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Podocytes are highly-specialized epithelial cells essentially required for the generation and the maintenance of the kidney filtration barrier. This elementary function is directly based on an elaborated cytoskeletal apparatus establishing a complex network of primary and secondary processes. Here, we identify the actin-bundling protein allograft-inflammatory-inhibitor 1 like (AIF1L) as a selectively expressed podocyte protein in vivo. We describe the distinct subcellular localization of AIF1L to actin stress fibers, focal adhesion complexes and the nuclear compartment of podocytes in vitro. Genetic deletion of AIF1L in immortalized human podocytes resulted in an increased formation of filopodial extensions and decreased actomyosin contractility. By the use of SILAC based quantitative proteomics analysis we describe the podocyte specific AIF1L interactome and identify several components of the actomyosin machinery such as MYL9 and UNC45A as potential AIF1L interaction partners. Together, these findings indicate an involvement of AIF1L in the stabilization of podocyte morphology by titrating actomyosin contractility and membrane dynamics.

The dibenzo[ b,f ]azepine skeleton is important in the pharmaceutical industry, not only in terms of existing commercial antidepressants, anxiolytics and anticonvulsants, but also in reengineering for other applications. More recently, the potential of the dibenzo[ b,f ]azepine moiety in organic light emitting diodes and dye-sensitized solar cell dyes has been recognised, while catalysts and molecular organic frameworks with dibenzo[ b,f ]azepine derived ligands have also been reported. This review provides a brief overview of the different synthetic strategies to dibenzo[ b,f ]azepines and other dibenzo[ b,f ]heteropines.

Steroid-resistant nephrotic syndrome (SRNS) frequently leads to end-stage renal disease, ultimately requiring kidney replacement therapies. SRNS is often caused by hereditary monogenic mutations, specifically affecting specialized epithelial cells (podocytes) of the glomerular filtration barrier. Mutations in several components of the nuclear pore complex, including NUP133 and NUP107, have been recently identified to cause hereditary SRNS. However, underlying pathomechanisms, eliciting podocyte-specific manifestations of these nucleoporopathies, remained largely elusive. Here, we generated an in vitro model of NUP133-linked nucleoporopathies using CRISPR/Cas9-mediated genome editing in human podocytes. Transcriptome, nuclear pore assembly, and cytoskeleton regulation of NUP133 loss-of-function, mutant, and wild-type podocytes were analyzed. Loss of NUP133 translated into a disruption of the nuclear pore, alterations of the podocyte-specific transcriptome, and impaired cellular protrusion generation. Surprisingly, comparative analysis of the described SRNS-related NUP133 mutations revealed only mild defects. Am impaired protein interaction in the Y-complex and decrease of NUP133 protein levels might be the primary and unifying consequence of mutant variants, leading to a partial loss-of-function phenotype and disease manifestation in susceptible cell types, such as podocytes.

Glomerular kidney disease causing nephrotic syndrome is a complex systemic disorder and is associated with significant morbidity in affected patient populations. Despite its clinical relevance, well-established models are largely missing to further elucidate the implications of uncontrolled urinary protein loss. To overcome this limitation, we generated a novel, inducible, podocyte-specific transgenic mouse model (Epb41l5fl/fl*Nphs1-rtTA-3G*tetOCre), developing nephrotic syndrome in adult mice. Animals were comprehensively characterized, including microbiome analysis and multiplexed immunofluorescence imaging. Induced knockout mice developed a phenotype consistent with focal segmental glomerular sclerosis (FSGS). Although these mice showed hallmark features of severe nephrotic syndrome (including proteinuria, hypoalbuminemia and dyslipidemia), they did not exhibit overt chronic kidney disease (CKD) phenotypes. Analysis of the gut microbiome demonstrated distinct dysbiosis and highly significant enrichment of the Alistipes genus. Moreover, Epb41l5-deficient mice developed marked organ pathologies, including extramedullary hematopoiesis of the spleen. Multiplex immunofluorescence imaging demonstrated red pulp macrophage proliferation and mTOR activation as driving factors of hematopoietic niche expansion. Thus, this novel mouse model for adult-onset nephrotic syndrome reveals the significant impact of proteinuria on extra-renal manifestations, demonstrating the versatility of this model for nephrotic syndrome-related research.

Glomerular disease due to podocyte malfunction is a major factor in the pathogenesis of chronic kidney disease. Identification of podocyte-specific signaling pathways is therefore a prerequisite to characterizing relevant disease pathways and developing novel treatment approaches. Here, we employed loss of function studies for EPB41L5 (Yurt) as a central podocyte gene to generate a cell type-specific disease model. Loss of Yurt in fly nephrocytes caused protein uptake and slit diaphragm defects. Transcriptomic and proteomic analysis of human EPB41L5 knockout podocytes demonstrated impaired mechanotransduction via the YAP/TAZ signaling pathway. Further analysis of specific inhibition of the YAP/TAZ-TEAD transcription factor complex by TEADi led to the identification of ARGHAP29 as an EPB41L5 and YAP/TAZ-dependently expressed podocyte RhoGAP. Knockdown of ARHGAP29 caused increased RhoA activation, defective lamellipodia formation, and increased maturation of integrin adhesion complexes, explaining similar phenotypes caused by loss of EPB41L5 and TEADi expression in podocytes. Detection of increased levels of ARHGAP29 in early disease stages of human glomerular disease implies a novel negative feedback loop for mechanotransductive RhoA—YAP/TAZ signaling in podocyte physiology and disease.

Purpose Extended thrombolysis in cerebral infarction (eTICI) score results of 2b or higher are known to be predictors for favorable outcome after acute stroke. Additionally, time is a major factor influencing outcome after ischemic stroke. Until today only little is known about the impact of time on angiographic results regarding the outcome after mechanical thrombectomy; however, this impact might be of interest if an initially unfavorable angiographic result has to be improved. Methods Retrospective study of 164 patients with large vessel occlusion of the anterior circulation treated by mechanical thrombectomy. Multiple logistic regression analysis of relevant periprocedural and procedural times in respect to the probability of achieving functional independence at 90 days in respect to different eTICI results was performed to build a time and TICI score-dependent model for outcome prediction in which the influence of time was assumed to be steady among the TICI grades. Results The probability of achieving a favorable outcome is significantly different between eTICI2b-50, 67, TICI2c and TICI3 results ( p  < 0.001). The odds for achieving a favorable outcome decrease over time and differ for each TICI category and time point. The individual odds for each patient, time point and TICI grade can be calculated based on this model. Conclusion The impact of periprocedural and procedural times and eTICI reperfusion results adds a new dimension to the decision-making process in patients with primary unfavorable angiographic results.

Scientific understanding of aquaculture interactions with the environment is limited, especially concerning the far-field transport and possible impacts of particulate wastes. A pilot study was carried out in southwest New Brunswick, Canada, in November 2008 to determine the size, settling velocity, and density of suspended particles at an active salmon aquaculture cage site. The model of Khelifa & Hill (2006) was fit to size-versus-settling velocity data to estimate the fractal dimension of flocs and the density of the component particles within flocs. Flocs had a larger fractal dimension and smaller component−particle density than in other studies, suggesting that particles from the aquaculture operation may be incorporated into suspended flocs with average settling velocities of 1 mm s⁻¹. Variability in particle size and packaging was interpreted in the context of near bed velocity, tidal stage, and wind speed and direction. This analysis indicated that advection dominated observed variations in particle size and packaging. Indicators of resuspension, aggregation, disaggregation, and deposition were not detected in the time series. Advection of flocs away from the study site provides a mechanism to transport wastes over distances greater than 1 km prior to deposition; thus a settling class of 1 mm s⁻¹ should be considered in depositional models of aquaculture wastes.

Aims The population-based incidence of pressure ulcers shows large differences between the 16 federal states in Germany. The present study analyses the association between state-specific pressure ulcer incidence and selected structural variables. Subjects and methods Based on the Diagnosis Related Groups used for diagnosis-specific hospital billing, the population-based incidence of pressure ulcers as primary and secondary diagnosis was calculated for each German state. Data were also stratified for grade (all pressure ulcers vs. grades 3 and 4 only). Ten variables derived from data collected by the German Federal Statistical Office were used to describe of state-specific healthcare structures. Results Significant correlations were seen between the state-specific incidence of pressure ulcers as primary and secondary diagnosis per 100,000 and the number of full-time employees in nursing homes per 100,000 ( p  < 0.1; correlation factor of –0.43 and –0.44, respectively), the number of patients per doctor in hospitals ( p  < 0.05; correlation factor 0.5 and 0.6, respectively) and for the state-specific incidence of pressure ulcers as primary diagnosis and the number of deaths per 100,000 ( p  < 0.05; correlation factor of 0.7). Conclusion Differences in the population-based incidence of pressure ulcers between the 16 German states seem to be influenced by structural differences in patient care. Further examination of these associations could lead to important political approaches for the reduction of pressure ulcers in Germany.

A study used closed-loop stripping and chiral gas chromatography to establish which of the four possible stereoisomers of lamoxirene functions as the naturally occurring sperm-releasing pheromone in Undaria pinnatifida.

BackgroundThe First-Pass Effect (FPE) in endovascular thrombectomy (EVT) for large vessel occlusion acute ischemic strokes (LVO-AIS) is associated with better outcomes. Previous studies showed an impact of procedure time (PT) on FPE. Six randomized controlled trials have shown the efficacy and safety of EVT in patients presenting with low Alberta Stroke Program Early CT Scores (ASPECTS). This study aims to explore if the benefits of FPE are modified by PT for these patients.MethodsThis retrospective analysis included EVT patients from 37 centers across the US and internationally. The primary endpoint was a good functional outcome, defined by 90-day modified Rankin Scale scores of 0–3. First pass success (FPS, defined as 1 pass vs ≥2 passes) was the primary study exposure, while PT was the secondary exposure, evaluated in both low ASPECTS and ASPECTS 6–10 subgroups. Youden's index determined the PT cut-off. Adjusted logistic regression models assessed the interaction between PT and FPS, with adjustments for confounders. Propensity score matching compared FPS impacts within ≤ 35-minute and > 35-minute PT groups for both ASPECT subgroups.ResultsOf the 5880 patients studied, 590 (10%) had low ASPECTS at presentation. FPE significantly correlated with higher odds of achieving good functional outcome (adjusted odds ratio [aOR]: 3.17, 95% CI: 2.04 - 5.20; P < 0.01). Longer PTs were independently associated with poorer outcomes (P < 0.01), with 35 minutes identified as the optimal PT cut-off. Significant interaction between PT and FPS was observed in the ASPECTS 6–10 subgroup (P < 0.01) (figure 1B) but not in the low ASPECTS group (P = 0.73). (figure 1A) In ASPECTS 6–10, patients achieving FPE within ≤35 minutes had a 16.5% higher predicted probability of a good outcome compared to those requiring ≥2 passes (73.2% vs 56.7%, P = 0.001). In low ASPECTS patients, FPS correlated with higher odds of a good outcome regardless of PT duration: ≤35 minutes (aOR: 2.76, CI: 1.45–3.31; P = 0.03) and >35 minutes (aOR: 1.56, CI: 1.11–2.32; P = 0.02).ConclusionFPE is influenced by procedure time (PT) exclusively in patients with ASPECTS 6–10; the clinical superiority diminishes in procedures extending beyond 35 minutes. However, in patients with low ASPECTS, achieving FPE, whether early or delayed, consistently correlates with higher odds of favorable functional outcomes compared to those requiring multiple attempts. Further investigation into the thrombectomy techniques and catheter choices that enhance FPE is essential.Abstract O-005 Figure 1DisclosuresR. Abo Kasem: None. A. Koo: None. B. Reeves: None. D. Renedo: None. I. Maier: None. A. Rai: None. P. Jabbour: None. J. Kim: None. J. Grossberg: None. A. Alawieh: None. S. Wolfe: None. R. Starke: None. M. Psychogios: None. M. Psychogios: None. A. Shaban: None. N. Goyal: None. J. Dye: None. A. Alaraj: None. M. Ezzeldin: None. S. Yoshimura: None. D. Fiorella: None. O. Tanweer: None. D. Romano: None. P. Navia: None. I. Fragata: None. J. Mascitelli: None. M. Levitt: None. C. Matouk: None. A. Spiotta: None.