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.
L’oncologie médicale connaît une révolution depuis l’introduction des inhibiteurs de checkpoints immunitaires (ICI) tels que les anticorps monoclonaux anti-CTLA-4 et anti-PD-1. Ces derniers ont été ...approuvés dans plus de 23 cancers et les approches combinant les immunothérapies ont démontré une efficacité redoutable. Ces bénéfices en termes de survie s’accompagnent d’une augmentation des effets indésirables liés à l’immunité (irAEs), conséquence d’une activation excessive du système immunitaire. Les irAEs représentent un nouveau type d’auto-immunité pouvant affecter presque tous les organes, responsable d’une morbi-mortalité importante. Actuellement, il n’existe pas de biomarqueurs permettant de prédire l’incidence et la gravité de ces toxicités. Nous avons mis au point une approche innovante pour l’identification de ces biomarqueurs avant l’initiation d’un traitement combinant anti-CTLA-4 et anti-PD-1. Notre approche consiste en la stimulation immunitaire ex vivo du sang total issu de patients ayant un mélanome éligible au traitement, en utilisant la technologie des tubes TruCulture en présence d’un activateur de lymphocytes T (cytostim) et d’anticorps monoclonaux (nivolumab±ipilimumab), avant l’initiation du traitement. Les prélèvements biologiques sont analysés en utilisant la technologie LUMINEX pour l’étude du profil protéomique des surnageants et la technologie NANOSTRING pour l’étude du profil transcriptomique des cellules sanguines. Les patients sont prospectivement suivis pendant 3 mois, puis 6 mois après l’initiation du traitement. Le suivi prospectif a mis en évidence une irAE sévère chez 60 % des patients (n=15), dont 67 % avec une atteinte digestive sévère, principalement des colites. L’étude immunologique a identifié plusieurs candidats biomarqueurs, dont la chimiokine MCP-1 et les cytokines IP-10 et IFN-g, permettant de prédire l’apparition d’une irAE sévère avant même l’initiation du traitement. L’analyse transcriptomique a confirmé l’implication de ces voies de signalisation et a mis en évidence l’activation la voie des interférons chez les patients qui développeront des colites sévères, ouvrant des perspectives mécanistiques sur la genèse des irAEs. Les irAEs représentent un défi majeur pour la médecine moderne, et des travaux intensifs sont nécessaires pour comprendre le développement des irAEs et identifier des biomarqueurs permettant leurs prédictions. La stimulation ex vivo du sang total, puis l’analyse intégrée des profils immunitaires ont permis d’identifier plusieurs biomarqueurs candidats qui pourraient prédire l’apparition d’irAEs sévères ainsi que des pistes mécanistiques.
Novel treatments of metastatic melanoma include the usage of checkpoint inhibitors such as anti-cytotoxic-T-lymphocyte-associated antigen (CTLA-4) or anti-programmed death-1 (PD-1) antibodies, which ...are immunomodulatory antibodies that enhance the immune response against tumors. While they have substantially improved the prognosis for patients, these therapies are associated with a large spectrum of immune-related adverse effects (irAEs). We report a patient developing pulmonary and cutaneous sarcoidosis after pembrolizumab therapy while complete regression of stage IV melanoma was perceived. Coincident development of sarcoidosis and metastatic melanoma as illustrated by this case report poses a diagnostic challenge because, in contrast to other irAEs, both diseases share common features such as pulmonary lesions, hilar adenopathies and skin nodules. Considering sarcoidosis as a potential side-effect of pembrolizumab treatment is crucial to avoid misdiagnosis with malignant lesions, hence careful description and reporting of such cases is primordial for patient care and may also provide us with insightful knowledge on the pathogenesis of immune-related diseases.
Nutraceuticals from natural sources have shown potential new leads in functional food products. Despite a broad range of health-promoting effects, these compounds are easily oxidized and unstable, ...making their utilization as nutraceutical ingredients limited. In this study, the encapsulated stingless bees' propolis in liposome was prepared using soy phosphatidylcholine and cholesterol by thin-film hydration technique. Three different formulations of phosphatidylcholine composition and cholesterol prepared by weight ratio was conducted to extract high propolis encapsulation. Physicochemical changes in the result of the encapsulation process are briefly discussed using scanning electron microscopy and Fourier Transform Infrared Spectroscopy. A dynamic light-scattering instrument was used to measure the hydrodynamic diameter, polydispersity index, and zeta potential. The increment of the liposomal size was observed when the concentration of extract loaded increased. In comparing three formulations, F2 (8:1 w/w) presented the best formulation as it yielded small nanoparticles of 275.9 nm with high encapsulation efficiency (66.9%). F1 (6:1 w/w) formed large particles of liposomes with 422.8 nm, while F3 (10:1 w/w) showed low encapsulation efficiency with (by) 38.7%. The liposome encapsulation will provide an effective nanocarrier system to protect and deliver the flavonoids extracted from stingless bees' propolis.
Propolis, Liposome formulation, FTIR spectroscopy, Polydispersity index, Zeta potential
Summary
Background
The outbreak of chilblain‐like lesions (CLL) during the COVID‐19 pandemic has been reported extensively, potentially related to SARS‐CoV‐2 infection, yet its underlying ...pathophysiology is unclear.
Objectives
To study skin and blood endothelial and immune system activation in CLL in comparison with healthy controls and seasonal chilblains (SC), defined as cold‐induced sporadic chilblains occurring during 2015 and 2019 with exclusion of chilblain lupus.
Methods
This observational study was conducted during 9–16 April 2020 at Saint‐Louis Hospital, Paris, France. All patients referred with CLL seen during this period of the COVID‐19 pandemic were included in this study. We excluded patients with a history of chilblains or chilblain lupus. Fifty patients were included.
Results
Histological patterns were similar and transcriptomic signatures overlapped in both the CLL and SC groups, with type I interferon polarization and a cytotoxic–natural killer gene signature. CLL were characterized by higher IgA tissue deposition and more significant transcriptomic activation of complement and angiogenesis factors compared with SC. We observed in CLL a systemic immune response associated with IgA antineutrophil cytoplasmic antibodies in 73% of patients, and elevated type I interferon blood signature in comparison with healthy controls. Finally, using blood biomarkers related to endothelial dysfunction and activation, and to angiogenesis or endothelial progenitor cell mobilization, we confirmed endothelial dysfunction in CLL.
Conclusions
Our findings support an activation loop in the skin in CLL associated with endothelial alteration and immune infiltration of cytotoxic and type I IFN‐polarized cells leading to clinical manifestations.
What is already known about this topic?
Chilblain‐like lesions have been reported during the COVID‐19 pandemic.
They are associated with systemic type I interferon polarization, but the precise pathophysiology is still unclear.
What does this study add?
We demonstrate cutaneous and systemic immune activation and vascular alteration.
Histological patterns were similar and transcriptomic signatures overlapped in chilblain‐like lesions and a comparator group with seasonal chilblains.
A systemic immune response was associated with high prevalence of IgA antineutrophil cytoplasmic antibodies and an elevated type I interferon signature.
We confirmed endothelial dysfunction in chilblain‐like lesions.
What is the translational message?
Chilblain‐like lesions and seasonal chilblains seem to share a common pathophysiology.
The strong type I interferon response can be explained by a viral trigger.
Similar endothelial dysfunctions have been described during mild COVID‐19.
Local or systemic anti‐inflammatory treatment could reverse cutaneous manifestations.
Linked Comment: S.M. Pilkington and R.E.B. Watson. Br J Dermatol 2021; 185:1090–1091.
Plain language summary available online
Occupancy grid map is a map representation that shows the occupancy of spaces, whether there is any object in a particular area or it is a free space. This map representation is also commonly known ...as a grid map. However, the accuracy of the occupancy grid map is highly dependent on the accuracy of the sensors. In this paper, low cost and noisy sensors such as infrared sensors were used with the occupancy grid map algorithm integrated with a neural network. The neural network was used to interpret adjacent sensor measurements into cell's occupancy value in the grid map. From the simulation experiments, it is observed that, that neural network-integrated algorithm has a better map estimate throughout robot's navigation with mean of 28% more accurate compared to occupancy grid map algorithm without neural network. This finding is beneficial for implementation with simultaneous localization and mapping or commonly known as SLAM problem. This is because SLAM algorithm makes use of both estimations of environment's map and robot's state. Thus, a better map estimate throughout the robot's journey can improve a robot's state estimate as well.
Abstract
The aim of this study was to investigate the removal Methylthioninium Chloride dye using cogon grass to treat the effluent. The effects of various parameters such as adsorbent dosage, dye ...concentration and contact time were studied. Funtional group properties of cogon grass had been characterized using Fourier transform infrared spectroscopy (FTIR). The adsorption process attained equilibrium around 50 minutes. The maximum adsorption capacity was calculated to be 46.30 mg/g with optimized condition of adsorbent dosage 0.1 g at temperature 30 °C for 50 minutes. The adsorption kinetics of Methylthioninium Chloride with cogon grass suit into non-linear pseudo-second order reaction model that refers to the amount of adsorbate and amount of solute adsorbed on adsorbent surface at equilibrium. It was also found that the Langmuir isotherm fit better (R
2
= 0.9959) compare to the Freundlich isotherm (R
2
= 0.4093). The high levels of color removals were achieved with low contact times; and the cogon grass can be effectively used as adsorbent of methylthioninium chloride in aqueous solutions. These results prove that cogon grass is highly potential to be used as low-cost adsorbent for the dye removal from industrial wastewater.
Ceramic foams are high-value products with multiple functions, such as thermal insulation, acoustic insulation, fireproof and freezing tolerance. Wide-ranging ceramic-foam applications can reduce ...energy consumption and indoor fire hazards. The utilisation of ceramic materials in manufacturing requires appropriate methods to reduce the problems associated with these features. Ceramic foams have excellent thermal stability and structural resilience against organic solvents and chemical corrosion. They can also be used in various engineering applications. Natural additives such as starch, sucrose and yolk are used to control the pore structure of the products. These additives serve as foaming and binding agents to enhance the stability of foaming slurry. The use of starch strengthening in the ceramic fabrication is widespread because of its low cost and reduced impact on the environment. The effects of starch addition on the mechanical properties of ceramic foams include increased density, linear shrinkage and compressive strength, as well as decreased porosity and water absorption. These effects depend on the contents of starch and sintering temperature. This review focuses on the use of starch as a binding agent for ceramic-foam fabrication.
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