Mechanisms of angiotensin II signaling on cytoskeleton of podocytes

Podozytzen sind essentiell für die selektive Permeabilität des glomerulären Filters. Die fortwährende Aktivierung des renalen Angiotensin-Systems ist entscheidend bei der Pathogenese der Podozytenschädigung und der Proteinurie. In dieser Arbeit konnte eine erhöhte Expressionen von Rac-1 und phosphorylierten ERM Proteinen (ezrin/radixin/moesin) in kultivierten Mauspodozyten, die Ang II Typ1 Rezeptor (AT1R) stabil überexprimieren und in Glomerula von AT1R transgenen Ratten gezeigt werden. In Mauspodozyten führte die Ang II Stimulation zu einer Sauerstoffradikal abhängigen Umstrukturierung des kortikalen F-Aktins. Zudem konnte nach Stimulation mit Ang II in Podozyten intrazellulär und an den fokalen Adhäsionen eine erniedrigte Expression von alpha Actinin-4 beobachtet werden. Der Ang II-induzierte Phänotypwechsel von einer stabilen, statischen Zelle zu einer migratorisch aktiven Zelle ist wahrscheinlich die Ursache für die Schädigung des Podozyten und führt somit zur Glomerulosklerose

Measurement and Simulation of Permeation and Diffusion in Native and Cultivated Tissue Constructs

Characterization of native skin or cultured 3D skin models with respect to permeability plays an important role for the development and testing of pharmaceuticals and cosmetics. Extensive efforts have been dedicated to determining the key parameters describing permeability and diffusion. Whereas respective methods are well established for native skin biopsies, only few are available for 3D skin models, as these have usually much lower dimensions. In this chapter, some fundamentals about permeation and diffusion as well as state of the art of measurement methods used for skin biopsies are summarized. An alternative method for the determination of the permeation in a membrane insert system and the use of a modular simulation to support permeability studies is presented and discussed

Diffusion Model-Augmented Behavioral Cloning

Imitation learning addresses the challenge of learning by observing an expert's demonstrations without access to reward signals from environments. Most existing imitation learning methods that do not require interacting with environments either model the expert distribution as the conditional probability p(a|s) (e.g., behavioral cloning, BC) or the joint probability p(s, a) (e.g., implicit behavioral cloning). Despite its simplicity, modeling the conditional probability with BC usually struggles with generalization. While modeling the joint probability can lead to improved generalization performance, the inference procedure can be time-consuming and it often suffers from manifold overfitting. This work proposes an imitation learning framework that benefits from modeling both the conditional and joint probability of the expert distribution. Our proposed diffusion model-augmented behavioral cloning (DBC) employs a diffusion model trained to model expert behaviors and learns a policy to optimize both the BC loss (conditional) and our proposed diffusion model loss (joint). DBC outperforms baselines in various continuous control tasks in navigation, robot arm manipulation, dexterous manipulation, and locomotion. We design additional experiments to verify the limitations of modeling either the conditional probability or the joint probability of the expert distribution as well as compare different generative models

Rapamycin attenuates PLA2R activation-mediated podocyte apoptosis via the PI3K/AKT/mTOR pathway

Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults without diabetes. Primary MN has been associated with circulating antibodies against native podocyte antigens, including phospholipase A2 receptor (PLA2R); however, precision therapy targeting the signaling cascade of PLA2R activation is lacking. Both PLA2R and the mammalian target of rapamycin (mTOR) exist in podocytes, but the interplay between these two proteins and their roles in MN warrants further exploration. This study aimed to investigate the crosstalk between PLA2R activation and mTOR signaling in a human podocyte cell line. We demonstrated that podocyte apoptosis was induced by Group IB secretory phospholipase A2 (sPLA2IB) in a concentration- and time-dependent manner via upregulation of phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and mTOR, and inhibited by rapamycin or LY294002. Furthermore, aberrant activation of the PI3K/AKT/mTOR pathway triggers both extrinsic (caspase-8 and caspase-3) and intrinsic (Bcl-2-associated X protein [BAX], B-cell lymphoma 2 [BCL-2], cytochrome c, caspase-9, and caspase-3) apoptotic cascades in podocytes. The therapeutic implications of our findings are that strategies to reduce PLA2R activation and PI3K/AKT/mTOR pathway inhibition in PLA2R-activated podocytes help protect podocytes from apoptosis. The therapeutic potential of rapamycin shown in this study provides cellular evidence supporting the repurposing of rapamycin for MN treatment

Science return of probing magnetospheric systems of ice giants

The magnetospheric systems of ice giants, as the ideal and the unique template of a typical class of exoplanets, have not been sufficiently studied in the past decade. The complexity of these asymmetric and extremely dynamic magnetospheres provides us a great chance to systematically investigate the general mechanism of driving the magnetospheres of such common exoplanets in the Universe, and the key factors of influencing the global and local magnetospheric structures of this type of planets. In this paper, we discuss the science return of probing magnetospheric systems of ice giants for the future missions, throughout different magnetospheric regions, across from the interaction with upstream solar wind to the downstream region of the magnetotail. We emphasize the importance of detecting the magnetospheric systems of ice giants in the next decades, which enables us to deeply understand the space enviroNMent and habitability of not only the ice giants themselves but also the analogous exoplanets which are widely distributed in the Universe

Epidemiology and outcomes of anal abscess in patients on chronic dialysis: a 14-year retrospective study

OBJECTIVES: We conducted this retrospective study to elucidate the clinical presentation and outcomes of anal abscess in chronic dialysis patients. METHODS: We performed a chart review of patients who were hospitalized for anal abscess from Jan. 2002 to Dec. 2015. A total of 3,074 episodes of anal abscess were identified. Of these, 43 chronic dialysis patients with first-time anal abscess were enrolled. Patients were divided into a surgical group and a nonsurgical group according to the treatment received during hospitalization. The baseline characteristics, clinical findings, treatments and outcomes were obtained and analyzed. The endpoints of this study were in-hospital mortality, one-year mortality and one-year recurrence. RESULTS: Of the 43 patients, 27 (62.7%) received surgical treatment, and 16 (37.2%) received antibiotic treatment alone. There was no significant difference in age, sex, body mass index, smoking habits, comorbidities, or dialysis characteristics between the two groups. Perianal abscess was the most common type of anal abscess, and 39.5% of patients experienced fistula formation. Most patients had mixed aerobic and anaerobic flora. Our data demonstrate that there was no significant difference in hospital stay, one-year survival or recurrence rate between the surgical group and nonsurgical group. However, there was a trend toward better in-hospital survival in patients who received surgical treatment (p=0.082). CONCLUSION: In chronic dialysis patients with anal abscess, there was no statistically significant difference in clinical presentation and outcomes between the surgical and nonsurgical groups, although the surgical group had a trend of better in-hospital survival