bluuebunny/crossref_metadata_2025 huggingface dataset:
Redes das literaturas de fronteiras como existência e pluralidade
Authors: Jasinski Isabel
Published: April 2021

Resumo A reflexão proposta neste artigo incide sobre a questão das redes da literatura em portunhol e outras línguas, nas obras Triple frontera dreams (2012) do escritor brasileiro Douglas Diegues, Xirú (2010) do paraguaio Damián Cabrera e Viralata (2015) do uruguaio Fabián Severo. Ao pensar como alguns escritores latino-americanos compartilham a experiência do espaço de fronteira, o portunhol e as línguas de fronteira como expressão literária, a publicação de suas obras nas duas primeiras décadas do século XXI e a edição independente delas, além da sua atuação nas redes sociais, a análise pretende abordar quais mecanismos tais autores acionam para criar suas narrativas como um lugar de fala, sem configurar um discurso da imanência nem da transcendência, mas buscando modos de articulação da singularidade que se caracterizem pela noção de “comunidade de existência”. A fronteira se caracteriza pela relação, seja de libertação ou de dominação, é um espaço praticado e assinalado pela pluralidade, que se manifesta como tensão social da convivência em Damián Cabrera, como melancolia de um sentido ausente, convertido em palavras e memórias inventadas em Fabián Severo, ou como gozo do presente pelo delírio em Douglas Diegues. Uma comunidade de existência que se manifesta na expressão desses escritores de fronteira, formando-se pelo contato e pela articulação de suas redes literárias.
Por una sociología del espacio editorial: el caso de César Aira y Beatriz Viterbo
Authors: Riveiro María Belén
Published: April 2021

Resumen Este artículo adopta la mirada de la sociología de la literatura y parte de estudiar la trayectoria de César Aira con la hipótesis de que es en los años noventa cuando se puede identificar su creciente consagración. Uno de los indicadores para ello es una presencia simultánea en espacios que se definen como lógicas opuestas: la academia y el mercado editorial. Una de las editoriales que se convierte en un espacio clave para Aira es Beatriz Viterbo, creada en 1991 por tres académicas de la Universidad de Rosario. En este artículo, me centro en la editorial Beatriz Viterbo para analizar, a partir de datos recabados con entrevistas en profundidad y trabajo de archivo, las condiciones de posibilidad de la creación de una editorial que, desde la universidad, pero de manera independiente a la institución, fomenta una manera autogestiva y resistente a los modos dominantes de producción editorial, y que habilita trayectorias editoriales atípicas como la de Aira.
Política e forma literária no último quartel do século XX
Authors: Antunes Benedito
Published: April 2021

Resumo Neste artigo são analisados Um copo de cólera (1978), de Raduan Nassar, e Estorvo (1991), de Chico Buarque, com a finalidade de se observar a possível relação entre a forma romanesca e os conflitos políticos do último quartel do século XX no Brasil. Parte-se da hipótese de que os elementos evocados nos livros configuram literariamente um impasse que remete ao contexto externo, permitindo, nesse movimento, uma percepção estética desse período. Trata-se, portanto, de uma tentativa de leitura dialética, nos moldes formulados por Antonio Candido e Roberto Schwarz, em que se procura aproximar a forma social da forma literária visando estabelecer perspectivas de compreensão tanto de uma quanto de outra. Como resultado, a análise sugere um processo de desnorteamento na luta pela transformação social.
A propriedade intelectual na judicialização da assistência farmacêutica: uma demanda estrutural em defesa do Sistema Único de Saúde
Authors: Coelho Tiago Lopes , Lopes Luciana de Melo Nunes , Campos Neto Orozimbo Henriques , Figueiredo Thales Pimenta de , Andrade Eli Iola Gurgel
Published: April 2021

Resumo Este trabalho investiga a participação do Sistema de Justiça no processo de efetivação do direito à saúde por meio do confronto de dois caminhos para a atuação judicial. De um lado, a forma predominante, marcada pela individualização das demandas, pela incapacidade de alcançar as falhas políticas que determinam a extensão da oferta de prestações em saúde e pelo potencial de desorganizar o Sistema Único de Saúde (SUS). De outro, uma perspectiva estrutural de atuação que aproxima a intervenção judicial dos conflitos determinantes para a consolidação e sustentabilidade do sistema público de saúde. A partir da análise de pedidos judiciais para acessar os fármacos ranibizumabe e bevacizumabe em Minas Gerais, investiga-se a mudança de cenário esperada no caso de uma atuação judicial estrutural pelo Supremo Tribunal Federal no tratamento das Ações Diretas de Inconstitucionalidade nº 4.234/DF e 5.529/DF. Os resultados apontam para a importância de o Sistema de Justiça privilegiar uma perspectiva estrutural. No atual contexto, marcado por ataques cada vez mais explícitos ao direito à saúde, é fundamental que o Sistema de Justiça participe do processo de efetivação do SUS de forma mais coerente e consciente dos conflitos que definem as possibilidades de construção de um sistema público universal. A crise econômica, o agravamento do subfinanciamento da saúde (em especial devido à Emenda Constitucional nº 95/2016) e o preço insustentável dos novos medicamentos - implicando sua crescente participação na totalidade dos gastos em saúde - apontam para a necessidade de que questões estruturais alcancem centralidade na judicialização da saúde.
Residual strength of reinforced concrete stub columns subject to moderate temperatures
Authors: Lima Eduardo Henrique Barros , Cardoso Daniel Carlos Taissum
Published: April 2021

abstract: This work aims to evaluate the residual strength of reinforced concrete stub columns subjected to moderate temperatures. To accomplish this task, an experimental program was carried out including compression tests on plain concrete specimens exposed to temperatures up to 600 ºC and on reinforced concrete stub columns with two different tie configurations heated at a constant rate for up to 120 min. The results show a loss of residual compressive strength with temperature and the beneficial influence of ties to prevent the spalling phenomenon, although samples with more ties exhibited lower capacity. Finally, the results were compared to the analytical prediction using a cross-sectional approach with idealized stress-strain relations, showing a good correlation. The applicability of the Isotherm 500 ºC method is discussed for moderate temperatures.
Longitudinal patterns in distribution of native and non-native fish species in a regulated temperate Neotropical river
Authors: Bertora Andrea , Grosman Fabián , Sanzano Pablo , Rosso Juan José
Published: April 2021

Abstract: Aim We evaluated the longitudinal patterns in distribution of native and non-native fish species in a hydrologically fragmented and environmentally variable lowland temperate river. Methods Four sites representing contrasting habitat and environmental conditions were sampled: a clear water reservoir, a turbid water lagoon and two river reaches with clear and turbid waters each. Environmental variables were measured in situ and in the laboratory. Fishes were sampled using trammel and beach seine nets. Results Two main environmental scenarios were identified: the upstream reaches, with colder, clearer and nutrient-oxygen poor waters (reservoir and its downstream river) and the downstream reaches, where turbidity, dissolved oxygen, water temperature, conductivity and nutrients largely increased (lagoon and its downstream river). Fourteen species with a high non-native/native (4:10) ratio were collected. Non-native species (NNS) were confined to lentic conditions, where the silverside Odontesthes bonariensis dominated. Native species (NS) better thrive in lotic conditions where the turbid scenario further favored tolerant species. Environmental conditions also seemed to influence the distribution of NNS. Fish assemblage structure considering either, all species, NNS or NS significantly differed among sampled reaches and habitat (lentic-lotic) conditions. Total fish abundance was higher in lentic reaches. Species richness and diversity were favored by the turbid scenario. Beta diversity was mostly explained by the replacement component revealing the substitution of species as the main pattern of variation. Water conductivity, nitrates and dissolved oxygen were the most important predictor variables in the best and most frequent explanatory models of fish assemblage structures. Conclusions Our results revealed that a low diversified Neotropical fish fauna is disrupted by habitat fragmentation due to the creation of artificial impoundments and the introduction of NNS. Environmental conditions further modulate the fish assemblage structure by affecting the distribution of species where tolerant species were favored by turbid, nutrient-rich waters with higher conductivity and pH.
Occurrence of non-native species in a subtropical coastal River, in Southern Brazil
Authors: Faria Larissa , Frehse Fabrício de Andrade , Occhi Thiago Vinícius Trento , Carvalho Barbara Maichak de , Pupo Daniel Vicente , Disaró Sibelle Trevisan , Vitule Jean Ricardo Simões
Published: April 2021

Abstract: Aim This paper aims to concatenate and update the records of non-native species in a subtropical River, in Southern Brazil, warning about their possible impacts in this and other water bodies. Methods Monitoring was carried out in the Guaraguaçu River, the largest River of the Paraná coastal plain, located in the Atlantic Rainforest biome. Fishes were sampled in two periods: from 2002 to 2007 (monthly) and from 2016 to 2018 (semiannually), and the other organisms were collected in isolated samplings. Results The monitoring recorded the presence of six non-native species of animals in this River – four species of fish (Clarias gariepinus, Ictalurus punctatus, Oreochromis niloticus and Salminus brasiliensis), one invertebrate (Macrobrachium rosenbergii) and one foraminifera (Ammoglobigerina globigeriniformis) introduced by escapes from aquaculture, sport fishing and ballast water. These introductions are problematic because they have the potential to impact upon the endangered native species in the River through predation, competition or novel diseases. Conclusions In Guaraguaçu River the increasing number of introductions is worrying because these species have in common a set of traits that turns them into potential invaders. It is of great importance to keep monitoring their populations in order to detect and minimize their negative impacts on native biota, once there is a conservation unit in the region (Guaraguaçu Ecological Station), with the aim to protect the environment in its pristine condition.
Organic matter decomposition in subtropical South America aquatic environments: a systematic and scientometric review
Authors: Gayer Pâmela Rodrigues , Moraes Andréa Luiza de Mattos de , Guimarães Pablo Santos , Barbosa Fabiana Gonçalves , Albertoni Edélti Faria , Hepp Luiz Ubiratan
Published: April 2021

Abstract: Aim To evaluate the general situation of studies on the decomposition of organic matter in aquatic environments in the subtropical region of South America. Methods We compiled publications (1990-2018) with a combination of words referring to decomposition, debris, aquatic environments and South American countries with subtropical climate. The characteristics of the publications were analysed over time. Results A total of 1,042 publications were found, with 106 specifically addressing the purpose of this study. For subtropical climates in South America, this research topic is incipient. Most studies were carried out in streams (39.6%) and studied the decomposition process and associated invertebrates (42.5%). There is a great deficiency of studies in lentic environments (e.g. lakes, 10%). Conclusion Studies on the decomposition of organic detritus in aquatic ecosystems in the subtropical region of South America are still emerging. While the knowledge about the role of shredders is more or less understood, the importance of microorganisms on the decomposition process still needs to be better evaluated. Finally, our study demonstrated that scientific collaboration boosted publication on the topic.
Loss Functions, Axioms, and Peer Review
Authors: Noothigattu Ritesh , Shah Nihar , Procaccia Ariel
Published: April 2021

It is common to see a handful of reviewers reject a highly novel paper, because they view, say, extensive experiments as far more important than novelty, whereas the community as a whole would have embraced the paper. More generally, the disparate mapping of criteria scores to final recommendations by different reviewers is a major source of inconsistency in peer review. In this paper we present a framework inspired by empirical risk minimization (ERM) for learning the community's aggregate mapping. The key challenge that arises is the specification of a loss function for ERM. We consider the class of L(p,q) loss functions, which is a matrix-extension of the standard class of Lp losses on vectors; here the choice of the loss function amounts to choosing the hyperparameters p and q. To deal with the absence of ground truth in our problem, we instead draw on computational social choice to identify desirable values of the hyperparameters p and q. Specifically, we characterize p=q=1 as the only choice of these hyperparameters that satisfies three natural axiomatic properties. Finally, we implement and apply our approach to reviews from IJCAI 2017.
Bio-inspired geotechnical engineering: principles, current work, opportunities and challenges
Authors: Martinez Alejandro , Dejong Jason , Akin Idil , Aleali Ali , Arson Chloe , Atkinson Jared , Bandini Paola , Baser Tugce , Borela Rodrigo , Boulanger Ross , Burrall Matthew , Chen Yuyan , Collins Clint , Cortes Douglas , Dai Sheng , DeJong Theodore , Del Dottore Emanuela , Dorgan Kelly , Fragaszy Richard , Frost J. David , Full Robert , Ghayoomi Majid , Goldman Daniel I. , Gravish Nicholas , Guzman Ivan L. , Hambleton James , Hawkes Elliot , Helms Michael , Hu David , Huang Lin , Huang Sichuan , Hunt Christopher , Irschick Duncan , Lin Hai Thomas , Lingwall Bret , Marr Alen , Mazzolai Barbara , McInroe Benjamin , Murthy Tejas , O'Hara Kyle , Porter Marianne , Sadek Salah , Sanchez Marcelo , Santamarina Carlos , Shao Lisheng , Sharp James , Stuart Hannah , Stutz Hans Henning , Summers Adam , Tao Julian , Tolley Michael , Treers Laura , Turnbull Kurtis , Valdes Rogelio , van Paassen Leon , Viggiani Gioacchino , Wilson Daniel , Wu Wei , Yu Xiong , Zheng Junxing
Published: April 2021

A broad diversity of biological organisms and systems interact with soil in ways that facilitate their growth and survival. These interactions are made possible by strategies that enable organisms to accomplish functions that can be analogous to those required in geotechnical engineering systems. Examples include anchorage in soft and weak ground, penetration into hard and stiff subsurface materials and movement in loose sand. Since the biological strategies have been ‘vetted’ by the process of natural selection, and the functions they accomplish are governed by the same physical laws in both the natural and engineered environments, they represent a unique source of principles and design ideas for addressing geotechnical challenges. Prior to implementation as engineering solutions, however, the differences in spatial and temporal scales and material properties between the biological environment and engineered system must be addressed. Current bio-inspired geotechnics research is addressing topics such as soil excavation and penetration, soil–structure interface shearing, load transfer between foundation and anchorage elements and soils, and mass and thermal transport, having gained inspiration from organisms such as worms, clams, ants, termites, fish, snakes and plant roots. This work highlights the potential benefits to both geotechnical engineering through new or improved solutions and biology through understanding of mechanisms as a result of cross-disciplinary interactions and collaborations.
The Molecular Basis of Familial Hemolytic Uremic Syndrome
Authors: CAPRIOLI JESSICA , BETTINAGLIO PAOLA , ZIPFEL PETER F. , AMADEI BARBARA , DAINA ERICA , GAMBA SARA , SKERKA CHRISTINE , MARZILIANO NICOLA , REMUZZI GIUSEPPE , NORIS MARINA
Published: April 2021

The aim of the present study was to clarify whether factor H mutations were involved in genetic predisposition to hemolytic uremic syndrome, by performing linkage and mutation studies in a large number of patients from those referred to the Italian Registry for Recurrent and Familial HUS/TTP. PCR and Western blot analyses were conducted to characterize the biochemical consequences of the mutations. Five mutations in the factor H gene were identified. Three, identified in two families and in a sporadic case, are heterozygous point mutations within the most C-terminal short consensus repeat 20 (SCR20) of factor H, resulting in single amino acid substitutions. The other two mutations introduce premature stop codons that interrupt the translation of factor H. A heterozygous nonsense mutation was identified in SCR8 in one family, and a homozygous 24-bp deletion within SCR20 was identified in a Bedouin family with a recessive mode of inheritance. Reverse transcription-PCR analysis of cDNA from peripheral blood leukocytes from the Bedouin family showed that the deletion lowered factor H mRNA levels. Although heterozygous mutations were associated with normal factor H levels and incomplete penetrance of the disease, the homozygous mutation in the Bedouin family resulted in severe reduction of factor H levels accompanied by very early disease onset. These data provide compelling molecular evidence that genetically determined deficiencies in factor H are involved in both autosomal-dominant and autosomal-recessive hemolytic uremic syndrome and identify SCR20 as a hot spot for mutations in the disease. The mutations identified here give an important hint to the relevance of the C-terminus of factor H in the control of the alternative complement activation pathway.
Cardiovascular Risk Factors in Renal Transplant Patients
Authors: LIGTENBERG GERRY , HENÉ RONALD J. , BLANKESTIJN PETER J. , KOOMANS HEIN A.
Published: April 2021

The hypertensive and hyperlipidemic effects of cyclosporin A (CsA) may contribute to the high cardiovascular morbidity in renal transplant patients and to the development of chronic transplant nephropathy. Tacrolimus is reported to have less effect on BP and lipids, but steroids, other drugs, and renal function may confound this. This study assessed 24-h BP and lipid profile in stable renal transplant recipients (n = 17) while they were receiving CsA, after 4 wk of receiving tacrolimus, and again after 4 wk of receiving CsA. Antihypertensives were stopped at least 3 wk before. A few patients used low-dose steroids and lipid-lowering drugs, which were not changed during the study. Mean daytime BP decreased from 149 ± 12 and 95 ± 8 mmHg to 138 ± 13 and 87 ± 9 mmHg (P < 0.001) after patients were switched to tacrolimus. Mean nighttime BP also decreased, from 140 ± 12/86 ± 7 mmHg to 132 ± 17/79 ± 10 mmHg (P < 0.05). Total and low-density lipoprotein cholesterol decreased from 6.1 ± 0.7 and 3.84 ± 0.79 mmol/L to 5.1 ± 0.8 and 2.98 ± 0.75 mmol/L (P < 0.001). Return to CsA caused an increase in BP and cholesterol to values similar as during the first CsA period. The conclusion is that tacrolimus has fewer unfavorable effects on BP and lipids than does CsA. Elective conversion from CsA to tacrolimus in stable renal transplant recipients may lead to attenuation of cardiovascular morbidity and chronic transplant nephropathy in the long term.
Angiotensin II Binding to Renomedullary Interstitial Cells Is Regulated by Osmolality
Authors: MARIC CHRISTINE , CASLEY DAVID , HARRIS PETER J. , ALCORN DAINE
Published: April 2021

Angiotensin II (Ang II) AT1A receptors are localized to renomedullary interstitial cells (RMIC) in the inner stripe of the outer medulla but not in the inner medulla. Thus, there seems to be a correlation between decreases in AT1A receptor binding to RMIC and increases in interstitial osmolality, suggesting that osmolality is important in determining Ang II binding to RMIC. Cultured RMIC were incubated in media of differing osmolalities (330, 630, 930, and 1230 mOsm/kgH2O). 125I-[Sar1, Ile8] Ang II binding to AT1A receptors on RMIC grown in hyperosmolal media (930 mOsm/kgH2O) was reduced compared with isoosmolal (330 mOsm/kgH2O) media and was progressively reduced with further increases of osmolality. Similar studies were performed using bradykinin (BK) as a control peptide. Binding of the BK receptor ligand 125I-[HPP-Hoe 140] to B2 receptors was not affected by varying osmolality of the media. Reverse transcriptase-PCR demonstrated the presence of the mRNA expression for both AT1A and B2 receptors at each osmolality. The conclusion is that osmolality modulates Ang II binding to RMIC; in these cells, this phenomenon is restricted to Ang II as BK binding is not affected. Osmolality-induced changes in Ang II binding may modulate the actions of this peptide on RMIC and provide an important mechanism by which these cells modulate renal medullary function.
Kinetics of Connective Tissue Growth Factor Expression during Experimental Proliferative Glomerulonephritis
Authors: ITO YASUHIKO , GOLDSCHMEDING ROEL , BENDE RICHARD J. , CLAESSEN NIKE , CHAND M. ANWAR , KLEIJ LIVIO , RABELINK TON J. , WEENING JAN J. , ATEN JAN
Published: April 2021

Connective tissue growth factor (CTGF) is a member of the CCN family of immediate early genes, which are involved in cell proliferation, migration, and matrix production. Recently, CTGF was observed to be strongly upregulated in human proliferative and fibrogenic renal disease. By in situ hybridization and reverse transcriptase-PCR, the expression of CTGF was investigated in experimental proliferative glomerulonephritis induced by injection of anti—Thy-1.1 antibody in the rat. CTGF expression in cultured rat mesangial cells and glomerular visceral epithelial cells (GVEC) was studied in response to transforming growth factor β (TGF-β), an essential pathogenetic factor in this model. In normal rat kidneys, only some GVEC expressed CTGF mRNA. In anti—Thy-1.1 nephritis, CTGF mRNA expression was strongly increased in extracapillary and mesangial proliferative lesions and in areas of periglomerular fibrosis. Early glomerular CTGF overexpression in GVEC coincided with a striking upregulation of TGF-β2 and to a lesser extent of TGF-β3. Glomerular CTGF mRNA expression was maximal at day 7, in association with increased TGF-β1 mRNA and protein expression. CTGF mRNA overexpression by parietal epithelial cells preceded the periglomerular appearance of α-smooth muscle actin—positive fibroblasts. In cultured mesangial cells, TGF-β1, -β2, and -β3 transiently increased the CTGF/glyceraldehyde phosphate dehydrogenase mRNA ratio up to threefold versus control at 4 h. In GVEC, upregulation of CTGF mRNA by these TGF-β isoforms was more sustained, being 8- to 16-fold versus control at 24 h. The kinetics of CTGF expression strongly suggest a role in glomerular repair, possibly downstream of TGF-β, in this model of transient renal injury.
Apoptosis and Caspase-3 in Experimental Anti-Glomerular Basement Membrane Nephritis
Authors: YANG BIN , JOHNSON TIMOTHY S. , THOMAS GRAHAM L. , WATSON PHILIP F. , WAGNER BART , NAHAS A. MEGUID EL
Published: April 2021

The caspase family is central to the proteolytic events of apoptosis. In particular, caspase-3 plays a key role in the execution of apoptosis. However, the importance of caspase-3 in renal cell apoptosis during kidney scarring has not been established. Here, nephrotoxic nephritis (NTN) was induced in Wistar Kyoto rats by a single intravenous injection of rabbit anti-rat glomerular basement membrane serum, with analysis at days 7, 15, 30, and 45 after injection. Cell apoptosis (in situ end labeling of DNA, light and electron microscopy), proliferation (proliferating cell nuclear antigen-positive cells), and inflammation (ED1-positive cells) all increased in NTN kidneys, peaking early (day 7) in the glomeruli and later (days 30 to 45) in the tubules and interstititum. The expression of caspase-3 mRNA (Northern blotting) was increased in NTN kidneys on days 7, 30, and 45 (173.3%, 228%, and 241.7%, respectively; P < 0.05). Western blotting showed that a 24-kD protein band (caspase-3 active subunit) increased with time in NTN kidneys (P < 0.01) and reached a maximum on day 45 (6.08-fold increase). A 32 kD band (caspase-3 precursor) was also increased on day 45 (3.92-fold; P < 0.01). Elevated caspase-3 activity (two- to threefold) was observed in NTN kidneys at all time points (P < 0.01). Upregulated expression of caspase-3 at all levels positively correlated with apoptosis, whereas both correlated closely with inflammation, proliferation, and subsequent fibrosis in glomeruli, tubules, and interstitium (P < 0.05). Inhibition of caspase-3 during the course of experimental nephritis may offer a new therapeutic approach for the prevention of renal apoptosis and the associated renal tubular atrophy and fibrosis.
Tracer Studies in the Rat Demonstrate Misdirected Filtration and Peritubular Filtrate Spreading in Nephrons with Segmental Glomerulosclerosis
Authors: KRIZ WILHELM , HARTMANN INGRID , HOSSER HILTRAUD , HA[Combining Diaeresis]HNEL BRUNHILDE , KRA[Combining Diaeresis]NZLIN BETTINA , PROVOOST ABARAHAM P. , GRETZ NORBERT
Published: April 2021

In two genetic models of “classic” focal segmental glomerulosclerosis (FSGS), the Milan normotensive and the Fawn-hooded hypertensive rats, tracer studies were performed to test the hypothesis that misdirected glomerular filtration and peritubular filtrate spreading are relevant mechanisms that contribute to nephron degeneration in this disease. Two exogenous tracers, lissamine green and horse spleen ferritin, were administered by intravenous injection and subsequently traced histologically in serial kidney sections. In contrast to control rats, both tracers in kidneys of Milan normotensive and Fawn-hooded hypertensive rats with established FSGS were found to accumulate extracellularly at the following sites: (1) within tuft adhesions to Bowman's capsule and associated paraglomerular spaces, (2) at the glomerulotubular junction contained within extensions of the paraglomerular spaces onto the tubule, and (3) within subepithelial peritubular spaces eventually encircling the entire proximal convolution of an affected nephron. This distribution strongly suggests the existence of misdirected filtration into tuft adhesions to Bowman's capsule and subsequent spreading of the filtrate around the entire circumference of a glomerulus and, alongside the glomerulotubular junction, onto the outer aspect of the corresponding tubule. This leads to an interstitial response that consists of the formation of a barrier of sheet-like fibroblast processes around the affected nephron, which confines the filtrate spreading and, subsequently, the destructive process to the affected nephron. No evidence was found that either misdirected filtration and peritubular filtrate spreading themselves or the associated tubulo-interstitial process led to the transfer of the injury from an affected nephron to an unaffected nephron. It is concluded that in the context of FSGS development, misdirected filtration and peritubular filtrate spreading are important damaging mechanisms that underlie the extension of glomerular injury to the corresponding tubulointerstitium, thus leading finally to degeneration of both the glomerulus and the tubule of a severely injured nephron.
Role of CFTR in Autosomal Recessive Polycystic Kidney Disease
Authors: NAKANISHI KOICHI , SWEENEY WILLIAM E. , MACRAE DELL KATHERINE , COTTON CALVIN U. , AVNER ELLIS D.
Published: April 2021

An extensive body of in vitro data implicates epithelial chloride secretion, mediated through cystic fibrosis transmembrane conductance regulator (CFTR) protein, in generating or maintaining fluid filled cysts in MDCK cells and in human autosomal dominant polycystic kidney disease (ADPKD). In contrast, few studies have addressed the pathophysiology of fluid secretion in cyst formation and enlargement in autosomal recessive polycystic kidney disease (ARPKD). Murine models of targeted disruptions or deletions of specific genes have created opportunities to examine the role of individual gene products in normal development and/or disease pathophysiology. The creation of a murine model of CF, which lacks functional CFTR protein, provides the opportunity to determine whether CFTR activity is required for renal cyst formation in vivo. Therefore, this study sought to determine whether renal cyst formation could be prevented by genetic complementation of the BPK murine model of ARPKD with the CFTR knockout mouse. The results of this study reveal that in animals that are homozygous for the cystic gene (bpk), the lack of functional CFTR protein on the apical surface of cystic epithelium does not provide protection against cyst growth and subsequent decline in renal function. Double mutant mice (bpk -/-; cftr -/-) developed massively enlarged kidneys and died, on average, 7 d earlier than cystic, non-CF mice (bpk -/-; cftr +/±). This suggests fundamental differences in the mechanisms of transtubular fluid secretion in animal models of ARPKD compared with ADPKD.
Klf6 Is a Zinc Finger Protein Expressed in a Cell-Specific Manner during Kidney Development
Authors: FISCHER EVELYNE A. , VERPONT MARIE-CHRISTINE , GARRETT-SINHA LEE ANN , RONCO PIERRE M. , ROSSERT JEROME A.
Published: April 2021

Molecular mechanisms that are responsible for the development of the renal collecting duct system during embryogenesis are still poorly understood. A mouse cDNA encoding a zinc finger protein, called Klf6, which is a member of the Kru[Combining Diaeresis]ppel-like family of transcription factors, has been cloned. Northern blot analyses showed that Klf6 was already expressed in 11.5-d postconception mouse embryos and that its expression persisted after birth. They also disclosed that Klf6 had a restricted pattern of expression. In situ hybridization experiments using mouse embryos showed that during kidney development, Klf6 was expressed selectively in the Wolffian duct and in its derivatives. During mesonephros development, it was expressed in the Wolffian duct but not in the mesonephric mesenchyme. Thereafter, Klf6 was expressed in the ureteric bud and its branches and in the collecting ducts, whereas it was not expressed in tubular structures that derive from the metanephric mesenchyme. Glomeruli were not labeled during early stages of differentiation, and it is only at the capillary stage that a staining of the mesangial area was observed, which persisted after birth. This pattern of expression is strikingly similar to the one of GATA-3, which is another zinc finger protein. It suggests that Klf6 may play a role during kidney development and in particular during the development of the renal collecting duct system, possibly in association with GATA-3.
Pharmacokinetic Interactions Augment Toxicities of Sirolimus/Cyclosporine Combinations
Authors: PODDER HEMANGSHU , STEPKOWSKI STANISLAW M. , NAPOLI KIMBERLY L. , CLARK JAMES , VERANI REGINA R. , CHOU TING-CHAO , KAHAN BARRY D.
Published: April 2021

This study correlated the dynamic effects of sirolimus (rapamycin; RAPA) and cyclosporine (CsA) alone versus in combination to produce renal dysfunction, myelosuppression, or hyperlipidemia, with their corresponding blood and tissue concentrations. After salt-depleted rats were treated with RAPA (0.4 to 6.4 mg/kg per d) and/or CsA (2.5 to 20.0 mg/kg per d) for 14 d, the GFR, lipid levels, bone marrow cellularity, and CsA/RAPA concentrations in whole blood versus liver or renal tissues were measured, and the median effect model was used to discern the type of drug interactions. Compared with vehicle controls (1.98 ± 0.34 ml/min), GFR values were reduced only by large doses of drug monotherapy, namely RAPA (3.2 mg/kg per d = 1.2 ± 0.02 ml/min or 6.4 mg/kg per d = 1.3 ± 0.2 ml/min; both P < 0.01) or CsA (10.0 mg/kg per d = 1.2 ± 0.1 ml/min or 20.0 mg/kg per d = 0.8 ± 0.4 ml/min; both P < 0.01). In contrast, hosts that were treated with smaller doses of CsA/RAPA combinations showed more pronounced effects in reduction of GFR values: 2.5/0.4 mg/kg per d, modestly (1.5 ± 0.5 ml/min; P < 0.01); 5.0/0.8 mg/kg per d, moderately (0.23 ± 0.01 ml/min; P < 0.001); and higher-dose groups, markedly. The exacerbation of renal dysfunction seemed to be due to a pharmacokinetic interaction of RAPA to greatly increase CsA concentrations in whole blood and, particularly, in kidney tissue. In contrast, the pharmacodynamic effects of CsA to potentiate two RAPA-mediated toxicities—myelosuppression and increased serum cholesterol/low-density lipoprotein cholesterol—occurred independently of pharmacokinetic interactions. RAPA aggravates CsA-induced renal dysfunction owing to a pharmacokinetic interaction, whereas CsA produces a pharmacodynamic effect that augments RAPA-induced myelosuppression and hyperlipidemia.
DNA Microarray Analysis of Complex Biologic Processes
Authors: KURELLA MANJULA , HSIAO LI-LI , YOSHIDA TAKUMI , RANDALL JEFFREY D. , CHOW GARY , SARANG SATINDER S. , JENSEN RODERICK V. , GULLANS STEVEN R.
Published: April 2021

DNA microarrays, or gene chips, allow surveys of gene expression, (i.e., mRNA expression) in a highly parallel and comprehensive manner. The pattern of gene expression produced, known as the expression profile, depicts the subset of gene transcripts expressed in a cell or tissue. At its most fundamental level, the expression profile can address qualitatively which genes are expressed in disease states. However, with the aid of bioinformatics tools such as cluster analysis, self-organizing maps, and principle component analysis, more sophisticated questions can be answered. Microarrays can be used to characterize the functions of novel genes, identify genes in a biologic pathway, analyze genetic variation, and identify therapeutic drug targets. Moreover, the expression profile can be used as a tissue or disease “fingerprint.” This review details the fabrication of arrays, data management tools, and applications of microarrays to the field of renal research and the future of clinical practice.
Induction of Collecting Duct Morphogenesis In Vitro by Heparin-Binding Epidermal Growth Factor-Like Growth Factor
Authors: TAKEMURA TSUKASA , HINO SATOSHI , KUWAJIMA HIROAKI , YANAGIDA HIDEHIKO , OKADA MITSURU , NAGATA MICHIO , SASAKI SEI , BARASCH JONATHAN , HARRIS RAYMOND C. , YOSHIOKA KAZUO
Published: April 2021

Heparin-binding epidermal growth factor-like growth factor (HB-EGF), a member of the epidermal growth factor family of growth factors, is synthesized as a membrane-an-chored precursor (proHB-EGF) that is capable of stimulating adjacent cells in a juxtacrine manner. ProHB-EGF is cleaved in a protein kinase C-dependent process, to yield the soluble form. It was observed that HB-EGF acts as a morphogen for the collecting duct system in developing kidneys. HB-EGF protein was expressed in the ureteric bud of embryonic kidneys. Cultured mouse ureteric bud cells (UBC) produced HB-EGF via protein kinase C activation. After stimulation with phorbol ester (12-O-tetradecanoylphorbol-13-acetate) or recombinant soluble HB-EGF, UBC cultured in three-dimensional collagen gels formed short tubules with varied abundant branches. When proHB-EGF-transfected UBC were stimulated with 12-O-tetradecanoylphorbol-13-acetate and cultured in collagen gels, they exhibited linear growth, forming long tubular structures with few branches at the time of appearance of proHB-EGF on the cell surface. The structures exhibited a strong resemblance to the early branching ureteric bud of embryonic kidneys. When UBC were cultured in the presence of transforming growth factor-β and soluble HB-EGF, they formed long tubules and few branches, similar to the structures observed in proHB-EGF-transfected UBC. These cells exhibited apical-basolateral polarization and expression of the water channel aquaporin-2. These findings indicate that soluble HB-EGF and proHB-EGF induce branching tubulogenesis in UBC in different ways. Juxtacrine activation by proHB-EGF or the synergic action of soluble HB-EGF with transforming growth factor-β is important for well balanced morphogenesis of the collecting duct system.
De Novo Demonstration and Co-localization of Free-Radical Production and Apoptosis Formation in Rat Kidney Subjected to Ischemia/Reperfusion
Authors: CHIEN CHIANG-TING , LEE PO-HUANG , CHEN CHAU-FONG , MA MING-CHIEH , LAI MING-KUEN , HSU SU-MING
Published: April 2021

Ischemia-induced oxidative damage to the reperfused kidney was examined. A modified chemiluminescence method, an in situ nitro blue tetrazolium perfusion technique, and a DNA fragmentation/apoptosis-related protein assay were adapted for demonstration de novo and co-localization of reactive oxygen species (ROS) production and apoptosis formation in rat kidneys subjected to ischemia/reperfusion injury. The results showed that prolonged ischemia potentiated proapoptotic mechanisms, including increases in the Bax/Bcl-2 ratio, CPP32 expression, and poly-(ADP-ribose)-polymerase fragments, and subsequently resulted in severe apoptosis, including increases in DNA fragmentation and apoptotic cell number in renal proximal tubules (PT) and distal tubules (DT) in a time-dependent manner. The increased level of ROS detected on the renal surface was correlated with that in blood and was intensified by a prolonged interval of ischemia. The main source of ROS synthesis was the PT epithelial cells. The ROS and apoptotic nuclei detected in the PT cells can be ameliorated by superoxide dismutase (SOD) treatment before reperfusion. However, the apoptotic nuclei remained in DT in the SOD-treated rats, indicating that formation of apoptosis in DT was not influenced by the small amounts of ROS produced. In PT and DT cell cultures, significant increases in apoptotic cells and ROS were evident in PT cells after hypoxia/reoxygenation insult. Furthermore, the oxidative damage in PT, but not in DT, can be alleviated by ROS scavengers SOD and hexa(sulfobutyl)fullerene, confirming that PT are vulnerable to ROS. These results lead us to conclude that ROS produced in significant amounts in PT epithelium under ischemia/reperfusion or hypoxia/reoxygenation conditions may be responsible for the apoptotic death of these cells.
Loop Diuretic Infusion Increases Thiazide-Sensitive Na+/Cl--Cotransporter Abundance
Authors: ABDALLAH JOSEPH G. , SCHRIER ROBERT W. , EDELSTEIN CHARLES , JENNINGS SUSAN D. , WYSE BRUCE , ELLISON DAVID H.
Published: April 2021

Chronic infusion of loop diuretics into animals induces structural and functional changes in the distal nephron. These changes include increases in the activity of the thiazide-sensitive Na+/Cl--cotransporter (NCC). The NCC was recently demonstrated to be an aldosterone-induced protein. These experiments were designed to test the hypotheses that chronic loop diuretic infusion, with replacement of NaCl losses, increases NCC protein abundance and that this effect results, in part, from stimulation by aldosterone. Sprague-Dawley rats received vehicle (group 1), furosemide (22 mg/100 g body wt per d) (group 2), or furosemide plus spironolactone (22 and 20 mg/100 g body wt per d, respectively) (group 3). Urine output was higher for groups 2 and 3 than for group 1 (151 ± 32, 149 ± 24, and 12 ± 4 ml, respectively; P < 0.0001). Immunoblot analysis of NCC protein demonstrated that loop diuretics increased NCC protein abundance by nearly 100% (from 2562 ± 30 to 5248 ± 151 arbitrary units, P < 0.01). Spironolactone decreased NCC protein abundance by 66% (to 3532 ± 113 units), compared with the furosemide-treated group (P < 0.005). Northern blot analysis of NCC mRNA demonstrated no significant effect of furosemide (NCC/glyceraldehyde-3-phosphate dehydrogenase ratios: group 1, 0.6 ± 0.12; group 2, 0.5 ± 0.05; P > 0.05, NS) These results indicate that increased NCC activity during chronic loop diuretic infusion is associated with increases in NCC protein abundance. A portion of the furosemide effect can be prevented by blockade of mineralocorticoid receptors.
Use of Positron Emission Tomography to Study AT1 Receptor Regulation In Vivo
Authors: SZABO ZSOLT , SPETH ROBERT C. , BROWN P. RANDY , KERENYI LEVENTE , KAO PAN FU , MATHEWS WILLIAM B. , RAVERT HAYDEN T. , HILTON JOHN , RAUSEO PAIGE , DANNALS ROBERT F. , ZHENG WEI , LEE SUNGHOU , SANDBERG KATHRYN
Published: April 2021

Increased sodium intake and enhanced sodium sensitivity are implicated in the pathogenesis of hypertension and in the control of a major regulator of BP, the type 1 angiotensin receptor (AT1 receptor). An in vivo technique to study changes of renal AT1 receptors by dietary sodium was developed that uses positron emission tomography (PET). PET revealed that renal cortical AT1 receptor binding was increased in sodium-loaded compared with sodium-deprived dogs, which correlated with ex vivo estimations of AT1 receptor numbers. Plasma renin activity, angiotensin II, and aldosterone were inversely related to changes in AT1 receptor binding. These results demonstrate, for the first time in vivo, that the renal AT1 receptor is inversely related to the activity of the renin angiotensin system, which may provide a compensatory mechanism to prevent inappropriate fluctuations in arterial BP. The ability to measure AT1 receptor binding in vivo has potential significance for clinical studies of AT1 receptors, because PET is a noninvasive imaging technique that is readily applicable in humans.
Inhibiting the Complement System Does Not Reduce Injury in Renal Ischemia Reperfusion
Authors: PARK PIERCE , HAAS MARK , CUNNINGHAM PATRICK N. , ALEXANDER JESSY J. , BAO LIHUA , GUTHRIDGE JOEL M. , KRAUS DAMIAN M. , HOLERS V. MICHAEL , QUIGG RICHARD J.
Published: April 2021

The complex pathogenesis of ischemia reperfusion injury (IRI) includes endothelial expression of adhesion molecules, leukocyte recruitment and activation, reactive oxygen species production, and apoptotic and necrotic cell death. A role for complement in IRI of different organs, including kidney, has been proposed on the basis of results of experiments that used pharmacologic inhibitors as well as animals that were deficient in individual complement proteins. Here, renal IRI in mice was examined. Animals that were deficient in C3 had partial protection from IRI induced by 27.5 min of bilateral renal ischemia, followed by 20 h of reperfusion (blood urea nitrogen [BUN] values, 46.6 ± 6.9 and 68.4 ± 7.9 mg/dl in C3 -/- and C3 +/+ mice; n = 7 and 8, respectively; P = 0.033). Given the reduction in IRI in C3 -/- mice, it was investigated, by use of the rodent C3 convertase inhibitor CR1-related gene/protein y-Ig (Crry-Ig), whether exogenous administration of a complement inhibitor could lessen renal injury. Despite the use of Crry-Ig in high doses, there was no significant reduction of injury induced by 20 to 30 min of ischemia followed by up to 30 h of reperfusion. Histologic examination revealed acute tubular necrosis and neutrophilic infiltration, both of which correlated significantly with BUN values (P < 0.001). Of interest, C3 deposition around renal tubules was significantly less in animals with IRI, compared with that in unmanipulated controls (P < 0.001). In Crry-Ig—treated animals, C3 deposition was inversely proportional to BUN values (r = -0.63; P < 0.001), which presumably indicates that severe vascular IRI allowed access of the 160 kD Crry-Ig to the interstitium. Thus, renal IRI in mice may have a partial complement dependence, yet pharmacologic inhibition of the complement system does not seem to be effective, likely because of the presence of other mediator systems that operate in parallel.
The Microinflammatory State in Uremia
Authors: KAYSEN GEORGE A.
Published: April 2021

Mortality is markedly elevated in patients with end-stage renal disease. The leading cause of death is cardiovascular disease. Lipoprotein levels are only slightly elevated in dialysis patients, and cardiovascular risk is inversely correlated with serum cholesterol, suggesting that a process other than hyperlipidemia plays a role in the incidence of cardiovascular disease. Hypoalbuminemia, ascribed to malnutrition, has been one of the most powerful risk factors that predict all-cause and cardiovascular mortality in dialysis patients. The presence of inflammation, as evidenced by increased levels of specific cytokines (interleukin-6 and tumor necrosis factor α) or acute-phase proteins (C-reactive protein and serum amyloid A), however, has been found to be associated with vascular disease in the general population as well as in dialysis patients. The process of inflammation, also called the acute-phase response, additionally causes loss of muscle mass and changes in plasma composition—decreases in serum albumin, prealbumin, and transferrin levels, also associated with malnutrition. Inflammation alters lipoprotein structure and function as well as endothelial structure and function to favor atherogenesis and increases the concentration of atherogenic proteins in serum, such as fibrinogen and lipoprotein (a). Inflammation in dialysis patients is episodic. The causes are likely to be multifactorial and include vascular access infection, less-than-sterile dialysate, dialysate back leak, and nonbiocompatible membranes in addition to clinically apparent infection. In addition, proinflammatory compounds, such as advanced glycation end products, accumulate in renal failure, and defense mechanisms against oxidative injury are reduced, contributing to inflammation and to its effect on the vascular endothelium.
Receptor for Advanced Glycation End Products on Human Synovial Fibroblasts
Authors: Hou Fan Fan , Jiang Jian Ping , Guo Jun Qi , Wang Guo Bao , Zhang Xun , Stern David M. , Schmidt Ann Marie , Owen William F.
Published: April 2021

An important component of amyloid fibrils in dialysis-related amyloidosis (DRA) is β2-microglobulin (β2m) modified with advanced glycation end products (AGE). The amyloid deposits are located principally in joint structures, with adjacent chronic inflammatory reaction characterized by monocyte infiltration. This study examined the interaction of AGE-β2m with human synovial fibroblasts and investigated the proinflammatory effects of that interaction. It was demonstrated that human synovial fibroblasts constitutively expressed the receptor for AGE (RAGE). RAGE expression was detected mainly in synovial intima and was upregulated in DRA synovium. 125I-AGE-β2m bound to immobilized human synovial fibroblasts in a specific, dose-dependent manner (K
d of approximately 138.0 nM), and binding was inhibited by anti-RAGE IgG. Incubation of human synovial fibroblasts with AGE-β2m induced degradation of this AGE-modified protein, as well as increased monocyte chemoattractant protein-1 (MCP-1) mRNA and protein expression. The amount of MCP-1 produced by AGE-β2m-stimulated human synovial fibroblasts was sufficient to induce the chemotaxis of monocytes. MCP-1 synthesis resulted from engagement of RAGE, because the increase in MCP-1 synthesis was attenuated by preincubation of human synovial fibroblasts with anti-RAGE IgG. These data provide evidence of RAGE-mediated perturbation of human synoviocytes, which may be involved in the pathogenesis of inflammatory processes associated with DRA.