bluuebunny/crossref_metadata_2025 huggingface dataset:
Why bison is becoming extinct
Authors: Aycock John
Published: January 2009

At some point in your career, you're going to implement a computer language. You probably won't be implementing Java or C++. You may not even recognize it as a language. Truth be told, there are an awful lot of domain-specific languages, or "little languages" [7] in common use:

configuration files,

HTML/XML documents,

shell scripts,

network protocols,

mail headers,

command-line arguments.

The list goes on. A number of programs allow you to write scripts to control their operation; infact, just the other day I downloaded a neural network simulator which provided a little programming language to steer the simulation.How will you implement your language? There's the ad hoc approach, of course, but it's not well suited to languages whose design is complex or frequently changing. You also end up writing code to perform tasks which can be effectively automated.You might also consider using existing languages like Tcl [18] and Python [6]. These languages are designed to either be embedded in an existing application, or easily extended. This is a good solution when it can be used, saving a lot of time and effort. However, there may be concerns about tying your language to one which is itself changing, or the syntax and semantics of your language may not match those of such a "host" language.A third approach is to use compiler tools to implement your language. Most were designed for the implementation of large programming languages, but the same principles and techniques apply equally well to little languages. This article is the story of one such tool -- a parser generator tool -- and more importantly, what sort of tool is going to replace it, and why.
Quality of Government: What You Get
Authors: Holmberg Sören , Rothstein Bo , Nasiritousi Naghmeh
Published: January 2009

In development policy, international organizations have shifted their focus to the importance of good governance and sound institutions. The theory behind this is that only with a high quality of government (QoG) can a country reap the benefits of economic growth and social development. We review the research behind this policy shift and offer a first benchmark statistical analysis. The first section contains a review of the conceptual discussion of what QoG means. Second, we present four salient approaches pertaining to the outcomes of QoG: the debates concerning QoG and democracy, economic growth, corruption, and the rule of law. The third section uses insights gained from these debates to focus on the policy outcomes of QoG—its effects on social well-being, public health, and environmental sustainability. We conclude by discussing possible pitfalls in future research on QoG and development.
T Cell Activation
Authors: Smith-Garvin Jennifer E. , Koretzky Gary A. , Jordan Martha S.
Published: January 2009

This year marks the 25th anniversary of the first Annual Review of Immunology article to describe features of the T cell antigen receptor (TCR). In celebration of this anniversary, we begin with a brief introduction outlining the chronology of the earliest studies that established the basic paradigm for how the engaged TCR transduces its signals. This review continues with a description of the current state of our understanding of TCR signaling, as well as a summary of recent findings examining other key aspects of T cell activation, including cross talk between the TCR and integrins, the role of costimulatory molecules, and how signals may negatively regulate T cell function.
MicroRNAs in Cancer
Authors: Garzon Ramiro , Calin George A. , Croce Carlo M.
Published: January 2009

MicroRNAs (miRNAs) are small, noncoding RNAs with important functions in development, cell differentiation, and regulation of cell cycle and apoptosis. MiRNA expression is deregulated in cancer by a variety of mechanisms including amplification, deletion, mutation, and epigenetic silencing. Several studies have now shown that miRNAs are involved in the initiation and progression of cancer. In this review, we briefly describe miRNA biogenesis and discuss how miRNAs can act as oncogenes and tumor suppressors. We also address the role of miRNAs in the diagnosis, prognosis, and treatment of cancer.
Nicotine Dependence: Biology, Behavior, and Treatment
Authors: Ray Riju , Schnoll Robert A. , Lerman Caryn
Published: January 2009

Despite great advances in the understanding and treatment of nicotine dependence, close to 21% of adults in the United States continue to smoke. Tobacco use is the single greatest cause of premature and preventable death in the United States. This article reviews the epidemiology, assessment, neurobiology, genetic etiology, and treatment of nicotine dependence. Enhanced understanding of these dimensions of nicotine dependence may help to advance progress toward lowering the prevalence rate of tobacco use in the U.S. and lowering the rate of tobacco-related morbidity and mortality.
MRI-Guided Focused Ultrasound Surgery
Authors: Jolesz Ferenc A.
Published: January 2009

MRI-guided focused ultrasound (MRgFUS) surgery is a noninvasive thermal ablation method that uses magnetic resonance imaging (MRI) for target definition, treatment planning, and closed-loop control of energy deposition. Integrating FUS and MRI as a therapy delivery system allows us to localize, target, and monitor in real time, and thus to ablate targeted tissue without damaging normal structures. This precision makes MRgFUS an attractive alternative to surgical resection or radiation therapy of benign and malignant tumors. Already approved for the treatment of uterine fibroids, MRgFUS is in ongoing clinical trials for the treatment of breast, liver, prostate, and brain cancer and for the palliation of pain in bone metastasis. In addition to thermal ablation, FUS, with or without the use of microbubbles, can temporarily change vascular or cell membrane permeability and release or activate various compounds for targeted drug delivery or gene therapy. A disruptive technology, MRgFUS provides new therapeutic approaches and may cause major changes in patient management and several medical disciplines.
Oral Iron Chelators
Authors: Cappellini Maria Domenica , Pattoneri Paolo
Published: January 2009

Deferoxamine (DFO) was the standard of care for transfusional iron overload for >40 years, requiring subcutaneous infusion for 8–12 h/day, 5–7 days/week. Oral iron chelators are an important development, offering the potential to improve compliance and patients’ quality of life. The oral, three-times-daily agent deferiprone appeared to be a promising advance; however, its use has been limited owing to serious adverse events, such as neutropenia and agranulocytosis. Therapy combining deferiprone with DFO has proved effective in the management of severe cardiac siderosis. Deferasirox is a novel, orally active agent that provides 24-h chelation with a once-daily dose. An extensive clinical trial program has demonstrated that deferasirox at appropriate doses is effective in reducing or maintaining iron burden in adult and pediatric patients. The clinical program demonstrated that deferasirox has a safety profile that is clinically manageable with regular monitoring.
Evolving Treatment of Advanced Colon Cancer
Authors: Segal Neil H. , Saltz Leonard B.
Published: January 2009

Colorectal cancer is a common malignancy worldwide. Despite significant developments in the treatment of this disease, it still causes considerable morbidity and mortality. Recent advances include both newer cytotoxic chemotherapies and novel biologic agents. Although overall progress has been more modest than had been hoped, substantial benefits have been achieved for some patients, and the number of treatment options has substantially increased. Perhaps most importantly, treatment regimens can now be selected and tailored toward the individual patient following an informed discussion between the patient and the treating oncologist. We present in detail these recent advances and provide some insight into several promising future strategies.
Extensively Drug-Resistant Tuberculosis: A New Face to an Old Pathogen
Authors: Shenoi Sheela , Friedland Gerald
Published: January 2009

The presence and consequences of resistance to drugs used for the treatment of tuberculosis have long been neglected. The recent detection and recognition of widespread multiple-drug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis have raised interest and concern among clinicians and public health authorities globally. In this article, we describe the current global status of drug-resistant tuberculosis. We discuss the development of resistance, current management, and strategies for control.
Chronic Consciousness Disorders
Authors: Bernat James L.
Published: January 2009

Although philosophers and cognitive neuroscientists have struggled to define human consciousness, physicians can identify and assess its two clinical dimensions: wakefulness and awareness. A comatose patient has neither wakefulness nor awareness; a patient in a vegetative state has wakefulness without awareness; and a minimally conscious patient has both, but awareness is impaired. Syndromes of unconsciousness have established diagnostic criteria, but they encompass a spectrum of severity of brain damage and have indistinct boundaries. Functional neuroimaging using PET and fMRI have provided a new and complementary way to assess consciousness. Several recent provocative studies suggest that fMRI in unresponsive patients may detect evidence of conscious awareness when a careful neurological examination cannot. If these findings are verified by future studies, functional neuroimaging technologies will alter clinical practices concerning the diagnosis, classification, and prognosis of unconscious patients, and will lead to a greater understanding of the biology of human consciousness.
Management of Breast Cancer in the Genome Era
Authors: Morrow Phuong Khanh H. , Hortobagyi Gabriel N.
Published: January 2009

The genomic era has been characterized by an exponential increase in the number of targets in the management of breast cancer. Prognostic profiling has helped to determine which tumors are more likely to be associated with poor disease-free survival. Gene expression profiles are being studied in order to improve predictions of response and toxicity. Epigenetics is being evaluated for its ability to influence estrogen receptor expression. However, these fields require further validation. This review discusses the advances in the management of breast cancer through genomic evaluation.
Redistricting: Reading Between the Lines
Authors: La Raja Raymond
Published: January 2009

The redistricting process evokes major questions about representative democracy, fairness, and political accountability. This article covers the state of the field along three dimensions. First, it explains how redistricting bears on questions about racial and minority representation. Second, it examines how redistricting influences electoral competition, focusing on the alleged power of partisans and incumbents to draw maps that eliminate all but token opposition. Third and last, it discusses the issues surrounding the redistricting process itself and how various procedural reforms may influence political outcomes. Although significant progress has been made in understanding how different redistricting schemes create various biases in the electoral system, a review of the literature shows that major questions have not been resolved regarding the effects of redistricting on electoral competition, partisan polarization, and representation of communities of interest, especially minorities. Moreover, there is insufficient evidence from empirical research to justify any particular reform of the redistricting process. In addition to filling these gaps, future work might also broaden the scope of research to assess how redistricting affects other aspects of democracy, including political participation, efficacy, and trust.
Social Policy in Developing Countries
Authors: Mares Isabela , Carnes Matthew E.
Published: January 2009

Drawing on recent work and data on social protection in the developing world, this essay evaluates the current state of the art and suggests several important new lines of research. We first examine the historical origin and evolution of social protection systems in developing countries, arguing that insufficient attention has been paid to the authoritarian roots of developing nations' social policy. As a preliminary effort to remedy this shortcoming in the literature, we offer a political logic for the observed variation in the character of institutions of social policy established by nondemocratic regimes. Next, we explore recent research examining linkages between models of economic development and welfare regimes in developing countries. Finally, we turn to the study of the political determinants of the social policy reforms that occurred in the final decades of the twentieth century, arguing that variation in reform across policy areas has been more complex than is generally appreciated in the literature. To explain this variation, we develop a theory that identifies the political coalitions supporting different policy outcomes.
Myostatin regulates fiber-type composition of skeletal muscle by regulating MEF2 and MyoD gene expression
Authors: Hennebry Alex , Berry Carole , Siriett Victoria , O'Callaghan Paul , Chau Linda , Watson Trevor , Sharma Mridula , Kambadur Ravi
Published: January 2009

Myostatin (Mstn) is a secreted growth factor belonging to the tranforming growth factor (TGF)-β superfamily. Inactivation of murine Mstn by gene targeting, or natural mutation of bovine or human Mstn, induces the double muscling (DM) phenotype. In DM cattle, Mstn deficiency increases fast glycolytic (type IIB) fiber formation in the biceps femoris (BF) muscle. Using Mstn null (−/−) mice, we suggest a possible mechanism behind Mstn-mediated fiber-type diversity. Histological analysis revealed increased type IIB fibers with a concomitant decrease in type IIA and type I fibers in the Mstn−/− tibialis anterior and BF muscle. Functional electrical stimulation of Mstn−/− BF revealed increased fatigue susceptibility, supporting increased type IIB fiber content. Given the role of myocyte enhancer factor 2 (MEF2) in oxidative type I fiber formation, MEF2 levels in Mstn−/− tissue were quantified. Results revealed reduced MEF2C protein in Mstn−/− muscle and myoblast nuclear extracts. Reduced MEF2-DNA complex was also observed in electrophoretic mobility-shift assay using Mstn−/− nuclear extracts. Furthermore, reduced expression of MEF2 downstream target genes MLC1F and calcineurin were found in Mstn−/− muscle. Conversely, Mstn addition was sufficient to directly upregulate MLC promoter-enhancer activity in cultured myoblasts. Since high MyoD levels are seen in fast fibers, we analyzed MyoD levels in the muscle. In contrast to MEF2C, MyoD levels were increased in Mstn−/− muscle. Together, these results suggest that while Mstn positively regulates MEF2C levels, it negatively regulates MyoD expression in muscle. We propose that Mstn could regulate fiber-type composition by regulating the expression of MEF2C and MyoD during myogenesis.
Regulation of connexin gene expression during skeletal muscle regeneration in the adult rat
Authors: Trovato-Salinaro A. , Belluardo N. , Frinchi M. , von Maltzahn J. , Willecke K. , Condorelli D. F. , Mudò G.
Published: January 2009

In the adult skeletal muscle, various kinds of trauma promote proliferation of satellite cells that differentiate into myoblasts forming new myofibers or to repair the damaged one. The aim of present work was to perform a comparative spatial and temporal analysis of connexin (Cx) 37, Cx39, Cx40, Cx43, and Cx45 expression in the adult regenerating skeletal muscle in response to crush injury. Within 24 h from injury, Cx37 expression was upregulated in the endothelial cells of blood vessels, and, 5 days after injury, Cx37-expressing cells were found inside the area of lesion and formed clusters generating new blood vessels with endothelial cells expressing Cx37. Three days after injury, Cx39 mRNA was selectively expressed in myogenin-positive cells, forming rows of closely apposed cell nuclei fusing in myotubes. Cx40 mRNA-labeled cells were observed within 24 h from injury in the endothelium of blood vessels, and, 5 days after lesion, Cx40-labeled cells were found inside the area of lesion-forming rows of myogenin-positive, closely apposed cells coexpressing Cx39. Within 24 h from lesion, both Cx43 and Cx45 mRNAs were upregulated in individual cells, and some of them were positive for M-cadherin. Three days after injury, a large number of both Cx43 and Cx45 mRNA-labeled and myogenin-positive cells were found inside the area of lesion. Taken together, these results show that at least four Cxs, out of five expressed in regenerating skeletal muscle, can be differentially involved in communication of myogenic cells during the process of cell proliferation, aggregation, and fusion to form new myotubes or to repair damaged myofibers.
REDD2 is enriched in skeletal muscle and inhibits mTOR signaling in response to leucine and stretch
Authors: Miyazaki Mitsunori , Esser Karyn A.
Published: January 2009

The protein kinase mammalian target of rapamycin (mTOR) is well established as a key regulator of skeletal muscle size. In this study, we determined that the stress responsive gene REDD2 (regulated in development and DNA damage responses 2) is a negative regulator of mTOR signaling and is expressed predominantly in skeletal muscle. Overexpression of REDD2 in muscle cells significantly inhibited basal mTOR signaling and diminished the response of mTOR to leucine addition or mechanical stretch. The inhibitory function of REDD2 on mTOR signaling seems to be mediated downstream or independent of Akt signaling and upstream of Rheb (Ras homolog enriched in brain). Knock down of tuberous sclerosis complex 2 (TSC2) using small interfering (si)RNA potently activated mTOR signaling and was sufficient to rescue REDD2 inhibition of mTOR activity, suggesting that REDD2 functions by modulating TSC2 function. Immunoprecipitation assays demonstrated that REDD2 does not directly interact with either TSC1 or TSC2. However, we found that REDD2 forms a complex with 14-3-3 protein and that increasing expression of REDD2 acts to competitively dissociate TSC2 from 14-3-3 and inhibits mTOR signaling. These findings demonstrate that REDD2 is a skeletal muscle specific inhibitory modulator of mTOR signaling and identify TSC2 and 14-3-3 as key molecular links between REDD2 and mTOR function.
Role of gut-brain axis in persistent abnormal feeding behavior in mice following eradication of Helicobacter pylori infection
Authors: Bercik Premysl , Verdú Elena F. , Foster Jane A. , Lu Jun , Scharringa Angela , Kean Iain , Wang Lu , Blennerhassett Patricia , Collins Stephen M.
Published: January 2009

Bacterial infection can trigger the development of functional GI disease. Here, we investigate the role of the gut-brain axis in gastric dysfunction during and after chronic H. pylori infection. Control and chronically H. pylori-infected Balb/c mice were studied before and 2 mo after bacterial eradication. Gastric motility and emptying were investigated using videofluoroscopy image analysis. Gastric mechanical viscerosensitivity was assessed by cardioautonomic responses to distension. Feeding patterns were recorded by a computer-assisted system. Plasma leptin, ghrelin, and CCK levels were measured using ELISA. IL-1β, TNF-α, proopiomelanocortin (POMC), and neuropeptide Y mRNAs were assessed by in situ hybridizations on frozen brain sections. Gastric inflammation was assessed by histology and immunohistochemistry. As shown previously, H. pylori-infected mice ate more frequently than controls but consumed less food per bout, maintaining normal body weight. Abnormal feeding behavior was accompanied by elevated plasma ghrelin and postprandial CCK, higher TNF-α (median eminence), and lower POMC (arcuate nucleus) mRNA. Infected mice displayed delayed gastric emptying and visceral hypersensitivity. Eradication therapy normalized gastric emptying and improved gastric sensitivity but had no effect on eating behavior. This was accompanied by persistently increased TNF-α in the brain and gastric CD3+ T-cell counts. In conclusion, chronic H. pylori infection in mice alters gastric emptying and mechanosensitivity, which improve after bacterial eradication. A feeding pattern reminiscent of early satiety persists after H. pylori eradication and is accompanied by increased TNF-α in the brain. The results support a role for altered gut-brain pathways in the maintenance of postinfective gut dysfunction.
Heritable pathologic cardiac hypertrophy in adulthood is preceded by neonatal cardiac growth restriction
Authors: Porrello Enzo R. , Bell James R. , Schertzer Jonathan D. , Curl Claire L. , McMullen Julie R. , Mellor Kimberley M. , Ritchie Rebecca H. , Lynch Gordon S. , Harrap Stephen B. , Thomas Walter G. , Delbridge Lea M. D.
Published: January 2009

The identification of genetic factors influencing cardiac growth independently of increased load is crucial to an understanding of the molecular and cellular basis of pathological cardiac hypertrophy. The central aim of this investigation was to determine how pathological hypertrophy in the adult can be linked with disturbances in cardiomyocyte growth and viability in early neonatal development. The hypertrophic heart rat (HHR) model is derived from the spontaneously hypertensive rat and exhibits marked cardiac hypertrophy, in the absence of a pressure load at maturity. Hearts were harvested from male HHR, and control strain normal heart rats (NHR), at different stages of postnatal development [neonatal (P2), 4 wk, 6 wk, 8 wk, 12 wk, 20 wk]. Isolated neonatal cardiomyocytes were prepared to evaluate cell size, number, and binucleation. At postnatal day 2, HHR hearts were considerably smaller than control NHR (4.3 ± 0.2 vs. 5.0 ± 0.1 mg/g, P < 0.05). Cardiac growth restriction in the neonatal HHR was associated with reduced myocyte size (length and width) and an increased proportion of binucleated cardiomyocytes. Furthermore, the number of cardiomyocytes isolated from HHR neonatal hearts was significantly less (∼29%) than NHR. We also observe that growth stress in the neonate is associated with accentuated PI3K and suppressed MAPK activation, although these signaling pathways are normalized in the adult heart exhibiting established hypertrophy. Thus, using the HHR model, we identified novel molecular and cellular mechanisms involving premature exit from the cell cycle, reduced cardiomyocyte endowment, and dysregulated trophic signaling during early development, which are implicated in the etiology of heritable cardiac hypertrophy in the adult.
Hypertension in mice lacking the CXCR3 chemokine receptor
Authors: Hsu Hsiang-Hao , Duning Kerstin , Meyer Hans Henning , Stölting Miriam , Weide Thomas , Kreusser Stefanie , van Le Truc , Gerard Craig , Telgmann Ralph , Brand-Herrmann Stefan-Martin , Pavenstädt Hermann , Bek Martin Johannes
Published: January 2009

The CXC chemokine receptor 3 (CXCR3) has been linked to autoimmune and inflammatory disease, allograft rejection, and ischemic nephropathy. CXCR3 is expressed on endothelial and smooth muscle cells. Although a recent study posited that antagonizing of CXCR3 function may reduce atherosclerosis, the role of CXCR3 in controlling physiological vascular functions remains unclear. This study demonstrates that disruption of CXCR3 leads to elevated mean arterial pressures in anesthetized and conscious mice, respectively. Stimulation of isolated resistance vessels with various vasoconstrictors showed increased contractibility in CXCR3−/− mice in response to angiotensin II (ANG II) and a decreased vasodilatation in response to acetylcholine (ACh). The increased contractibility was related to higher ANG II type 1 receptor (AT1R) expression, whereas the decreased vasodilatation was related to lower M3-ACh receptor expression in the mesenteric arteries of CXCR3−/− mice compared with wild-type mice. The vasodilatatory response to ACh could be antagonized by the nonselective ACh receptor antagonist atropine and the selective M3 receptor antagonist 4-DAMP, but not by M1, M2, and M4 receptor antagonists. Additionally, EMSA studies revealed that transcription factors SP-1 and EGR-1 interact as a complex with the murine AT1R promoter region. Furthermore, we could show increased expression of SP-1 in CXCR3−/− mice indicating an imbalanced SP-1 and EGR-1 complex formation which causes increased AT1R expression and hypertension. The data indicate that CXCR3 receptor is important in vascular contractility and hypertension, possibly through upregulated AT1R expression.
Glomerular endothelial cell fenestrations: an integral component of the glomerular filtration barrier
Authors: Satchell Simon C. , Braet Filip
Published: January 2009

Glomerular endothelial cell (GEnC) fenestrations are analogous to podocyte filtration slits, but their important contribution to the glomerular filtration barrier has not received corresponding attention. GEnC fenestrations are transcytoplasmic holes, specialized for their unique role as a prerequisite for filtration across the glomerular capillary wall. Glomerular filtration rate is dependent on the fractional area of the fenestrations and, through the glycocalyx they contain, GEnC fenestrations are important in restriction of protein passage. Hence, dysregulation of GEnC fenestrations may be associated with both renal failure and proteinuria, and the pathophysiological importance of GEnC fenestrations is well characterized in conditions such as preeclampsia. Recent evidence suggests a wider significance in repair of glomerular injury and in common, yet serious, conditions, including diabetic nephropathy. Study of endothelial cell fenestrations is challenging because of limited availability of suitable in vitro models and by the requirement for electron microscopy to image these sub-100-nm structures. However, extensive evidence, from glomerular development in rodents to in vitro studies in human GEnC, points to vascular endothelial growth factor (VEGF) as a key inducer of fenestrations. In systemic endothelial fenestrations, the intracellular pathways through which VEGF acts to induce fenestrations include a key role for the fenestral diaphragm protein plasmalemmal vesicle-associated protein-1 (PV-1). The role of PV-1 in GEnC is less clear, not least because of controversy over existence of GEnC fenestral diaphragms. In this article, the structure-function relationships of GEnC fenestrations will be evaluated in depth, their role in health and disease explored, and the outlook for future study and therapeutic implications of these peculiar structures will be approached.
Glomerular 20-HETE, EETs, and TGF-β1 in diabetic nephropathy
Authors: Luo Pengcheng , Zhou Yiqiang , Chang Hsin-Hsin , Zhang Jie , Seki Tsugio , Wang Cong-Yi , Inscho Edward W. , Wang Mong-Heng
Published: January 2009

The early stage of diabetic nephropathy (DN) is linked to proteinuria. Transforming growth factor (TGF)-β1 increases glomerular permeability to albumin (Palb), whereas 20-HETE and EETs reduce Palb. To investigate the impact of hyperglycemia and hyperlipidemia on 20-HETE, EETs, and TGF-β1 in the glomeruli, rats were divided into four groups: ND rats were fed a normal diet, HF rats were fed a high-fat diet, STZ rats were treated with 35 mg/kg of streptozotocin, and HF/STZ rats were fed a HF diet and treated with STZ. After 10 wk on these regimens, blood glucose, urinary albumin, serum cholesterol, serum triglyceride levels, and the kidney-to-body weight ratio were significantly elevated in STZ and HF/STZ rats compared with HF and ND rats. STZ and HF/STZ rats had histopathologic changes and abnormal renal hemodynamics. Expression of glomerular CYP4A, enzymes for 20-HETE production, was significantly decreased in STZ rats, whereas expression of glomerular CYP2C and CYP2J, enzymes for EETs production, was significantly decreased in both STZ and HF/STZ rats. Moreover, glomerular TGF-β1 levels were significantly greater in STZ and HF/STZ rats than in HF and ND rats. Five-week treatment of STZ rats with clofibrate induced glomerular CYP4A expression and 20-HETE production, but reduced glomerular TGF-β1 and urinary protein excretion. These results demonstrate that hyperglycemia increases TGF-β1 but decreases 20-HETE and EETs production in the glomeruli, changes that may be important in causing glomerular damage in the early stage of DN.
TGF-β upregulation drives tertiary lymphoid organ formation and kidney dysfunction in calcineurin A-α heterozygous mice
Authors: Kelly Fiona M. , Reddy Ramesh N. , Roberts Brian R. , Gangappa Shivaprakash , Williams Ifor R. , Gooch Jennifer L.
Published: January 2009

Calcineurin is an important intracellular signaling molecule which can be inhibited by cyclosporin resulting in immune suppression and nephrotoxicity. Previously, we reported that homozygous loss of the α isoform of calcineurin impairs kidney development and function and mimics many features of cyclosporin nephrotoxicity. However, early lethality of null mice prevented further study of renal changes. Alternatively, we examined aged heterozygous (CnAα+/−) mice. In addition to renal dysfunction and inflammation, we find that CnAα+/− mice spontaneously develop tertiary lymphoid aggregates in the kidney, small intestine, liver, and lung. Lymphoid aggregates contain both T cells and B cells and exhibited organization suggestive of tertiary lymphoid organs (TLOs). Kidney function and TLO formation were highly correlated suggesting that this process may contribute to nephrotoxicity. Consistent with previous findings, transforming growth factor (TGF)-β is significantly increased in CnAα+/− mice. Neutralization of TGF-β attenuated TLO formation and improved kidney function. In conclusion, we report that haploinsufficiency of CnAα causes uregulation of TGF-β which contributes to chronic inflammation and formation of TLOs. While the process that leads to TLOs formation in transplant allografts is unknown, TLOs are associated with poor clinical prognosis. This study suggests that calcineurin inhibition itself may lead to TLO formation and that TGF-β may be a novel therapeutic target.
Basolateral expression of the ammonia transporter family member Rh C glycoprotein in the mouse kidney
Authors: Kim Hye-Young , Verlander Jill W. , Bishop Jesse M. , Cain Brian D. , Han Ki-Hwan , Igarashi Peter , Lee Hyun-Wook , Handlogten Mary E. , Weiner I. David
Published: January 2009

Ammonia metabolism and transport are critical for acid-base homeostasis. The ammonia transporter family member Rh C glycoprotein (Rhcg) is expressed in distal renal tubular segments, and its expression is regulated in parallel with renal ammonia metabolism. However, there are inconsistencies in its reported subcellular distribution, with both apical and basolateral Rhcg reported in rat and human kidney and only apical expression in mouse kidney. Because the membrane location of Rhcg is critical for understanding its physiological role, we reassessed mouse Rhcg localization using refined immunolocalization methods. Two antibodies directed against different Rhcg-specific epitopes identified both apical and basolateral Rhcg immunolabel in mouse kidney. Immunogold electron microscopy both confirmed basolateral plasma membrane Rhcg expression and showed that apical immunolabel represented expression in both the apical plasma membrane and in subapical cytoplasmic vesicles. Immunoblots and Northern blots identified similar bands in Balb/c and C57BL/6 kidneys, suggesting basolateral Rhcg may result from alternative trafficking. Basolateral Rhcg intensity was strain dependent, with less basolateral Rhcg expression in the Balb/c mouse compared with the C57BL/6 mouse. In mice with collecting duct-specific Rhcg gene deletion, generated using Cre-loxP techniques, neither apical nor basolateral Rhcg immunolabel was identified in the collecting duct, confirming that basolateral Rhcg was the product of the same gene product as apical Rhcg. Although basolateral Rhcg expression differed between C57BL/6 and Balb/c mice, Rh B glycoprotein, which is exclusively basolateral, was expressed at similar levels in the two strains. We conclude that Rhcg is present in both the apical and basolateral plasma membrane in the mouse kidney, where it is likely to contribute to renal ammonia metabolism.
Rho-kinase inhibition reduces pressure-mediated autoregulatory adjustments in afferent arteriolar diameter
Authors: Inscho Edward W. , Cook Anthony K. , Webb R. Clinton , Jin Li-Ming
Published: January 2009

Preglomerular resistance is regulated by calcium influx- and mobilization-dependent mechanisms; however, the role of Rho-kinase in calcium sensitization in the intact kidney has not been carefully examined. Experiments were performed to test the hypothesis that Rho-kinase inhibition blunts pressure-mediated afferent arteriolar autoregulatory behavior and vasoconstrictor responses evoked by angiotensin II and P2X1receptor activation. Rat kidneys were studied in vitro using the blood-perfused juxtamedullary nephron technique. Autoregulatory behavior was assessed before and during Rho-kinase inhibition with Y-27632 (1.0 μM; n = 5). Control diameter averaged 14.3 ± 0.8 μm and increased to 18.1 ± 0.9 μm ( P < 0.05) during Y-27632 treatment. In the continued presence of Y-27632, reducing perfusion pressure to 65 mmHg slightly increased diameter to 18.7 ± 1.0 μm. Subsequent pressure increases to 130 and 160 mmHg yielded afferent arteriolar diameters of 17.5 ± 0.8 and 16.6 ± 0.6 μm ( P < 0.05). This 11% decline in diameter is significantly smaller than the 40% decrease obtained in untreated kidneys. The inhibitory effects of Y-27632 on autoregulatory behavior were concentration dependent. Angiotensin II responses were blunted by Y-27632. Angiotensin II (1.0 nM) reduced afferent diameter by 17 ± 1% in untreated arterioles and by 6 ± 2% during exposure to Y-27632. The P2X1receptor agonist, α, β-methylene ATP, reduced afferent arteriolar diameter by 8 ± 1% but this response was eliminated during exposure to Y-27632. Western blot analysis confirms expression of the Rho-kinase signaling pathway. Thus, Rho-kinase may be important in pressure-mediated autoregulatory adjustments in preglomerular resistance and responsiveness to angiotensin II and autoregulatory P2X1receptor agonists.
Chronic blockade of 20-HETE synthesis reduces polycystic kidney disease in an orthologous rat model of ARPKD
Authors: Park Frank , Sweeney William E. , Jia Guangfu , Akbulut Talha , Mueller Benjamin , Falck J. Russell , Birudaraju Saritha , Roman Richard J. , Avner Ellis D.
Published: January 2009

20-Hydroxyeicosatetraenoic acid (20-HETE) has been implicated as a potential mediator in epithelial cell proliferation and cyst formation in polycystic kidney disease (PKD). In the present study, we studied the effects of chronic blockade of 20-HETE synthesis in an orthologous rodent model of autosomal recessive polycystic kidney disease (ARPKD), the PCK rat. RT-PCR analysis indicated that the expression of CYP4A1, CYP4A2, CYP4A3, and CYP4A8 mRNA was increased two- to fourfold in cystic PCK compared with noncystic Sprague-Dawley rat kidneys. Daily administration of a 20-HETE synthesis inhibitor, HET-0016 (10 mg·kg−1·day−1ip) for 4–7 wk significantly reduced kidney size by 24% from 4.95 ± 0.19 g in vehicle-treated PCK rats to 3.76 ± 0.15 g ( n = 4). Collecting tubule morphometric cystic indices were reduced in HET-0016-treated PCK rats (2.1 ± 0.2; n = 4) compared with vehicle-treated PCK rats (4.4 ± 0.1; n = 4). The cellular mechanism by which 20-HETE may play a role in cyst formation has not been well characterized, but there was a significantly lower ( P < 0.05) level of intracellular cAMP and decreased phosphorylation (activation) of ERK1/2 protein in PCK rat kidneys ( n = 3) treated with HET-0016 . These studies indicate a potential role of 20-HETE in cyst formation in the orthologous rodent PCK model of ARPKD.
Intermittent hypoxia activates peptidylglycine α-amidating monooxygenase in rat brain stem via reactive oxygen species-mediated proteolytic processing
Authors: Sharma Suresh D. , Raghuraman Gayatri , Lee Myeong-Seon , Prabhakar Nanduri R. , Kumar Ganesh K.
Published: January 2009

Intermittent hypoxia (IH) associated with sleep apneas leads to cardiorespiratory abnormalities that may involve altered neuropeptide signaling. The effects of IH on neuropeptide synthesis have not been investigated. Peptidylglycine α-amidating monooxygenase (PAM; EC 1.14.17.3) catalyzes the α-amidation of neuropeptides, which confers biological activity to a large number of neuropeptides. PAM consists of O2-sensitive peptidylglycine α-hydroxylating monooxygenase (PHM) and peptidyl-α-hydroxyglycine α-amidating lyase (PAL) activities. Here, we examined whether IH alters neuropeptide synthesis by affecting PAM activity and, if so, by what mechanisms. Experiments were performed on the brain stem of adult male rats exposed to IH (5% O2for 15 s followed by 21% O2for 5 min; 8 h/day for up to 10 days) or continuous hypoxia (0.4 atm for 10 days). Analysis of brain stem extracts showed that IH, but not continuous hypoxia, increased PHM, but not PAL, activity of PAM and that the increase of PHM activity was associated with a concomitant elevation in the levels of α-amidated forms of substance P and neuropeptide Y. IH increased the relative abundance of 42- and 35-kDa forms of PHM (∼1.6- and 2.7-fold, respectively), suggesting enhanced proteolytic processing of PHM, which appears to be mediated by an IH-induced increase of endoprotease activity. Kinetic analysis showed that IH increases Vmaxbut has no effect on Km. IH increased generation of reactive oxygen species in the brain stem, and systemic administration of antioxidant prevented IH-evoked increases of PHM activity, proteolytic processing of PHM, endoprotease activity, and elevations in substance P and neuropeptide Y amide levels. Taken together, these results demonstrate that IH activates PHM in rat brain stem via reactive oxygen species-dependent posttranslational proteolytic processing and further suggest that PAM activation may contribute to IH-mediated peptidergic neurotransmission in rat brain stem.
Data-Driven Significance Estimation for Precise Spike Correlation
Authors: Grün Sonja
Published: January 2009

The mechanisms underlying neuronal coding and, in particular, the role of temporal spike coordination are hotly debated. However, this debate is often confounded by an implicit discussion about the use of appropriate analysis methods. To avoid incorrect interpretation of data, the analysis of simultaneous spike trains for precise spike correlation needs to be properly adjusted to the features of the experimental spike trains. In particular, nonstationarity of the firing of individual neurons in time or across trials, a spike train structure deviating from Poisson, or a co-occurrence of such features in parallel spike trains are potent generators of false positives. Problems can be avoided by including these features in the null hypothesis of the significance test. In this context, the use of surrogate data becomes increasingly important, because the complexity of the data typically prevents analytical solutions. This review provides an overview of the potential obstacles in the correlation analysis of parallel spike data and possible routes to overcome them. The discussion is illustrated at every stage of the argument by referring to a specific analysis tool (the Unitary Events method). The conclusions, however, are of a general nature and hold for other analysis techniques. Thorough testing and calibration of analysis tools and the impact of potentially erroneous preprocessing stages are emphasized.
Bayesian Correction for Attenuation of Correlation in Multi-Trial Spike Count Data
Authors: Behseta Sam , Berdyyeva Tamara , Olson Carl R. , Kass Robert E.
Published: January 2009

When correlation is measured in the presence of noise, its value is decreased. In single-neuron recording experiments, for example, the correlation of selectivity indices in a pair of tasks may be assessed across neurons, but, because the number of trials is limited, the measured index values for each neuron will be noisy. This attenuates the correlation. A correction for such attenuation was proposed by Spearman more than 100 yr ago, and more recent work has shown how confidence intervals may be constructed to supplement the correction. In this paper, we propose an alternative Bayesian correction. A simulation study shows that this approach can be far superior to Spearman's, both in accuracy of the correction and in coverage of the resulting confidence intervals. We demonstrate the usefulness of this technology by applying it to a set of data obtained from the frontal cortex of a macaque monkey while performing serial order and variable reward saccade tasks. There the correction results in a substantial increase in the correlation across neurons in the two tasks.
A Simple Quantitative Method for Analyzing Electrographic Status Epilepticus in Rats
Authors: Lehmkuhle M. J. , Thomson K. E. , Scheerlinck P. , Pouliot W. , Greger B. , Dudek F. E.
Published: January 2009

Electrographic status epilepticus (ESE) is a medical emergency consisting of repetitive seizures and may result in death or severe brain damage. Epilepsy can develop following ESE. The properties of ESE (e.g., duration and intensity) are variable, as are the effects of putative therapeutic treatments. Therefore a straightforward method to quantify different components of ESE would be beneficial for both researchers and clinicians. A frequency range close to the gamma band was selected for extraction of seizure-related activity from the EEG. This filtering strategy reduced motion artifacts and other noise sources in the electrophysiological recordings, thus increasing the signal-to-noise ratio of the EEG spike activity. EEG spiking was quantified using an energy operator and modeled by an eighth-order polynomial. In a benzodiazepine-resistant rat model of pilocarpine-induced ESE, the efficacy of various pharmaceutical agents at suppressing ESE was analyzed with this and other methods on data collected for ≤24 h after ESE induction. This approach allows for the objective, quantitative, and rapid assessment of the effects of both short- and long-lasting pharmacological manipulations on ESE and other forms of prolonged repetitive electrical activity.
Is Host Ectoparasite Load Related to Echeneid Fish Presence?
Authors: Mucientes Gonzalo R. , Queiroz Nuno , Pierce Simon J. , Sazima Ivan , Brunnschweiler Juerg M.
Published: January 2009

This study used field data of echeneid and ectoparasite associations with free-swimming whale sharks (Rhincodon typus) and captured mako sharks (Isurus oxyrinchus) to test whether (1) echeneid presence was positively correlated with ectoparasite presence; and (2) the number of ectoparasites was negatively correlated with the number of echeneid fish. Data from whale and mako sharks do not support the first hypothesis whereas data from mako sharks yields support for the second hypothesis. The results indicate that echeneids do regulate the number of ectoparasites on at least some host species, but these benefits may be contingent on the echeneid species.
PPAR‐δ in Vascular Pathophysiology
Authors: Wang Nanping
Published: January 2009

Peroxisome proliferator‐activated receptors belong to the superfamily of ligand‐dependent nuclear receptor transcription factors, which include three subtypes: PPAR‐α, β/δ, and γ. PPAR‐δ, play important roles in the regulation of cell growth and differentiation as well as tissue wound and repair. Emerging evidence has also demonstrated that PPAR‐δ is implicated in lipids and glucose metabolism. Most recently, the direct effects of PPAR‐δ on cardiovascular processes such as endothelial function and angiogenesis have also been investigated. Therefore, it is suggested that PPAR‐δ may have critical roles in cardiovascular pathophysiology and is a potential target for therapeutic intervention of cardiovascular disorders such as atherosclerosis.
Synthesis, Characterization, and In Vitro Cytotoxic Activities of Benzaldehyde Thiosemicarbazone Derivatives and Their Palladium (II) and Platinum (II) Complexes against Various Human Tumor Cell Lines
Authors: Hernándeza Wilfredo , Paz Juan , Vaisberg Abraham , Spodine Evgenia , Richter Rainer , Beyer Lothar
Published: January 2009

The palladium (II) bis‐chelate Pd and platinum (II) tetranuclear complexes of benzaldehyde thiosemicarbazone derivatives have been synthesized, and characterized by elemental analysis and IR, FAB(+)‐mass and NMR ( 1H,  13C) spectroscopy. The complex [HL2 = m‐CN‐benzaldehyde thiosemicarbazone] shows a square‐planar geometry with two deprotonated ligands (L) coordinated to PdII through the nitrogen and sulphur atoms in a transarrangement, while the complex [HL4 = 4‐phenyl‐1‐benzaldehyde thiosemicarbazone] has a tetranuclear geometry with four tridentate ligands coordinated to four PtII ions through the carbon (aromatic ring), nitrogen, and sulphur atoms where the ligands are deprotonated at the NH group. The in vitro antitumor activity of the ligands and their complexes was determined against different human tumor cell lines, which revealed that the palladium (II) and platinum (II) complexes are more cytotoxic than their ligands with IC50 values at the range of 0.07–3.67 μM. The tetranuclear complex , with the phenyl group in the terminal amine of the ligand, showed higher antiproliferative activity (CI50 = 0.07–0.12 μM) than the other tested palladium (II) complexes.
Peroxisome Proliferator‐Activated Receptors and Hepatitis C Virus‐Induced Insulin Resistance
Authors: Negro Francesco
Published: January 2009

Insulin resistance and type 2 diabetes are associated with hepatitis C virus infection. A wealth of clinical and experimental data suggests that the virus is directly interfering with the insulin signalling in hepatocytes. In the case of at least one viral genotype (the type 3a), insulin resistance seems to be directly mediated by the downregulation of the peroxisome proliferator‐activated receptor γ. Whether and how this interaction may be manipulated pharmacologically, in order to improve the responsiveness to antivirals of insulin resistant chronic hepatitis C, patients remain to be fully explored.
Solitary Amyloid Tumor of the Tongue Base
Authors: Akyildiz S. , Doganavsargil B. , Göde S. , Veral A.
Published: January 2009

The purpose of this article is to present a rare case of localized, solitary amyloid tumor of tongue base and emphasize some of the characteristic features of challenging clinical and histopathologic diagnosis. In this paper, we focused on the clinical and pathological specifications of this rare tumor, so any unnecessary examinations or measures may be spared. Negative staining of amyloid material with AAC and osseous metaplasia noted in the histopathologic examination may not be thought as definite criteria for localized amyloidosis, but a supporter of localized, solitary amyloid tumor diagnosis.