Pyroptosis in Neutrophils: Multimodal Integration of Inflammasome and Regulated Cell Death Signaling Pathways

Pyroptosis is a proinflammatory mode of lytic cell death mediated by accumulation of plasma membrane (PM) macropores composed of gasdermin-family (GSDM) proteins. It facilitates two major functions in innate immunity: (i) elimination of intracellular replicative niches for pathogenic bacteria; and (ii) non-classical secretion of IL-1 family cytokines that amplify host-beneficial inflammatory responses to microbial infection or tissue damage. Physiological roles for gasdermin D (GSDMD) in pyroptosis and IL-1β release during inflammasome signaling have been extensively characterized in macrophages. This involves cleavage of GSDMD by caspase-1 to generate GSDMD macropores that mediate IL-1β efflux and progression to pyroptotic lysis. Neutrophils, which rapidly accumulate in large numbers at sites of tissue infection or damage, become the predominant local source of IL-1β in coordination with their potent microbiocidal capacity. Similar to macrophages, neutrophils express GSDMD and utilize the same spectrum of diverse inflammasome platforms for caspase-1-mediated cleavage of GSDMD. Distinct from macrophages, neutrophils possess a remarkable capacity to resist progression to GSDMD-dependent pyroptotic lysis to preserve their viability for efficient microbial killing while maintaining GSDMD-dependent mechanisms for export of bioactive IL-1β. Rather, neutrophils employ cell-specific mechanisms to conditionally engage GSDMD-mediated pyroptosis in response to bacterial pathogens that use neutrophils as replicative niches. GSDMD and pyroptosis have also been mechanistically linked to induction of NETosis, a signature neutrophil pathway that expels decondensed nuclear DNA into extracellular compartments for immobilization and killing of microbial pathogens. This review summarizes a rapidly growing number of recent studies that have produced new insights, unexpected mechanistic nuances, and some controversies regarding the regulation of, and roles for, neutrophil inflammasomes, pyroptosis, and GSDMs in diverse innate immune responses

Setting a precautionary catch limit for Antarctic krill

A revised precautionary catch limit for Antarctic krill (Euphausia superba) in the Scotia Sea of 4 million tons was recently adopted by the Commission for the Conservation of Antarctic Marine Living Resources (CCAMLR). The limit was based on a total biomass of 44.3 million tons, as estimated from an acoustic and net survey of krill across the Scotia Sea sector of the Southern Ocean, and a harvest rate of 9.1%, as determined from an analysis of the risks of exceeding defined conservation criteria. We caution, however, that before the fishery can expand to the 4-inillion-ton level it will be necessary to establish mechanisms to avoid concentration of fishing effort, particularly in proximity to colonies of land-breeding krill predators, and to consider the effects of krill immigrating into the region from multiple sources

The treatment of psychotic major depression: is there a role for adjunctive psychotherapy?

Psychotherapy and Psychosomatics, 76(5): pp. 271-277.Background: Psychotic depression is a relatively prevalent mood disorder associated with greater symptom severity, a poorer course of illness and higher levels of functional impairment compared with nonpsychotic depression. Separate lines of investigation suggest that various forms of cognitive- behavioral therapy are efficacious for treating severe forms of nonpsychotic depression as well as primary psychotic disorders. However, there currently are no empirically supported psychotherapies specifically designed for treating psychotic depression. Method: We review the efficacy of current somatic treatments for the disorder and discuss the limited data to date on potentially useful psychotherapeutic approaches. In particular, we describe the clinical improvement observed in a subgroup of hospitalized patients with psychotic depression treated with Acceptance and Commitment Therapy as part of a larger clinical trial. Results: Pilot results demonstrated that Acceptance and Commitment Therapy was associated with clinically significant reductions in acute symptom severity and impairment compared with treatment as usual. Conclusion: The findings suggest that patients with psychotic depression can benefit from psychotherapy. Clinical and research recommendations in this area are presented

Developmental stage of oligodendrocytes determines their response to activated microglia in vitro

<p>Abstract</p> <p>Background</p> <p>Oligodendrocyte progenitor cells (OPCs) and mature oligodendrocytes are both lost in central nervous system injury and disease. Activated microglia may play a role in OPC and oligodendrocyte loss or replacement, but it is not clear how the responses of OPCs and oligodendrocytes to activated microglia differ.</p> <p>Methods</p> <p>OPCs and microglia were isolated from rat cortex. OPCs were induced to differentiate into oligodendrocytes with thyroid hormone in defined medium. For selected experiments, microglia were added to OPC or oligodendrocyte cultures. Lipopolysaccharide was used to activate microglia and microglial activation was confirmed by TNFα ELISA. Cell survival was assessed with immunocytochemistry and cell counts. OPC proliferation and oligodendrocyte apoptosis were also assessed.</p> <p>Results</p> <p>OPCs and oligodendrocytes displayed phenotypes representative of immature and mature oligodendrocytes, respectively. Activated microglia reduced OPC survival, but increased survival and reduced apoptosis of mature oligodendrocytes. Activated microglia also underwent cell death themselves.</p> <p>Conclusion</p> <p>Activated microglia may have divergent effects on OPCs and mature oligodendrocytes, reducing OPC survival and increasing mature oligodendrocyte survival. This may be of importance because activated microglia are present in several disease states where both OPCs and mature oligodendrocytes are also reacting to injury. Activated microglia may simultaneously have deleterious and helpful effects on different cells after central nervous system injury.</p

Natural Training Hydration Status, Sweat Rates, and Perception of Sweat Losses During Crossfit Training

International Journal of Exercise Science 9(5): 576-586, 2016. This study assessed 30 male and 20 female well-trained CrossFit (XF) athletes’ natural hydration statuses, fluid intake, and absolute and estimated sweat losses during training sessions lasting 30-47 min. Participants provided a pre-workout urine sample for assessment of hydration by urine specific gravity (USG). Nude pre- and post-workout body mass and fluid intakes were measured to determine sweat losses. To evaluate perception of total sweat loss, participants were asked to estimate their total sweat loss to compare against actual sweat loss. Mean sweat losses did not exceed 1% body mass for men (range = 0.31-1.58% body mass) or women (range = 0.53-1.34% body mass), but sweat rates were nearly double for men (1.663 ± 0.478 L/h) vs. women (0.886 ± 0.274 L/h). Pre-exercise USG indicated euhydration for the majority of participants (32/50 samples = USG \u3c 1.020). Only one participant had a USG \u3e1.030. Mean sweat loss (0.746 ± 0.305 L) and mean sweat loss prediction (0.655 ± 0.404 L) were not significantly different (p = 0.12), and accuracy did not differ (p = 0.44) between men (-9.5 ± 53.7%) and women (+4.3 ± 70.9). No relationship (r = 0.095) was found between sweat loss prediction and fluid intake. Despite high sweat rates, no athletes lost greater than 2% body mass during a strenuous workout. This data combined with consistently normal pre-exercise USG and high fluid intake during exercise suggests ad libitum fluid intake is sufficient to ensure euhydration in the majority of XF participants

Adaptive-optics Optical Coherence Tomography Processing Using a Graphics Processing Unit

Graphics processing units are increasingly being used for scientific computing for their powerful parallel processing abilities, and moderate price compared to super computers and computing grids. In this paper we have used a general purpose graphics processing unit to process adaptive-optics optical coherence tomography (AOOCT) images in real time. Increasing the processing speed of AOOCT is an essential step in moving the super high resolution technology closer to clinical viability

Modeling Neonatal Intraventricular Hemorrhage through Intraventricular Injection of Hemoglobin.

Neonatal intraventricular hemorrhage (IVH) is a common consequence of premature birth and leads to brain injury, posthemorrhagic hydrocephalus (PHH), and lifelong neurological deficits. While PHH can be treated by temporary and permanent cerebrospinal fluid (CSF) diversion procedures (ventricular reservoir and ventriculoperitoneal shunt, respectively), there are no pharmacological strategies to prevent or treat IVH-induced brain injury and hydrocephalus. Animal models are needed to better understand the pathophysiology of IVH and test pharmacological treatments. While there are existing models of neonatal IVH, those that reliably result in hydrocephalus are often limited by the necessity for large-volume injections, which may complicate modeling of the pathology or introduce variability in the clinical phenotype observed. Recent clinical studies have implicated hemoglobin and ferritin in causing ventricular enlargement after IVH. Here, we develop a straightforward animal model that mimics the clinical phenotype of PHH utilizing small-volume intraventricular injections of the blood breakdown product hemoglobin. In addition to reliably inducing ventricular enlargement and hydrocephalus, this model results in white matter injury, inflammation, and immune cell infiltration in periventricular and white matter regions. This paper describes this clinically relevant, simple method for modeling IVH-PHH in neonatal rats using intraventricular injection and presents methods for quantifying ventricle size post injection

Self-Control in Cyberspace: Applying Dual Systems Theory to a Review of Digital Self-Control Tools

Many people struggle to control their use of digital devices. However, our understanding of the design mechanisms that support user self-control remains limited. In this paper, we make two contributions to HCI research in this space: first, we analyse 367 apps and browser extensions from the Google Play, Chrome Web, and Apple App stores to identify common core design features and intervention strategies afforded by current tools for digital self-control. Second, we adapt and apply an integrative dual systems model of self-regulation as a framework for organising and evaluating the design features found. Our analysis aims to help the design of better tools in two ways: (i) by identifying how, through a well-established model of self-regulation, current tools overlap and differ in how they support self-control; and (ii) by using the model to reveal underexplored cognitive mechanisms that could aid the design of new tools.Comment: 11.5 pages (excl. references), 6 figures, 1 tabl

The Radio-Loud Fraction of Quasars is a Strong Function of Redshift and Optical Luminosity

Using a sample of optically-selected quasars from the Sloan Digital Sky Survey, we have determined the radio-loud fraction (RLF) of quasars as a function of redshift and optical luminosity. The sample contains more than 30,000 objects and spans a redshift range of 0<z<5 and a luminosity range of -30<M_i<-22. We use both the radio-to-optical flux ratio (R parameter) and radio luminosity to define radio-loud quasars. After breaking the correlation between redshift and luminosity due to the flux-limited nature of the sample, we find that the RLF of quasars decreases with increasing redshift and decreasing luminosity. The relation can be described in the form of log(RLF/(1-RLF)) = b_0 + b_z log(1+z) + b_M (M_{2500}+26), where M_{2500} is the absolute magnitude at rest-frame 2500A, and b_z, b_M10 to define radio-loud quasars, we find that b_0=-0.132+/-0.116, b_z=-2.052+/-0.261, and b_M=-0.183+/-0.025. The RLF at z=0.5 declines from 24.3% to 5.6% as luminosity decreases from M_{2500}=-26 to M_{2500}=-22, and the RLF at M_{2500}=-26 declines from 24.3% to 4.1% as redshift increases from 0.5 to 3, suggesting that the RLF is a strong function of both redshift and luminosity. We also examine the impact of flux-related selection effects on the RLF determination using a series of tests, and find that the dependence of the RLF on redshift and luminosity is highly likely to be physical, and the selection effects we considered are not responsible for the dependence.Comment: 23 pages, 8 figures. Accepted for publication in Ap

Specific glycosaminoglycan chain length and sulfation patterns are required for cell uptake of tau versus α-synuclein and β-amyloid aggregates

Transcellular propagation of protein aggregate “seeds” has been proposed to mediate the progression of neurodegenerative diseases in tauopathies and α-synucleinopathies. We previously reported that tau and α-synuclein aggregates bind heparan sulfate proteoglycans (HSPGs) on the cell surface, promoting cellular uptake and intracellular seeding. However, the specificity and binding mode of these protein aggregates to HSPGs remain unknown. Here, we measured direct interaction with modified heparins to determine the size and sulfation requirements for tau, α-synuclein, and β-amyloid (Aβ) aggregate binding to glycosaminoglycans (GAGs). Varying the GAG length and sulfation patterns, we next conducted competition studies with heparin derivatives in cell-based assays. Tau aggregates required a precise GAG architecture with defined sulfate moieties in the N- and 6-O-positions, whereas the binding of α-synuclein and Aβ aggregates was less stringent. To determine the genes required for aggregate uptake, we used CRISPR/Cas9 to individually knock out the major genes of the HSPG synthesis pathway in HEK293T cells. Knockouts of the extension enzymes exostosin 1 (EXT1), exostosin 2 (EXT2), and exostosin-like 3 (EXTL3), as well as N-sulfotransferase (NDST1) or 6-O-sulfotransferase (HS6ST2) significantly reduced tau uptake, consistent with our biochemical findings, and knockouts of EXT1, EXT2, EXTL3, or NDST1, but not HS6ST2 reduced α-synuclein uptake. In summary, tau aggregates display specific interactions with HSPGs that depend on GAG length and sulfate moiety position, whereas α-synuclein and Aβ aggregates exhibit more flexible interactions with HSPGs. These principles may inform the development of mechanism-based therapies to block transcellular propagation of amyloid protein–based pathologies