bluuebunny/crossref_metadata_2025 huggingface dataset:
Nonsuicidal Self‐Injury in Adolescents: Characterization of the Disorder and the Issue of Distress and Impairment
Authors: Zetterqvist Maria
Published: August 2016

Nonsuicidal self‐injury disorder (NSSID) is a condition in need of further study to assess the validity of the potential diagnosis and its suggested criteria. This study examined the NSSID diagnosis and investigated the distress/impairment criterion by comparing community adolescents who met all criteria for NSSID (n = 186) to adolescents with five or more nonsuicidal self‐injury (NSSI) episodes (n = 314), and to a group of adolescents who met all criteria but negated that their NSSI caused them any distress or impairment, thus failing to meet criterion E (n = 29). The NSSID group delimited from the ≥ 5 NSSI group by reporting significantly more frequent and severe self‐injurious thoughts and behaviors, as well as having more experiences of negative life events and higher levels of trauma symptoms. There were also some differences between the NSSID group and adolescents without distress/impairment, which together contribute valuable information on the potential NSSID diagnosis, as well as the discussion of criterion E.
Describing and Measuring the Pathway to Suicide Attempts: A Preliminary Study
Authors: Millner Alexander J. , Lee Michael D. , Nock Matthew K.
Published: August 2016

To die by suicide, one must think about suicide, make a plan, and then carry it out. Prior research has examined the presence and predictors of these outcomes; however, virtually no studies have characterized how these steps unfold along the pathway to suicide. A novel instrument was administered to 30 recent suicide attempters. Results revealed that although the median onset for suicidal ideation occurs 1 to 5 years prior to attempting, the median for 6 of the 10 steps measured was within 6 hours of attempting. Overall, 86.5% of proximal planning steps took place within 1 week of attempting and 66.6% occurred within 12 hours.
Optimal cue combination and landmark‐stability learning in the head direction system
Authors: Jeffery Kate J. , Page Hector J. I. , Stringer Simon M.
Published: August 2016

Maintaining a sense of direction requires combining information from static environmental landmarks with dynamic information about self‐motion. This is accomplished by the head direction system, whose neurons – head direction cells – encode specific head directions. When the brain integrates information in sensory domains, this process is almost always ‘optimal’ – that is, inputs are weighted according to their reliability. Evidence suggests cue combination by head direction cells may also be optimal. The simplicity of the head direction signal, together with the detailed knowledge we have about the anatomy and physiology of the underlying circuit, therefore makes this system a tractable model with which to discover how optimal cue combination occurs at a neural level. In the head direction system, cue interactions are thought to occur on an attractor network of interacting head direction neurons, but attractor dynamics predict a winner‐take‐all decision between cues, rather than optimal combination. However, optimal cue combination in an attractor could be achieved via plasticity in the feedforward connections from external sensory cues (i.e. the landmarks) onto the ring attractor. Short‐term plasticity would allow rapid re‐weighting that adjusts the final state of the network in accordance with cue reliability (reflected in the connection strengths), while longer term plasticity would allow long‐term learning about this reliability. Although these principles were derived to model the head direction system, they could potentially serve to explain optimal cue combination in other sensory systems more generally.

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A Physiologically Based Pharmacokinetic Model of Isoniazid and Its Application in Individualizing Tuberculosis Chemotherapy
Authors: Cordes Henrik , Thiel Christoph , Aschmann Hélène E. , Baier Vanessa , Blank Lars M. , Kuepfer Lars
Published: August 2016

Due to its high early bactericidal activity, isoniazid (INH) plays an essential role in tuberculosis treatment. Genetic polymorphisms of
N
-acetyltransferase type 2 (NAT2) cause a trimodal distribution of INH pharmacokinetics in slow, intermediate, and fast acetylators. The success of INH-based chemotherapy is associated with acetylator and patient health status. Still, a standard dose recommended by the FDA is administered regardless of acetylator type or immune status, even though adverse effects occur in 5 to 33% of all patients. Slow acetylators have a higher risk of development of drug-induced toxicity, while fast acetylators and immune-deficient patients face lower treatment success rates. To mechanistically assess the trade-off between toxicity and efficacy, we developed a physiologically based pharmacokinetic (PBPK) model describing the NAT2-dependent pharmacokinetics of INH and its metabolites. We combined the PBPK model with a pharmacodynamic (PD) model of antimycobacterial drug effects in the lungs. The resulting PBPK/PD model allowed the simultaneous simulation of treatment efficacies at the site of infection and exposure to toxic metabolites in off-target organs. Subsequently, we evaluated various INH dosing regimens in NAT2-specific immunocompetent and immune-deficient virtual populations. Our results suggest the need for acetylator-specific dose adjustments for optimal treatment outcomes. A reduced dose for slow acetylators substantially lowers the exposure to toxic metabolites and thereby the risk of adverse events, while it maintains sufficient treatment efficacies. Vice versa, intermediate and fast acetylators benefit from increased INH doses and a switch to a twice-daily administration schedule. Our analysis outlines how PBPK/PD modeling may be used to design and individualize treatment regimens.
Characterization of
In Vitro
Resistance Development to the Novel Echinocandin CD101 in Candida Species
Authors: Locke Jeffrey B. , Almaguer Amanda L. , Zuill Douglas E. , Bartizal Ken
Published: August 2016

CD101 is a novel echinocandin with a long half-life undergoing clinical development for treatment of candidemia/invasive candidiasis and vulvovaginal candidiasis. The potential for and mechanisms underlying the development of resistance to CD101 in
Candida
species were investigated by using spontaneous resistance and serial passage selection methodologies. Four
Candida
spp. (
C. albicans
,
C. glabrata
,
C. parapsilosis
, and
C. krusei
) were chosen for resistance characterization with CD101, anidulafungin, and caspofungin. The frequency of spontaneous, single-step mutations conferring reduced susceptibility to CD101 at 1× the agar growth inhibition concentration was low across all species, with median frequencies ranging from 1.35 × 10
−8
to 3.86 × 10
−9
, similar to ranges generated for anidulafungin and caspofungin. Serial passage of
Candida
spp. on agar plates containing drug gradients demonstrated a low potential for resistance development, with passage 20 CD101-selected strains possessing increases in MICs equivalent to or lower than those for the majority of strains generated under selection with anidulafungin and caspofungin. A total of 12
fks
“hot spot” mutations were identified, typically in strains with the highest MIC shifts. Cross-resistance was broadly observed among the 3 echinocandins evaluated, with no CD101-selected mutants (with or without
fks
hot spot mutations) exhibiting reduced susceptibility to CD101 but not also to anidulafungin and/or caspofungin. Consistent with currently approved echinocandins, CD101 demonstrates a low potential for resistance development, which could be further enhanced
in vivo
by the high maximum concentration of drug in serum (
C
max
)/area under the concentration-time curve (AUC) plasma drug exposure achieved with once-weekly dosing of CD101.
Experimental Induction of Bacterial Resistance to the Antimicrobial Peptide Tachyplesin I and Investigation of the Resistance Mechanisms
Authors: Hong Jun , Hu Jianye , Ke Fei
Published: August 2016

Tachyplesin I is a 17-amino-acid cationic antimicrobial peptide (AMP) with a typical cyclic antiparallel β-sheet structure that is a promising therapeutic for infections, tumors, and viruses. To date, no bacterial resistance to tachyplesin I has been reported. To explore the safety of tachyplesin I as an antibacterial drug for wide clinical application, we experimentally induced bacterial resistance to tachyplesin I by using two selection procedures and studied the preliminary resistance mechanisms.
Aeromonas hydrophila
XS91-4-1,
Pseudomonas aeruginosa
CGMCC1.2620, and
Escherichia coli
ATCC 25922 and F41 showed resistance to tachyplesin I under long-term selection pressure with continuously increasing concentrations of tachyplesin I. In addition,
P. aeruginosa
and
E. coli
exhibited resistance to tachyplesin I under UV mutagenesis selection conditions. Cell growth and colony morphology were slightly different between control strains and strains with induced resistance. Cross-resistance to tachyplesin I and antimicrobial agents (cefoperazone and amikacin) or other AMPs (pexiganan, tachyplesin III, and polyphemusin I) was observed in some resistant mutants. Previous studies showed that extracellular protease-mediated degradation of AMPs induced bacterial resistance to AMPs. Our results indicated that the resistance mechanism of
P. aeruginosa
was not entirely dependent on extracellular proteolytic degradation of tachyplesin I; however, tachyplesin I could induce increased proteolytic activity in
P. aeruginosa
. Most importantly, our findings raise serious concerns about the long-term risks associated with the development and clinical use of tachyplesin I.
The
RTA3
Gene, Encoding a Putative Lipid Translocase, Influences the Susceptibility of Candida albicans to Fluconazole
Authors: Whaley Sarah G. , Tsao Sarah , Weber Sandra , Zhang Qing , Barker Katherine S. , Raymond Martine , Rogers P. David
Published: August 2016

The
RTA3
gene, coding for a member of the Rta1p-like lipid-translocating exporter family, is coordinately upregulated with the ATP-binding cassette transporter genes
CDR1
and
CDR2
in azole-resistant clinical isolates of
Candida albicans
that carry activating mutations in the transcription factor Tac1p. We show here that deleting
RTA3
in an azole-resistant clinical isolate carrying a Tac1p-activating mutation lowered fluconazole resistance by 2-fold, while overexpressing
RTA3
in an azole-susceptible clinical isolate resulted in enhanced fluconazole tolerance associated with trailing growth in a liquid microtiter plate assay. We also demonstrate that an Rta3p-green fluorescent protein (GFP) fusion protein localizes predominantly to the plasma membrane, consistent with a putative function for Rta3p as a lipid translocase.
Rare Spontaneous Loss of Multiresistance Gene Carrying IncI/ST12 Plasmid in Escherichia coli in Pig Microbiota
Authors: Mourand Gwenaelle , Touzain Fabrice , Jouy Eric , Fleury Mickael Alain , Denamur Erick , Kempf Isabelle
Published: August 2016

Resistance to extended-spectrum cephalosporins (ESCs) is a matter of considerable concern for public health. Here, we studied the spontaneous loss of an extended-spectrum beta-lactamase (ESBL)-encoding plasmid from a rifampin-resistant
Escherichia coli
isolate orally inoculated into pigs under controlled conditions. Fecal samples were collected and cultured on rifampin-supplemented medium, and the resistance of the
E. coli
isolates to ESCs was studied by phenotypic tests, PCR detection of plasmid genes, and complete sequencing. The results showed that only 3 out of 353 rifampin-resistant
E. coli
isolates were ESC susceptible, and PCR and bioinformatics analysis confirmed the loss of the plasmid. These
in vivo
experiments indicate that the loss of an ESBL-encoding plasmid seems a rare event in gut microbiota.
In Vitro
Evaluation of the Activity of Imipenem-Relebactam against 451 Recent Clinical Isolates of Bacteroides Group and Related Species
Authors: Snydman David R. , Jacobus Nilda V. , McDermott Laura A.
Published: August 2016

We evaluated the
in vitro
activity of imipenem-relebactam (imipenem-MK7655) against 451 recent clinical isolates within the
Bacteroides
group and related species. Relebactam did not enhance or inhibit the activity of imipenem against
Bacteroides fragilis
or other
Bacteroides
species. No synergistic or antagonistic effect was observed. The MICs of imipenem-relebactam were equal to or within one dilution of the MICs of these isolates to imipenem.
High Prevalence of Hypervirulent Klebsiella pneumoniae Infection in China: Geographic Distribution, Clinical Characteristics, and Antimicrobial Resistance
Authors: Zhang Yawei , Zhao Chunjiang , Wang Qi , Wang Xiaojuan , Chen Hongbin , Li Henan , Zhang Feifei , Li Shuguang , Wang Ruobing , Wang Hui
Published: August 2016

Hypervirulent
Klebsiella pneumoniae
(hvKP) is traditionally defined by hypermucoviscosity, but data based on genetic background are limited. Antimicrobial-resistant hvKP has been increasingly reported but has not yet been systematically studied.
K. pneumoniae
isolates from bloodstream infections, hospital-acquired pneumonia, and intra-abdominal infections were collected from 10 cities in China during February to July 2013. Clinical data were collected from medical records. All
K. pneumoniae
isolates were investigated by antimicrobial susceptibility testing, string test, extended-spectrum β-lactamase (ESBL) gene detection, capsular serotypes, virulence gene profiles, and multilocus sequence typing. hvKP was defined by aerobactin detection. Of 230
K. pneumoniae
isolates, 37.8% were hvKP. The prevalence of hvKP varied among different cities, with the highest rate in Wuhan (73.9%) and the lowest in Zhejiang (8.3%). Hypermucoviscosity and the presence of K1, K2, K20, and
rmpA
genes were strongly associated with hvKP (
P
< 0.001). A significantly higher incidence of liver abscess (
P
= 0.026), sepsis (
P
= 0.038), and invasive infections (
P
= 0.043) was caused by hvKP. Cancer (odds ratio [OR], 2.285) and diabetes mellitus (OR, 2.256) appeared to be independent variables associated with hvKP infections by multivariate analysis. Importantly, 12.6% of hvKP isolates produced ESBLs, and most of them carried
bla
CTX-M
genes. Patients with neutropenia (37.5% versus 5.6%;
P
= 0.020), history of systemic steroid therapy (37.5% versus 5.6%;
P
= 0.020), and combination therapy (62.5% versus 16.7%;
P
= 0.009) were more likely to be infected with ESBL-producing hvKP. The prevalence of hvKP is high in China and has a varied geographic distribution. ESBL-producing hvKP is emerging, suggesting an urgent need to enhance clinical awareness, especially for immunocompromised patients receiving combination therapy.
Glutamate Racemase Is the Primary Target of β-Chloro-
d
-Alanine in Mycobacterium tuberculosis
Authors: Prosser Gareth A. , Rodenburg Anne , Khoury Hania , de Chiara Cesira , Howell Steve , Snijders Ambrosius P. , de Carvalho Luiz Pedro S.
Published: August 2016

The increasing global prevalence of drug resistance among many leading human pathogens necessitates both the development of antibiotics with novel mechanisms of action and a better understanding of the physiological activities of preexisting clinically effective drugs. Inhibition of peptidoglycan (PG) biosynthesis and cross-linking has traditionally enjoyed immense success as an antibiotic target in multiple bacterial pathogens, except in
Mycobacterium tuberculosis
, where it has so far been underexploited.
d
-Cycloserine, a clinically approved antituberculosis therapeutic, inhibits enzymes within the
d
-alanine subbranch of the PG-biosynthetic pathway and has been a focus in our laboratory for understanding peptidoglycan biosynthesis inhibition and for drug development in studies of
M. tuberculosis
. During our studies on alternative inhibitors of the
d
-alanine pathway, we discovered that the canonical alanine racemase (Alr) inhibitor β-chloro–
d
-alanine (BCDA) is a very poor inhibitor of recombinant
M. tuberculosis
Alr, despite having potent antituberculosis activity. Through a combination of enzymology, microbiology, metabolomics, and proteomics, we show here that BCDA does not inhibit the
d
-alanine pathway in intact cells, consistent with its poor
in vitro
activity, and that it is instead a mechanism-based inactivator of glutamate racemase (MurI), an upstream enzyme in the same early stage of PG biosynthesis. This is the first report to our knowledge of inhibition of MurI in
M. tuberculosis
and thus provides a valuable tool for studying this essential and enigmatic enzyme and a starting point for future MurI-targeted antibacterial development.
MgtC as a Host-Induced Factor and Vaccine Candidate against Mycobacterium abscessus Infection
Authors: Le Moigne Vincent , Belon Claudine , Goulard Céline , Accard Geoffrey , Bernut Audrey , Pitard Bruno , Gaillard Jean-Louis , Kremer Laurent , Herrmann Jean-Louis , Blanc-Potard Anne-Béatrice
Published: August 2016

Mycobacterium abscessus
is an emerging pathogenic mycobacterium involved in pulmonary and mucocutaneous infections, presenting a serious threat for patients with cystic fibrosis (CF). The lack of an efficient treatment regimen and the emergence of multidrug resistance in clinical isolates require the development of new therapeutic strategies against this pathogen. Reverse genetics has revealed genes that are present in
M. abscessus
but absent from saprophytic mycobacteria and that are potentially involved in pathogenicity. Among them,
MAB_3593
encodes MgtC, a known virulence factor involved in intramacrophage survival and adaptation to Mg
2+
deprivation in several major bacterial pathogens. Here, we demonstrated a strong induction of
M. abscessus
MgtC at both the transcriptional and translational levels when bacteria reside inside macrophages or upon Mg
2+
deprivation. Moreover, we showed that
M. abscessus
MgtC was recognized by sera from
M. abscessus
-infected CF patients. The intramacrophage growth (J774 or THP1 cells) of a
M. abscessus
knockout
mgtC
mutant was, however, not significantly impeded. Importantly, our results indicated that inhibition of MgtC
in vivo
through immunization with
M. abscessus
mgtC
DNA, formulated with a tetrafunctional amphiphilic block copolymer, exerted a protective effect against an aerosolized
M. abscessus
challenge in CF (ΔF508 FVB) mice. The formulated DNA immunization was likely associated with the production of specific MgtC antibodies, which may stimulate a protective effect by counteracting MgtC activity during
M. abscessus
infection. These results emphasize the importance of
M. abscessus
MgtC
in vivo
and provide a basis for the development of novel therapeutic tools against pulmonary
M. abscessus
infections in CF patients.
Use of a Multiplex Transcript Method for Analysis of Pseudomonas aeruginosa Gene Expression Profiles in the Cystic Fibrosis Lung
Authors: Gifford Alex H. , Willger Sven D. , Dolben Emily L. , Moulton Lisa A. , Dorman Dana B. , Bean Heather , Hill Jane E. , Hampton Thomas H. , Ashare Alix , Hogan Deborah A.
Published: August 2016

The discovery of therapies that modulatePseudomonas aeruginosavirulence or that can eradicate chronicP. aeruginosalung infections associated with cystic fibrosis (CF) will be advanced by an improved understanding ofP. aeruginosabehaviorin vivo. We demonstrate the use of multiplexed Nanostring technology to monitor relative abundances ofP. aeruginosatranscripts across clinical isolates, in serial samples, and for the purposes of comparing microbial physiologyin vitroandin vivo. The expression of 75 transcripts encoded by genes implicated in CF lung disease was measured in a variety ofP. aeruginosastrains as well as RNA serial sputum samples from fourP. aeruginosa-colonized subjects with CF collected over 6 months. We present data on reproducibility, the results from different methods of normalization, and demonstrate high concordance between transcript relative abundance data obtained by Nanostring or transcriptome sequencing (RNA-Seq) analysis. Furthermore, we address considerations regarding sequence variation between strains during probe design. Analysis ofP. aeruginosagrownin vitroidentified transcripts that correlated with the different phenotypes commonly observed in CF clinical isolates.P. aeruginosatranscript profiles in RNA from CF sputum indicated alginate productionin vivo, and transcripts involved in quorum-sensing regulation were less abundant in sputum than strains grown in the laboratory.P. aeruginosagene expression patterns from sputum clustered closely together relative to patterns for laboratory-grown cultures; in contrast, laboratory-grownP. aeruginosashowed much greater transcriptional variation with only loose clustering of strains with different phenotypes. The clustering within and between subjects was surprising in light of differences in inhaled antibiotic and respiratory symptoms, suggesting that the pathways represented by these 75 transcripts are stable in chronic CFP. aeruginosalung infections.
Attachment of Actinobacillus suis H91-0380 and Its Isogenic Adhesin Mutants to Extracellular Matrix Components of the Tonsils of the Soft Palate of Swine
Authors: Bujold Adina R. , MacInnes Janet I.
Published: August 2016

Tonsils conduct immune surveillance of antigens entering the upper respiratory tract. Despite their immunological function, they are also sites of persistence and invasion of bacterial pathogens.
Actinobacillus suis
is a common resident of the tonsils of the soft palate in pigs, but under certain circumstances it can invade, causing septicemia and related sequelae. Twenty-four putative adhesins are predicted in the
A. suis
genome, but to date, little is known about how they might participate in colonization or invasion. To better understand these processes, swine tonsil lysates were characterized by mass spectrometry. Fifty-nine extracellular matrix (ECM) proteins were identified, including small leucine-rich proteoglycans, integrins, and other cell surface receptors. Additionally, attachment of the wild type and 3 adhesin mutants to 5 ECM components was evaluated. Exponential cultures of wild-type
A. suis
adhered significantly more than stationary cultures to all ECM components studied except collagen I. During exponential growth, the
A. suis
Δ
flp1
mutant attached less to collagen IV while the Δ
ompA
mutant attached less to all ECMs. The Δ
comE1
strain attached less to collagen IV, fibronectin, and vitronectin during exponential growth and exhibited differential attachment to collagen I over short adherence time points. These results suggest that Flp1, OmpA, and ComE1 are important during early stages of attachment to ECM components found in tonsils, which supports the notion that other adhesins have compensatory effects during later stages of attachment.
Resistance of Mice of the 129 Background to Yersinia pestis Maps to Multiple Loci on Chromosome 1
Authors: Tencati Michael , Tapping Richard I.
Published: August 2016

Yersinia pestisis a Gram-negative bacterium that is the causative agent of bubonic and pneumonic plague. It is commonly acquired by mammals such as rodents and humans via the bite of an infected flea. We previously reported that multiple substrains of the 129 mouse background are resistant to pigmentation locus-negative (pgm−)Yersinia pestisand that this phenotype maps to a 30-centimorgan (cM) region located on chromosome 1. In this study, we have further delineated this plague resistance locus to a region of less than 20 cM through the creation and phenotyping of recombinant offspring arising from novel crossovers in this region. Furthermore, our experiments have revealed that there are at least two alleles in this initial locus, both of which are required for resistance on a susceptible C57BL/6 background. These two alleles work intranssince resistance is restored in offspring possessing one allele contributed by each parent. Our studies also indicated that the Slc11a1 gene (formerly known as Nramp1) located within the chromosome1 locus is not responsible for conferring resistance to 129 mice.
Leishmania donovani-Induced Prostaglandin E2 Generation Is Critically Dependent on Host Toll-Like Receptor 2–Cytosolic Phospholipase A2 Signaling
Authors: Bhattacharjee Amrita , Majumder Saikat , Das Shibali , Ghosh Sweta , Biswas Satabdi , Majumdar Subrata
Published: August 2016

Visceral leishmaniasis (VL) is the second-largest parasitic killer disease after malaria. During VL, the protozoan
Leishmania donovani
induces prostaglandin E2 (PGE2) generation within host macrophages to aid parasite survival. PGE2 significantly influences leishmanial pathogenesis, as
L. donovani
proliferation is known to be attenuated in PGE2-inhibited macrophages. Here, we report for the first time that signaling via macrophage Toll-like receptor 2 (TLR2) plays an instrumental role in inducing PGE2 release from
L. donovani
-infected macrophages. This signaling cascade, mediated via the TLR2–phosphatidylinositol 3-kinase (PI3K)–phospholipase C (PLC) signaling pathway, was found to be indispensable for activation of two major enzymes required for PGE2 generation: cytosolic phospholipase A2 (cPLA2) and cyclooxygenase 2 (Cox2). Inhibition of cPLA2, but not secreted phospholipase A2 (sPLA2) or calcium-independent phospholipase A2 (iPLA2), arrested
L. donovani
infection. During infection, cPLA2 activity increased >7-fold in a calcium-dependent and extracellular signal-regulated kinase (ERK)-dependent manner, indicating that elevation of intracellular calcium and ERK-mediated phosphorylation was necessary for
L. donovani
-induced cPLA2 activation. For transcriptional upregulation of cyclooxygenase 2, activation of the calcium-calcineurin-nuclear factor of activated T cells (NFAT) signaling was required in addition to the TLR2-PI3K-PLC pathway. Detailed studies by site-directed mutagenesis of potential NFAT binding sites and chromatin immunoprecipitation (ChIP) analysis revealed that the binding of macrophage NFATc2, at the −73/−77 site on the
cox2
promoter, induced
L. donovani
-driven
cox2
transcriptional activation. Collectively, these findings highlight the contribution of TLR2 downstream signaling toward activation of cPLA2 and Cox2 and illustrate how the TLR2-PI3K-PLC pathway acts in a concerted manner with calcium-calcineurin-NFATc2 signaling to modulate PGE2 release from
L. donovani
-infected macrophages.
Neonatal Fc Receptor Regulation of Lung Immunoglobulin and CD103
+
Dendritic Cells Confers Transient Susceptibility to Tuberculosis
Authors: Vogelzang Alexis , Lozza Laura , Reece Stephen T. , Perdomo Carolina , Zedler Ulrike , Hahnke Karin , Oberbeck-Mueller Dagmar , Dorhoi Anca , Kaufmann Stefan H. E.
Published: August 2016

The neonatal Fc receptor (FcRn) extends the systemic half-life of IgG antibodies by chaperoning bound Fc away from lysosomal degradation inside stromal and hematopoietic cells. FcRn also transports IgG across mucosal barriers into the lumen, and yet little is known about how FcRn modulates immunity in the lung during homeostasis or infection. We infected wild-type (WT) and FcRn-deficient (
fcgrt
−/−
) mice with
Pseudomonas aeruginosa
or
Mycobacterium tuberculosis
to investigate whether recycling and transport of IgG via FcRn influences innate and adaptive immunity in the lung in response to bacterial infection. We found that FcRn expression maintains homeostatic IgG levels in lung and leads to preferential secretion of low-affinity IgG ligands into the lumen.
Fcgrt
−/−
animals exhibited no evidence of developmental impairment of innate immunity in the lung and were able to efficiently recruit neutrophils in a model of acute bacterial pneumonia. Although local humoral immunity in lung increased independently of the presence of FcRn during tuberculosis, there was nonetheless a strong impact of FcRn deficiency on local adaptive immunity. We show that the quantity and quality of IgG in airways, as well as the abundance of dendritic cells in the lung, are maintained by FcRn. FcRn ablation transiently enhanced local T cell immunity and neutrophil recruitment during tuberculosis, leading to a lower bacterial burden in lung. This novel understanding of tissue-specific modulation of mucosal IgG isotypes in the lung by FcRn sheds light on the role of mucosal IgG in immune responses in the lung during homeostasis and bacterial disease.
The Aryl Hydrocarbon Receptor Modulates Production of Cytokines and Reactive Oxygen Species and Development of Myocarditis during Trypanosoma cruzi Infection
Authors: Barroso Andréia , Gualdrón-López Melisa , Esper Lísia , Brant Fátima , Araújo Ronan R. S. , Carneiro Matheus B. H. , Ávila Thiago V. , Souza Danielle G. , Vieira Leda Q. , Rachid Milene A. , Tanowitz Herbert B. , Teixeira Mauro M. , Machado Fabiana S.
Published: August 2016

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor involved in controlling several aspects of immune responses, including the activation and differentiation of specific T cell subsets and antigen-presenting cells, thought to be relevant in the context of experimental
Trypanosoma cruzi
infection. The relevance of AhR for the outcome of
T. cruzi
infection is not known and was investigated here. We infected wild-type (WT) mice and AhR knockout (AhR KO) mice with
T. cruzi
(Y strain) and determined levels of parasitemia, myocardial inflammation and fibrosis, expression of AhR/cytokines/suppressor of cytokine signaling (SOCS) (spleen/heart), and production of nitric oxide (NO), reactive oxygen species (ROS), and peroxynitrite (ONOO
−
) (spleen). AhR expression was increased in the heart of infected WT mice. Infected AhR KO mice displayed significantly reduced parasitemia, inflammation, and fibrosis of the myocardium. This was associated with an anticipated increased immune response characterized by increased levels of inflammatory cytokines and reduced expression of SOCS2 and SOCS3 in the heart.
In vitro
, AhR deficiency caused impairment in parasite replication and decreased levels of ROS production. In conclusion, AhR influences the development of murine Chagas disease by modulating ROS production and regulating the expression of key physiological regulators of inflammation, SOCS1 to -3, associated with the production of cytokines during experimental
T. cruzi
infection.
A
Coccidioides posadasii CPS1
Deletion Mutant Is Avirulent and Protects Mice from Lethal Infection
Authors: Narra Hema P. , Shubitz Lisa F. , Mandel M. Alejandra , Trinh Hien T. , Griffin Kurt , Buntzman Adam S. , Frelinger Jeffrey A. , Galgiani John N. , Orbach Marc J.
Published: August 2016

The
CPS1
gene was identified as a virulence factor in the maize pathogen
Cochliobolus heterostrophus
. Hypothesizing that the homologous gene in
Coccidioides posadasii
could be important for virulence, we created a Δ
cps1
deletion mutant which was unable to cause disease in three strains of mice (C57BL/6, BALB/c, or the severely immunodeficient NOD-
scid
,γ
c

null

[NSG]). Only a single colony was recovered from 1 of 60 C57BL/6 mice following intranasal infections of up to 4,400 spores. Following administration of very high doses (10,000 to 2.5 × 10
7
spores) to NSG and BALB/c mice, spherules were observed in lung sections at time points from day 3 to day 10 postinfection, but nearly all appeared degraded with infrequent endosporulation. Although the role of
CPS1
in virulence is not understood, phenotypic alterations and transcription differences of at least 33 genes in the Δ
cps1
strain versus
C. posadasii
is consistent with both metabolic and regulatory functions for the gene. The
in vitro
phenotype of the Δ
cps1
strain showed slower growth of mycelia with delayed and lower spore production than
C. posadasii
, and
in vitro
spherules were smaller. Vaccination of C57BL/6 or BALB/c mice with live Δ
cps1
spores either intranasally, intraperitoneally, or subcutaneously resulted in over 95% survival with mean residual lung fungal burdens of <1,000 CFU from an otherwise lethal
C. posadasii
intranasal infection. Considering its apparently complete attenuation of virulence and the high degree of resistance to
C. posadasii
infection when used as a vaccine, the Δ
cps1
strain is a promising vaccine candidate for preventing coccidioidomycosis in humans or other animals.
Interaction of Erp Protein of Mycobacterium tuberculosis with Rv2212 Enhances Intracellular Survival of Mycobacterium smegmatis
Authors: Ganaie Arsheed Ahmad , Trivedi Garima , Kaur Amanpreet , Jha Sidharth Shankar , Anand Shashi , Rana Vibhuti , Singh Amit , Kumar Shekhar , Sharma Charu
Published: August 2016

The
Mycobacterium tuberculosis
e
xported
r
epetitive
p
rotein (RvErp) is a crucial virulence-associated factor as determined by its role in the survival and multiplication of mycobacteria in cultured macrophages and
in vivo
. Although attempts have been made to understand the function of Erp protein, its exact role in
Mycobacterium
pathogenesis is still elusive. One way to determine this is by searching for novel interactions of RvErp. Using a yeast two-hybrid assay, an adenylyl cyclase (AC), Rv2212, was found to interact with RvErp. The interaction between RvErp and Rv2212 is direct and occurs at the endogenous level. The Erp protein of
Mycobacterium smegmatis
(MSMEG_6405, or MsErp) interacts neither with Rv2212 nor with Ms_4279, the
M. smegmatis
homologue of Rv2212. Deletion mutants of Rv2212 revealed its adenylyl cyclase domain to be responsible for the interaction. RvErp enhances Rv2212-mediated cyclic AMP (cAMP) production. Also, the biological significance of the interaction between RvErp and Rv2212 was demonstrated by the enhanced survival of
M. smegmatis
within THP-1 macrophages. Taken together, these studies address a novel mechanism by which Erp executes its function.

IMPORTANCE
RvErp is one of the important virulence factors of
M. tuberculosis
. This study describes a novel function of RvErp protein of
M. tuberculosis
by identifying Rv2212 as its interacting protein. Rv2212 is an adenylyl cyclase (AC) and produces cAMP, one of the prime second messengers that regulate the intracellular survival of mycobacteria. Therefore, the significance of investigating novel interactions of RvErp is paramount in unraveling the mechanisms governing the intracellular survival of mycobacteria.
Effects of
tcpB
Mutations on Biogenesis and Function of the Toxin-Coregulated Pilus, the Type IVb Pilus of Vibrio cholerae
Authors: Gao Yang , Hauke Caitlyn A. , Marles Jarrad M. , Taylor Ronald K.
Published: August 2016

Vibrio cholerae
is the etiological agent of the acute intestinal disorder cholera. The toxin-coregulated pilus (TCP), a type IVb pilus, is an essential virulence factor of
V. cholerae
. Recent work has shown that TcpB is a large minor pilin encoded within the
tcp
operon. TcpB contributes to efficient pilus formation and is essential for all TCP functions. Here, we have initiated a detailed targeted mutagenesis approach to further characterize this salient TCP component. We have identified (thus far) 20 residues of TcpB which affect either the steady-state level of TcpB or alter one or more TCP functions. This study provides a solid framework for further understanding of the complex role of TcpB and will be of use upon determination of the crystal structure of TcpB or related minor pilin orthologs of type IVb pilus systems.

IMPORTANCE
Type IV pili, such as the toxin-coregulated pilus (TCP) in
V. cholerae
, are bacterial appendages that often act as essential virulence factors. Minor pilins, like TcpB, of these pili systems often play integral roles in pilus assembly and function. In this study, we have generated mutations in
tcpB
to determine residues of importance for TCP stability and function. Combined with a predicted tertiary structure, characterization of these mutants allows us to better understand critical residues in TcpB and the role they may play in the mechanisms underlying minor pilin functions.
Factors affecting illness in the developing world: chronic disease, mental health and traditional medicine cures
Authors: Douthit Nathan T , Astatk Hailemariam Alemu
Published: August 2016

This is a case report of a 24-year-old Ethiopian woman with a medical history of hepatosplenic schistosomiasis. She suffers from chronic liver failure and portal hypertension. She has been hospitalised for ‘hysteria’ in the past but did not receive follow-up, outpatient treatment or psychiatric evaluation. After discontinuing her medications and leaving her family to use holy water, a religious medicine used by many Ethiopians, she was found at a nearby monastery. She was non-communicative and difficult to arouse. The patient was rushed to nearby University of Gondar Hospital where she received treatment for hepatic encephalopathy and spontaneous bacterial peritonitis. Her illness is the result of neglected tropical disease, reliance on traditional medicine as opposed to biomedical services and the poor state of psychiatric care in the developing world.
Graft-versus-host disease: unexpected presentation with simultaneous hepatitis and pancreatitis
Authors: Fernandes Samuel Raimundo , Alves Antonio T , Cortes Margarida Barreto , Cortez-Pinto Helena
Published: August 2016

We report the case of a 37-year-old man with a previous bone marrow transplantation presenting with abdominal pain, diarrhoea and jaundice. Laboratory evaluation showed marked elevated liver enzymes, amylase and lipase with ultrasonographic evidence of acute alithiasic pancreatitis. Liver biopsy was compatible with graft-versus-host disease and toxic hepatitis. The patient rapidly improved after increasing immunosuppression. Although gastrointestinal manifestations are common in graft-versus-host disease, clinical acute pancreatitis is rarely seen. Patients with graft versus host are seldom managed by gastroenterologists and hepatologists. An awareness of this condition is essential for the experienced clinician.
Connectivity of certain simplicial complexes associated to a handlebody
Authors: Guo Qilong , Liu Qing
Published: August 2016

In this paper, we prove three simplicial complexes associate to a handlebody, which are separating disk complex, half disk complex and disk pants graph, are connected.
FRACTAL AND CHAOS ANALYSIS FOR DYNAMICS OF RADON EXHALATION FROM URANIUM MILL TAILINGS
Authors: LI YONGMEI , TAN WANYU , TAN KAIXUAN , LIU ZEHUA , XIE YANSHI
Published: August 2016

Tailings from mining and milling of uranium ores potentially are large volumes of low-level radioactive materials. A typical environmental problem associated with uranium tailings is radon exhalation, which can significantly pose risks to environment and human health. In order to reduce these risks, it is essential to study the dynamical nature and underlying mechanism of radon exhalation from uranium mill tailings. This motivates the conduction of this study, which is based on the fractal and chaotic methods (e.g. calculating the Hurst exponent, Lyapunov exponent and correlation dimension) and laboratory experiments of the radon exhalation rates. The experimental results show that the radon exhalation rate from uranium mill tailings is highly oscillated. In addition, the nonlinear analyses of the time series of radon exhalation rate demonstrate the following points: (1) the value of Hurst exponent much larger than 0.5 indicates non-random behavior of the radon time series; (2) the positive Lyapunov exponent and non-integer correlation dimension of the time series imply that the radon exhalation from uranium tailings is a chaotic dynamical process; (3) the required minimum number of variables should be five to describe the time evolution of radon exhalation. Therefore, it can be concluded that the internal factors, including heterogeneous distribution of radium, and randomness of radium decay, as well as the fractal characteristics of the tailings, can result in the chaotic evolution of radon exhalation from the tailings.
IN SITU PHOTOELECTRON SPECTROSCOPY INVESTIGATION OF INTERFACE COUPLING BETWEEN METALS AND MoO3 THIN FILMS
Authors: WANG FEI , HU FANG , ZHANG XUE-AO , XU HUI
Published: August 2016

Metal nanoparticles or nanoclusters have been widely used to functionalize semiconductor metal oxide nanostructures-based gas sensors or photodetectors to significantly enhance the device performance. It is crucial to reach a thorough understanding of the interfacial coupling between the metal nanoclusters and the metal oxide nanostructures. Here, in situ X-ray photoelectron spectroscopy (XPS) and ultraviolet photoelectron spectroscopy (UPS) have been used to investigate the interfacial interactions between metals (Au and Co) and molybdenum trioxide (MoO3) films. In spite of the high work function ([Formula: see text]6.8[Formula: see text]eV) of the thermally evaporated MoO3 films, only weak interaction is observed at the Au/MoO3 interface. Au clusters or films can remain their neutral and nonchemically reacted state on MoO3 film. In contrast, the interfacial chemical reaction between Co and MoO3 is significantly strong. A band-bending in MoO3 and two interface states have been observed at the Co/MoO3 interface.
Factors that Influence the Rate and Intensity of Adoption of Improved Irrigation Technologies in Alberta, Canada
Authors: Wang Jinxia , Bjornlund Henning , Klein K. K. , Zhang Lijuan , Zhang Wencui
Published: August 2016

Despite the importance of adopting improved irrigation technologies to increase on-farm irrigation efficiency, our understanding of what determines farmers’ adoption decisions in southern Alberta remains relatively poor. The overall goals of this study are to examine the extent of adoption (proportion of all irrigators that have started the adoption process), how far along they are in the adoption process, and the intensity of adoption (percentage of irrigated land on which the technology is adopted) of improved irrigation technologies in southern Alberta, and to assess the major factors that influenced farmers’ adoption decisions. The data were collected in a farm-household survey conducted in the 12 largest irrigation districts (IDs) as well as among private irrigators in southern Alberta. Results show that adoption of improved irrigation technologies is widespread at various levels of intensity. By 2011, 81.3% of farmers had started the adoption process, are now using some kind of improved technology to apply water to their crops, and used it on 76.8% of all irrigated land. The most commonly used irrigation technology is a low pressure center pivot system. Receiving support services following the adoption decision played an important role in increasing the intensity of adoption. Obtaining information on irrigation technologies from individual farmers or farmers’ associations, and extension agencies significantly influenced farmers’ decisions to adopt. Farmers who increased their social capital through attending meetings related to agricultural production practices were more likely to adopt while farmers who participated in recreational or social organizations were less likely to adopt. Finally, the extent and intensity of adoption are higher for those with corporate farm structure, larger families, more generations of ownership and higher education.
The Influence of Gender-Ethnic Intersectionality on Gender Stereotypes about IT Skills and Knowledge
Authors: Trauth Eileen M. , Cain Curtis C. , Joshi K.D. , Kvasny Lynette , Booth Kayla M.
Published: August 2016

One line of investigation in attempting to better understand the gender imbalance in the information technology (IT) field is to examine gender stereotypes about the skills and knowledge in the IT profession. A survey of 4046 university students in the United States was conducted to examine gender stereotypes held by contemporary university students (White, Black and Latino men and women) about the skills and knowledge in the IT profession. The Individual Differences Theory of Gender and IT was used as the motivating theory for this study because it enabled the incorporation of gender-ethnic intersectionality in the research design. The results revealed that while gender stereotypes about the skills and knowledge involved in the IT profession do exist, they are not uniform across all members of a gender group. The men tended to rate all of the skills as more masculine than did the women respondents. Technical skills were more consistently stereotyped by both men and women in each of the gender-ethnic groups than were nontechnical skills. However, gender stereotypes about nontechnical skills were more contested and revealed both within-gender and within-ethnicity variation. The women students' rating of nontechnical skills as less masculine than the men suggests that these nontechnical skills are being incorporated into the women's sense of gender identity. These results show that gender-ethnic intersectionality provides one important explanation for within-gender variation in gender stereotypes that are held by contemporary university students. These findings suggest promising avenues for interventions to address not only the masculine gender stereotyping of skills in the IT profession, but also differential gender stereotyping of technical vs. nontechnical skills and variation in gender stereotyping by the intersectionality of gender-ethnic groups.
Compiling a gesture recognition application for a low-power spatial architecture
Authors: Phothilimthana Phitchaya Mangpo , Schuldt Michael , Bodik Rastislav
Published: August 2016

Energy efficiency is one of the main performance goals when designing processors for embedded systems. Typically, the simpler the processor, the less energy it consumes. Thus, an ultra-low power multicore processor will, likely have very small distributed memory with a simple interconnect. To compile for such an architecture, a partitioning strategy that can tune between space and communication minimization is crucial to fit a program in its limited resources and achieve good performance. A careful program layout design is also critical. Aside fulfilling the space constraint, a compiler needs to be able to optimize for program latency to satisfy a certain timing requirement as well. To satisfy all aforementioned constraints, we present a flexible code partitioning strategy and light-weight mechanisms to express parallelism and program layout. First, we compare two strategies for partitioning program structures and introduce a language construct to let programmers choose which strategies to use and when. The compiler then partitions program structures with a mix of both strategies. Second, we add supports for programmer-specified parallelism and program layout through imposing additional spatial constraints to the compiler. We evaluate our compiler by implementing an accelerometer-based gesture recognition application on GA144, a recent low-power minimalistic multicore architecture. When compared to MSP430, GA144 is overall 19x more energy-efficient and 23x faster when running this application. Without these inventions, this application would not be able to fit on GA144.
Event-driven network programming
Authors: McClurg Jedidiah , Hojjat Hossein , Foster Nate , Černý Pavol
Published: August 2016

Software-defined networking (SDN) programs must simultaneously describe static forwarding behavior and dynamic updates in response to events. Event-driven updates are critical to get right, but difficult to implement correctly due to the high degree of concurrency in networks. Existing SDN platforms offer weak guarantees that can break application invariants, leading to problems such as dropped packets, degraded performance, security violations, etc. This paper introduces EVENT-DRIVEN CONSISTENT UPDATES that are guaranteed to preserve well-defined behaviors when transitioning between configurations in response to events. We propose NETWORK EVENT STRUCTURES (NESs) to model constraints on updates, such as which events can be enabled simultaneously and causal dependencies between events. We define an extension of the NetKAT language with mutable state, give semantics to stateful programs using NESs, and discuss provably-correct strategies for implementing NESs in SDNs. Finally, we evaluate our approach empirically, demonstrating that it gives well-defined consistency guarantees while avoiding expensive synchronization and packet buffering.