Mycobacterium tuberculosis Type VII Secreted Effector EsxH Targets Host ESCRT to Impair Trafficking

Mycobacterium tuberculosis (Mtb) disrupts anti-microbial pathways of macrophages, cells that normally kill bacteria. Over 40 years ago, D'Arcy Hart showed that Mtb avoids delivery to lysosomes, but the molecular mechanisms that allow Mtb to elude lysosomal degradation are poorly understood. Specialized secretion systems are often used by bacterial pathogens to translocate effectors that target the host, and Mtb encodes type VII secretion systems (TSSSs) that enable mycobacteria to secrete proteins across their complex cell envelope; however, their cellular targets are unknown. Here, we describe a systematic strategy to identify bacterial virulence factors by looking for interactions between the Mtb secretome and host proteins using a high throughput, high stringency, yeast two-hybrid (Y2H) platform. Using this approach we identified an interaction between EsxH, which is secreted by the Esx-3 TSSS, and human hepatocyte growth factor-regulated tyrosine kinase substrate (Hgs/Hrs), a component of the endosomal sorting complex required for transport (ESCRT). ESCRT has a well-described role in directing proteins destined for lysosomal degradation into intraluminal vesicles (ILVs) of multivesicular bodies (MVBs), ensuring degradation of the sorted cargo upon MVB-lysosome fusion. Here, we show that ESCRT is required to deliver Mtb to the lysosome and to restrict intracellular bacterial growth. Further, EsxH, in complex with EsxG, disrupts ESCRT function and impairs phagosome maturation. Thus, we demonstrate a role for a TSSS and the host ESCRT machinery in one of the central features of tuberculosis pathogenesis

The baboon (Papio anubis) extracranial carotid artery: An anatomical guide for endovascular experimentation

BACKGROUND: As novel endovascular strategies are developed for treating neurological disease, there is an increasing need to evaluate these techniques in relevant preclinical models. The use of non-human primates is especially critical given their structural and physiological homology with humans. In order to conduct primate endovascular studies, a comprehensive understanding of the carotid anatomy is necessary. We therefore performed a detailed examination of the vessel lengths, lumen diameters and angles of origin of the baboon extracranial carotid system. METHODS: We characterized the extracranial carotid system often male baboons (Papio anubis, range 15.1–28.4 kg) by early post-mortem dissection. Photographic documentation of vessel lengths, lumen diameters, and angles of origin were measured for each segment of the carotid bilaterally. RESULTS: The common carotid arteries averaged 94.7 ± 1.7 mm (left) and 87.1 ± 1.6 mm (right) in length. The average minimal common carotid lumen diameters were 3.0 ± 0.3 mm (left) and 2.9 ± 0.2 mm (right). Each animal had a common brachiocephalic artery arising from the aorta which bifurcated into the left common carotid artery and right braciocephalic artery after 21.5 ± 1.6 mm. The vascular anatomy was found to be consistent among animals despite a wide range of animal weights. CONCLUSIONS: The consistency in the Papio anubis extracranial carotid system may promote the use of this species in the preclinical investigation of neuro-interventional therapies

The InfraRed Imaging Spectrograph (IRIS) for TMT: latest science cases and simulations

The Thirty Meter Telescope (TMT) first light instrument IRIS (Infrared Imaging Spectrograph) will complete its preliminary design phase in 2016. The IRIS instrument design includes a near-infrared (0.85 - 2.4 micron) integral field spectrograph (IFS) and imager that are able to conduct simultaneous diffraction-limited observations behind the advanced adaptive optics system NFIRAOS. The IRIS science cases have continued to be developed and new science studies have been investigated to aid in technical performance and design requirements. In this development phase, the IRIS science team has paid particular attention to the selection of filters, gratings, sensitivities of the entire system, and science cases that will benefit from the parallel mode of the IFS and imaging camera. We present new science cases for IRIS using the latest end-to-end data simulator on the following topics: Solar System bodies, the Galactic center, active galactic nuclei (AGN), and distant gravitationally-lensed galaxies. We then briefly discuss the necessity of an advanced data management system and data reduction pipeline.Comment: 15 pages, 7 figures, SPIE (2016) 9909-0

Left gaze bias in humans, rhesus monkeys and domestic dogs

While viewing faces, human adults often demonstrate a natural gaze bias towards the left visual field, that is, the right side of the viewee’s face is often inspected first and for longer periods. Using a preferential looking paradigm, we demonstrate that this bias is neither uniquely human nor limited to primates, and provide evidence to help elucidate its biological function within a broader social cognitive framework. We observed that 6-month-old infants showed a wider tendency for left gaze preference towards objects and faces of different species and orientation, while in adults the bias appears only towards upright human faces. Rhesus monkeys showed a left gaze bias towards upright human and monkey faces, but not towards inverted faces. Domestic dogs, however, only demonstrated a left gaze bias towards human faces, but not towards monkey or dog faces, nor to inanimate object images. Our findings suggest that face- and species-sensitive gaze asymmetry is more widespread in the animal kingdom than previously recognised, is not constrained by attentional or scanning bias, and could be shaped by experience to develop adaptive behavioural significance

MeCP2 deficiency results in robust Rett-like behavioural and motor deficits in male and female rats

Since the identification of MECP2 as the causative gene in the majority of Rett Syndrome (RTT) cases, transgenic mouse models have played a critical role in our understanding of this disease. The use of additional mammalian RTT models offers the promise of further elucidating critical early mechanisms of disease as well as providing new avenues for translational studies. We have identified significant abnormalities in growth as well as motor and behavioural function in a novel zincfinger nuclease model of RTT utilizing both male and female rats throughout development. Male rats lacking MeCP2 (Mecp2ZFN/y) were noticeably symptomatic as early as postnatal day 21, with most dying by postnatal day 55, while females lacking one copy of Mecp2 (Mecp2ZFN/þ) displayed a more protracted disease course. Brain weights of Mecp2ZFN/y and Mecp2ZFN/þ rats were significantly reduced by postnatal day 14 and 21, respectively. Early motor and breathing abnormalities were apparent in Mecp2ZFN/y rats, whereas Mecp2ZFN/þ rats displayed functional irregularities later in development. The large size of this species will provide profound advantages in the identification of early disease mechanisms and the development of appropriately timed therapeutics. The current study establishes a foundational basis for the continued utilization of this rat model in future RTT research

A Precise Measurement of the Neutron Magnetic Form Factor GMn in the Few-GeV2 Region

The neutron elastic magnetic form factor GMn has been extracted from quasielastic electron scattering data on deuterium with the CEBAF Large Acceptance Spectrometer (CLAS) at Jefferson Lab. The kinematic coverage of the measurement is continuous from Q2=1 GeV2 to 4.8 GeV2. High precision was achieved by employing a ratio technique in which many uncertainties cancel, and by a simultaneous in-situ calibration of the neutron detection efficiency, the largest correction to the data. Neutrons were detected using the CLAS electromagnetic calorimeters and the time-of-flight scintillators. Data were taken at two different electron beam energies, allowing up to four semi-independent measurements of GMn to be made at each value of Q2. The dipole parameterization is found to provide a good description of the data over the measured Q2 range.Comment: 14 pages, 5 figures, revtex4, submitted to Physical Review Letters, Revised version has changes recommended by journal referee