764 research outputs found
Old friends form alliance against podocytes
Wang and colleagues identify the activation of Wnt signaling as an important downstream event in transforming growth factor-β-mediated podocyte injury. Supported by other recent studies, canonical Wnt signaling is emerging as a critical stress pathway in podocytes and may be exploited for therapeutic strategies in the treatment of glomerulopathies
From genetics to personalized nephrology : kidney research at a tipping point
Non peer reviewe
Traction force microscopy with optimized regularization and automated Bayesian parameter selection for comparing cells
Adherent cells exert traction forces on to their environment, which allows
them to migrate, to maintain tissue integrity, and to form complex
multicellular structures. This traction can be measured in a perturbation-free
manner with traction force microscopy (TFM). In TFM, traction is usually
calculated via the solution of a linear system, which is complicated by
undersampled input data, acquisition noise, and large condition numbers for
some methods. Therefore, standard TFM algorithms either employ data filtering
or regularization. However, these approaches require a manual selection of
filter- or regularization parameters and consequently exhibit a substantial
degree of subjectiveness. This shortcoming is particularly serious when cells
in different conditions are to be compared because optimal noise suppression
needs to be adapted for every situation, which invariably results in systematic
errors. Here, we systematically test the performance of new methods from
computer vision and Bayesian inference for solving the inverse problem in TFM.
We compare two classical schemes, L1- and L2-regularization, with three
previously untested schemes, namely Elastic Net regularization, Proximal
Gradient Lasso, and Proximal Gradient Elastic Net. Overall, we find that
Elastic Net regularization, which combines L1 and L2 regularization,
outperforms all other methods with regard to accuracy of traction
reconstruction. Next, we develop two methods, Bayesian L2 regularization and
Advanced Bayesian L2 regularization, for automatic, optimal L2 regularization.
Using artificial data and experimental data, we show that these methods enable
robust reconstruction of traction without requiring a difficult selection of
regularization parameters specifically for each data set. Thus, Bayesian
methods can mitigate the considerable uncertainty inherent in comparing
cellular traction forces
P2Y2R Signaling Is Involved in the Onset of Glomerulonephritis
Endogenously released adenosine-5’-triphosphate (ATP) is a key regulator of physiological function and inflammatory responses in the kidney. Genetic or pharmacological inhibition of purinergic receptors has been linked to attenuation of inflammatory disorders and hence constitutes promising new avenues for halting and reverting inflammatory renal diseases. However, the involvement of purinergic receptors in glomerulonephritis (GN) has only been incompletely mapped. Here, we demonstrate that induction of GN in an experimental antibody-mediated GN model results in a significant increase of urinary ATP-levels and an upregulation of P2Y2R expression in resident kidney cells as well as infiltrating leukocytes pointing toward a possible role of the ATP/P2Y2R-axis in glomerular disease initiation. In agreement, decreasing extracellular ATP-levels or inhibition of P2R during induction of antibody-mediated GN leads to a reduction in all cardinal features of GN such as proteinuria, glomerulosclerosis, and renal failure. The specific involvement of P2Y2R could be further substantiated by demonstrating the protective effect of the lack of P2Y2R in antibody-mediated GN. To systematically differentiate between the function of P2Y2R on resident renal cells versus infiltrating leukocytes, we performed bone marrow-chimera experiments revealing that P2Y2R on hematopoietic cells is the main driver of the ATP/P2Y2R-mediated disease progression in antibody-mediated GN. Thus, these data unravel an important pro-inflammatory role for P2Y2R in the pathogenesis of GN
Proteomics : A Tool to Study Platelet Function
Acknowledgments: Authors acknowledge Laxmikanth Kollipara for the critical review and Julia Lill for support with figures preparation. The Figure 2 was created in Biorender.Peer reviewedPublisher PD
Dichotomous Responses to Chronic Fetal Hypoxia Lead to a Predetermined Aging Phenotype
Hypoxia-induced intrauterine growth restriction increases the risk for cardiovascular, renal, and other chronic diseases in adults, representing thus a major public health problem. Still, not much is known about the fetal mechanisms that predispose these individuals to disease. Using a previously validated mouse model of fetal hypoxia and bottom-up proteomics, we characterize the response of the fetal kidney to chronic hypoxic stress. Fetal kidneys exhibit a dichotomous response to chronic hypoxia, comprising on the one hand cellular adaptations that promote survival (glycolysis, autophagy, and reduced DNA and protein synthesis), but on the other processes that induce a senescence-like phenotype (infiltration of inflammatory cells, DNA damage, and reduced proliferation). Importantly, chronic hypoxia also reduces the expression of the antiaging proteins klotho and Sirt6, a mechanism that is evolutionary conserved between mice and humans. Taken together, we uncover that predetermined aging during fetal development is a key event in chronic hypoxia, establishing a solid foundation for Barker’s hypothesis of fetal programming of adult diseases. This phenotype is associated with a characteristic biomarker profile in tissue and serum samples, exploitable for detecting and targeting accelerated aging in chronic hypoxic human diseases
Stimulus - response curves of a neuronal model for noisy subthreshold oscillations and related spike generation
We investigate the stimulus-dependent tuning properties of a noisy ionic
conductance model for intrinsic subthreshold oscillations in membrane potential
and associated spike generation. On depolarization by an applied current, the
model exhibits subthreshold oscillatory activity with occasional spike
generation when oscillations reach the spike threshold. We consider how the
amount of applied current, the noise intensity, variation of maximum
conductance values and scaling to different temperature ranges alter the
responses of the model with respect to voltage traces, interspike intervals and
their statistics and the mean spike frequency curves. We demonstrate that
subthreshold oscillatory neurons in the presence of noise can sensitively and
also selectively be tuned by stimulus-dependent variation of model parameters.Comment: 19 pages, 7 figure
The use of urinary proteomics in the assessment of suitability of mouse models for ageing
Ageing is a complex process characterised by a systemic and progressive deterioration of biological functions. As ageing is associated with an increased prevalence of age-related chronic disorders, understanding its underlying molecular mechanisms can pave the way for therapeutic interventions and managing complications. Animal models such as mice are commonly used in ageing research as they have a shorter lifespan in comparison to humans and are also genetically close to humans. To assess the translatability of mouse ageing to human ageing, the urinary proteome in 89 wild-type (C57BL/6) mice aged between 8–96 weeks was investigated using capillary electrophoresis coupled to mass spectrometry (CE-MS). Using age as a continuous variable, 295 peptides significantly correlated with age in mice were identified. To investigate the relevance of using mouse models in human ageing studies, a comparison was performed with a previous correlation analysis using 1227 healthy subjects. In mice and humans, a decrease in urinary excretion of fibrillar collagens and an increase of uromodulin fragments was observed with advanced age. Of the 295 peptides correlating with age, 49 had a strong homology to the respective human age-related peptides. These ortholog peptides including several collagen (N = 44) and uromodulin (N = 5) fragments were used to generate an ageing classifier that was able to discriminate the age among both wild-type mice and healthy subjects. Additionally, the ageing classifier depicted that telomerase knock-out mice were older than their chronological age. Hence, with a focus on ortholog urinary peptides mouse ageing can be translated to human ageing
Cytoprotective Activated Protein C Averts Nlrp3 Inflammasome–Induced Ischemia-Reperfusion Injury Via Mtorc1 Inhibition
Cytoprotection by activated protein C (aPC) after ischemia-reperfusion injury (IRI) is associated with apoptosis inhibition. However, IRI is hallmarked by inflammation, and hence, cell-death forms disjunct from immunologically silent apoptosis are, in theory, more likely to be relevant. Because pyroptosis (ie, cell death resulting from inflammasome activation) is typically observed in IRI, we speculated that aPC ameliorates IRI by inhibiting inflammasome activation. Here we analyzed the impact of aPC on inflammasome activity in myocardial and renal IRIs. aPC treatment before or after myocardial IRI reduced infarct size and Nlrp3 inflammasome activation in mice. Kinetic in vivo analyses revealed that Nlrp3 inflammasome activation preceded myocardial injury and apoptosis, corroborating a pathogenic role of the Nlrp3 inflammasome. The constitutively active Nlrp3A350V mutation abolished the protective effect of aPC, demonstrating that Nlrp3 suppression is required for aPC-mediated protection from IRI. In vitro aPC inhibited inflammasome activation in macrophages, cardiomyocytes, and cardiac fibroblasts via proteinase-activated receptor 1 (PAR-1) and mammalian target of rapamycin complex 1 (mTORC1) signaling. Accordingly, inhibiting PAR-1 signaling, but not the anticoagulant properties of aPC, abolished the ability of aPC to restrict Nlrp3 inflammasome activity and tissue damage in myocardial IRI. Targeting biased PAR-1 signaling via parmodulin-2 restricted mTORC1 and Nlrp3 inflammasome activation and limited myocardial IRI as efficiently as aPC. The relevance of aPC-mediated Nlrp3 inflammasome suppression after IRI was corroborated in renal IRI, where the tissue protective effect of aPC was likewise dependent on Nlrp3 inflammasome suppression. These studies reveal that aPC protects from IRI by restricting mTORC1-dependent inflammasome activation and that mimicking biased aPC PAR-1 signaling using parmodulins may be a feasible therapeutic approach to combat IRI
Experimental Multi-state Quantum Discrimination in the Frequency Domain with Quantum Dot Light
The quest for the realization of effective quantum state discrimination
strategies is of great interest for quantum information technology, as well as
for fundamental studies. Therefore, it is crucial to develop new and more
efficient methods to implement discrimination protocols for quantum states.
Among the others, single photon implementations are more advisable, because of
their inherent security advantage in quantum communication scenarios. In this
work, we present the experimental realization of a protocol employing a
time-multiplexing strategy to optimally discriminate among eight non-orthogonal
states, encoded in the four-dimensional Hilbert space spanning both the
polarization degree of freedom and photon energy. The experiment, built on a
custom-designed bulk optics analyser setup and single photons generated by a
nearly deterministic solid-state source, represents a benchmarking example of
minimum error discrimination with actual quantum states, requiring only linear
optics and two photodetectors to be realized. Our work paves the way for more
complex applications and delivers a novel approach towards high-dimensional
quantum encoding and decoding operations
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