bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sodium Hydrogen Exchangers Contribute to Arenavirus Cell Entry
Authors: Iwasaki Masaharu , Ngo Nhi , de la Torre Juan C. 
Published: October 2013

ABSTRACT

Several arenaviruses, chiefly Lassa virus (LASV), cause hemorrhagic fever (HF) disease in humans and pose a great public health concern in the regions in which they are endemic. Moreover, evidence indicates that the worldwide-distributed prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) is a neglected human pathogen of clinical significance. The limited existing armamentarium to combat human-pathogenic arenaviruses underscores the importance of developing novel antiarenaviral drugs, a task that would be facilitated by the identification and characterization of virus-host cell factor interactions that contribute to the arenavirus life cycle. A genome-wide small interfering RNA (siRNA) screen identified sodium hydrogen exchanger 3 (NHE3) as required for efficient multiplication of LCMV in HeLa cells, but the mechanisms by which NHE activity contributed to the life cycle of LCMV remain unknown. Here we show that treatment with the NHE inhibitor 5-(
N
-ethyl-
N
-isopropyl) amiloride (EIPA) resulted in a robust inhibition of LCMV multiplication in both rodent (BHK-21) and human (A549) cells. EIPA-mediated inhibition was due not to interference with virus RNA replication, gene expression, or budding but rather to a blockade of virus cell entry. EIPA also inhibited cell entry mediated by the glycoproteins of the HF arenaviruses LASV and Junin virus (JUNV). Pharmacological and genetic studies revealed that cell entry of LCMV in A549 cells depended on actin remodeling and Pak1, suggesting a macropinocytosis-like cell entry pathway. Finally, zoniporide, an NHE inhibitor being explored as a therapeutic agent to treat myocardial infarction, inhibited LCMV propagation in culture cells. Our findings indicate that targeting NHEs could be a novel strategy to combat human-pathogenic arenaviruses.
The Innate Immune Factor Apolipoprotein L1 Restricts HIV-1 Infection
Authors: Taylor Harry E. , Khatua Atanu K. , Popik Waldemar 
Published: October 2013

ABSTRACTApolipoprotein L1 (APOL1) is a major component of the human innate immune response against African trypanosomes. Although the mechanism of the trypanolytic activity of circulating APOL1 has been recently clarified, the intracellular function(s) of APOL1 in human cells remains poorly defined. Like that of many genes linked to host immunity, APOL1 expression is induced by proinflammatory cytokines gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α). Additionally, IFN-γ-polarized macrophages that potently restrict HIV-1 replication express APOL1, which suggests that APOL1 may contribute to HIV-1 suppression. Here, we report that APOL1 inhibits HIV-1 replication by multiple mechanisms. We found that APOL1 protein targeted HIV-1 Gag for degradation by the endolysosomal pathway. Interestingly, we found that APOL1 stimulated both endocytosis and lysosomal biogenesis by promoting nuclear localization of transcription factor EB (TFEB) and expression of TFEB target genes. Moreover, we demonstrated that APOL1 depletes cellular viral accessory protein Vif, which counteracts the host restriction factor APOBEC3G, via a pathway involving degradation of Vif in lysosomes and by secretion of Vif in microvesicles. As a result of Vif depletion by APOL1, APOBEC3G was not degraded and reduced infectivity of progeny virions. In support of this model, we also showed that endogenous expression of APOL1 in differentiated U937 monocytic cells stimulated with IFN-γ resulted in a reduced production of virus particles. This finding supports the hypothesis that induction of APOL1 contributes to HIV-1 suppression in differentiated monocytes. Deciphering the precise mechanism of APOL1-mediated HIV-1 restriction may facilitate the design of unique therapeutics to target HIV-1 replication.
Reselection of a Genomic Upstream Open Reading Frame in Mouse Hepatitis Coronavirus 5′-Untranslated-Region Mutants
Authors: Wu Hung-Yi , Guan Bo-Jhih , Su Yu-Pin , Fan Yi-Hsin , Brian David A. 
Published: October 2013

ABSTRACT

An AUG-initiated upstream open reading frame (uORF) encoding a potential polypeptide of 3 to 13 amino acids (aa) is found within the 5′ untranslated region (UTR) of >75% of coronavirus genomes based on 38 reference strains. Potential CUG-initiated uORFs are also found in many strains. The AUG-initiated uORF is presumably translated following genomic 5′-end cap-dependent ribosomal scanning, but its function is unknown. Here, in a reverse-genetics study with mouse hepatitis coronavirus, the following were observed. (i) When the uORF AUG-initiating codon was replaced with a UAG stop codon along with a U112A mutation to maintain a uORF-harboring stem-loop 4 structure, an unimpaired virus with wild-type (WT) growth kinetics was recovered. However, reversion was found at all mutated sites within five virus passages. (ii) When the uORF was fused with genomic (main) ORF1 by converting three in-frame stop codons to nonstop codons, a uORF-ORF1 fusion protein was made, and virus replicated at WT levels. However, a frameshifting G insertion at virus passage 7 established a slightly 5′-extended original uORF. (iii) When uAUG-eliminating deletions of 20, 30, or 51 nucleotides (nt) were made within stem-loop 4, viable but debilitated virus was recovered. However, a C80U mutation in the first mutant and an A77G mutation in the second appeared by passage 10, which generated alternate uORFs that correlated with restored WT growth kinetics.
In vitro
, the uORF-disrupting nondeletion mutants showed enhanced translation of the downstream ORF1 compared with the WT. These results together suggest that the uORF represses ORF1 translation yet plays a beneficial but nonessential role in coronavirus replication in cell culture.
Ultradeep Pyrosequencing and Molecular Modeling Identify Key Structural Features of Hepatitis B Virus RNase H, a Putative Target for Antiviral Intervention
Authors: Hayer Juliette , Rodriguez Christophe , Germanidis Georgios , Deléage Gilbert , Zoulim Fabien , Pawlotsky Jean-Michel , Combet Christophe 
Published: October 2013

ABSTRACT

Last-generation nucleoside/nucleotide analogues are potent against hepatitis B virus (HBV) and have a high barrier to resistance. However, delayed responses have been observed in patients previously exposed to other drugs of the same class, long-term resistance is possible, and cure of infection cannot be achieved with these therapies, emphasizing the need for alternative therapeutic approaches. The HBV RNase H represents an interesting target because its enzyme activity is essential to the HBV life cycle. The goal of our study was to characterize the structure of the HBV RNase H by computing a 3-dimensional molecular model derived from
E. coli
RNase H and analyzing 2,326 sequences of all HBV genotypes available in public databases and 958,000 sequences generated by means of ultradeep pyrosequencing of sequences from a homogenous population of 73 treatment-naive patients infected with HBV genotype D. Our data revealed that (i) the putative 4th catalytic residue displays unexpected variability that could be explained by the overlap of the HBx gene and has no apparent impact on HBV replicative capacity and that (ii) the C-helix-containing basic protrusion, which is required to guide the RNA/DNA heteroduplex into the catalytic site, is highly conserved and bears unique structural properties that can be used to target HBV-specific RNase H inhibitors without cross-species activity. The model shows substantial differences from other known RNases H and paves the way for functional and structural studies as a prerequisite to the development of new inhibitors of the HBV cell cycle specifically targeting RNase H activity.
Acupuncture with Non-Steroidal Anti-Inflammatory Drugs (Nsaids) versus Acupuncture Or Nsaids Alone for the Treatment of Chronic Neck Pain: An Assessor-Blinded Randomised Controlled Pilot Study
Authors: Cho Jae-Heung , Nam Dong-Hyun , Kim Ki-Tack , Lee Jun-Hwan 
Published: October 2013

Objective To investigate the feasibility and sample size required for a full-scale randomised controlled trial of the effectiveness of acupuncture with non-steroidal anti-inflammatory drugs (NSAIDs) for chronic neck pain compared with acupuncture or NSAID treatment alone. Methods A total of 45 patients with chronic neck pain participated in the study. For 3 weeks the acupuncture with NSAIDs treatment group took NSAIDs (zaltoprofen, 80 mg) daily while receiving acupuncture treatment three times a week. The acupuncture treatment group received treatment three times a week and the NSAID treatment group took NSAIDs daily. The primary outcomes were to determine the feasibility and to calculate the sample size. As secondary outcomes, pain intensity and pain-related symptoms for chronic neck pain were measured. Results With regard to enrolment and dropout rates, 88.2% of patients consented to be recruited to the trial and 15.6% of participants were lost to follow-up. The sample size for a full-scale trial was estimated to be 120 patients. Although preliminary, there was a significant change in the visual analogue scale (VAS) for neck pain intensity between the baseline measurement and each point of assessment in all groups. However, there was no difference in VAS scores between the three groups. Conclusions This pilot study has provided the feasibility and sample size for a full-scale trial of acupuncture with NSAIDs for chronic neck pain compared with acupuncture or NSAID treatment alone. Further research is needed to validate the effects of acupuncture with NSAIDs. Clinical Trial Registration NIH ClinicalTrials.gov NCT01205958.
Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of Dalantercept, an Activin Receptor–like Kinase-1 Ligand Trap, in Patients with Advanced Cancer
Authors: Bendell Johanna C. , Gordon Michael S. , Hurwitz Herbert I. , Jones Suzanne F. , Mendelson David S. , Blobe Gerard C. , Agarwal Neeraj , Condon Carolyn H. , Wilson Dawn , Pearsall Amelia E. , Yang Yijun , McClure Ty , Attie Kenneth M. , Sherman Matthew L. , Sharma Sunil 
Published: October 2013

Abstract
Purpose: The angiogenesis inhibitor dalantercept (formerly ACE-041) is a soluble form of activin receptor–like kinase-1 (ALK1) that prevents activation of endogenous ALK1 by bone morphogenetic protein-9 (BMP9) and BMP10 and exhibits antitumor activity in preclinical models. This first-in-human study of dalantercept evaluated its safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity in adults with advanced solid tumors.
Experimental Design: Patients in dose-escalating cohorts received dalantercept subcutaneously at one of seven dose levels (0.1–4.8 mg/kg) every 3 weeks until disease progression. Patients in an expansion cohort received dalantercept at 0.8 or 1.6 mg/kg every 3 weeks until disease progression.
Results: In 37 patients receiving dalantercept, the most common treatment-related adverse events were peripheral edema, fatigue, and anemia. Edema and fluid retention were dose-limiting toxicities and responded to diuretic therapy. No clinically significant, treatment-related hypertension, proteinuria, gross hemorrhage, or gastrointestinal perforations were observed. One patient with refractory squamous cell cancer of the head and neck had a partial response, and 13 patients had stable disease according to RECISTv1.1, eight of whom had prolonged periods (≥12 weeks) of stable disease. Correlative pharmacodynamic markers included tumor metabolic activity and tumor blood flow, which decreased from baseline in 63% and 82% of evaluable patients, respectively, and telangiectasia in eight patients.
Conclusion: Dalantercept was well-tolerated at doses up to 1.6 mg/kg, with a safety profile distinct from inhibitors of the VEGF pathway. Dalantercept displayed promising antitumor activity in patients with advanced refractory cancer, and multiple phase II studies are underway. Clin Cancer Res; 20(2); 480–9. ©2013 AACR.
Bryostatin Improves Survival and Reduces Ischemic Brain Injury in Aged Rats After Acute Ischemic Stroke
Authors: Tan Zhenjun , Turner Ryan C. , Leon Rachel L. , Li Xinlan , Hongpaisan Jarin , Zheng Wen , Logsdon Aric F. , Naser Zachary J. , Alkon Daniel L. , Rosen Charles L. , Huber Jason D. 
Published: October 2013

Background and Purpose—
Bryostatin, a potent protein kinase C (PKC) activator, has demonstrated therapeutic efficacy in preclinical models of associative memory, Alzheimer disease, global ischemia, and traumatic brain injury. In this study, we tested the hypothesis that administration of bryostatin provides a therapeutic benefit in reducing brain injury and improving stroke outcome using a clinically relevant model of cerebral ischemia with tissue plasminogen activator reperfusion in aged rats.

Methods—
Acute cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery (MCAO) in 18- to 20-month-old female Sprague–Dawley rats using an autologous blood clot with tissue plasminogen activator–mediated reperfusion. Bryostatin was administered at 6 hours post-MCAO, then at 3, 6, 9, 12, 15, and 18 days after MCAO. Functional assessment was conducted at 2, 7, 14, and 21 days after MCAO. Lesion volume and hemispheric swelling/atrophy were performed at 2, 7, and 21 days post-MCAO. Histological assessment of PKC isozymes was performed at 24 hours post-MCAO.

Results—
Bryostatin-treated rats showed improved survival post-MCAO, especially during the first 4 days. Repeated administration of bryostatin post-MCAO resulted in reduced infarct volume, hemispheric swelling/atrophy, and improved neurological function at 21 days post-MCAO. Changes in αPKC expression and εPKC expression in neurons were noted in bryostatin-treated rats at 24 hours post-MCAO.

Conclusions—
Repeated bryostatin administration post-MCAO protected the brain from severe neurological injury post-MCAO. Bryostatin treatment improved survival rate, reduced lesion volume, salvaged tissue in infarcted hemisphere by reducing necrosis and peri-infarct astrogliosis, and improved functional outcome after MCAO.
El cartel de los sapos
Authors: Duarte Mauricio 
Published: October 2013

In Colombia, society has come to be organized in terms of a division between those with and those without links to narcotrafficking. This moral boundary recently experienced a symbolic disturbance with the entrance on the country’s cultural scene of Andrés López López, a former Colombian drug trafficker, and his El cartel de los sapos (2008). An examination of the discursive and political strategies employed in this book, in which drug trafficking is referred to through the metaphor “bacteria,” allows us to understand the construction of a narrator who calls attention to the hypocrisy of the government and society regarding the reincorporation of narcotraffickers into civilian life while provoking a national debate on the difference between history and fiction. En Colombia, la sociedad ha llegado a organizarse en términos de una división entre aquellos que tienen y no vínculos con el narcotráfico. Este límite moral experimentó un reciente disturbio simbólico con la entrada de Andrés López López, un ex-narcotraficante colombiano, y su libro El cartel de los sapos (2008) en la escena cultural del país. Un análisis de las estrategias discursivas y políticas empleadas en este libro, en el que el tráfico de drogas se define a través de la metáfora de la “bacteria,” nos permite entender la construcción de un narrador que devela la hipocresía gubernamental y social con respecto a la reincorporación de los narcotraficantes en la vida civil al mismo tiempo que provoca un debate nacional sobre la diferencia entre historia y ficción.
Bare Life in Ciudad Juárez
Authors: Eisenhammer Stephen 
Published: October 2013

At least 60,000 people have been killed in Mexico since former President Felipe Calderón declared war on drugs in 2006. Much of the worst violence has centered on the border city of Ciudad Juárez. Despite the death toll, the killings have received scant academic attention. A study based on field research and using Giorgio Agamben’s theory of homo sacer to construct a theoretical framework proposes that the violence is rooted in Juárez’s role as an export processing zone, where cheap labor diminishes the value of life. It connects the recent drug-related violence with the murders of hundreds of women in the city during the 1990s and early 2000s. Han muerto por lo menos 60,000 personas en México desde que el anterior presidente, Felipe Calderón, declaraba una guerra contra el narcotráfico en 2006. Una gran parte de la peor violencia se ha centrado en la ciudad fronteriza de Ciudad Juárez. Pese al gran número de muertos, las matanzas han recibido poca atención académica. Un estudio basado en investigación de campo y aplicando la teoría de “homo sacer” de Giorgio Agamben propone que la violencia tiene sus raices en el hecho de que en Juárez, como zona de exportación, la mano de obra abaratada disminuye el valor de la vida. Se conecta la narcoviolencia con los homicidios de cientos de mujeres en la ciudad durante la década de 1990 y comienzos de la de 2000.
Candidemia in the critically ill: initial therapy and outcome in mechanically ventilated patients
Authors: Ferrada Marcela A , Quartin Andrew A , Kett Daniel H , Morris Michele I 
Published: October 2013

Abstract

Background
Mortality among critically ill patients with candidemia is very high. We sought to determine whether the choice of initial antifungal therapy is associated with survival among these patients, using need for mechanical ventilatory support as a marker of critical illness.

Methods
Cohort analysis of outcomes among mechanically ventilated patients with candidemia from the 24 North American academic medical centers contributing to the Prospective Antifungal Therapy (PATH) Alliance registry. Patients were included if they received either fluconazole or an echinocandin as initial monotherapy.

Results
Of 5272 patients in the PATH registry at the time of data abstraction, 1014 were ventilated and concomitantly had candidemia, with 689 eligible for analysis. 28-day survival was higher among the 374 patients treated initially with fluconazole than among the 315 treated with an echinocandin (66% versus 51%, P < .001). Initial fluconazole therapy remained associated with improved survival after adjusting for non-treatment factors in the overall population (hazard ratio .75, 95% CI .59–.96), and also among patients with albicans infection (hazard ratio .62, 95% CI .44–.88). While not statistically significant, fluconazole appeared to be associated with higher mortality among patients infected with glabrata (HR 1.13, 95% CI .70–1.84).

Conclusions
Among ventilated patients with candidemia, those receiving fluconazole as initial monotherapy were significantly more likely to survive than those treated with an echinocandin. This difference persisted after adjustment for non-treatment factors.
Factors associated with receipt of adjuvant chemotherapy among married women with breast cancer
Authors: Zhang Yan , Gao Hua , Bu Yulan , Fan Xiuzhen , Jia Jihui 
Published: October 2013

Abstract

Background
Adjuvant chemotherapies are recommended for most women after breast cancer surgery, and can greatly affect the patients’ survival. We describe and evaluate possible factors influencing receipt of postoperative adjuvant chemotherapy among breast cancer patients in China.

Methods
A total of 1,431 women diagnosed with breast cancer from 1997 to 2005 were enrolled. We reviewed medical records and abstracted information about these patients. Details on social-demographic factors and clinical-pathological characteristics of participants were collected and analyzed. To meet our objectives, the patient’s age at diagnosis, comorbidities, menstrual status, rural/urban status, tumor size, lymph node status, distant metastasis, tumor stage and hormone receptor status were estimated.

Results
Overall, 936 of these 1,431 patients (65.41%) received adjuvant chemotherapy. Receipt of chemotherapy was significantly associated with age at diagnosis, rural–urban disparities, and lymph node status of patients, though no significant difference was found between the age <50 and age 50 to 64 groups. Moderate association was also observed between hormone receptor status and receipt of adjuvant chemotherapy, though it was still not statistically significant.

Conclusions
Our study suggests that age at diagnosis, rural–urban disparities and lymph node status of breast cancer patients are independent predictors for receipt of adjuvant chemotherapy among married Chinese women. Further investigations are warranted, and related public health education needs to be expanded in China.
Fluorescence energy transfer in quantum dot/azo dye complexes in polymer track membranes
Authors: Gromova Yulia A , Orlova Anna O , Maslov Vladimir G , Fedorov Anatoly V , Baranov Alexander V 
Published: October 2013

Abstract
Fluorescence resonance energy transfer in complexes of semiconductor CdSe/ZnS quantum dots with molecules of heterocyclic azo dyes, 1-(2-pyridylazo)-2-naphthol and 4-(2-pyridylazo) resorcinol, formed at high quantum dot concentration in the polymer pore track membranes were studied by steady-state and transient PL spectroscopy. The effect of interaction between the complexes and free quantum dots on the efficiency of the fluorescence energy transfer and quantum dot luminescence quenching was found and discussed.
Neurochemical Characterisation of Lamina II Inhibitory Interneurons that Express GFP in the PrP-GFP Mouse
Authors: Iwagaki Noboru , Garzillo Francesca , Polgár Erika , Riddell John S , Todd Andrew J 
Published: October 2013

Background Inhibitory interneurons in the superficial dorsal horn play important roles in modulating sensory transmission, and these roles are thought to be performed by distinct functional populations. We have identified 4 non-overlapping classes among the inhibitory interneurons in the rat, defined by the presence of galanin, neuropeptide Y, neuronal nitric oxide synthase (nNOS) and parvalbumin. The somatostatin receptor sst2A is expressed by −50% of the inhibitory interneurons in this region, and is particularly associated with nNOS- and galanin-expressing cells. The main aim of the present study was to test whether a genetically-defined population of inhibitory interneurons, those expressing green fluorescent protein (GFP) in the PrP-GFP mouse, belonged to one or more of the neurochemical classes identified in the rat. Results The expression of sst2A and its relation to other neurochemical markers in the mouse was similar to that in the rat, except that a significant number of cells co-expressed nNOS and galanin. The PrP-GFP cells were entirely contained within the set of inhibitory interneurons that possessed sst2A receptors, and virtually all expressed nNOS and/or galanin. GFP was present in ˜3–4% of neurons in the superficial dorsal horn, corresponding to ˜16% of the inhibitory interneurons in this region. Consistent with their sst2A-immunoreactivity, all of the GFP cells were hyperpolarised by somatostatin, and this was prevented by administration of a selective sst2 receptor antagonist or a blocker of G-protein-coupled inwardly rectifying K+ channels. Conclusions These findings support the view that neurochemistry provides a valuable way of classifying inhibitory interneurons in the superficial laminae. Together with previous evidence that the PrP-GFP cells form a relatively homogeneous population in terms of their physiological properties, they suggest that these neurons have specific roles in processing sensory information in the dorsal horn.