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Glomerular filtration rate (GFR), or the rate of primary urine formation, is the key indicator of renal function. Studies have demonstrated that GFR exhibits significant circadian rhythmicity and, that these rhythms are disrupted in a number of pathologies. Here, we tested a hypothesis that the circadian rhythm of GFR is driven by intrinsic glomerular circadian clocks. We used mice lacking the circadian clock protein BMAL1 specifically in podocytes, highly specialized glomerular cells critically involved in the process of glomerular filtration (Bmal1 lox/lox /Nphs2-rtTA/LC1 or, cKO mice). Circadian transcriptome profiling performed on isolated glomeruli from control and cKO mice revealed that the circadian clock controls expression of multiple genes encoding proteins essential for normal podocyte function. Direct assessment of glomerular filtration by inulin clearance demonstrated that circadian rhythmicity in GFR was lost in cKO mice that displayed an ultradian rhythm of GFR with 12-h periodicity. The disruption of circadian rhythmicity in GFR was paralleled by significant changes in circadian patterns of urinary creatinine, sodium, potassium and water excretion and by alteration in the diurnal pattern of plasma aldosterone levels. Collectively, these results indicate that the intrinsic circadian clock in podocytes participate in circadian rhythmicity of GFR.

Circadian rhythmicity in renal function suggests rhythmic adaptations in renal metabolism. To decipher the role of the circadian clock in renal metabolism, we studied diurnal changes in renal metabolic pathways using integrated transcriptomic, proteomic, and metabolomic analysis performed on control mice and mice with an inducible deletion of the circadian clock regulator Bmal1 in the renal tubule (cKOt). With this unique resource, we demonstrated that approximately 30% of RNAs, approximately 20% of proteins, and approximately 20% of metabolites are rhythmic in the kidneys of control mice. Several key metabolic pathways, including NAD+ biosynthesis, fatty acid transport, carnitine shuttle, and β-oxidation, displayed impairments in kidneys of cKOt mice, resulting in perturbed mitochondrial activity. Carnitine reabsorption from primary urine was one of the most affected processes with an approximately 50% reduction in plasma carnitine levels and a parallel systemic decrease in tissue carnitine content. This suggests that the circadian clock in the renal tubule controls both kidney and systemic physiology.

In the late 1960s, pioneer works by Keeler [...]

Renal excretion of water and major electrolytes exhibits a significant circadian rhythm. This functional periodicity is believed to result, at least in part, from circadian changes in secretion/reabsorption capacities of the distal nephron and collecting ducts. Here, we studied the molecular mechanisms underlying circadian rhythms in the distal nephron segments, i.e., distal convoluted tubule (DCT) and connecting tubule (CNT) and the cortical collecting duct (CCD). Temporal expression analysis performed on microdissected mouse DCT/CNT or CCD revealed a marked circadian rhythmicity in the expression of a large number of genes crucially involved in various homeostatic functions of the kidney. This analysis also revealed that both DCT/CNT and CCD possess an intrinsic circadian timing system characterized by robust oscillations in the expression of circadian core clock genes (clock, bma11, npas2, per, cry, nr1d1) and clock-controlled Par bZip transcriptional factors dbp, hlf, and tef. The clock knockout mice or mice devoid of dbp/hlf/tef (triple knockout) exhibit significant changes in renal expression of several key regulators of water or sodium balance (vasopressin V2 receptor, aquaporin-2, aquaporin-4, αENaC). Functionally, the loss of clock leads to a complex phenotype characterized by partial diabetes insipidus, dysregulation of sodium excretion rhythms, and a significant decrease in blood pressure. Collectively, this study uncovers a major role of molecular clock in renal function.

Even though wind energy is one of the most mature renewable technologies, it is in continuous development not only because of the trend towards larger wind turbines but also because of the development of new technological solutions. The gearbox is one of the components of the drive train in which the industry is concentrating more effort on research and development. Larger rotor blades lead to more demanding requirements for this component as a consequence of a higher mechanical torque and multiplication ratio (due to lower rotational speed of blades while the rotational speed on the generator side remains at similar values). In addition, operating conditions become increasingly demanding in terms of reliability, performance, and compactness. This paper analyses the different gearbox arrangements that are implemented by manufacturers of onshore wind turbines, as well as their market penetration (including different aspects that affect the design of the gearbox, such as drive train configuration and turbine size). The analysis carried out shows a clear convergence towards gearboxes with three stages. However, there is a noticeable diversity in the types of gears used, depending to a large extent on the preferences of each manufacturer but also on the nominal power of the wind turbine and drive train configuration.

Peroxisomes are specialized cellular organelles involved in a variety of metabolic processes. In humans, mutations leading to complete loss of peroxisomes cause multiorgan failure (Zellweger's spectrum disorders, ZSD), including renal impairment. However, the (patho)physiological role of peroxisomes in the kidney remains unknown. We addressed the role of peroxisomes in renal function in mice with conditional ablation of peroxisomal biogenesis in the renal tubule (cKO mice). Functional analyses did not reveal any overt kidney phenotype in cKO mice. However, infant male cKO mice had lower body and kidney weights, and adult male cKO mice exhibited substantial reductions in kidney weight and kidney weight/body weight ratio. Stereological analysis showed an increase in mitochondria density in proximal tubule cells of cKO mice. Integrated transcriptome and metabolome analyses revealed profound reprogramming of a number of metabolic pathways, including metabolism of glutathione and biosynthesis/biotransformation of several major classes of lipids. Although this analysis suggested compensated oxidative stress, challenge with high-fat feeding did not induce significant renal impairments in cKO mice. We demonstrate that renal tubular peroxisomes are dispensable for normal renal function. Our data also suggest that renal impairments in patients with ZSD are of extrarenal origin.

Additive manufacturing (AM) processes has been gaining interest for the last few years within a number of sectors including the industrial, the medical or the aerospace. To this regard, the characterization of mechanical properties of AM parts have been recently addressed for determining their elastic behaviour, strength, fatigue properties, among others. In this context, this paper addresses a preliminary investigation on formability of Ti6Al4V selective laser melted sheets under conventional forming. To this regard, conventional forming tests were carried out including tensile tests, double notched tensile tests and Erichsen cupping tests, in order to obtain a variety of strain states resulting in uniaxial tension, plane strain and biaxial strain, respectively. The results obtain provided the process window for deforming plastically this kind of materials, allow assessing the corresponding modes of failure and associated mechanisms and pointed out the importance of post-processing heat treatments for increasing the material ductility.

In this paper, we revisit the formability of tube expansion by single point incremental forming to account for the material strain hardening and the non-proportional loading paths that were not taken into consideration in a previously published analytical model of the process built upon a rigid perfectly plastic material. The objective is to provide a new insight on the reason why the critical strains at failure of tube expansion by single point incremental forming are far superior to those of conventional tube expansion by rigid tapered conical punches. For this purpose, we replaced the stress triaxiality ratio that is responsible for the accumulation of damage and cracking by tension in monotonic, proportional loading paths, by integral forms of the stress triaxiality ratio that are more adequate for the non-proportional paths resulting from the loading and unloading cycles of incremental tube expansion. Experimental and numerical simulation results plotted in the effective strain vs. stress triaxiality space confirm the validity of the new damage accumulation approach for handling the non-proportional loading paths that oscillate cyclically from shearing to biaxial stretching, as the single point hemispherical tool approaches, contacts and moves away from a specific location of the incrementally expanded tube surface.

Single Point Incremental Forming (SPIF) is a flexible and economic manufacturing process with a strong potential for manufacturing small and medium batches of highly customized parts. Formability and failure in SPIF have been intensively discussed in recent years, especially because this process allows stable plastic deformation well above the conventional forming limits, as this enhanced formability is only achievable within a certain range of process parameters depending on the material type. This paper analyzes formability and failure of AISI304-H111 sheets deformed by SPIF compared to conventional testing conditions (including Nakazima and stretch-bending tests). With this purpose, experimental tests in SPIF and stretch-bending were carried out and a numerical model of SPIF is performed. The results allow the authors to establish the following contributions regarding SPIF: (i) the setting of the limits of the formability enhancement when small tool diameters are used, (ii) the evolution of the crack when failure is attained and (iii) the determination of the conditions upon which necking is suppressed, leading directly to ductile fracture in SPIF.

Special topic volume with invited peer-reviewed papers only.