Cilia at the node of mouse embryos sense fluid flow for left-right determination via Pkd2

Unidirectional fluid flow plays an essential role in the breaking of left-right (L-R) symmetry in mouse embryos, but it has remained unclear how the flow is sensed by the embryo. We report that the Ca2+ channel Polycystin-2 (Pkd2) is required specifically in the perinodal crown cells for sensing the nodal flow. Examination of mutant forms of Pkd2 shows that the ciliary localization of Pkd2 is essential for correct L-R patterning. Whereas Kif3a mutant embryos, which lack all cilia, failed to respond to an artificial flow, restoration of primary cilia in crown cells rescued the response to the flow. Our results thus suggest that nodal flow is sensed in a manner dependent on Pkd2 by the cilia of crown cells located at the edge of the node.CREST of the Japan Science and Technology Corporation; NIH [P30 DK090744]; Human Frontier Science Program [ST00246/2003C]; Deutsche Forschungsgemeinschaft [PE 853/2]; Japan Society for the Promotion of Science; American Heart Association [R10682]info:eu-repo/semantics/publishedVersio

Coccydynia

Coccydynia is a term that refers to pain in the region of the coccyx. Most cases are associated with abnormal mobility of the coccyx which may trigger a chronic inflammatory process leading to degeneration of this structure. In some patients this instability may be detected on dynamic radiographs. Nonsurgical management remains the gold standard treatment for coccydynia, consisting of decreased sitting, seat cushioning, coccygeal massage, stretching, manipulation, local injection of steroids or anesthetics, and postural adjustments. Those patients who fail these conservative modalities may potentially benefit from coccygectomy. However, surgical intervention is typically reserved for patients with evidence of advanced coccygeal instability (e.g., subluxation or hypermobility) or spicule formation, as this population appears to exhibit the greatest improvement postoperatively

Crosstalk between cilia and autophagy: implication for human diseases

Macroautophagy/autophagy is a self-degradative process necessary for cells to maintain their energy balance during development and in response to nutrient deprivation. Autophagic processes are tightly regulated and have been found to be dysfunctional in several pathologies. Increasing experimental evidence points to the existence of an interplay between autophagy and cilia. Cilia are microtubule-based organelles protruding from the cell surface of mammalian cells that perform a variety of motile and sensory functions and, when dysfunctional, result in disorders known as ciliopathies. Indeed, selective autophagic degradation of ciliary proteins has been shown to control ciliogenesis and, conversely, cilia have been reported to control autophagy. Moreover, a growing number of players such as lysosomal and mitochondrial proteins are emerging as actors of the cilia-autophagy interplay. However, some of the published data on the cilia-autophagy axis are contradictory and indicate that we are just starting to understand the underlying molecular mechanisms. In this review, the current knowledge about this axis and challenges are discussed, as well as the implication for ciliopathies and autophagy-associated disorders

Inhibition of PFKFB3 Hampers the Progression of Atherosclerosis and Promotes Plaque Stability

Aims: 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB)3-mediated glycolysis is pivotal in driving macrophage- and endothelial cell activation and thereby inflammation. Once activated, these cells play a crucial role in the progression of atherosclerosis. Here, we analyzed the expression of PFKFB3 in human atherosclerotic lesions and investigated the therapeutic potential of pharmacological inhibition of PFKFB3 in experimental atherosclerosis by using the glycolytic inhibitor PFK158. Methods and Results: PFKFB3 expression was higher in vulnerable human atheromatous carotid plaques when compared to stable fibrous plaques and predominantly expressed in plaque macrophages and endothelial cells. Analysis of advanced plaques of human coronary arteries revealed a positive correlation of PFKFB3 expression with necrotic core area. To further investigate the role of PFKFB3 in atherosclerotic disease progression, we treated 6–8 weeks old male Ldlr–/– mice. These mice were fed a high cholesterol diet for 13 weeks, of which they were treated for 5 weeks with the glycolytic inhibitor PFK158 to block PFKFB3 activity. The incidence of fibrous cap atheroma (advanced plaques) was reduced in PFK158-treated mice. Plaque phenotype altered markedly as both necrotic core area and intraplaque apoptosis decreased. This coincided with thickening of the fibrous cap and increased plaque stability after PFK158 treatment. Concomitantly, we observed a decrease in glycolysis in peripheral blood mononuclear cells compared to the untreated group, which alludes that changes in the intracellular metabolism of monocyte and macrophages is advantageous for plaque stabilization. Conclusion: High PFKFB3 expression is associated with vulnerable atheromatous human carotid and coronary plaques. In mice, high PFKFB3 expression is also associated with a vulnerable plaque phenotype, whereas inhibition of PFKFB3 activity leads to plaque stabilization. This data implies that inhibition of inducible glycolysis may reduce inflammation, which has the ability to subsequently attenuate atherogenesis

Turbidity and Other Effects Resulting from Trafalgar Sandbank Dredging and Palmar Beach Nourishment

Beach-nourishment requirements on the southwestern Spanish coast have led to a significant increase in offshore dredging. Following a new research line, assessment of changes recorded in physicochemical and biological parameters due to dredging and dumping operations was performed at the Cape of Trafalgar and Palmar Beach during June and July 2008. Turbidity, salinity, pH, dissolved oxygen, temperature, and suspended-sediment data were collected at 10 stations. At the end of the study, a three-campaign monitoring program was implemented for 1 year to assess the possible effects on biological communities and sediment properties. The relevant results, such as the average extent of the sediment plume (< 400 m) and its persistence in the environment (< 10 min), are discussed in this paper. A precise correlation between turbidity and suspended sediments and the recovery time of ecological balance were also established. Furthermore, minimal and reversible effects caused by dredging and dumping operations in this type of marine environment were identified

Refocusing multiple stressor research around the targets and scales of ecological impacts

Ecological communities face a variety of environmental and anthropogenic stressors acting simultaneously. Stressor impacts can combine additively or can interact, causing synergistic or antagonistic effects. Our knowledge of when and how interactions arise is limited, as most models and experiments only consider the effect of a small number of non-interacting stressors at one or few scales of ecological organization. This is concerning because it could lead to significant underestimations or overestimations of threats to biodiversity. Furthermore, stressors have been largely classified by their source rather than by the mechanisms and ecological scales at which they act (the target). Here, we argue, first, that a more nuanced classification of stressors by target and ecological scale can generate valuable new insights and hypotheses about stressor interactions. Second, that the predictability of multiple stressor effects, and consistent patterns in their impacts, can be evaluated by examining the distribution of stressor effects across targets and ecological scales. Third, that a variety of existing mechanistic and statistical modelling tools can play an important role in our framework and advance multiple stressor research

Refining Kidney Survival in 383 Genetically Characterized Patients With Nephronophthisis

Introduction: Nephronophthisis (NPH) comprises a group of rare disorders accounting for up to 10% of end-stage kidney disease (ESKD) in children. Prediction of kidney prognosis poses a major challenge. We assessed differences in kidney survival, impact of variant type, and the association of clinical characteristics with declining kidney function. Methods: Data was obtained from 3 independent sources, namely the network for early onset cystic kidney diseases clinical registry (n = 105), an online survey sent out to the European Reference Network for Rare Kidney Diseases (n = 60), and a literature search (n = 218). Results: A total of 383 individuals were available for analysis: 116 NPHP1, 101 NPHP3, 81 NPHP4 and 85 NPHP11/TMEM67 patients. Kidney survival differed between the 4 cohorts with a highly variable median age at onset of ESKD as follows: NPHP3, 4.0 years (interquartile range 0.3–12.0); NPHP1, 13.5 years (interquartile range 10.5–16.5); NPHP4, 16.0 years (interquartile range 11.0–25.0); and NPHP11/TMEM67, 19.0 years (interquartile range 8.7–28.0). Kidney survival was significantly associated with the underlying variant type for NPHP1, NPHP3, and NPHP4. Multivariate analysis for the NPHP1 cohort revealed growth retardation (hazard ratio 3.5) and angiotensin-converting enzyme inhibitor (ACEI) treatment (hazard ratio 2.8) as 2 independent factors associated with an earlier onset of ESKD, whereas arterial hypertension was linked to an accelerated glomerular filtration rate (GFR) decline. Conclusion: The presented data will enable clinicians to better estimate kidney prognosis of distinct patients with NPH and thereby allow personalized counseling

Biodiversity increases and decreases ecosystem stability

International audienc

Fluid flow and interlinked feedback loops establish left-right asymmetric decay of Cerl2 mRNA

Breaking of left-right symmetry in mouse embryos requires fluid flow at the node, but the precise action of the flow has remained unknown. Here we show that the left-right asymmetry of Cerl2 expression around the node, a target of the flow, is determined post-transcriptionally by decay of Cerl2 mRNA in a manner dependent on its 3' untranslated region. Cerl2 mRNA is absent specifically from the apical region of crown cells on the left side of the node. Preferential decay of Cerl2 mRNA on the left is initiated by the leftward flow and further enhanced by the operation of Wnt-Cerl2 interlinked feedback loops, in which Wnt3 upregulates Wnt3 expression and promotes Cerl2 mRNA decay, whereas Cerl2 promotes Wnt degradation. Mathematical modelling and experimental data suggest that these feedback loops behave as a bistable switch that can amplify in a noise-resistant manner a small bias conferred by fluid flow.Ministry of Education, Culture, Sports, Science, and Technology of Japan; Core Research for Evolutional Science and Technology (CREST) of the Japan Science and Technology Corporation (JST); GCOE of Osaka University; FCTinfo:eu-repo/semantics/publishedVersio