bluuebunny/crossref_metadata_2025 huggingface dataset:
Endothelin A Receptor Blockade Prevents Capillary/Myocyte Mismatch in the Heart of Uremic Animals
Authors: AMANN KERSTIN , MÜNTER KLAUS , WESSELS SABINE , WAGNER JÜRGEN , BALAJEW VITALI , HERGENRÖDER STEFAN , MALL GERHARD , RITZ EBERHARD
Published: April 2021

In the heart of uremic animals and patients, the number of capillaries per volume of myocardium is reduced. Immunohistochemical studies demonstrated increased cardiac endothelin-1 (ET-1) expression in the left ventricle of uremic animals. Therefore, whether treatment with a selective ETA-receptor antagonist prevented such capillary-myocyte mismatch was investigated. Twenty-four h after subtotal nephrectomy, rats were left untreated or started on treatment with the ETA-receptor antagonist LU 135252 (20 mg/kg per d) and with the angiotensin-converting enzyme (ACE) inhibitor trandolapril (0.3 mg/kg per d), respectively. BP was monitored by telemetry. Myocardial capillary length density was analyzed by stereologic techniques that avoid anisotropy artifacts. In addition, cardiac ET-1 protein and mRNA were measured using immunohistochemistry, in situ hybridization, and quantitative reverse transcription—PCR. Changes in cardiac ETA-and ETB-PCR. receptor mRNA were measured using reverse transcription—PCR. Fifteen wk after subtotal nephrectomy, significantly reduced left ventricular capillary length density (3307 ± 535 mm/mm3) was found compared with sham-operated controls (3995 ± 471 mm/mm3); this was also seen in animals that were treated with trandolapril (3503 ± 533 mm/mm3) but not in animals that were treated with LU 135252 (3800 ± 303 mm/mm3). The results support a role of ET-1 in the genesis of left ventricular capillary/myocyte mismatch in uremia.
Comparative Effects of Cerivastatin and Fenofibrate on the Atherogenic Lipoprotein Phenotype in Proteinuric Renal Disease
Authors: DEIGHAN CHRISTOPHER J. , CASLAKE MURIEL J. , MCCONNELL MICHAEL , BOULTON-JONES J. MICHAEL , PACKARD CHRISTOPHER J.
Published: April 2021

Patients with nephrotic-range proteinuria have impaired clearance of triglyceride-rich lipoproteins. This results in the atherogenic lipoprotein phenotype (mild hypertriglyceridemia, low high-density lipoproteins [HDL], and excess small, dense low-density lipoproteins [LDLIII]). Excess remnant lipoproteins (RLP) are linked to hypertriglyceridemia and may contribute to the atherogenicity of nephrotic dyslipidemia. A randomized crossover study compared the effects of a statin (cerivastatin) and a fibrate (fenofibrate) on LDLIII and RLP in 12 patients with nephrotic-range proteinuria. Cerivastatin reduced cholesterol (21%, P < 0.01), triglyceride (14%, P < 0.05), LDL cholesterol (LDL-C; 23%, P < 0.01), total LDL (18%, P < 0.01), and LDLIII concentration (27% P < 0.01). %LDLIII, RLP-C, and RLP triglyceride (RLP-TG) were unchanged. Plasma LDLIII reduction with cerivastatin treatment correlated with LDL-C reduction (r2 = 34%, P < 0.05). Fenofibrate lowered cholesterol (19%), triglyceride (41%), very low-density lipoprotein cholesterol (52%), LDLIII concentration (49%), RLP-C (35%), and RLP-TG (44%; all P < 0.01). Fenofibrate also reduced %LDLIII from 60 to 33% (P < 0.01). HDL-C (19%, P < 0.01) increased with fenofibrate treatment; LDL-C and total LDL were unchanged. The reduction in LDLIII concentration and RLP-C with fenofibrate treatment correlated with plasma triglyceride reduction (LDLIII r2 = 67%, P < 0.001; RLP cholesterol r2 = 58%, P < 0.005). Serum creatinine increased with fenofibrate treatment (14%, P < 0.01); however, creatinine clearance was unchanged. LDLIII concentration was 187 ± 85 mg/dl after cerivastatin treatment and 133 ± 95 mg/dl after fenofibrate treatment. Cerivastatin and fenofibrate reduce LDLIII concentration in nephrotic-range proteinuria. However, atherogenic concentrations of LDLIII remain prevalent after either treatment. Fenofibrate but not cerivastatin reduces remnant lipoproteins. The two treatments seem to reduce LDLIII by different mechanisms, suggesting a potential role for combination therapy to optimize lowering of LDLIII and RLP.
Clinical and Genetic Evaluation of Familial Steroid-Responsive Nephrotic Syndrome in Childhood
Authors: FUCHSHUBER ARNO , GRIBOUVAL OLIVIER , RONNER VERA , KROISS SABINE , KARLE STEPHANIE , BRANDIS MATTHIAS , HILDEBRANDT FRIEDHELM
Published: April 2021

Steroid-responsive idiopathic nephrotic syndrome (SSINS) is the most common form of nephrotic syndrome in childhood. This article reports a cohort of familial SSINS with disease onset in childhood. The clinical course in terms of age at onset, symptoms during the initial phase, renal morphology, and outcome was evaluated. Furthermore, linkage to NPHS2, the gene for autosomal-recessive steroid-resistant INS on chromosome 1, was examined. Two families with haplotypes consistent with linkage to NPHS2 were evaluated for mutations in the NPHS2 gene. Familial SSINS (32 patients from 15 families, minimal change NS in 12 of 12 biopsies) was found to be a clinically homogeneous entity. Interfamilial and intrafamilial variability with respect to the age at disease onset was low, indicating a strong genetic influence on disease onset. By linkage studies and mutational analysis, familial SSINS was found to be genetically distinct from NPHS2. This is the first report of a large cohort of familial SSINS. Exclusion of linkage to NPHS2 makes likely the existence of a distinct gene locus for SSINS.
Podocytes Respond to Mechanical Stress In Vitro
Authors: ENDLICH NICOLE , KRESS KAI R. , REISER JOCHEN , UTTENWEILER DIETMAR , KRIZ WILHELM , MUNDEL PETER , ENDLICH KARLHANS
Published: April 2021

Glomerular capillary pressure is thought to affect the structure and function of glomerular cells. However, it is unknown whether podocytes are intrinsically sensitive to mechanical forces. In the present study, differentiated mouse podocytes were cultured on flexible silicone membranes. Biaxial cyclic stress (0.5 Hz and 5% linear strain) was applied to the membranes for up to 3 d. Mechanical stress reduced the size of podocyte cell bodies, and processes became thin and elongated. Podocytes did not align in the inhomogeneous force field. Whereas the network of microtubules and that of the intermediate filament vimentin exhibited no major changes, mechanical stress induced a reversible reorganization of the actin cytoskeleton: transversal stress fibers (SF) disappeared and radial SF that were connected to an actin-rich center (ARC) formed. Epithelial and fibroblast cell lines did not exhibit a comparable stress-induced reorganization of the F-actin. Confocal and electron microscopy revealed an ellipsoidal and dense filamentous structure of the ARC. Myosin II, α-actinin, and the podocyte-specific protein synaptopodin were present in radial SF, but, opposite to F-actin, they were not enriched in the ARC. The formation of the ARC and of radial SF in response to mechanical stress was inhibited by nonspecific blockade of Ca2+ influx with Ni2+ (1 mM), by Rho kinase inhibition with Y-27632 (10 μM), but not by inhibition of stretch-activated cation channels with Gd3+ (50 μM). In summary, mechanical stress induces a unique reorganization of the actin cytoskeleton in podocytes, featuring radial SF and an ARC, which differ in protein composition. The F-actin reorganization in response to mechanical stress depends on Ca2+ influx and Rho kinase. The present study provides the first direct evidence that podocytes are mechanosensitive.
Upregulation of the Secretory-Type Na+/K+/2Cl--Cotransporter in the Kidney by Metabolic Acidosis and Dehydration in Rats
Authors: IKEBE MIKA , NONOGUCHI HIROSHI , NAKAYAMA YUSHI , TASHIMA YUKA , TOMITA KIMIO
Published: April 2021

The functional role and mechanisms of regulation of the Na+/K+/2Cl--cotransporter NKCC1 in the kidney have not yet been clarified. NKCC1 mRNA and protein expression in control rats, rats with dehydration (2 d), and rats with metabolic acidosis (NH4Cl in the food for 6 to 7 d) was examined using reverse transcription-PCR and Western blotting. In contrast to the abundant NKCC1 mRNA expression in the terminal inner medullary collecting ducts in mice, expression was found to be most abundant in the outer medullary collecting ducts (OMCD) in rats. Dehydration and metabolic acidosis increased NKCC1 mRNA expression three- to fivefold not only in the OMCD but also in the cortical collecting ducts and inner medullary collecting ducts. Dehydration and metabolic acidosis increased NKCC1 protein expression twofold in the membrane fraction from the outer medulla. NKCC1 protein expression was observed not in the microdissected medullary thick ascending limbs but in the OMCD, and it was stimulated twofold by dehydration and metabolic acidosis. Incubation of OMCD in low-pH medium increased NKCC1 mRNA expression. In summary, NKCC1 mRNA and protein expression is upregulated with dehydration and metabolic acidosis. NKCC1 may play an important role in adaptation to these physiologic conditions. Low pH and possibly hypertonicity stimulate NKCC1 mRNA expression in OMCD.
Expression of Angiotensinogen mRNA and Protein in Angiotensin II-Dependent Hypertension
Authors: KOBORI HIROYUKI , HARRISON-BERNARD LISA M. , NAVAR L. GABRIEL
Published: April 2021

Chronic elevations in circulating angiotensin II (AngII) levels produce sustained hypertension and increased intrarenal AngII contents through multiple mechanisms, which may include sustained or increased local production of AngII. This study was designed to test the hypothesis that chronic AngII infusion increases renal angiotensinogen mRNA and protein levels, thus contributing to the increase in intrarenal AngII levels. AngII (80 ng/min) was infused subcutaneously for 13 d into Sprague-Dawley rats, using osmotic minipumps. Control rats underwent sham operations. By day 12, systolic arterial BP increased to 184 ± 3 mmHg in AngII-treated rats, whereas values for sham-treated rats remained at control levels (125 ± 1 mmHg). Plasma renin activity was markedly suppressed (0.2 ± 0.1 versus 5.3 ± 1.2 ng AngI/ml per h); however, renal AngII contents were significantly increased in AngII-treated rats (273 ± 29 versus 99 ± 18 fmol/g). Western blot analyses of plasma and liver protein using a polyclonal anti-angiotensinogen antibody demonstrated two specific immunoreactive bands, at 52 and 64 kD, whereas kidney tissue exhibited one band, at 52 kD. Densitometric analyses demonstrated that AngII infusion did not alter plasma (52- or 64-kD), renal (52-kD), or hepatic (52-kD) angiotensinogen protein levels; however, there was a significant increase in hepatic expression of the highly glycosylated 64-kD angiotensinogen protein, of almost fourfold (densitometric value/control value ratios of 3.79 ± 1.16 versus 1.00 ± 0.35). Renal and hepatic expression of angiotensinogen mRNA, which was examined by semiquantitative reverse transcription-PCR, was significantly increased in AngII-treated rats, compared with shamtreated rats (kidney, densitometric value/glyceraldehyde-3-phosphate dehydrogenase mRNA value ratios of 0.82 ± 0.11 versus 0.58 ± 0.04; liver, densitometric value/glyceraldehyde-3-phosphate dehydrogenase mRNA value ratios of 2.34 ± 0.07 versus 1.32 ± 0.15). These results indicate that increases in circulating AngII levels increase intrarenal angiotensinogen mRNA levels, which may contribute to the sustained renal AngII-generating capacity that paradoxically occurs in AngII-treated hypertensive rats.
Characterization and Signaling of the AT4 Receptor in Human Proximal Tubule Epithelial (HK-2) Cells
Authors: HANDA RAJASH K.
Published: April 2021

125I-divalinal-angiotensin IV (metabolically resistant analog of angiotensin IV) was used as a receptor ligand to identify the expression and properties of the angiotensin AT4 receptor in epithelial HK-2 cells (an immortalized cell line derived from adult human proximal tubules). Saturation binding isotherms revealed that HK-2 cells contain a saturable 125I-divalinal-angiotensin IV binding site with an affinity of 3 nmol/L and a density of 508 fmol/mg protein. An analysis of ligand specificity showed that only angiotensin AT4 receptor ligands (angiotensin IV and divalinal-angiotensin IV) competed with both a high- and low-affinity binding site. GTPγS and dithiothreitol did not affect 125I-Ang IV or 125I-divalinal-Ang IV binding, suggesting that the AT4 receptor was not G-protein coupled and did not require sulfhydryl bonds for receptor affinity. Activation of the AT4 receptor caused a complex concentration-dependent rise in [Ca2+]i, an elevation in [Na+]i, and increased mitogen-activated protein kinase activity. These results suggest that human proximal tubule epithelial cells contain functional AT4 receptors that are pharmacologically similar to the AT4 receptor described in more distal segments of the nephron. Furthermore, the AT4 receptor uses several intracellular signaling pathways to convey information.
Prognostic Value of Angiotensin-I Converting Enzyme I/D Polymorphism for Nephropathy in Type 1 Diabetes Mellitus
Authors: HADJADJ SAMY , BELLOUM RIADH , BOUHANICK BÉATRICE , GALLOIS YVES , GUILLOTEAU GÉRARD , CHATELLIER GILLES , ALHENC-GELAS FRANC[COMBINING CEDILLA]OIS , MARRE MICHEL
Published: April 2021

Angiotensin-I converting enzyme (ACE) regulates renal hemodynamics. Its insertion/deletion (I/D) polymorphism, which determines most of ACE interindividual variance, was proposed as a genetic marker for diabetic nephropathy. A substitution (M235T) polymorphism in angiotensinogen (AGT) may interact with ACE I/D polymorphism for the risk of diabetic nephropathy, but their prognostic values have to be established by follow-up studies. A total of 310 type 1 diabetes mellitus patients who attended the diabetic clinic in Angers (France) took part in a prospective, observational, follow-up study. Glycohemoglobin, BP, plasma creatinine, and urinary albumin excretion were determined periodically. Nephropathy was classified as absent, incipient (microalbuminuria), established (proteinuria), advanced (plasma creatinine ≥ 150 μmol/L), and terminal (renal replacement therapy). The main end point was the occurrence of a renal event defined as the progression to a higher stage of diabetic nephropathy. At baseline, 251 (81%) patients had no nephropathy, 35 (11%) had incipient nephropathy, 18 (6%) had established nephropathy, and 6 (2%) had advanced nephropathy. The ACE I/D and M235T AGT polymorphisms were in Hardy-Weinberg equilibrium in the patients. The median duration of follow-up was 6 yr (range, 2 to 9 yr). The occurrence of renal events was significantly influenced by ACE genotype (log-rank II versus ID versus DD, P < 0.03) with a dominant deleterious effect of the D allele: ID or DD versus II (adjusted hazard ratio, 5.0; 95% confidence interval, 1.5 to 16.6). Other contributors were high glycohemoglobin and systolic BP. In the patients who initially were free of nephropathy, baseline plasma ACE concentration was higher in patients who progressed to microalbuminuria (571 ± 231 versus 466 ± 181 μg/L; P = 0.0032); the D allele independently favored the occurrence of incipient nephropathy (adjusted hazard ratio, 4.5; 95% confidence interval, 1.1 to 19.4); other contributors were male gender, baseline systolic BP, and urinary albumin excretion. The AGT M235T polymorphism was not associated with renal events. The D allele of the ACE I/D polymorphism is an independent risk factor for both the onset and the progression of diabetic nephropathy in type 1 diabetes mellitus patients.
Suppression of Constitutive but Not IL-1β-Inducible Expression of Monocyte Chemoattractant Protein-1 in Mesangial Cells by Retinoic Acids
Authors: LUCIO-CAZANA JAVIER , NAKAYAMA KENJI , XU QIHE , KONTA TSUNEO , MORENO-MANZANO VICTORIA , FURUSU AKIRA , KITAMURA MASANORI
Published: April 2021

Retinoic acid regulates a wide range of biologic processes, including inflammation. This study investigated the effect of all-trans-retinoic acid (t-RA) on the constitutive and cytokine-inducible expression of monocyte chemoattractant protein 1 (MCP-1) in rat mesangial cells. Serum-deprived mesangial cells exhibited substantial levels of MCP-1 mRNA, and the expression was markedly upregulated by interleukin-1β (IL-1β). Pretreatment with t-RA abrogated the constitutive mRNA expression but did not inhibit the IL-1β-inducible expression. The similar effects were observed by 9-cis-RA. The suppressive effect of t-RA required retinoic acid receptors. t-RA did not affect the stability of MCP-1 mRNA, indicating that its suppressive effect was at the transcriptional level. Experiments that used pharmacologic and genetic inhibitors showed that the IL-1β-inducible MCP-1 expression was dependent on nuclear factor-κB (NF-κB) and independent of activator protein 1 (AP-1). In contrast, the constitutive expression of MCP-1 was dependent on both NF-κB and AP-1. t-RA substantially inhibited the constitutive activity of AP-1 but did not inhibit NF-κB activity in mesangial cells. These data suggested that (1) constitutive and IL-1β-inducible expression of MCP-1 was differently regulated by AP-1 and NF-κB and (2) t-RA inhibited selectively the constitutive expression of MCP-1 via intervention in the AP-1 pathway.
CD40 Is Expressed on Human Peritoneal Mesothelial Cells and Upregulates the Production of Interleukin-15 and RANTES
Authors: BASOK ANNA , SHNAIDER ALLA , MAN LIMOR , CHAIMOVITZ CIDIO , DOUVDEVANI AMOS
Published: April 2021

Limited data are available concerning the interaction between lymphocytes and human peritoneal mesothelial cells (HPMC) during peritonitis. CD40 is a member of the tumor necrosis factor (TNF) family of receptors whose ligand (CD154) is mainly expressed on the membrane of activated CD4-positive lymphocytes. CD154-CD40 cross-linking is a central event in antigen presentation, B-cell activation by T cells, and regulation of cytokine secretion from various types of cells. The goal of this study was to demonstrate in vitro the presence of CD40 on HPMC and to test its functionality in inducing interleukin-15 (IL-15) and RANTES. We assayed the levels of CD40 by reverse transcription-PCR and flow cytometry and IL-15 and RANTES by enzyme-linked immunosorbent assay. Genetically modified L cells that express elevated levels of CD154 (CD40L cells) were used to stimulate CD40. HPMC express CD40 mRNA and protein. After stimulation with interferon-γ (IFNγ, 5U/ml) or TNFα (1 ng/ml), there was a small increase in CD40 mRNA and protein levels; when both cytokines were applied, the increase in CD40 levels was more than threefold. CD40 ligation induced IL-15 production by HPMC and was additive to IFNγ stimulation. CD40 ligation was strongly synergistic with IFNγ in induction of RANTES (20-fold as compared with unstimulated HPMC), whereas neither ligation nor IFNγ alone could induce RANTES. Pretreatment of HPMC with TNFα and IFNγ increased the response to CD40 ligation in magnitudes that correlated with the elevation of CD40 levels induced by the pretreatment. To conclude, the presence of a functional CD40 on HPMC whose ligation induced IL-15 and RANTES production was detected. It is possible that this receptor acts as a major mediator of T-cell—regulated immune and inflammatory response during peritonitis.
Thrombospondin-1 Is the Key Activator of TGF-β1 in Human Mesangial Cells Exposed to High Glucose
Authors: YEVDOKIMOVA NATALIA , WAHAB NADIA ABDEL , MASON ROGER M.
Published: April 2021

Elevated levels of transforming growth factor-β1 (TGF-β1) are synthesized by human mesangial cells that are cultured in medium that contains high concentrations of glucose and mediate increased synthesis of fibronectin (FN), plasminogen activator inhibitor-1 (PAI-1), and changes in the expression of other genes. TGF-β1 is synthesized as a latent complex. Previous work indicated that high-glucose conditions also upregulate expression of thrombospondin-1 (TSP-1), a potential activator of latent TGF-β1. With the use of the synthetic peptide GGWSHW, an inhibitor of the TSP-1 activation mechanism, endogenous TSP-1 is shown to be responsible for converting high levels of latent TGF-β1 to bioactive growth factor over 3 wk of exposure of mesangial cells to 30 mM D-glucose. Peptide inhibition of TGF-β1 activation by TSP-1 in high-glucose conditions completely suppressed increases in FN and PAI-1 expression. Treating mesangial cells maintained in high glucose with a TSP-1 antisense oligonucleotide reduced TSP-1 expression to levels found in 4 mM D-glucose cultures, prevented TGF-β1 activation, and normalized expression of FN.
Activated Coagulation Factor X: A Novel Mitogenic Stimulus for Human Mesangial Cells
Authors: MONNO RAFFAELLA , GRANDALIANO GIUSEPPE , FACCIO ROBERTA , RANIERI ELENA , MARTINO CARMELA , GESUALDO LORETO , SCHENA FRANCESCO P.
Published: April 2021

Intraglomerular activation of the coagulation cascade is a common feature of mesangioproliferative glomerulonephritis. Besides thrombin, very little is known about the cellular effects of other components of the coagulation system. This study investigated the effect of activated factor X (FXa) on cultured human mesangial cells. This serine protease induced a significant and dose-dependent increase in DNA synthesis. In addition to its mitogenic effect, FXa caused a striking upregulation of platelet-derived growth factor (PDGF) A and B chain gene expression. Next, the intracellular mitogenic signaling pathways activated by FXa were investigated. FXa induced a rapid spike in cytosolic calcium concentration followed by a sustained plateau. This response was not influenced by the downregulation of thrombin receptors. In addition, FXa stimulated a significant upregulation of different tyrosine-phosphorylated proteins. One of these phosphorylated cellular proteins was represented by the c-jun N-terminal kinase, a member of the mitogen-activated protein kinase family. To evaluate the role of FXa enzymatic activity and of PDGF autocrine secretion, FXa-induced DNA synthesis was studied in the presence of leupeptin, a specific serine protease inhibitor, and neutralizing anti-PDGF antibody. To investigate the role of tyrosine kinase (TK) activation on FXa mitogenic effect, FXa-stimulated thymidine uptake was evaluated in the presence of genistein and herbimycin A, two powerful and specific TK inhibitors. FXa-elicited DNA synthesis was also examined after protein kinase C (PKC) downregulation by prolonged incubation with phorbol-12-myristate-13-acetate to study the influence of the phospholipase C-PKC axis. The proliferative effect of FXa required its proteolytic activity, and the activation of TK was only partially dependent on PKC activation while it was PDGF independent. Finally, it was shown by reverse transcription-PCR that mesangial cells do not express the signaling splicing variant of the putative FXa receptor, effector protease receptor-1. In conclusion, the present study demonstrated that FXa is a powerful mitogenic factor for human mesangial cells, and it induces its cellular effect not through effector protease receptor-1, but most likely by binding a protease-activated receptor and activating phospholipase C—PKC and TK signaling pathways.
Role of the Increase in p21 in Cisplatin-Induced Acute Renal Failure in Rats
Authors: MIYAJI TAKEHIKO , KATO AKIHIKO , YASUDA HIDEO , FUJIGAKI YOSHIHIDE , HISHIDA AKIRA
Published: April 2021

The goal of this study was to clarify the role of p21, a cyclin-dependent kinase inhibitor, in acute renal failure (ARF). This was accomplished with the examination of the renal expression of p21 in cisplatin (CDDP)-induced ARF and in rechallenge injury with CDDP. The injection of CDDP (5 mg/kg) into rats induced increases in serum creatinine and tubular damage and the number of in situ DNA nick end labeling—positive cells, which peaked at day 5, followed by recovery to control levels by day 14. The rechallenge with the same dose of CDDP 14 d after the first dose of CDDP induced significantly less injury and no significant increase in in situ DNA nick end labeling—positive cells. The first CDDP dose significantly increased p53-positive nuclei at day 1, which disappeared by day 5, and the number of p21-positive nuclei, which had two peaks on days 3 and 9. The number of proliferating cell nuclear antigen (PCNA)-positive nuclei peaked at days 3 and 12. A significant increase in the incorporation of 5-bromo 2′-deoxyuridine (BrdU) was found at day 5 and peaked at day 7. The second injection of CDDP induced significant increases in the number of p21-, p53-, and PCNA-positive nuclei within 2 d but did not affect the incorporation of BrdU. These findings suggested that (1) CDDP induced two peaks of the increase in p21; (2) the first peak occurred shortly after CDDP and was accompanied by overexpression of p53 and PCNA but not with BrdU incorporation, possibly reflecting G1 arrest and DNA repair; (3) the second peak of p21 occurred through an p53-independent pathway and may contribute to cell differentiation; and (4) the overexpression of p21 and PCNA in rechallenge injury may contribute to acquired resistance in CDDP-induced ARF via enhanced DNA repair.
Calcitriol Controls the Epithelial Calcium Channel in Kidney
Authors: HOENDEROP JOOST G. J. , MU[Combining Diaeresis]LLER DOMINIK , VAN DER KEMP ANNEMIETE W. C. M. , HARTOG ANITA , SUZUKI MAKOTO , ISHIBASHI KENICHI , IMAI MASASHI , SWEEP FRED , WILLEMS PETER H. G. M. , OS CAREL H. VAN , BINDELS RENÉ J. M.
Published: April 2021

The recently cloned epithelial Ca2+ channel (ECaC), which is expressed primarily in 1,25-dihydroxyvitamin D3 (1,25(OH)2D3)-responsive Ca2+ -transporting epithelia, is postulated to constitute the rate-limiting step in active Ca2+ reabsorption. In the present study, the effect of 1,25(OH)2D3 was investigated on ECaC mRNA and protein levels in kidneys of rats that were raised on a vitamin D—depleting diet. This diet decreased the serum 1,25(OH)2D3 concentration significantly, which was accompanied by a marked drop in serum Ca2+ level. Both 1,25(OH)2D3 and Ca2+ levels were normalized within 48 h after 1,25(OH)2D3 administration. In 1,25(OH)2D3-deficient rats, ECaC mRNA and protein levels of the kidney cortex were significantly decreased compared with the repleted animals, suggesting that 1,25(OH)2D3 exerts its stimulatory effect on Ca2+ reabsorption via increased ECaC expression. In agreement with this observation, the elucidated human ECaC promoter contains several consensus vitamin D—responsive elements. ECaC was restricted to the apical membrane of the distal part of the distal convoluted and the connecting tubule. This conclusion was based on only minor overlap with the localization of the thiazide-sensitive NaCl co-transporter and complete co-localization with the 1,25(OH)2D3-dependent Ca2+ binding protein, calbindin-D28K. In conclusion, ECaC, present in the distal part of the nephron, is an important target for 1,25(OH)2D3-mediated Ca2+ reabsorption.
Renal Monoclonal Immunoglobulin Deposition Disease
Authors: LIN JULIE , MARKOWITZ GLEN S. , VALERI ANTHONY M. , KAMBHAM NEERAJA , SHERMAN WILLIAM H. , APPEL GERALD B. , D'AGATI VIVETTE D.
Published: April 2021

This study reports the clinicopathologic findings and outcome in 34 patients with renal monoclonal immunoglobulin deposition disease (MIDD), which included 23 light-chain DD (LCDD), 5 light- and heavy-chain DD (LHCDD), and 6 heavy-chain DD (HCDD). A total of 23 patients had pure MIDD, whereas 11 patients had LCDD with coexistent myeloma cast nephropathy (LCDD & MCN). Renal biopsy diagnosis preceded clinical evidence of dysproteinemia in 68% of all cases. By immunofluorescence, the composition of deposits included 11κ/1λ (LCDD), 3IgGκ/2IgGλ (LHCDD), 5γ/1α (HCDD), and 10κ/1λ (LCDD & MCN). Patients with pure MIDD presented with mean serum creatinine of 4.2 mg/dl, nephrotic proteinuria, and hypertension. Cases of HCDD were associated with a CH1 deletion and frequently had hypocomplementemia and a positive hepatitis C virus antibody but negative hepatitis C virus PCR. LCDD & MCN is a morphologically and clinically distinct entity from pure MIDD, presenting with higher creatinine (mean, 7.8 mg/dl; P = 0.01), greater dialysis dependence (64 versus 26%; P = 0.053), subnephrotic proteinuria, and less nodular glomerulopathy (18 versus 100%; P < 0.0001). Multiple myeloma was more frequently diagnosed in LCDD & MCN than in pure MIDD (91 versus 31%; P = 0.025). Renal and patient survivals were significantly worse in patients with LCDD & MCN (mean, 4 and 22 mo, respectively), compared with patients with pure MIDD (mean, 22 and 54 mo). Chemotherapy stabilized or improved renal function in 10 of 15 patients (67%) with pure MIDD who presented with creatinine of <5.0 mg/dl, emphasizing the importance of early detection. On multivariate analysis, initial creatinine was the only predictor of renal and patient survival in pure MIDD, underscoring the prognostic significance of the renal involvement.
Özgül Öğrenme Güçlüğü Olan Öğrencilerin Okuma Becerilerinin İncelenmesi
Authors: GÖKDEMİR Mert , YAKUT Ayşe Dilşad
Published: April 2021

Araştırmanın genel amacı, özgül öğrenme güçlüğü olan öğrencilerin doğru okuma, okuduğunu anlama ve okuma hızı becerilerini inceleyerek öğrencilerin sınıf ve yaş seviyesindeki performanslarını belirlemektir. Araştırma Konya ilinde özel eğitim ve rehabilitasyon merkezlerinde öğrenim gören özgül öğrenme güçlüğü olan 79 üçüncü sınıf öğrencisi ile yürütülmüştür. Öğrencilerin doğru okuma, okuduğunu anlama ve okuma hızı becerilerini değerlendirebilmek amacıyla kullanılan “Sesli Okuma Becerisi ve Okuduğunu Anlama Testi II” kullanılmıştır. Öğrencilerin %98.73’inin (n= 78) doğru okuma, %100’ünün (n= 79) okuduğunu anlama ve %100’ünün (n= 79) okuma hızı becerilerinde kronolojik yaş ve sınıf seviyesinin altında performans gösterdikleri ortaya çıkmıştır. Doğru okuma, okuduğunu anlama ve okuma hızı becerilerinin birbirlerini etkilediği tespit edilmiştir. Elde edilen bulgular ilgili alanyazın ışığında tartışılmıştır.
Ortaokul Türkçe Ders Kitaplarında Haber Bültenlerinde En Sık Kullanılan İlk 2.000 Söz Varlığı Unsurunun Yer Alma Durumu
Authors: ÇOLAKOĞLU Bülent Kahraman
Published: April 2021

Bu çalışma, MEB’in yayımladığı ortaokul Türkçe ders kitaplarında, haber bültenlerinde en sık kullanılan ilk 2.000 söz varlığı unsurunun [temel kelimeler (isimler, isim soylu kelimeler; fiiller, fiil soylu kelimeler; görevli kelimeler, anlamlı-görevli kelimeler), deyimler, ikilemeler, kalıp sözler] yer alma durumunu belirlemek amacıyla yapılmıştır. MEB Talim ve Terbiye Kurulunun 28.05.2018 - 78, 25.06.2018 - 12254648 tarih ve sayılı kararlarıyla kabul edilen, MEB yayınları arasında yer alan ve ortaokullarda okutulan 5, 6, 7 ve 8. sınıf Türkçe ders kitapları ile haber bültenlerinde en sık kullanılan ilk 2.000 söz varlığı unsurunun sıralandığı liste bu araştırma kapsamında inceleme, değerlendirme ve karşılaştırmaya tabi tutulmuştur. Bir durum çalışması olan bu araştırmada bütüncül çoklu durum deseninden yararlanılmıştır. Doküman incelemesi, veri toplama aracı olarak kullanılmış; elde edilen verilerin anlamlandırılması sürecinde içerik analizi uygulanmıştır. Araştırma sonucunda dört sınıf düzeyindeki Türkçe ders kitabında da öğrencilerin, haber bültenlerinde en sık kullanılan ilk 2.000 söz varlığı unsurunun yaklaşık dörtte üçüyle muhatap olduğu, dörtte biriyle de karşılaşmadığı tespit edilmiştir.
Density and Danger: Social Distancing as Racialised Population Management
Authors: Hodge Caroline
Published: April 2021

A ubiquitous facet of collective social life in the age of COVID-19, social distancing(that is, the set of practices that aims to reduce the number of people in public spaces and maximise the distance between them) works to suppress viral spread by de-densifying public spaces; it redistributes people who are vectors for the virusby pushing them into their own domestic spaces. While the scale of these manoeuvres is in some ways unprecedented, the toll that the virus and its primary means of mitigation—social distancing—extracts along racial lines is at once unequal and deeply familiar. In this Position Piece, I examine social distancing as de-densification within a larger history of family planning and racialised population management in the context of ongoing fieldwork on the material and affective implications of contraceptive use in the American Midwest. In probing the grammar of social distancing—its distinctions between ‘essential’ and ‘non-essential’ workers, services, and spaces and the ways in which such distinctions unequally distribute the labour of de-densification and its impacts on family planning—I elucidate how COVID-19 managements do not simply reveal existing racial disparities, but make them anew at a time when the fabrics of social reproduction are increasingly under strain. The dynamics of social distancing can thus be understood as continuous with ongoing attempts at racialised population management. Such an understanding opens a space for political action foreclosed by a narrow view of social distancing as crisis response.
Following Tanya’s Lead: The Mirage and Hope of Social Medicine Research
Authors: Franklin Joshua
Published: April 2021

Entrenched structural inequalities raise challenging questions of how socially-oriented research initiatives are likely to improve health for marginalised people. The recent inclusion of transgender women in the National HIV Behavioral Surveillance (NHBS), an ongoing initiative funded by the Centers for Disease Control and Prevention (CDC) to study the HIV epidemic in the US, is designed to redress the exclusion of transgender people from past HIV research and to confront the disproportionate burden of HIV on transgender women through the production of specific knowledge about HIV risk factors in this population. The hope is that such research will ameliorate the burden of HIV among transgender women. Building on a decade-long ethnographic engagement with transgender activists and health practitioners, I delve into tensions between the health research that sustains this horizon of hope and what I call the ‘mirage’ of social medicine research. My interlocutors call out this mirage of scientific optimism in which ‘all the answers are already known’, suggesting that health research oriented towards social justice simply begets more research. Nonetheless, my interlocutors engaged with me, a physician-anthropologist trainee, in order to insist on the ethical necessity of including transgender people in health research even as they exposed the limits of such inclusion and, more broadly, the limits of medicine’s power to redress social injustice. We should follow their lead, embracing neither futility and hopelessness nor the mirage of medical salvation, in order to build collaborative relationships in the service of a more caring social medicine.
Types of Vocalizations in Self-Expression and Self-Inquiry
Authors: Zirko Alena
Published: April 2021

The author discusses vocalizations as using non-verbal voice sounds in self-expression and self-inquiry. The purpose of the study was to investigate the experience of self-expression and self-inquiry through vocalizations in the situations of valuing and evaluating. The researcher hypothesized that placing an individual in a safe place for self-expression on the conditions of valuing creates more authentic and genuine feelings, helping to reveal their authentic voice. On the contrary, placing a person under conditions of evaluating and impressiveness leads to a less authentic feeling and sounding. Two groups of participants were separated. The expressive group was created using the condition of valuing. The impressive group was created using the condition of evaluating. Participants in both groups used their voices to express themselves performing research tasks and then filled out the survey applications reflecting the sounder’s body, voice, feelings and listener’s feelings during the research. The application’s indicators were grouped into six factors: “Psychophysiological authenticity”, “Psychological authenticity”, “Satisfaction”, “Vocalization change”, “Perceived emotional involvement”, and “Perceived satisfaction”. The multilinear mixed effect regression models were built to investigate the influence of the research conditions on these factors and their dynamics. The t-test was used to compare the results between the groups. Significant differences were revealed with the factors “Psychophysiological authenticity”, “Psychological authenticity”, “Satisfaction”, and “Perceived satisfaction”. They were greater in the expressive group than they were in the impressive group. The indicators of “Perceived satisfaction” were growing.
Тест на понимание эмоций: адаптация русскоязычной версии на российской выборке детей дошкольного возраста
Authors: Веракса Н.Е. , Веракса А.Н. , Гаврилова М.Н. , Бухаленкова Д.А. , Тарасова С.
Published: April 2021

В статье представлены результаты адаптации русскоязычной версии методики Тест на понимание эмоций (Test of Emotion Comprehension; Pons, Harris, 2000). Адаптация методики проводилась в период с 2019 по 2020 г. на выборке 596 детей 5–6 лет. Спустя год 351 ребенок был повторно протестирован для оценки способности методики отражать возрастную динамику в развитии понимания эмоций. В целях изучения теоретической структуры, лежащей в основе инструмента, был применен конфирматорный факторный анализ. Эмпирические данные, полученные на российской выборке, подтвердили высокое соответствие русскоязычной версии инструмента ее оригинальной теоретической модели. Результат применения Q-теста Кохрана равенства пропорций указал на приемлемую надежность методики на основе внутренней согласованности ее компонентов. Валидность методики подтверждается наличием умеренных положительных связей общего уровня понимания эмоций и отдельных компонентов теста с распознаванием эмоций по лицевой экспрессии (Affect Recognition subtest NEPSY-II). Как и в оригинальной версии теста, на российской выборке не были выявлены гендерные различия ни по одному из компонентов теста. Анализ связанных с возрастом различий в успешности выполнения методики детьми при первичном и повторном тестировании показал, что количество правильных ответов по всем компонентам методики значимо увеличилось через год после первого обследования, что свидетельствует о способности методики отражать возрастную динамику. В результате работ по адаптации теста были получены российские нормы для детей 5–6 и 6–7 лет. Использование теста в дальнейшем открывает широкие возможности для международного сотрудничества в эмпирических целях для изучения природы понимания эмоций в дошкольном возрасте и в практических для диагностики или разработки программ эмоционального развития детей.
TEK PARTİLİ DÖNEMDEN ÇOK PARTİLİ DÖNEME MARAŞ’TA GÜNDELİK HAYAT VE DEĞİŞEN MODERN YAŞAM ALGISI
Authors: Aydın Tülay
Published: April 2021

Bu çalışmada bir taşra kenti olan Maraş’ta Cumhuriyetin değişim isteği ve uygulamalarının gündelik hayata yansımaları ele alınacaktır. Çalışma sadece bu dönem ile sınırlı kalmayıp tek parti dönemi pratikleri ile çok partili hayata geçişten sonra birçok ülkede olduğu gibi Türkiye’de de yönünü ve eğilimini Avrupa’dan Amerika’ya doğru çeviren yeni bir yönetim anlayışının sıradan yaşam üzerindeki etkilerini de ele almayı planlamaktadır. Bilindiği üzere çok partili hayata geçişle beraber Türkiye’de sadece siyasal yetkinin devri gerçekleşmemiş aynı zamanda bir mental ve düşünsel değişim başlamış ve bu değişim kaçınılmaz olarak hayatın her alanında bugün dahi görülür izler bırakmıştır. Devlet odaklı değişimin Maraş gündelik yaşamında bulduğu yanıtlar; tek ve çok partili hayat evrelerindeki kadın-erkek görünümleri, gündelik hayatın önemli alışkanlıkları, sinema, tiyatro, konser, kütüphane, parklar gibi toplumsal mekân izlenimleri ile incelenecektir. Bu incelemede temel hareket noktası Kemalist program ve DP iktidarının bu programdan sapar gibi görünen tematik söylem farklılıklarının gündelik hayatta sıradan insan üzerindeki etkilerinin ne olduğu sorusu olacaktır.
Virtual Origins of Public Law
Authors: Isaev I. A.
Published: April 2021

The paper analyzes the main processes that gave rise to such a phenomenon as “public law”. The problem of public law is one of the fundamental problems of jurisprudence. A classical dichotomy of public and private law will never lose its significance, and the search for their harmonious interaction only heightens the interest of thinkers around the world in this issue. We should agree that addressing such issues is always secondto-none, as it gives grounds for the development of the best legal regulation acceptable for a particular society. The very notion of “publicness” has gone a long way to finally gaining a foothold in the political and legal lexicon. In the Digestas of Justinian, the famous Roman jurist Ulpian writes: “Public law, which (refers) to the position of the Roman state, private law, which (refers) to the benefit of individuals; there is the useful for the society and the useful for a private individual. Public law includes the sacreds (sacra), the ministry of priests, the position of magistrates” (D.1.1.1.2). Thus, from the ancient Roman forum through medieval corporations to the political parties of modern times, the public space was certainly controlled by the state in some way or another. It was the intervention of the state in the private sphere that determined the nature of “public” in general and public law in particular. These processes have defined both modern political landscapes and the system of public legal institutions. Although, to a large extent, the motivations that affected the formation of public law were dogmatic, formal and virtual, or imaginary in nature, their influence adopted quite real features and led to practical political and legal consequences.
The Development of International Environmental Law at the Present Stage: The Review of Activities, International Treaties and Case Law
Authors: Salia M. R.
Published: April 2021

The international community is experiencing the beginning of a new era in the development of international environmental law, where the rights to healthy environment are protected not only by international intergovernmental and non-governmental organizations, States, but also by young activists around the world. Since 2020, States have committed themselves to implementing nationally determined contributions made in accordance with the 2015 Paris Agreement. (The Russian Federation is one of the Parties to this Agreement). The Fifth Montevideo Programme for the Development and Periodic Review of Environmental Law implemented under the auspices of UNEP was also launched in 2020. Thus, the UN is trying to intensify the process of improving and implementing international rules of law of international environmental law into the national legislation of Member States. The review of international and national practices on environmental disputes indicates a trend towards an increase in this type of disputes, which in turn shows an increase in the level of legal culture and legal consciousness of citizens. These are people who are not indifferent to their future and the future of the next generations, to a healthy environment and to a prosperous life on the Earth. It is important to understand that, in accordance with the principles of international environmental law, such as “the environment is the common concern of mankind” and “the relationship between the protection of the environment and peace , development, human rights and fundamental freedoms”, the responsibility for pollution (in broader understanding) is borne by each of us: citizens, companies, States, international organizations, and everyone should be interested in achieving the goal of protecting it.
Choosing between Persistent Engagement and Deterrence in the American Cyber security Strategy
Authors: Sebekin S.
Published: April 2021

The article examines the adoption by the United States of a new policy for ensuring cybersecurity, a strategy of peristent engagement in cyberspace, and how it is related to the strategy of cyber deterrence that remained dominant for a long time. The strategy of persistent engagement implies the constant conduct of cyber operations that do not reach the level of an armed conflict and combining purely defensive activities with offense. Such strategy is designed to prevent US rivals from carrying out malicious actions in cyberspace and to preserve strategic advantages of the United States by imposing additional costs on opponents and creating tactical friction for them. According to experts, persistent engagement perfectly suits the unique characteristics of cyberspace (interconnectedness and the condition of constant contact), unlike a strategy of deterrence that is suitable for traditional areas of military operations. Nevertheless, the US leadership is not ready to abandon the cyber deterrence strategy, and it is looking for ways to conceptually combine the two strategies. The paper presents the key characteristics of persistent engagement, some of which are: 1) cyber operations do not reach the level of an armed conflict; 2) persistent engagement is not an armed conflict; 3) creating "tactical friction" and imposing costs on US opponents; 4) preventive defense. Expert opinions on the prospects of persistent engagement are presented and analyzed. The paper demonstrates the analysis potential advantages and drawbacks of this approach. American specialists expect that persistent engagement will lead to an automatic formation of criteria for acceptable behavior in the process of strategic competition. Among the obvious drawbacks of the analyzed approach, one can single out a possible international escalation due to its application. The author analyzes the transformation of the “conceptual” status of cyberspace and the institutional changes, caused by this new strategic approach. The conclusions regarding the prospects for this strategy are ambiguous. Its effectiveness, safety and risks will become known only with time during the actual application of this strategy and the accumulation of empirical experience. The relevance of the work is due to the current strategic situation between the United States and Russia. Understanding the United States' approaches to cybersecurity and the key strategic changes in them is crucial not only to formulate Russia`s cybersecurity policy, but also to build a constructive dialogue with the United States on cybersecurity issues.