bluuebunny/crossref_metadata_2025 huggingface dataset:
Favipiravir Pharmacokinetics in Nonhuman Primates and Insights for Future Efficacy Studies of Hemorrhagic Fever Viruses
Authors: Madelain Vincent , Guedj Jérémie , Mentré France , Nguyen Thi Huyen Tram , Jacquot Frédéric , Oestereich Lisa , Kadota Takumi , Yamada Koichi , Taburet Anne-Marie , de Lamballerie Xavier , Raoul Hervé
Published: October 2016

Favipiravir is an RNA polymerase inhibitor that showed strong antiviral efficacy
in vitro
and in small-animal models of several viruses responsible for hemorrhagic fever (HF), including Ebola virus. The aim of this work was to characterize the complex pharmacokinetics of favipiravir in nonhuman primates (NHPs) in order to guide future efficacy studies of favipiravir in large-animal models. Four different studies were conducted in 30 uninfected cynomolgus macaques of Chinese (
n
= 17) or Mauritian (
n
= 13) origin treated with intravenous favipiravir for 7 to 14 days with maintenance doses of 60 to 180 mg/kg of body weight twice a day (BID). A pharmacokinetic model was developed to predict the plasma concentrations obtained with different dosing regimens, and the model predictions were compared to the 50% effective concentration (EC
50
) of favipiravir against several viruses. Favipiravir pharmacokinetics were described by a model accounting for concentration-dependent aldehyde oxidase inhibition. The enzyme-dependent elimination rate increased over time and was higher in NHPs of Mauritian origin than in those of Chinese origin. Maintenance doses of 100 and 120 mg/kg BID in Chinese and Mauritian NHPs, respectively, are predicted to achieve median trough plasma free concentrations above the EC
50
for Lassa and Marburg viruses until day 7. For Ebola virus, higher doses are required. After day 7, a 20% dose increase is needed to compensate for the increase in drug clearance over time. These results will help rationalize the choice of dosing regimens in future studies evaluating the antiviral effect of favipiravir in NHPs and support its development against a variety of HF viruses.
Changing Epidemiology of Group B Streptococcus Susceptibility to Fluoroquinolones and Aminoglycosides in France
Authors: Hays Constantin , Louis Mathilde , Plainvert Céline , Dmytruk Nicolas , Touak Gérald , Trieu-Cuot Patrick , Poyart Claire , Tazi Asmaa
Published: October 2016

Group B
Streptococcus
(GBS) is the leading cause of neonatal invasive infections and an emerging pathogen in the elderly. Our objectives were to describe the evolution of GBS resistance to antibiotics in France and to investigate the emergence of fluoroquinolone (FQ)-resistant isolates. A total of 8,757 unrelated GBS isolates were collected and tested for antibiotic susceptibility from 2007 to 2014 according to EUCAST recommendations. All isolates were susceptible to penicillin G, amoxicillin, and vancomycin. Resistance to macrolides decreased from 47.0% to 30.0%, whereas high-level resistance to aminoglycosides, especially amikacin, increased from 6.4% to 8.8% and 24 isolates (0.3%) were highly resistant to gentamicin. FQ resistance gradually increased from 0.2% in 2007 (
n
= 1) to 1.5% in 2014 (
n
= 18,
P
< 0.01). Capsular polysaccharide (CPS) genotyping, multilocus sequence typing, and sequencing of the quinolone resistance-determining region (QRDR) showed that GBS isolates of sequence type 19 (ST-19) CPS type V were largely overrepresented in FQ-resistant isolates (
n
= 30, 45.5%). All 30 strains displayed the same QRDR mutations and were often associated with cross-resistance to macrolides (93.3%) and gentamicin (30%). In conclusion, we report the rise of FQ- and aminoglycoside-resistant GBS in France over an 8-year study period, an evolution likely linked to the clonal expansion of ST-19 CPS V-resistant isolates. This study emphasizes the need for a continuous surveillance of GBS epidemiology and antibiotic susceptibility.
Updated Multiplex PCR for Detection of All Six Plasmid-Mediated
qnr
Gene Families
Authors: Kraychete Gabriela Bergiante , Botelho Larissa Alvarenga Batista , Campana Eloiza Helena , Picão Renata Cristina , Bonelli Raquel Regina
Published: October 2016

Plasmid-mediated
qnr
genes have been reported in bacteria worldwide and are widely associated with other relevant determinants of resistance in multiresistance plasmids. Here, we provide an update on a previously described multiplex PCR in order to detect all six
qnr
families (including
qnrA
,
qnrS
,
qnrB
,
qnrC
,
qnrD
, and
qnrVC
) described until now. The proposed method makes possible the screening of these genes, reducing cost and time, and it may demonstrate an underestimated prevalence of the latest variants described.
Deciphering the Resistome of the Widespread Pseudomonas aeruginosa Sequence Type 175 International High-Risk Clone through Whole-Genome Sequencing
Authors: Cabot Gabriel , López-Causapé Carla , Ocampo-Sosa Alain A. , Sommer Lea M. , Domínguez María Ángeles , Zamorano Laura , Juan Carlos , Tubau Fe , Rodríguez Cristina , Moyà Bartolomé , Peña Carmen , Martínez-Martínez Luis , Plesiat Patrick , Oliver Antonio
Published: October 2016

Whole-genome sequencing (WGS) was used for the characterization of the frequently extensively drug resistant (XDR)
Pseudomonas aeruginosa
sequence type 175 (ST175) high-risk clone. A total of 18 ST175 isolates recovered from 8 different Spanish hospitals were analyzed; 4 isolates from 4 different French hospitals were included for comparison. The typical resistance profile of ST175 included penicillins, cephalosporins, monobactams, carbapenems, aminoglycosides, and fluoroquinolones. In the phylogenetic analysis, the four French isolates clustered together with two isolates from one of the Spanish regions. Sequence variation was analyzed for 146 chromosomal genes related to antimicrobial resistance, and horizontally acquired genes were explored using online databases. The resistome of ST175 was determined mainly by mutational events; resistance traits common to all or nearly all of the strains included specific
ampR
mutations leading to
ampC
overexpression, specific mutations in
oprD
conferring carbapenem resistance, or a
mexZ
mutation leading to MexXY overexpression. All isolates additionally harbored an
aadB
gene conferring gentamicin and tobramycin resistance. Several other resistance traits were specific to certain geographic areas, such as a streptomycin resistance gene,
aadA13
, detected in all four isolates from France and in the two isolates from the Cantabria region and a
glpT
mutation conferring fosfomycin resistance, detected in all but these six isolates. Finally, several unique resistance mutations were detected in single isolates; particularly interesting were those in genes encoding penicillin-binding proteins (PBP1A, PBP3, and PBP4). Thus, these results provide information valuable for understanding the genetic basis of resistance and the dynamics of the dissemination and evolution of high-risk clones.
Using MRSA Screening Tests To Predict Methicillin Resistance in Staphylococcus aureus Bacteremia
Authors: Butler-Laporte Guillaume , Cheng Matthew P. , Cheng Alexandre P. , McDonald Emily G. , Lee Todd C.
Published: October 2016

Bloodstream infections with
Staphylococcus aureus
are clinically significant and are often treated with empirical methicillin resistance (MRSA, methicillin-resistant
S. aureus
) coverage. However, vancomycin has associated harms. We hypothesized that MRSA screening correlated with resistance in
S. aureus
bacteremia and could help determine the requirement for empirical vancomycin therapy. We reviewed consecutive
S. aureus
bacteremias over a 5-year period at two tertiary care hospitals. MRSA colonization was evaluated in three ways: as tested within 30 days of bacteremia (30-day criterion), as tested within 30 days but accounting for any prior positive results (ever-positive criterion), or as tested in known-positive patients, with patients with unknown MRSA status being labeled negative (known-positive criterion). There were 409
S. aureus
bacteremias: 302 (73.8%) methicillin-susceptible
S. aureus
(MSSA) and 107 (26.2%) MRSA bacteremias. In the 167 patients with MSSA bacteremias, 7.2% had a positive MRSA test within 30 days. Of 107 patients with MRSA bacteremia, 68 were tested within 30 days (54 positive; 79.8%), and another 21 (19.6%) were previously positive. The 30-day criterion provided negative predictive values (NPV) exceeding 90% and 95% if the prevalence of MRSA in
S. aureus
bacteremia was less than 33.4% and 19.2%, respectively. The same NPVs were predicted at MRSA proportions below 39.7% and 23.8%, respectively, for the ever-positive criterion and 34.4% and 19.9%, respectively, for the known-positive criterion. In MRSA-colonized patients, positive predictive values exceeded 50% at low prevalence. MRSA screening could help avoid empirical vancomycin therapy and its complications in stable patients and settings with low-to-moderate proportions of MRSA bacteremia.
Gentamicin Susceptibility among a Sample of Multidrug-Resistant Neisseria gonorrhoeae Isolates in India
Authors: Bala Manju , Singh Vikram , Bhargava Aradhana , Kakran Monika , Joshi Naveen Chandra , Bhatnagar Ravi
Published: October 2016

Antimicrobial susceptibility testing of 258
Neisseria gonorrhoeae
isolates by Etest determined that 60.1% were multidrug resistant (MDR), while 5% of the strains had decreased susceptibility to currently recommended extended-spectrum cephalosporins (ESCs). Among these, 84.5% of MDR strains and 76.9% of strains that had decreased susceptibility to ESCs were susceptible to gentamicin. No MDR isolate was resistant to gentamicin. These
in vitro
results suggest that gentamicin might be an effective treatment option for the MDR strains and in dual therapy for gonorrhea. However, further research regarding the clinical treatment outcomes is essential.
Beauvericin Potentiates Azole Activity via Inhibition of Multidrug Efflux, Blocks Candida albicans Morphogenesis, and Is Effluxed via Yor1 and Circuitry Controlled by Zcf29
Authors: Shekhar-Guturja Tanvi , Tebung Walters Aji , Mount Harley , Liu Ningning , Köhler Julia R. , Whiteway Malcolm , Cowen Leah E.
Published: October 2016

Invasive fungal infections are a leading cause of human mortality. Effective treatment is hindered by the rapid emergence of resistance to the limited number of antifungal drugs, demanding new strategies to treat life-threatening fungal infections. Here, we explore a powerful strategy to enhance antifungal efficacy against leading human fungal pathogens by using the natural product beauvericin. We found that beauvericin potentiates the activity of azole antifungals against azole-resistant
Candida
isolates via inhibition of multidrug efflux and that beauvericin itself is effluxed via Yor1. As observed in
Saccharomyces cerevisiae
, we determined that beauvericin inhibits TOR signaling in
Candida albicans
. To further characterize beauvericin activity in
C. albicans
, we leveraged genome sequencing of beauvericin-resistant mutants. Resistance was conferred by mutations in transcription factor genes
TAC1
, a key regulator of multidrug efflux, and
ZCF29
, which was uncharacterized. Transcriptional profiling and chromatin immunoprecipitation coupled to microarray analyses revealed that Zcf29 binds to and regulates the expression of multidrug transporter genes. Beyond drug resistance, we also discovered that beauvericin blocks the
C. albicans
morphogenetic transition from yeast to filamentous growth in response to diverse cues. We found that beauvericin represses the expression of many filament-specific genes, including the transcription factor
BRG1
. Thus, we illuminate novel circuitry regulating multidrug efflux and establish that simultaneously targeting drug resistance and morphogenesis provides a promising strategy to combat life-threatening fungal infections.
Cyclic di-AMP Released from Staphylococcus aureus Biofilm Induces a Macrophage Type I Interferon Response
Authors: Gries Casey M. , Bruger Eric L. , Moormeier Derek E. , Scherr Tyler D. , Waters Christopher M. , Kielian Tammy
Published: October 2016

Staphylococcus aureus
is a leading cause of community- and nosocomial-acquired infections, with a propensity for biofilm formation.
S. aureus
biofilms actively skew the host immune response toward an anti-inflammatory state; however, the biofilm effector molecules and the mechanism(s) of action responsible for this phenomenon remain to be fully defined. The essential bacterial second messenger cyclic diadenylate monophosphate (c-di-AMP) is an emerging pathogen-associated molecular pattern during intracellular bacterial infections, as c-di-AMP secretion into the infected host cytosol induces a robust type I interferon (IFN) response. Type I IFNs have the potential to exacerbate infectious outcomes by promoting anti-inflammatory effects; however, the type I IFN response to
S. aureus
biofilms is unknown. Additionally, while several intracellular proteins function as c-di-AMP receptors in
S. aureus
, it has yet to be determined if any extracellular role for c-di-AMP exists and its release during biofilm formation has not yet been demonstrated. This study examined the possibility that c-di-AMP released during
S. aureus
biofilm growth polarizes macrophages toward an anti-inflammatory phenotype via type I interferon signaling. DacA, the enzyme responsible for c-di-AMP synthesis in
S. aureus
, was highly expressed during biofilm growth, and 30 to 50% of total c-di-AMP produced from
S. aureus
biofilm was released extracellularly due to autolytic activity.
S. aureus
biofilm c-di-AMP release induced macrophage type I IFN expression via a STING-dependent pathway and promoted
S. aureus
intracellular survival in macrophages. These findings identify c-di-AMP as another mechanism for how
S. aureus
biofilms promote macrophage anti-inflammatory activity, which likely contributes to biofilm persistence.
Interleukin-17A (IL-17A) and IL-17F Are Critical for Antimicrobial Peptide Production and Clearance of Staphylococcus aureus Nasal Colonization
Authors: Archer Nathan K. , Adappa Nithin D. , Palmer James N. , Cohen Noam A. , Harro Jan M. , Lee Steven K. , Miller Lloyd S. , Shirtliff Mark E.
Published: October 2016

Approximately 20% of the population is persistently colonized by
Staphylococcus aureus
in the nares. Th17-like immune responses mediated by the interleukin-17 (IL-17) family of cytokines and neutrophils are becoming recognized as relevant host defense mechanisms for resolution of
S. aureus
mucocutaneous infections. Since antimicrobial peptides are regulated by the IL-17 cytokines, we sought to determine the role of IL-17 cytokines in production of antimicrobial peptides in a murine model of
S. aureus
nasal carriage. We discovered that nasal tissue supernatants have antistaphylococcal activity, and mice deficient in both IL-17A and IL-17F lost the ability to clear
S. aureus
nasal colonization. IL-17A was found to be sufficient for nasal mBD-3 production
ex vivo
and was required for CRAMP, mBD-3, and mBD-14 expression in response to
S. aureus
colonization
in vivo
. These data were confirmed in a clinical study of nasal secretions in which elevated levels of the human forms of these antimicrobial peptides were found in nasal secretions from healthy human subjects when they were colonized with
S. aureus
but not in secretions from noncolonized subjects. Together, these data provide evidence for the importance of IL-17A regulation of antimicrobial peptides and IL-17F in the clearance of
S. aureus
nasal carriage.
Enoyl-Acyl Carrier Protein Reductase I (FabI) Is Essential for the Intracellular Growth of Listeria monocytogenes
Authors: Yao Jiangwei , Ericson Megan E. , Frank Matthew W. , Rock Charles O.
Published: October 2016

Enoyl-acyl carrier protein reductase catalyzes the last step in each elongation cycle of type II bacterial fatty acid synthesis and is a key regulatory protein in bacterial fatty acid synthesis. Genes of the facultative intracellular pathogen
Listeria monocytogenes
encode two functional enoyl-acyl carrier protein isoforms based on their ability to complement the temperature-sensitive growth phenotype of
Escherichia coli
strain JP1111 [
fabI
(Ts)]. The FabI isoform was inactivated by the FabI selective inhibitor AFN-1252, but the FabK isoform was not affected by the drug, as expected. Inhibition of FabI by AFN-1252 decreased endogenous fatty acid synthesis by 80% and lowered the growth rate of
L. monocytogenes
in laboratory medium. Robust exogenous fatty acid incorporation was not detected in
L. monocytogenes
unless the pathway was partially inactivated by AFN-1252 treatment. However, supplementation with exogenous fatty acids did not restore normal growth in the presence of AFN-1252. FabI inactivation prevented the intracellular growth of
L. monocytogenes
, showing that neither FabK nor the incorporation of host cellular fatty acids was sufficient to support the intracellular growth of
L. monocytogenes
. Our results show that FabI is the primary enoyl-acyl carrier protein reductase of type II bacterial fatty acid synthesis and is essential for the intracellular growth of
L. monocytogenes
.
Dynamic Interactions of a Conserved Enterotoxigenic Escherichia coli Adhesin with Intestinal Mucins Govern Epithelium Engagement and Toxin Delivery
Authors: Kumar Pardeep , Kuhlmann F. Matthew , Bhullar Kirandeep , Yang Hyungjun , Vallance Bruce A. , Xia Lijun , Luo Qingwei , Fleckenstein James M.
Published: October 2016

At present, there is no vaccine for enterotoxigenic
Escherichia coli
(ETEC), an important cause of diarrheal illness. Nevertheless, recent microbial pathogenesis studies have identified a number of molecules produced by ETEC that contribute to its virulence and are novel antigenic targets to complement canonical vaccine approaches. EtpA is a secreted two-partner adhesin that is conserved within the ETEC pathovar. EtpA interacts with the tips of ETEC flagella to promote bacterial adhesion, toxin delivery, and intestinal colonization by forming molecular bridges between the bacteria and the epithelial surface. However, the nature of EtpA interactions with the intestinal epithelium remains poorly defined. Here, we demonstrate that EtpA interacts with glycans presented by transmembrane and secreted intestinal mucins at epithelial surfaces to facilitate pathogen-host interactions that culminate in toxin delivery. Moreover, we found that a major effector molecule of ETEC, the heat-labile enterotoxin (LT), may enhance these interactions by stimulating the production of the gel-forming mucin MUC2. Our studies suggest, however, that EtpA participates in complex and dynamic interactions between ETEC and the gastrointestinal mucosae in which host glycoproteins promote bacterial attachment while simultaneously limiting the epithelial engagement required for effective toxin delivery. Collectively, these data provide additional insight into the intricate nature of ETEC interactions with the intestinal epithelium that have potential implications for rational approaches to vaccine design.
The Type III Secretion System Effector SeoC of Salmonella enterica subsp. salamae and S. enterica subsp. arizonae ADP-Ribosylates Src and Inhibits Opsonophagocytosis
Authors: Pollard Dominic J. , Young Joanna C. , Covarelli Valentina , Herrera-León Silvia , Connor Thomas R. , Fookes Maria , Walker Danielle , Echeita Aurora , Thomson Nicholas R. , Berger Cedric N. , Frankel Gad
Published: October 2016

Salmonella
species utilize type III secretion systems (T3SSs) to translocate effectors into the cytosol of mammalian host cells, subverting cell signaling and facilitating the onset of gastroenteritis. In this study, we compared a draft genome assembly of
Salmonella enterica
subsp.
salamae
strain 3588/07 against the genomes of
S. enterica
subsp.
enterica
serovar Typhimurium strain LT2 and
Salmonella bongori
strain 12419.
S. enterica
subsp.
salamae
encodes the
Salmonella
pathogenicity island 1 (SPI-1), SPI-2, and the locus of enterocyte effacement (LEE) T3SSs. Though several key
S
. Typhimurium effector genes are missing (e.g.,
avrA
,
sopB
, and
sseL
),
S. enterica
subsp.
salamae
invades HeLa cells and contains homologues of
S. bongori sboK
and
sboC
, which we named
seoC
. SboC and SeoC are homologues of EspJ from enteropathogenic and enterohemorrhagic
Escherichia coli
(EPEC and EHEC, respectively), which inhibit Src kinase-dependent phagocytosis by ADP-ribosylation. By screening 73 clinical and environmental
Salmonella
isolates, we identified EspJ homologues in
S. bongori
,
S. enterica
subsp.
salamae
, and
Salmonella enterica
subsp.
arizonae
. The β-lactamase TEM-1 reporter system showed that SeoC is translocated by the SPI-1 T3SS. All the
Salmonella
SeoC/SboC homologues ADP-ribosylate Src E310
in vitro
. Ectopic expression of SeoC/SboC inhibited phagocytosis of IgG-opsonized beads into Cos-7 cells stably expressing green fluorescent protein (GFP)-FcγRIIa. Concurrently,
S. enterica
subsp.
salamae
infection of J774.A1 macrophages inhibited phagocytosis of beads, in a
seoC
-dependent manner. These results show that
S. bongori
,
S. enterica
subsp.
salamae
, and
S. enterica
subsp.
arizonae
share features of the infection strategy of extracellular pathogens EPEC and EHEC and shed light on the complexities of the T3SS effector repertoires of
Enterobacteriaceae
.
Protein Malnutrition Impairs Intestinal Epithelial Cell Turnover, a Potential Mechanism of Increased Cryptosporidiosis in a Murine Model
Authors: Liu J. , Bolick D. T. , Kolling G. L. , Fu Z. , Guerrant R. L.
Published: October 2016

Malnutrition and cryptosporidiosis form a vicious cycle and lead to acute and long-term growth impairment in children from developing countries. Insights into mechanisms underlying the vicious cycle will help to design rational therapies to mitigate this infection. We tested the effect of short-term protein malnutrition on
Cryptosporidium parvum
infection in a murine model by examining stool shedding, tissue burden, and histologic change and explored the mechanism underlying the interaction between malnutrition and cryptosporidiosis through immunostaining and immunoblotting. Protein malnutrition increased stool shedding and the number of intestine-associated
C. parvum
organisms, accompanied by significant suppression of
C. parvum
-induced caspase 3 activity and expression of PCNA and Ki67, but activation of the Akt survival pathway in intestinal epithelial cells. We find that even very brief periods of protein malnutrition may enhance (or intensify) cryptosporidiosis by suppressing
C. parvum
-induced cell turnover and caspase-dependent apoptosis of intestinal epithelial cells. This implicates a potential strategy to attenuate
C. parvum
's effects by modulating apoptosis and promoting regeneration in the intestinal epithelium.
Antibodies Targeting Hsa and PadA Prevent Platelet Aggregation and Protect Rats against Experimental Endocarditis Induced by Streptococcus gordonii
Authors: Mancini Stefano , Menzi Carmen , Oechslin Frank , Moreillon Philippe , Entenza José Manuel
Published: October 2016

Streptococcus gordonii
and related species of oral viridans group streptococci (VGS) are common etiological agents of infective endocarditis (IE). We explored vaccination as a strategy to prevent VGS-IE, using a novel antigen-presenting system based on non-genetically modified
Lactococcus lactis
displaying vaccinogens on its surface. Hsa and PadA are surface-located
S. gordonii
proteins implicated in platelet adhesion and aggregation, which are key steps in the pathogenesis of IE. This function makes them ideal targets for vaccination against VGS-IE. In the present study, we report the use of nonliving
L. lactis
displaying at its surface the N-terminal region of Hsa or PadA by means of the cell wall binding domain of
Lactobacillus casei
A2 phage lysine LysA2 (Hsa-LysA2 and PadA-LysA2, respectively) and investigation of their ability to elicit antibodies in rats and to protect them from
S. gordonii
experimental IE. Immunized and control animals with catheter-induced sterile aortic valve vegetations were inoculated with 10
6
CFU of
S. gordonii
. The presence of IE was evaluated 24 h later. Immunization of rats with
L. lactis
Hsa-LysA2,
L. lactis
PadA-LysA2, or both protected 6/11 (55%), 6/11 (55%), and 11/12 (91%) animals, respectively, from
S. gordonii
IE (
P
< 0.05 versus controls). Protection correlated with the induction of high levels of functional antibodies against both Hsa and PadA that delayed or totally inhibited platelet aggregation by
S. gordonii
. These results support the value of
L. lactis
as a system for antigen delivery and of Hsa and PadA as promising candidates for a vaccine against VGS-IE.
Human Papillomavirus
Authors: Burd Eileen M. , Dean Christina L.
Published: October 2016

Individuals with inherited immunodeficiencies, autoimmune disorders, organ or bone marrow transplantation, or infection with human immunodeficiency virus (HIV) are at increased risk of infection with both low-risk and high-risk human papillomavirus (HPV) types. Chronic immunosuppression provides an environment for persistent HPV infection which carries a higher risk of malignant transformation. Screening guidelines have been developed or advocated for processes that have detectable premalignant lesions, such as anal cancer or cervical cancer. For other anatomic locations, such as cutaneous, penile, and oropharyngeal, a biopsy of suspicious lesions is necessary for diagnosis. HPV cannot be cultured from clinical specimens in the laboratory, and diagnosis relies on cytologic, histologic, or molecular methods.
Chronic Hepatitis B, C, and D
Authors: Cobb Bryan R. , Valsamakis Alexandra
Published: October 2016

Chronic hepatitis B, C, and D virus infections contribute significantly to the morbidity and mortality of immunocompromised individuals. To contextualize discussion of these infections in immunocompromised patients, this paper provides an overview of aspects of infection in normal hosts. It then describes differences in disease, diagnostic testing, and therapeutic management observed in immunocompromised patients.
Importance of Soil Amendments: Survival of Bacterial Pathogens in Manure and Compost Used as Organic Fertilizers
Authors: Sharma Manan , Reynnells Russell
Published: October 2016

Biological soil amendments (BSAs) such as manure and compost are frequently used as organic fertilizers to improve the physical and chemical properties of soils. However, BSAs have been known to be a reservoir for enteric bacterial pathogens such as enterohemorrhagic
Escherichia coli
(EHEC),
Salmonella
spp., and
Listeria
spp. There are numerous mechanisms by which manure may transfer pathogens to growing fruits and vegetables, and several outbreaks of infections have been linked to manure-related contamination of leafy greens. In the United States several commodity-specific guidelines and current and proposed federal rules exist to provide guidance on the application of BSAs as fertilizers to soils, some of which require an interval between the application of manure to soils and the harvest of fruits and vegetables. This review examines the survival, persistence, and regrowth/resuscitation of bacterial pathogens in manure, biosolids, and composts. Moisture, along with climate and the physicochemical properties of soil, manure, or compost, plays a significant role in the ability of pathogens to persist and resuscitate in amended soils. Adaptation of enteric bacterial pathogens to the nonhost environment of soils may also extend their persistence in manure- or compost-amended soils. The presence of antibiotic-resistance genes in soils may also be increased by manure application. Overall, BSAs applied as fertilizers to soils can support the survival and regrowth of pathogens. BSAs should be handled and applied in a manner that reduces the prevalence of pathogens in soils and the likelihood of transfer of food-borne pathogens to fruits and vegetables. This review will focus on two BSAs—raw manure and composted manure (and other feedstocks)—and predominantly on the survival of enteric bacterial pathogens in BSAs as applied to soils as organic fertilizers.
Investigation on possible systematics and side processes
Authors: Bernabei R. , Belli P. , Di Marco A. , d’Angelo A. , Incicchitti A. , Cappella F. , Cerulli R. , Dai C. J. , Ma X. H. , Ye Z. P.
Published: October 2016

This paper gathers the main arguments and reasons which allowed one to exclude either systematic effects or side processes as possible sources of the annual modulation observed in the former DAMA/NaI and the latter DAMA/LIBRA–phase1 datasets.
Influence of sintering temperature on structure, microstructure and piezoelectric properties of doped BZT–BCT ceramics
Authors: Dang Anh Tuan , Vo Thanh Tung , Truong Van Chuong , Le Van Hong
Published: October 2016

This work reports the influence of sintering temperature on structure, microstructure and piezoelectric properties of 0.48 Ba(Zr[Formula: see text]Ti[Formula: see text])O3–0.52 (Ba[Formula: see text]Ca[Formula: see text])TiO3(BZT–BCT) doped with ZnO nanoparticle ceramics manufactured by a conventional solid state reaction method. By increasing sintering temperature, the piezoelectric behaviors were improved and rose up to the best parameters at a sintering temperature of 1450[Formula: see text]C ([Formula: see text] pC/N and [Formula: see text]). The corresponding properties of undoped BZT–BCT ceramics were investigated as a comparison. The received results show that the sintering behavior and piezo-parameters of doped BZT–BCT samples are better than the undoped BZT–BCT samples at each sintering temperature.
Tunable far-field acoustic imaging by two-dimensional sonic crystal with concave incident surface
Authors: Shen Feng-Fu , Lu Dan-Feng , Zhu Hong-Wei , Ji Chang-Ying , Shi Qing-Fan
Published: October 2016

An additional concave incident surface comprised of two-dimensional (2D) sonic crystals (SCs) is employed to tune the acoustic image in the far-field region. The tunability is realized through changing the curvature of the concave surface. To explain the tuning mechanism, a simple ray-trace analysis is demonstrated based on the wave-beam negative refractive law. Then, a numerical confirmation is carried out. Results show that both the position and the intensity of the image can be tuned by the introduced concave surface.
Conductivities of zinc oxide by finite block spins
Authors: Jo Tae Hoon , Yun Myoung Soo , Koo Je Huan , Kwon Gi Chung
Published: October 2016

In the current work, we have demonstrated the phase of ZnO by reference to block theory, in which the phase may be considered to show a paramagnetic ordering between block spins, which in turn comprise random spins that have a majority of individual spins in a given direction. By making use of the Curie–Weiss law of block spins for zinc oxide, we obtained the susceptibility for the lower approximation of the Brillouin function and calculated the resistivity. The resistivity of ZnO mainly stems from spin glass-like disorders according to our analysis.
Nearest-Neighbor Searching Under Uncertainty II
Authors: Agarwal Pankaj K. , Aronov Boris , Har-Peled Sariel , Phillips Jeff M. , Yi Ke , Zhang Wuzhou
Published: October 2016

Nearest-neighbor search, which returns the nearest neighbor of a query point in a set of points, is an important and widely studied problem in many fields, and it has a wide range of applications. In many of them, such as sensor databases, location-based services, face recognition, and mobile data, the location of data is imprecise. We therefore study nearest-neighbor queries in a probabilistic framework in which the location of each input point is specified as a probability distribution function. We present efficient algorithms for (i) computing all points that are nearest neighbors of a query point with nonzero probability and (ii) estimating the probability of a point being the nearest neighbor of a query point, either exactly or within a specified additive error.
Robust Quantitative Comparative Statics for a Multimarket Paradox
Authors: Harks Tobias , Falkenhausen Philipp Von
Published: October 2016

We introduce a quantitative approach to comparative statics that allows to bound the maximum effect of an exogenous parameter change on a system’s equilibrium. The motivation for this approach is a well-known paradox in multimarket Cournot competition, where a positive price shock on a monopoly market may actually reduce the monopolist’s profit. We use our approach to quantify for the first time the worst-case profit reduction for multimarket oligopolies exposed to arbitrary positive price shocks. For markets with affine price functions and firms with convex cost technologies, we show that the relative profit loss of
any
firm is at most 25%, no matter how many firms compete in the oligopoly. We further investigate the impact of positive price shocks on total profit of all firms as well as on social welfare. We find tight bounds also for these measures showing that total profit and social welfare decreases by at most 25% and 16.6%, respectively. Finally, we show that in our model, mixed, correlated, and coarse correlated equilibria are essentially unique, thus, all our bounds apply to these game solutions, as well.
ICT-Based Fall Prevention System for Older Adults
Authors: Ogonowski Corinna , Aal Konstantin , Vaziri Daryoush , Rekowski Thomas Von , Randall Dave , Schreiber Dirk , Wieching Rainer , Wulf Volker
Published: October 2016

Falls and their consequences are arguably most important events for transition from independent living to institutional care for older adults. Information and communication technology (ICT)-based support of fall prevention and fall risk assessment under the control of the user has a tremendous potential to, over time, prevent falls and reduce associated harm and costs. Our research uses participative design and a persuasive health approach to allow for seamless integration of an ICT-based fall prevention system into older adults’ everyday life. Based on a 6-month field study with 12 participants, we present qualitative results regarding the system use and provide insights into attitudes and practices of older adults concerning fall prevention and ICT-supported self-management of health. Our study demonstrates how it can lead to positive aspects of embodiment and health literacy through continuous monitoring of personal results, improved technical confidence, and quality of life. Implications are provided for designing similar systems.
Applying the Norman 1986 User-Centered Model to Post-WIMP UIs
Authors: Poor G. Michael , Jaffee Samuel D. , Leventhal Laura Marie , Ringenberg Jordan , Klopfer Dale S. , Zimmerman Guy , Klein Brandi A.
Published: October 2016

In recent decades, “post-WIMP” interactions have revolutionized user interfaces (UIs) and led to improved user experiences. However, accounts of post-WIMP UIs typically do not provide theoretical explanations of why these UIs lead to superior performance. In this article, we use Norman’s 1986 model of interaction to describe how post-WIMP UIs enhance users’ mental representations of UI and task. In addition, we present an empirical study of three UIs; in the study, participants completed a standard three-dimensional object manipulation task. We found that the post-WIMP UI condition led to enhancements of mental representation of UI and task. We conclude that the Norman model is a good theoretical framework to study post-WIMP UIs. In addition, by studying post-WIMP UIs in the context of the Norman model, we conclude that mental representation of task may be influenced by the interaction itself; this supposition is an extension of the original Norman model.
Next Generation Virtual Memory Management
Authors: McKinley Kathryn S.
Published: October 2016

The goal of virtual memory is an abstraction of infinite and private memory for every process. Unfortunately, the insatiable memory demands of modern applications increasingly violate this abstraction by exposing capacity, bandwidth, and performance limitations of modern hardware. Furthermore, emerging memory technologies are likely to exacerbate this problem. For instance, non-volatile memory differs from DRAM due to its asymmetric read/write performance and thus will likely be an addition rather than a drop-in replacement for DRAM. This talk will describe these problems and recent architecture and software innovations that address of some of them. If adopted, these solutions will impose substantial challenges for operating system memory management, which has evolved very slowly over the past 30 years. I will draw lessons from the past 15 years of garbage collection advances to suggest some promising directions for innovation.
Cell-Specific Targeting of Genetically Encoded Tools for Neuroscience
Authors: Sjulson Lucas , Cassataro Daniela , DasGupta Shamik , Miesenböck Gero
Published: October 2016

Genetically encoded tools for visualizing and manipulating neurons in vivo have led to significant advances in neuroscience, in large part because of the ability to target expression to specific cell populations of interest. Current methods enable targeting based on marker gene expression, development, anatomical projection pattern, synaptic connectivity, and recent activity as well as combinations of these factors. Here, we review these methods, focusing on issues of practical implementation as well as areas for future improvement.
Obstructive Sleep Apnea: Update and Future
Authors: Lim Diane C. , Pack Allan I.
Published: October 2016

Obstructive sleep apnea (OSA) is a worldwide disease whose prevalence is increasing as obesity rates increase. The link between obesity and OSA is likely to be the deposition of fat in the tongue, compromising upper airway size. The role of obesity varies in different ethnic groups, with Chinese being particularly sensitive to increases in weight. OSA lends itself to a personalized approach to diagnosis and therapy. For example, different clinical OSA subtypes likely benefit from therapy in different ways. Hypoglossal nerve stimulation is a useful second-line therapy in patients who cannot tolerate continous positive airway pressure (CPAP) machines or intraoral devices. Technological advances allow patients to participate in their own care, and doing so improves CPAP compliance. We are entering a future where we can focus efforts to predict and prevent OSA on an individual level.
The pipeline of physiology courses in community colleges: to university, medical school, and beyond
Authors: McFarland Jenny , Pape-Lindstrom Pamela
Published: October 2016

Community colleges are significant in the landscape of undergraduate STEM (science technology, engineering, and mathematics) education (9), including biology, premedical, and other preprofessional education. Thirty percent of first-year medical school students in 2012 attended a community college. Students attend at different times in high school, their first 2 yr of college, and postbaccalaureate. The community college pathway is particularly important for traditionally underrepresented groups. Premedical students who first attend community college are more likely to practice in underserved communities (2). For many students, community colleges have significant advantages over 4-yr institutions. Pragmatically, they are local, affordable, and flexible, which accommodates students' work and family commitments. Academically, community colleges offer teaching faculty, smaller class sizes, and accessible learning support systems. Community colleges are fertile ground for universities and medical schools to recruit diverse students and support faculty. Community college students and faculty face several challenges (6, 8). There are limited interactions between 2- and 4-yr institutions, and the ease of transfer processes varies. In addition, faculty who study and work to improve the physiology education experience often encounter obstacles. Here, we describe barriers and detail existing resources and opportunities useful in navigating challenges. We invite physiology educators from 2- and 4-yr institutions to engage in sharing resources and facilitating physiology education improvement across institutions. Given the need for STEM majors and health care professionals, 4-yr colleges and universities will continue to benefit from students who take introductory biology, physiology, and anatomy and physiology courses at community colleges.
Peroxisome Proliferator-Activated ReceptorαReduces Endothelin-1-Caused Cardiomyocyte Hypertrophy by Inhibiting Nuclear Factor-κB and Adiponectin
Authors: Jen Hsu-Lung , Liu Po-Len , Chen Yung-Hsiang , Yin Wei-Hsian , Chen Jaw-Wen , Lin Shing-Jong
Published: October 2016

Peroxisome proliferator-activated receptorα(PPARα) plays a role in the pathogenesis of cardiac hypertrophy, although its underlying mechanism remains unclear. The purpose of this study was to evaluate the effect of PPARαactivation on endothelin-1- (ET-1-) caused cardiomyocyte hypertrophy and explore its underlying mechanisms. Human cardiomyocytes (HCMs) were cultured with or without ET-1, whereafter the inhibitory effects of fenofibrate, a PPARαactivator, on cell size and adiponectin protein were tested. We examined the activation of extracellular signal-regulated kinase (ERK) and p38 proteins caused by ET-1 and the inhibition of the ERK and p38 pathways on ET-1-induced cell size and adiponectin expression. Moreover, we investigated the interaction of PPARαwith adiponectin and nuclear factor-κB (NF-κB) by electrophoretic mobility shift assays and coimmunoprecipitation. ET-1 treatment significantly increased cell size, suppressed PPARαexpression, and enhanced the expression of adiponectin. Pretreatment with fenofibrate inhibited the increase in cell size and enhancement of adiponectin expression. ET-1 significantly activated the ERK and p38 pathways, whereas PD98059 and SB205380, respectively, inhibited them. Our results suggest that activated PPARαcan decrease activation of adiponectin and NF-κB and inhibit ET-1-induced cardiomyocyte hypertrophy.
Asteraceae Artemisia campestris and Artemisia herba-alba Essential Oils Trigger Apoptosis and Cell Cycle Arrest in Leishmania infantum Promastigotes
Authors: Aloui Zohra , Messaoud Chokri , Haoues Meriam , Neffati Noura , Bassoumi Jamoussi Imen , Essafi-Benkhadir Khadija , Boussaid Mohamed , Guizani Ikram , Karoui Habib
Published: October 2016

We report the chemical composition and anti‐Leishmania and antioxidant activity of Artemisia campestris L. and Artemisia herba‐alba Asso. essential oils (EOs). Our results showed that these extracts exhibit different antioxidant activities according to the used assay. The radical scavenging effects determined by DPPH assay were of IC50 = 3.3 mg/mL and IC50 = 9.1 mg/mL for Artemisia campestris and Artemisia herba‐alba essential oils, respectively. However, antioxidant effects of both essential oils, determined by ferric‐reducing antioxidant power (FRAP) assay, were in the same range (2.3 and 2.97 mg eq EDTA/g EO, resp.), while the Artemisia herba‐alba essential oil showed highest chelating activity of Fe2+ ions (27.48 mM Fe2+). Interestingly, we showed that both EOs possess dose‐dependent activity against Leishmania infantum promastigotes with IC50 values of 68 μg/mL and 44 μg/mL for A. herba‐alba and A. campestris, respectively. We reported, for the first time, that antileishmanial activity of both EOs was mediated by cell apoptosis induction and cell cycle arrest at the sub‐G0/G1 phase. All our results showed that EOs from A. herba‐alba and A. campestris plants are promising candidates as anti‐Leishmania medicinal products.
Connecting (T)issues: How Research in Fascia Biology Can Impact Integrative Oncology
Authors: Langevin Helene M. , Keely Patricia , Mao Jun , Hodge Lisa M. , Schleip Robert , Deng Gary , Hinz Boris , Swartz Melody A. , de Valois Beverley A. , Zick Suzanna , Findley Thomas
Published: October 2016

Complementary and integrative treatments, such as massage, acupuncture, and yoga, are used by increasing numbers of cancer patients to manage symptoms and improve their quality of life. In addition, such treatments may have other important and currently overlooked benefits by reducing tissue stiffness and improving mobility. Recent advances in cancer biology are underscoring the importance of connective tissue in the local tumor environment. Inflammation and fibrosis are well-recognized contributors to cancer, and connective tissue stiffness is emerging as a driving factor in tumor growth. Physical-based therapies have been shown to reduce connective tissue inflammation and fibrosis and thus may have direct beneficial effects on cancer spreading and metastasis. Meanwhile, there is currently little knowledge on potential risks of applying mechanical forces in the vicinity of tumors. Thus, both basic and clinical research are needed to understand the full impact of integrative oncology on cancer biology as well as whole person health. Cancer Res; 76(21); 6159–62. ©2016 AACR.
Alternative Polyadenylation in Triple-Negative Breast Tumors Allows NRAS and c-JUN to Bypass PUMILIO Posttranscriptional Regulation
Authors: Miles Wayne O. , Lembo Antonio , Volorio Angela , Brachtel Elena , Tian Bin , Sgroi Dennis , Provero Paolo , Dyson Nicholas
Published: October 2016

Alternative polyadenylation (APA) is a process that changes the posttranscriptional regulation and translation potential of mRNAs via addition or deletion of 3′ untranslated region (3′ UTR) sequences. To identify posttranscriptional-regulatory events affected by APA in breast tumors, tumor datasets were analyzed for recurrent APA events. Motif mapping of the changed 3′ UTR regions found that APA-mediated removal of Pumilio regulatory elements (PRE) was unusually common. Breast tumor subtype–specific APA profiling identified triple-negative breast tumors as having the highest levels of APA. To determine the frequency of these events, an independent cohort of triple-negative breast tumors and normal breast tissue was analyzed for APA. APA-mediated shortening of NRAS and c-JUN was seen frequently, and this correlated with changes in the expression of downstream targets. mRNA stability and luciferase assays demonstrated APA-dependent alterations in RNA and protein levels of affected candidate genes. Examination of clinical parameters of these tumors found those with APA of NRAS and c-JUN to be smaller and less proliferative, but more invasive than non-APA tumors. RT-PCR profiling identified elevated levels of polyadenylation factor CSTF3 in tumors with APA. Overexpression of CSTF3 was common in triple-negative breast cancer cell lines, and elevated CSTF3 levels were sufficient to induce APA of NRAS and c-JUN. Our results support the hypothesis that PRE-containing mRNAs are disproportionately affected by APA, primarily due to high sequence similarity in the motifs utilized by polyadenylation machinery and the PUM complex. Cancer Res; 76(24); 7231–41. ©2016 AACR.