Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field

The legality and economic impact of compensated kidney donation

With the increasing number of ESRD patients in the Philippines, and the prevalence of kidney trade black market, it is now time to consider formally allowing compensated voluntary live non-related donation and its impact the local medical industry, in addressing the shortage of kidney organs amongst patients and the revenue-effect to accredited transplant hospitals. This study seeks to determine if compensated kidney donation should be allowed by the government to address transplant shortage and protect donors

Energy Minimization under Uncertainty using Coordinated Multi-phase Synthesis Techniques

Energy minimization is one of the premiere design objectives in modern inte-grated circuits (ICs). Currently, there is a pressing need to reduce energy con-sumption in systems that span a wide array of form factors, ranging from mobilephones/tablets, where simultaneously maximizing battery lifetime and satisfyinguser experience is of paramount importance, to data centers/super-computers,where even a small reduction in energy can translate to billions of dollars savedin operating costs. However, as transistors continue to scale deeper into the sub-micron regime, producing energy efficient designs has become more challenging.Leakage power has increased significantly with respect to its total power con-tribution, which in turn is exponentially dependent on operating temperature;moreover, this is further exacerbated by increased device densities. Furthermore,the impact of process variation in the design flow under these scenarios requires in-creased attention, as small random alterations on a device (e.g., threshold-voltagevariations) can greatly impact overall energy and delay yields. Thus, as we con-tinue to delve into the billion transistor era and beyond, new techniques are neededto adapt to the continuously evolving physical landscape of IC technology.This thesis presents several systematic and coordinated methods that simul-taneously address energy and performance objectives for nano-scale technologies.We introduce a multi-phase IC synthesis framework with an emphasis on opti-mization parameters that, in recent years, have become more pronounced in near-and super-threshold technology regimes; these parameters include gate switchingactivity, input vector control, load capacitance, and operating temperature. Wepresent new gate-level and structural transformation techniques that, when per-formed in a coordinated fashion, enable more energy efficient designs later in thedesign flow. These techniques include gate sizing and threshold-voltage selection,circuit unfolding, and re-timing. Each technique accounts for the aforementionedparameters in generating ultra-low energy designs that satisfy the specified perfor-mance target. We also present a scenario-based approach for optimization underuncertainty in order to address the impact of process variatio

The role of cell death in interleukin-1beta activation and secretion

© 2016 Dr. Stephanie Ana ConosThe innate immune system can detect the presence of danger and pathogens through receptors that activate both inflammatory cytokine production and cell death. These programmed cell death pathways therefore play critical roles in protecting the host through driving protective inflammation and innate immunity. This thesis focuses on the cell death pathways of pyroptosis, apoptosis and necroptosis; the ways in which these signalling pathways overlap, as well as mechanisms by which these pathways activate inflammation and innate immunity through the cytokine interleukin-1b (IL-1b). Pyroptosis is a lytic form of cell death activated upon innate immune receptor sensing of pathogens or damage to host cells. This caspase dependent form of cell death is driven by the activation of inflammatory caspases upon multiprotein platforms termed inflammasomes. These same caspases simultaneously process and activate inflammatory cytokines such as IL-1b and interleukin-18 (IL-18). Pyroptosis is therefore associated with the release of cytokines and other cellular proteins through rupture of the plasma membrane. What remains under contention is whether cell death is required for IL-1b release or whether active secretion of IL-1b can occur. I address this topic using molecular tools that allowed direct activation of the inflammatory caspase, caspase-1, limiting simultaneous activation of inflammatory signalling pathways. In doing so I experimentally separate the two functions of caspase-1, pyroptotic cell death and cytokine activation, providing evidence that IL-1b can be actively secreted from cells. The same molecular tools allow me to directly examine whether the apoptotic caspase, caspase-8, is capable of activating IL-1b through enzymatic processing. This is important as it is usually assumed that apoptotic caspases kill cells in an immunologically silent manner. By demonstrating the ability of caspase-8 to directly activate pro-inflammatory IL-1b I am contributing to a growing field of literature highlighting the inflammatory potential of caspase-8 signalling. Finally, this thesis explores the molecular mechanisms through which mixed lineage kinase-like (MLKL) mediated necroptotic signalling activates innate immunity via the activation of caspase-1. Like pyroptosis, necroptosis is an inflammatory and lytic form of cell death that results in the release of pro-inflammatory cellular contents. In addition, it has been shown to induce the formation of the NOD (nucleotide-binding oligomerization domain)-like receptor family pyrin domain containing protein-3 (NLRP3) inflammasome to drive caspase-1 activation. I investigate the mechanisms by which necroptosis activates this inflammasome, demonstrating that this activation is a cell intrinsic process, activated prior to the total rupture of the plasma membrane and death of cells. In addition, I examine the contribution of NLRP3-caspase-1 activation of IL-1b to innate immune responses that are triggered in healthy bystander cells following necroptotic cell death. Notably, these results reveal that MLKL-dependent activation of IL-1b has a greater role to play in activating neighbouring innate immune cells then MLKL-driven necroptosis alone. The pathways of apoptosis, pyroptosis and necroptosis all contribute to immunity. In addition, they are each implicated in a range of inflammatory diseases. As such, understanding the crosstalk between these pathways of programmed cell death, as well as the ways in which these pathways can activate inflammation, will be necessary to be able to accurately therapeutically target these pathways in distinct inflammatory diseases

Gate Sizing Under Uncertainty

International audienceWe present a gate sizing approach to efficiently utilize gate switching activity (SA) and gate input vector control leakage (IVC) uncertainty factors in the objective function in order enable more efficient power and speed yield trade-offs. Our algorithm conducts iterative gate freezing and unlocking with cut-based search for the most beneficial gate sizes under delay constraints. In an iterative flow, we interchangeably conduct gate sizing and IVC refinement to adapt to new circuit configurations. We evaluate our approach on benchmarks in 45 nm technology and demonstrate up to 62 % (29 % avg.) energy savings compared to a traditional objective function that does not consider SA and IVC. We further adapt our approach to optimize yield objectives by addressing processing variation (PV). Significant improvements were achieved under identical timing yield targets of up to 84 % max (55 % avg.) and 74 % max (25 % avg.) mean-power savings for selected ISCAS-85 and ITC-99 benchmarks, respectively

Gate Sizing Under Uncertainty

International audienceWe present a gate sizing approach to efficiently utilize gate switching activity (SA) and gate input vector control leakage (IVC) uncertainty factors in the objective function in order enable more efficient power and speed yield trade-offs. Our algorithm conducts iterative gate freezing and unlocking with cut-based search for the most beneficial gate sizes under delay constraints. In an iterative flow, we interchangeably conduct gate sizing and IVC refinement to adapt to new circuit configurations. We evaluate our approach on benchmarks in 45 nm technology and demonstrate up to 62 % (29 % avg.) energy savings compared to a traditional objective function that does not consider SA and IVC. We further adapt our approach to optimize yield objectives by addressing processing variation (PV). Significant improvements were achieved under identical timing yield targets of up to 84 % max (55 % avg.) and 74 % max (25 % avg.) mean-power savings for selected ISCAS-85 and ITC-99 benchmarks, respectively

Gate Sizing in the Presence of Gate Switching Activity and Input Vector Control

Abstract—We introduce a novel gate sizing approach that considers both the gate switching activity (SA) and gate input vector control leakage (IVC). We first extract SA using simulation and find promising input vectors. Next, in an iterative framework, we interchangeably conduct gate sizing and refining the IVC. As dictated by the new objective function, our algorithm conducts iterative gate freezing and unlocking with cut-based search for the most beneficial gate sizes under delay constraints. We evaluate our approach on standard benchmarks in 45 nm technology, showing promising improvement, achieving up to 62 % (29 % avg.) energy savings compared to the traditional objective function. I

Targeting RIP Kinases in Chronic Inflammatory Disease

Chronic inflammatory disorders are characterised by aberrant and exaggerated inflammatory immune cell responses. Modes of extrinsic cell death, apoptosis and necroptosis, have now been shown to be potent drivers of deleterious inflammation, and mutations in core repressors of these pathways underlie many autoinflammatory disorders. The receptor-interacting protein (RIP) kinases, RIPK1 and RIPK3, are integral players in extrinsic cell death signalling by regulating the production of pro-inflammatory cytokines, such as tumour necrosis factor (TNF), and coordinating the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome, which underpin pathological inflammation in numerous chronic inflammatory disorders. In this review, we firstly give an overview of the inflammatory cell death pathways regulated by RIPK1 and RIPK3. We then discuss how dysregulated signalling along these pathways can contribute to chronic inflammatory disorders of the joints, skin, and gastrointestinal tract, and discuss the emerging evidence for targeting these RIP kinases in the clinic