bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasmodium berghei Sporozoites Acquire Virulence and Immunogenicity during Mosquito Hemocoel Transit
Authors: Sato Yuko , Montagna Georgina N. , Matuschewski Kai
Published: December 2013

Malaria is a vector-borne disease caused by the single-cell eukaryote
Plasmodium
. The infectious parasite forms are sporozoites, which originate from midgut-associated oocysts, where they eventually egress and reach the mosquito hemocoel. Sporozoites actively colonize the salivary glands in order to be transmitted to the mammalian host. Whether residence in the salivary glands provides distinct and vital cues for the development of infectivity remains unsolved. In this study, we systematically compared the infectivity of
Plasmodium berghei
sporozoites isolated from the mosquito hemocoel and salivary glands. Hemocoel sporozoites display a lower proportion of gliding motility but develop into liver stages when added to cultured hepatoma cells or after intravenous injection into mice. Mice infected by hemocoel sporozoites had blood infections similar to those induced by sporozoites liberated from salivary glands. These infected mice display indistinguishable systemic inflammatory cytokine responses and develop experimental cerebral malaria. When used as metabolically active, live attenuated vaccine, hemocoel sporozoites elicit substantial protection against sporozoite challenge infections. Collectively, these findings show that salivary gland colonization does not influence parasite virulence in the mammalian host when sporozoites are administered intravenously. This conclusion has important implications for
in vitro
sporozoite production and manufacturing of whole-sporozoite vaccines.
Three Antagonistic Cyclic di-GMP-Catabolizing Enzymes Promote Differential Dot/Icm Effector Delivery and Intracellular Survival at the Early Steps of Legionella pneumophila Infection
Authors: Allombert Julie , Lazzaroni Jean-Claude , Baïlo Nathalie , Gilbert Christophe , Charpentier Xavier , Doublet Patricia , Vianney Anne
Published: December 2013

Legionella pneumophila
is an intracellular pathogen which replicates within protozoan cells and can accidently infect alveolar macrophages, causing an acute pneumonia in humans. The second messenger cyclic di-GMP (c-di-GMP) has been shown to play key roles in the regulation of various bacterial processes, including virulence. While investigating the function of the 22 potential c-di-GMP-metabolizing enzymes of the
L. pneumophila
Lens strain, we found three that directly contribute to its ability to infect both protozoan and mammalian cells. These three enzymes display diguanylate cyclase (Lpl0780), phosphodiesterase (Lpl1118), and bifunctional diguanylate cyclase/phosphodiesterase (Lpl0922) activities, which are all required for the survival and intracellular replication of
L. pneumophila
. Mutants with deletions of the corresponding genes are efficiently taken up by phagocytic cells but are partially defective for the escape of the
Legionella
-containing vacuole (LCV) from the host degradative endocytic pathway and result in lower survival. In addition, Lpl1118 is required for efficient endoplasmic reticulum recruitment to the LCV. Trafficking and biogenesis of the LCV are dependent upon the orchestrated actions of several type 4 secretion system Dot/Icm effectors proteins, which exhibit differentially altered translocation in the three mutants. While translocation of some effectors remained unchanged, others appeared over- and undertranslocated. A general translocation offset of the large repertoire of Dot/Icm effectors may be responsible for the observed defects in the trafficking and biogenesis of the LCV. Our results suggest that
L. pneumophila
uses cyclic di-GMP signaling to fine-tune effector delivery and ensure effective evasion of the host degradative pathways and establishment of a replicative vacuole.
Interleukin-3-Deficient Mice Have Increased Resistance to Blood-Stage Malaria
Authors: Auclair Sarah R. , Roth Kenneth E. , Saunders Bryan L. , Ogborn Kathryn M. , Sheikh Abdalla A. , Naples Julianne , Young Anna Marie P. , Boisen Dorottya K. , Tavangar Amelia T. , Welch Jane E. , Lantz Chris S.
Published: December 2013

The contribution of interleukin-3 (IL-3), a hematopoietic growth factor and immunoregulatory cytokine, to resistance to blood-stage malaria was investigated by infecting IL-3-deficient (knockout [KO]) mice withPlasmodium bergheiNK65. Male IL-3 KO mice, but not female mice, were more resistant to infection than wild-type (WT) mice, as evidenced by lower peak parasitemia and prolonged survival. Both male and female IL-3 KO mice had increased splenomegaly and were more anemic than corresponding WT mice. Anemia was compensated for by an increase in bone marrow and splenic erythropoiesis in IL-3 KO mice, as evidenced by higher levels of erythroid progenitors. Plasma levels of gamma interferon (IFN-γ) and CXCL9 (monokine induced by IFN-γ [MIG]) were found to be significantly reduced in IL-3 KO mice during early stages of infection. In contrast, granulocyte colony-stimulating factor (G-CSF) levels were significantly higher, and the percentage of peripheral blood neutrophils lower, in infected IL-3 KO mice than in WT counterparts. Overall, our results indicate that IL-3 plays a critical role in suppressing protective immunity toP. bergheiNK65 infection and that it is involved in inhibiting the development of splenomegaly, anemia, and erythropoiesis. IL-3 also influences IFN-γ, CXCL9, and G-CSF production in response to infection. The abnormal responses seen in infected IL-3 KO mice may be due to the lack of IL-3 during development, to the lack of IL-3 in the infected mature mice, or to both.
Invasion-Inhibitory Antibodies Elicited by Immunization with Plasmodium vivax Apical Membrane Antigen-1 Expressed in Pichia pastoris Yeast
Authors: Vicentin Elaine C. , Françoso Kátia S. , Rocha Mariana V. , Iourtov Dmitri , dos Santos Fernanda L. , Kubrusly Flávia S. , Sakauchi Maria A. , Raw Isaias , Nosten Francois , Rénia Laurent , Rodrigues Mauricio M. , Russell Bruce , Soares Irene S.
Published: December 2013

In a recent vaccine trial performed with African children, immunization with a recombinant protein based on
Plasmodium falciparum
apical membrane antigen 1 (AMA-1) conferred a significant degree of strain-specific resistance against malaria. To contribute to the efforts of generating a vaccine against
Plasmodium vivax
malaria, we expressed the ectodomain of
P. vivax
AMA-1 (PvAMA-1) as a secreted soluble protein in the methylotrophic yeast
Pichia pastoris
. Recognized by a high percentage of sera from individuals infected by
P. vivax
, this recombinant protein was found to have maintained its antigenicity. The immunogenicity of this protein was evaluated in mice using immunization protocols that included homologous and heterologous prime-boost strategies with plasmid DNA and recombinant protein. We used the following formulations containing different adjuvants: aluminum salts (Alum),
Bordetella pertussis
monophosphoryl lipid A (MPLA), flagellin FliC from
Salmonella enterica
serovar Typhimurium, saponin Quil A, or incomplete Freund's adjuvant (IFA). The formulations containing the adjuvants Quil A or IFA elicited the highest IgG antibody titers. Significant antibody titers were also obtained using a formulation developed for human use containing MPLA or Alum plus MPLA. Recombinant PvAMA-1 produced under “conditions of good laboratory practice” provided a good yield, high purity, low endotoxin levels, and no microbial contaminants and reproduced the experimental immunizations. Most relevant for vaccine development was the fact that immunization with PvAMA-1 elicited invasion-inhibitory antibodies against different Asian isolates of
P. vivax
. Our results show that AMA-1 expressed in
P. pastoris
is a promising antigen for use in future preclinical and clinical studies.
Eosinophil Deficiency Compromises Lung Defense against Aspergillus fumigatus
Authors: Lilly Lauren M. , Scopel Michaella , Nelson Michael P. , Burg Ashley R. , Dunaway Chad W. , Steele Chad
Published: December 2013

Exposure to the moldAspergillus fumigatusmay result in allergic bronchopulmonary aspergillosis, chronic necrotizing pulmonary aspergillosis, or invasive aspergillosis (IA), depending on the host's immune status. Neutrophil deficiency is the predominant risk factor for the development of IA, the most life-threatening condition associated withA. fumigatusexposure. Here we demonstrate that in addition to neutrophils, eosinophils are an important contributor to the clearance ofA. fumigatusfrom the lung. AcuteA. fumigatuschallenge in normal mice induced the recruitment of CD11b+Siglec F+Ly-6GloLy-6CnegCCR3+eosinophils to the lungs, which was accompanied by an increase in lungEpx(eosinophil peroxidase) mRNA levels. Mice deficient in the transcription factor dblGATA1, which exhibit a selective deficiency in eosinophils, demonstrated impairedA. fumigatusclearance and evidence of germinating organisms in the lung. Higher burden correlated with lower mRNA expression ofEpx(eosinophil peroxidase) andPrg2(major basic protein) as well as lower interleukin 1β (IL-1β), IL-6, IL-17A, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and CXCL1 levels. However, examination of lung inflammatory cell populations failed to demonstrate defects in monocyte/macrophage, dendritic cell, or neutrophil recruitment in dblGATA1-deficient mice, suggesting that the absence of eosinophils in dlbGATA1-deficient mice was the sole cause of impaired lung clearance. We show that eosinophils generated from bone marrow have potent killing activity againstA. fumigtausin vitro, which does not require cell contact and can be recapitulated by eosinophil whole-cell lysates. Collectively, our data support a role for eosinophils in the lung response afterA. fumigatusexposure.
The Phosphoenolpyruvate Phosphotransferase System in Group A Streptococcus Acts To Reduce Streptolysin S Activity and Lesion Severity during Soft Tissue Infection
Authors: Gera Kanika , Le Tuquynh , Jamin Rebecca , Eichenbaum Zehava , McIver Kevin S.
Published: December 2013

Obtaining essential nutrients, such as carbohydrates, is an important process for bacterial pathogens to successfully colonize host tissues. The phosphoenolpyruvate phosphotransferase system (PTS) is the primary mechanism by which bacteria transport sugars and sense the carbon state of the cell. The group A streptococcus (GAS) is a fastidious microorganism that has adapted to a variety of niches in the human body to elicit a wide array of diseases. A ΔptsImutant (enzyme I [EI] deficient) generated in three different strains of M1T1 GAS was unable to grow on multiple carbon sources (PTS and non-PTS). Complementation withptsIexpressed under its native promoter in single copy was able to rescue the growth defect of the mutant. In a mouse model of GAS soft tissue infection, all ΔptsImutants exhibited a significantly larger and more severe ulcerative lesion than mice infected with the wild type. Increased transcript levels ofsagAand streptolysin S (SLS) activity during exponential-phase growth was observed. We hypothesized that early onset of SLS activity would correlate with the severity of the lesions induced by the ΔptsImutant. In fact, infection of mice with a ΔptsI sagBdouble mutant resulted in a lesion comparable to that of either the wild type or asagBmutant alone. Therefore, a functional PTS is not required for subcutaneous skin infection in mice; however, it does play a role in coordinating virulence factor expression and disease progression.
The Adaptor CARD9 Is Required for Adaptive but Not Innate Immunity to Oral Mucosal Candida albicans Infections
Authors: Bishu Shrinivas , Hernández-Santos Nydiaris , Simpson-Abelson Michelle R. , Huppler Anna R. , Conti Heather R. , Ghilardi Nico , Mamo Anna J. , Gaffen Sarah L.
Published: December 2013

Oropharyngeal candidiasis (OPC [thrush]) is an opportunistic infection caused by the commensal fungus
Candida albicans
. OPC is common in individuals with HIV/AIDS, infants, patients on chemotherapy, and individuals with congenital immune defects. Immunity to OPC is strongly dependent on the interleukin-23 (IL-23)/IL-17R axis, as mice and humans with defects in IL-17R signaling (
IL17F
,
ACT1
,
IL-17RA
) or in genes that direct Th17 differentiation (
STAT3
,
STAT1
,
CARD9
) are prone to mucocutaneous candidiasis. Conventional Th17 cells are induced in response to
C. albicans
infection via signals from C-type lectin receptors, which signal through the adaptor CARD9, leading to production of Th17-inducing cytokines such as IL-6, IL-1β, and IL-23. Recent data indicate that IL-17 can also be made by numerous innate cell subsets. These innate “type 17” cells resemble conventional Th17 cells, but they can be activated without need for prior antigen exposure. Because
C. albicans
is not a commensal organism in rodents and mice are thus naive to this fungus, we had the opportunity to assess the role of CARD9 in innate versus adaptive responses using an OPC infection model. As expected, CARD9
−/−
mice failed to mount an adaptive Th17 response following oral
Candida
infection. Surprisingly, however, CARD9
−/−
mice had preserved innate IL-17-dependent responses to
Candida
and were almost fully resistant to OPC. Thus, CARD9 is important primarily for adaptive immunity to
C. albicans
, whereas alternate recognition systems appear to be needed for effective innate responses.
Role of Epidermal Growth Factor Receptor Signaling in the Interaction of Neisseria meningitidis with Endothelial Cells
Authors: Slanina Heiko , Mündlein Sabrina , Hebling Sabrina , Schubert-Unkmeir Alexandra
Published: December 2013

Neisseria meningitidis, the causative agent of meningitis and septicemia, attaches to and invades various cell types. Both steps induce and/or require tyrosine phosphorylation of host cell proteins. Here, we used a phospho array platform to identify active receptor tyrosine kinases (RTKs) and key signaling nodes inN. meningitidis-infected brain endothelial cells to decipher RTK-dependent signaling pathways necessary for bacterial uptake. We detected several activated RTKs, including the ErbB family receptors epidermal growth factor receptor (EGFR), ErbB2, and ErbB4. We found that pharmacological inhibition and genetic ablation of ErbB receptor tyrosine phosphorylation and expression resulted in decreased bacterial uptake and heterologous expression of EGFR, ErbB2, or ErbB4 in Chinese ovary hamster (CHO-K1) cells, which do not express of EGFR and ErbB4; the decrease caused a significant increase in meningococcal invasion. Activation of EGFR and ErbB4 was mediated by transactivation via the common ligand HB-EGF (heparin-binding EGF-like ligand), which was significantly elevated in infected cell culture supernatants. We furthermore determined thatN. meningitidisinduced phosphorylation of EGFR at Tyr845 independent of ligand binding, which required c-Src activation and was involved in mediating uptake ofN. meningitidisinto eukaryotic cells. Increased uptake was repressed by expression of EGFR Y845F, which harbored a point mutation in the kinase domain. In addition, activation of ErbB4 at its autophosphorylation site, Tyr1284, and phosphorylation of ErbB2 Thr686 were observed. Altogether, our results provide evidence that EGFR, ErbB2, and ErbB4 are activated in response toN. meningitidisinfection and shed new light on the role of ErbB signaling in meningococcal infection biology.
Neither Dectin-2 nor the Mannose Receptor Is Required for Resistance to Coccidioides immitis in Mice
Authors: Viriyakosol Suganya , Jimenez Maria del Pilar , Saijo Sinobu , Fierer Joshua
Published: December 2013

We investigated the roles of the mannose receptor (MR) and Dectin-2 in resistance to pulmonary coccidioidomycosis in C57BL/6 (B6) mice and in the interaction of myeloid cells with spherules, using B6 mice with targeted mutations in
Mrc1
and
Clec4n
. Spherules are the tissue form of
Coccidioides
, and we determined that the MR on bone marrow-derived dendritic cells (BMDC) was important for recognition of spherules (formalin-killed spherules [FKS]) and for secretion of interleukin 10 (IL-10) and proinflammatory cytokines in response to FKS by both elicited macrophages and BMDC. Infected MR knockout (KO) mice produced more IL-10 in their lungs than did B6 mice, and MR KO mice also made more protective Th-17 cytokines. In contrast to the MR, Dectin-2 was not required for recognition of FKS by BMDC or for the production of cytokines by BMDC in response to FKS. However, Dectin-2 KO was required for stimulation of elicited peritoneal macrophages. Despite that, lung cytokine levels were not significantly different in Dectin-2 KO mice and B6 mice 14 days after infection, except for IL-1β, which was higher in Dectin-2 KO lungs. Although both Dectin-2
−/−
and MR
−/−
myeloid cells had reduced proinflammatory cytokine responses to FKS
in vitro
, neither MR nor Dectin-2 deficiency reduced the resistance of B6 mice to pulmonary coccidioidomycosis.
Filifactor alocis Infection and Inflammatory Responses in the Mouse Subcutaneous Chamber Model
Authors: Wang Qian , Jotwani Ravi , Le Junyi , Krauss Jennifer L. , Potempa Jan , Coventry Susan C. , Uriarte Silvia M. , Lamont Richard J.
Published: December 2013

Recent microbiome studies have implicated a role for
Filifactor alocis
in periodontal disease. In this study, we investigated the colonization and survival properties of
F. alocis
in a mouse subcutaneous chamber model of infection and characterized host innate immune responses. An infection of 10
9
F. alocis
successfully colonized all chambers; however, the infection was cleared after 72 h.
F. alocis
elicited a local inflammatory response with neutrophils recruited into the chambers at 2 h postinfection along with an increase in levels of the proinflammatory cytokines interleukin 1β (IL-1β), IL-6, and tumor necrosis factor (TNF).
F. alocis
also induced apoptosis in chamber epithelial cells and neutrophils. Consistent with resolution of infection, neutrophil numbers and cytokine levels returned to baseline by 72 h. Fluorescent
in situ
hybridization (FISH) and quantitative PCR demonstrated that
F. alocis
exited the chambers and spread to the spleen, liver, lung, and kidney. Massive neutrophil infiltration was observed in the spleen and lungs, and the recruited neutrophils were in close proximity to the infecting bacteria. Significant epithelial injury was observed in the kidneys. Infection of all tissues was resolved after 7 days. This first
in vivo
study of the pathogenicity of
F. alocis
shows that in the chamber model the organism can establish a proinflammatory, proapoptotic local infection which is rapidly resolved by the host concordant with neutrophil influx. Moreover,
F. alocis
can spread to, and transiently infect, remote tissues where neutrophils can also be recruited.
Identification of a Crucial Residue Required for Staphylococcus aureus LukAB Cytotoxicity and Receptor Recognition
Authors: DuMont Ashley L. , Yoong Pauline , Liu Xiang , Day Christopher J. , Chumbler Nicole M. , James David B. A. , Alonzo Francis , Bode Nadine J. , Lacy D. Borden , Jennings Michael P. , Torres Victor J.
Published: December 2013

The bicomponent leukotoxins produced by
Staphylococcus aureus
kill host immune cells through osmotic lysis by forming β-barrel pores in the host plasma membrane. The current model for bicomponent pore formation proposes that octameric pores, comprised of two separate secreted polypeptides (S and F subunits), are assembled from water-soluble monomers in the extracellular milieu and multimerize on target cell membranes. However, it has yet to be determined if all staphylococcal bicomponent leukotoxin family members exhibit these properties. In this study, we report that leukocidin A/B (LukAB), the most divergent member of the leukotoxin family, exists as a heterodimer in solution rather than two separate monomeric subunits. Notably, this property was found to be associated with enhanced toxin activity. LukAB also differs from the other bicomponent leukotoxins in that the S subunit (LukA) contains 33- and 10-amino-acid extensions at the N and C termini, respectively. Truncation mutagenesis revealed that deletion of the N terminus resulted in a modest increase in LukAB cytotoxicity, whereas the deletion of the C terminus rendered the toxin inactive. Within the C terminus of LukA, we identified a glutamic acid at position 323 that is critical for LukAB cytotoxicity. Furthermore, we discovered that this residue is conserved and required for the interaction between LukAB and its cellular target CD11b. Altogether, these findings provide an in-depth analysis of how LukAB targets neutrophils and identify novel targets suitable for the rational design of anti-LukAB inhibitors.
Requirement of the Pseudomonas aeruginosa CbrA Sensor Kinase for Full Virulence in a Murine Acute Lung Infection Model
Authors: Yeung Amy T. Y. , Janot Laure , Pena Olga M. , Neidig Anke , Kukavica-Ibrulj Irena , Hilchie Ashley , Levesque Roger C. , Overhage Joerg , Hancock Robert E. W.
Published: December 2013

Pseudomonas aeruginosa
is an opportunistic pathogen that is a major cause of respiratory tract and other nosocomial infections. The sensor kinase CbrA is a central regulator of carbon and nitrogen metabolism and
in vitro
also regulates virulence-related processes in
P. aeruginosa
. Here, we investigated the role of CbrA in two murine models of infection. In both peritoneal infections in leukopenic mice and lung infection models, the
cbrA
mutant was less virulent since substantially larger numbers of
cbrA
mutant bacteria were required to cause the same level of infection as wild-type or complemented bacteria. In contrast, in the chronic rat lung model the
cbrA
mutant grew and persisted as well as the wild type, indicating that the decrease of
in vivo
virulence of the
cbrA
mutant did not result from growth deficiencies on particular carbon substrates observed
in vitro
. In addition, a mutant in the cognate response regulator CbrB showed no defect in virulence in the peritoneal infection model, ruling out the involvement of certain alterations of virulence properties in the
cbrA
mutant including defective swarming motility, increased biofilm formation, and cytotoxicity, since these alterations are controlled through CbrB. Further investigations indicated that the mutant was more susceptible to uptake by phagocytes
in vitro
, resulting in greater overall bacterial killing. Consistent with the virulence defect, it took a smaller number of
Dictyostelium discoideum
amoebae to kill the
cbrA
mutant than to kill the wild type. Transcriptional analysis of the
cbrA
mutant during
D. discoideum
infection led to the conclusion that CbrA played an important role in the iron metabolism, protection of
P. aeruginosa
against oxidative stress, and the regulation of certain virulence factors.
Children with Invasive Staphylococcus aureus Disease Exhibit a Potently Neutralizing Antibody Response to the Cytotoxin LukAB
Authors: Thomsen Isaac P. , DuMont Ashley L. , James David B. A , Yoong Pauline , Saville Benjamin R. , Soper Nicole , Torres Victor J. , Creech C. Buddy
Published: December 2013

Despite the importance of
Staphylococcus aureus
as a common invasive bacterial pathogen, the humoral response to infection remains inadequately defined, particularly in children. The purpose of this study was to assess the humoral response to extracellular staphylococcal virulence factors, including the bicomponent leukotoxins, which are critical for the cytotoxicity of
S. aureus
toward human neutrophils. Children with culture-proven
S. aureus
infection were prospectively enrolled and stratified by disease type. Fifty-three children were enrolled in the study, of which 90% had invasive disease. Serum samples were obtained during the acute (within 48 h) and convalescent (4 to 6 weeks postinfection) phases, at which point both IgG titers against
S. aureus
exotoxins were determined, and the functionality of the generated antibodies was evaluated. Molecular characterization of clinical isolates was also performed. We observed a marked rise in antibody titer from acute-phase to convalescent-phase sera for LukAB, the most recently described
S. aureus
bicomponent leukotoxin. LukAB production by the isolates was strongly correlated with cytotoxicity
in vitro
, and sera containing anti-LukAB antibodies potently neutralized cytotoxicity. Antibodies to
S. aureus
antigens were detectable in healthy pediatric controls but at much lower titers than in sera from infected subjects. The discovery of a high-titer, neutralizing antibody response to LukAB during invasive infections suggests that this toxin is produced
in vivo
and that it elicits a functional humoral response.
Hindbrain lactostasis regulates hypothalamic AMPK activity and metabolic neurotransmitter mRNA and protein responses to hypoglycemia
Authors: Gujar Amit D. , Ibrahim Baher A. , Tamrakar Pratistha , Cherian Ajeesh Koshy , Briski Karen P.
Published: December 2013

Nerve cell metabolic activity is monitored in multiple brain regions, including the hypothalamus and hindbrain dorsal vagal complex (DVC), but it is unclear if individual metabolosensory loci operate autonomously or interact to coordinate central nervous system (CNS) reactivity to energy imbalance. This research addressed the hypothesis that hypoglycemia-associated DVC lactoprivation stimulates hypothalamic AMPK activity and metabolic neurotransmitter expression. As DVC catecholaminergic neurons express biomarkers for metabolic monitoring, we investigated whether these cells are a source of lactate deficit signaling to the hypothalamus. Caudal fourth ventricle (CV4) infusion of the glucose metabolite l-lactate during insulin-induced hypoglycemia reversed changes in DVC A2 noradrenergic, arcuate neuropeptide Y (NPY) and pro-opiomelanocortin (POMC), and lateral hypothalamic orexin-A (ORX) neuronal AMPK activity, coincident with exacerbation of hypoglycemia. Hindbrain lactate repletion also blunted hypoglycemic upregulation of arcuate NPY mRNA and protein. This treatment did not alter hypoglycemic paraventricular oxytocin (OT) and lateral hypothalamic ORX mRNA profiles, but exacerbated or reversed adjustments in OT and ORX neuropeptide synthesis, respectively. CV4 delivery of the monocarboxylate transporter inhibitor, 4-CIN, increased A2 phosphoAMPK (pAMPK), elevated circulating glucose, and stimulated feeding, responses that were attenuated by 6-hydroxydopamine pretreatment. 4-CIN-infused rats exhibited increased (NPY, ORX neurons) or decreased (POMC neurons) pAMPK concurrent with hyperglycemia. These data show that hindbrain lactoprivic signaling regulates hypothalamic AMPK and key effector neurotransmitter responses to hypoglycemia. Evidence that A2 AMPK activity is lactate-dependent, and that DVC catecholamine cells are critical for lactoprivic control of glucose, feeding, and hypothalamic AMPK, implies A2 derivation of this metabolic regulatory stimulus.
Prohormone supplement 3β-hydroxy-5α-androst-1-en-17-one enhances resistance training gains but impairs user health
Authors: Granados Jorge , Gillum Trevor L. , Christmas Kevin M. , Kuennen Matthew R.
Published: December 2013

Prohormone supplements (PS) are recognized not to impart anabolic or ergogenic effects in men, but the research supporting these conclusions is dated. The Anabolic Steroid Control Act was amended in 2004 to classify androstenedione and 17 additional anabolic compounds as controlled substances. The viability of PS that entered the market after that time have not been evaluated. Seventeen resistance-trained men (23 ± 1 yr; 13.1 ± 1.5% body fat) were randomly assigned to receive either 330 mg/day of 3β-hydroxy-5α-androst-1-en-17-one (Prohormone; n = 9) or sugar (Placebo; n = 8) per os and complete a 4-wk (16 session) structured resistance-training program. Body composition, muscular strength, circulating lipids, and markers of liver and kidney dysfunction were assessed at study onset and termination. Prohormone increased lean body mass by 6.3 ± 1.2%, decreased fat body mass by 24.6 ± 7.1%, and increased their back squat one repetition maximum and competition total by 14.3 ± 1.5 and 12.8 ± 1.1%, respectively. These improvements exceeded ( P < 0.05) Placebo, which increased lean body mass by 0.5 ± 0.8%, reduced fat body mass by 9.5 ± 3.6%, and increased back squat one repetition maximum and competition total by 5.7 ± 1.7 and 5.9 ± 1.7%, respectively. Prohormone also experienced multiple adverse effects. These included a 38.7 ± 4.0% reduction in HDL ( P < 0.01), a 32.8 ± 15.05% elevation in LDL ( P < 0.01), and elevations of 120.0 ± 22.6 and 77.4 ± 12.0% in LDL-to-HDL and cholesterol-to-HDL ratios, respectively (both P < 0.01). Prohormone also exhibited elevations in serum creatinine (19.6 ± 4.3%; P < 0.01) and aspartate transaminase (113.8 ± 61.1%; P = 0.05), as well as reductions in serum albumin (5.1 ± 1.9%; P = 0.04), alkaline phosphatase (16.4 ± 4.7%; P = 0.04), and glomerular filtration rate (18.0 ± 3.3%; P = 0.04). None of these values changed (all P > 0.05) in Placebo. The oral PS 3β-hydroxy-5α-androst-1-en-17-one improves body composition and muscular strength. However, these changes come at a significant cost. Cardiovascular health and liver function are particularly compromised. Given these findings, we feel the harm associated with this particular PS outweighs any potential benefit.
Age- and location-dependent differences in store depletion-induced h-channel plasticity in hippocampal pyramidal neurons
Authors: Clemens Ann M. , Johnston Daniel
Published: December 2013

Disruptions of endoplasmic reticulum (ER) Ca2+ homeostasis are heavily linked to neuronal pathology. Depletion of ER Ca2+ stores can result in cellular dysfunction and potentially cell death, although adaptive processes exist to aid in survival. We examined the age and region dependence of one postulated, adaptive response to ER store-depletion (SD), hyperpolarization-activated cation-nonspecific ( h)-channel plasticity in neurons of the dorsal and ventral hippocampus (DHC and VHC, respectively) from adolescent and adult rats. With the use of whole-cell patch-clamp recordings from the soma and dendrites of CA1 pyramidal neurons, we observed a change in h-sensitive measurements in response to SD, induced by treatment with cyclopiazonic acid, a sarcoplasmic reticulum/ER Ca2+-ATPase blocker. We found that whereas DHC and VHC neurons in adolescent animals respond to SD with a perisomatic expression of SD h plasticity, adult animals express SD h plasticity with a dendritic and somatodendritic locus of plasticity in DHC and VHC neurons, respectively. Furthermore, SD h plasticity in adults was dependent on membrane potential and on the activation of L-type voltage-gated Ca2+ channels. These results suggest that cellular responses to the impairment of ER function, or ER stress, are dependent on brain region and age and that the differential expression of SD h plasticity could provide a neural basis for region- and age-dependent disease vulnerabilities.
A Technical, Economic, and Environmental Performance of Grid‐Connected Hybrid (Photovoltaic‐Wind) Power System in Algeria
Authors: Saheb-Koussa Djohra , Koussa Mustapha , Said Nourredine
Published: December 2013

This paper studies the technical, economic, and environmental analysis of wind and photovoltaic power systems connected to a conventional grid. The main interest in such systems is on‐site consumption of the produced energy, system hybridization, pooling of resources, and contribution to the environment protection. To ensure a better management of system energy, models have been used for determining the power that the constituting subsystems can deliver under specific weather conditions. Simulation is performed using MATLAB‐SIMULINK. While, the economic and environmental study is performed using HOMER software. From an economic point of view, this allows to compare the financial constraints on each part of the system for the case of Adrar site which is located to the northern part of the south of Algeria. It also permits to optimally size and select the system presenting the best features on the basis of two parameters, that is, cost and effectiveness. From an environmental point of view, this study allows highlighting the role of renewable energy in reducing gas emissions related to greenhouse effects. In addition, through a set of sensitivity analysis, it is found that the wind speed has more effects on the environmental and economic performances of grid‐connected hybrid (photovoltaic‐wind) power systems.
Projectile Impact Point Prediction Based on Self-Propelled Artillery Dynamics and Doppler Radar Measurements
Authors: Khalil Mostafa , Rui Xiaoting , Zha Qicheng , Yu Hailong , Hendy Hossam
Published: December 2013

Any trajectory calculation method has three primary sources of errors, which are model error, parameter error, and initial state error. In this paper, based on initial projectile flight trajectory data measured using Doppler radar system; a new iterative method is developed to estimate the projectile attitude and the corresponding impact point to improve the second shot hit probability. In order to estimate the projectile initial state, the launch dynamics model of practical 155 mm self-propelled artillery is defined, and hence, the vibration characteristics of the self-propelled artillery is obtained using the transfer matrix method of linear multibody system MSTMM. A discrete time transfer matrix DTTM-4DOF is developed using the modified point mass equations of motion to compute the projectile trajectory and set a direct algebraic relation between any two successive radar data. During iterations, adjustments to the repose angle are made until an agreement with acceptable tolerance occurs between the Doppler radar measurements and the estimated values. Simulated Doppler radar measurements are generated using the nonlinear six-degree-of-freedom trajectory model using the resulted initial disturbance. Results demonstrate that the data estimated using the proposed algorithm agrees well with the simulated Doppler radar data obtained numerically using the nonlinear six-degree-of-freedom model.
Stability and Hopf Bifurcation in an HIV-1 Infection Model with Latently Infected Cells and Delayed Immune Response
Authors: Wang Haibin , Xu Rui
Published: December 2013

An HIV-1 infection model with latently infected cells and delayed immune response is investigated. By analyzing the corresponding characteristic equations, the local stability of each of feasible equilibria is established and the existence of Hopf bifurcations at the CTL-activated infection equilibrium is also studied. By means of suitable Lyapunov functionals and LaSalle’s invariance principle, it is proved that the infection-free equilibrium is globally asymptotically stable if the basic reproduction ratio for viral infectionR0≤1; if the basic reproduction ratio for viral infectionR0>1and the basic reproduction ratio for CTL immune responseR1≤1, the CTL-inactivated infection equilibrium is globally asymptotically stable. If the basic reproduction ratio for CTL immune responseR1>1, the global stability of the CTL-activated infection equilibrium is also derived when the time delayτ=0. Numerical simulations are carried out to illustrate the main results.
Genistein Derivatives Regioisomerically Substituted at 7‐O‐ and 4′‐O‐ Have Different Effect on the Cell Cycle
Authors: Byczek A. , Zawisza-Puchalka J. , Gruca A. , Papaj K. , Grynkiewicz G. , Rusin M. , Szeja W. , Rusin A.
Published: December 2013

Our previous studies on antiproliferative properties of genistein derivatives substituted at C7 hydroxyl group of the ring A revealed some compounds with antimitotic properties. The aim of this work was to synthesize their analogues substituted at the 4′‐position of the ring B in genistein and to define their antiproliferative mechanism of action in selected cancer cell lines in vitro. C4′‐substituted glycoconjugates were obtained in a three‐step procedure: (1) alkylation with an ω‐bromoester; (2) deacylation; (3) Ferrier‐type rearrangement glycosylation with acylated glycals. Biological effects including antiproliferative effects of the compounds, cell cycle, DNA lesions (ATM activation, H2A.X phosphorylation, and micronuclei formation), and autophagy were studied in human cancer cell lines. Some of the tested derivatives potently inhibited cell proliferation. The presence of a substituent at the 4′‐position of the ring B in genistein correlated to a p53‐independent G1 cell‐cycle arrest. The derivatives substituted at C4′ did not induce DNA lesions and appeared to be nongenotoxic. The tested compounds induced autophagy and caused remarkable decrease of cell volume.
Existence and Global Exponential Stability of Equilibrium for Impulsive Cellular Neural Network Models with Piecewise Alternately Advanced and Retarded Argument
Authors: Chiu Kuo-Shou
Published: December 2013

We introduce impulsive cellular neural network models with piecewise alternately advanced and retarded argument (in short IDEPCA). The model with the advanced argument is system with strong anticipation. Some sufficient conditions are established for the existence and global exponential stability of a unique equilibrium. The approaches are based on employing Banach’s fixed point theorem and a new IDEPCA integral inequality of Gronwall type. The criteria given are easily verifiable, possess many adjustable parameters, and depend on impulses and piecewise constant argument deviations, which provides exibility for the design and analysis of cellular neural network models. Several numerical examples and simulations are also given to show the feasibility and effectiveness of our results.
A Novel Photocatalyst with Ferromagnetic Core Used for the Treatment of Olive Oil Mill Effluents from Two‐Phase Production Process
Authors: Ochando-Pulido Javier Miguel , Hodaifa Gassan , Víctor-Ortega María Dolores , Martínez-Ferez Antonio
Published: December 2013

Photocatalytic degradation of olive oil mill wastewater from two‐phase continuous centrifugation process was studied. A novel photocatalyst with ferromagnetic properties was characterized and investigated. The degradation capacity of the photocatalytic process of olive oil washing wastewater (OMW) and mixture of olives and olive oil (1 v/v) washing wastewaters (MOMW) was demonstrated. At lab‐scale, the %COD removal and residence time (τ) for MOMW and OMW were 58.4% (τ = 2 h) and 21.4% (τ = 3 h), respectively. On the other hand, at pilot scale, 23.4% CODremoval, 19.2% total phenolsremoval, and 28.1% total suspended solidsremoval were registered at the end of the UV/TiO2 process for OMW, whereas 58.3% CODremoval, 27.5% total phenolsremoval, and 25.0% total suspended solidsremoval for MOMW. Also, before the UV/TiO2 reaction, a pH‐T flocculation operation as pretreatment was realized. The overall efficiency of the treatment process for MOMW was up to 91% of CODremoval, in contrast with 33.2% of CODremoval for OMW.
Clinically Diagnosed Insomnia and Risk of All-Cause and Diagnosis-Specific Disability Pension: A Nationwide Cohort Study
Authors: Jansson Catarina , Alexanderson Kristina , Kecklund Göran , Åkerstedt Torbjörn
Published: December 2013

Background. Insomnia and disability pension are major health problems, but few population-based studies have examined the association between insomnia and risk of disability pension.Methods. We conducted a prospective nationwide cohort study based on Swedish population-based registers including all 5,028,922 individuals living in Sweden on December 31, 2004/2005, aged 17–64 years, and not on disability or old age pension. Those having at least one admission/specialist visit with a diagnosis of disorders of initiating and maintaining sleep (insomnias) (ICD-10: G47.0) during 2000/2001–2005 were compared to those with no such inpatient/outpatient care. All-cause and diagnosis-specific incident disability pension were followed from 2006 to 2010. Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were estimated by Cox regression.Results. In models adjusted for prior sickness absence, sociodemographic factors, and inpatient/specialized outpatient care, associations between insomnia and increased risks of all-cause disability pension (IRR 1.35, 95% CI 1.09–1.67) and disability pension due to mental diagnoses (IRR 1.86, 95% CI 1.38–2.50) were observed. After further adjustment for insomnia medications these associations disappeared. No associations between insomnia and risk of disability pension due to cancer, circulatory, or musculoskeletal diagnoses were observed.Conclusion. Insomnia seems to be positively associated with all-cause disability pension and disability pension due to mental diagnoses.
Cusps of Bishop Spherical Indicatrixes and Their Visualizations
Authors: Liu Haiming , Pei Donghe
Published: December 2013

The main result of this paper is using Bishop Frame and “Type-2 Bishop Frame” to study the cusps of Bishop spherical images and type-2 Bishop spherical images which are deeply related to a space curve and to make them visualized by computer. We find that the singular points of the Bishop spherical images and type-2 Bishop spherical images correspond to the point where Bishop curvatures and type-2 Bishop curvatures vanished and their derivatives are not equal to zero. As applications and illustration of the main results, two examples are given.
On the Anonymity of Identity-Based Encryption
Authors: Luo Song , Hu Ning
Published: December 2013

Anonymity of identity-based encryption (IBE) means that given a ciphertext, one cannot distinguish the target identity from a random identity. In this paper, we thoroughly discuss the anonymity of IBE systems. We found that the current definition of anonymity is obscure to describe some IBE systems, such as Gentry IBE system. Furthermore, current definition cannot express the degree of anonymity. So we divide the degree of anonymity into weak anonymity and strong anonymity based on indistinguishability between different games. For weakly anonymous IBE systems, the target identity in a ciphertext cannot be distinguished from a random identity. For strongly anonymous IBE systems, the whole ciphertext cannot be distinguished from a random tuple. We also discuss the type of anonymity and divide it into two types. Type 1 means that a random tuple can be seen as a valid ciphertext, while type 2 cannot. Based on our new definitions, we show that three famous IBE systems, Gentry IBE system, Boyen-Waters IBE system, and Lewko IBE system, have strong but different types of anonymity.
A Little Quantum Help for Cosmic Censorship and a Step Beyond All That
Authors: Pappas Nikolaos
Published: December 2013

The hypothesis of cosmic censorship (CCH) plays a crucial role in classical general relativity, namely, to ensure that naked singularities would never emerge, since it predicts that whenever a singularity is formed an event horizon would always develop around it as well, to prevent the former from interacting directly with the rest of the Universe. Should this not be so, naked singularities could eventually form, in which case phenomena beyond our understanding and ability to predict could occur, since at the vicinity of the singularity both predictability and determinism break down even at the classical (e.g., nonquantum) level. More than 40 years after it was proposed, the validity of the hypothesis remains an open question. We reconsider CCH in both its weak and strong versions, concerning point-like singularities, with respect to the provisions of Heisenberg’s uncertainty principle. We argue that the shielding of the singularities from observers at infinity by an event horizon is also quantum mechanically favored, but ultimately it seems more appropriate to accept that singularities never actually form in the usual sense; thus no naked singularity danger exists in the first place.
Innate and Adaptive Responses to Heat Shock Proteins in Behcet’s Disease
Authors: Direskeneli H.
Published: December 2013

Behcet’s disease (BD) is a systemic, chronic inflammatory disorder with both innate and adaptive immune responses. Heat shock proteins (HSP) are highly conserved molecules in different species with scavenger activity and involved in correct folding of newly synthesized proteins. T and B cell responses against HSPs are observed in BD patients in bothαβandγδT-cell populations. 60-kD HSP (HSP60) is also shown to be recognized by pattern recognition receptors such as toll-like receptors (TLR) and is suggested to be an endogenous “danger” signal to the immune system with rapid inflammatory cytokine releases and enhancement of adaptive Th1-type responses. Elucidating the exact role of HSPs in BD pathogenesis might pave the way to less toxic therapeutic approaches to BD, such as antibacterial therapies and immunomodulation.
Properties and Iterative Methods for theQ-Lasso
Authors: Alghamdi Maryam A. , Alghamdi Mohammad Ali , Shahzad Naseer , Xu Hong-Kun
Published: December 2013

We introduce theQ-lasso which generalizes the well-known lasso of Tibshirani (1996) withQa closed convex subset of a Euclideanm-space for some integerm≥1. This setQcan be interpreted as the set of errors within given tolerance level when linear measurements are taken to recover a signal/image via the lasso. Solutions of theQ-lasso depend on a tuning parameterγ. In this paper, we obtain basic properties of the solutions as a function ofγ. Because of ill posedness, we also applyl1-l2regularization to theQ-lasso. In addition, we discuss iterative methods for solving theQ-lasso which include the proximal-gradient algorithm and the projection-gradient algorithm.
Degradation of Diuron byPhanerochaete chrysosporium: Role of Ligninolytic Enzymes and Cytochrome P450
Authors: Coelho-Moreira Jaqueline da Silva , Bracht Adelar , Souza Aline Cristine da Silva de , Oliveira Roselene Ferreira , Sá-Nakanishi Anacharis Babeto de , Souza Cristina Giatti Marques de , Peralta Rosane Marina
Published: December 2013

The white-rot fungusPhanerochaete chrysosporiumwas investigated for its capacity to degrade the herbicide diuron in liquid stationary cultures. The presence of diuron increased the production of lignin peroxidase in relation to control cultures but only barely affected the production of manganese peroxidase. The herbicide at the concentration of 7 μg/mL did not cause any reduction in the biomass production and it was almost completely removed after 10 days. Concomitantly with the removal of diuron, two metabolites, DCPMU [1-(3,4-dichlorophenyl)-3-methylurea] and DCPU [(3,4-dichlorophenyl)urea], were detected in the culture medium at the concentrations of 0.74 μg/mL and 0.06 μg/mL, respectively. Crude extracellular ligninolytic enzymes were not efficient in thein vitrodegradation of diuron. In addition, 1-aminobenzotriazole (ABT), a cytochrome P450 inhibitor, significantly inhibited both diuron degradation and metabolites production. Significant reduction in the toxicity evaluated by theLactuca sativaL. bioassay was observed in the cultures after 10 days of cultivation. In conclusion,P. chrysosporiumcan efficiently metabolize diuron without the accumulation of toxic products.
A Method for the Measurement of Photons Number and Squeezing Parameter in a Quantum Cavity
Authors: Naeimi Ghasem , Khademi Siamak , Heibati Ozra
Published: December 2013

Measurement of photons number in a quantum cavity is very difficult and the photons number is changed after each measurement. Recently, many efforts have been done for the nondemolition measurement methods. Haroche et al. succeed in recognizing existence or nonexistence of one photon in a quantum cavity. In this paper, we employ their experimental setup for a quantum nondemolition measurement and pump a coherent state in their quantum cavity. In this case, we could detect more photons in the quantum cavity by a measurement of a displaced Wigner function. It is also shown that the measurement of more than one photon is possible by the Haroche method by measuring just one point of displaced Wigner function. Furthermore, if the cavity field is filled by a superposition of two number states, the average number of photons within the cavity would be measurable. We show that their setup is also suitable to apply for the measurement of the squeezing parameter for the squeezed state of photons number in the quantum cavity successfully.