bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Respiratory Syncytial Virus Vaccine Vectored by a Stable Chimeric and Replication-Deficient Sendai Virus Protects Mice without Inducing Enhanced Disease
Authors: Wiegand Marian Alexander , Gori-Savellini Gianni , Gandolfo Claudia , Papa Guido , Kaufmann Christine , Felder Eva , Ginori Alessandro , Disanto Maria Giulia , Spina Donatella , Cusi Maria Grazia 
Published: March 2017

ABSTRACT
Respiratory syncytial virus (RSV) is a major cause of severe respiratory infections in children and elderly people, and no marketed vaccine exists. In this study, we generated and analyzed a subunit vaccine against RSV based on a novel genome replication-deficient Sendai virus (SeV) vector. We inserted the RSV F protein, known to be a genetically stable antigen, into our vector in a specific way to optimize the vaccine features. By exchanging the ectodomain of the SeV F protein for its counterpart from RSV, we created a chimeric vectored vaccine that contains the RSV F protein as an essential structural component. In this way, the antigen is actively expressed on the surfaces of vaccine particles in its prefusion conformation, and as recently reported for other vectored vaccines, the occurrence of silencing mutations of the transgene in the vaccine genome can be prevented. In addition, its active gene expression contributes to further stimulation of the immune response. In order to understand the best route of immunization, we compared vaccine efficacies after intranasal (i.n.) or intramuscular (i.m.) immunization of BALB/c mice. Via both routes, substantial RSV-specific immune responses were induced, consisting of serum IgG and neutralizing antibodies, as well as cytotoxic T cells. Moreover, i.n. immunization was also able to stimulate specific mucosal IgA in the upper and lower respiratory tract. In virus challenge experiments, animals were protected against RSV infection after both i.n. and i.m. immunization without inducing vaccine-enhanced disease. Above all, the replication-deficient SeV appeared to be safe and well tolerated.

IMPORTANCE
Respiratory syncytial virus (RSV) is a major cause of respiratory diseases in young children and elderly people worldwide. There is a great demand for a licensed vaccine. Promising existing vaccine approaches based on live-attenuated vaccines or viral vectors have suffered from unforeseen drawbacks related to immunogenicity and attenuation. We provide a novel RSV vaccine concept based on a genome replication-deficient Sendai vector that has many favorable vaccine characteristics. The specific vaccine design guarantees genetic stability of the transgene; furthermore, it supports a favorable presentation of the antigen, activating the adaptive response, features that other vectored vaccine approaches have often had difficulties with. Wide immunological and pathological analyses in mice confirmed the validity and efficacy of this approach after both parenteral and mucosal administration. Above all, this concept is suitable for initiating clinical studies, and it could also be applied to other infectious diseases.
A Neonatal Murine Model of Coxsackievirus A6 Infection for Evaluation of Antiviral and Vaccine Efficacy
Authors: Zhang Zhenjie , Dong Zhaopeng , Wei Qingjuan , Carr Michael J. , Li Juan , Ding Shujun , Tong Yigang , Li Dong , Shi Weifeng 
Published: March 2017

ABSTRACT

Hand, foot, and mouth disease (HFMD) is a global health concern. Family
Picornaviridae
members, particularly enterovirus A71 (EVA71) and coxsackievirus A16 (CVA16), are the primary etiological agents of HFMD; however, a third enterovirus A species, CVA6, has been recently associated with epidemic outbreaks. Study of the pathogenesis of CVA6 infection and development of antivirals and vaccines are hindered by a lack of appropriate animal models. We have developed and characterized a murine model of CVA6 infection that was employed to evaluate the antiviral activities of different drugs and the protective efficacies of CVA6-inactivated vaccines. Neonatal mice were susceptible to CVA6 infection via intramuscular inoculation, and the susceptibility of mice to CVA6 infection was age and dose dependent. Five-day-old mice infected with 10
5.5
50% tissue culture infective doses of the CVA6 WF057R strain consistently exhibited clinical signs, including reduced mobility, lower weight gain, and quadriplegia with significant pathology in the brain, hind limb skeletal muscles, and lungs of the infected mice in the moribund state. Immunohistochemical analysis and quantitative reverse transcription-PCR (qRT-PCR) analyses showed high viral loads (11 log
10
/mg) in skeletal muscle, and elevated levels of interleukin-6 (IL-6; >2,000 pg/ml) were associated with severe viral pneumonia and encephalitis. Ribavirin and gamma interferon administered prophylactically diminished CVA6-associated pathology
in vivo
, and treatment with IL-6 accelerated the death of neonatal mice. Both specific anti-CVA6 serum and maternal antibody play important roles in controlling CVA6 infection and viral replication. Collectively, these findings indicate that this neonatal murine model will be invaluable in future studies to develop CVA6-specific antivirals and vaccines.

IMPORTANCE
Although coxsackievirus A6 (CVA6) infections are commonly mild and self-limiting, a small proportion of children may have serious complications, such as encephalitis, acute flaccid paralysis, and neurorespiratory syndrome, leading to fatalities. We have established a mouse model of CVA6 infection by inoculation of neonatal mice with a CVA6 clinical isolate that produced consistent pathological outcomes. Here, using this model of CVA6 infection, we found that high levels of IL-6 were associated with severe viral pneumonia and encephalitis, as in an evaluation of antiviral efficacy
in vivo
, IL-6 had no protective effect and instead accelerated death in neonatal mice. We demonstrated that, as antiviral drugs, both gamma interferon and ribavirin played important protective roles in the early stages of infection, with increased survival in treated neonatal mice challenged with CVA6. Moreover, active and passive immunization with the inactivated vaccines and anti-CVA6 serum also protected mice against homologous challenge infections.
Attenuated Human Parainfluenza Virus Type 1 Expressing Ebola Virus Glycoprotein GP Administered Intranasally Is Immunogenic in African Green Monkeys
Authors: Lingemann Matthias , Liu Xueqiao , Surman Sonja , Liang Bo , Herbert Richard , Hackenberg Ashley D. , Buchholz Ursula J. , Collins Peter L. , Munir Shirin 
Published: March 2017

ABSTRACT

The recent 2014-2016 Ebola virus (EBOV) outbreak prompted increased efforts to develop vaccines against EBOV disease. We describe the development and preclinical evaluation of an attenuated recombinant human parainfluenza virus type 1 (rHPIV1) expressing the membrane-anchored form of EBOV glycoprotein GP, as an intranasal (i.n.) EBOV vaccine. GP was codon optimized and expressed either as a full-length protein or as an engineered chimeric form in which its transmembrane and cytoplasmic tail (TMCT) domains were replaced with those of the HPIV1 F protein in an effort to enhance packaging into the vector particle and immunogenicity. GP was inserted either preceding the N gene (pre-N) or between the N and P genes (N-P) of rHPIV1 bearing a stabilized attenuating mutation in the P/C gene (C
Δ170
). The constructs grew to high titers and efficiently and stably expressed GP. Viruses were attenuated, replicating at low titers over several days, in the respiratory tract of African green monkeys (AGMs). Two doses of candidates expressing GP from the pre-N position elicited higher GP neutralizing serum antibody titers than the N-P viruses, and unmodified GP induced higher levels than its TMCT counterpart. Unmodified EBOV GP was packaged into the HPIV1 particle, and the TMCT modification did not increase packaging or immunogenicity but rather reduced the stability of GP expression during
in vivo
replication. In conclusion, we identified an attenuated and immunogenic i.n. vaccine candidate expressing GP from the pre-N position. It is expected to be well tolerated in humans and is available for clinical evaluation.

IMPORTANCE
EBOV hemorrhagic fever is one of the most lethal viral infections and lacks a licensed vaccine. Contact of fluids from infected individuals, including droplets or aerosols, with mucosal surfaces is an important route of EBOV spread during a natural outbreak, and aerosols also might be exploited for intentional virus spread. Therefore, vaccines that protect against mucosal as well as systemic inoculation are needed. We evaluated a version of human parainfluenza virus type 1 (HPIV1) bearing a stabilized attenuating mutation in the P/C gene (C
Δ170
) as an intranasal vaccine vector to express the EBOV glycoprotein GP. We evaluated expression from two different genome positions (pre-N and N-P) and investigated the use of vector packaging signals. African green monkeys immunized with two doses of the vector expressing GP from the pre-N position developed high titers of GP neutralizing serum antibodies. The attenuated vaccine candidate is expected to be safe and immunogenic and is available for clinical development.
Tracking the Subtle Mutations Driving Host Sensing by the Plant Pathogen
Streptomyces scabies
Authors: Jourdan Samuel , Francis Isolde M. , Deflandre Benoit , Loria Rosemary , Rigali Sébastien 
Published: March 2017

ABSTRACT

The acquisition of genetic material conferring the arsenal necessary for host virulence is a prerequisite on the path to becoming a plant pathogen. More subtle mutations are also required for the perception of cues signifying the presence of the target host and optimal conditions for colonization. The decision to activate the pathogenic lifestyle is not “taken lightly” and involves efficient systems monitoring environmental conditions. But how can a pathogen trigger the expression of virulence genes in a timely manner if the main signal inducing its pathogenic behavior originates from cellulose, the most abundant polysaccharide on earth? This situation is encountered by
Streptomyces scabies
, which is responsible for common scab disease on tuber and root crops. We propose here a series of hypotheses of how
S. scabies
could optimally distinguish whether cello-oligosaccharides originate from decomposing lignocellulose (nutrient sources, saprophyte) or, instead, emanate from living and expanding plant tissue (virulence signals, pathogen) and accordingly adapt its physiological response.
When the client cannot pay
Authors: Fordyce Peter 
Published: March 2017

THIS series gives readers the opportunity to consider and contribute to discussion of some of the ethical dilemmas that can arise in veterinary practice. Each month, a case scenario is presented, followed by discussion of some of the issues involved.In addition, a possible way forward is suggested; however, there is rarely a cut‐and‐dried answer in such cases, and readers may wish to suggest an alternative approach. This month's dilemma, ‘When the client cannot pay’, was submitted and is discussed by Peter Fordyce. Readers with comments to contribute are invited to send them as soon as possible, so that they can be considered for publication in the next issue.The series is being coordinated by Steven McCulloch, a practising vet with a PhD in the ethics of veterinary policy. It aims to provide a framework that will help practitioners find solutions when facing similar dilemmas.
Low voltage electrophoresis chip with multi-segments synchronized scanning
Authors: Gu Wenwen , Wen Zhiyu , Xu Yi 
Published: March 2017

For low voltage electrophoresis chip, there is always a problem that the samples are truncated and peaks are broadened, as well as longer time for separation. In this paper, a low voltage electrophoresis separation model was established, and the separation conditions were discussed. A new driving mode was proposed for applying low voltage, which was called multi-segments synchronized scanning. By using this driving mode, the reversed electric field that existed between the multi-segments can enrich samples and shorten the sample zone. The low voltage electrophoresis experiments using multi-segments synchronized scanning were carried out by home-made silicon-PDMS-based chip. The fluorescein isothiocyanate (FITC) labeled lysine and phenylalanine mixed samples with the concentration of 10[Formula: see text] mol/L were successfully separated under the optimal conditions of 10 mmol/L borax buffer (pH = 10.0), 200 V/cm separation electric field and electrode switch time of 2.5 s. The separation was completed with a resolution of 2.0, and the peak time for lysine and phenylalanine was 4 min and 6 min, respectively.
Preparation of high-oriented molybdenum thin films using DC reactive magnetronsputtering
Authors: Shang Zhengguo , Li Dongling , Yin She , Wang Shengqiang 
Published: March 2017

Since molybdenum (Mo) thin film has been used widely recently, it attracts plenty of attention, like it is a good candidate of back contact material for CuIn[Formula: see text]Ga[Formula: see text]Se[Formula: see text]S[Formula: see text] (CIGSeS) solar cells development; thanks to its more conductive and higher adhesive property. Besides, molybdenum thin film is an ideal material for aluminum nitride (AlN) thin film preparation and attributes to the tiny (−1.0%) lattice mismatch between Mo and AlN. As we know that the quality of Mo thin film is mainly dependent on process conditions, it brings a practical significance to study the influence of process parameters on Mo thin film properties. In this work, various sputtering conditions are employed to explore the feasibility of depositing a layer of molybdenum film with good quality by DC reactive magnetron sputtering. The influence of process parameters such as power, gas flow, substrate temperature and process time on the crystallinity and crystal orientation of Mo thin films is investigated. X-ray diffraction (XRD) measurements and atomic force microscope (AFM) are used to characterize the properties and surface roughness, respectively. According to comparative analysis on the results, process parameters are optimized. The full width at half maximum (FWHM) of the rocking curves of the (110) Mo is decreased to 2.7[Formula: see text], and the (110) Mo peaks reached [Formula: see text] counts. The grain size and the surface roughness have been measured as 20 Å and 3.8 nm, respectively, at 200[Formula: see text]C.
Oral N-acetylcysteine and exercise tolerance in mild chronic obstructive pulmonary disease
Authors: Hirai Daniel M. , Jones Joshua H. , Zelt Joel T. , da Silva Marianne L. , Bentley Robert F. , Edgett Brittany A. , Gurd Brendon J. , Tschakovsky Michael E. , O’Donnell Denis E. , Neder J. Alberto 
Published: March 2017

Heightened oxidative stress is implicated in the progressive impairment of skeletal muscle vascular and mitochondrial function in chronic obstructive pulmonary disease (COPD). Whether accumulation of reactive oxygen species contributes to exercise intolerance in the early stages of COPD is unknown. The purpose of the present study was to determine the effects of oral antioxidant treatment with N-acetylcysteine (NAC) on respiratory, cardiovascular, and locomotor muscle function and exercise tolerance in patients with mild COPD. Thirteen patients [forced expiratory volume in 1 s (FEV1)-to-forced vital capacity ratio < lower limit of normal (LLN) and FEV1 ≥ LLN) were enrolled in a double-blind, randomized crossover study to receive NAC (1,800 mg/day) or placebo for 4 days. Severe-intensity constant-load exercise tests were performed with noninvasive measurements of central hemodynamics (stroke volume, heart rate, and cardiac output via impedance cardiography), arterial blood pressure, pulmonary ventilation and gas exchange, quadriceps muscle oxygenation (near-infrared spectroscopy), and estimated capillary blood flow. Nine patients completed the study with no major adverse clinical effects. Although NAC elevated plasma glutathione by ~27% compared with placebo ( P < 0.05), there were no differences in exercise tolerance (placebo: 325 ± 47 s, NAC: 336 ± 51 s), central hemodynamics, arterial blood pressure, pulmonary ventilation or gas exchange, locomotor muscle oxygenation, or capillary blood flow from rest to exercise between conditions ( P > 0.05 for all). In conclusion, modulation of plasma redox status with oral NAC treatment was not translated into beneficial effects on central or peripheral components of the oxygen transport pathway, thereby failing to improve exercise tolerance in nonhypoxemic patients with mild COPD. NEW & NOTEWORTHY Acute antioxidant treatment with N-acetylcysteine (NAC) elevated plasma glutathione but did not modulate central or peripheral components of the O2 transport pathway, thereby failing to improve exercise tolerance in patients with mild chronic obstructive pulmonary disease (COPD).
Systems-based analysis of dendritic nonlinearities reveals temporal feature extraction in mouse L5 cortical neurons
Authors: Kalmbach Brian E. , Gray Richard , Johnston Daniel , Cook Erik P. 
Published: March 2017

What do dendritic nonlinearities tell a neuron about signals injected into the dendrite? Linear and nonlinear dendritic components affect how time-varying inputs are transformed into action potentials (APs), but the relative contribution of each component is unclear. We developed a novel systems-identification approach to isolate the nonlinear response of layer 5 pyramidal neuron dendrites in mouse prefrontal cortex in response to dendritic current injections. We then quantified the nonlinear component and its effect on the soma, using functional models composed of linear filters and static nonlinearities. Both noise and waveform current injections revealed linear and nonlinear components in the dendritic response. The nonlinear component consisted of fast Na+spikes that varied in amplitude 10-fold in a single neuron. A functional model reproduced the timing and amplitude of the dendritic spikes and revealed that they were selective to a preferred input dynamic (~4.5 ms rise time). The selectivity of the dendritic spikes became wider in the presence of additive noise, which was also predicted by the functional model. A second functional model revealed that the dendritic spikes were weakly boosted before being linearly integrated at the soma. For both our noise and waveform dendritic input, somatic APs were dependent on the somatic integration of the stimulus, followed a subset of large dendritic spikes, and were selective to the same input dynamics preferred by the dendrites. Our results suggest that the amplitude of fast dendritic spikes conveys information about high-frequency features in the dendritic input, which is then combined with low-frequency somatic integration.NEW & NOTEWORTHY The nonlinear response of layer 5 mouse pyramidal dendrites was isolated with a novel systems-based approach. In response to dendritic current injections, the nonlinear component contained mostly fast, variable-amplitude, Na+spikes. A functional model accounted for the timing and amplitude of the dendritic spikes and revealed that dendritic spikes are selective to a preferred input dynamic, which was verified experimentally. Thus, fast dendritic nonlinearities behave as high-frequency feature detectors that influence somatic action potentials.
NR4A3 Suppresses Lymphomagenesis through Induction of Proapoptotic Genes
Authors: Deutsch Alexander J.A. , Rinner Beate , Pichler Martin , Prochazka Katharina , Pansy Katrin , Bischof Marco , Fechter Karoline , Hatzl Stefan , Feichtinger Julia , Wenzl Kerstin , Frisch Marie-Therese , Stiegelbauer Verena , Prokesch Andreas , Krogsdam Anne , Sill Heinz , Thallinger Gerhard G. , Greinix Hildegard T. , Wang Chenguang , Beham-Schmid Christine , Neumeister Peter 
Published: March 2017

Abstract
Nuclear orphan receptor NR4A1 exerts an essential tumor suppressor function in aggressive lymphomas. In this study, we investigated the hypothesized contribution of the related NR4A family member NR4A3 to lymphomagenesis. In aggressive lymphoma patients, low expression of NR4A3 was associated with poor survival. Ectopic expression or pharmacological activation of NR4A3 in lymphoma cell lines led to a significantly higher proportion of apoptotic cells. In a mouse NSG xenograft model of lymphoma (stably transduced SuDHL4 cells), NR4A3 expression abrogated tumor growth, compared with vector control and uninduced cells that formed massive tumors. Transcript analysis of four different aggressive lymphoma cell lines overexpressing either NR4A3 or NR4A1 revealed that apoptosis was driven similarly by induction of BAK, Puma, BIK, BIM, BID, and Trail. Overall, our results showed that NR4A3 possesses robust tumor suppressor functions of similar impact to NR4A1 in aggressive lymphomas. Cancer Res; 77(9); 2375–86. ©2017 AACR.
Krüppel-like Transcription Factor KLF10 Suppresses TGFβ-Induced Epithelial-to-Mesenchymal Transition via a Negative Feedback Mechanism
Authors: Mishra Vivek Kumar , Subramaniam Malayannan , Kari Vijayalakshmi , Pitel Kevin S. , Baumgart Simon J. , Naylor Ryan M. , Nagarajan Sankari , Wegwitz Florian , Ellenrieder Volker , Hawse John R. , Johnsen Steven A. 
Published: March 2017

Abstract
TGFβ–SMAD signaling exerts a contextual effect that suppresses malignant growth early in epithelial tumorigenesis but promotes metastasis at later stages. Longstanding challenges in resolving this functional dichotomy may uncover new strategies to treat advanced carcinomas. The Krüppel-like transcription factor, KLF10, is a pivotal effector of TGFβ/SMAD signaling that mediates antiproliferative effects of TGFβ. In this study, we show how KLF10 opposes the prometastatic effects of TGFβ by limiting its ability to induce epithelial-to-mesenchymal transition (EMT). KLF10 depletion accentuated induction of EMT as assessed by multiple metrics. KLF10 occupied GC-rich sequences in the promoter region of the EMT-promoting transcription factor SLUG/SNAI2, repressing its transcription by recruiting HDAC1 and licensing the removal of activating histone acetylation marks. In clinical specimens of lung adenocarcinoma, low KLF10 expression associated with decreased patient survival, consistent with a pivotal role for KLF10 in distinguishing the antiproliferative versus prometastatic functions of TGFβ. Our results establish that KLF10 functions to suppress TGFβ-induced EMT, establishing a molecular basis for the dichotomy of TGFβ function during tumor progression. Cancer Res; 77(9); 2387–400. ©2017 AACR.