The Multifaceted Function of Granzymes in Sepsis: Some Facts and a Lot to Discover

Sepsis is a serious global health problem. In addition to a high incidence, this syndrome has a high mortality and is responsible for huge health expenditure. The pathophysiology of sepsis is very complex and it is not well-understood yet. However, it is widely accepted that the initial phase of sepsis is characterized by a hyperinflammatory response while the late phase is characterized by immunosuppression and immune anergy, increasing the risk of secondary infections. Granzymes (Gzms) are a family of serine proteases classified according to their cleavage specificity. Traditionally, it was assumed that all Gzms acted as cytotoxic proteases. However, recent evidence suggests that GzmB is the one with the greatest cytotoxic capacity, while the cytotoxicity of others such as GzmA and GzmK is not clear. Recent studies have found that GzmA, GzmB, GzmK, and GzmM act as pro-inflammatory mediators. Specially, solid evidences show that GzmA and GzmK function as extracellular proteases that regulate the inflammatory response irrespectively of its ability to induce cell death. Indeed, studies in animal models indicate that GzmA is involved in the cytokine release syndrome characteristic of sepsis. Moreover, the GZM family also could regulate other biological processes involved in sepsis pathophysiology like the coagulation cascade, platelet function, endothelial barrier permeability, and, in addition, could be involved in the immunosuppressive stage of sepsis. In this review, we provide a comprehensive overview on the contribution of these novel functions of Gzms to sepsis and the new therapeutic opportunities emerging from targeting these proteases for the treatment of this serious health problem

Upper limit on damage zone thickness controlled by seismogenic depth

The thickness of fault damage zones, a characteristic length of the cross‐fault distribution of secondary fractures, significantly affects fault stress, earthquake rupture, ground motions, and crustal fluid transport. Field observations indicate that damage zone thickness scales with accumulated fault displacement at short displacements but saturates at a few hundred meters for displacements larger than a few kilometers. To explain this transition of scaling behavior, we conduct 3D numerical simulations of dynamic rupture with off‐fault inelastic deformation on long strike‐slip faults. We find that the distribution of coseismic inelastic strain is controlled by the transition from crack‐like to pulse‐like rupture propagation associated with saturation of the seismogenic depth. The yielding zone reaches its maximum thickness when the rupture becomes a stable pulse‐like rupture. Considering fracture mechanics theory, we show that seismogenic depth controls the upper bound of damage zone thickness on mature faults by limiting the efficiency of stress concentration near earthquake rupture fronts. We obtain a quantitative relation between limiting damage zone thickness, background stress, dynamic fault strength, off‐fault yield strength, and seismogenic depth, which agrees with first‐order field observations. Our results help link dynamic rupture processes with field observations and contribute to a fundamental understanding of damage zone properties

Agronomic Management of Indigenous Mycorrhizas

Many of the advantages conferred to plants by arbuscular mycorrhiza (AM) are associated to the ability of AM plants to explore a greater volume of soil through the extraradical mycelium. Sieverding (1991) estimates that for each centimetre of colonized root there is an increase of 15 cm3 on the volume of soil explored, this value can increase to 200 cm3 depending on the circumstances. Due to the enhancement of the volume of soil explored and the ability of the extraradical mycelium to absorb and translocate nutrients to the plant, one of the most obvious and important advantages resulting from mycorrhization is the uptake of nutrients. Among of which the ones that have immobilized forms in soil, such as P, assume particular significance. Besides this, many other benefits are recognized for AM plants (Gupta et al, 2000): water stress alleviation (Augé, 2004; Cho et al, 2006), protection from root pathogens (Graham, 2001), tolerance to toxic heavy metals and phytoremediation (Audet and Charest, 2006; Göhre and Paszkowski, 2006), tolerance to adverse conditions such as very high or low temperature, high salinity (Sannazzaro et al, 2006), high or low pH (Yano and Takaki, 2005) or better performance during transplantation shock (Subhan et al, 1998). The extraradical hyphae also stabilize soil aggregates by both enmeshing soil particles (Miller e Jastrow, 1992) and producing a glycoprotein, golmalin, which may act as a glue-like substance to adhere soil particles together (Wright and Upadhyaya, 1998). Despite the ubiquous distribution of mycorrhizal fungi (Smith and Read, 2000) and only a relative specificity between host plants and fungal isolates (McGonigle and Fitter, 1990), the obligate nature of the symbiosis implies the establishment of a plant propagation system, either under greenhouse conditions or in vitro laboratory propagation. These techniques result in high inoculum production costs, which still remains a serious problem since they are not competitive with production costs of phosphorus fertilizer. Even if farmers understand the significance of sustainable agricultural systems, the reduction of phosphorus inputs by using AM fungal inocula alone cannot be justified except, perhaps, in the case of high value crops (Saioto and Marumoto, 2002). Nurseries, high income horticulture farmers and no-agricultural application such as rehabilitation of degraded or devegetated landscapes are examples of areas where the use of commercial inoculum is current. Another serious problem is quality of commercial available products concerning guarantee of phatogene free content, storage conditions, most effective application methods and what types to use. Besides the information provided by suppliers about its inoculum can be deceiving, as from the usually referred total counts, only a fraction may be effective for a particular plant or in specific soil conditions. Gianinazzi and Vosátka (2004) assume that progress should be made towards registration procedures that stimulate the development of the mycorrhizal industry. Some on-farm inoculum production and application methods have been studied, allowing farmers to produce locally adapted isolates and generate a taxonomically diverse inoculum (Mohandas et al, 2004; Douds et al, 2005). However the inocula produced this way are not readily processed for mechanical application to the fields, being an obstacle to the utilization in large scale agriculture, especially row crops, moreover it would represent an additional mechanical operation with the corresponding economic and soil compaction costs. It is well recognized that inoculation of AM fungi has a potential significance in not only sustainable crop production, but also environmental conservation. However, the status quo of inoculation is far from practical technology that can be widely used in the field. Together a further basic understanding of the biology and diversity of AM fungi is needed (Abbott at al, 1995; Saito and Marumoto, 2002). Advances in ecology during the past decade have led to a much more detailed understanding of the potential negative consequences of species introductions and the potential for negative ecological consequences of invasions by mycorrhizal fungi is poorly understood. Schwartz et al, (2006) recommend that a careful assessment documenting the need for inoculation, and the likelihood of success, should be conducted prior to inoculation because inoculations are not universally beneficial. Agricultural practices such as crop rotation, tillage, weed control and fertilizer apllication all produce changes in the chemical, physical and biological soil variables and affect the ecological niches available for occupancy by the soil biota, influencing in different ways the symbiosis performance and consequently the inoculum development, shaping changes and upset balance of native populations. The molecular biology tools developed in the latest years have been very important for our perception of these changes, ensuing awareness of management choice implications in AM development. In this context, for extensive farming systems and regarding environmental and economic costs, the identification of agronomic management practices that allow controlled manipulation of the fungal community and capitalization of AM mutualistic effect making use of local inoculum, seem to be a wise option for mycorrhiza promotion and development of sustainable crop production

Autism as a disorder of neural information processing: directions for research and targets for therapy

The broad variation in phenotypes and severities within autism spectrum disorders suggests the involvement of multiple predisposing factors, interacting in complex ways with normal developmental courses and gradients. Identification of these factors, and the common developmental path into which theyfeed, is hampered bythe large degrees of convergence from causal factors to altered brain development, and divergence from abnormal brain development into altered cognition and behaviour. Genetic, neurochemical, neuroimaging and behavioural findings on autism, as well as studies of normal development and of genetic syndromes that share symptoms with autism, offer hypotheses as to the nature of causal factors and their possible effects on the structure and dynamics of neural systems. Such alterations in neural properties may in turn perturb activity-dependent development, giving rise to a complex behavioural syndrome many steps removed from the root causes. Animal models based on genetic, neurochemical, neurophysiological, and behavioural manipulations offer the possibility of exploring these developmental processes in detail, as do human studies addressing endophenotypes beyond the diagnosis itself

Stability of Organic Carbon Components in Shale: Implications for Carbon Cycle

Stability and mobility of organic matter in shale is significant from the perspective of carbon cycle. Shale can only be an effective sink provided that the organic carbon present is stable and immobile from the host sites and, not released easily during geological processes such as low pressure-temperature burial diagenesis and higher pressure-temperature subduction. To examine this, three Jurassic shale samples of known mineralogy and total organic carbon content, with dominantly continental source of organic matter, belonging to the Haynesville-Bossier Formation were combusted by incremental heating from temperature of 200 to 1400°C. The samples were analyzed for their carbon and nitrogen release profiles, bulk δ13C composition and C/N atomic ratio, based on which, at least four organic carbon components are identified associated with different minerals such as clay, carbonate, and silicate. They have different stability depending on their host sites and occurrences relative to the mineral phases and consequently, released at different temperature during combustion. The components identified are denoted as, C-1 (organic carbon occurring as free accumulates at the edge or mouth of pore spaces), C-2 (associated with clay minerals, adsorbed or as organomineral nanocomposites; with carbonate minerals, biomineralized and/or occluded), C-3(a) (occurring with silicate minerals, biomineralized and/or occluded) and C-3(b) (graphitized carbon). They show an increasing stability and decreasing mobility from C-1 to C-3(b). Based on the stability of the different OC components, shale is clearly an efficient sink for the long term C cycle as, except for C-1 which forms a very small fraction of the total and is released at temperature of ∼200°C, OC can be efficiently locked in shale surviving conditions of burial diagenesis and, subduction at fore arc regions in absence of infiltrating fluids. Under low fluid flux, C-3(b) can be efficiently retained as a refractory phase in the mantle when subducted. It is evident that the association and interaction of the organic matter with the different minerals play an important role in its retention in the shale

The home environment and childhood obesity in low-income households: indirect effects via sleep duration and screen time

Background Childhood obesity disproportionally affects children from low-income households. With the aim of informing interventions, this study examined pathways through which the physical and social home environment may promote childhood overweight/obesity in low-income households. Methods Data on health behaviors and the home environment were collected at home visits in low-income, urban households with either only normal weight (n = 48) or predominantly overweight/obese (n = 55) children aged 6–13 years. Research staff conducted comprehensive, in-person audits of the foods, media, and sports equipment in each household. Anthropometric measurements were collected, and children’s physical activity was assessed through accelerometry. Caregivers and children jointly reported on child sleep duration, screen time, and dietary intake of foods previously implicated in childhood obesity risk. Path analysis was used to test direct and indirect associations between the home environment and child weight status via the health behaviors assessed. Results Sleep duration was the only health behavior associated with child weight status (OR = 0.45, 95% CI: 0.27, 0.77), with normal weight children sleeping 33.3 minutes/day longer on average than overweight/obese children. The best-fitting path model explained 26% of variance in child weight status, and included paths linking chaos in the home environment, lower caregiver screen time monitoring, inconsistent implementation of bedtime routines, and the presence of a television in children’s bedrooms to childhood overweight/obesity through effects on screen time and sleep duration. Conclusions This study adds to the existing literature by identifying aspects of the home environment that influence childhood weight status via indirect effects on screen time and sleep duration in children from low-income households. Pediatric weight management interventions for low-income households may be improved by targeting aspects of the physical and social home environment associated with sleep

Mental Health Status of Healthcare Workers During the COVID-19 Outbreak An International Study

Background: The COVID-19 pandemic is a massive health crisis that has exerted enormous physical and psychological pressure. Mental healthcare for healthcare workers (HCWs) should receive serious consideration. This study served to determine the mental-health outcomes of 1,556 HCWs from 45 countries who participated in the COVID-19 IMPACT project, and to examine the predictors of the outcomes during the first pandemic wave. Methods: Outcomes assessed were self-reported perceived stress, depression symptom, and sleep changes. The predictors examined included sociodemographic factors and perceived social support. Results: The results demonstrated that half of the HCWs had moderate levels of perceived stress and symptoms of depression. Half of the HCWs (n = 800, 51.4%) had similar sleeping patterns since the pandemic started, and one in four slept more or slept less. HCWs reported less perceived stress and depression symptoms and higher levels of perceived social support than the general population who participated in the same project. Predictors associated with higher perceived stress and symptoms of depression among HCWs included female sex, not having children, living with parents, lower educational level, and lower social support. Discussion: The need for establishing ways to mitigate mental-health risks and adjusting psychological interventions and support for HCWs seems to be significant as the pandemic continues

Establishment and Validation of Computational Model for MT1-MMP Dependent ECM Degradation and Intervention Strategies

MT1-MMP is a potent invasion-promoting membrane protease employed by aggressive cancer cells. MT1-MMP localizes preferentially at membrane protrusions called invadopodia where it plays a central role in degradation of the surrounding extracellular matrix (ECM). Previous reports suggested a role for a continuous supply of MT1-MMP in ECM degradation. However, the turnover rate of MT1-MMP and the extent to which the turnover contributes to the ECM degradation at invadopodia have not been clarified. To approach this problem, we first performed FRAP (Fluorescence Recovery after Photobleaching) experiments with fluorescence-tagged MT1-MMP focusing on a single invadopodium and found very rapid recovery in FRAP signals, approximated by double-exponential plots with time constants of 26 s and 259 s. The recovery depended primarily on vesicle transport, but negligibly on lateral diffusion. Next we constructed a computational model employing the observed kinetics of the FRAP experiments. The simulations successfully reproduced our FRAP experiments. Next we inhibited the vesicle transport both experimentally, and in simulation. Addition of drugs inhibiting vesicle transport blocked ECM degradation experimentally, and the simulation showed no appreciable ECM degradation under conditions inhibiting vesicle transport. In addition, the degree of the reduction in ECM degradation depended on the degree of the reduction in the MT1-MMP turnover. Thus, our experiments and simulations have established the role of the rapid turnover of MT1-MMP in ECM degradation at invadopodia. Furthermore, our simulations suggested synergetic contributions of proteolytic activity and the MT1-MMP turnover to ECM degradation because there was a nonlinear and marked reduction in ECM degradation if both factors were reduced simultaneously. Thus our computational model provides a new in silico tool to design and evaluate intervention strategies in cancer cell invasion

Mental health and adherence to covid-19 protective behaviors among cancer patients during the covid-19 pandemic: An international, multinational cross-sectional study

A population-based cross-sectional study was conducted during the first COVID-19 wave, to examine the impact of COVID-19 on mental health using an anonymous online survey, enrolling 9565 individuals in 78 countries. The current sub-study examined the impact of the pandemic and the associated lockdown measures on the mental health, and protective behaviors of cancer patients in comparison to non-cancer participants. Furthermore, 264 participants from 30 different countries reported being cancer patients. The median age was 51.5 years, 79.9% were female, and 28% had breast cancer. Cancer participants reported higher self-efficacy to follow recommended national guidelines regarding COVID-19 protective behaviors compared to non-cancer participants (p < 0.01). They were less stressed (p < 0.01), more psychologically flexible (p < 0.01), and had higher levels of positive affect compared to non-cancer participants. Amongst cancer participants, the majority (80.3%) reported COVID-19, not their cancer, as their priority during the first wave of the pandemic and females reported higher levels of stress compared to males. In conclusion, cancer participants appeared to have handled the unpredictable nature of the first wave of the pandemic efficiently, with a positive attitude towards an unknown and otherwise frightening situation. Larger, cancer population specific and longitudinal studies are warranted to ensure adequate medical and psychological care for cancer patients