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.

Mechanisms of pathogenicity and the quest for genetic modifiers of kidney disease in branchiootorenal syndrome.

Backgound: Branchiootorenal (BOR) syndrome is an autosomal dominant disorder caused by pathogenic variants and clinically characterized by auricular malformations with hearing loss, branchial arch anomalies, and congenital anomalies of the kidney and urinary tract. BOR phenotypes are highly variable and heterogenous. While random monoallelic expression is assumed to explain this phenotypic heterogeneity, the potential role of modifier genes has not yet been explored.

Towards understanding policy design through text-as-data approaches: The policy design annotations (POLIANNA) dataset.

Despite the importance of ambitious policy action for addressing climate change, large and systematic assessments of public policies and their design are lacking as analysing text manually is labour-intensive and costly. POLIANNA is a dataset of policy texts from the European Union (EU) that are annotated based on theoretical concepts of policy design, which can be used to develop supervised machine learning approaches for scaling policy analysis. The dataset consists of 20,577 annotated spans, drawn from 18 EU climate change mitigation and renewable energy policies.

Defective claudin-10 causes a novel variation of HELIX syndrome through compromised tight junction strand assembly.

Formation of claudin-10 based tight junctions (TJs) is paramount to paracellular Na transport in multiple epithelia. Sequence variants in have been linked to HELIX syndrome, a salt-losing tubulopathy with altered handling of divalent cations accompanied by dysfunctional salivary, sweat, and lacrimal glands. Here, we investigate molecular basis and phenotypic consequences of a newly identified homozygous variant that translates into a single amino acid substitution within the fourth transmembrane helix of claudin-10.

Claudin-10a Deficiency Shifts Proximal Tubular Cl Permeability to Cation Selectivity Claudin-2 Redistribution.

Background: The tight junction proteins claudin-2 and claudin-10a form paracellular cation and anion channels, respectively, and are expressed in the proximal tubule. However, the physiologic role of claudin-10a in the kidney has been unclear.

Methods: To investigate the physiologic role of claudin-10a, we generated claudin-10a-deficient mice, confirmed successful knockout by Southern blot, Western blot, and immunofluorescence staining, and analyzed urine and serum of knockout and wild-type animals.

Governing complex societal problems: The impact of private on public regulation through technological change.

When addressing complex societal problems, public regulation is increasingly complemented by private regulation. Extant literature has provided valuable insights into the effectiveness of such complex governance structures, with most empirical studies focusing on how public regulation influences private regulation. Conversely, the impact of private on public regulation is less well studied.

Matching clinical and genetic diagnoses in autosomal dominant polycystic kidney disease reveals novel phenocopies and potential candidate genes.

Purpose: Autosomal dominant polycystic kidney disease (ADPKD) represents the most common hereditary nephropathy. Despite growing evidence for genetic heterogeneity, ADPKD diagnosis is still primarily based upon clinical imaging criteria established before discovery of additional PKD genes. This study aimed at assessing the diagnostic value of genetic verification in clinical ADPKD.

Anodal transcranial direct current stimulation (tDCS) over supplementary motor area (SMA) but not pre-SMA promotes short-term visuomotor learning.

Background: Non-invasive brain stimulation such as transcranial direct current stimulation (tDCS) has been shown to modulate cortical excitability and thereby influencing motor behaviour and learning.

Hypothesis: While there is increasing knowledge about the importance of the primary motor cortex (M1) in short- and long-term motor skill learning, little is known about the role of secondary motor areas such as the supplementary and pre-supplementary motor area (SMA/pre-SMA) especially in short-term motor performance. Since SMA but not pre-SMA is directly connected to M1, we hypothesize that anodal tDCS over SMA but not pre-SMA will facilitate visuomotor learning.

Enhancing the effect of repetitive I-wave paired-pulse TMS (iTMS) by adjusting for the individual I-wave periodicity.

Background: Repeated application of paired-pulse TMS over the primary motor cortex (M1) in human subjects with an inter-pulse interval (IPI) of 1.5 ms (iTMS(1.5 ms)) has been shown to significantly increase paired-pulse MEP (ppMEP) amplitudes during the stimulation period and increased single-pulse MEP amplitudes for up to 10 minutes after termination of iTMS.