bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heat Shock Protein 70 Enhances Mucosal Immunity against Human Norovirus When Coexpressed from a Vesicular Stomatitis Virus Vector
Authors: Ma Yuanmei , Duan Yue , Wei Yongwei , Liang Xueya , Niewiesk Stefan , Oglesbee Michael , Li Jianrong 
Published: February 2014

ABSTRACTHuman norovirus (NoV) accounts for 95% of nonbacterial gastroenteritis worldwide. Currently, there is no vaccine available to combat human NoV as it is not cultivable and lacks a small-animal model. Recently, we demonstrated that recombinant vesicular stomatitis virus (rVSV) expressing human NoV capsid protein (rVSV-VP1) induced strong immunities in mice (Y. Ma and J. Li, J. Virol. 85:2942–2952, 2011). To further improve the safety and efficacy of the vaccine candidate, heat shock protein 70 (HSP70) was inserted into the rVSV-VP1 backbone vector. A second construct was generated in which the firefly luciferase (Luc) gene was inserted in place of HSP70 as a control for the double insertion. The resultant recombinant viruses (rVSV-HSP70-VP1 and rVSV-Luc-VP1) were significantly more attenuated in cell culture and viral spread in mice than rVSV-VP1. At the inoculation dose of 1.0 × 106PFU, rVSV-HSP70-VP1 triggered significantly higher vaginal IgA than rVSV-VP1 and significantly higher fecal and vaginal IgA responses than rVSV-Luc-VP1, although serum IgG and T cell responses were similar. At the inoculation dose of 5.0 × 106PFU, rVSV-HSP70-VP1 stimulated significantly higher T cell, fecal, and vaginal IgA responses than rVSV-VP1. Fecal and vaginal IgA responses were also significantly increased when combined vaccination of rVSV-VP1 and rVSV-HSP70 was used. Collectively, these data indicate that (i) insertion of an additional gene (HSP70 or Luc) into the rVSV-VP1 backbone further attenuates the VSV-based vaccinein vitroandin vivo, thus improving the safety of the vaccine candidate, and (ii) HSP70 enhances the human NoV-specific mucosal and T cell immunities triggered by a VSV-based human NoV vaccine.IMPORTANCEHuman norovirus (NoV) is responsible for more than 95% of acute nonbacterial gastroenteritis worldwide. Currently, there is no vaccine for this virus. Development of a live attenuated vaccine for human NoV has not been possible because it is uncultivable. Thus, a live vector-based vaccine may provide an alternative vaccine strategy. In this study, we developed a vesicular stomatitis virus (VSV)-based human NoV vaccine candidate. We constructed rVSV-HSP70-VP1, coexpressing heat shock protein (HSP70) and capsid (VP1) genes of human NoV, and rVSV-Luc-VP1, coexpressing firefly luciferase (Luc) and VP1 genes. We found that VSVs with a double gene insertion were significantly more attenuated than VSV with a single VP1 insertion (rVSV-VP1). Furthermore, we found that coexpression or coadministration of HSP70 from VSV vector significantly enhanced human NoV-specific mucosal immunity. Collectively, we developed an improved live vectored vaccine candidate for human NoV which will be useful for future clinical studies.
Local Control of Repeated-Dose Rectal Challenges in DNA/MVA-Vaccinated Macaques Protected against a First Series of Simian Immunodeficiency Virus Challenges
Authors: Kannanganant Sunil , Gangadhara Salaija , Lai Lilin , Lawson Benton , Kozlowski Pamela A. , Robinson Harriet L. , Amara Rama Rao 
Published: February 2014

ABSTRACT
Here, we report the results of a late boost and three additional series of simian immunodeficiency virus (SIV) challenges in seven DNA/modified vaccinia virus Ankara (MVA)-vaccinated rhesus macaques who resisted a first series of rectal challenges. During 29 additional challenges delivered over 2.3 years, all animals became infected. However, 13 blips of virus in six macaques and anamnestic Env-specific rectal IgA responses in three of the six suggested that local control of infections was occurring during the serial challenge.
Varicella-Zoster Virus and Herpes Simplex Virus 1 Can Infect and Replicate in the Same Neurons whether Co- or Superinfected
Authors: Sloutskin Anna , Yee Michael B. , Kinchington Paul R. , Goldstein Ronald S. 
Published: February 2014

ABSTRACT
The two human neurotropic alphaherpesviruses varicella-zoster virus (VZV) and herpes simplex virus type 1 (HSV1) both establish latency in sensory ganglia. Human trigeminal ganglia are known to frequently harbor both viruses, and there is evidence to suggest the presence of both VZV and HSV1 DNA in the same neuron. We ask here whether VZV and HSV1 can exclude themselves and each other and whether they can productively infect the same cells in human neurons and human foreskin fibroblasts (HFF). Simultaneous infection (coinfection) or consecutive infection (superinfection) was assessed using cell-free HSV1 and VZV expressing fluorescent reporter proteins. Automated analysis was carried out to detect singly and dually infected cells. We demonstrate that VZV and HSV1 both display efficient superinfection exclusion (SE) in HFF, with each virus excluding either itself or the other virus. While SE also occurred in neurons, it was with much lower efficiency. Both alphaherpesviruses productively infected the same neurons, whether applied simultaneously or even consecutively, albeit at lower frequencies.

IMPORTANCE
Superinfection exclusion by VZV for itself or the related neurotropic alphaherpesvirus HSV1 has been studied here for the first time. We find that while these viruses display classic SE in fibroblasts, SE is less efficient for both HSV1 and VZV in human neurons. The ability of multiple VZV strains to productively infect the same neurons has important implications in terms of recombination of both wild-type and vaccine strains in patients.
A Critical Determinant of Neurological Disease Associated with Highly Pathogenic Tick-Borne Flavivirus in Mice
Authors: Yoshii Kentaro , Sunden Yuji , Yokozawa Kana , Igarashi Manabu , Kariwa Hiroaki , Holbrook Michael R , Takashima Ikuo 
Published: February 2014

ABSTRACT
Tick-borne encephalitis virus (TBEV) and Omsk hemorrhagic fever virus (OHFV) are highly pathogenic tick-borne flaviviruses; TBEV causes neurological disease in humans, while OHFV causes a disease typically identified with hemorrhagic fever. Although TBEV and OHFV are closely related genetically, the viral determinants responsible for these distinct disease phenotypes have not been identified. In this study, chimeric viruses incorporating components of TBEV and OHFV were generated using infectious clone technology, and their pathological characteristics were analyzed in a mouse model to identify virus-specific determinants of disease. We found that only four amino acids near the C terminus of the NS5 protein were primarily responsible for the development of neurological disease. Mutation of these four amino acids had no effect on viral replication or histopathological features, including inflammatory responses, in mice. These findings suggest a critical role for NS5 in stimulating neuronal dysfunction and degeneration following TBEV infection and provide new insights into the molecular mechanisms underlying the pathogenesis of tick-borne flaviviruses.

IMPORTANCE
Tick-borne encephalitis virus (TBEV) and Omsk hemorrhagic fever virus (OHFV) belong to the tick-borne encephalitis serocomplex, genus
Flavivirus
, family
Flaviviridae
. Although TBEV causes neurological disease in humans while OHFV causes a disease typically identified with hemorrhagic fever. In this study, we investigated the viral determinants responsible for the different disease phenotypes using reverse genetics technology. We identified a cluster of only four amino acids in nonstructural protein 5 primarily involved in the development of neurological disease in a mouse model. Moreover, the effect of these four amino acids was independent of viral replication property and did not affect the formation of virus-induced lesions in the brain directly. These data suggest that these amino acids may be involved in the induction of neuronal dysfunction and degeneration in virus-infected neurons, ultimately leading to the neurological disease phenotype. These findings provide new insight into the molecular mechanisms of tick-borne flavivirus pathogenesis.
The Stability of Herpes Simplex Virus 1 ICP0 Early after Infection Is Defined by the RING Finger and the U
L
13 Protein Kinase
Authors: Zhu Zhi , Du Te , Zhou Guoying , Roizman Bernard 
Published: February 2014

ABSTRACT

Herpes simplex virus 1 (HSV-1)-infected cell protein 0 (ICP0) is a multifunctional protein that plays a key role in overcoming numerous facets of host innate immunity. A key function of ICP0 that requires an intact RING finger domain is that of an ubiquitin E3 ligase: ICP0 interacts with at least three ubiquitin-conjugating enzymes of which one, UbcH5a, is required for degradation of PML and SP100. A preceding report showed that ICP0 is highly unstable at very early times after infection but becomes stable at later times. We report here that (i) the degradation of ICP0 is not infected cell specific, (ii) the degradation does not require the interaction of ICP0 with either UbcH5a, UbcH6, or UbcH9, (iii) ICP0 is degraded both early and late in cells infected with a mutant lacking the U
L
13 protein kinase, (iv) ICP0 encoded by wild-type virus or the ΔU
L
13 mutant is stable in cells transfected with a plasmid encoding U
L
13 before infection, (v) ICP0 carrying mutations in the RING finger domain is stable both early and late in infection, and, finally, (vi) in cells infected with both wild type and RING finger mutant only the wild-type ICP0 is rapidly degraded at early times. The results suggest that the stability of ICP0 is mediated by the U
L
13 protein kinase and that the target of proteolysis is a site at or near the RING domain of ICP0.

IMPORTANCE
ICP0, a major regulatory protein of HSV-1, turns over rapidly early in infection but becomes stable at late times. We report that stabilization requires the presence of U
L
13 protein kinase and that an ICP0 with mutations in RING finger is stable. In mixed infections mutant ICP0 is stable, whereas the wild-type ICP0 is degraded. Our findings suggest that the lifestyle of HSV-1 requires an ICP0 that turns over rapidly if late proteins are absent.
Defective Interfering Influenza Virus RNAs: Time To Reevaluate Their Clinical Potential as Broad-Spectrum Antivirals?
Authors: Dimmock Nigel J. , Easton Andrew J. 
Published: February 2014

ABSTRACTDefective interfering (DI) RNAs are highly deleted forms of the infectious genome that are made by most families of RNA viruses. DI RNAs retain replication and packaging signals, are synthesized preferentially over infectious genomes, and are packaged as DI virus particles which can be transmitted to susceptible cells. Their ability to interfere with the replication of infectious virus in cell culture and their potential as antivirals in the clinic have long been known. However, until now, no realistic formulation has been described. In this review, we consider the early evidence of antiviral activity by DI viruses and, using the example of DI influenza A virus, outline developments that have led to the production of a cloned DI RNA that is highly active in preclinical studies not only against different subtypes of influenza A virus but also against heterologous respiratory viruses. These data suggest the timeliness of reassessing the potential of DI viruses as a novel class of antivirals that may have general applicability.
Nelfinavir Inhibits Maturation and Export of Herpes Simplex Virus 1
Authors: Kalu Nene N. , Desai Prashant J. , Shirley Courtney M. , Gibson Wade , Dennis Phillip A. , Ambinder Richard F. 
Published: February 2014

ABSTRACT
Nelfinavir (NFV) is an HIV-1 protease inhibitor with demonstrated antiviral activity against herpes simplex virus 1 (HSV-1) and several other herpesviruses. However, the stages of HSV-1 replication inhibited by NFV have not been explored. In this study, we investigated the effects of NFV on capsid assembly and envelopment. We confirmed the inhibitory effects of NFV on HSV-1 replication by plaque assay and found that treatment with NFV did not affect capsid assembly, activity of the HSV-1 maturational protease, or formation of DNA-containing capsids in the nucleus. Confocal and electron microscopy studies showed that these capsids were transported to the cytoplasm but failed to complete secondary envelopment and subsequent exit from the cell. Consistent with the microscopy results, a light-scattering band corresponding to enveloped virions was not evident following sucrose gradient rate-velocity separation of lysates from drug-treated cells. Evidence of a possibly related effect of NFV on viral glycoprotein maturation was also discovered. NFV also inhibited the replication of an HSV-1 thymidine kinase mutant resistant to nucleoside analogues such as acyclovir. Given that NFV is neither a nucleoside mimic nor a known inhibitor of nucleic acid synthesis, this was expected and suggests its potential as a coinhibitor or alternate antiviral therapeutic agent in cases of resistance.

IMPORTANCE
Nelfinavir (NFV) is a clinically important antiviral drug that inhibits production of infectious HIV. It was reported to inhibit herpesviruses in cell culture. Herpes simplex virus 1 (HSV-1) infections are common and often associated with several diseases. The studies we describe here confirm and extend earlier findings by investigating how NFV interferes with HSV-1 replication. We show that early steps in virus formation (e.g., assembly of DNA-containing capsids in the nucleus and their movement into the cytoplasm) appear to be unaffected by NFV, whereas later steps (e.g., final envelopment in the cytoplasm and release of infectious virus from the cell) are severely restricted by the drug. Our findings provide the first insight into how NFV inhibits HSV-1 replication and suggest that this drug may have applications for studying the herpesvirus envelopment process. Additionally, NFV may have therapeutic value alone or in combination with other antivirals in treating herpesvirus infections.
Safe Handover : Safe Patients - The Electronic Handover System
Authors: Till Alex , Sall Hanish , Wilkinson Jonathan 
Published: February 2014

AbstractFailure of effective handover is a major preventable cause of patient harm. We aimed to promote accurate recording of high-quality clinical information using an Electronic Handover System (EHS) that would contribute to a sustainable improvement in effective patient care and safety. Within our hospital the human factors associated with poor communication were compromising patient care and unnecessarily increasing the workload of staff due to the poor quality of handovers. Only half of handovers were understood by the doctors expected to complete them, and more than half of our medical staff felt it posed a risk to patient safety. We created a standardised proforma for handovers that contained specific sub-headings, re-classified patient risk assessments, and aided escalation of care by adding prompts for verbal handover. Sources of miscommunication were removed, accountability for handovers provided, and tasks were re-organised to reduce the workload of staff. Long-term, three-month data showed that each sub-heading achieved at least 80% compliance (an average improvement of approximately 40% for the overall quality of handovers). This translated into 91% of handovers being subjectively clear to junior doctors. 87% of medical staff felt we had reduced a risk to patient safety and 80% felt it increased continuity of care. Without guidance, doctors omit key information required for effective handover. All organisations should consider implementing an electronic handover system as a viable, sustainable and safe solution to handover of care that allows patient safety to remain at the heart of the NHS.
Lenticulostriate aneurysms: a case series and review of the literature
Authors: Vargas Jan , Walsh Kevin , Turner Raymond , Chaudry Imran , Turk Aquilla , Spiotta Alejandro 
Published: February 2014

IntroductionAneurysms of lenticulostriate artery (LSA) perforators are uncommon. There are few data on their natural history, and opinions differ on the treatment strategies.ObjectiveWe report a case series and summarize the most recent literature with current treatment recommendations. We propose an anatomical classification for these entities.MethodsA retrospective review of all patients who were diagnosed with an LSA aneurysm on cerebral angiogram was performed. An extensive online literature search was performed to identify other studies reporting on the diagnosis and management of ruptured and unruptured lenticulostriate aneurysms.Results48 cases were identified in the literature and reviewed: 27 patients were treated surgically; five cases were treated with endovascular therapy; two cases underwent gamma knife radiosurgery; and 13 cases were managed conservatively. We classified these aneurysms into three types: type 1 describes aneurysms arising from the middle cerebral artery next to a perforating LSA; type 2 is an LSA aneurysm from which the perforating artery or arteries arise—the type 2A subtype is one in which the aneurysm neck incorporates the origin of the perforating arteries and the type 2B describes perforating arteries arising from the dome of the aneurysm; and type 3 describes a fusiform aneurysm beyond the first loop or turn of an LSA.ConclusionsLSA aneurysms are rare entities that present several treatment challenges. We have summarized the cumulative experience with these lesions and proposed a classification scheme that has treatment implications.
DETERMINISM VS. NONDETERMINISM FOR TWO-WAY AUTOMATA: Representing the Meaning of States by Logical Formulæ
Authors: HROMKOVIČ JURAJ , KRÁLOVIČ RASTISLAV , KRÁLOVIČ RICHARD , ŠTEFANEC RICHARD 
Published: February 2014

The question whether nondeterminism is more powerful than determinism for two-way automata is one of the most famous old open problems on the border between formal language theory and automata theory. An exponential gap between the number of states of two-way nondeterministic finite automata (2NFA) and their deterministic counterparts (2DFA) was proved only for some restricted versions of two-way automata up to now. This problem is also related to the famous DLOG vs. NLOG problem. A superpolynomial gap between 2NFAs and 2DFAs on words of polynomial length in the parameter of a complete language of Sipser and Sakoda for the 2DFA vs. 2NFAs problem would imply that DLOG is a proper subset of NLOG. The first goal of this paper is first to survey the attempts to solve the 2DFA vs. 2NFA problem. After that we discus why this problem is so hard in spite of the fact that one has a very clear intuition why nondeterminism has to be more powerful than determinism for this computing model. It seems that the hardness lies in the fact that, when trying to prove lower bounds on the number of states of 2DFAs, we are not able to force the states to have a clear meaning. When designing an automaton, we always assign an unambiguous interpretation to each state. In an attempt to capture the concept of meaning of states we introduce a new restriction on the two-way automata: Each state is assigned a logical formula expressing some properties of the input word, and transitions of the automaton must be designed in such a way that the assigned formula is true whenever the automaton is in the given state. In our approach we use propositional formulæ with various interpreted atoms. For two possible logics we prove an exponential gap between 2NFAs and 2DFAs. Moreover, using our concept of assigning meaning to the states of 2DFAs we show that there is no exponential gap between general 2NFAs and 2DFAs on inputs of a polynomial length of the complete language of Sakoda and Sipser.
Regional controls on Lower Tertiary sandstone distribution in the North Sea and NE Atlantic margin basins
Authors: Mudge David C. 
Published: February 2014

Abstract
Widely distributed deep-water fan sandstones of early Tertiary age form the reservoir for one of the most successful and prolific plays in the North Sea and NE Atlantic margin. Stratigraphic interpretation of a large well database provides the basis for mapping sand distribution and depositional environments in these two hydrocarbon provinces. Sand thickness maps for five Paleocene–Lower Eocene plays illustrate the intimate relationship between pre-existing structural features and sand distribution and facies in the North Sea. Large-scale depositional environment mapping gives an insight into the similarities and differences between basin evolution and sand distribution in North Sea and NE Atlantic margin basins. Both provinces were affected by the same succession of pre-break-up and syn-break-up tectonic and magmatic events that led to early Eocene continental separation and the formation of the NE Atlantic. The impact of these events was muted within the North Sea, which was protected from Paleocene rifting on the NE Atlantic margin by the Scotland–Shetland hinterland and from Paleocene–early Eocene volcanism by its more distant location. However, it was the combination of tectonic and thermal uplift of this clastic source area that contributed the large volumes of sand that accumulated in both these provinces.
Spontaneous Reversion of the Angiogenic Phenotype to a Nonangiogenic and Dormant State in Human Tumors
Authors: Rogers Michael S. , Novak Katherine , Zurakowski David , Cryan Lorna M. , Blois Anna , Lifshits Eugene , Bø Trond H. , Oyan Anne M. , Bender Elise R. , Lampa Michael , Kang Soo-Young , Naxerova Kamila , Kalland Karl-Henning , Straume Oddbjorn , Akslen Lars A. , Watnick Randolph S. , Folkman Judah , Naumov George N. 
Published: February 2014

Abstract
The angiogenic switch, a rate-limiting step in tumor progression, has already occurred by the time most human tumors are detectable. However, despite significant study of the mechanisms controlling this switch, the kinetics and reversibility of the process have not been explored. The stability of the angiogenic phenotype was examined using an established human liposarcoma xenograft model. Nonangiogenic cells inoculated into immunocompromised mice formed microscopic tumors that remained dormant for approximately 125 days (vs. &lt;40 days for angiogenic cells) whereupon the vast majority (&gt;95%) initiated angiogenic growth with second-order kinetics. These original, clonally derived angiogenic tumor cells were passaged through four in vivo cycles. At each cycle, a new set of single-cell clones was established from the most angiogenic clone and characterized for in vivo for tumorigenic activity. A total of 132 single-cell clones were tested in the second, third, and fourth in vivo passage. Strikingly, at each passage, a portion of the single-cell clones formed microscopic, dormant tumors. Following dormancy, like the original cell line, these revertant tumors spontaneously switched to the angiogenic phenotype. Finally, revertant clones were transcriptionally profiled and their angiogenic output determined. Collectively, these data demonstrate that the angiogenic phenotype in tumors is malleable and can spontaneously revert to the nonangiogenic phenotype in a population of human tumor cells.
Implications: Leveraging the rate of reversion to the nonangiogenic phenotype and tumor dormancy may be a novel anticancer strategy. Mol Cancer Res; 12(5); 754–64. ©2014 AACR.