Disrupted uromodulin trafficking is rescued by targeting TMED cargo receptors.

The trafficking dynamics of uromodulin (UMOD), the most abundant protein in human urine, play a critical role in the pathogenesis of kidney disease. Monoallelic mutations in the UMOD gene cause autosomal dominant tubulointerstitial kidney disease (ADTKD-UMOD), an incurable genetic disorder that leads to kidney failure. The disease is caused by the intracellular entrapment of mutant UMOD in kidney epithelial cells, but the precise mechanisms mediating disrupted UMOD trafficking remain elusive.

Technical note: Does scan resolution or downsampling impact the analysis of trabecular bone architecture?

The "gold standard" for the assessment of trabecular bone structure is high-resolution micro-CT. In this technical note, we test the influence of initial scan resolution and post hoc downsampling on the quantitative and qualitative analysis of trabecular bone in a Gorilla tibia. We analyzed trabecular morphology in the right distal tibia of one Gorilla gorilla individual to investigate the impact of variation in voxel size on measured trabecular variables.

Immunosuppression with cyclosporine versus tacrolimus shows distinctive nephrotoxicity profiles within renal compartments.

Aim: Calcineurin inhibitors (CNIs) are the backbone for immunosuppression after solid organ transplantation. Although successful in preventing kidney transplant rejection, their nephrotoxic side effects contribute to allograft injury. Renal parenchymal lesions occur for cyclosporine A (CsA) as well as for the currently favored tacrolimus (Tac).

Trabecular architecture of the distal femur in extant hominids.

Extant great apes are characterized by a wide range of locomotor, postural and manipulative behaviours that each require the limbs to be used in different ways. In addition to external bone morphology, comparative investigation of trabecular bone, which (re-)models to reflect loads incurred during life, can provide novel insights into bone functional adaptation. Here, we use canonical holistic morphometric analysis (cHMA) to analyse the trabecular morphology in the distal femoral epiphysis of Homo sapiens (n = 26), Gorilla gorilla (n = 14), Pan troglodytes (n = 15) and Pongo sp.

Enriched Single-Nucleus RNA-Sequencing Reveals Unique Attributes of Distal Convoluted Tubule Cells.

Significance Statement: High-resolution single-nucleus RNA-sequencing data indicate a clear separation between primary sites of calcium and magnesium handling within distal convoluted tubule (DCT). Both DCT1 and DCT2 express Slc12a3, but these subsegments serve distinctive functions, with more abundant magnesium-handling genes along DCT1 and more calcium-handling genes along DCT2. The data also provide insight into the plasticity of the distal nephron-collecting duct junction, formed from cells of separate embryonic origins.

Association of High-Sensitivity Cardiac Troponin T With 30-Day and 5-Year Mortality After Cardiac Surgery.

Background: The relevance of perioperative myocardial injury (PMI) after cardiac surgery for 30-day mortality and long-term survival remains to be determined.

Objectives: This study assessed the association of PMI after cardiac surgery, reflected by postoperative troponin release, with 30-day mortality and long-term survival after: 1) coronary artery bypass grafting (CABG); 2) isolated aortic valve replacement (AVR) surgery; and 3) all other cardiac surgeries.

Methods: A consecutive cohort of 8,292 patients undergoing cardiac surgery with serial perioperative high-sensitivity cardiac troponin T (hs-cTnT) measurements was retrospectively analyzed.

Transgenic angiotensin-converting enzyme 2 overexpression in the rat vasculature protects kidneys from ageing-induced injury.

Chronic kidney disease is one of the leading causes of morbidity and mortality especially among the aged population. A decline in kidney function with ageing comparable to ageing-related processes in human kidneys has also been described in Sprague-Dawley (SD) rats. The renin-angiotensin-system (RAS) plays a pivotal role in the pathophysiology of cardiovascular and kidney disease and is a successful therapeutic target.

Hip joint load prediction using inverse bone remodeling with homogenized FE models: Comparison to micro-FE and influence of material modeling strategy.

Background And Objective: Measuring physiological loading conditions in vivo can be challenging, as methods are invasive or pose a high modeling effort. However, the physiological loading of bones is also imprinted in the bone microstructure due to bone (re)modeling. This information can be retrieved by inverse bone remodeling (IBR).

Urinary T Cells Identify Renal Antineutrophil Cytoplasmic Antibody-Associated Vasculitis and Predict Prognosis: A Proof of Concept Study.

Introduction: Necrotizing crescentic glomerulonephritis is a major contributor to morbidity and mortality in Antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). Because therapy relies on immunosuppressive agents with potentially severe adverse effects, a reliable noninvasive biomarker of disease activity is needed to guide treatment.

Methods: We used flow cytometry to quantify T cell subsets in blood and urine samples from 95 patients with AAV and 8 controls to evaluate their biomarker characteristics.

The deep trabecular structure of first metacarpals in extant hominids.

Objectives: Recent studies have associated subarticular trabecular bone distribution in the extant hominid first metacarpal (Mc1) with observed thumb use, to infer fossil hominin thumb use. Here, we analyze the entire Mc1 to test for interspecific differences in: (1) the absolute volume of trabecular volume fraction, (2) the distribution of the deeper trabecular network, and (3) the distribution of trabeculae in the medullary cavity, especially beneath the Mc1 disto-radial flange.

Materials And Methods: Trabecular bone was imaged using micro-computed tomography in a sample of Homo sapiens (n = 11), Pan paniscus (n = 10), Pan troglodytes (n = 11), Gorilla gorilla (n = 10) and Pongo sp.

LRP2 contributes to planar cell polarity-dependent coordination of motile cilia function.

Motile cilia are protruding organelles on specialized epithelia that beat in a synchronous fashion to propel extracellular fluids. Coordination and orientation of cilia beating on individual cells and across tissues is a complex process dependent on planar cell polarity (PCP) signaling. Asymmetric sorting of PCP pathway components, essential to establish planar polarity, involves trafficking along the endocytic path, but the underlying regulatory processes remain incompletely understood.

Studies in Zebrafish and Rat Models Support Dual Blockade of EP2 and EP4 (Prostaglandin E Receptors Type 2 and 4) for Renoprotection in Glomerular Hyperfiltration and Albuminuria.

Background: Glomerular hyperfiltration (GH) is an important mechanism in the development of albuminuria in hypertension. Upregulation of COX2 (cyclooxygenase 2) and prostaglandin E (PGE) was linked to podocyte damage in GH. We explored the potential renoprotective effects of either separate or combined pharmacological blockade of EP2 (PGE receptor type 2) and EP4 (PGE receptor type 4) in GH.

A Density-Dependent Target Stimulus for Inverse Bone (Re)modeling with Homogenized Finite Element Models.

Inverse bone (re)modeling (IBR) can infer physiological loading conditions from the bone microstructure. IBR scales unit loads, imposed on finite element (FE) models of a bone, such that the trabecular microstructure is homogeneously loaded and the difference to a target stimulus is minimized. Micro-FE (µFE) analyses are typically used to model the microstructure, but computationally more efficient, homogenized FE (hFE) models, where the microstructure is replaced by an equivalent continuum, could be used instead.

Annexin A1 exerts renoprotective effects in experimental crescentic glomerulonephritis.

Non-resolving inflammation plays a critical role during the transition from renal injury towards end-stage renal disease. The glucocorticoid-inducible protein annexin A1 has been shown to function as key regulator in the resolution phase of inflammation, but its role in immune-mediated crescentic glomerulonephritis has not been studied so far. Acute crescentic glomerulonephritis was induced in annexin A1-deficient and wildtype mice using a sheep serum against rat glomerular basement membrane constituents.

Single-cell transcriptomics reveals common epithelial response patterns in human acute kidney injury.

Background: Acute kidney injury (AKI) occurs frequently in critically ill patients and is associated with adverse outcomes. Cellular mechanisms underlying AKI and kidney cell responses to injury remain incompletely understood.

Methods: We performed single-nuclei transcriptomics, bulk transcriptomics, molecular imaging studies, and conventional histology on kidney tissues from 8 individuals with severe AKI (stage 2 or 3 according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria).

Assessing and improving the validity of COVID-19 autopsy studies - A multicentre approach to establish essential standards for immunohistochemical and ultrastructural analyses.

Background: Autopsy studies have provided valuable insights into the pathophysiology of COVID-19. Controversies remain about whether the clinical presentation is due to direct organ damage by SARS-CoV-2 or secondary effects, such as overshooting immune response. SARS-CoV-2 detection in tissues by RT-qPCR and immunohistochemistry (IHC) or electron microscopy (EM) can help answer these questions, but a comprehensive evaluation of these applications is missing.

Major cardiac surgery with recombinant FIX Fc fusion protein replacement in hemophilia B: a case report.

The introduction of extended factor IX (FIX) products has significantly facilitated the treatment of hemophilia B patients. However, optimal perioperative management remains a topic of hot debate, particularly in surgeries with high bleeding risk. For the first time, we report here a patient with mild hemophilia B and degenerative aneurysms of aortic root and ascending aorta undergoing elective Bentall's operation with full cardiopulmonary bypass, who was successfully managed with eftrenonacog alfa (Alprolix), a recombinant FIX Fc fusion protein (rFIXFc).

Renal Deletion of LRRC8/VRAC Channels Induces Proximal Tubulopathy.

Background: Volume-regulated anion channels (VRACs) are heterohexamers of LRRC8A with LRRC8B, -C, -D, or -E in various combinations. Depending on the subunit composition, these swelling-activated channels conduct chloride, amino acids, organic osmolytes, and drugs. Despite VRACs' role in cell volume regulation, and large osmolarity changes in the kidney, neither the localization nor the function of VRACs in the kidney is known.

Disease relevance of rare VPS13B missense variants for neurodevelopmental Cohen syndrome.

Autosomal recessive Cohen syndrome is a neurodevelopmental disorder characterized by postnatal microcephaly, intellectual disability, and a typical facial gestalt. Genetic variants in VPS13B have been found to cause Cohen syndrome, but have also been linked to autism, retinal disease, primary immunodeficiency, and short stature. While it is well established that loss-of-function mutations of VPS13B cause Cohen syndrome, the relevance of missense variants for the pathomechanism remains unexplained.

A computational framework for canonical holistic morphometric analysis of trabecular bone.

Bone is a remarkable, living tissue that functionally adapts to external loading. Therefore, bone shape and internal structure carry information relevant to many disciplines, including medicine, forensic science, and anthropology. However, morphometric comparisons of homologous regions across different individuals or groups are still challenging.

Immunosuppressive calcineurin inhibitor cyclosporine A induces proapoptotic endoplasmic reticulum stress in renal tubular cells.

Current immunosuppressive strategies in organ transplantation rely on calcineurin inhibitors cyclosporine A (CsA) or tacrolimus (Tac). Both drugs are nephrotoxic, but CsA has been associated with greater renal damage than Tac. CsA inhibits calcineurin by forming complexes with cyclophilins, whose chaperone function is essential for proteostasis.

Influence of Nuclear Localization Sequences on the Intracellular Fate of Gold Nanoparticles.

Directing nanoparticles to the nucleus by attachment of nuclear localization sequences (NLS) is an aim in many applications. Gold nanoparticles modified with two different NLS were studied while crossing barriers of intact cells, including uptake, endosomal escape, and nuclear translocation. By imaging of the nanoparticles and by characterization of their molecular interactions with surface-enhanced Raman scattering (SERS), it is shown that nuclear translocation strongly depends on the particular incubation conditions.

Preparation of Samples for Large-Scale Automated Electron Microscopy of Tissue and Cell Ultrastructure.

Manual selection of targets in experimental or diagnostic samples by transmission electron microscopy (TEM), based on single overview and detail micrographs, has been time-consuming and susceptible to bias. Substantial information and throughput gain may now be achieved by the automated acquisition of virtually all structures in a given EM section. Resulting datasets allow the convenient pan-and-zoom examination of tissue ultrastructure with preserved microanatomical orientation.