Apoptotic cell death inhibits oncogenesis at multiple stages, ranging from transformation to metastasis. Consequently, in order for cancer to develop and progress, apoptosis must be inhibited. Cell ...death also plays major roles in cancer treatment, serving as the main effector function of many anti-cancer therapies. In this review, we discuss the role of apoptosis in the development and treatment of cancer. Specifically, we focus upon the mitochondrial pathway of apoptosis-the most commonly deregulated form of cell death in cancer. In this process, mitochondrial outer membrane permeabilisation or MOMP represents the defining event that irrevocably commits a cell to die. We provide an overview of how this pathway is regulated by BCL-2 family proteins and describe ways in which cancer cells can block it. Finally, we discuss exciting new approaches aimed at specifically inducing mitochondrial apoptosis in cancer cells, outlining their potential pitfalls, while highlighting their considerable therapeutic promise.
Necroptosis is a form of programmed cell death that depends on the activation of receptor interacting protein kinase-1 (RIPK1) and RIPK3 by receptors such as tumor necrosis factor (TNF) receptor-1. ...Structural studies indicate that activation of RIPK3 by RIPK1 involves the formation of oligomers via interactions of the RIP homotypic interaction motif (RHIM) domains shared by both proteins; however, the molecular mechanisms by which this occurs are not fully understood. To gain insight into this process, we constructed versions of RIPK3 that could be induced to dimerize or oligomerize in response to a synthetic drug. Using this system, we find that although the formation of RIPK3 dimers is itself insufficient to trigger cell death, this dimerization seeds a RHIM-dependent complex, the propagation and stability of which is controlled by caspase-8 and RIPK1. Consistent with this idea, we find that chemically enforced oligomerization of RIPK3 is sufficient to induce necroptosis, independent of the presence of the RHIM domain, TNF stimulation or RIPK1 activity. Further, although RIPK1 contributes to TNF-mediated RIPK3 activation, we find that RIPK1 intrinsically suppresses spontaneous RIPK3 activation in the cytosol by controlling RIPK3 oligomerization. Cells lacking RIPK1 undergo increased spontaneous RIPK3-dependent death on accumulation of the RIPK3 protein, while cells containing a chemically inhibited or catalytically inactive form of RIPK1 are protected from this form of death. Together, these data indicate that RIPK1 can activate RIPK3 in response to receptor signaling, but also acts as a negative regulator of spontaneous RIPK3 activation in the cytosol.
Apoptosis is dependent upon caspase activation leading to substrate cleavage and, ultimately, cell death. Although required for the apoptotic phenotype, it has become apparent that cells frequently ...die even when caspase function is blocked. This process, termed caspase-independent cell death (CICD), occurs in response to most intrinsic apoptotic cues, provided that mitochondrial outer membrane permeabilization has occurred. Death receptor ligation can also trigger a form of CICD termed necroptosis. In this review, we will examine the molecular mechanisms governing CICD, highlight recent findings demonstrating recovery from conditions of CICD and discuss potential pathophysiological functions of these processes.
The water surface response to subcritical turbulent flow over a backward-facing step (BFS) is studied via high-resolution large-eddy simulation (LES). The LES method is validated first using data of ...previously reported experiments. The LES-predicted water surface is decomposed into different types of gravity waves as well as turbulence-driven forced waves. Analysis of the LES data reveals the interplay between low-frequency large-scale turbulence structures, which are the result of flow separation from the step and reattachment behind the step, and the dynamics of the water surface. The water surface deformation is mainly the result of freely propagating gravity waves and forced waves, owing to turbulence in the form of rollers and/or hairpin vortices. Gravity waves with zero group velocity define the characteristic spatial and temporal scales of the surface deformations at higher frequencies, while large eddies determine their low-frequency modulation. These deformations are mainly confined in lateral bands that propagate downstream following the advection of the near-surface streamwise vortices (rollers) that are shed from the step. Steeper surface waves are observed in regions of negative perturbation velocity gradient and down-welling, downstream of the larger rollers, and are associated with thin isolated regions of high vorticity near the surface. The investigation of such a complex flow has shown that the decomposition of the water surface fluctuations into its different physical components may be used to identify the dynamics of the underlying flow structure.
Inhibition by ammoniacal nitrogen, consisting of free ammonia (NH3) and ammonium ion (NH4+), has been widely investigated for anaerobic digestion. However, despite the large amount of research on the ...subject, ammoniacal nitrogen inhibition still threatens many anaerobic digesters. This paper presents (i) a method to reliably characterise ammoniacal nitrogen inhibition and (ii) a robust inhibition modelling approach. Results showed that NH3 and NH4+ inhibition need to be jointly determined, which can only be done by performing inhibition tests at various total ammoniacal nitrogen (TAN) concentrations and pH values. These test conditions were reliably achieved using the salts NH4HCO3 and NH4Cl without pH adjustment, rather than by using NH4Cl with pH adjustment. The use of only salts showed a lower pH change during the inhibition test (∼1.5 days), thereby decreasing the uncertainty in TAN speciation and strengthening the test and model outputs. A threshold inhibition function satisfactorily described (R2 > 0.99) the joint inhibition of NH3 and NH4+ on three distinct inocula, and provided a better description of the inhibition testing results than a non-competitive inhibition function (R2 ∼0.70). The key advantage of the proposed threshold inhibition function is its capacity to identify the inhibition lower limit (concentration where inhibition starts; KImin) and upper limit (concentration where inhibition is complete; KImax). The threshold inhibition function also identifies the 50% inhibition concentration (KI50) at the midpoint of KImin and KImax. Finally, experimental and model results show that at pH 7.3–7.7 and TAN concentrations above 2000 mgN·L−1, both NH3 and NH4+ contribute significantly to overall inhibition.
•Method to quantify free ammonia and ammonium inhibition on acetoclastic methanogens.•NH3 & NH4+ inhibition has to be jointly determined using various TAN and pH values.•NH4Cl and NH4HCO3 are preferred over NH4Cl with pH adjustment.•Under typical AD conditions, both NH3 and NH4+ contribute to inhibition.•A threshold inhibition function reliably describes NH3 and NH4+ inhibition.
This paper investigates anaerobic co-digestion of pig manure and algae (Scenedesmus sp.) with and without extraction of intracellular algal co-products, with views towards the development of a ...biorefinery concept for lipid, protein and/or biogas production. Protein and/or lipids were extracted from Scenedesmus sp. using free nitrous acid pre-treatments and solvent-based Soxhlet extraction, respectively. Processing increased algae methane yield between 29% and 37% compared to raw algae (VS basis), but reduced the amount of algae available for digestion. Co-digestion experiments showed a synergy between pig manure and raw algae that increased raw algae methane yield from 0.163 to 0.245 m(3) CH4 kg(-1)VS. No such synergy was observed when algal residues were co-digested with pig manure. Finally, experimental results were used to develop a high-level concept for an integrated biorefinery processing pig manure and onsite cultivated algae, evaluating methane production and co-product recovery per mass of pig manure entering the refinery.
Interaction of tumour cells with their microenvironment impacts on all aspects of cancer, ranging from development through to treatment response. In this issue, Dvorak and colleagues(1) reveal a ...novel tumour/microenvironment relationship that may drive leukemia pathogenesis. Specifically, they find that leukemic cells secrete chromatin-complexed DNA that, in turn, triggers a variety of harmful effects, including cell death, in neighbouring stromal cells. Through this toxicity, DNA-mediated bone marrow destruction could promote disease progression by allowing leukemic cells to exit the bone marrow into the circulation.
This study examined how objective measures of sleep change across shift-cycles, and the impact of this on sleep quality and fatigue. Forty maritime pilots were recruited from Australian ports. Sleep ...wake-behaviour (timing and length), and self-reported sleep quality and fatigue, were assessed to determine any impact of roster status and 'on-call' status. On-roster pilots experienced reduced night time sleep duration compared to those off-roster (57 ± 8.8 min), while working on-call also diminished night time sleep duration (126 ± 11.3 min) and quality, compared to workers not on-call. Fatigue scores indicated that participants were not fully recovered prior to commencing rostered night shift, while sleep quality was significantly worse following sleep that occurred after a night shift, compared to after a day shift. These findings potentially support workplace negotiations to change future shift cycles, and to adopt monitoring systems that may mitigate the risk of fatigue-related accidents and chronic health outcomes. Practitioner summary: Long and irregular work hours of maritime pilotage can compromise worker performance and safety. This observational study found that on-roster pilots experience reduced sleep duration compared to those off-roster, while working on-call further diminishes sleep duration and quality. Future workload/fatigue monitoring systems may mitigate fatigue-related accidents and adverse chronic health outcomes.
Abbreviations: ANOVA: analysis of variance; ANCOVA: analysis of covariance; BMI: body mass index; CVD: cardiovascular disease; h: hours; mins: minutes; SE: standard error of the mean; SD: standard deviation; SO: sleep opportunities; TST: total sleep time; WASO: wake after sleep onset
Stringent phosphorus discharge standards (i.e. 0.15–0.3 g P.m−3) in the Baltic area will compel wastewater treatment practice to augment enhanced biological phosphorus removal (EBPR) with chemical ...precipitation using metal salts. This study examines control of iron chemical dosing for phosphorus removal under dynamic loading conditions to optimize operational aspects of a membrane biological reactor (MBR) pilot plant. An upgraded version of the Benchmark Simulation Model No. 2 (BSM2) with an improved physico-chemical framework (PCF) is used to develop a plant-wide model for the pilot plant. The PCF consists of an equilibrium approach describing ion speciation and pairing, kinetic minerals precipitation (such as hydrous ferric oxides (HFO) and FePO4) as well as adsorption and co-precipitation. Model performance is assessed against data sets from the pilot plant, evaluating the capability to describe water and sludge lines across the treatment process under steady-state operation. Simulated phosphorus differed as little as 5–10% (relative) from measured phosphorus, indicating that the model was representative of reality. The study also shows that environmental factors such as pH, as well operating conditions such as Fe/P molar ratios (1, 1.5 and 2), influence the concentration of dissolved phosphate in the effluent. The time constant of simultaneous precipitation in the calibrated model, due to a step change decrease/increase in FeSO4 dosage, was found to be roughly 5 days, indicating a slow dynamic response due to a multi-step process involving dissolution, oxidation, precipitation, aging, adsorption and co-precipitation. The persistence effect of accumulated iron-precipitates (HFO particulates) in the activated sludge seemed important for phosphorus removal, and therefore solids retention time plays a crucial role according to the model. The aerobic tank was deemed to be the most suitable dosing location for FeSO4 addition, due to high dissolved oxygen levels and good mixing conditions. Finally, dynamic model-based analyses show the benefits of using automatic control when dosing chemicals.
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•A plant-wide model calibrated against extensive pilot-plant data describing phosphorus (P) dynamics with iron (Fe) dosing.•Good agreement between measured and modelled P (5–10% (relative) difference).•P concentration strongly depends on pH, Fe/P ratio and influent P load.•P removal control strategies substantially reduce FeSO4 dose.•Model shows aerobic tanks are the most suitable dosing location for FeSO4, due to fast oxidation of Fe2+ to Fe3+.
Estimating river discharge requires simultaneous measurement of velocity and flow depth. While surface velocities are relatively easy to measure using noncontact techniques, depth measurement usually ...requires physically intrusive instrumentation. This limits our capability to remotely monitor discharge in natural rivers subject to bed level variations. This work tests the potential to estimate the surface velocity, the water depth, the depth average velocity, and then discharge of a river using only a sequence of images of the dynamic water surface. The method is based on a comparison between the spatiotemporal Fourier spectra of the pixel intensities of these images and the theoretical dispersion relations of turbulence‐generated surface fluctuations and gravity‐capillary waves. The method is validated through the analysis of water surface videos obtained with fixed cameras from two river sections equipped with conventional discharge gauging. The applicability of the approach is demonstrated and the measurement uncertainties are quantified. The method is affected by two main sources of uncertainty: one derives from the estimation of the velocity index and the other from the obtainable resolution of the Fourier analysis. This resolution strongly controls the observation of depth and/or velocity variations in space and in time. The technique has advantages over current approaches: it has clear physical foundations; the equipment is low cost and is highly mobile; it does not need artificial tracers or physical equipment to measure depth; and it can directly provide estimates of the key flow parameters just from time series of images of the water surface.
Plain Language Summary
Continuous river flow discharge measurement is of great importance for managing natural water resources and flood risks. Current remote measurements that can be performed without immersing sensors only determine the velocity of the very upper surface layer of the river. River water surfaces have distinct patterns of waves. This work demonstrates that by remotely observing the dynamics of water surface waves using a low‐cost video camera and using wave theory, it is possible to estimate the surface water velocity, water depth, depth‐average velocity, and therefore the flow rate.
Key Points
Water surface fluctuations of a river surface react systematically to changes in the flow depth and velocity
Depth, velocity, and discharge are estimated remotely by fitting theoretical relations to the spectra of images of the water surface
The uncertainty of the estimates is governed by the size of river surface covered by the images, limiting the achievable spatial resolution
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