Invasion of the central nervous system by Cryptococcus neoformans requires a secreted fungal metalloprotease.

UnlabelledCryptococcus spp. cause life-threatening fungal infection of the central nervous system (CNS), predominantly in patients with a compromised immune system. Why Cryptococcus neoformans has this remarkable tropism for the CNS is not clear. Recent research on cerebral pathogenesis of C. neoformans revealed a predominantly transcellular migration of cryptococci across the brain endothelium; however, the identities of key fungal virulence factors that function specifically to invade the CNS remain unresolved. Here we found that a novel, secreted metalloprotease (Mpr1) that we identified in the extracellular proteome of C. neoformans (CnMpr1) is required for establishing fungal disease in the CNS. Mpr1 belongs to a poorly characterized M36 class of fungalysins that are expressed in only some fungal species. A strain of C. neoformans lacking the gene encoding Mpr1 (mpr1Δ) failed to breach the endothelium in an in vitro model of the human blood-brain barrier (BBB). A mammalian host infected with the mpr1Δ null strain demonstrated significant improvement in survival due to a reduced brain fungal burden and lacked the brain pathology commonly associated with cryptococcal disease. The in vivo studies further indicate that Mpr1 is not required for fungal dissemination and Mpr1 likely targets the brain endothelium specifically. Remarkably, the sole expression of CnMPR1 in Saccharomyces cerevisiae resulted in a robust migration of yeast cells across the brain endothelium, demonstrating Mpr1's specific activity in breaching the BBB and suggesting that Mpr1 may function independently of the hyaluronic acid-CD44 pathway. This distinct role for Mpr1 may develop into innovative treatment options and facilitate a brain-specific drug delivery platform.ImportanceCryptococcus neoformans is a medically relevant fungal pathogen causing significant morbidity and mortality, particularly in immunocompromised individuals. An intriguing feature is its strong neurotropism, and consequently the hallmark of cryptococcal disease is a brain infection, cryptococcal meningoencephalitis. For C. neoformans to penetrate the central nervous system (CNS), it first breaches the blood-brain barrier via a transcellular pathway; however, the identities of fungal factors required for this transmigration remain largely unknown. In an effort to identify extracellular fungal proteins that could mediate interactions with the brain endothelium, we undertook a proteomic analysis of the extracellular proteome and identified a secreted metalloprotease (Mpr1) belonging to the M36 class of fungalysins. Here we found that Mpr1 promotes migration of C. neoformans across the brain endothelium and into the CNS by facilitating attachment of cryptococci to the endothelium surface, thus underscoring the critical role of M36 proteases in fungal pathogenesis

School feeding or general food distribution? Quasi-experimental evidence on the educational impacts of emergency food assistance during conflict in Mali

This study relies on a unique precrisis baseline and five-year follow-up to investigate the effects of emergency school feeding and generalised food distribution (GFD) on children’s schooling during conflict in Mali. It estimates programme impact on child enrolment, absenteeism, and attainment by using a difference in differences weighted estimator. School feeding led to increases in enrolment by 10 percentage points and to around an additional half-year of completed schooling. Attendance among boys in households receiving GFD, however, declined by about 20 per cent relative to the comparison group. Disaggregating by conflict intensity showed that receipt of any food assistance led to a rise in enrolment mostly in high-intensity conflict areas and that the negative effects of GFD on attendance were also concentrated in the most affected areas. School feeding mostly raised attainment among children in areas not in the immediate vicinity of conflict. Programme receipt triggered adjustments in child labour. School feeding led to lower participation and time spent in work among girls, while GFD raised children’s labour, particularly among boys. The educational implications of food assistance should be considered in planning humanitarian responses to bridge the gap between emergency assistance and development by promoting children’s education

Micro-beam and pulsed laser beam techniques for the micro-fabrication of diamond surface and bulk structures

Micro-fabrication in diamond is involved in a wide set of emerging technologies, exploiting the exceptional characteristics of diamond for application in bio-physics, photonics, radiation detection. Micro ion-beam irradiation and pulsed laser irradiation are complementary techniques, which permit the implementation of complex geometries, by modification and functionalization of surface and/or bulk material, modifying the optical, electrical and mechanical characteristics of the material. In this article we summarize the work done in Florence (Italy) concerning ion beam and pulsed laser beam micro-fabrication in diamond.Comment: 14 pages, 5 figure

Examination of Fluconazole-Induced Alopecia in an Animal Model and Human Cohort.

Fluconazole-induced alopecia is a significant problem for patients receiving long-term therapy. We evaluated the hair cycle changes of fluconazole in a rat model and investigated potential molecular mechanisms. Plasma and tissue levels of retinoic acid were not found to be causal. Human patients with alopecia attributed to fluconazole also underwent detailed assessment and in both our murine model and human cohort fluconazole induced telogen effluvium. Future work further examining the mechanism of fluconazole-induced alopecia should be undertaken

Response of microchannel plates to single particles and to electromagnetic showers

We report on the response of microchannel plates (MCPs) to single relativistic particles and to electromagnetic showers. Particle detection by means of secondary emission of electrons at the MCP surface has long been proposed and is used extensively in ion time-of-flight mass spectrometers. What has not been investigated in depth is their use to detect the ionizing component of showers. The time resolution of MCPs exceeds anything that has been previously used in calorimeters and, if exploited effectively, could aid in the event reconstruction at high luminosity colliders. Several prototypes of photodetectors with the amplification stage based on MCPs were exposed to cosmic rays and to 491 MeV electrons at the INFN-LNF Beam-Test Facility. The time resolution and the efficiency of the MCPs are measured as a function of the particle multiplicity, and the results used to model the response to high-energy showers.Comment: Paper submitted to NIM

Response of microchannel plates in ionization mode to single particles and electromagnetic showers

Hundreds of concurrent collisions per bunch crossing are expected at future hadron colliders. Precision timing calorimetry has been advocated as a way to mitigate the pileup effects and, thanks to their excellent time resolution, microchannel plates (MCPs) are good candidate detectors for this goal. We report on the response of MCPs, used as secondary emission detectors, to single relativistic particles and to electromagnetic showers. Several prototypes, with different geometries and characteristics, were exposed to particle beams at the INFN-LNF Beam Test Facility and at CERN. Their time resolution and efficiency are measured for single particles and as a function of the multiplicity of particles. Efficiencies between 50% and 90% to single relativistic particles are reached, and up to 100% in presence of a large number of particles. Time resolutions between 20ps and 30ps are obtained.Comment: 20 pages, 9 figures. Paper submitted to NIM

Usefulness of panoramic 344°-viewing in Crohn's disease capsule endoscopy : a proof of concept pilot study with the novel PillCam™ Crohn's system

Background: A new capsule endoscopy (CE) system featuring two advanced optics for 344\ub0-viewing and a prolonged operative time has been recently developed for Crohn's disease (CD) patients. Hence, we evaluated, for the first time, the performance of this novel CE and the add-on value of the 344\ub0-viewing in a multi-center real-life setting. Methods: Consecutive patients with suspected or established CD received the PillCam\u2122 Crohn's System as supplementary diagnostic work-up focused on the small-bowel between June 2017 and June 2018. Technical and clinical data, including the panenteric CE diagnostic yield, the Lewis score and the impact of small-bowel findings on clinical management during a 6-months follow-up (new diagnosis, staging or treatment upgrade) were collected, thereby evaluating the added value of the 344\ub0 panoramic-view (lesions detected by camera A and B) over the standard 172\ub0-view (lesions detected by one camera only). Results: Among 41 patients (aged 43 \ub1 20 years), 73% underwent CE for suspected CD and 27% for established CD. The rate of complete enteroscopy was 90%. No technical failure or retention occurred. Compared to the standard 172\ub0 view, the panoramic 344\ub0-view revealed a greater number of patients with a relevant lesion (56.1% vs. 39.0%; P = 0.023), resulting in higher Lewis score (222,8 vs. 185.7; P = 0.031), and improved clinical management (48.8% vs. 31.7%, P = 0.023). Conclusions: The panoramic 344\ub0-view increases small-bowel CE accuracy, thereby improving the clinical management of CD patients with mild small-bowel active disease. This system should be regarded as a new standard for both small-bowel diagnosis and monitoring in inflammatory bowel diseases