Role of autophagy genetic variants for the risk of Candida infections.

Candida albicans can cause candidemia in neutropenic and critically ill patients and oropharyngeal candidiasis in human immunodeficiency virus (HIV)-positive patients with low CD4(+) counts. Because all patients at risk do not develop Candida infections, it is possible that a patient's genetic background might play a role in his or her susceptibility to infection. Autophagy mediates pathogen clearance and modulation of inflammation. Our aim was to assess the effect of genetic variations in the ATG16L1 and IRGM autophagy genes on the susceptibility of patients with candidemia and oropharyngeal candidiasis. We assessed genetic variations in the ATG16L1 and IRGM genes in a cohort of candidemia patients of both African and European origin. In addition, we evaluated the effect of these polymorphisms on the susceptibility to oropharyngeal candidiasis of an HIV-positive cohort from Tanzania. Functional studies have been performed to assess the effect of the ATG16L1 and IRGM genetic variants on both in vitro and in vivo cytokine production. The results indicate that ATG16L1 variants modulate production of tumor necrosis factor-alpha, but not other cytokines, while no effects were seen in the presence of IRGM polymorphisms. In addition, no significant associations between the single-nucleotide polymorphisms in the ATG16L1 and IRGM genetic variants and the incidence of candidemia or oropharyngeal candidiasis were identified. Despite moderate effects on the modulation of proinflammatory cytokine production, genetic variation in the autophagy genes ATG16L1 and IRGM has a minor impact on the susceptibility to both mucosal and systemic Candida infections.

CX3CR1-dependent renal macrophage survival promotes Candida control and host survival.

Systemic Candida albicans infection causes high morbidity and mortality and is associated with neutropenia; however, the roles of other innate immune cells in pathogenesis are poorly defined. Here, using a mouse model of systemic candidiasis, we found that resident macrophages accumulated in the kidney, the main target organ of infection, and formed direct contacts with the fungus in vivo mainly within the first few hours after infection. Macrophage accumulation and contact with Candida were both markedly reduced in mice lacking chemokine receptor CX3CR1, which was found almost exclusively on resident macrophages in uninfected kidneys. Infected Cx3cr1-/- mice uniformly succumbed to Candida-induced renal failure, but exhibited clearance of the fungus in all other organs tested. Renal macrophage deficiency in infected Cx3cr1-/- mice was due to reduced macrophage survival, not impaired proliferation, trafficking, or differentiation. In humans, the dysfunctional CX3CR1 allele CX3CR1-M280 was associated with increased risk of systemic candidiasis. Together, these data indicate that CX3CR1-mediated renal resident macrophage survival is a critical innate mechanism of early fungal control that influences host survival in systemic candidiasis.

Toll-like receptor 1 polymorphisms increase susceptibility to candidemia.

BACKGROUND: Candidemia is a severe invasive fungal infection with high mortality. Recognition of Candida species is mediated through pattern recognition receptors such as Toll-like receptors (TLRs). This study assessed whether genetic variation in TLR signaling influences susceptibility to candidemia. METHODS: Thirteen mostly nonsynonymous single nucleotide polymorphisms (SNPs) in genes encoding TLRs and signaling adaptors MyD88 and Mal/TIRAP were genotyped in 338 patients (237 white, 93 African American, 8 other race) with candidemia and 351 noninfected controls (263 white, 88 African American). The SNPs significant in univariate analysis were further analyzed with multivariable logistic regression to determine association with clinical outcomes. Functional consequences of these polymorphisms were assessed via in vitro stimulation assays. RESULTS: Analyses of TLR SNPs revealed that 3 TLR1 SNPs (R80T, S248N, I602S) were significantly associated with candidemia susceptibility in whites. This association was not found in African Americans, likely due to lower power in this smaller study population. Furthermore, these TLR1 polymorphisms displayed impaired cytokine release by primary monocytes. No associations with susceptibility to candidemia were observed for SNPs in TLR2, TLR4, TLR6, TLR9, MyD88, or TIRAP. CONCLUSIONS: Nonsynonymous SNPs in TLR1 are associated with impaired TLR1 function, decreased cytokine responses, and predisposition to candidemia in whites.

Cytokine gene polymorphisms and the outcome of invasive candidiasis: a prospective cohort study.

BACKGROUND: Candida bloodstream infections cause significant morbidity and mortality among hospitalized patients. Although clinical and microbiological factors affecting prognosis have been identified, the impact of genetic variation in the innate immune responses mediated by cytokines on outcomes of infection remains to be studied. METHODS: A cohort of 338 candidemia patients and 351 noninfected controls were genotyped for single-nucleotide polymorphisms (SNPs) in 6 cytokine genes (IFNG, IL10, IL12B, IL18, IL1ß, IL8) and 1 cytokine receptor gene (IL12RB1). The association of SNPs with both candidemia susceptibility and outcome were assessed. Concentrations of pro- and antiinflammatory cytokines were measured in in vitro peripheral blood mononuclear cell stimulation assays and in serum from infected patients. RESULTS: None of the cytokine SNPs studied were associated with susceptibility to candidemia. Persistent fungemia occurred in 13% of cases. In the multivariable model, persistent candidemia was significantly associated with (odds ratio [95% confidence interval]): total parenteral nutrition (2.79 [1.26-6.17]), dialysis dependence (3.76 [1.46-8.64]), and the SNPs IL10 rs1800896 (3.45 [1.33-8.93]) and IL12B rs41292470 (5.36 [1.51-19.0]). In vitro production capacity of interleukin-10 and interferon-γ was influenced by these polymorphisms, and significantly lower proinflammatory cytokine concentrations were measured in serum from patients with persistent fungemia. CONCLUSIONS: Polymorphisms in IL10 and IL12B that result in low production of proinflammatory cytokines are associated with persistent fungemia in candidemia patients. This provides insights for future targeted management strategies for patients with Candida bloodstream infections.

Genetic variation in the dectin-1/CARD9 recognition pathway and susceptibility to candidemia.

BACKGROUND: Candidemia is an important cause of morbidity and mortality in critically ill patients or patients undergoing invasive treatments. Dectin-1 is the main ß-glucan receptor, and patients with a complete deficiency of either dectin-1 or its adaptor molecule CARD9 display persistent mucosal infections with Candida albicans. The role of genetic variation of DECTIN-1 and CARD9 genes on the susceptibility to candidemia is unknown. METHODS: We assessed whether genetic variation in the genes encoding dectin-1 and CARD9 influence the susceptibility to candidemia and/or the clinical course of the infection in a large cohort of American and Dutch candidemia patients (n = 331) and noninfected matched controls (n = 351). Furthermore, functional studies have been performed to assess the effect of the DECTIN-1 and CARD9 genetic variants on cytokine production in vitro and in vivo in the infected patients. RESULTS: No significant association between the single-nucleotide polymorphisms DECTIN-1 Y238X and CARD9 S12N and the prevalence of candidemia was found, despite the association of the DECTIN-1 238X allele with impaired in vitro and in vivo cytokine production. CONCLUSIONS: Whereas the dectin-1/CARD9 signaling pathway is nonredundant in mucosal immunity to C. albicans, a partial deficiency of ß-glucan recognition has a minor impact on susceptibility to candidemia.

Molecularly inherent voltage-controlled conductance switching.

Molecular electronics has been proposed as a pathway for high-density nanoelectronic devices. This pathway involves the development of a molecular memory device based on reversible switching of a molecule between two conducting states in response to a trigger, such as an applied voltage. Here we demonstrate that voltage-triggered switching is indeed a molecular phenomenon by carrying out studies on the same molecule using three different experimental configurations-scanning tunnelling microscopy, crossed-wire junction, and magnetic-bead junction. We also demonstrate that voltage-triggered switching is distinctly different from stochastic switching, essentially a transient (time-dependent) phenomenon that is independent of the applied voltage.

Effect of surface immobilization on intramolecular and intermolecular electron transfer in a chromophore-donor-acceptor assembly.

A chromophore-donor-acceptor assembly [Ru(bpyCOOH)(bpyCH(2)MV(2+)) (bpyCH(2)PTZ)](4+)(1) (where bpyCOOH = 4-carboxylic acid-4'-methyl-2,2'-bipyridine, bpyCH(2)MV(2+) = 1-[(4'-methyl-2,2'-bipyridin-4-yl)methyl]-1'-methyl-4,4'-bipyridinediium, and bpyCH(2)PTZ = 10-[(4'-methyl-2,2'-bipyridin-4-yl)methyl]phenothiazine) has been adsorbed on the surface of nanocrystalline ZrO(2) and its excited state properties studied by emission and transient absorption spectroscopy. In deaerated acetonitrile solution, the complex emits weakly with an emission quantum yield of phi(em) approximately equal to 0.01 with an excited-state lifetime of tau approximately equal to 20 ps. Emission from the surface-adsorbed complex is intense, with phi(em) approximately equal to 0.4 and tau approximately equal to 40 ns. The increase in emission on the surface is likely due to a significant inhibition to the electron-transfer quenching of the metal-to-ligand charge transfer (MLCT) excited state caused by surface adsorption-induced changes in the redox potentials. Transient (nanosecond time scale) absorption monitoring, following laser flash photolysis, reveals the presence of a transient or transients that are formed during the flash. Transient spectral changes that occur during and after the flash are consistent with the formation and decay of the intermediate ZrO(2)-[Ru(bpyCOOH)(bpyCH(2)MV(+*))(bpyCH(2)PTZ(+*))](4+). It returns to the ground state by both intramolecular and intermolecular processes. Intramolecular electron transfer occurs with k(BET) = 6.3 x 10(6) s(-1) (tau = 160 ns), which is comparable to the rate constant for back-electron transfer in solution. The back-electron transfer is a second-order process and is much slower, with k(BET) = 390 M(-1) s(-1) (tau = 2.6 ms).

Sensitization and stabilization of TiO(2) photoanodes with electropolymerized overlayer films of ruthenium and zinc polypyridyl complexes: a stable aqueous photoelectrochemical cell.

Overlayer thin films of vinylbipyridine (vbpy)-containing Ru and Zn complexes have been formed on top of ruthenium dye complexes adsorbed to TiO(2) by reductive electropolymerization. The goal was to create an efficient, water-stable photoelectrode or electrodes. An adsorbed-[Ru(vbpy)(2)(dcb)](PF(6))(2)/poly-[Ru(vbpy)(3)](PF(6))(2) surface composite displays excellent stability toward dissolution in water, but the added overlayer film greatly decreases incident photon-to-current conversion efficiencies (IPCE) in propylene carbonate with I(3)(-)/I(-) as the carrier couple. An ads-[Ru(vbpy)(2)(dcb)](PF(6))(2)/poly-[Zn(vbpy)(3)](PF(6))(2) composite displays no loss in IPCE compared to ads-[Ru(vbpy)(2)(dcb)](PF(6))(2) but is susceptible to film breakdown in the presence of water by solvolysis and loss of the cross-linking Zn(2+) ions. Success was attained with an ads-[Ru(vbpy)(2)(dcb)](PF(6))(2)/poly-[Ru(vbpy)(2)(dppe)](PF(6))(2) composite. In this case the electropolymerized layer is transparent in the visible. The composite electrode is stable in water, the IPCE in propylene carbonate with I(3)(-)/I(-) is comparable to the adsorbed complex, and a significant IPCE is observed in water with the quinone/hydroquinone carrier couple. The assembly [(bpy)(2)(CN)Ru(CN)Ru(vbpy)(2)(NC)Ru(CN)(bpy)(2)](PF(6))(2) ([Ru(CN)Ru(NC)Ru](PF(6))(2)) adsorbs spontaneously on TiO(2), and electropolymerization of thin layers of the assembly to give ads-[Ru(CN)Ru(NC)Ru](PF(6))(2)/poly-[Ru(CN)Ru(NC)Ru](PF(6))(2) enhances IPCE and has no deleterious effect on the IPCE/Ru.

Effect of bond-length alternation in molecular wires.

Current-voltage (I-V) characteristics for metal-molecule-metal junctions formed from three classes of molecules measured with a simple crossed-wire molecular electronics test-bed are reported. Junction conductance as a function of molecular structure is consistent with I-V characteristics calculated from extended Hückel theory coupled with a Green's function approach, and can be understood on the basis of bond-length alternation.

Sensitization of TiO(2) by Phosphonate-Derivatized Proline Assemblies.

Surface electrochemical and photoelectrochemical measurements on ITO (In(2)O(3):Sn) or TiO(2) of two proline assemblies are reported. Surface coverage on ITO of Pbp-pra(Ru(II)b(2)m)-OH(PF(6))(2) and Bpb-pra(Ru(II)b(2)m)-OCH(3)(CF(3)CO(2))(2) are (1.5-2.4) x 10(-)(10) mol/cm(2), comparable to monolayer coverages of (1.5-2.5) x 10(-)(10) mol/cm(2) for [Ru(bpy)(2)(4,4'-(CO(2)H)(2)bpy)](PF(6))(2) and [Ru(bpy)(2)(4,4'-(PO(3)H(2))(2)bpy)](Br)(2). Incident photon-to-current conversion efficiency (IPCE) measured in Gräztel-type photovoltaic cells are sensitive to subtle structural differences in the assemblies. IPCE values for Pbp-pra(Ru(II)b(2)m)-OH(PF(6))(2) and Bpb-pra(Ru(II)b(2)m)-OCH(3)(CF(3)CO(2))(2) are 2% and <0.1%, which are compared to 23% for both [Ru(bpy)(2)(4,4'-(PO(3)H(2))(2)bpy)](Br)(2) and [Ru(bpy)(2)(4,4'-(CO(2)H)(2)bpy)](PF(6))(2) under the same conditions.