bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Randomized Trial Investigating the Efficacy and Safety of Water Soluble Micellar Paclitaxel (Paccal Vet) for Treatment of Nonresectable Grade 2 or 3 Mast Cell Tumors in Dogs
Authors: Vail D.M. , von Euler H. , Rusk A.W. , Barber L. , Clifford C. , Elmslie R. , Fulton L. , Hirschberger J. , Klein M. , London C. , Martano M. , McNiel E.A. , Morris J.S. , Northrup N. , Phillips B. , Polton G. , Post G. , Rosenberg M. , Ruslander D. , Sahora A. , Siegel S. , Thamm D. , Westberg S. , Winter J. , Khanna C. 
Published: March 2012

BackgroundEffective treatments for dogs with advanced stage mast cell tumors (MCT) remain a pressing need. A micellar formulation of paclitaxel (paclitaxel [micellar]) has shown promise in early‐phase studies.Hypothesis/ObjectivesThe objective was to demonstrate greater activity for paclitaxel (micellar) compared with lomustine. The null hypothesis was μp = μL (ie, proportion of responders for the paclitaxel [micellar] and lomustine groups, respectively).AnimalsTwo hundred and fifty‐two dogs with advanced stage nonresectable grade 2 or 3 MCT.MethodsProspective multicenter randomized double‐blind positive‐controlled clinical trial. The primary endpoint was confirmed overall response rate (CORR) at 14 weeks. A secondary endpoint, biologic observed response rate (BORR), also was calculated. Safety was assessed by the characterization and grading of adverse events (AE).ResultsOverall CORR (7% versus 1%; P = .048) and BORR (23% versus 10%; P = .012) were greater for paclitaxel (micellar) compared with lomustine. Paclitaxel (micellar)‐treated dogs were 6.5 times more likely to have a confirmed response and 3.1 times more likely to experience a biologic observed response. The majority of AE with paclitaxel (micellar) were transient and clinically manageable. Twenty‐seven dogs (33%) receiving lomustine were discontinued because of hepatopathy compared with 3 dogs (2%) receiving paclitaxel (micellar) (P < .0001; odds ratio 26.7).Conclusions and Clinical ImportancePaclitaxel (micellar)'s activity and safety profile are superior to lomustine. The addition of an active and novel taxane to the veterinary armamentarium could fill a substantial need and, as its mechanism of action and AE profile do not overlap with currently available TKI, its availability could lead to effective combination protocols.
Investigation of the neuroanatomical substrates of reward seeking following protracted abstinence in mice
Authors: Madsen Heather B. , Brown Robyn M. , Short Jennifer L. , Lawrence Andrew J. 
Published: March 2012

Key points
Persistent vulnerability to relapse represents a major challenge in the treatment of drug addiction. The brain circuitry that underlies relapse‐like behaviour can be investigated using animal models.
This study compared the brains of mice that had relapsed to morphine with mice that had relapsed to sucrose following abstinence. We found that while some brain regions were implicated in both drug and food seeking, other specific parts of the brain were activated for either sucrose or morphine relapse.
Common regions included those with established involvement in reward and relapse‐like behaviour. In addition we found some regions not previously linked to these behaviours.
Overall, while our findings support existing literature regarding relapse‐like behaviour in rats, we have additionally identified brain regions outside this established circuitry which are worthy of further investigation.
Abstract  Persistent vulnerability to relapse represents a major challenge in the treatment of drug addiction. The brain circuitry that underlies relapse‐like behaviour can be investigated using animal models of drug seeking. As yet there have been no comprehensive brain mapping studies that have specifically examined the neuroanatomical substrates of cue‐induced opiate seeking following abstinence in a mouse operant paradigm. The aim of this study was to compare the brain regions involved in sucrose vs. morphine seeking following protracted abstinence in mice. Male CD1 mice were trained to respond for either sucrose (10% w/v) or intravenous morphine (0.1 mg kg−1 per infusion) in an operant paradigm in the presence of a discrete cue. Once stable responding was established, mice were subjected to abstinence in their home cages for 3 weeks and then perfused for tissue collection, or returned to the operant chambers to assess cue‐induced reward seeking before being perfused for tissue collection. Brain tissue was processed for Fos immunohistochemistry and Fos expression was quantified in a range of brain nuclei. We identified unique patterns of neuronal activation for sucrose and morphine seeking mice as well as some overlap. Structures activated in both ‘relapse’ groups included the anterior cingulate and orbitofrontal cortex, nucleus accumbens shell, bed nucleus of the stria terminalis, substantia nigra pars compacta, ventral tegmental area, hippocampus, periaqueductal grey, locus coeruleus and lateral habenula. Structures that were more activated in morphine seeking mice included the nucleus accumbens core, basolateral amygdala, substantia nigra pars reticulata, and the central nucleus of the amygdala. The dorsal raphe was the only structure examined that was specifically activated in sucrose seeking mice. Overall our findings support a cortico‐striatal limbic circuit driving opiate seeking, and we have identified some additional circuitry potentially relevant to reward seeking following abstinence.
Myostatin inhibition induces muscle fibre hypertrophy prior to satellite cell activation
Authors: Wang Qian , McPherron Alexandra C. 
Published: March 2012

Key points
There is disagreement about whether muscle hypertrophy requires the activation and fusion of satellite cells, the quiescent muscle stem cells, to the multinucleated post‐mitotic muscle fibre.
Although the growth factor myostatin is clearly a negative regulator of muscle size, previous studies regarding its role in maintaining satellite cell quiescence have yielded conflicting results.
We injected mice with a myostatin inhibitor and the DNA labelling agent bromodeoxyuridine to label proliferating cells and found that a small number of satellite cells are activated after the onset of hypertrophy.
We also found that myostatin null mice are not resistant to age‐related muscle mass or satellite cell loss.
Our results suggest that myostatin inhibition in adult mice causes hypertrophy mainly by acting on myofibres rather than satellite cells, which results in an increase in the cytoplasmic volume to DNA ratio.
L-Selectin and P-Selectin Are Novel Biomarkers of Cervicovaginal Inflammation for Preclinical Mucosal Safety Assessment of Anti-HIV-1 Microbicide
Authors: Zhong Maohua , He Benxia , Yang Jingyi , Bao Rong , Zhang Yan , Zhou Dihan , Chen Yaoqing , Li Liangzhu , Han Chen , Yang Yi , Sun Ying , Cao Yuan , Li Yaoming , Shi Wei , Jiang Shibo , Zhang Xiaoyan , Yan Huimin 
Published: March 2012

ABSTRACTA major obstacle thwarting preclinical development of microbicides is the lack of a validated biomarker of cervicovaginal inflammation. Therefore, the present study aims to identify novel noninvasive soluble markers in a murine model for assessment of microbicide mucosal safety. By performing cytokine antibody array analysis, we identified two adhesion molecules, L-selectin and P-selectin, which significantly increased when mucosal inflammation was triggered by nonoxynol-9 (N9), an anti-HIV-1 microbicide candidate that failed clinical trials, in a refined murine model of agent-induced cervicovaginal inflammation. We found that patterns of detection of L-selectin and P-selectin were obviously different from those of the two previously defined biomarkers of cervicovaginal inflammation, monocyte chemotactic protein 1 (MCP-1) and interleukin 6 (IL-6). The levels of these two soluble selectins correlated better than those of MCP-1 and IL-6 with the duration and severity of mucosal inflammation triggered by N9 and two approved proinflammatory compounds, benzalkonium chloride (BZK) and sodium dodecyl sulfate (SDS), but not by two nonproinflammatory compounds, carboxymethyl celluose (CMC; microbicide excipients) and tenofovir (TFV; microbicide candidate). These data indicated that L-selectin and P-selectin can serve as additional novel cervicovaginal inflammation biomarkers for preclinical mucosal safety evaluation of candidate microbicides for the prevention of infection with HIV and other sexually transmitted pathogens.
Prevalence of
qnr
,
aac(6
′
)-Ib-cr
,
qepA
, and
oqxAB
in Escherichia coli Isolates from Humans, Animals, and the Environment
Authors: Chen Xiang , Zhang Weiqiu , Pan Weijuan , Yin Jiajun , Pan Zhiming , Gao Song , Jiao Xinan 
Published: March 2012

ABSTRACT

qnr
,
aac(6
′
)-Ib-cr
,
qepA
, and
oqxAB
genes were detected in 5.7%, 4.9%, 2.6%, and 20.2% of 1,022
Escherichia coli
isolates from humans, animals, and the environment, respectively, collected between 1993 and 2010 in China. The prevalence of
oqxAB
in porcine isolates (51.0%) was significantly higher than that in other isolates. This is the first report of
oqxAB
-positive isolates from ducks and geese and as early as 1994 from chickens.
Targeting Persisters for Tuberculosis Control
Authors: Zhang Ying , Yew Wing Wai , Barer Michael R. 
Published: March 2012

ABSTRACT

Mycobacterial persisters, the survivors from antibiotic exposure, necessitate the lengthy treatment of tuberculosis (TB) and pose a significant challenge for our control of the disease. We suggest that persisters in TB are heterogeneous in nature and comprise various proportions of the population depending on the circumstances; the mechanisms of their formation are complex and may be related to those required for persistence in chronic infection. Results from recent studies implicate multiple pathways for persister formation, including energy production, the stringent response, global regulators, the
trans
-translation pathway, proteasomal protein degradation, toxin-antitoxin modules, and transporter or efflux mechanisms. A combination of specifically persister-targeted approaches, such as catching them when active and susceptible either by stimulating them to “wake up” or by intermittent drug dosing, the development of new drugs, the use of appropriate drug combinations, and combined chemotherapy and immunotherapy, may be needed for more effective elimination of persisters and better treatment of TB. Variations in levels of persister formation and in host genetics can play a role in the outcome of clinical treatment, and thus, these may entail personalized treatment regimens.
Neutrophils Mediate Maturation and Efflux of Lung Dendritic Cells in Response to Aspergillus fumigatus Germ Tubes
Authors: Park Stacy J. , Burdick Marie D. , Mehrad Borna 
Published: March 2012

ABSTRACTInvasive aspergillosis is a life-threatening complication of neutrophil deficiency or dysfunction. Neutropenia has previously been associated with enhanced influx of CD11b-expressing conventional dendritic cells to the lungs in response toAspergillusspecies, but whether neutrophils directly modulate the function of dendritic cells in this infection is not known. We hypothesized that, in the setting of intrapulmonary challenge withAspergillus, neutrophils promote the maturation and traffic of lung conventional dendritic cells to draining mediastinal lymph nodes. We report that neutropenia results in a marked accumulation of dendritic cells in the lungs of mice challenged withAspergillusbut greatly diminishes their egress to mediastinal lymph nodes independent of neutrophil microbicidal functions. Furthermore, the phenotype of lung dendritic cells was more immature in neutropenic animals than in nonneutropenic mice exposed to the microorganism. Consistent with this, coincubation with neutrophils greatly enhanced the upregulation of costimulatory molecules on dendritic cells exposed toAspergillus in vitro, a process that was dependent on cell contact and the dendritic cell receptor DC-SIGN. Taken together, our data support an immunomodulatory cross talk between neutrophils and dendritic cells in the context of host response toAspergillusthat promotes the maturation and efflux of lung dendritic cells.
Susceptibility of Inbred Mice to Rickettsia parkeri
Authors: Grasperge Britton J. , Reif Kathryn E. , Morgan Timothy D. , Sunyakumthorn Piyanate , Bynog Joseph , Paddock Christopher D. , Macaluso Kevin R. 
Published: March 2012

ABSTRACTRickettsia parkeri, a member of the spotted fever groupRickettsia, is the causative agent of American boutonneuse fever in humans. Despite the increased recognition of human cases, limited information is available regarding the infection of invertebrate and vertebrate hosts for this emerging tick-borne disease. Toward the development of a viable transmission model and to further characterize the pathology associated withR. parkeriinfection, inbred mouse strains (A/J, BALB/c, C3H/HeJ, and C3H/HeN) were intravenously and intradermally inoculated with 105low-passage-numberR. parkeri(Portsmouth strain), and infection, gross pathology, and histopathology were scored. Additionally, a quantitative real-time PCR (qPCR) was performed to estimate rickettsial load in heart, lung, spleen, and liver tissues of infected mice at 19 days postinoculation. Of the A/J, BALB/c, and C3H/HeN mice, none displayed universal pathology consistent with sustained infection. Compared to age-matched control mice, the intravenously inoculated C3H/HeJ mice exhibited marked facial edema and marked splenomegaly upon gross examination, while the intradermally inoculated mice developed characteristic eschar-like lesions. The C3H/HeJ mice also exhibited the greatest concentrations of rickettsial DNA from heart, lung, liver, and spleen samples when examined by qPCR. The similarity of the pathology of human disease and sustained infection suggests that the C3H/HeJ strain of mice is a promising candidate for subsequent experiments to examine the tick transmission, dissemination, and pathology ofR. parkeririckettsiosis.
Surface Proteome of “Mycobacterium avium subsp. hominissuis” during the Early Stages of Macrophage Infection
Authors: McNamara Michael , Tzeng Shin-Cheng , Maier Claudia , Zhang Li , Bermudez Luiz E. 
Published: March 2012

ABSTRACT

“
Mycobacterium avium
subsp.
hominissuis
” is a robust and pervasive environmental bacterium that can cause opportunistic infections in humans. The bacterium overcomes the host immune response and is capable of surviving and replicating within host macrophages. Little is known about the bacterial mechanisms that facilitate these processes, but it can be expected that surface-exposed proteins play an important role. In this study, the selective biotinylation of surface-exposed proteins, streptavidin affinity purification, and shotgun mass spectrometry were used to characterize the surface-exposed proteome of
M. avium
subsp.
hominissuis
. This analysis detected more than 100 proteins exposed at the bacterial surface of
M. avium
subsp.
hominissuis
. Comparisons of surface-exposed proteins between conditions simulating early infection identified several groups of proteins whose presence on the bacterial surface was either constitutive or appeared to be unique to specific culture conditions. This proteomic profile facilitates an improved understanding of
M. avium
subsp.
hominissuis
and how it establishes infection. Additionally, surface-exposed proteins are excellent targets for the host adaptive immune system, and their identification can inform the development of novel treatments, diagnostic tools, and vaccines for mycobacterial disease.
Quorum-Sensing and BvrR/BvrS Regulation, the Type IV Secretion System, Cyclic Glucans, and BacA in the Virulence of Brucella ovis: Similarities to and Differences from Smooth Brucellae
Authors: Martín-Martín Ana I. , Sancho Pilar , de Miguel María Jesús , Fernández-Lago Luis , Vizcaíno Nieves 
Published: March 2012

ABSTRACT

Brucella ovis
is a rough bacterium—lacking O-polysaccharide chains in the lipopolysaccharide—that is virulent in its natural host and whose virulence mechanisms remain almost unexplored. In a search for additional traits that distinguish
B. ovis
from smooth
Brucella
, which require O-polysaccharide chains for virulence, we have analyzed the significance in
B. ovis
of the main virulence factors described for smooth
Brucella
. Attempts to obtain strains of virulent
B. ovis
strain PA that are mutated in the BvrR/BvrS two-component regulatory system were unsuccessful, suggesting the requirement of that system for
in vitro
survival, while the inactivation of
bacA
—in contrast to the results seen with smooth
Brucella
—did not affect splenic colonization in mice or behavior in J774.A1 murine macrophages. Defects in the synthesis of cyclic ß-1,2 glucans reduced the uptake of
B. ovis
PA in macrophages and, although the intracellular multiplication rate was unaffected, led to attenuation in mice. Growth of strains with mutations in the type IV secretion system (encoded by the
virB
operon) and the quorum-sensing-related regulator VjbR was severely attenuated in the mouse model, and although the mutant strains internalized like the parental strain in J774.A1 murine macrophages, they were impaired for intracellular replication. As described for
B. melitensis
, VjbR regulates the transcription of the
virB
operon positively, and the
N
-dodecanoyl-
dl
-homoserine lactone (C
12
-HSL) autoinducer abrogates this effect. In contrast, no apparent VjbR-mediated regulation of the
fliF
flagellar gene was observed in
B. ovis
, probably due to the two deletions detected upstream of
fliF
. These results, together with others reported in the text, point to similarities between rough virulent
B. ovis
and smooth
Brucella
species as regards virulence but also reveal distinctive traits that could be related to the particular pathogenicity and host tropism characteristics of
B. ovis
.
The Multiple Signaling Systems Regulating Virulence in Pseudomonas aeruginosa
Authors: Nadal Jimenez Pol , Koch Gudrun , Thompson Jessica A. , Xavier Karina B. , Cool Robbert H. , Quax Wim J. 
Published: March 2012

SUMMARYCell-to-cell communication is a major process that allows bacteria to sense and coordinately react to the fluctuating conditions of the surrounding environment. In several pathogens, this process triggers the production of virulence factors and/or a switch in bacterial lifestyle that is a major determining factor in the outcome and severity of the infection. Understanding how bacteria control these signaling systems is crucial to the development of novel antimicrobial agents capable of reducing virulence while allowing the immune system of the host to clear bacterial infection, an approach likely to reduce the selective pressures for development of resistance. We provide here an up-to-date overview of the molecular basis and physiological implications of cell-to-cell signaling systems in Gram-negative bacteria, focusing on the well-studied bacteriumPseudomonas aeruginosa. All of the known cell-to-cell signaling systems in this bacterium are described, from the most-studied systems, i.e.,N-acyl homoserine lactones (AHLs), the 4-quinolones, the global activator of antibiotic and cyanide synthesis (GAC), the cyclic di-GMP (c-di-GMP) and cyclic AMP (cAMP) systems, and the alarmones guanosine tetraphosphate (ppGpp) and guanosine pentaphosphate (pppGpp), to less-well-studied signaling molecules, including diketopiperazines, fatty acids (diffusible signal factor [DSF]-like factors), pyoverdine, and pyocyanin. This overview clearly illustrates that bacterial communication is far more complex than initially thought and delivers a clear distinction between signals that are quorum sensing dependent and those relying on alternative factors for their production.
Phylogenetic Framework and Molecular Signatures for the Main Clades of the Phylum Actinobacteria
Authors: Gao Beile , Gupta Radhey S. 
Published: March 2012

SUMMARYThe phylumActinobacteriaharbors many important human pathogens and also provides one of the richest sources of natural products, including numerous antibiotics and other compounds of biotechnological interest. Thus, a reliable phylogeny of this large phylum and the means to accurately identify its different constituent groups are of much interest. Detailed phylogenetic and comparative analyses of >150 actinobacterial genomes reported here form the basis for achieving these objectives. In phylogenetic trees based upon 35 conserved proteins, most of the main groups ofActinobacteriaas well as a number of their superageneric clades are resolved. We also describe large numbers of molecular markers consisting of conserved signature indels in protein sequences and whole proteins that are specific for either allActinobacteriaor their different clades (viz., orders, families, genera, and subgenera) at various taxonomic levels. These signatures independently support the existence of different phylogenetic clades, and based upon them, it is now possible to delimit the phylumActinobacteria(excludingCoriobacteriia) and most of its major groups in clear molecular terms. The species distribution patterns of these markers also provide important information regarding the interrelationships among different main orders ofActinobacteria. The identified molecular markers, in addition to enabling the development of a stable and reliable phylogenetic framework for this phylum, also provide novel and powerful means for the identification of different groups ofActinobacteriain diverse environments. Genetic and biochemical studies on theseActinobacteria-specific markers should lead to the discovery of novel biochemical and/or other properties that are unique to different groups ofActinobacteria.
Impact of the Deepwater Horizon well blowout on the economics of US Gulf fisheries
Authors: Sumaila U. Rashid , Cisneros-Montemayor Andrés M. , Dyck Andrew , Huang Ling , Cheung William , Jacquet Jennifer , Kleisner Kristin , Lam Vicky , McCrea-Strub Ashley , Swartz Wilf , Watson Reg , Zeller Dirk , Pauly Daniel 
Published: March 2012

Marine oil spills usually harm organisms at two interfaces: near the water surface and on shore. However, because of the depth of the April 2010 Deepwater Horizon well blowout, deeper parts of the Gulf of Mexico are likely impacted. We estimate the potential negative economic effects of this blowout and oil spill on commercial and recreational fishing, as well as mariculture (marine aquaculture) in the US Gulf area, by computing potential losses throughout the fish value chain. We find that the spill could, in the next 7 years, result in (midpoint) present value losses of total revenues, total profits, wages, and economic impact of US$3.7, US$1.9, US$1.2, and US$8.7 billion, respectively. Commercial and recreational fisheries would likely suffer the most losses, with a respective estimated US$1.6 and US$1.9 billion of total revenue losses, US$0.8 and US$1.1 billion in total profit losses, and US$4.9 and US$3.5 billion of total economic losses.