miller C. Ryan , Tarrant Teresa K. , Rogers Arlin B. , Dudley Andrew C. , Perou Charles M. , Zamboni William C. 
Published: September 2014

Abstract
Purpose: Tumor cells are surrounded by a complex microenvironment. The purpose of our study was to evaluate the role of heterogeneity of the tumor microenvironment in the variability of nanoparticle (NP) delivery and efficacy.
Experimental Designs: C3(1)-T-Antigen genetically engineered mouse model (C3-TAg) and T11/TP53Null orthotopic syngeneic murine transplant model (T11) representing human breast tumor subtypes basal-like and claudin-low, respectively, were evaluated. For the pharmacokinetic studies, non-liposomal doxorubicin (NL-doxo) or polyethylene glycol tagged (PEGylated) liposomal doxorubicin (PLD) was administered at 6 mg/kg i.v. x1. Area under the concentration versus time curve (AUC) of doxorubicin was calculated. Macrophages, collagen, and the amount of vasculature were assessed by IHC. Chemokines and cytokines were measured by multiplex immunochemistry. NL-doxo or PLD was administered at 6 mg/kg i.v. weekly x6 in efficacy studies. Analyses of intermediary tumor response and overall survival were performed.
Results: Plasma AUC of NL-doxo and PLD encapsulated and released doxorubicin was similar between two models. However, tumor sum total AUC of PLD was 2-fold greater in C3-TAg compared with T11 (P &lt; 0.05). T11 tumors showed significantly higher expression of CC chemokine ligand (CCL) 2 and VEGF-a, greater vascular quantity, and decreased expression of VEGF-c compared with C3-TAg (P &lt; 0.05). PLD was more efficacious compared with NL-doxo in both models.
Conclusion: The tumor microenvironment and/or tumor cell features of breast cancer affected NP tumor delivery and efficacy, but not the small-molecule drug. Our findings reveal the role of the tumor microenvironment in variability of NP delivery and therapeutic outcomes. Clin Cancer Res; 20(23); 6083–95. ©2014 AACR.
LY2875358, a Neutralizing and Internalizing Anti-MET Bivalent Antibody, Inhibits HGF-Dependent and HGF-Independent MET Activation and Tumor Growth
Authors: Liu Ling , Zeng Wei , Wortinger Mark A. , Yan S. Betty , Cornwell Paul , Peek Victoria L. , Stephens Jennifer R. , Tetreault Jonathan W. , Xia Jinqi , Manro Jason R. , Credille Kelly M. , Ballard Darryl W. , Brown-Augsburger Patricia , Wacheck Volker , Chow Chi-Kin , Huang Lihua , Wang Yong , Denning Irene , Davies Julian , Tang Ying , Vaillancourt Peter , Lu Jirong 
Published: September 2014

Abstract
Purpose: MET, the receptor for hepatocyte growth factor (HGF), has been implicated in driving tumor proliferation and metastasis. High MET expression is correlated with poor prognosis in multiple cancers. Activation of MET can be induced either by HGF-independent mechanisms such as gene amplification, specific genetic mutations, and transcriptional upregulation or by HGF-dependent autocrine or paracrine mechanisms.
Experimental Design/Results: Here, we report on LY2875358, a novel humanized bivalent anti-MET antibody that has high neutralization and internalization activities, resulting in inhibition of both HGF-dependent and HGF-independent MET pathway activation and tumor growth. In contrast to other bivalent MET antibodies, LY2875358 exhibits no functional agonist activity and does not stimulate biologic activities such as cell proliferation, scattering, invasion, tubulogenesis, or apoptosis protection in various HGF-responsive cells and no evidence of inducing proliferation in vivo in a monkey toxicity study. LY2875358 blocks HGF binding to MET and HGF-induced MET phosphorylation and cell proliferation. In contrast to the humanized one-armed 5D5 anti-MET antibody, LY2875358 induces internalization and degradation of MET that inhibits cell proliferation and tumor growth in models where MET is constitutively activated. Moreover, LY2875358 has potent antitumor activity in both HGF-dependent and HGF-independent (MET-amplified) xenograft tumor models. Together, these findings indicate that the mechanism of action of LY2875358 is different from that of the one-armed MET antibody.
Conclusions: LY2875358 may provide a promising therapeutic strategy for patients whose tumors are driven by both HGF-dependent and HGF-independent MET activation. LY2875358 is currently being investigated in multiple clinical studies. Clin Cancer Res; 20(23); 6059–70. ©2014 AACR.
A Synthetic Lethal Screen Reveals Enhanced Sensitivity to ATR Inhibitor Treatment in Mantle Cell Lymphoma with ATM Loss-of-Function
Authors: Menezes Daniel L. , Holt Jenny , Tang Yan , Feng Jiajia , Barsanti Paul , Pan Yue , Ghoddusi Majid , Zhang Wei , Thomas George , Holash Jocelyn , Lees Emma , Taricani Lorena 
Published: September 2014

Abstract
Mechanisms to maintain genomic integrity are essential for cells to remain viable. Not surprisingly, disruption of key DNA damage response pathway factors, such as ataxia telangiectasia-mutated (ATM)/ataxia telangiectasia and RAD3-related (ATR) results in loss of genomic integrity. Here, a synthetic lethal siRNA-screening approach not only confirmed ATM but identified additional replication checkpoint proteins, when ablated, enhanced ATR inhibitor (ATRi) response in a high-content γ-H2AX assay. Cancers with inactivating ATM mutations exhibit impaired DNA double-stranded break (DSB) repair and rely on compensatory repair pathways for survival. Therefore, impairing ATR activity may selectively sensitize cancer cells to killing. ATR inhibition in an ATM-deficient context results in phosphorylation of DNA-dependent protein kinase catalytic subunits (DNA-PKcs) and leads to induction of γ-H2AX. Using both in vitro and in vivo models, ATR inhibition enhanced efficacy in ATM loss-of-function mantle cell lymphoma (MCL) compared with ATM wild-type cancer cells. In summary, single-agent ATR inhibitors have therapeutic utility in the treatment of cancers, like MCL, in which ATM function has been lost.
Implications: These data suggest that single-agent ATR inhibitors have therapeutic utility and that ATR uses a complex and coordinated set of proteins to maintain genomic stability that could be further exploited. Mol Cancer Res; 13(1); 120–9. ©2014 AACR.
Hypoxia- or PDGF-BB-dependent paxillin tyrosine phosphorylation in pulmonary hypertension is reversed by HIF-1α depletion or imatinib treatment
Authors: Veith Christine , Zakrzewicz Dariusz , Dahal Bhola Kumar , Bálint Zoltán , Murmann Kirsten , Wygrecka Malgorzata , Seeger Werner , Schermuly Ralph Theo , Kwapiszewska Grazyna , Weissmann Norbert 
Published: September 2014

SummaryChronic exposure to hypoxia induces a pronounced remodelling of the pulmonary vasculature leading to pulmonary hypertension (PH). The remodelling process also entails increased proliferation and decreased apoptosis of pulmonary arterial smooth muscle cells (PASMC), processes regulated by the cytoskeletal protein paxillin. In this study, we aimed to examine the molecular mechanisms leading to deregulation of paxillin in PH. We detected a time-dependent increase in paxillin tyrosine 31 (Y31) and 118 (Y118) phosphorylation following hypoxic exposure (1 % O2) or platelet-derived growth factor (PDGF)-BB stimulation of primary human PASMC. In addition, both, hypoxia- and PDGF-BB increased the nuclear localisation of phospho-paxillin Y31 as indicated by immunofluorescence staining in human PASMC. Elevated paxillin tyrosine phosphorylation in human PASMC was attenuated by hypoxia-inducible factor (HIF)-1α depletion or by treatment with the PDGF-BB receptor antagonist, imatinib. Moreover, we observed elevated paxillin Y31 and Y118 phosphorylation in the pulmonary vasculature of chronic hypoxic mice (21 days, 10 % O2) which was reversible by imatinib-treatment. PDGF-BB-dependent PASMC proliferation was regulated via the paxillin-Erk1/2-cyclin D1 pathway. In conclusion, we suggest paxillin up-regulation and phosphorylation as an important mechanism of vascular remodelling underlying pulmonary hypertension.Note: Parts of the doctoral thesis of Christine Veith are integrated into this report.
The relevance of coagulation in cardiovascular disease: what do the biomarkers tell us?
Authors: Rumley Ann , Lowe Gordon 
Published: September 2014

SummarySeveral haemostatic factors have been associated with incident arterial cardiovascular disease in prospective studies and meta-analyses. Plasma fibrinogen shows a strong and consistent association with risk; however, this may reflect its inflammatory marker status, and causality remains to be proven. The common haemostatic gene polymorphisms for factor II, factor V and the von Willebrand factor: Factor VIII (non-O blood group) show significant associations with coronary heart disease (CHD) risk, consistent with potential causality. Increased D-dimer and t-PA antigen levels are associated with CHD risk, suggesting roles for coagulation activation and endothelial disturbance. There is little evidence for associations with CVD with other haemostatic factors.
Dietary omega-3 alpha-linolenic acid does not prevent venous thrombosis in mice
Authors: Stivala Simona , Savarese Gianluigi , Camici Giovanni G. , Lüscher Thomas F. , Wagner Denisa , Reiner Martin , Martinod Kimberly , Beer Jürg 
Published: September 2014

SummaryVenous thromboembolism (VTE) is a leading cause of cardiovascular death. Omega-3 fatty acids (n-3 FA) exhibit protective effects against cardiovascular disease. Others and our group have reported that the plant-derived n-3 FA alpha-linolenic acid (ALA) displays antiinflammatory, anticoagulant and antiplatelet effects, thereby reducing atherosclerosis and arterial thrombosis in mice fed a high ALA diet. Since procoagulant factors such as tissue factor and fibrin as well as platelets and leukocytes are crucially involved in the development of VTE, we investigated possible protective effects of dietary ALA on venous thrombus formation in a mouse model of stenosis- and furthermore, in a mouse model of endothelial injury-induced venous thrombosis. Four week old C57BL/6 mice underwent four weeks of high (7.3g%) or low ALA (0.03g%) treatment before being exposed to inferior vena cava (IVC) stenosis for 48 hours or laser injury of the endothelium of the internal jugular vein (IJV). Thrombus generation frequency, thrombus size and composition (IVC stenosis group) and time to thrombus formation (endothelial injury group) were assessed. In addition, plasma glycocalicin, a marker of platelet activation, platelet P-selectin and activated integrin expression as well as plasma thrombin generation was determined, but did not reveal any significant differences between he groups. Despite its protective properties against arterial thrombus formation, dietary ALA did not protect against venous thrombosis neither in the IVC stenosis nor the endothelial injury model, further indicating that the biological processes involved in arterial and venous thrombosis are different.