High-fidelity qutrit entangling gates for superconducting circuits.

Ternary quantum information processing in superconducting devices poses a promising alternative to its more popular binary counterpart through larger, more connected computational spaces and proposed advantages in quantum simulation and error correction. Although generally operated as qubits, transmons have readily addressable higher levels, making them natural candidates for operation as quantum three-level systems (qutrits). Recent works in transmon devices have realized high fidelity single qutrit operation. Nonetheless, effectively engineering a high-fidelity two-qutrit entanglement remains a central challenge for realizing qutrit processing in a transmon device. In this work, we apply the differential AC Stark shift to implement a flexible, microwave-activated, and dynamic cross-Kerr entanglement between two fixed-frequency transmon qutrits, expanding on work performed for the ZZ interaction with transmon qubits. We then use this interaction to engineer efficient, high-fidelity qutrit CZ† and CZ gates, with estimated process fidelities of 97.3(1)% and 95.2(3)% respectively, a significant step forward for operating qutrits on a multi-transmon device.

Hardware-Efficient Microwave-Activated Tunable Coupling between Superconducting Qubits.

Generating high-fidelity, tunable entanglement between qubits is crucial for realizing gate-based quantum computation. In superconducting circuits, tunable interactions are often implemented using flux-tunable qubits or coupling elements, adding control complexity and noise sources. Here, we realize a tunable ZZ interaction between two transmon qubits with fixed frequencies and fixed coupling, induced by driving both transmons off resonantly. We show tunable coupling over 1 order of magnitude larger than the static coupling, and change the sign of the interaction, enabling cancellation of the idle coupling. Further, this interaction is amenable to large quantum processors: the drive frequency can be flexibly chosen to avoid spurious transitions, and because both transmons are driven, it is resilient to microwave cross talk. We apply this interaction to implement a controlled phase (CZ) gate with a gate fidelity of 99.43(1)% as measured by cycle benchmarking, and we find the fidelity is limited by incoherent errors.

Urban stormwater inputs to an adapted coastal wetland: role in water treatment and impacts on wetland biota.

The Lake Pertobe wetland system is a semi-natural wetland that has been modified primarily for recreational use. However, this lake system receives stormwater from much of the central business district of Warrnambool City (Victoria, Australia) and serves as a buffer zone between the stormwater system and the Merri River and Merri Marine Sanctuary. This work considers the impact of stormwater inputs on Lake Pertobe and the effectiveness of the lake in protecting the associated marine sanctuary. Sediment contaminants (including heavy metals and polycyclic aromatic hydrocarbons (PAHs)) and water quality parameters within the lake, groundwater and stormwater system were measured. Water quality parameters were highly variable between stormwater drains and rain events. Suspended solids rapidly settled along open drains and shortly after entering the lake. Groundwater inputs increased both salinity and dissolved nitrogen in some stormwater drains. Some evidence of bioaccumulation of metals in the food chain was identified and sediment concentrations of several PAHs were very high. The lake acted as a sink for PAHs and some metals and reductions in Escherichia coli, biological oxygen demand and total phosphorus were observed, affording some protection to the associated marine sanctuary. Nutrient retention was inadequate overall and it was identified that managing the lake primarily as a recreational facility impacted on the effectiveness of stormwater treatment in the system.

Post intrastromal corneal ring segments insertion complicated by Candida parapsilosis keratitis.

This case report describes the clinical and histopathologic features, including molecular confirmation, of fungal keratitis after intrastromal corneal ring segments placement for keratoconus. A 52-year-old woman underwent insertion of Intacs(®) corneal implants for treatment of keratoconus. Extrusion of the implants was noted 5 months post insertion and replaced. Three months later, monocular infiltrates and an epithelial defect were observed. The Intacs were removed and the infiltrates were treated with ofloxacin and prednisolone acetate. Microbial cultures and stains were negative. The patient demonstrated flares and exacerbation one month later. Mycoplasma and/or fungus were suspected and treated without improvement. Therapeutic keratoplasty was performed 10 months following initial placement of the corneal ring implants. The keratectomy specimen was analyzed by light microscopy and a panfungal polymerase chain reaction assay. A histopathologic diagnosis of Candida parapsilosis keratitis was made and confirmed by polymerase chain reaction. One year postoperatively, a systemic workup of the patient was done with no signs of recurrence. This rare report of fungal keratitis following Intacs insertion is the first reported case of C. parapsilosis complicating Intacs implantation.

Molecular detection of Bartonella henselae for the diagnosis of cat scratch disease and bacillary angiomatosis of the conjunctiva.

PURPOSE: The purpose of this study was to evaluate clinical cases of cat scratch disease (CSD) and bacillary angiomatosis involving the conjunctiva by special stains and transmission electron microscopy (TEM) and to compare these findings with the results from species-specific polymerase chain reaction (PCR) analysis of the same specimens. METHODS: Six potential cases of CSD and 2 possible cases of bacillary angiomatosis of the conjunctiva were analyzed by light microscopy, the Warthin-Starry technique, TEM, and PCR. DNA isolated from cultured Bartonella henselae, B. bacilliformis, B. quintana, and B. elizabethae were used as control templates for establishment of the PCR sensitivity and specificity. Cultured DNA was also used as appropriate positive controls during analysis of the clinical specimens. RESULTS: The histological studies, electron microscopy, and the PCR analysis confirmed the identification of the bacilli within the involved tissues. Furthermore, molecular diagnosis by PCR allowed for speciation of the infecting Bartonella organisms in 6 of the 8 cases and correlated with the histological findings. CONCLUSIONS: The PCR-based identification of Bartonella correlated well with the results of light microscopy and TEM and provided a simple and rapid method of diagnosis to the species level. The molecular analysis may prove to be beneficial in enhancing the current diagnostic techniques for CSD and bacillary angiomatosis.

Cat-scratch uveitis confirmed by histological, serological, and molecular diagnoses.

PURPOSE: To report a case of a cat-scratch uveitis caused by Bartonella henselae, which was confirmed by histology, serology, and polymerase chain reaction (PCR) methodology. METHODS: An iris nodule was biopsied from a 4-year-old child who was scratched by a kitten on the side of his face and developed redness of the eye associated with cervical lymphadenopathy. Sections of the iridectomy specimen were stained with hematoxylin-eosin, periodic acid-Schiff, and Warthin-Starry technique for histopathologic evaluation. Additionally, serologic tests and molecular diagnosis using B. henselae-specific PCR were performed. RESULTS: Histopathologically, sections of the iridectomy specimen showed a zonal granulomatous inflammation with a central iris necrotic abscess surrounded by a mantle of epithelioid histiocytes and more peripherally by lymphocytes and plasma cells. The Warthin-Starry stain disclosed scattered short bacilli within the necrotic abscess morphologically compatible with B. henselae. Report of serologic tests for B. henselae disclosed a negative immunoglobulin G antibody (negative: less than 12) and a positive immunoglobulin M antibody of 18 (positive: greater than 15). Other serologic studies including Toxocara, histoplasmin, blastomycin, coccidioidin, aspergillin, and Chlamydia were all negative. PCR was positive for B. henselae DNA. CONCLUSIONS: Our case showed a unilateral chronic granulomatous iritis with the histopathologic features compatible with CSD caused by B. henselae bacillus as demonstrated in the iris biopsy and confirmed by serology and PCR technique. This case is an example of a relatively rare uveal manifestation of CSD.

The RIM101 signal transduction pathway regulates Candida albicans virulence during experimental keratomycosis.

PURPOSE: To examine the role of the fungal RIM101 signal transduction pathway in the pathogenesis of Candida albicans keratitis. METHODS: C. albicans wild-type strain SC5314, prototrophic mutant control DAY185, and homozygous fungal mutants for the rim8, rim13, rim20, rim101, and phr1 genes were evaluated in vitro using proliferation and filamentation assays. Scarified corneas of BALB/c and C57BL/6J mice were topically inoculated and observed daily for keratitis severity. Corneal adaptation and pathogenicity were assessed ex vivo by maintaining infected porcine corneas for 3 days in an explantation culture system for histologic evaluation of hyphal penetration. RESULTS: All C. albicans strains had similar growth kinetics, and SC5314 and DAY185 demonstrated pH-induced filamentation. Fungal mutants had reduced hyphal formation at alkaline and neutral pH, but normal acidic assays ascertained that mutant strains did not have a generalized filamentation defect. SC5314 and DAY185 caused moderate to severe keratitis in mice, whereas fungal strains lacking constituents of the RIM101 pathway had significantly (P<0.05) attenuated severity in vivo. Three days after inoculation of porcine corneas, SC5314 and DAY185 produced hyphae that penetrated 28% and 25%, respectively, of the corneal thickness, and all five mutant strains showed significantly (P<0.05) less stromal penetration. CONCLUSIONS: The RIM101 signal transduction pathway plays an important role in the development of C. albicans keratitis. The fungal pathway intermediates Rim8p, Rim13p, Rim20p, and Rim101p and the downstream cell-wall protein Phr1p are pivotal in the process of corneal invasion by C. albicans.

Morphogenic and genetic differences between Candida albicans strains are associated with keratomycosis virulence.

PURPOSE: To correlate the morphogenic and molecular traits that affect fungal virulence in human corneas. METHODS: C. albicans wild-type strains SC5314 and VE175 were compared using in vitro growth kinetics, filamentation assays, and microarray analysis. Corneal virulence was assessed ex vivo by inoculating C. albicans onto superficially scarified human corneas that were processed after 1 and 3 days to measure hyphal penetration. For comparison, DSY459, a C. albicans homozygous deletion mutant deficient in secreted aspartyl proteinases (SAP) 4, 5, and 6, was evaluated. RESULTS: C. albicans strain SC5314 was highly filamentous in vitro and more invasive in human corneal explants while VE175 demonstrated limited filamentation and less corneal invasion. Among 6,655 C. albicans genes, 9.0% significantly (p<.05) differed by 2 fold or more between SC5314 and VE175. Genes involved in fungal filamentation that were upregulated in strain SC5314 compared to VE175 included SAP5, SAP6, and other hypha-associated genes. Compared to wild-type strains, DSY459 had intermediate filamentation and stromal penetration. CONCLUSIONS: Fungal genes involved in filamentation likely contribute to virulence differences between wild-type strains of C. albicans. The corneal pathogenicity of C. albicans involves the morphogenic transformation of yeasts into hyphae.

Slitlamp biomicroscopy and photographic image analysis of herpes simplex virus stromal keratitis.

OBJECTIVE: To validate photographic bioimaging for evaluating the severity of herpes simplex virus keratitis. METHODS: Stromal keratitis of patients in the Herpetic Eye Disease Study was clinically measured with a slitbeam micrometer and then photographed at trial entry. Calibrated images of 169 eyes were analyzed for the size, location, and density of stromal keratitis and endotheliitis, with shape factor as a function of area and perimeter. Validity was assessed by comparing clinical and computerized measurements and by correlating the keratitis area with visual acuity. Logistic regression explored characteristics associated with larger or denser corneal inflammation. RESULTS: Stromal keratitis had a median area of 22.4 mm(2) (interquartile range, 12.8-31.6 mm(2)) with a median shape factor of 0.69 (interquartile range, 0.56-0.79); 126 eyes (75%) had their midpoint within 2 mm of the cornea's geometric center. Photoanalytical area estimates of herpetic stromal keratitis correlated closely with clinical measurements (correlation coefficient, 0.83). Eyes with larger stromal keratitis had worse vision (correlation coefficient, 0.32) and were more likely to have iritis (P = .01). Necrotizing stromal keratitis was significantly whiter (P = .02). CONCLUSIONS: Image analysis validly assesses the disciform geometry of herpetic stromal keratitis and confirms that increased severity is associated with uveitis and reduced vision.

Expression of matrix metalloproteinases during experimental Candida albicans keratitis.

PURPOSE: This study was designed to investigate the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) during the inception and progression of experimental keratomycosis. METHODS: Scarified corneas of adult BALB/c mice were topically inoculated with Candida albicans strain SC5314 and monitored for disease severity. Infected and mock-infected corneas were compared at 1 day post inoculation (p.i.) with a murine gene microarray. Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) determined MMP and TIMP levels at 1, 3, and 7 days p.i. for infected, mock-infected, and normal corneas. Immunostaining localized target proteins at 1 day p.i. RESULTS: Eyes inoculated with C. albicans developed corneal infection with a mean clinical score of 8.2+/-0.8 at 1 day p.i. Compared to controls at 1 day p.i., MMP-8, -9, -10, -12, -13, -19, and TIMP-1 were significantly upregulated from fivefold to 375-fold by microarray and from threefold to 78-fold by real-time RT-PCR. Upregulated MMPs and TIMP-1 in the corneal epithelium and stroma of infected eyes correlated with the influx of acute inflammatory cells. Neither MMP-8 nor -13 expression was affected by mechanical trauma, but both increased >100-fold during the week after the onset of fungal keratitis. TIMP-1 expression rose from 21-fold more than controls at 1 day to 46-fold at 7 days p.i. by RT-PCR. CONCLUSIONS: Transcriptional and translational levels of MMP-8, -9, -13, and TIMP-1 increase during the early stages of C. albicans keratitis, confirming findings for MMP-9 and TIMP-1 in other infectious keratitis models and suggesting roles for MMP-8 and -13.

Gene profiling and signaling pathways of Candida albicans keratitis.

PURPOSE: To compare the global gene expression patterns in uninfected and fungus-infected mouse corneas at the onset of Candida albicans keratitis. METHODS: Fungal keratitis was generated by scarifying the corneal epithelium of BALB/c mice followed by topical inoculation with Candida albicans. Corneal infection was allowed to progress for one day, and total RNA was then extracted from excised corneas. Microarray was performed to detect 45,102 murine genes and processed to identify genetic regulation of signaling pathways. Selected genes encoding interleukins (IL), chemokine ligands, and other cytokines were confirmed by quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: Compared to mock-inoculated control eyes, genetic microarray analysis of Candida albicans keratitis showed that 3,977 genes (8.8%) changed at least twofold and 1,672 genes (3.7%) changed at least fourfold. Hierarchical clustering identified that upregulated genes affected immune and inflammatory responses, intercellular signaling, and cellular proliferation. Pathways having more than 20% of their genes significantly upregulated signaled leukocyte extravasation, increased interleukin production, and affected toll-like receptors. Upregulated transcript levels for IL-1beta and IL-6 were confirmed by real-time RT-PCR. CONCLUSIONS: Host gene expression during the initial stage of Candida albicans keratitis involves pathways contributing to acute inflammation mediated by interleukins and other signals of leukocyte recruitment. This murine study confirms the involvement of innate immunity in the cornea during the initiation of Candida albicans keratitis.

Corneal virulence of Candida albicans strains deficient in Tup1-regulated genes.

PURPOSE: To evaluate the role of rbt genes downstream of Tup1p, a transcription factor regulating fungal filamentation, in experimental Candida albicans keratitis. METHODS: Corneas of BALB/c mice were scarified and topically inoculated with 10(5) or 10(6) colony-forming units (CFU) of a wild-type human isolate of C. albicans (SC5314), a mutant strain with a transposon-induced homozygous disruption of the rbt1 gene (Tn7-rbt1), its control (DAY286), homozygous rbt knockout mutants deficient in rbt1 (BCa7-4) or rbt4 (BCa11-3), or their parental control (CAF2-1). Eyes were scored daily for clinical severity of fungal keratitis and were examined histopathologically. RESULTS: With a 10(5) CFU inoculum, the CAF2-1 control and its mutant derivatives (BCa7-4 and BCa11-3) produced significantly lower keratitis scores than did the moderately severe keratitis induced by control strains SC5314 and DAY286 and the Tn7-rbt1 mutant (P < 0.05). At a 10(6) CFU inoculum, all strains induced severe disease except for the rbt4-deficient mutant. Fungal keratitis caused by Tn7-rbt1 was as severe as that of control strains (P > 0.2), and the BCa7-4 mutant initially caused severe disease that gradually waned (P < 0.02). However, the BCa11-3 mutant produced moderate disease that was significantly less severe than that induced by control strains (P < 0.04) and resolved within 1 week. CONCLUSIONS: The rbt4 gene of C. albicans is a potential virulence factor in posttraumatic corneal infection. Genetically regulated hyphal morphogenesis appears to be involved in the initial pathogenesis of experimental keratomycosis.

Expression of matrix metalloproteinases 2 and 9 in experimental corneal injury and fungal keratitis.

PURPOSE: Levels of matrix metalloproteinases (MMPs) can be modulated during corneal infection, but little is known about MMP profiles during fungal keratitis. The purpose of this study was to determine the effect of corneal trauma and immunosuppressive treatment on the expression kinetics of MMP-2 and MMP-9 during experimental keratomycosis. METHODS: Corneas of immunocompetent and cyclophosphamide-treated adult BALB/c mice were topically inoculated with 1 x 10 culturable units of Fusarium solani or mock-inoculated with or without superficial corneal scarification. Eyes were scored daily for disease severity and processed for zymography after 1.5 hours, 6 hours, 1 day, 4 days, or 8 days. Gelatinase activity was densitometrically quantitated and normalized to MMP-2 and MMP-9 controls. RESULTS: MMP-9 levels in nontraumatized eyes transiently increased at 6 hours after fungal exposure, but this increase was inhibited by cyclophosphamide treatment. Corneal injury significantly induced early MMP-9 expression that returned to baseline levels within 4 days. Cyclophosphamide pretreatment reduced and delayed MMP-9 after scarification. Fusarium exposure dampened the MMP-9 response to corneal trauma in immunocompetent and cyclophosphamide-treated animals. Ocular levels of MMP-2 were not affected by scarification, fungal exposure, or immunosuppressive treatment. CONCLUSIONS: Ocular MMP-9 levels, but not MMP-2 levels, increased soon after corneal injury. A similar, although muted, MMP-9 response occurs during early filamentous fungal keratitis, with a kinetic profile similar to corneal disease progression. The early stage of ulcerative keratitis may involve selective regulation of corneal matrix metalloproteinases, suggesting an initial opportunity for therapeutic intervention.

Genetically regulated filamentation contributes to Candida albicans virulence during corneal infection.

Candida albicans is a commensal fungus of the normal flora yet causes opportunistic infection following trauma or surgery and during immunosuppression. C. albicans virulence factors include morphogenesis into invasive filaments, adherence to host cells, and secretion of proteases. This study evaluated the role of fungal hyphal extension in experimental C. albicans keratitis using genetically altered yeast strains. Scarified corneas of adult BALB/c mice were topically inoculated with wild-type (SC5314) or 10 transposon-induced mutant strains of C. albicans and monitored for 4 days post inoculation (PI). In vitro growth kinetics and the yeast strains' ability to bud into pseudohyphae or hyphae were also compared. The wild-type human isolate had a high degree of virulence in the murine cornea, and four fungal strains deficient in genes regulating adherence or encoding membrane proteins did not significantly differ from the parental strain (P>0.3). Five yeast strains deficient in genes involved in filamentation resulted in fully or partially attenuated keratomycosis (P<0.0001). The overall growth kinetics of wild-type and mutant strains were similar in rich media (P>0.9), but mutants with deficient morphogenesis had reduced filamentation in vitro. Phenotypic switching from yeasts to filamentous forms facilitates the establishment and progression of experimental corneal disease by C. albicans.

Candida albicans strain-dependent virulence and Rim13p-mediated filamentation in experimental keratomycosis.

PURPOSE: To compare the virulence of wild-type Candida albicans strains in a murine model of corneal candidiasis and to investigate the role of fungal filamentation in disease progression. METHODS: Scarified corneas of immunocompetent or cyclophosphamide-treated BALB/c mice were topically inoculated with one of three human isolates of C. albicans, a homozygous mutant of the pH-dependent filamentation gene rim13 or a mutant reference strain control. Mock-inoculated eyes served as negative controls. Corneal disease was categorized daily for 8 days with quantitative fungal culturing of eyes at 6 hours, 1 day, 4 days, and 8 days after infection and histopathologic examination at 1 day and 4 days after infection. RESULTS: Corneal disease severity differed significantly among wild-type strains (P < or = 0.02). The rim13(-/-) mutant Tn7-rim13 was fully attenuated, whereas the mutant control DAY286 was fully virulent. Pretreatment of mice with cyclophosphamide increased susceptibility to wild-type C. albicans and partially rescued the attenuated phenotype of the genetically deficient rim13(-/-) fungal mutant. All strains replicated with similar kinetics in vitro, and wild-type strains had similar clearance from infected eyes. Histopathologic findings correlated with disease severity. CONCLUSIONS: Wild-type strains of C. albicans that differ significantly in ocular pathogenicity correlate with the ability of yeast to produce pseudohyphae and hyphae and to invade corneal tissue. Full attenuation of the fungal rim13(-/-) mutant is the first direct demonstration of a hyphal morphogenesis-related gene as a specific virulence factor for C. albicans during corneal infection.

Mechanisms for human cytomegalovirus-induced cytoplasmic p53 sequestration in endothelial cells.

Human cytomegalovirus (HCMV) infection results in endothelial dysfunction, typically known as dysregulated apoptosis, and aberrant expression and sub-cellular localization of p53, a tumor suppressor that accumulates at the late stage of infection. In this study, we examined three hypotheses that could be responsible for HCMV-induced cytoplasmic p53 accumulation at the later stage of infection: hyperactive nuclear export, cytoplasmic p53 tethering and delayed p53 degradation. Leptomycin B treatment, a nuclear export inhibitor, was unable to reduce cytoplasmic p53, thereby eliminating the hyperactive nuclear export mechanism. The findings that nascent p53 still entered nuclei after the nuclear export inhibition indicated that cytoplasmic tethering may play a minor role. Cytoplasmic p53 was still observed after the translation activities were blocked by cycloheximide. There was more than an eight-fold increase in the cytoplasmic p53 half-life with abnormal p53 ubiquitination. Taken together, these results suggest that delayed degradation could be responsible for the cytoplasmic p53 accumulation. The general slow-down of the proteasomal activity and the dysregulated p53 ubiquitination process at the later stage of infection could contribute to the reduced cytoplasmic p53 degradation and might be relevant to dysregulated endothelial apoptosis. The HCMV-induced changes in p53 dynamics could contribute to endothelial dysfunction.

Pathways of corneal and ocular surface inflammation: a perspective from the cullen symposium.

The goal of this symposium was to coalesce information presented by 22 investigators in the field of corneal and ocular surface inflammation into common pathways of inflammation. The perspective elucidated in this article defines the components of the normal ocular surface immune architecture and describes the consensus reached on the mechanisms/pathways involved in 1) acute inflammation; 2) late-stage (chronic) response; and 3) allergic disease. Seven diagrams didactically illustrate mechanisms. This paper is the introductory article in a supplement containing 18 articles by the symposium participants.

Inflammatory response to fungal keratitis.

Ocular fungal infections occur worldwide and are important contributors to vision loss. While many aspects of the microbe and host interaction involved in fungal keratitis remain undefined, two aspects known to affect susceptibility are disruption of the epithelial barrier and immunosuppression of the host. Our recent pathogenesis studies using an experimental murine model have provided insight into the influence of these factors on keratomycosis. Increased susceptibility was associated with greater neutrophilic infiltration, greater fungal invasion of the corneal stroma, up-regulation of matrix metalloproteinase-9, and morphogenic switching from yeast to hyphae. Understanding the pathogenic events of fungal keratitis will identify potential targets for therapeutic intervention of these sight-threatening infections.