In this review article, we will first provide a brief overview of the ErbB receptor-ligand system and its importance in developmental and physiological processes. We will then review the literature ...regarding the role of ErbB receptors and their ligands in the maladaptive remodeling of lung tissue, with special emphasis on idiopathic pulmonary fibrosis (IPF). Here we will focus on the pathways and cellular processes contributing to epithelial-mesenchymal miscommunication seen in this pathology. We will also provide an overview of the in vivo studies addressing the efficacy of different ErbB signaling inhibitors in experimental models of lung injury and highlight how such studies may contribute to our understanding of ErbB biology in the lung. Finally, we will discuss what we learned from clinical applications of the ErbB1 signaling inhibitors in cancer in order to advance clinical trials in IPF.
Excessive inflammation-associated coagulation is a feature of infectious diseases, occurring in such conditions as bacterial sepsis and COVID-19. It can lead to disseminated intravascular ...coagulation, one of the leading causes of mortality worldwide. Recently, type I interferon (IFN) signaling has been shown to be required for tissue factor (TF; gene name F3) release from macrophages, a critical initiator of coagulation, providing an important mechanistic link between innate immunity and coagulation. The mechanism of release involves type I IFN-induced caspase-11 which promotes macrophage pyroptosis. Here we find that F3 is a type I IFN-stimulated gene. Furthermore, F3 induction by lipopolysaccharide (LPS) is inhibited by the anti-inflammatory agents dimethyl fumarate (DMF) and 4-octyl itaconate (4-OI). Mechanistically, inhibition of F3 by DMF and 4-OI involves suppression of Ifnb1 expression. Additionally, they block type I IFN- and caspase-11-mediated macrophage pyroptosis, and subsequent TF release. Thereby, DMF and 4-OI inhibit TF-dependent thrombin generation. In vivo, DMF and 4-OI suppress TF-dependent thrombin generation, pulmonary thromboinflammation, and lethality induced by LPS, E. coli, and S. aureus, with 4-OI additionally attenuating inflammation-associated coagulation in a model of SARS-CoV-2 infection. Our results identify the clinically approved drug DMF and the pre-clinical tool compound 4-OI as anticoagulants that inhibit TF-mediated coagulopathy via inhibition of the macrophage type I IFN-TF axis.
Optimal control (OC) algorithms such as differential dynamic programming (DDP) take advantage of the derivatives of the dynamics to control physical systems efficiently. Yet, these algorithms are ...prone to failure when dealing with non-smooth dynamical systems. This can be attributed to factors such as the existence of discontinuities in the dynamics derivatives or the presence of non-informative gradients. On the contrary, reinforcement learning (RL) algorithms have shown better empirical results in scenarios exhibiting non-smooth effects (contacts, frictions, etc.). Our approach leverages recent works on randomized smoothing (RS) to tackle non-smoothness issues commonly encountered in optimal control and provides key insights on the interplay between RL and OC through the prism of RS methods. This naturally leads us to introduce the randomized Differential Dynamic Programming (RDDP) algorithm accounting for deterministic but non-smooth dynamics in a very sample-efficient way. The experiments demonstrate that our method can solve classic robotic problems with dry friction and frictional contacts, where classical OC algorithms are likely to fail, and RL algorithms require, in practice, a prohibitive number of samples to find an optimal solution.
The measurement of beta-hydroxybutyrate (BOHB) carries high significance for the diagnosis, prognosis as well as treatment decisions in canine and feline diabetic ketoacidosis. The aim of this study ...was to establish clinically usable cut-off values for BHOB measurements in dogs and cats using the glucometer GlucoMen
LX Plus.
We measured BOHB with the GlucoMen
LX Plus in 4 patient groups (diabetic ketoacidosis, diabetic non-ketoacidic, catabolic non-diabetic status, control). These were classified based upon medical history and laboratory findings (pH, glucose-, HCO
concentrations, anion gap). The data was analyzed in a ROC-curve-analysis in order to create cut-off values.
A total of 47 dogs and 55 cats were included into the study. In the differentiation between the two diabetic groups, cut-off values for dogs and cats amounted to 2.55 mmol/l and 4.05 mmol/l, respectively. Here, good sensitivity (100 %) and specificity (82 % and 100 %, respectively) were attained. In the comparison of the catabolic non-diabetic status group and the individuals with diabetic ketosis, the analysis resulted in a cut-off value of 0.25 mmol/l in dogs and 0.25 mmol/l in cats, carrying poor sensitivity (58 % and 59 %, respectively) and specificity (90 %).
Measurements with the GlucoMen
LX Plus are suitable for a reliable differentiation between ketoacidosis and ketosis in dogs and cats. Here, the determined cut-off values carried high sensitivity and specificity. A distinction between non-diabetic catabolic individuals and patients with diabetic catabolic states, however, cannot be achieved with adequate consistency.
The established cut-off values aid in the treatment decision-making process as well as the assessment of prognosis and treatment success in diabetic ketoacidosis. In representing a point of care technique, the method allows for direct owner communication of the results and immediate adjustment of the treatment regime. Concerning the initial diagnosis or a differentiation between non-diabetic and diabetic catabolic states, however, the presented method alone is not sufficient, therefore additional diagnostic procedures are warranted in order to ascertain a correct diagnosis.
The detection of ketone bodies in urinary samples often underestimates the degree of ketonuria and may lead to false negative results due to the lack of detection of β-hydroxybutyrate. In human ...medicine, the standard method used to quantify and monitor ketonemia is the measurement of β-hydroxybutyrate in whole blood samples which is associated with a higher sensitivity. For this, only few devices have to date been evaluated in veterinary medicine. These have shown limitations in areas of high β-hydroxybutyrate concentrations. The aim of the study was to compare the portable ketone meter GlucoMen
LX PLUS with a reference method for measurement of β-hydroxybutyrate in canine and feline venous blood samples.
In this prosepctive study, a total of 47 dogs and 55 cats were enrolled. These cases comprised patients with diabetic ketoacidosis, diabetes mellitus and catabolic metabolism as well as healthy individuals. Comparison between the GlucoMen
LX PLUS ketone meter and an enzymatic reaction method by an automated chemistry analyzer was performed. Measurement results of dogs and cats were evaluated separately.
There was a high correlation between measurement values of the GlucoMen
LX PLUS and the enzymatic reaction laboratory method in dogs (R = 0.99, p < 0.001) and cats (R = 0.98, p < 0.001). Mean difference was 0.01 mmol/l (SD ± 0.20) in dogs and 0.05 mmol/l (SD ± 0.29) in cats. In 44 % of all dogs and cats the GlucoMen
LX PLUS measured lower values in comparison to the reference method. Greater differences between the 2 measurement methods were apparent in both high and low β-hydroxybutyrate concentration ranges (dogs, R = -0.762 and cats, R = -0.86). In high concentration areas, the GlucoMen
LX PLUS led to slightly lower results, whereas in low concentration areas slightly higher values were measured.
The GlucoMen
LX PLUS shows a strong correlation with the standard reference method and is useful for measurement of β-hydroxybutyrate in canine and feline venous blood samples. Limitations can be seen in high concentration ranges of β-hydroxybutyrate in which the GlucoMen
LX PLUS resulted in slightly lower measurement values.
The GlucoMen
LX PLUS is a cost-effective portable device representing a viable alternative to urinary ketone body measurement.
The high incidence of thrombotic events suggests a possible role of the contact system pathway in COVID-19 pathology. In this study, we determined the altered levels of factor XII (FXII) and its ...activation products in critically ill patients with COVID-19 in comparison with patients with severe acute respiratory distress syndrome related to the influenza virus (acute respiratory distress syndrome ARDS-influenza). Compatible with those data, we found rapid consumption of FXII in COVID-19 but not in ARDS-influenza plasma. Interestingly, the lag phase in fibrin formation, triggered by the FXII activator kaolin, was not prolonged in COVID-19, as opposed to that in ARDS-influenza. Confocal and electron microscopy showed that increased FXII activation rate, in conjunction with elevated fibrinogen levels, triggered formation of fibrinolysis-resistant, compact clots with thin fibers and small pores in COVID-19. Accordingly, clot lysis was markedly impaired in COVID-19 as opposed to that in ARDS-influenza. Dysregulated fibrinolytic system, as evidenced by elevated levels of thrombin-activatable fibrinolysis inhibitor, tissue-plasminogen activator, and plasminogen activator inhibitor-1 in COVID-19 potentiated this effect. Analysis of lung tissue sections revealed widespread extra- and intravascular compact fibrin deposits in patients with COVID-19. A compact fibrin network structure and dysregulated fibrinolysis may collectively contribute to a high incidence of thrombotic events in COVID-19.
•Elevated fibrinogen, in conjunction with accelerated formation of FXIIa, may promote compact fibrin clot architecture in COVID-19.•A dense fibrin network and dysregulated fibrinolysis collectively contribute to a high incidence of thrombotic events in COVID-19.
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State-of-the-art reinforcement learning is now able to learn versatile locomotion, balancing and push-recovery capabilities for bipedal robots in simulation. Yet, the reality gap has mostly been ...overlooked and the simulated results hardly transfer to real hardware. Either it is unsuccessful in practice because the physics is over-simplified and hardware limitations are ignored, or regularity is not guaranteed, and unexpected hazardous motions can occur. This paper presents a reinforcement learning framework capable of learning robust standing push recovery for bipedal robots that smoothly transfer to reality, providing only instantaneous proprioceptive observations. By combining original termination conditions and policy smoothness conditioning, we achieve stable learning, sim-to-real transfer and safety using a policy without memory nor explicit history. Reward engineering is then used to give insights into how to keep balance. We demonstrate its performance in reality on the lower-limb medical exoskeleton Atalante.
Optimal control (OC) algorithms such as Differential Dynamic Programming (DDP) take advantage of the derivatives of the dynamics to efficiently control physical systems. Yet, in the presence of ...nonsmooth dynamical systems, such class of algorithms are likely to fail due, for instance, to the presence of discontinuities in the dynamics derivatives or because of non-informative gradient. On the contrary, reinforcement learning (RL) algorithms have shown better empirical results in scenarios exhibiting non-smooth effects (contacts, frictions, etc). Our approach leverages recent works on randomized smoothing (RS) to tackle non-smoothness issues commonly encountered in optimal control, and provides key insights on the interplay between RL and OC through the prism of RS methods. This naturally leads us to introduce the randomized Differential Dynamic Programming (R-DDP) algorithm accounting for deterministic but non-smooth dynamics in a very sample-efficient way. The experiments demonstrate that our method is able to solve classic robotic problems with dry friction and frictional contacts, where classical OC algorithms are likely to fail and RL algorithms require in practice a prohibitive number of samples to find an optimal solution.
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