The insect nephrocyte is a podocyte-like cell with a filtration slit diaphragm.

The nephron is the basic structural and functional unit of the vertebrate kidney. It is composed of a glomerulus, the site of ultrafiltration, and a renal tubule, along which the filtrate is modified. Although widely regarded as a vertebrate adaptation, 'nephron-like' features can be found in the excretory systems of many invertebrates, raising the possibility that components of the vertebrate excretory system were inherited from their invertebrate ancestors. Here we show that the insect nephrocyte has remarkable anatomical, molecular and functional similarity to the glomerular podocyte, a cell in the vertebrate kidney that forms the main size-selective barrier as blood is ultrafiltered to make urine. In particular, both cell types possess a specialized filtration diaphragm, known as the slit diaphragm in podocytes or the nephrocyte diaphragm in nephrocytes. We find that fly (Drosophila melanogaster) orthologues of the major constituents of the slit diaphragm, including nephrin, NEPH1 (also known as KIRREL), CD2AP, ZO-1 (TJP1) and podocin, are expressed in the nephrocyte and form a complex of interacting proteins that closely mirrors the vertebrate slit diaphragm complex. Furthermore, we find that the nephrocyte diaphragm is completely lost in flies lacking the orthologues of nephrin or NEPH1-a phenotype resembling loss of the slit diaphragm in the absence of either nephrin (as in human congenital nephrotic syndrome of the Finnish type, NPHS1) or NEPH1. These changes markedly impair filtration function in the nephrocyte. The similarities we describe between invertebrate nephrocytes and vertebrate podocytes provide evidence suggesting that the two cell types are evolutionarily related, and establish the nephrocyte as a simple model in which to study podocyte biology and podocyte-associated diseases.This work was supported by Wellcome Trust grants awarded to H.S. (072441 and 079221, H.W., B.D., H.S.); Deutsche Forschungsgemeinschaft (SFB 590) awarded to Elisabeth Knust (F.G.), ARC 1242 (H.W., B.D., H.S., F.G.); MEC grant awarded to M.R-G. (BFU2007-62201, S.P-S., M.R-G.); Fundación Ramón Areces grant to the CBMSO (M.R-G.); EC grant LSHG-CT-2004-511978 to MYORES (M.R-G.); an FPU fellowship from the MEC awarded to A.G-L.Peer reviewe

Genetic architecture of subcortical brain structures in 38,851 individuals

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease

Genetic architecture of subcortical brain structures in 38,851 individuals

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease

Novel genetic loci underlying human intracranial volume identified through genome-wide association

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five novel loci for intracranial volume and confirmed two known signals. Four of the loci are also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic=0.748), which indicated a similar genetic background and allowed for the identification of four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, Parkinson’s disease, and enriched near genes involved in growth pathways including PI3K–AKT signaling. These findings identify biological underpinnings of intracranial volume and provide genetic support for theories on brain reserve and brain overgrowth

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

L-Arginine and Tetrahydrobiopterin for the treatment of pulmonary arterial hypertension in a rodent model

Pulmonal-arterielle Hypertension (PAH) ist eine lebensbedrohliche Erkrankung, bei der es durch progressive Veränderungen zu einer zunehmenden Einengung bis hin zum Verschluss einzelner Gefäße im pulmonalen Gefäßbett kommt. Veränderungen im Signalweg der endothelialen Stickstoff-Synthase (eNOS) scheinen nicht nur bei der Entstehung der Krankheit, sondern auch in der Therapie der PAH eine Rolle zu spielen. Die körpereigene Stickstoff-Synthese durch die eNOS ist abhängig von der Verfügbarkeit des Substrats L-Arginin (LA) und dem Cofaktor Tetrahydrobiopterin (BH4). Die kombinierte Gabe beider Substanzen wurde bisher nicht in vivo evaluiert und hat möglicherweise einen synergistischen Effekt. Im Rahmen der vorliegenden Studie wurde ein experimentelles Tiermodell der PAH aus unilateraler Pneumonektomie und Monocrotalin etabliert. In 62 männlichen Sprague-Dawley Ratten wurden mittels telemetrischer Messung, hämodynamische und funktionelle sowie post mortem morphometrische Parameter einer oral verabreichten LA, BH4 oder Kombinationstherapie gegenüber einer Kontrollgruppe verglichen. Die Verabreichung von LA, BH4 und der Kombinationstherapie führten zu einer signifikanten Verminderung des pulmonal-arteriellen Drucks, einer Aktivitätssteigerung und einer Zunahme des Körpergewichts. Zudem zeigten sich eine verringerte Rechtsherzhypertrophie und ein verringertes Remodeling von kleinen pulmonal-arteriellen Gefäßen. Obwohl die eNOS-mRNA Expression signifikant durch die Therapie reduziert wurde, zeigte sich der Gesamt-eNOS- Protein-Gehalt im Vergleich zur Kontrollkohorte unverändert. In der Kombinationsgruppe zeigten sich keine signifikanten Unterschiede in hämodynamischen, funktionellen oder morphometrischen Parametern im Vergleich zu einer isolierten LA oder BH4 Therapie. Anhand der gewonnenen Daten kann kein klinisch relevanter Vorteil einer oral verabreichten Kombinationstherapie aus LA und BH4 gezeigt werden. Vom aktuellen Standpunkt kann die orale Kombinationstherapie daher nicht als Therapie der PAH im Menschen empfohlen werden.Pulmonary arterial hypertension (PAH) is a life threatening disease that is characterized by progressive narrowing and subsequent occlusion of pulmonary vessels. Alterations in the nitric oxide (NO) pathway seem to play an important role in development and therapy of the disease. Endogenous NO production in the vessel wall by the endothelial nitric oxide synthase (eNOS) is regulated by the availability of the main substrate L-Arginine (LA) and its cofactor Tetrahydrobiopterin (BH4). The combined administration of both substances could have favorable synergistic effects, but has not been tested in vivo before. We established an animal model of experimental PAH by combination of unilateral pneumonectomy and monocrotaline. In a total of 62 male Sprague-Dawley rats we telemetrically monitored therapy effects and compared hemodynamic, functional and morphometric parameters of an oral LA, BH4 or combined therapy versus a control cohort. LA, BH4 as well as the combination of both substantially lowered PAP, increased activity and body weight, decreased right ventricular hypertrophy and vascular remodeling of small pulmonary arteries. Although a down regulated eNOS mRNA expression was found for the therapy groups, the total eNOS protein content by immunohistochemistry and western blot studies did not differ compared to control rats. For the combined therapy group, no significant differences were found with respect to hemodynamic, functional or morphometric parameters in comparison with the LA or BH4 monotherapy groups. Our experimental study did not reveal a clinically relevant synergism of a combined administration of LA and BH4. These results do not encourage the translation into human PAH therapy.submitted by Dr. med. univ. Catharina Rahel SchreiberZusammenfassung in deutscher SpracheAbweichender Titel laut Übersetzung der Verfasserin/des VerfassersMedizinische Universität, Dissertation, 2017OeB

Antiplatelet Usage Impacts Clot Density in Acute Anterior Circulation Ischemic Stroke

We explored whether clot density in middle cerebral artery (MCA) occlusion is related to clinical variables, stroke etiology, blood constituents, and prestroke medication. We performed a retrospective chart review of patients with acute ischemic stroke of the anterior circulation admitted to two Central European stroke centers. The acquisition of non-contrast enhanced CT (NECT) and CT angiography (CTA) within 4.5 h of symptom onset was obligatory. We assessed the site of MCA occlusion as well as density, area, and length of the clot in 150 patients. The Hounsfield unit values for the clot were divided with contralateral MCA segment to yield relative Hounsfield Unit ratio (rHU). The site of the vessel occlusion (M1 vs. M2) and antiplatelet usage, but not stroke etiology, significantly influenced rHU. We found an inverse correlation of rHU with erythrocyte count (p &lt; 0.001). The multivariate analysis revealed that a higher rHU (i.e., clot being more hyperdense) was more likely with the use of antiplatelets (OR 4.24, CI 1.10–16.31, p = 0.036). Erythrocyte (OR 0.18, CI 0.05–0.55, p = 0.003), and thrombocyte counts (OR 0.99, CI 0.98–0.99, p = 0.029) were associated with odds for more hypodense clots (lower rHU). Our study disclosed that antiplatelet therapy impacts the composition of intracranial clots of the anterior circulation