bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human Cytomegalovirus Infection Causes Premature and Abnormal Differentiation of Human Neural Progenitor Cells
Authors: Luo Min Hua , Hannemann Holger , Kulkarni Amit S. , Schwartz Philip H. , O'Dowd John M. , Fortunato Elizabeth A. 
Published: January 2010

ABSTRACTCongenital human cytomegalovirus (HCMV) infection is a leading cause of birth defects, largely manifested as central nervous system (CNS) disorders. The principal site of manifestations in the mouse model is the fetal brain's neural progenitor cell (NPC)-rich subventricular zone. Our previous human NPC studies found these cells to be fully permissive for HCMV and a usefulin vitromodel system. In continuing work, we observed that under culture conditions favoring maintenance of multipotency, infection caused NPCs to quickly and abnormally differentiate. This phenotypic change required active viral transcription. Whole-genome expression analysis found rapid downregulation of genes that maintain multipotency and establish NPCs’ neural identity. Quantitative PCR, Western blot, and immunofluorescence assays confirmed that the mRNA and protein levels of four hallmark NPC proteins (nestin, doublecortin, sex-determining homeobox 2, and glial fibrillary acidic protein) were decreased by HCMV infection. The decreases required active viral replication and were due, at least in part, to proteasomal degradation. Our results suggest that HCMV infection causesin uteroCNS defects by inducing both premature and abnormal differentiation of NPCs.
Assessment of Seasonal Influenza A Virus-Specific CD4 T-Cell Responses to 2009 Pandemic H1N1 Swine-Origin Influenza A Virus
Authors: Ge Xinhui , Tan Venus , Bollyky Paul L. , Standifer Nathan E. , James Eddie A. , Kwok William W. 
Published: January 2010

ABSTRACT

Very limited evidence has been reported to show human adaptive immune responses to the 2009 pandemic H1N1 swine-origin influenza A virus (S-OIV). We studied 17 S-OIV peptides homologous to immunodominant CD4 T epitopes from hemagglutinin (HA), neuraminidase (NA), nuclear protein (NP), M1 matrix protein (MP), and PB1 of a seasonal H1N1 strain. We concluded that 15 of these 17 S-OIV peptides would induce responses of seasonal influenza virus-specific T cells. Of these, seven S-OIV sequences were identical to seasonal influenza virus sequences, while eight had at least one amino acid that was not conserved. T cells recognizing epitopes derived from these S-OIV antigens could be detected
ex vivo
. Most of these T cells expressed memory markers, although none of the donors had been exposed to S-OIV. Functional analysis revealed that specific amino acid differences in the sequences of these S-OIV peptides would not affect or partially affect memory T-cell responses. These findings suggest that without protective antibody responses, individuals vaccinated against seasonal influenza A may still benefit from preexisting cross-reactive memory CD4 T cells reducing their susceptibility to S-OIV infection.
Viral Protein Determinants of Lassa Virus Entry and Release from Polarized Epithelial Cells
Authors: Schlie Katrin , Maisa Anna , Freiberg Fabian , Groseth Allison , Strecker Thomas , Garten Wolfgang 
Published: January 2010

ABSTRACTThe epithelium plays a key role in the spread of Lassa virus. Transmission from rodents to humans occurs mainly via inhalation or ingestion of droplets, dust, or food contaminated with rodent urine. Here, we investigated Lassa virus infection in cultured epithelial cells and subsequent release of progeny viruses. We show that Lassa virus enters polarized Madin-Darby canine kidney (MDCK) cells mainly via the basolateral route, consistent with the basolateral localization of the cellular Lassa virus receptor α-dystroglycan. In contrast, progeny virus was efficiently released from the apical cell surface. Further, we determined the roles of the glycoprotein, matrix protein, and nucleoprotein in directed release of nascent virus. To do this, a virus-like-particle assay was developed in polarized MDCK cells based on the finding that, when expressed individually, both the glycoprotein GP and matrix protein Z form virus-like particles. We show that GP determines the apical release of Lassa virus from epithelial cells, presumably by recruiting the matrix protein Z to the site of virus assembly, which is in turn essential for nucleocapsid incorporation into virions.
Phosphorylation-Mediated Negative Regulation of RIG-I Antiviral Activity
Authors: Gack Michaela U. , Nistal-Villán Estanislao , Inn Kyung-Soo , García-Sastre Adolfo , Jung Jae U. 
Published: January 2010

ABSTRACT
Recognition of invading viruses by the host is elicited by cellular sensors which trigger signaling cascades that lead to type I interferon (IFN) gene expression. Retinoic acid-inducible gene I (RIG-I) has emerged as a key receptor for the detection of viral RNA in the cytosol, inducing IFN-mediated innate immune responses to limit viral replication through its interaction with MAVS (also called IPS-1, CARDIF, or VISA). Upon the recognition of viral RNA, the Lys-172 residue of RIG-I undergoes ubiquitination induced by tripartite motif protein 25 (TRIM25), an essential protein for antiviral signal transduction. Here we demonstrate that phosphorylation represents another regulatory mechanism for RIG-I-mediated antiviral activity. Using protein purification and mass spectrometry analysis, we identified three phosphorylation sites in the amino-terminal caspase recruitment domains (CARDs) of RIG-I. One of these residues, Thr-170, is located in close proximity to Lys-172, and we speculated that its phosphorylation may affect Lys-172 ubiquitination and functional activation of RIG-I. Indeed, a RIG-I mutant carrying a phosphomimetic Glu residue in place of Thr-170 loses TRIM25 binding, Lys-172 ubiquitination, MAVS binding, and downstream signaling ability. This suggests that phosphorylation of RIG-I at Thr-170 inhibits RIG-I-mediated antiviral signal transduction. Immunoblot analysis with a phospho-specific antibody showed that the phosphorylation of the RIG-I Thr-170 residue is present under normal conditions but rapidly declines upon viral infection. Our results indicate that Thr-170 phosphorylation and TRIM25-mediated Lys-172 ubiquitination of RIG-I functionally antagonize each other. While Thr-170 phosphorylation keeps RIG-I latent, Lys-172 ubiquitination enables RIG-I to form a stable complex with MAVS, thereby inducing IFN signal transduction.
Identification of Host Factors Involved in Borna Disease Virus Cell Entry through a Small Interfering RNA Functional Genetic Screen
Authors: Clemente Roberto , Sisman Eugene , Aza-Blanc Pedro , de la Torre Juan C. 
Published: January 2010

ABSTRACTBorna disease virus (BDV), the prototypic member of theBornaviridaefamily, within the orderMononegavirales, is highly neurotropic and constitutes an important model system for the study of viral persistence in the central nervous system (CNS) and associated disorders. The virus surface glycoprotein (G) has been shown to direct BDV cell entry via receptor-mediated endocytosis, but the mechanisms governing cell tropism and propagation of BDV within the CNS are unknown. We developed a small interfering RNA (siRNA)-based screening to identify cellular genes and pathways that specifically contribute to BDV G-mediated cell entry. Our screen relied on silencing-mediated increased survival of cells infected with rVSVΔG*/BDVG, a cytolytic recombinant vesicular stomatitis virus expressing BDV G that mimics the cell tropism and entry pathway of bona fide BDV. We identified 24 cellular genes involved in BDV G-mediated cell entry. Identified genes are known to participate in a broad range of distinct cellular functions, revealing a complex process associated with BDV cell entry. The siRNA-based screening strategy we have developed should be applicable to identify cellular genes contributing to cell entry mediated by surface G proteins of other viruses.
Measles Virus Selectively Blind to Signaling Lymphocytic Activation Molecule (SLAM; CD150) Is Attenuated and Induces Strong Adaptive Immune Responses in Rhesus Monkeys
Authors: Leonard Vincent H. J. , Hodge Gregory , Reyes-del Valle Jorge , McChesney Michael B. , Cattaneo Roberto 
Published: January 2010

ABSTRACTThe signaling lymphocytic activation molecule (SLAM; CD150) is the immune cell receptor for measles virus (MV). To assess the importance of the SLAM-MV interactions for virus spread and pathogenesis, we generated a wild-type IC-B MV selectively unable to recognize human SLAM (SLAM-blind). This virus differs from the fully virulent wild-type IC-B strain by a single arginine-to-alanine substitution at amino acid 533 of the attachment protein hemagglutinin and infects cells through SLAM about 40 times less efficiently than the isogenic wild-type strain.Ex vivo, this virus infects primary lymphocytes at low levels regardless of SLAM expression. When a group of six rhesus monkeys (Macaca mulatta) was inoculated intranasally with the SLAM-blind virus, no clinical symptoms were documented. Only one monkey had low-level viremia early after infection, whereas all the hosts in the control group had high viremia levels. Despite minimal, if any, viremia, all six hosts generated neutralizing antibody titers close to those of the control monkeys while MV-directed cellular immunity reached levels at least as high as in wild-type-infected monkeys. These findings prove formally that efficient SLAM recognition is necessary for MV virulence and pathogenesis. They also suggest that the selectively SLAM-blind wild-type MV can be developed into a vaccine vector.
An Ascovirus-Encoded RNase III Autoregulates Its Expression and Suppresses RNA Interference-Mediated Gene Silencing
Authors: Hussain Mazhar , Abraham Alexander M. , Asgari Sassan 
Published: January 2010

ABSTRACT

RNase III proteins play vital roles in processing of several types of RNA molecules and gene silencing. Recently, it has been discovered that some plant and animal viruses encode RNase III-like proteins as well. Genome sequencing of four virus species belonging to the
Ascoviridae
family has revealed sequence conservation of an RNase III open reading frame among the viruses. These have not been explored in ascoviruses, and therefore their role in host-virus interaction is unknown. Here, we confirmed expression of
Heliothis virescens ascovirus
(HvAV-3e) open reading frame 27 (
orf27
) that encodes an RNase III-like protein after infection and demonstrated dsRNA specific endoribonuclease activity of the encoded protein. Analysis of the expression patterns of
orf27
in virus-infected insect cells and a bacterial expression system revealed autoregulation of this protein over time. Moreover, HvAV-3e RNase III was found essential for virus DNA replication and infection using RNA interference (RNAi)-mediated gene silencing. In addition, using green fluorescent protein gene as a marker, we provide evidence that RNase III is involved in the suppression of gene silencing. To our knowledge, this is the first insect virus-encoded RNase III described and shown to suppress host cell RNAi defense mechanism.
Poly(A) at the 3′ End of Positive-Strand RNA and VPg-Linked Poly(U) at the 5′ End of Negative-Strand RNA Are Reciprocal Templates during Replication of Poliovirus RNA
Authors: Steil Benjamin P. , Kempf Brian J. , Barton David J. 
Published: January 2010

ABSTRACT
A 3′ poly(A) tail is a common feature of picornavirus RNA genomes and the RNA genomes of many other positive-strand RNA viruses. We examined the manner in which the homopolymeric poly(A) and poly(U) portions of poliovirus (PV) positive- and negative-strand RNAs were used as reciprocal templates during RNA replication. Poly(A) sequences at the 3′ end of viral positive-strand RNA were transcribed into VPg-linked poly(U) products at the 5′ end of negative-strand RNA during PV RNA replication. Subsequently, VPg-linked poly(U) sequences at the 5′ ends of negative-strand RNA templates were transcribed into poly(A) sequences at the 3′ ends of positive-strand RNAs. The homopolymeric poly(A) and poly(U) portions of PV RNA products of replication were heterogeneous in length and frequently longer than the corresponding homopolymeric sequences of the respective viral RNA templates. The data support a model of PV RNA replication wherein reiterative transcription of homopolymeric templates ensures the synthesis of long 3′ poly(A) tails on progeny RNA genomes.
Osteonecrosis of the jaw: a rare and devastating side effect of bisphosphonates
Authors: Ryan P , Saleh I , Stassen L F A 
Published: January 2010

Abstract
Evidence has emerged that bisphosphonate use in cancer patients is associated with osteonecrosis of the jaw. This form of osteonecrosis has been termed bisphosphonate induced osteonecrosis of the jaw (BIONJ). BIONJ is commonly precipitated by a tooth extraction in patients treated with long term, potent, high dose intravenous bisphosphonates for the management of myeloma, breast or prostate cancer. The overall prevalence of BIONJ is about 5% in patients with these malignancies. Current evidence shows that the risk of BIONJ in non-cancerous patients, such as those with osteoporosis, is very low and appears to be comparable with that of the general population. Prescribing physicians need to encourage cancer patients to see their dentists before the initiation of bisphosphonate treatment, and regularly thereafter.
Management of thyroid disorders in primary care: challenges and controversies
Authors: Todd C H 
Published: January 2010

Abstract
Thyroid diseases are common, and most can be safely and effectively managed in primary care. Two of the most common reasons for thyroid function testing are fatigue and obesity, but the vast majority of affected patients do not have hypothyroidism. There is no plausible basis for the assertion that hypothyroidism commonly occurs despite normal thyroid function tests. In primary hypothyroidism all patients, except the elderly and those with ischaemic heart disease, can safely be started on a full replacement dose of thyroxine; the aim is to restore thyroid stimulating hormone (TSH) to normal. Triiodothyronine (T3) has no role in the treatment of primary hypothyroidism. Subclinical thyroid disease should not be treated except in certain well defined situations. Its main importance lies in the increased risk of progression to overt thyroid disease. The development of hyperthyroidism is easily overlooked, and it is important to maintain a high index of suspicion, especially in the elderly. The most common causes are Graves’ disease and thyroiditis (especially postpartum), and in the elderly toxic nodular goitre and amiodarone. Patients taking amiodarone should have their thyroid function checked every 6 months. Patients with overt hyperthyroidism should be referred for specialist management; β-blockers and sometimes anti-thyroid drugs may be initiated in primary care. Most thyroid nodules, especially those detected incidentally on ultrasound scanning, are benign. Indications for referral include newly occurring nodules &gt;1cm in diameter, painful nodules, and nodules that are increasing in size.
Primary immunodeficiency diseases: a practical guide for clinicians
Authors: Turvey S E , Bonilla F A , Junker A K 
Published: January 2010

Abstract
Primary immunodeficiency diseases (PIDs) are genetically determined disorders of the immune system resulting in greatly enhanced susceptibility to infectious disease, autoimmunity and malignancy. While individual PIDs are rare, as a group, it is estimated that between 1:2000 and 1:10 000 live births are affected by a PID. Moreover, PIDs can present at any age from birth to adulthood, posing a considerable challenge for the practising physician to know when and how to work-up a patient for a possible immune defect. In this review, we outline the basic organisation of the human immune system and the types of infections that occur when elements of the immune system are dysfunctional. Importantly, we provide practical guidelines for identifying patients who should be referred for assessment of possible immunodeficiency and an overview of screening investigations and effective therapeutic options available for these patients.
Management of the first seizure: an evidence based approach
Authors: Seneviratne U 
Published: January 2010

AbstractThe first seizure is more common than epilepsy. A detailed history is vital in the assessment in order to reveal unreported minor seizures such as myoclonic jerks, simple partial seizures and absences in the past. The first seizure could be provoked or unprovoked. Provoked seizures have a lower risk or recurrence. Electroencephalogram (EEG) studies and neuroimaging are essential components in the diagnostic work up. Abnormal neurological status and abnormal EEG are the most significant predictors of seizure recurrence. Antiepileptic drug (AED) treatment after the first seizure significantly reduces seizure recurrence rate in the first 2 years. However it does not appear to change the long term outlook. There are some patients who would benefit from AED treatment after the first seizure. This paper discusses the current evidence on this multifaceted clinical problem which would help formulate a rational management plan.
FAST-TIA: a prospective evaluation of a nurse-led anterior circulation TIA clinic
Authors: Banerjee S , Natarajan I , Biram R , Sutton K , Ekeng G , Ames D , Chataway J 
Published: January 2010

Abstract

Background
Transient ischaemic attacks (TIAs) carry a significant early risk of stroke. New national guidelines state patients should be seen within 7 days of the incident, with higher-risk patients being seen within 24 h. Meeting these targets across the NHS poses a significant challenge. A novel approach to TIA assessment has been developed using a nurse-led rapid-access anterior circulation TIA clinic.

Methods
This was a prospective evaluation of all patients attending the FAST-TIA clinic between November 2003 and December 2006. Diagnostic yield of neurovascular events among patients seen through the TIA service and median time from referral to assessment and from event to assessment were measured.

Results
282 patients were eligible for investigation, and seen through the clinic over a period of 38 months. A vascular event was diagnosed in 242 (86%). TIA was diagnosed in 133 (55%), minor ischaemic stroke in 77 (32%), haemorrhagic stroke in three (1%), and an ocular event in 29 (12%). Median time from referral to assessment was 3 days (interquartile range (IQR) 1–7), and from event to assessment it was 7 days (IQR 3–18). 34% of patients were seen within 24 h of referral.

Conclusions
This model has a high diagnostic rate of 86% vascular events, significantly higher than current national averages of ∼55%. Current national guidelines for early assessment of patients (published subsequent to this study) are achievable using this service. The FAST-TIA model is an easily reproducible and pragmatic method of improving the diagnostic yield of TIA services, while keeping within national targets.
Role of medical intervention in slowing the growth of small abdominal aortic aneurysms
Authors: Cooper D G , King J A , Earnshaw J J 
Published: January 2010

Abstract
Abdominal aortic aneurysm is a common—but preventable—cause of death in elderly men; 4% of men at the age of 65 years have an aorta &gt;3 cm in diameter. Continued expansion runs the risk of aneurysm rupture, a condition that is fatal in all but 15% of individuals. A national screening programme has commenced that aims to reduce the number of deaths from aneurysm rupture by 50%. The programme will detect a large number of men with a small aneurysm who are not in imminent danger of rupture, but who will join a regular ultrasound programme of surveillance. If the aneurysm expansion rate could be reduced, fewer men would be at risk of aneurysm rupture, and fewer would need elective aneurysm repair. A considerable amount is known about the pathophysiology of aneurysm growth. Exploring pharmacological means to delay or reduce aneurysm growth could make a considerable contribution to any screening programme. A number of case control studies have suggested that some antihypertensive drugs, non-steroidal anti-inflammatory drugs, antibiotics, and statins may reduce aneurysm growth rates. Data from controlled studies have provided less secure conclusions. Use of these medications, together with lifestyle modification such as stopping smoking, could become standard advice to men with a small aortic aneurysm. Further studies of novel agents and larger controlled trials of existing drugs are warranted.
Endobronchial stenting in the management of large airway pathology
Authors: Ranu H , Madden B P 
Published: January 2010

Abstract
Endobronchial interventions including the deployment of endobronchial stents have a clear role in the management of central airway problems. The use of endobronchial stents has rapidly increased since the first airway stent was developed in the 1960s and with the subsequent manufacture of improved silicone and metallic stents. They provide effective relief for symptoms of intrinsic and extrinsic airway obstruction secondary to a wide range of pathologies including lung cancer, lymphoma, thyroid carcinoma and benign disease such as tracheal strictures and tracheobronchomalacia. Endobronchial stents can also seal defects within the airway including malignant broncho-oesophageal fistulae and posterior wall tracheal tears. They can be placed safely under conscious sedation at flexible bronchoscopy or under general anaesthetic at rigid bronchoscopy. Rigid bronchoscopy under general anaesthesia provided by a multidisciplinary team is safe with few contraindications. Complications of endobronchial stents include infection, granulation tissue formation and metallic stent fracture sometimes requiring removal, although serious life-threatening complications are very rare. Increasing numbers of patients are being referred to specialist centres for airway intervention. This article reviews the history of endobronchial stents, the different stents available, and the indications, outcomes and complications involved in deploying endobronchial stents.
Structuring the verification of heap-manipulating programs
Authors: Nanevski Aleksandar , Vafeiadis Viktor , Berdine Josh 
Published: January 2010

Most systems based on separation logic consider only restricted forms of implication or non-separating conjunction, as full support for these connectives requires a non-trivial notion of variable context, inherited from the logic of bunched implications (BI). We show that in an expressive type theory such as Coq, one can avoid the intricacies of BI, and support full separation logic very efficiently, using the native structuring primitives of the type theory.
Our proposal uses reflection to enable equational reasoning about heaps, and Hoare triples with binary postconditions to further facilitate it. We apply these ideas to Hoare Type Theory, to obtain a new proof technique for verification of higher-order imperative programs that is general, extendable, and supports very short proofs, even without significant use of automation by tactics. We demonstrate the usability of the technique by verifying the fast congruence closure algorithm of Nieuwenhuis and Oliveras, employed in the state-of-the-art Barcelogic SAT solver.