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antifungal susceptibility testing and genotyping characterization of cryptococcus neoformans and gattii isolates from hiv-infected patients of ribeirão preto, são paulo, brazil.cryptococcosis is a leading invasive fungal infection in immunocompromised patients. considering the high prevalence and severity of these infections in immunocompromised patients attended at hc-fmrp-usp, the present research aimed to characterize the clinical isolates of cryptococcus strains by biochemical and molecular methods and evaluate antifungal susceptibility of clinical isolates. fifty isolates from 32 hiv-positive patients were obtained at hc-fmrp-usp. most of the isolates (78.1%) were ...201627680174
systematic functional analysis of kinases in the fungal pathogen cryptococcus neoformans.cryptococcus neoformans is the leading cause of death by fungal meningoencephalitis; however, treatment options remain limited. here we report the construction of 264 signature-tagged gene-deletion strains for 129 putative kinases, and examine their phenotypic traits under 30 distinct in vitro growth conditions and in two different hosts (insect larvae and mice). clustering analysis of in vitro phenotypic traits indicates that several of these kinases have roles in known signalling pathways, and ...201627677328
activity of vt-1129 against cryptococcus neoformans clinical isolates with high fluconazole mics.although antifungal drug resistance in the human fungal pathogen cryptococcus neoformans is relatively uncommon, fluconazole-resistant strains are problematic for preemptive treatment of cryptococcal antigenemia or during cryptococcal meningitis consolidation therapy. we analyzed activity of the experimental antifungal vt-1129 on 51 clinical cryptococcus neoformans isolates previously screened for fluconazole resistance; with an emphasis on fluconazole dose-dependent (mic 16-32 μg/ml) or resista ...201627664991
equine pulmonary cryptococcosis: a comparative literature review and evaluation of fluconazole monotherapy.cryptococcus is the most common fungal respiratory pathogen in australian horses, manifesting primarily as pulmonary granulomas. disease severity at presentation is dependent on the athletic use of the horse. the diagnosis and estimation of disease severity are centred around clinical findings, cytological evaluation of respiratory tract secretions, diagnostic imaging, and antigen titre testing. both the lateral flow assay and the latex cryptococcal antigen titre are used, and important similari ...201727655152
pulsed dye laser treatment of primary cryptococcal laryngitis: a novel approach to an uncommon disease.an 82-year-old supplemental oxygen dependent woman with severe copd presented with an eight month history of worsening hoarseness and stridor. office laryngoscopy revealed laryngeal edema and ulcerative masses throughout the larynx. in-office biopsies were positive for cryptococcus neoformans. this report details a novel approach to the treatment of cryptococcal laryngitis, a combination of in-office pulsed-dye laser (pdl) ablation and medical therapy. despite treatment with oral fluconazole, th ...201727654751
pattern, clinical characteristics, and outcome of meningitis among hiv-infected adults admitted in a tertiary hospital in north western tanzania: a cross-sectional study.background. limited information exists on the etiologies, clinical characteristics, and outcomes of meningitis among hiv-infected patients in africa. we conducted a study to determine the etiology, clinical characteristics, and outcomes of meningitis among hiv-infected adults. methods. a prospective cross-sectional hospital based study was conducted among hiv-infected patients aged ≥18 years admitted to the medical wards with symptoms and signs of meningitis. sociodemographic and clinical inform ...201627651801
genetic and environmental influences on the germination of basidiospores in the cryptococcus neoformans species complex.in basidiomycetous fungi, the viability of basidiospores is an important component of sexual fitness. however, relatively little is known about the genetic and environmental factors influencing basidiospore germination. in this study, we used human opportunistic yeast pathogens, cryptococcus neoformans and cryptococcus deneoformans, as models to investigate the potential effects of selected genetic and environmental factors on basidiospore germination. a total of five strains with known genome s ...201627644692
chemical inhibitors of non-homologous end joining increase targeted construct integration in cryptococcus neoformans.the development of a biolistic transformation protocol for cryptococcus neoformans over 25 years ago ushered in a new era of molecular characterization of virulence in this previously intractable fungal pathogen. however, due to the low rate of homologous recombination in this species, the process of creating targeted gene deletions using biolistic transformation remains inefficient. to overcome the corresponding difficulty achieving molecular genetic modifications, members of the cryptococcus c ...201627643854
endoscopic ultrasound fine-needle aspiration diagnosis of cryptococcus neoformans. 201727639329
cryptococcus neoformans population diversity and clinical outcomes of hiv-associated cryptococcal meningitis patients in zimbabwe.hiv and cryptococcal meningitis co-infection is a major public health problem in most developing countries. cryptococcus neoformans sensu stricto is responsible for the majority of hiv-associated cryptococcosis cases in sub-saharan africa. despite the available information, little is known about cryptococcal population diversity and its association with clinical outcomes in patients with hiv-associated cryptococcal meningitis in sub-saharan africa. in a prospective cohort, we investigated the pr ...201627638836
molecular identification, antifungal resistance and virulence of cryptococcus neoformans and cryptococcus deneoformans isolated in seville, spain.cryptococcal meningitis is one of the leading causes of death in hiv/aids patients. our aim was to in order to characterise the epidemiology, antifungal susceptibility pattern and virulence of 28 cyptococcus sp. strains recovered from 12 aids patients during two years in a spanish single institution. antifungal susceptibility testing was performed according to the clsi protocols. clinical strains were molecularly characterised by serotyping, mating type, pcr fingerprinting (m13 and gaca4 microsa ...201727633849
comparison of bact/alert fan and fan plus bottles with conventional medium for culturing cerebrospinal fluid.we compared the bact/alert system fan and fan plus media to conventional media for culturing cerebrospinal fluid (csf) with 2,545 samples. fan/fan plus bottles showed better performance for isolating microorganisms in csf than conventional media (positive rate, 7.2% [182/2,545] versus 3.1% [80/2,545]). the incremental recovery rate of cryptococcus neoformans from fan plus bottles was higher than that from fan bottles.201627629894
unique roles of the unfolded protein response pathway in fungal development and differentiation.cryptococcus neoformans, a global fungal meningitis pathogen, employs the unfolded protein response pathway. this pathway, which consists of an evolutionarily conserved ire1 kinase/endoribonuclease and a unique transcription factor (hxl1), modulates the endoplasmic reticulum stress response and pathogenicity. here, we report that the unfolded protein response pathway governs sexual and unisexual differentiation of c. neoformans in an ire1-dependent but hxl1-independent manner. the ire1∆ mutants ...201627629591
cryptococcal cellulitis on the shin of an immunosuppressed patient.cryptococcus neoformans is a common fungus found throughout the environment that causes opportunistic disease in immunocompromised individuals. infection of humans with c neoformans usually manifests as lung disease through inhalation of spores or meningoencephalitis by involvement of the central nervous system. rarely, dissemination in the form of cutaneous lesions can occur in individuals with long term immunosuppression. we present a patient with c. neoformans manifesting as cellulitis with f ...201627617599
calcineurin targets involved in stress survival and fungal virulence.calcineurin governs stress survival, sexual differentiation, and virulence of the human fungal pathogen cryptococcus neoformans. calcineurin is activated by increased ca2+ levels caused by stress, and transduces signals by dephosphorylating protein substrates. herein, we identified and characterized calcineurin substrates in c. neoformans by employing phosphoproteomic tio2 enrichment and quantitative mass spectrometry. the identified targets include the transactivator crz1 as well as novel subst ...201627611567
in vitro antifungal susceptibility profiles of cryptococcus species isolated from hiv-associated cryptococcal meningitis patients in zimbabwe.cryptococcus neoformans is the leading cause of cryptococcosis in hiv-infected subjects worldwide. treatment of cryptococcosis is based on amphotericin b, flucytosine, and fluconazole. in zimbabwe, little is known about antifungal susceptibility of cryptococcus. sixty-eight genotyped cryptococcus isolates were tested for antifungal profiles. amphotericin b, isavuconazole, and voriconazole showed higher activity than other triazoles. fluconazole and flucytosine were less effective, with geometric ...201627608538
lung epithelium is the major source of il-33 and is regulated by il-33-dependent and il-33-independent mechanisms in pulmonary cryptococcosis.inhalation of the fungus cryptococcus neoformans (c. neoformans) results in pulmonary cryptococcosis associated with il-33-dependent type 2 immunity. lung epithelium represents the initial contact site of infection. the role of il-33 in type 2 immunity has been analyzed, but the source of this cytokine and its effect on lung epithelial cell function in pulmonary cryptococcosis remained unclear. in mice infected with c. neoformans, we identified alveolar type 2 epithelial cells as major source of ...201627596810
cryptococcal meningitis complicating sarcoidosis.cryptococcal meningitis is an uncommon but severe complication of sarcoidosis.201627583871
a small protein associated with fungal energy metabolism affects the virulence of cryptococcus neoformans in mammals.the pathogenic yeast cryptococcus neoformans causes cryptococcosis, a life-threatening fungal disease. c. neoformans has multiple virulence mechanisms that are non-host specific, induce damage and interfere with immune clearance. microarray analysis of c. neoformans strains serially passaged in mice associated a small gene (cnag_02591) with virulence. this gene, hereafter identified as hva1 (hypervirulence-associated protein 1), encodes a protein that has homologs of unknown function in plant an ...201627583447
glutathione may have implications in the design of 3-bromopyruvate treatment protocols for both fungal and algal infections as well as multiple myeloma.in different fungal and algal species, the intracellular concentration of reduced glutathione (gsh) correlates closely with their susceptibility to killing by the small molecule alkylating agent 3-bromopyruvate (3bp). additionally, in the case of cryptococcus neoformans cells 3bp exhibits a synergistic effect with buthionine sulfoximine (bso), a known gsh depletion agent. this effect was observed when 3bp and bso were used together at concentrations respectively of 4-5 and almost 8 times lower t ...201627582536
identification of disseminated cryptococcosis using maldi-tof ms and clinical evaluation.disseminated cryptococcosis is rare but can often become severe with a poor outcome. given recent reports that matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (maldi-tof ms) analyser is useful for cryptococcus species identification, it was applied retrospectively to past cases of disseminated cryptococcosis at our hospital over the past 10 years, and their clinical courses were reviewed. for each case, the retained cryptococcus spp. were used for identification usin ...201627581774
localized cutaneous cryptococcosis: summary of reported cases in japan.a 68-year-old male plasterer with no history of trauma presented to our clinic in march 2012 with a 16×14-mm ulcer that developed following a crushed small papule on the right anterior chest. in april 2012, the patient was referred to another hospital, where cutaneous cryptococcosis was diagnosed based on discharge culture results. the patient was treated with oral itraconazole at a dose of 150 mg/day for 10 weeks; however, the ulcer remained unchanged and he discontinued the treatment. in may 2 ...201627581773
intron retention-dependent gene regulation in cryptococcus neoformans.the biological impact of alternative splicing is poorly understood in fungi, although recent studies have shown that these microorganisms are usually intron-rich. in this study, we re-annotated the genome of c. neoformans var. neoformans using rna-seq data. comparison with c. neoformans var. grubii revealed that more than 99% of orf-introns are in the same exact position in the two varieties whereas utr-introns are much less evolutionary conserved. we also confirmed that alternative splicing is ...201627577684
cysteinyl leukotrienes as novel host factors facilitating cryptococcus neoformans penetration into the brain.cryptococcus neoformas infection of the central nervous system (cns) continues to be an important cause of mortality and morbidity, and a major contributing factor is our incomplete knowledge of the pathogenesis of this disease. here, we provide the first direct evidence that c. neoformans exploits host cysteinyl leukotrienes (lts), formed via lt biosynthetic pathways involving cytosolic phospholipase a2 α (cpla2 α) and 5-lipoxygenase (5-lo) and acting via cysteinyl leukotriene type 1 receptor ( ...201727573789
geographic distribution of patients affected by cryptococcus neoformans/cryptococcus gattii species complexes meningitis, pigeon and tree populations in southern brazil.cryptococcal meningitis is mainly caused by members of the c. neoformans/c. gattii species complexes. the ecological niches of cryptococcus species have extensively been studied, but its epidemiological relationship with meningitis cases is still unknown. in this study, we estimate the relationship between cryptococcal meningitis cases and tree and pigeon populations, the classical niches of members of c. neoformans/c. gattii sensu lato. we analysed the records of every patient whose cerebrospin ...201727561904
emestrins: anti-cryptococcus epipolythiodioxopiperazines from podospora australis.eleven emestrin-type epipolythiodioxopiperazines, including four new compounds, emestrins h-k (1-4), were isolated from the crude extracts of two strains of the coprophilous fungus podospora australis. the structures of 1-4 were established primarily by analysis of nmr data, and the absolute configuration of c-6 in 1 was independently assigned using the modified mosher method. four of the known emestrins obtained (emestrins c-e and mpc1001c) were found to selectively inhibit the growth of crypto ...201627557418
extended n-terminal region of the essential phosphorelay signaling protein ypd1 from cryptococcus neoformans contributes to structural stability, phosphostability and binding of calcium ions.rapid response to external stimuli is crucial for survival and proliferation of microorganisms. pathogenic fungi employ histidine-to-aspartate multistep phosphorelay systems to respond to environmental stress, progress through developmental stages and to produce virulence factors. because these his-to-asp phosphorelay systems are not found in humans, they are potential targets for the development of new antifungal therapies. here we report the characterization of the histidine phosphotransfer (h ...201627549628
fungal infection in the brain: what we learned from intravital imaging.approximately 1.2 billion people suffer from fungal diseases worldwide. arguably, the most serious manifestation occurs when pathogenic fungi infect the brain, often causing fatal meningoencephalitis. for most fungi, infection occurs via the vascular route. the organism must first be arrested in the brain microvasculature and transmigrate into the brain parenchyma across the blood-brain barrier. as a result, host immune cells are recruited into the brain to contain the fungi. however, it remains ...201627532000
population genetic analysis reveals a high genetic diversity in the brazilian cryptococcus gattii vgii population and shifts the global origin from the amazon rainforest to the semi-arid desert in the northeast of brazil.cryptococcus neoformans and cryptococcus gattii are responsible globally for almost one million cryptococcosis cases yearly, mostly in immunocompromised patients, such as those living with hiv. infections due to c. gattii have mainly been described in tropical and subtropical regions, but its adaptation to temperate regions was crucial in the species evolution and highlighted the importance of this pathogenic yeast in the context of disease. cryptococcus gattii molecular type vgii has come to th ...201627529479
point-of-care testing for cryptococcal disease among hospitalized human immunodeficiency virus-infected adults in ethiopia.in a cross-sectional study among hospitalized human immunodeficiency virus (hiv)-infected patients in ethiopia, we sought to determine the rates and predictors of cryptococcal disease and evaluate the test performance of a recently introduced point-of-care test for cryptococcus neoformans detection in various biological samples. we tested serum, urine, and fingerstick blood samples from each patient with a cryptococcal antigen lateral flow assay (crag lfa; immuno mycologic inc., norman, ok). cer ...201627527636
detection of zoonotic pathogens in wild birds in the cross-border region austria - czech republic.to assess the importance of wild birds as a reservoir of zoonotic pathogens in austria and the czech republic, we sampled 1,325 wild birds representing 13 orders, 32 families, and 81 species. the majority belonged to orders columbiformes (43%), passeriformes (25%), and to birds of prey: accipitriformes, strigiformes, and falconiformes (15%). we collected cloacal swabs from 1,191 birds for bacterial culture and 1,214 triple swabs (conjunctiva, choana, cloaca) for dna and rna isolation. the cloaca ...201627525596
[a pediatric case of hiv who diagnosed by virtue of disseminated cryptococcus infection].cryptococcus neoformans is an important opportunistic pathogen that causes serious mortality and morbidity in aids patients. although its incidence has decreased with proper antiretroviral treatment (art), it is still a major concern in areas with low socioeconomic hiv endemic countries with poor sources of therapy. in our country, pediatric hiv infection and so, hiv-related opportunistic infections are very rare. in order to pay attention to this unusual collaboration; herein, we presented a pe ...201627525403
diagnostic challenges of cryptococcus neoformans in an immunocompetent individual masquerading as chronic hydrocephalus.cryptococcus neoformans can cause disseminated meningoencephalitis and evade immunosurveillance with expression of a major virulence factor, the polysaccharide capsule. direct diagnostic assays often rely on the presence of the cryptococcal glucuronoxylomannan capsular antigen (crag) or visualization of the capsule. strain specific phenotypic traits and environmental conditions influence differences in expression that can thereby compromise detection and timely diagnosis. immunocompetent hosts m ...201627525140
[retrospective study of neuromeningeal cryptococcosis in patients infected with hiv in the infectious diseases unit of university hospital of casablanca, morocco].to report the cases of neuromeningeal cryptococcosis and to describe the clinical, paraclinical, therapeutic and outcomes of patients.201627520534
networks of fibers and factors: regulation of capsule formation in cryptococcus neoformans.the ability of the pathogenic fungus cryptococcus neoformans to cause life-threatening meningoencephalitis in immunocompromised individuals is due in large part to elaboration of a capsule consisting of polysaccharide fibers. the size of the cell-associated capsule is remarkably responsive to a variety of environmental and host conditions, but the mechanistic details of the regulation, synthesis, trafficking, and attachment of the polysaccharides are poorly understood. recent studies reveal a co ...201627516877
pathology of thyroid in acquired immunodeficiency syndrome.the course of human immunodeficiency virus infection and the acquired immunodeficiency syndrome can be complicated by a variety of endocrine abnormalities, including abnormalities of thyroid gland.201727510660
a 'suicide' crispr-cas9 system to promote gene deletion and restoration by electroporation in cryptococcus neoformans.loss-of-function mutagenesis is an important tool used to characterize gene functions, and the crispr-cas9 system is a powerful method for performing targeted mutagenesis in organisms that present low recombination frequencies, such as the serotype d strains of cryptococcus neoformans. however, when the crispr-cas9 system persists in the host cells, off-target effects and cas9 cytotoxicity may occur, which might block subsequent genetic manipulation. here, we report a method of spontaneously eli ...201627503169
etiology and clinical features of 229 cases of bloodstream infection among chinese hiv/aids patients: a retrospective cross-sectional study.bloodstream infections (bsis) are prevalent among people living with hiv/aids. the etiology varies in different regions and different periods. we aimed to survey the etiological and clinical features of bsis in hiv patients in mainland china. we assessed all hiv patients with a positive blood culture in a chinese teaching hospital from september 2009 through december 2014. we excluded those with specimens likely to have been contaminated. we used pearson's chi-squared test to measure the differe ...201627502930
risk factors for cryptococcal meningitis: a single united states center experience.cryptococcal meningitis carries a high mortality. further understanding of immune suppression factors associated with neuroinvasive infection will improve risk stratification and enhance early diagnosis and treatment with antifungal therapy. the aim of the study was to corroborate established or find novel clinical predictors for cryptococcal meningitis. we performed a matched case-control study of cryptococcus infection in immunocompromised patients with or without cryptococcal meningitis. data ...201627502502
cryptococcus neoformans ugt1 encodes a udp-galactose/udp-galnac transporter.cryptococcus neoformans, an opportunistic fungal pathogen, produces a glycan capsule to evade the immune system during infection. this definitive virulence factor is composed mainly of complex polysaccharides, which are made in the secretory pathway by reactions that utilize activated nucleotide sugar precursors. although the pathways that synthesize these precursors are known, the identity and the regulation of the nucleotide sugar transporters (nsts) responsible for importing them into luminal ...201727496760
identification of multiple cryptococcal fungicidal drug targets by combined gene dosing and drug affinity responsive target stability screening.cryptococcus neoformans is a pathogenic fungus that is responsible for up to half a million cases of meningitis globally, especially in immunocompromised individuals. common fungistatic drugs, such as fluconazole, are less toxic for patients but have low efficacy for initial therapy of the disease. effective therapy against the disease is provided by the fungicidal drug amphotericin b; however, due to its high toxicity and the difficulty in administering its intravenous formulation, it is impera ...201627486194
synergy and antagonism between iron chelators and antifungal drugs in cryptococcus.fungal infections remain very difficult to treat, and developing new antifungal drugs is difficult and expensive. recent approaches therefore seek to augment existing antifungals with synergistic agents that can lower the therapeutic dose, increase efficacy and prevent resistance from developing. iron limitation can inhibit microbial growth, and iron chelators have been employed to treat fungal infections. in this study, chequerboard testing was used to explore combinations of iron chelators wit ...201627474467
participation of purines in the modulation of inflammatory response in rats experimentally infected by cryptococcus neoformans.the present study was carried out to assess the participation of purines in the activation and modulation of inflammatory response of rats experimentally infected by cryptococcus neoformans. twenty four wistar rats were divided into two groups of 12 animals each: group a - uninfected control group and group b - infected by c. neoformans. blood was collected 20 and 50 days post-infection (pi) from six animals of each group in order to verify purine levels (adenosine triphosphate (atp), adenosine ...201627469575
molecular epidemiology reveals genetic diversity among 363 isolates of the cryptococcus neoformans and cryptococcus gattii species complex in 61 ivorian hiv-positive patients.cryptococcal meningitis is a severe opportunistic infection in hiv-infected patients. in ivory coast, despite the availability of antiretroviral treatment (art), this infection is still prevalent. the study investigates the genetic diversity of 363 clinical isolates of cryptococcus from 61 ivorian hiv-positive patients, the occurrence of mixed infections and the in vitro antifungal susceptibility of the isolates. serotyping was performed via lac1 and cap64 gene amplification. genotyping was perf ...201627461533
synthesis and biological evaluation of 3,5-dimethoxystilbene analogs.in our continuing effort to discover natural product-based pest management agents, derivatives of 3,5-dimethoxystilbene were synthesized yielding 27 new and six known compounds. compounds 11 and 12 showed strong aedes aegypti larvicidal activity (lc50 45.31 and 49.93 μm, respectively). furthermore, 11 and 12 exhibited high effectiveness against larvae of pesticide-susceptible and pyrethroid-resistant strains of ae. aegypti; activity against the adult mosquitoes was low. compounds 6f, 6g, and 6i ...201627450661
cryptococcal meningitis initially presenting with eye symptoms in an immunocompetent patient: a case report.although cryptococcal meningitis (cm) typically occurs in immunocompromised hosts, immunocompetent humans are susceptible to cm. in humans with an intact immune system, cm presents with signs and symptoms typical of meningitis, including fever, headache and neck stiffness. the present study reported the case of a female immunocompetent patient who presented visual blurring in both eyes and bilateral papilledema for ~1 month. following hospital admission, the patient was diagnosed with optic nerv ...201627446330
cryptococcal disease in hiv-infected children.cryptococcus neoformans is an encapsulated fungal pathogen that is remarkable for its tendency to cause meningoencephalitis, especially in patients with aids. while disease is less common in children than adults, it remains an important cause of morbidity and mortality among hiv-infected children without access to anti-retroviral therapy. this review highlights recent insights into both the biology and treatment of cryptococcosis with a special emphasis on the pediatric literature.201627443557
predominance of cryptococcus neoformans var. grubii multilocus sequence type 5 and emergence of isolates with non-wild-type minimum inhibitory concentrations to fluconazole: a multi-centre study in china.there are few data on the molecular epidemiology of cryptococcosis in china. here we investigated the species distribution, molecular types and antifungal susceptibilities of 312 cryptococcus neoformans species complex isolates from ten hospitals over 5 years. isolates were identified by internal transcribed spacer (its) sequencing and by two matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (maldi-tof ms) systems. multilocus sequence typing (mlst) was used to verify s ...201627432767
synthesis of part structures of cryptococcus neoformans serotype c capsular polysaccharide.cryptococcus neoformans is a fungal pathogen that can cause life-threatening infections in immunocompromised patients. the development of a vaccine based on the capsular polysaccharide of c. neoformans is still an open challenge due to the heterogeneity of the capsular polysaccharide and the difficulty of identifying protective epitopes. therefore, construction of structurally defined part structures of the c. neoformans gxm capsule is in great demand. herein is presented the synthesis of a 3-o- ...201627423877
the simultaneous occurrence of histoplasmosis and cryptococcal fungemia: a case report and review of the literature.simultaneous infections with cryptococcus neoformans and histoplasma capsulatum are rare and typically occur in immunocompromised individuals, particularly aids patients. because both of those fungi can spur the development of latent infections, it is generally unknown which organism was first present. the diagnosis of one fungus can hide the diagnosis of the other, leading to underdiagnoses and poor prognosis. we report a case of c. neoformans and h. capsulatum co-infection. we also performed a ...201627423433
disruption of early tumor necrosis factor alpha signaling prevents classical activation of dendritic cells in lung-associated lymph nodes and development of protective immunity against cryptococcal infection.anti-tumor necrosis factor alpha (anti-tnf-α) therapies have been increasingly used to treat inflammatory diseases and are associated with increased risk of invasive fungal infections, including cryptococcus neoformans infection. using a mouse model of cryptococcal infection, we investigated the mechanism by which disruption of early tnf-α signaling results in the development of nonprotective immunity against c. neoformans we found that transient depletion of tnf-α inhibited pulmonary fungal cle ...201627406560
antifungal amide alkaloids from the aerial parts of piper flaviflorum and piper sarmentosum.sixty-three amide alkaloids, including three new, piperflaviflorine a (1), piperflaviflorine b (2), and sarmentamide d (4), and two previously synthesized ones, (1e,3s)-1-cinnamoyl-3- hydroxypyrrolidine (3) and n-[7'-(4'-methoxyphenyl)ethyl]-2-methoxybenzamide (5), were isolated from the aerial parts of piper flaviflorum and piper sarmentosum. their structures were elucidated by detailed spectroscopic analysis and, in case of 3, by single-crystal x-ray diffraction. most of the isolates were test ...201727405106
a case of cryptococcus neoformans meningitis in a patient with abnormal levels of isolated immunological markers.cryptococcal meningitis is considered rare in immunocompetent patients and is mainly a disease of immunocompromised patients. we report a case of cryptococcal meningitis, due to cryptococcus neoformans, in an apparently healthy individual with abnormal levels of isolated immunological markers. regardless of the patient's immune status, the result of the disease can be serious unless the disease is diagnosed early.201627402508
neutrophil swarming toward cryptococcus neoformans is mediated by complement and leukotriene b4.swarming behavior of neutrophils has been noticed in both sterile injury and infection models and the mechanisms are being unveiled. so far, no in vitro model has been established to study neutrophil swarming to microbes. in the current study, using live-cell imaging, we observed in vitro neutrophil swarming toward cryptococcus neoformans, a fungal pathogen causing human meningoencephalitis. complement c3 and cd11b expression are essential for neutrophils to form cell swarms surrounding c. neofo ...201627402276
opposing pka and hog1 signals control the post-transcriptional response to glucose availability in cryptococcus neoformans.the pathogenic fungus cryptococcus neoformans must adapt to glucose-limited conditions in the lung and glucose replete conditions upon dissemination to the brain. we report that glucose controls ribosome biogenesis and translation by modulating mrna decay through a balance of pka and hog1 signalling. glucose signalling through pka stabilized ribosomal protein (rp) mrnas whereas glucose starvation destabilized rp transcripts through hog1. glucose starvation-induced oxidative stress response genes ...201627387858
identification of qtls associated with virulence related traits and drug resistance in cryptococcus neoformans.cryptococcus neoformans is a basidiomycete fungus capable of causing deadly meningoenchephilitis, primarily in immunocompromised individuals. formerly, c. neoformans was composed of two divergent lineages, but these have recently been elevated to species status, now c. neoformans (formerly c. neoformans var. grubii) and c. deneoformans (formerly c. neoformans var. neoformans). while both species can cause deadly infections in humans, c. neoformans is much more prevalent in clinical settings than ...201627371951
the membrane phospholipid binding protein annexin a2 promotes phagocytosis and nonlytic exocytosis of cryptococcus neoformans and impacts survival in fungal infection.cryptococcus neoformans is a fungal pathogen with a unique intracellular pathogenic strategy that includes nonlytic exocytosis, a phenomenon whereby fungal cells are expunged from macrophages without lysing the host cell. the exact mechanism and specific proteins involved in this process have yet to be completely defined. using murine macrophages deficient in the membrane phospholipid binding protein, annexin a2 (anxa2), we observed a significant decrease in both phagocytosis of yeast cells and ...201627371724
the lysine biosynthetic enzyme lys4 influences iron metabolism, mitochondrial function and virulence in cryptococcus neoformans.the lysine biosynthesis pathway via α-aminoadipate in fungi is considered an attractive target for antifungal drugs due to its absence in mammalian hosts. the iron-sulfur cluster-containing enzyme homoaconitase converts homocitrate to homoisocitrate in the lysine biosynthetic pathway, and is encoded by lys4 in the model yeast saccharomyces cerevisiae. in this study, we identified the ortholog of lys4 in the human fungal pathogen, cryptococcus neoformans, and found that lys4 expression is regulat ...201627353379
requirement of the isocitrate lyase gene icl1 for vps41-mediated starvation response in cryptococcus neoformans.cryptococcus neoformans is a major cause of fungal meningitis in individuals with impaired immunity. our previous studies have shown that the vps41 gene plays a critical role in the survival of cryptococcus neoformans under nitrogen starvation; however, the molecular mechanisms underlying vps41-mediated starvation response remain to be elucidated. in the present study, we show that, under nitrogen starvation, vps41 strongly enhanced icl1 expression in c. neoformans and that overexpression of icl ...201627350614
multicenter evaluation of biofire filmarray meningitis/encephalitis panel for detection of bacteria, viruses, and yeast in cerebrospinal fluid specimens.rapid diagnosis and treatment of infectious meningitis and encephalitis are critical to minimize morbidity and mortality. comprehensive testing of cerebrospinal fluid (csf) often includes gram stain, culture, antigen detection, and molecular methods, paired with chemical and cellular analyses. these methods may lack sensitivity or specificity, can take several days, and require significant volume for complete analysis. the filmarray meningitis/encephalitis (me) panel is a multiplexed in vitro di ...201627335149
suppressive effects of mycoviral proteins encoded by magnaporthe oryzae chrysovirus 1 strain a on conidial germination of the rice blast fungus.magnaporthe oryzae chrysovirus 1 strain a (mocv1-a) is the causal agent of growth repression and attenuated virulence (hypovirulence) of the rice blast fungus, magnaporthe oryzae. we previously revealed that heterologous expression of the mocv1-a orf4 protein resulted in cytological damage to the yeasts saccharomyces cerevisiae and cryptococcus neoformans. since the orf4 protein is one of the components of viral particles, we evaluated the inhibitory effects of the purified virus particle agains ...201627329666
isavuconazole is effective for the treatment of experimental cryptococcal meningitis.we evaluated the efficacy of isavuconazole against cryptococcal meningitis. treatment with either oral isavuconazole (120 mg/kg and 240 mg/kg twice a day [bid]) or fluconazole as the positive control significantly improved survival in mice infected intracranially with either cryptococcus neoformans usc1597 or h99 and significantly reduced brain fungal burdens for both isolates. concentrations of isavuconazole in plasma and brain tissue also demonstrated that the greatest improvements in survival ...201627324761
effects of ctr4 deletion on virulence and stress response in cryptococcus neoformans.roles of the high-affinity copper transporter ctr4 in the virulence of cryptococcus neoformans remain to be fully determined. here we demonstrate that ctr4 plays a necessary role in virulence and tolerance to a number of stress conditions. we first observed, with the method of flame atomic absorption spectrometry, that deletion of ctr4 resulted in a significant decrease in intracellular copper level, confirming the role of ctr4 as a copper transporter in c. neoformans. furthermore, ctr4 was crit ...201627317510
amino acid substitution in cryptococcus neoformans lanosterol 14-α-demethylase involved in fluconazole resistance in clinical isolates.the molecular basis of fluconazole resistance in cryptococcus neoformans has been poorly studied. a common azole resistance mechanism in candida species is the acquisition of point mutations in the erg11 gene encoding the enzyme lanosterol 14-α-demethylase, target of the azole class of drugs. in c. neoformans only two mutations were described in this gene. in order to evaluate other mutations that could be implicated in fluconazole resistance in c. neoformans we studied the genomic sequence of t ...201727311753
synthesis of a glucuronic acid-containing thioglycoside trisaccharide building block and its use in the assembly of cryptococcus neoformans capsular polysaccharide fragments.as part of an ongoing project aimed at identifying protective capsular polysaccharide epitopes for the development of vaccine candidates against the fungal pathogen cryptococcus neoformans, the synthesis and glycosylation properties of a naphthalenylmethyl (nap) orthogonally protected trisaccharide thioglycoside, a common building block for construction of serotype b and c capsular polysaccharide structures, were investigated. ethyl (benzyl 2,3,4-tri-o-benzyl-β-d-glucopyranosyl- uronate)-(1→2)-[ ...201527308199
relative contributions of prenylation and postprenylation processing in cryptococcus neoformans pathogenesis.prenyltransferase enzymes promote the membrane localization of their target proteins by directing the attachment of a hydrophobic lipid group at a conserved c-terminal caax motif. subsequently, the prenylated protein is further modified by postprenylation processing enzymes that cleave the terminal 3 amino acids and carboxymethylate the prenylated cysteine residue. many prenylated proteins, including ras1 and ras-like proteins, require this multistep membrane localization process in order to fun ...201727303728
the zinc finger protein mig1 regulates mitochondrial function and azole drug susceptibility in the pathogenic fungus cryptococcus neoformans.the opportunistic pathogen cryptococcus neoformans causes fungal meningoencephalitis in immunocompromised individuals. in previous studies, we found that the hap complex in this pathogen represses genes encoding mitochondrial respiratory functions and tricarboxylic acid (tca) cycle components under low-iron conditions. the orthologous hap2/3/4/5 complex in saccharomyces cerevisiae exerts a regulatory influence on mitochondrial functions, and hap4 is subject to glucose repression via the carbon c ...201727303693
antifungal efficacy of amphotericin b encapsulated fibrin microsphere for treating cryptococcus neoformans infection in swiss albino mice.a natural and biocompatible fibrin microsphere is one of the most promising dual delivery vehicle as compared to other traditionally designed delivery modalities. it represents sustained delivery of encapsulated drug and is easily biodegradable in the blood circulation. in the present study, we evaluated the systemic augmentation of the antifungal activity of amphotericin b loaded in fibrin microsphere (amb-fibrin microsphere) against cryptococcosis in swiss albino mice. mice infected with crypt ...201727294976
role of laccase in the virulence of talaromyces marneffei: a common link between aids-related fungal pathogens? 201627282335
pd@ag nanosheets in combination with amphotericin b exert a potent anti-cryptococcal fungicidal effect.silver nanoparticles have received considerable interest as new "nanoantibiotics" with the potential to kill drug-resistant microorganisms. recently, a class of new core-shell nanostructures, pd@ag nanosheets (pd@ag nss), were created using deposition techniques and demonstrated excellent inhibitory effects on various bacteria in vitro. in this study, we evaluated the antifungal activity of pd@ag nss against common invasive fungal pathogens. among these organisms, cryptococcus neoformans complex ...201627271376
custom-made quorum sensing for a eukaryote.quorum-sensing systems, common in prokaryotes, enable bacteria to coordinately regulate behavior with population density. reporting recently in cell host & microbe, homer et al. (2016) characterize an elegant eukaryotic quorum-sensing pathway in the human pathogenic fungus cryptococcus neoformans.201627270036
repurposing of aspirin and ibuprofen as candidate anti-cryptococcus drugs.the usage of fluconazole and amphotericin b in clinical settings is often limited by, among other things, drug resistance development and undesired side effects. thus, there is a constant need to find new drugs to better manage fungal infections. toward this end, the study described in this paper considered the repurposing of aspirin (acetylsalicylic acid) and ibuprofen as alternative drugs to control the growth of cryptococcal cells. in vitro susceptibility tests, including a checkerboard assay ...201627246782
modulation of macrophage inflammatory nuclear factor κb (nf-κb) signaling by intracellular cryptococcus neoformans.cryptococcus neoformans (cn) is a common facultative intracellular pathogen that can cause life-threatening fungal meningitis in immunocompromised individuals. shortly after infection, cn is detectable as both extra- and intracellular yeast particles, with cn being capable of establishing long-lasting latent infections within host macrophages. although recent studies have shown that shed capsular polysaccharides and intact extracellular cn can compromise macrophage function through modulation of ...201627231343
investigation of the antifungal activity of carvacrol against strains of cryptococcus neoformans.cryptococcus neoformans is the etiologic agent of opportunistic systemic fungal infection cryptococcosis, which affects individuals with compromised immune systems. thus, natural products research has become important, since monoterpenes such as carvacrol, a promising molecule in the search antifungal agents, have shown significant biological activity.201627225838
intracellular action of a secreted peptide required for fungal virulence.quorum sensing (qs) is a bacterial communication mechanism in which secreted signaling molecules impact population function and gene expression. qs-like phenomena have been reported in eukaryotes with largely unknown contributing molecules, functions, and mechanisms. we identify qsp1, a secreted peptide, as a central signaling molecule that regulates virulence in the fungal pathogen cryptococcus neoformans. qsp1 is a direct target of three transcription factors required for virulence, and qsp1δ ...201627212659
reversible hearing loss following cryptococcal meningitis: case study.sensorineural hearing loss is a recognised complication of cryptococcal meningitis. the mechanism of hearing loss in patients with cryptococcal meningitis is different from that in bacterial meningitis.201627210482
environmental distribution of cryptococcus neoformans and c. gattii around the mediterranean basin.in order to elucidate the distribution of cryptococcus neoformans and c. gattii in the mediterranean basin, an extensive environmental survey was carried out during 2012-2015. a total of 302 sites located in 12 countries were sampled, 6436 samples from 3765 trees were collected and 5% of trees were found to be colonized by cryptococcal yeasts. cryptococcus neoformans was isolated from 177 trees and c. gattii from 13. cryptococcus neoformans colonized 27% of ceratonia, 10% of olea, platanus and p ...201627188887
molecular characterization of environmental cryptococcus neoformans vnii isolates in jos, plateau state, nigeria.cryptococcus neoformans and cryptococcus gattii are encapsulated yeasts able to cause fatal neurological infections in both human and other mammals. cryptococcosis is the most common fungal infection of the central nervous system and has a huge burden in sub-saharan africa and south east asia. bird excreta are considered an environmental reservoir for c. neoformans in urban areas, therefore a study aimed at isolating and characterizing this yeast is important in disease management. in this study ...201627184613
quercetin and rutin as potential agents antifungal against cryptococcus spp.amphotericin b is a fungicidal substance that is treatment of choice for most systemic fungal infections affecting as cryptococcosis the immunocompromised patients. however, severe side effects have limited the utility of this drug. the aim of this study was to evaluate the antifungal effect of the combination of amphotericin b with quercetin or rutin and as a protective of citotoxic effect. the antifungal activity to amphotericin b, quercetin and rutin alone and in combination was determined in ...201727166572
induction of protective immunity to cryptococcal infection in mice by a heat-killed, chitosan-deficient strain of cryptococcus neoformans.cryptococcus neoformans is a major opportunistic fungal pathogen that causes fatal meningoencephalitis in immunocompromised individuals and is responsible for a large proportion of aids-related deaths. the fungal cell wall is an essential organelle which undergoes constant modification during various stages of growth and is critical for fungal pathogenesis. one critical component of the fungal cell wall is chitin, which in c. neoformans is predominantly deacetylated to chitosan. we previously re ...201627165801
lipid flippase subunit cdc50 mediates drug resistance and virulence in cryptococcus neoformans.cryptococcus neoformans is a human fungal pathogen and a major cause of fungal meningitis in immunocompromised individuals. treatment options for cryptococcosis are limited. of the two major antifungal drug classes, azoles are active against c. neoformans but exert a fungistatic effect, necessitating long treatment regimens and leaving open an avenue for emergence of azole resistance. drugs of the echinocandin class, which target the glucan synthase and are fungicidal against a number of other f ...201627165800
belatacept and mediastinal histoplasmosis in a kidney transplant patient.in transplantation immunosuppression enhances the appearance of opportunist infections. an ideal balance between the prevention of rejection, the lowest risk of infections and the highest rates of graft survival is a continuous challenge. lower doses of immunosuppression may diminish the risk of infections, metabolic and hemodynamic complications or even of malignancy, but may expose patients to episodes of acute rejection. new drugs are being developed to improve graft survival at the lowest ri ...201627152295
corrigendum: impact of resistance to fluconazole on virulence and morphological aspects of cryptococcus neoformans and cryptococcus gattii isolates.[this corrects the article on p. 153 in vol. 7, pmid: 26909069.].201627148225
favorable evolution of cryptococcal meningitis in the context of flucytosine resistance.cryptococcal meningitis is a critical illness affecting 0.2% to 5% solid-organ transplant recipients with a 40% to 50% mortality. we report the case of a 48-year-old lung transplant recipient, who, 15 months after a right lung graft, kept parakeets and developed meningitis due to cryptococcus neoformans. immunosuppressive treatment was based on a quadruple sequential immunosuppressive therapy that included induction therapy with thymoglobulin, followed by corticosteroids, calcineurin inhibitors, ...201627143150
evaluation of antifungal combination against cryptococcus spp.the second cause of death among systemic mycoses, cryptococcosis treatment represents a challenge since that 5-flucytosine is not currently available in brazil. looking for alternatives, this study evaluated antifungal agents, alone and combined, correlating susceptibility to genotypes. eighty cryptococcus clinical isolates were genotyped by ura5 gene restriction fragment length polymorphism. antifungal susceptibility was assessed following clsi-m27a3 for amphotericin (amb), 5-flucytosine (5fc), ...201627135278
cryptococcus neoformans var. grubii-induced arthritis with encephalitic dissemination in a dog and review of published literature.this article describes the clinical, pathological, and immunohistochemical findings associated with cryptococcus neoformans var. grubii in a 4-year-old female boxer dog from uberlândia, minas gerais, southeastern brazil. clinically, there was a swelling at the right metatarsal region and the hock joint with enlargement of regional lymph nodes. radiographical evaluation revealed lysis of the tarsal bone; cytology demonstrated cryptococcal intralesional organisms at the swollen joint. despite empi ...201627126588
cryptococcosis in non-hiv/non-transplant patients: a brazilian case series.cryptococcosis is a classical systemic opportunistic mycosis, primarily occurring among patients with significant immunologic impairment. however, this disease could also affect patients without any recognized immunologic defects, that is, phenotypically normal patients. the medical records of 29 non-hiv/nontransplant patients with cryptococcal disease during the period 2007-2014 were retrospectively reviewed. the most common site of infection was the central nervous system (n = 25, 86.2%), foll ...201627118805
the zip family zinc transporters support the virulence of cryptococcus neoformans.zinc is an essential element in living organisms and a cofactor for various metalloproteins. to disseminate and survive, a pathogenic microbe must obtain zinc from the host, which is an environment with extremely limited zinc availability. in this study, we investigated the roles of the zip family zinc transporters zip1 and zip2 in the human pathogenic fungus cryptococcus neoformans zip1 and zip2 are homologous to zrt1 and zrt2 of the model fungus, saccharomyces cerevisiae, respectively. we foun ...201627118799
intravascular clearance of disseminating cryptococcus neoformans in the brain can be improved by enhancing neutrophil recruitment in mice.extrapulmonary dissemination of cryptococcus neoformans (c. neoformans) is one of the most critical steps in the development of meningoencephalitis. here, we report that clearance of the disseminating c. neoformans occurs within the brain microvasculature. interestingly, the efficiency of the intravascular clearance in the brain is reduced compared to that in the lung. intravascular clearance is mainly mediated by neutrophils, and complement c5a receptor signaling is crucial for mediating neutro ...201627109176
fisetin as a promising antifungal agent against cryptocococcus neoformans species complex.the aim of this study was to investigate the mechanisms of action of fisetin, a flavonol with antifungal activity previously evaluated against the cryptococcus neoformans species complex.201627107205
cryptococcus neoformans isolates from yaoundé human immunodeficiency virus-infected patients exhibited intra-individual genetic diversity and variation in antifungal susceptibility profiles between isolates from the same patient.cryptococcal meningitis is a dreadful opportunistic fungal infection amongst human immunodeficiency virus (hiv)-infected patients. one complication in the management of the disease is the possible infection of a patient by two or more different strains of cryptococcus neoformans. this study investigated the intra-individual genetic diversity and antifungal susceptibility of c. neoformans isolates from yaoundé (cameroon) hiv-infected patients with cryptococcal meningitis. twenty-five clinical iso ...201627100672
transcriptional control of sexual development in cryptococcus neoformans.developmental processes are essential for the normal life cycles of many pathogenic fungi, and they can facilitate survival in challenging environments, including the human host. sexual development of the human fungal pathogen cryptococcus neoformans not only produces infectious particles (spores) but has also enabled the evolution of new disease-related traits such as drug resistance. transcription factor networks are essential to the development and pathogenesis of c. neoformans, and a variety ...201627095452
computational analysis reveals a key regulator of cryptococcal virulence and determinant of host response.cryptococcus neoformans is a ubiquitous, opportunistic fungal pathogen that kills over 600,000 people annually. here, we report integrated computational and experimental investigations of the role and mechanisms of transcriptional regulation in cryptococcal infection. major cryptococcal virulence traits include melanin production and the development of a large polysaccharide capsule upon host entry; shed capsule polysaccharides also impair host defenses. we found that both transcription and tran ...201627094327
disseminated cryptococcal infection resulting in acute respiratory distress syndrome (ards) as the initial clinical presentation of aids.cryptococcosis is a cosmopolitan but rare opportunistic mycosis which is usually caused by cryptococcus neoformans. although the most common and worrisome disease manifestation is meningoencephalitis, pulmonary cryptococcosis has the potential to be lethal. the diagnosis of cryptococcal pneumonia is challenging, given its non-specific clinical and radiographic features. respiratory failure leading to acute respiratory distress syndrome as a consequence of cryptococcal disease has been infrequent ...201627086819
glucosylceramide administration as a vaccination strategy in mouse models of cryptococcosis.cryptococcus neoformans is an opportunistic fungal pathogen and the causative agent of the disease cryptococcosis. cryptococcosis is initiated as a pulmonary infection and in conditions of immune deficiency disseminates to the blood stream and central nervous system, resulting in life-threatening meningoencephalitis. a number of studies have focused on the development of a vaccine against cryptococcus, primarily utilizing protein-conjugated components of the cryptococcus polysaccharide capsule a ...201627082428
dap12 inhibits pulmonary immune responses to cryptococcus neoformans.cryptococcus neoformans is an opportunistic fungal pathogen that is inhaled into the lungs and can lead to life-threatening meningoencephalitis in immunocompromised patients. currently, the molecular mechanisms that regulate the mammalian immune response to respiratory cryptococcal challenge remain poorly defined. dap12, a signaling adapter for multiple pattern recognition receptors in myeloid and natural killer (nk) cells, has been shown to play both activating and inhibitory roles during lung ...201627068093
molecular epidemiology and in vitro antifungal susceptibility testing of 108 clinical cryptococcus neoformans sensu lato and cryptococcus gattii sensu lato isolates from denmark.cryptococcosis is mainly caused by members of the cryptococcus gattii/cryptococcus neoformans species complexes. here, we report the molecular characterisation and in vitro antifungal susceptibility of danish clinical cryptococcal isolates. species, genotype, serotype and mating type were determined by amplified fragment length polymorphism (aflp) fingerprinting and qpcr. eucast e.def 7.2 mics were determined for amphotericin b, flucytosine, fluconazole, voriconazole and isavuconazole. most isol ...201627061834
in vitro analysis of metabolites secreted during infection of lung epithelial cells by cryptococcus neoformans.cryptococcus neoformans is an encapsulated basidiomycetous yeast commonly associated with pigeon droppings and soil. the opportunistic pathogen infects humans through the respiratory system and the metabolic implications of c. neoformans infection have yet to be explored. studying the metabolic profile associated with the infection could lead to the identification of important metabolites associated with pulmonary infection. therefore, the aim of the study was to simulate cryptococcal infection ...201627054608
triclosan demonstrates synergic effect with amphotericin b and fluconazole and induces apoptosis-like cell death in cryptococcus neoformans.cryptococcus neoformans is an opportunistic fungus that causes fatal meningoencephalitis especially in aids patients. there is an increasing need for discovery of new anti-cryptococcal drugs due to emergence of resistance cases in recent years. in this study, we aim to elucidate the antifungal effect of triclosan against c. neoformans.201627047474
cryptococcus tetragattii as a major cause of cryptococcal meningitis among hiv-infected individuals in harare, zimbabwe.hiv-associated cryptococcal meningitis is commonly caused by cryptococcus neoformans, whilst infections with cryptococcus gattii sensu lato are historically rare. despite available studies, little is known about the occurrence of c. gattii sensu lato infections among hiv-infected individuals in zimbabwe.201627038502
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