Gasdermins in Apoptosis: New players in an Old Game.

Apoptosis is a form of programmed cell death (PCD) that plays critical physiological roles in removing superfluous or dangerous cell populations that are unneeded or threatening to the health of the host organism. Although the molecular pathways leading to activation of the apoptotic program have been extensively studied and characterized starting in the 1970s, new evidence suggests that members of the gasdermin superfamily are novel pore-forming proteins that augment apoptosis by permeabilizing the mitochondria and participate in the final stages of the apoptotic program by inducing secondary necrosis/pyroptosis. These findings may explain outstanding questions in the field such as why certain gasdermin members sensitize cells to apoptosis, and why some apoptotic cells also show morphological features of necrosis. Furthermore, the interplay between the gasdermins and apoptosis may also explain why genetic and epigenetic alterations in these genes cause diseases and disorders like cancer and hearing loss. This review focuses on our current understanding of the function of several gasdermin superfamily members, their role in apoptosis, and how they may contribute to pathophysiological conditions

Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death.

Apoptosis is a genetically regulated cell suicide programme mediated by activation of the effector caspases 3, 6 and 7. If apoptotic cells are not scavenged, they progress to a lytic and inflammatory phase called secondary necrosis. The mechanism by which this occurs is unknown. Here we show that caspase-3 cleaves the GSDMD-related protein DFNA5 after Asp270 to generate a necrotic DFNA5-N fragment that targets the plasma membrane to induce secondary necrosis/pyroptosis. Cells that express DFNA5 progress to secondary necrosis, when stimulated with apoptotic triggers such as etoposide or vesicular stomatitis virus infection, but disassemble into small apoptotic bodies when DFNA5 is deleted. Our findings identify DFNA5 as a central molecule that regulates apoptotic cell disassembly and progression to secondary necrosis, and provide a molecular mechanism for secondary necrosis. Because DFNA5-induced secondary necrosis and GSDMD-induced pyroptosis are dependent on caspase activation, we propose that they are forms of programmed necrosis

Gasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation.

Gasdermin E (GSDME/DFNA5) cleavage by caspase-3 liberates the GSDME-N domain, which mediates pyroptosis by forming pores in the plasma membrane. Here we show that GSDME-N also permeabilizes the mitochondrial membrane, releasing cytochrome c and activating the apoptosome. Cytochrome c release and caspase-3 activation in response to intrinsic and extrinsic apoptotic stimuli are significantly reduced in GSDME-deficient cells comparing with wild type cells. GSDME deficiency also accelerates cell growth in culture and in a mouse model of melanoma. Phosphomimetic mutation of the highly conserved phosphorylatable Thr6 residue of GSDME, inhibits its pore-forming activity, thus uncovering a potential mechanism by which GSDME might be regulated. Like GSDME-N, inflammasome-generated gasdermin D-N (GSDMD-N), can also permeabilize the mitochondria linking inflammasome activation to downstream activation of the apoptosome. Collectively, our results point to a role of gasdermin proteins in targeting the mitochondria to promote cytochrome c release to augment the mitochondrial apoptotic pathway

Studies of Error Sources in Geodetic VLBI

Achieving the goal of millimeter uncertainty in three dimensional geodetic positioning on a global scale requires significant improvement in the precision and accuracy of both random and systematic error sources. For this investigation we proposed to study errors due to instrumentation in Very Long Base Interferometry (VLBI) and due to the atmosphere. After the inception of this work we expanded the scope to include assessment of error sources in GPS measurements, especially as they affect the vertical component of site position and the measurement of water vapor in the atmosphere. The atmosphere correction 'improvements described below are of benefit to both GPS and VLBI

Environmental impact assessment: Smith Gardens slope stabilization and long plat applications

Smith Gardens, Inc is a supplier of garden products in the northwest. Operating as a family-owned business, owned by Terry and Carolyn Smith, the company has been functioning for over 100 years. The site (1265 Marine Drive) is located just outside the Urban Growth Area of Bellingham and is over 15 acres. There are two applications for this property: (1) a proposal to subdivide the parcel and build 15 new houses, and (2) to stabilize the bluff near Bellingham Bay, which is at the south tip of the property

Energy materiality : a conceptual review of multi-disciplinary approaches

This jointly authored essay reviews recent scholarship in the social sciences, broadly understood, that focuses on the materiality of energy. Although this work is extraordinarily diverse in its disciplinary and interdisciplinary influences and its theoretical and methodological commitments, we discern four areas of convergence and divergence that we term the locations, uses, relationalities, and analytical roles of energy materiality. We trace these convergences and divergences through five recent scholarly conversations: materiality as a constraint on actors’ behavior; historical energy systems; mobility, space and scale; discourse and power via energy materialities; and energy becoming material.Peer reviewe

Small Unmanned Aircraft Electromagnetic Interference (EMI) Initial Assessment

With many applications envisioned for small Unmanned Aircraft Systems (sUAS), and potentially millions of sUAS expected to be in operation in the future, the electromagnetic interference environment associated with the sUAS is of interest to understanding the potential performance impacts on the sUAS command and control communications link as well as the sUAS payload and payload links. As part of NASA"TM"s UAS Traffic Management (UTM) Project, flight experiments are planned to characterize the RF environment at altitudes up to 400 ft to better understand how UTM command and control links can be expected to perform. The flight experiments will use an RF channel sensing payload attached to an sUAS. In terms of the payload being capable of measuring relatively low level signals at altitude, electromagnetic interference (EMI) emanating from the sUAS vehicle itself could potentially complicate the measurement process. For this reason, NASA was interested in measuring the EMI performance of the sUAS planned for these flight experiments, a DJI model S1000. The S1000 was thus measured in a controlled EMI test chamber at the NASA Ames Research Center. The S1000 is a carbon fiber based platform with eight rotors. As such, the EMI test results represent potential performance of a number of similar sUAS types. sUAS platforms significantly different from the S1000 may also require EMI testing, and the method employed for NASA"TM"s S1000 EMI tests can be applied to other platforms. In this paper we describe the UTM project, the RF channel sensing payload, the EMI testing method and EMI test results for the S1000, and discuss the implications of these results

Realisation of a low frequency SKA Precursor: The Murchison Widefield Array

The Murchison Widefield Array is a low frequency (80-300 MHz) SKA Precursor, comprising 128 aperture array elements distributed over an area of 3 km diameter. The MWA is located at the extraordinarily radio quiet Murchison Radioastronomy Observatory in the mid-west of Western Australia, the selected home for the Phase 1 and Phase 2 SKA low frequency arrays. The MWA science goals include: 1) detection of fluctuations in the brightness temperature of the diffuse redshifted 21 cm line of neutral hydrogen from the epoch of reionisation; 2) studies of Galactic and extragalactic processes based on deep, confusion-limited surveys of the full sky visible to the array; 3) time domain astrophysics through exploration of the variable radio sky; and 4) solar imaging and characterisation of the heliosphere and ionosphere via propagation effects on background radio source emission. This paper will focus on a brief discussion of the as-built MWA system, highlighting several novel characteristics of the instrument, and a brief progress report (as of June 2012) on the final construction phase. Practical completion of the MWA is expected in November 2012, with commissioning commencing from approximately August 2012 and operations commencing near mid 2013. A brief description of recent science results from the MWA prototype instrument is given

Person-centered counseling with Malay clients: spirituality as an indicator of personal growth

A qualitative study was carried out to explore the inner experiences and personal growth of one male and three female Malay university student clients undergoing twelve sessions of person-centered counseling. Data analysis was based on the verbatim accounts of the counseling sessions, Interpersonal Process Recall (IPR) interviews, clients’ journal entries and their non-verbal expressions throughout the sessions. The findings manifest that in the non-directive, egalitarian and person-centered counseling relationship, constructive changes were experienced by the Malay clients in the study, including getting in touch with their religious realization