Identification and Phenotypic Characterization of Hsp90 Phosphorylation Sites That Modulate Virulence Traits in the Major Human Fungal Pathogen Candida albicans

The highly conserved, ubiquitous molecular chaperone Hsp90 is a key regulator of cellular proteostasis and environmental stress responses. In human pathogenic fungi, which kill more than 1.6 million patients each year worldwide, Hsp90 governs cellular morphogenesis, drug resistance, and virulence. Yet, our understanding of the regulatory mechanisms governing fungal Hsp90 function remains sparse. Post-translational modifications are powerful components of nature’s toolbox to regulate protein abundance and function. Phosphorylation in particular is critical in many cellular signaling pathways and errant phosphorylation can have dire consequences for the cell. In the case of Hsp90, phosphorylation affects its stability and governs its interactions with co-chaperones and clients. Thereby modulating the cell’s ability to cope with environmental stress. Candida albicans, one of the leading human fungal pathogens, causes ~750,000 life-threatening invasive infections world-wide with unacceptably high mortality rates. Yet, it remains unknown if and how Hsp90 phosphorylation affects C. albicans virulence traits. Here, we show that phosphorylation of Hsp90 is critical for expression of virulence traits. We combined proteomics, molecular evolution analyses and structural modelling with molecular biology to characterize the role of Hsp90 phosphorylation in this non-model pathogen. We demonstrated that phosphorylation negatively affects key virulence traits, such as the thermal stress response, morphogenesis, and drug susceptibility. Our results provide the first record of a specific Hsp90 phosphorylation site acting as modulator of fungal virulence. Post-translational modifications of Hsp90 could prove valuable in future exploitations as antifungal drug targets

Ischemic Brain Injury Secondary to Severe Systemic Loxoscelism

Systemic loxoscelism is a rare complication from the bite of spiders in the genus Loxosceles.These bites usually cause painful indurated skin reactions, including necrosis,and occasionally cause systemic complications, such as rhabdomyolysis, acute renalfailure, and disseminated intravascular coagulation. Our case had multiple systemiccomplications, including bilateral globus pallidus infarcts with right arm weakness

Fibromyalgia in migraine: a retrospective cohort study

Abstract Background Migraine is a common and disabling disorder. Fibromyalgia has been shown to be commonly comorbid in patients with migraine and can intensify disability. The aim of this study was to determine if patients with co-morbid fibromyalgia and migraine report more depressive symptoms, have more headache related disability, or report higher intensity of headache as compared to patients with migraine only. Cases of comorbid fibromyalgia and migraine were identified using a prospectively maintained headache database at Mayo Clinic Rochester. One-hundred and fifty seven cases and 471 controls were identified using this database and the Mayo Clinic electronic medical record. Findings Depressive symptoms as assessed by PHQ-9, intensity of headache, and migraine related disability as assessed by MIDAS were primary measures used to compare migraine patients with comorbid fibromyalgia versus those without. Patients with comorbid fibromyalgia reported significantly higher PHQ-9 scores (OR 1.08, p < .0001) and headache intensity scores (OR 1.149, p = .007). There was no significant difference in migraine related disability (OR 1.002, p = .075). Patients with fibromyalgia were more likely to score in a higher category of depression severity (OR 1.467, p < .0001) and more likely to score in a higher category of migraine related disability (OR 1.23, p = .004). Conclusion Patients with comorbid fibromyalgia and migraine report more depressive symptoms, higher headache intensity, and are more likely to have severe headache related disability as compared to controls without fibromyalgia. Clinicians who care for patients with migraine may consider screening for comorbid fibromyalgia particularly in patients with moderate to severe depressive symptoms, high headache intensity and/or high headache related disability. This is the first matched study to look at these characterisitcs, and it replicates previous findings from unmatched studies

Nuclear Mitochondrial DNA Mutation Causing a Leber Hereditary Optic Neuropathy Phenotypic Expression

Leber hereditary optic neuropathy (LHON) is associated with mutations of the mitochondrial (mt) DNA. The most common point mutations are positions 11778, 3460, and 14484 of subunit ND4, ND1 and ND6, respectively resulting in mitochondrial complex 1 deficiency. We report the first known case of a LHON "plus" phenotypic expression associated with pathogenic mutations of a nuclear (n) DNA gene that encodes NDUFAF5, a mitochondrial complex I assembly factor

Diagnostic Dilemma in Primary Blastomyces dermatitidis Meningitis: Role of Neurosurgical Biopsy

A 52-year-old male on chronic prednisone for polymyalgia rheumatica presented with a subacute history of headaches, nausea, phonophobia, intermittent diplopia and gait instability. He was hospitalized 2 weeks prior to presentation with extensive evaluations only notable for leptomeningeal inflammation on MRI. His symptoms progressively worsened and he developed aphasia. He was transferred to our facility where extensive spinal fluid examinations were repeated and were again nondiagnostic. Ultimately, a diagnostic skull-based biopsy was performed which demonstrated Blastomyces dermatitidis fungal meningitis. Despite extensive sampling and cultures, only 1 of the intraoperative samples yielded diagnostic results. This underscores the low sensitivity of current methods to diagnose CNS blastomycosis. This case suggests that a neurosurgical biopsy may be necessary and should be considered early in the diagnostic process, especially if a definitive diagnosis is elusive. If a biopsy is performed, sampling should be ample and from multiple areas. Following the diagnosis, our patient was treated with liposomal amphotericin B and then voriconazole with a good clinical response