bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influenza A Virus Polymerase Is a Site for Adaptive Changes during Experimental Evolution in Bat Cells
Authors: Poole Daniel S. , Yú Shuǐqìng , Caì Yíngyún , Dinis Jorge M. , Müller Marcel A. , Jordan Ingo , Friedrich Thomas C. , Kuhn Jens H. , Mehle Andrew 
Published: August 2014

ABSTRACT
The recent identification of highly divergent influenza A viruses in bats revealed a new, geographically dispersed viral reservoir. To investigate the molecular mechanisms of host-restricted viral tropism and the potential for transmission of viruses between humans and bats, we exposed a panel of cell lines from bats of diverse species to a prototypical human-origin influenza A virus. All of the tested bat cell lines were susceptible to influenza A virus infection. Experimental evolution of human and avian-like viruses in bat cells resulted in efficient replication and created highly cytopathic variants. Deep sequencing of adapted human influenza A virus revealed a mutation in the PA polymerase subunit not previously described, M285K. Recombinant virus with the PA M285K mutation completely phenocopied the adapted virus. Adaptation of an avian virus-like virus resulted in the canonical PB2 E627K mutation that is required for efficient replication in other mammals. None of the adaptive mutations occurred in the gene for viral hemagglutinin, a gene that frequently acquires changes to recognize host-specific variations in sialic acid receptors. We showed that human influenza A virus uses canonical sialic acid receptors to infect bat cells, even though bat influenza A viruses do not appear to use these receptors for virus entry. Our results demonstrate that bats are unique hosts that select for both a novel mutation and a well-known adaptive mutation in the viral polymerase to support replication.

IMPORTANCE
Bats constitute well-known reservoirs for viruses that may be transferred into human populations, sometimes with fatal consequences. Influenza A viruses have recently been identified in bats, dramatically expanding the known host range of this virus. Here we investigated the replication of human influenza A virus in bat cell lines and the barriers that the virus faces in this new host. Human influenza A and B viruses infected cells from geographically and evolutionarily diverse New and Old World bats. Viruses mutated during infections in bat cells, resulting in increased replication and cytopathic effects. These mutations were mapped to the viral polymerase and shown to be solely responsible for adaptation to bat cells. Our data suggest that replication of human influenza A viruses in a nonnative host drives the evolution of new variants and may be an important source of genetic diversity.
A Synthetic Biology Approach for a Vaccine Platform against Known and Newly Emerging Serotypes of Bluetongue Virus
Authors: Nunes Sandro Filipe , Hamers Claude , Ratinier Maxime , Shaw Andrew , Brunet Sylvie , Hudelet Pascal , Palmarini Massimo 
Published: August 2014

ABSTRACT
Bluetongue is one of the major infectious diseases of ruminants and is caused by bluetongue virus (BTV), an arbovirus existing in nature in at least 26 distinct serotypes. Here, we describe the development of a vaccine platform for BTV. The advent of synthetic biology approaches and the development of reverse genetics systems has allowed the rapid and reliable design and production of pathogen genomes which can be subsequently manipulated for vaccine production. We describe BTV vaccines based on “synthetic” viruses in which the outer core proteins of different BTV serotypes are incorporated into a common tissue-culture-adapted backbone. As a means of validation for this approach, we selected two BTV-8 synthetic reassortants and demonstrated their ability to protect sheep against virulent BTV-8 challenge. In addition to further highlight the possibilities of genome manipulation for vaccine production, we also designed and rescued a synthetic BTV chimera containing a VP2 protein, including regions derived from both BTV-1 and BTV-8. Interestingly, while the parental viruses were neutralized only by homologous antisera, the chimeric proteins could be neutralized by both BTV-1 and BTV-8 antisera. These data suggest that neutralizing epitopes are present in different areas of the BTV VP2 and likely “bivalent” strains eliciting neutralizing antibodies for multiple strains can be obtained.

IMPORTANCE
Overall, this vaccine platform can significantly reduce the time taken from the identification of new BTV strains to the development and production of new vaccines, since the viral genomes of these viruses can be entirely synthesized
in vitro
. In addition, these vaccines can be brought quickly into the market because they alter the approach, but not the final product, of existing commercial products.
Curing Mice with Large Tumors by Locally Delivering Combinations of Immunomodulatory Antibodies
Authors: Dai Min , Yip Yuen Yee , Hellstrom Ingegerd , Hellstrom Karl Erik 
Published: August 2014

Abstract
Purpose: Immunomodulatory mAbs can treat cancer, but cures are rare except for small tumors. Our objective was to explore whether the therapeutic window increases by combining mAbs with different modes of action and injecting them into tumors.
Experimental Design: Combinations of mAbs to CD137/PD-1/CTLA-4 or CD137/PD-1/CTLA-4/CD19 were administrated intratumorally to mice with syngeneic tumors (B16 and SW1 melanoma, TC1 lung carcinoma), including tumors with a mean surface of approximately 80 mm2. Survival and tumor growth were assessed. Immunologic responses were evaluated using flow cytometry and qRT-PCR.
Results: More than 50% of tumor-bearing mice had complete regression and long-term survival after tumor injection with mAbs recognizing CD137/PD-1/CTLA-4/CD19 with similar responses in three models. Intratumoral injection was more efficacious than intraperitoneal injection in causing rejection also of untreated tumors in the same mice. The three-mAb combination could also induce regression, but was less efficacious. There were few side effects, and therapy-resistant tumors were not observed. Transplanted tumor cells rapidly caused a Th2 response with increased CD19 cells. Successful therapy shifted this response to the Th1 phenotype with decreased CD19 cells and increased numbers of long-term memory CD8 effector cells and T cells making IFNγ and TNFα.
Conclusions: Intratumoral injection of mAbs recognizing CD137/PD-1/CTLA-4/CD19 can eradicate established tumors and reverse a Th2 response with tumor-associated CD19 cells to Th1 immunity, whereas a combination lacking anti-CD19 is less effective. There are several human cancers for which a similar approach may provide clinical benefit. Clin Cancer Res; 21(5); 1127–38. ©2014 AACR.
See related commentary by Dronca and Dong, p. 944
Does pelvic floor muscle training abolish symptoms of urinary incontinence? A randomized controlled trial
Authors: Celiker Tosun O , Kaya Mutlu E , Ergenoglu AM , Yeniel AO , Tosun G , Malkoc M , Askar N , Itil IM 
Published: August 2014

Objective: To determine whether symptoms of urinary incontinence is reduced by pelvic floor muscle training, to determine whether urinary incontinence can be totally eliminated by strengthening the pelvic floor muscle to grade 5 on the Oxford scale. Design: Prospective randomized controlled clinical trial. Setting: Outpatient urogynecology department. Subjects: One hundred thirty cases with stress and mixed urinary incontinence. Intervention: All participants were randomly allocated to the pelvic floor muscle training group or control group. A 12-week home based exercise program, prescribed individually, was performed by the pelvic floor muscle training group. Main measures: Urinary incontinence symptoms (Incontinence Impact Questionnaire-7, Urogenital Distress Inventory-6, bladder diary, stop test and pad test) were assessed, and the pelvic floor muscle strength was measured for (PERFECT testing, perineometric and ultrasound) all participants before and after 12 weeks of treatment. Results: The pelvic floor muscle training group had significant improvement in their symptoms of urinary incontinence ( P=0.001) and an increase in pelvic floor muscle strength ( P=0.001, by the dependent t test) compared with the control group. All the symptoms of urinary incontinence were significantly decreased in the patients that had reached pelvic floor muscle strength of grade 5 and continued the pelvic floor muscle training ( P<0.05). Conclusion: The study demonstrated that pelvic floor muscle training is effective in reducing the symptoms of stress and mixed urinary incontinence and in increasing pelvic floor muscle strength.
The effect of renin–angiotensin system blockade on renal protection in chronic kidney disease patients with hyperkalemia
Authors: Lee Ju-Hyun , Kwon Young Eun , Park Jung Tak , Lee Mi Jung , Oh Hyung Jung , Han Seung Hyeok , Kang Shin-Wook , Choi Kyu Hun , Yoo Tae-Hyun 
Published: August 2014

Hypothesis: The aim of this study was to determine the effects of renin–angiotensin system (RAS) blockade maintenance on renal protection in chronic kidney disease (CKD) patients with hyperkalemia occurring during treatment with RAS blockade. Materials and methods: CKD III or IV patients, who were prescribed with RAS blockers and also had hyperkalemia, were included. The study population was divided into two groups based on maintenance or withdrawal of RAS blocker. Renal outcomes (doubling of creatinine or end-stage renal disease) and incidence of hyperkalemia were compared between the two groups. Results: Out of 258 subjects who developed hyperkalemia during treatment with RAS blockers, 150 (58.1%) patients continued on RAS blockades, while RAS blockades were discontinued for more than 3 months in the remaining 108 patients. Renal event-free survival was significantly higher in the maintenance group compared with the withdrawal group. Cox proportional hazard ratio for renal outcomes was 1.35 (95% CI: 1.08–1.92, p=0.04) in the withdrawal group compared with the maintenance group. However, the incidence of hyperkalemia and hyperkalemia-related hospitalization or mortality did not differ between the two groups. Conclusions: This study demonstrated that the maintenance of RAS blockade is beneficial for the preservation of renal function and relatively tolerable in patients with CKD and hyperkalemia occurring during treatment with RAS blockade.
The relationship between three X-linked genes and the risk for hypertension among northeastern Han Chinese
Authors: Li Jinxin , Feng Min , Wang Yanli , Li Yaodong , Zhang Yanyi , Li Lei , Xiong Jian , Lu Changzhu , Wang Bin , Cheng Zuheng , Tang Baopeng , Niu Wenquan 
Published: August 2014

Background and objective: Incidences of hypertension are increasing and this condition is more common in men than in women. We selected six well-characterized polymorphisms from three X-linked genes (ACE2, AGTR2, apelin) aiming to investigate their interactive association with hypertension among northeastern Han Chinese. Methods and results: This was a case-control study involving 1009 hypertensive patients and 756 normotensive controls. All polymorphisms except rs3761581 in the apelin gene satisfied the Hardy-Weinberg equilibrium in females. The genotype and allele distributions of rs1403543 in the AGTR2 gene and rs56204867 in the apelin gene differed significantly between patients and controls for both genders, even after the Bonferroni correction ( P<0.05/6). The risk prediction was significant for rs1403543 and rs56204867 under both additive and dominant models for both genders. In haplotype analysis, significance was seen for haplotype G-T-G-G-A (alleles in order of rs1978124, rs2106809, rs1403543, rs5194 and rs56204867), which was overrepresented in patients (5.15% versus 1.10% in controls, PSim=0.004). Interaction analysis indicated that all derived multifactor dimensionality reduction (MDR) models were non-significant for both genders. Conclusion: Our findings demonstrate that genetic defects in AGTR2 and apelin genes by themselves may play an independent leading role in determining susceptibility to hypertension in both genders.
“Swan Neck Deformity” of the Second Toe Corrected by Flexor Digitorum Longus to Flexor Digitorum Brevis Tenodesis
Authors: Lui Tun Hing 
Published: August 2014

“Swan neck deformity” of the second toe is a rare deformity. It is a hyperextension of the proximal interphalangeal joint. The patient may complain of painful callosity underneath the proximal interphalangeal joint. Surgical correction should be considered if conservative treatment fails to relieve the pressure point. The optimal surgical option for this deformity has not yet been defined. We report a case of swan neck deformity of the second toe that was successfully corrected by flexor digitorum longus to brevis tenodesis. Levels of Evidence: Therapeutic Level IV: Case Report
Myc-induced SUMOylation is a therapeutic vulnerability for B-cell lymphoma
Authors: Hoellein Alexander , Fallahi Mohammad , Schoeffmann Stephanie , Steidle Sabine , Schaub Franz X. , Rudelius Martina , Laitinen Iina , Nilsson Lisa , Goga Andrei , Peschel Christian , Nilsson Jonas A. , Cleveland John L. , Keller Ulrich 
Published: August 2014

Key Points
The Myc oncoprotein targets central regulators of the SUMOylation machinery, resulting in a hyper-SUMOylation state in Myc-induced lymphoma. Targeting SUMOylation by genetic or pharmacologic means represents a novel therapeutic option for lymphomas with MYC involvement.
Geotechnical and Geophysical Long-term Monitoring at a Levee of Red River in Vietnam
Authors: Weller Andreas , Lewis Ronald , Canh Tran , Möller Marcus , Scholz Bernhard 
Published: August 2014

The stability or safety of a levee during flooding depends on both the temporal development of the amplitude of the hydraulic loads in surface water and ground water and the change of soil parameters within the levee and subsoil. Therefore, a levee monitoring system should record the temporal development of the hydraulic loads of surface water and the resulting variations of water flow within the levee and subsoil. Long-term monitoring has been performed at a levee of Red River in Thai Binh province in Vietnam. The monitoring system consists of a permanent electrode array for resistivity imaging and geotechnical tools including tensiometers, frequency-domain reflectometry sensors and an observation well. The components were installed after a detailed inspection of the levee and foundation by drilling, sampling, and a geoelectrical survey. The levee monitoring system provided time series of the sensor data that were related to the variation of pore water pressure and water distribution. Additionally, the water level in the river and the precipitation rate were recorded. A two-dimensional transient finite element modeling of the seepage and groundwater flow was performed using the database of a single flood season. The resulting hydraulic model was used for a stability analysis. It could be shown that the stability calculations taking into account the transient development of the seepage line allows a more favorable safety factor in the stability analysis in comparison with the conventional steady state approach. According to our experience with the prototype of a levee monitoring system (LMS), the water level registration in the river, a tensiometer in the levee body and an observation well behind the levee should constitute the basic configuration of a LMS. The addition of more components improves the reliability of the system even in the case of failures of single sensors.
Rheological changes induced by clast fragmentation in debris flows
Authors: Caballero Lizeth , Sarocchi Damiano , Soto Enrique , Borselli Lorenzo 
Published: August 2014

AbstractOn the basis of rotating drum analogue experiments, we describe a fragmentation process acting within debris flows during transport and its influence on rheologic behavior. Our hypothesis is based on a detailed textural analysis including granulometry, clast morphology, and rheologic properties of the fluid matrix. Results of the experiments point out that breakage of certain granulometric classes produces fine particles like fine sand and silt. The population growth of fine clasts with time leads to an increase in yield strength and viscosity that progressively modifies the rheologic behavior. From a textural point of view, this is reflected in a bimodal granulometric distribution. Up to now this characteristic has been explained as the effect of bulking and/or sedimentation processes during transport. Our experimental results show that the type of fragmentation depends on particle size and is the consequence of strong clast‐clast interaction and clast‐fluid interactions. Coarse particles develop small fractures which cause the loss of sharp edges and asperities. Medium‐sized particles develop through‐going fractures that cause them to break apart. The latter process explains why intermediate granulometric classes progressively diminish with time in debris flows. Analogue experiments enable us to study the efficacy of clast fragmentation in modifying the textural character and flow behavior of debris flows without the influence of external factors such as erosion and sedimentation. The obtained results constitute the base of a new approach for modeling debris flow dynamics.
Reassessment of satellite‐based estimate of aerosol climate forcing
Authors: Ma Xiaoyan , Yu Fangqun , Quaas Johannes 
Published: August 2014

AbstractLarge uncertainties exist in estimations of aerosol direct radiative forcing and indirect radiative forcing, and the values derived from global modeling differ substantially with satellite‐based calculations. Following the approach of Quaas et al. (2008; hereafter named Quaas2008), we reassess satellite‐based clear‐ and cloudy‐sky radiative forcings and their seasonal variations by employing updated satellite products from 2004 to 2011 in combination with the anthropogenic aerosol optical depth (AOD) fraction obtained from model simulations using the Goddard Earth Observing System‐Chemistry‐Advanced Particle Microphysics (GEOS‐Chem‐APM). Our derived annual mean aerosol clear‐sky forcing (−0.59 W m−2) is lower, while the cloudy‐sky forcing (−0.34 W m−2) is higher than the corresponding results (−0.9 W m−2 and −0.2 W m−2, respectively) reported in Quaas2008. Our study indicates that the derived forcings are sensitive to the anthropogenic AOD fraction and its spatial distribution but insensitive to the temporal resolution used to obtain the regression coefficients, i.e., monthly or seasonal based. The forcing efficiency (i.e., the magnitude per anthropogenic AOD) for the clear‐sky forcing based on this study is 19.9 W m−2, which is about 5% smaller than Quaas2008's value of 21.1 W m−2. In contrast, the efficiency for the cloudy‐sky forcing of this study (11 W m−2) is more than a factor of 2 larger than Quaas2008's value of 4.7 W m−2. Uncertainties tests indicate that anthropogenic fraction of AOD strongly affects the computed forcings while using aerosol index instead of AOD from satellite data as aerosol proxy does not appear to cause any significant differences in regression slopes and derived forcings.
Characterizing tropical Pacific water vapor and radiative biases in CMIP5 GCMs: Observation‐based analyses and a snow and radiation interaction sensitivity experiment
Authors: Li J.‐L. F. , Lee W.‐L. , Waliser D. E. , Stachnik Justin P. , Fetzer Eric , Wong Sun , Yue Qing 
Published: August 2014

AbstractSignificant systematic biases in the moisture fields within the tropical Pacific trade wind regions are found in the Coupled Model Intercomparison Project (CMIP3/CMIP5) against profile and total column water vapor (TotWV) estimates from the Atmospheric Infrared Sounder and TotWV from the Special Sensor Microwave/Imager. Positive moisture biases occur in conjunction with significant biases of eastward low‐level moisture convergence north of the South Pacific Convergence Zone and south of the Intertropical Convergence Zone—the V‐shaped regions. The excessive moisture there is associated with overestimates of reflected upward shortwave (RSUT), underestimates of outgoing longwave radiation (RLUT) at the top of atmosphere (TOA), and underestimates of downward shortwave flux at the surface (RSDS) compared to Clouds and the Earth's Energy System, Energy Balance and Filled data. We characterize the impacts of falling snow and its radiation interaction, which are not included in most CMIP5 models, on the moisture fields using the National Center for Atmospheric Research‐coupled global climate model (GCM). A number of differences in the model simulation without snow‐radiation interactions are consistent with biases in the CMIP5 simulations. These include effective low‐level eastward/southeastward wind and surface wind stress anomalies, and an increase in TotWV, vertical profile of moisture, and cloud amounts in the V‐shaped region. The anomalous water vapor and cloud amount might be associated with the model increase of RSUT and decrease of RLUT at TOA and decreased RSDS in clear and all sky in these regions. These findings hint at the importance of water vapor‐radiation interactions in the CMIPS/CMIP5 model simulations that exclude the radiative effect of snow.
Multidomain Hybrid Hydrogels: Spatially Resolved Photopatterned Synthetic Nanomaterials Combining Polymer and Low‐Molecular‐Weight Gelators
Authors: Cornwell Daniel J. , Okesola Babatunde O. , Smith David K. 
Published: August 2014

AbstractA simple approach to a patterned multidomain gel is reported, combining a pH‐responsive low‐molecular‐weight gelator (LMWG) and a photoinducible polymer gelator (PG). Using SEM (scanning electron microscopy), NMR spectroscopy, and CD, we demonstrate that self‐assembly of the LMWG network occurs in the presence of the PG network, but that the PG has an influence on LMWG assembly kinetics and morphology. The application of a mask during photoirradiation allows patterning of the PG network; we define the resulting system as a “multidomain gel”—one domain consists of a LMWG, whereas the patterned region contains both LMWG and PG networks. The different domains have different properties with regard to diffusion of small molecules, and both gelator networks can control diffusion rates to give systems capable of controlled release. Such materials may have future applications in multikinetic control of drug release, or as patterned scaffolds for directed tissue engineering.
Vanadium‐katalysierte lösungsmittelfreie Synthese quartärer α‐Trifluormethylnitrile mittels elektrophiler Trifluormethylierung
Authors: Früh Natalja , Togni Antonio 
Published: August 2014

AbstractDie direkte elektrophile Trifluormethylierung von Silylketeniminen (SKIs) mit hypervalenten Iodreagentien führt zur Bildung von quartären α‐Trifluormethylnitrilen in guter Ausbeute. Diese neue Reaktion wurde mit einer Auswahl substituierter SKIs unter lösungsmittelfreien Bedingungen mithilfe eines Vanadium(IV)‐Katalysators (5 Mol‐%) durchgeführt. Die somit erhaltenen Produkte können in wertvolle Bausteine für die fluororganische Chemie überführt werden.
Facile CH Bond Formation by Reductive Elimination at a Dinuclear Metal Site
Authors: Adams Richard D. , Rassolov Vitaly , Wong Yuen Onn 
Published: August 2014

AbstractThe electronically unsaturated dirhenium complex [Re2(CO)8(µ‐AuPPh3)(µ‐Ph)] (1) was obtained from the reaction of [Re2(CO)8{µ‐η2‐C(H)C(H)nBu}(µ‐H)] with [Au(PPh3)Ph]. The bridging {AuPPh3} group was replaced by a bridging hydrido ligand to yield the unsaturated dirhenium complex [Re2(CO)8(µ‐H)(µ‐Ph)] (2) by reaction of 1 with HSnPh3. Compound 2 reductively eliminates benzene upon addition of NCMe at 25 °C. The electronic structure of 2 and the mechanism of the reductive elimination of the benzene molecule in its reaction with NCMe were investigated by DFT computational analyses.