Lactate signalling regulates fungal β-glucan masking and immune evasion

AJPB: This work was supported by the European Research Council (STRIFE, ERC- 2009-AdG-249793), The UK Medical Research Council (MR/M026663/1), the UK Biotechnology and Biological Research Council (BB/K017365/1), the Wellcome Trust (080088; 097377). ERB: This work was supported by the UK Biotechnology and Biological Research Council (BB/M014525/1). GMA: Supported by the CNPq-Brazil (Science without Borders fellowship 202976/2014-9). GDB: Wellcome Trust (102705). CAM: This work was supported by the UK Medical Research Council (G0400284). DMM: This work was supported by UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC/K000306/1). NARG/JW: Wellcome Trust (086827, 075470,101873) and Wellcome Trust Strategic Award in Medical Mycology and Fungal Immunology (097377). ALL: This work was supported by the MRC Centre for Medical Mycology and the University of Aberdeen (MR/N006364/1).Peer reviewedPostprin

Hyphal Development in Candida albicans Requires Two Temporally Linked Changes in Promoter Chromatin for Initiation and Maintenance

Phenotypic plasticity is common in development. For Candida albicans, the most common cause of invasive fungal infections in humans, morphological plasticity is its defining feature and is critical for its pathogenesis. Unlike other fungal pathogens that exist primarily in either yeast or hyphal forms, C. albicans is able to switch reversibly between yeast and hyphal growth forms in response to environmental cues. Although many regulators have been found involved in hyphal development, the mechanisms of regulating hyphal development and plasticity of dimorphism remain unclear. Here we show that hyphal development involves two sequential regulations of the promoter chromatin of hypha-specific genes. Initiation requires a rapid but temporary disappearance of the Nrg1 transcriptional repressor of hyphal morphogenesis via activation of the cAMP-PKA pathway. Maintenance requires promoter recruitment of Hda1 histone deacetylase under reduced Tor1 (target of rapamycin) signaling. Hda1 deacetylates a subunit of the NuA4 histone acetyltransferase module, leading to eviction of the NuA4 acetyltransferase module and blockage of Nrg1 access to promoters of hypha-specific genes. Promoter recruitment of Hda1 for hyphal maintenance happens only during the period when Nrg1 is gone. The sequential regulation of hyphal development by the activation of the cAMP-PKA pathway and reduced Tor1 signaling provides a molecular mechanism for plasticity of dimorphism and how C. albicans adapts to the varied host environments in pathogenesis. Such temporally linked regulation of promoter chromatin by different signaling pathways provides a unique mechanism for integrating multiple signals during development and cell fate specification

Failure of Antithrombotic Therapy and Risk of Stroke in Patients With Symptomatic Intracranial Stenosis

BACKGROUND AND PURPOSE: We sought to determine if patients with intracranial stenosis who have a TIA or stroke on antithrombotic therapy are at particularly high risk for recurrent stroke. METHODS: We compared baseline features and the rates of stroke or vascular death and stroke in the territory of the symptomatic artery between patients ON (n=299) vs. OFF (n=269) antithrombotics at the time of their qualifying event for the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial. RESULTS: In univariate analyses, there was no difference in the rates of stroke or vascular death (21 vs. 23%, HR (ON/OFF) = 0.91 (95%CI: 0.64–1.29), p= 0.59) or stroke in territory (13 vs. 14%, HR (ON/OFF) = 0.90 (95%CI: 0.57–1.39), p=0.61) between patients ON vs. OFF antithrombotics at the time of their qualifying event. A multivariable analysis adjusted for the difference in risk factors between patients ON and OFF antithrombotic therapy also showed no significant differences in the combined endpoint of stroke or vascular death (HR (ON/OFF) = 0.86, 95%CI: 0.55–1.34, p=0.51) or stroke in territory (HR (ON/OFF) = 1.01., 95%CI: 0.58–1.77, p=0.97) between patients ON vs. OFF antithrombotic therapy at the time of qualifying event. CONCLUSIONS: Intracranial stenosis patients who fail antithrombotic therapy are not at higher risk of stroke than those who do not fail antithrombotic therapy. Given our finding that patients ON and OFF antithrombotic therapy are both at high risk for stroke in the territory, intracranial stenting trials should not be limited to just those who fail antithrombotic therapy

The Role of the Frontal Lobe in Complex Walking Among Patients With Parkinson's Disease and Healthy Older Adults: An fNIRS Study

BACKGROUND: Gait is influenced by higher order cognitive and cortical control mechanisms. Functional near infrared spectroscopy (fNIRS) has been used to examine frontal activation during walking in healthy older adults, reporting increased oxygenated hemoglobin (HbO2) levels during dual task walking (DT), compared with usual walking. OBJECTIVE: To investigate the role of the frontal lobe during DT and obstacle negotiation, in healthy older adults and patients with Parkinson's disease (PD). METHODS: Thirty-eight healthy older adults (mean age 70.4 +/- 0.9 years) and 68 patients with PD (mean age 71.7 +/- 1.1 years,) performed 3 walking tasks: (a) usual walking, (b) DT walking, and (c) obstacles negotiation, with fNIRS and accelerometers. Linear-mix models were used to detect changes between groups and within tasks. RESULTS: Patients with PD had higher activation during usual walking (P < .030). During DT, HbO2 increased only in healthy older adults (P < .001). During obstacle negotiation, HbO2 increased in patients with PD (P = .001) and tended to increase in healthy older adults (P = .053). Higher DT and obstacle cost (P < .003) and worse cognitive performance were observed in patients with PD (P = .001). CONCLUSIONS: A different pattern of frontal activation during walking was observed between groups. The higher activation during usual walking in patients with PD suggests that the prefrontal cortex plays an important role already during simple walking. However, higher activation relative to baseline during obstacle negotiation and not during DT in the patients with PD demonstrates that prefrontal activation depends on the nature of the task. These findings may have important implications for rehabilitation of gait in patients with PD