bluuebunny/crossref_metadata_2025_split huggingface dataset:
APOBEC3 Inhibition of Mouse Mammary Tumor Virus Infection: the Role of Cytidine Deamination versus Inhibition of Reverse Transcription
Authors: MacMillan Alyssa L. , Kohli Rahul M. , Ross Susan R. 
Published: March 2013

ABSTRACT

The apolipoprotein B editing complex 3 (APOBEC3) family of proteins is a group of intrinsic antiviral factors active against a number of retroviral pathogens, including HIV in humans and mouse mammary tumor virus (MMTV) in mice. APOBEC3 restricts its viral targets through cytidine deamination of viral DNA during reverse transcription or via deaminase-independent means. Here, we used virions from the mammary tissue of MMTV-infected inbred wild-type mice with different allelic APOBEC3 variants (APOBEC3
BALB
and APOBEC3
BL/6
) and knockout mice to determine whether cytidine deamination was important for APOBEC3's anti-MMTV activity. First, using anti-murine APOBEC3 antiserum, we showed that both APOBEC3 allelic variants are packaged into the cores of milk-borne virions produced
in vivo
. Next, using an
in vitro
deamination assay, we determined that virion-packaged APOBEC3 retains its deamination activity and that allelic differences in APOBEC3 affect the sequence specificity. In spite of this
in vitro
activity, cytidine deamination by virion-packaged APOBEC3 of MMTV early reverse transcription DNA occurred only at low levels. Instead, the major means by which
in vivo
virion-packaged APOBEC3 restricted virus was through inhibition of early reverse transcription in both cell-free virions and
in vitro
infection assays. Moreover, the different wild-type alleles varied in their ability to inhibit this step. Our data suggest that while APOBEC3-mediated cytidine deamination of MMTV may occur, it is not the major means by which APOBEC3 restricts MMTV infection
in vivo
. This may reflect the long-term coexistence of MMTV and APOBEC3 in mice.
1918 Influenza Virus Hemagglutinin (HA) and the Viral RNA Polymerase Complex Enhance Viral Pathogenicity, but Only HA Induces Aberrant Host Responses in Mice
Authors: Watanabe Tokiko , Tisoncik-Go Jennifer , Tchitchek Nicolas , Watanabe Shinji , Benecke Arndt G. , Katze Michael G. , Kawaoka Yoshihiro 
Published: March 2013

ABSTRACT
The 1918 pandemic influenza virus was the most devastating infectious agent in human history, causing fatal pneumonia and an estimated 20 to 50 million deaths worldwide. Previous studies indicated a prominent role of the hemagglutinin (HA) gene in efficient replication and high virulence of the 1918 virus in mice. It is, however, still unclear whether the high replication ability or the 1918 influenza virus HA gene is required for 1918 virus to exhibit high virulence in mice. Here, we examined the biological properties of reassortant viruses between the 1918 virus and a contemporary human H1N1 virus (A/Kawasaki/173/2001 [K173]) in a mouse model. In addition to the 1918 influenza virus HA, we demonstrated the role of the viral RNA replication complex in efficient replication of viruses in mouse lungs, whereas only the HA gene is responsible for lethality in mice. Global gene expression profiling of infected mouse lungs revealed that the 1918 influenza virus HA was sufficient to induce transcriptional changes similar to those induced by the 1918 virus, despite difference in lymphocyte gene expression. Increased expression of genes associated with the acute-phase response and the protein ubiquitination pathway were enriched during infections with the 1918 and 1918HA/K173 viruses, whereas reassortant viruses bearing the 1918 viral RNA polymerase complex induced transcriptional changes similar to those seen with the K173 virus. Taken together, these data suggest that HA and the viral RNA polymerase complex are critical determinants of Spanish influenza pathogenesis, but only HA, and not the viral RNA polymerase complex and NP, is responsible for extreme host responses observed in mice infected with the 1918 influenza virus.
MicroRNA-27a Regulates Lipid Metabolism and Inhibits Hepatitis C Virus Replication in Human Hepatoma Cells
Authors: Shirasaki Takayoshi , Honda Masao , Shimakami Tetsuro , Horii Rika , Yamashita Taro , Sakai Yoshio , Sakai Akito , Okada Hikari , Watanabe Risa , Murakami Seishi , Yi MinKyung , Lemon Stanley M. , Kaneko Shuichi 
Published: March 2013

ABSTRACT

The replication and infectivity of the lipotropic hepatitis C virus (HCV) are regulated by cellular lipid status. Among differentially expressed microRNAs (miRNAs), we found that miR-27a was preferentially expressed in HCV-infected liver over hepatitis B virus (HBV)-infected liver. Gene expression profiling of Huh-7.5 cells showed that miR-27a regulates lipid metabolism by targeting the lipid synthetic transcription factor RXRα and the lipid transporter ATP-binding cassette subfamily A member 1. In addition, miR-27a repressed the expression of many lipid metabolism-related genes, including
FASN
,
SREBP1
,
SREBP2
,
PPAR
α, and
PPAR
γ, as well as
ApoA1
,
ApoB100
, and
ApoE3
, which are essential for the production of infectious viral particles. miR-27a repression increased the cellular lipid content, decreased the buoyant density of HCV particles from 1.13 to 1.08 g/cm
3
, and increased viral replication and infectivity. miR-27a overexpression substantially decreased viral infectivity. Furthermore, miR-27a enhanced
in vitro
interferon (IFN) signaling, and patients who expressed high levels of miR-27a in the liver showed a more favorable response to pegylated IFN and ribavirin combination therapy. Interestingly, the expression of miR-27a was upregulated by HCV infection and lipid overload through the adipocyte differentiation transcription factor C/EBPα. In turn, upregulated miR-27a repressed HCV infection and lipid storage in cells. Thus, this negative feedback mechanism might contribute to the maintenance of a low viral load and would be beneficial to the virus by allowing it to escape host immune surveillance and establish a persistent chronic HCV infection.
Higher maternal education is associated with favourable growth of young children in different countries
Authors: Lakshman Rajalakshmi , Zhang Jing , Zhang Jianduan , Koch Felix S , Marcus Claude , Ludvigsson Johnny , Ong Ken K , Sobko Tanja 
Published: March 2013

BackgroundChildhood growth affects long-term health and could contribute to health inequalities that persist throughout life.MethodsWe compared growth data of 4-year-old to 6-year-old children born 1997–2002 in UK (n=15 168), Sweden (n=6749) and rural China (n=10 327). SD scores (SDS) were calculated against the WHO Growth Standard. Obesity and overweight were defined by the International Obesity Taskforce cut-offs, and stunting, underweight and thinness by height, weight or body mass index (BMI)<−2 SDS. Associations with maternal education were standardised by calculating the Slope Index of Inequality (SII).ResultsMean SDS height, weight and BMI in the UK (−0.01, 0.42, 0.62, respectively) and Sweden (0.45, 0.59, 0.45) were higher than in China (−0.98, −0.82, −0.29). Higher maternal education was consistently associated with taller offspring height SDS (SII: UK 0.25; Sweden 0.17; China 1.06). Underweight and stunting were less common in the UK (prevalence: 0.6% and 2.2%, respectively) and Sweden (0.3% and 0.6%) than in China (9.5% and 16.4%), where these outcomes were inversely associated with maternal education (SII: −25.8% and −12.7%). Obesity prevalence in the UK, Sweden and China was 4.8%, 3.7% and 0.4%, respectively. Maternal education was inversely associated with offspring obesity in the UK (SII: −3.3%) and Sweden (−2.8%), but not in China (+0.3%).ConclusionsHigher maternal education was associated with more favourable growth in young children: lower obesity and overweight in the UK and Sweden, and lower stunting and underweight in rural China. Public health strategies to optimise growth in early childhood need to acknowledge socioeconomic factors, but possibly with a different emphasis in different settings.
The Role of Versican in Modulating Breast Cancer Cell Self-renewal
Authors: Du William Weidong , Fang Ling , Yang Xiangling , Sheng Wang , Yang Bing L. , Seth Arun , Zhang Yaou , Yang Burton B. , Yee Albert J. 
Published: March 2013

Abstract
Versican is highly expressed during the early stages of tissue development and its expression is elevated during wound repair and tumor growth. There is little literature on the potential role of breast cancer stem cells on the cellular–extracellular matrix interactions involving versican. An anti-versican short hairpin RNA (shRNA) was used to observe the effect of reduction of versican on breast cancer self-renewal. A versican G3 construct was exogenously expressed in breast cancer cell lines. Colony formation and mammosphere formation assays were conducted; flow cytometry was applied to analyze the prevalence of side population cells. The versican G3- and vector-transfected 66c14 cells were injected transdermally into BALB/c mice as a 10-fold dilution series from 1 × 105 to 1 × 102 cells per mouse. Versican G3 domain enhanced breast cancer self-renewal in both experimental in vitro and in vivo models. Versican G3–transfected cells contained high levels of side population cells, formed more mammospheres when cultured in the serum-free medium, and formed a greater number and larger colonies. Reduction of versican's functionality through anti-versican shRNA or knocking out the EGF-like motifs reduced the effect of versican on enhancing mammosphere and colony formation. Versican-enhanced self-renewal played a role in enhanced chemotherapeutic drug resistance, relating partly to the upregulated expression of EGF receptor (EGFR) signaling. Versican is highly expressed in breast cancer progenitor cells and was maintained at high levels before cell differentiation. Overexpression of versican enhanced breast cancer self-renewal through EGFR/AKT/GSK-3β (S9P) signaling and conferred resistant to chemotherapeutic drugs tested. Mol Cancer Res; 11(5); 443–55. ©2013 AACR.
Embryological-Origin–Dependent Differences in Homeobox Expression in Adult Aorta
Authors: Trigueros-Motos Laia , González-Granado José M. , Cheung Christine , Fernández Patricia , Sánchez-Cabo Fátima , Dopazo Ana , Sinha Sanjay , Andrés Vicente 
Published: March 2013

Objective—
Different vascular beds show differing susceptibility to the development of atherosclerosis, but the molecular mechanisms underlying these differences are incompletely understood. This study aims to identify factors that contribute to the phenotypic heterogeneity of distinct regions of the adult vasculature.

Approach and Results—

High-throughput mRNA profiling in adult mice reveals higher expression of the homeobox paralogous genes 6 to 10 (
Hox6-10
) in the athero-resistant thoracic aorta (TA) than in the athero-susceptible aortic arch (AA). Higher homeobox gene expression also occurs in rat and porcine TA, and is maintained in primary smooth muscle cells isolated from TA (TA–SMCs) compared with cells from AA (AA–SMCs). This region-specific homeobox gene expression pattern is also observed in human embryonic stem cells differentiated into neuroectoderm–SMCs and paraxial mesoderm–SMCs, which give rise to AA–SMCs and TA–SMCs, respectively. We also find that, compared with AA and AA–SMCs, TA and TA–SMCs have lower activity of the proinflammatory and proatherogenic nuclear factor-κB (NF-κB) and lower expression of NF-κB target genes, at least in part attributable to HOXA9-dependent inhibition. Conversely, NF-κB inhibits
HOXA9
promoter activity and mRNA expression in SMCs.

Conclusion—

Our findings support a model of Hox6-10–specified positional identity in the adult vasculature that is established by embryonic cues independently of environmental factors and is conserved in different mammalian species. Differential homeobox gene expression contributes to maintaining phenotypic differences between SMCs from athero-resistant and athero-susceptible regions, at least in part through feedback regulatory mechanisms involving inflammatory mediators, for example, reciprocal inhibition between
HOXA9
and NF-κB.
Combined In Vivo Depletion of Glycoprotein VI and C-Type Lectin-Like Receptor 2 Severely Compromises Hemostasis and Abrogates Arterial Thrombosis in Mice
Authors: Bender Markus , May Frauke , Lorenz Viola , Thielmann Ina , Hagedorn Ina , Finney Brenda A. , Vögtle Timo , Remer Katharina , Braun Attila , Bösl Michael , Watson Steve P. , Nieswandt Bernhard 
Published: March 2013

Objective—
Platelet inhibition is a major strategy to prevent acute ischemic cardiovascular and cerebrovascular events, which may, however, be associated with an increased bleeding risk. The (hem)immunoreceptor tyrosine activation motif–bearing platelet receptors, glycoprotein VI (GPVI) and C-type lectin-like receptor 2 (CLEC-2), might be promising antithrombotic targets because they can be depleted from circulating platelets by antibody treatment, leading to sustained antithrombotic protection, but only moderately increased bleeding times in mice.

Approach and Results—
We investigated whether both (hem)immunoreceptor tyrosine activation motif–bearing receptors can be targeted simultaneously and what the in vivo consequences of such a combined therapeutic GPVI/CLEC-2 deficiency are. We demonstrate that isolated targeting of either GPVI or CLEC-2 in vivo does not affect expression or function of the respective other receptor. Moreover, simultaneous treatment with both antibodies resulted in the sustained loss of both GPVI and CLEC-2, while leaving other activation pathways intact. However, GPVI/CLEC-2–depleted mice displayed a dramatic hemostatic defect and profound impairment of arterial thrombus formation. Furthermore, a strongly diminished hemostatic response could also be reproduced in mice genetically lacking GPVI and CLEC-2.

Conclusions—
These results demonstrate that GPVI and CLEC-2 can be simultaneously downregulated in platelets in vivo and reveal an unexpected functional redundancy of the 2 receptors in hemostasis and thrombosis. These findings may have important implications of the potential use of anti-GPVI and anti–CLEC-2–based agents in the prevention of thrombotic diseases.
Total Adiponectin and Risk of Symptomatic Lower Extremity Peripheral Artery Disease in Men
Authors: Joosten Michel M. , Joshipura Kaumudi J. , Pai Jennifer K. , Bertoia Monica L. , Rimm Eric B. , Mittleman Murray A. , Mukamal Kenneth J. 
Published: March 2013

Objective—
Lower concentrations of adiponectin have been linked to subsequent risk of coronary heart disease in healthy individuals. Whether similar relationships exist for the development of systemic atherosclerosis, such as peripheral artery disease (PAD), is uncertain. We investigated the association between total adiponectin and risk of lower extremity PAD.

Approach and Results—

We performed a prospective, nested case–control study among 18 225 male participants of the Health Professionals Follow-up Study who were free of diagnosed cardiovascular disease at the time of blood draw (1993–1995). During 14 years of follow-up, 143 men developed PAD. Using risk set sampling, controls were selected in a 3:1 ratio and matched on age, smoking status, fasting status, and date of blood draw (n=429). Median (interquartile range) adiponectin concentrations at baseline were lower among cases compared with controls (4.1 [3.2–5.5] versus 5.4 [3.8–7.5] µg/mL;
P
<0.001). A log-linear inverse association was evident over the full spectrum of adiponectin concentrations with PAD risk after controlling for baseline cardiovascular risk factors using restricted spline conditional logistic regression. Adiponectin was associated with a 42% lower risk of PAD per SD increase in natural log-transformed adiponectin (relative risk, 0.58; 95% confidence interval, 0.45–0.74) after adjustment for cardiovascular risk factors. The relative risk was attenuated (relative risk, 0.68; 95% confidence interval, 0.51–0.92) after further accounting for high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, C-reactive protein, and cystatin C. Additional adjustment for hemoglobin A
1c
, triglycerides, and γ-glutamyltransferase had little impact on this association (relative risk, 0.68; 95% confidence interval, 0.50–0.92).

Conclusions—
Total adiponectin is inversely associated with risk of symptomatic lower extremity PAD in men.
Accuracy of Diffusion-Weighted Imaging in the Diagnosis of Stroke in Patients With Suspected Cerebral Infarct
Authors: Brunser Alejandro M. , Hoppe Arnold , Illanes Sergio , Díaz Violeta , Muñoz Paula , Cárcamo Daniel , Olavarria Verónica , Valenzuela Marcela , Lavados Pablo 
Published: March 2013

Background and Purpose—
The accuracy of diffusion-weighted imaging (DWI) for the diagnosis of acute cerebral ischemia among patients with suspected ischemic stroke arriving to an emergency room has not been studied in depth.

Methods—
DWI was performed in 712 patients with acute or subacute focal symptoms that suggested an acute ischemic stroke (AIS), 609 of them with AIS.

Results—
DWI demonstrated a sensitivity of 90% and specificity of 97%, a positive likelihood ratio of 31 and a negative likelihood ratio of 0.1 for detecting AIS. The overall accuracy was 95%. Of those patients who demonstrated abnormal DWI studies, 99.5% were AIS patients, and of those patients with normal DWI studies 63% were stroke mimics.

Conclusions—
DWI is accurate in detecting AIS in unselected patients with suspected AIS; a negative study should alert for nonischemic conditions.
Occult Atrial Fibrillation in Cryptogenic Stroke
Authors: Ritter Martin A. , Kochhäuser Simon , Duning Thomas , Reinke Florian , Pott Christian , Dechering Dirk G. , Eckardt Lars , Ringelstein E. Bernd 
Published: March 2013

Background and Purpose—
A significant number of patients with cryptogenic stroke suffer from intermittent atrial fibrillation (iAF) which was not detected during the standard diagnostic procedures. We investigated whether implantation of an insertable cardiac monitor (ICM) is feasible in patients with cryptogenic stroke, and compared the iAF detection rate of the ICM with 7-day Holter monitoring.

Methods—
Sixty patients (median age 63; interquartile range, 48.5–72 years) with acute cryptogenic stroke were included. ICM was implanted 13 days (interquartile range; 10–65 days) after the qualifying event. Seven-day Holter was performed after the ICM was implanted.

Results—

The iAF was detected by the ICM in 10 patients (17%; 95% CI, 7% to 26%). Only 1 patient (1.7%; 95% CI, 0% to 5%) had iAF during 7-day Holter monitoring as well (
P
=0.0077). Episodes of iAF lasting 2 minutes or more were detected 64 (range, 1–556) days after implantation. There were no recurrent strokes during the observation period. The implantation procedure was well tolerated with no adverse events; the daily data transmission protocol was easy to handle by the patients.

Conclusions—
ICM implantation for the detection of iAF during outpatient follow-up is feasible in patients with cryptogenic stroke. ICMs offer a much higher diagnostic yield than 7-day Holter monitoring.
Higher Ambulatory Blood Pressure Relates to New Cerebral Microbleeds
Authors: Klarenbeek Pim , van Oostenbrugge Robert J. , Rouhl Rob P.W. , Knottnerus Iris L.H. , Staals Julie 
Published: March 2013

Background and Purpose—
Elevated blood pressure (BP) is associated with the presence of cerebral microbleeds (CMBs) in cross-sectional studies. However, longitudinal studies did not show a convincing relationship. We aimed to determine the association between elevated BP levels and the occurrence of new CMBs after a 2-year follow-up in first-ever lacunar stroke patients using ambulatory BP monitoring.

Methods—
Ninety-six first-ever lacunar stroke patients underwent brain MRI and ambulatory BP monitoring at baseline and after 2-year follow-up. We used logistic regression analyses to assess the association of BP levels with new CMBs.

Results—
We found new CMBs in 17 patients (18%). Higher 24-hour, day and night systolic BP (odds ratio, 2.69; 95% confidence interval, 1.40–5.21 per SD increase for 24-hour BP) and diastolic BP (odds ratio, 2.13; 95% confidence interval, 1.15–3.90 per SD increase for 24-hour BP) at baseline were associated with the development of new CMBs independent of age and sex. BP levels decreased during follow-up in both patients with and without new CMBs. Unlike BP levels at baseline, there was no difference in BP levels at follow-up between patients with and without new CMBs.

Conclusions—
Both higher systolic and diastolic BP levels were associated with the development of new CMBs in a population of lacunar stroke patients. Decrease of BP levels during follow-up did not halt progression of CMBs; however, it remains to be determined whether (early) intervention with antihypertensive drugs can slow down progression of CMBs.
The role of psychopathology in stalking by adult strangers and acquaintances
Authors: McEwan Troy E , Strand Susanne 
Published: March 2013

Objective: Individuals who stalk strangers and acquaintances are under-studied, although there is some evidence suggesting a greater prevalence of psychopathology than is present in those who stalk former partners. This study investigated the nature and prevalence of psychopathology in a sample of stranger and acquaintance stalkers and whether psychopathology was associated with increased duration or serial stalking in this group. It was hypothesised that mental illness, and specifically psychosis, would be more prevalent among strangers and acquaintances than among ex-intimate stalkers. Method: Two hundred and eleven stalkers (10% female; mean age = 35, SD = 10.8; 71 ex-intimates) were recruited between 2002 and 2007 from a specialist service in Melbourne, Australia. Each underwent psychiatric and psychological assessment and disorders were diagnosed according to DMS-IV-TR criteria. Non-parametric independent sample tests were used to examine associations between relationship type and psychopathology, and to identify individual and stalking-related characteristics associated with increased duration and serial stalking. Results: Axis I disorders were significantly more prevalent among strangers and acquaintances than ex-intimates (71% vs 48%, OR = 2.6, 95% CI = 1.4 to 4.7), as were psychotic disorders (29% vs 9%, OR = 4.4, 95% CI = 1.8 to 10.9). Psychosis was significantly associated with increased duration of stalking behaviour ( U = 3043, p < 0.001). Those with a personality disorder were twice as likely to have stalked multiple times (OR = 2.4, 95% CI = 1.2 to 5.0). Conclusions: Those who stalk strangers and acquaintances are often mentally ill and psychopathology is associated with more persistent and recurrent stalking behaviour. Although limited by the use of clinical interview rather than structured assessment, these findings strongly support the argument for routine mental health assessment of stranger and acquaintance stalkers who become involved with the criminal justice system.