bluuebunny/crossref_metadata_2025 huggingface dataset:
An Anti-Inflammatory Role of VEGFR2/Src Kinase Inhibitor in Herpes Simplex Virus 1-Induced Immunopathology
Authors: Sharma Shalini , Mulik Sachin , Kumar Naveen , Suryawanshi Amol , Rouse Barry T.
Published: April 2011

Corneal neovascularization represents a key step in the blinding inflammatory stromal keratitis (SK) lesion caused by ocular infection with herpes simplex virus (HSV). In this report, we describe a novel approach for limiting the angiogenesis caused by HSV infection of the mouse eye. We show that topical or systemic administration of the Src kinase inhibitor (TG100572) that inhibits downstream molecules involved in the vascular endothelial growth factor (VEGF) signaling pathway resulted in markedly diminished levels of HSV-induced angiogenesis and significantly reduced the severity of SK lesions. Multiple mechanisms were involved in the inhibitory effects. These included blockade of IL-8/CXCL1 involved in inflammatory cells recruitment that are a source of VEGF, diminished cellular infiltration in the cornea, and reduced proliferation and migration of CD4
+
T cells into the corneas. As multiple angiogenic factors (VEGF and basic fibroblast growth factor [bFGF]) play a role in promoting angiogenesis during SK and since Src kinases are involved in signaling by many of them, the use of Src kinase inhibition represents a promising way of limiting the severity of SK lesions the most common cause of infectious blindness in the Western world.
Rescue of Infectious Particles from Preassembled Alphavirus Nucleocapsid Cores
Authors: Snyder Jonathan E. , Azizgolshani Odisse , Wu Bingbing , He Yingpei , Lee Aih Cheun , Jose Joyce , Suter Daniel M. , Knobler Charles M. , Gelbart William M. , Kuhn Richard J.
Published: April 2011

Alphaviruses are small, spherical, enveloped, positive-sense, single-stranded, RNA viruses responsible for considerable human and animal disease. Using microinjection of preassembled cores as a tool, a system has been established to study the assembly and budding process of Sindbis virus, the type member of the alphaviruses. We demonstrate the release of infectious virus-like particles from cells expressing Sindbis virus envelope glycoproteins following microinjection of Sindbis virus nucleocapsids purified from the cytoplasm of infected cells. Furthermore, it is shown that nucleocapsids assembled
in vitro
mimic those isolated in the cytoplasm of infected cells with respect to their ability to be incorporated into enveloped virions following microinjection. This system allows for the study of the alphavirus budding process independent of an authentic infection and provides a platform to study viral and host requirements for budding.
Cytomegalovirus e127 Protein Interacts with the Inhibitory CD200 Receptor
Authors: Foster-Cuevas Mildred , Westerholt Tina , Ahmed Mohamed , Brown Marion H. , Barclay A. Neil , Voigt Sebastian
Published: April 2011

CD200 is a cell surface glycoprotein that binds an inhibitory receptor (CD200R) on myeloid cells. CD200 orthologues are present in many species of virus, and we show that the rat cytomegalovirus CD200 orthologue (e127) is expressed at the cell surface on infected cells. It binds the host CD200R with the same affinity as that of the host protein, and thus this protein acts as a close mimic of the host protein and has the potential to downregulate immune responses to the virus.
Enzyme Digests Eliminate Nonfunctional Env from HIV-1 Particle Surfaces, Leaving Native Env Trimers Intact and Viral Infectivity Unaffected
Authors: Crooks Ema T. , Tong Tommy , Osawa Keiko , Binley James M.
Published: April 2011

HIV-1 viruses and virus-like particles (VLPs) bear nonnative “junk” forms of envelope (Env) glycoprotein that may undermine the development of antibody responses against functional gp120/gp41 trimers, thereby blunting the ability of particles to elicit neutralizing antibodies. Here, we sought to better understand the nature of junk Env with a view to devising strategies for its removal. Initial studies revealed that native trimers were surprisingly stable in the face of harsh conditions, suggesting that junk Env is unlikely to arise by trimer dissociation or gp120 shedding. Furthermore, the limited gp120 shedding that occurs immediately after synthesis of primary HIV-1 isolate Envs is not caused by aberrant cleavage at the tandem gp120/gp41 cleavage sites, which were found to cleave in a codependent manner. A major VLP contaminant was found to consist of an early, monomeric form of gp160 that is glycosylated in the endoplasmic reticulum (gp160ER) and then bypasses protein maturation and traffics directly into particles. gp160ER was found to bind two copies of monoclonal antibody (MAb) 2G12, consistent with its exclusively high-mannose glycan profile. These findings prompted us to evaluate enzyme digests as a way to remove aberrant Env. Remarkably, sequential glycosidase-protease digests led to a complete or near-complete removal of junk Env from many viral strains, leaving trimers and viral infectivity largely intact. “Trimer VLPs” may be useful neutralizing antibody immunogens.
Spatial Relationships between Markers for Secretory and Endosomal Machinery in Human Cytomegalovirus-Infected Cells versus Those in Uninfected Cells
Authors: Das Subhendu , Pellett Philip E.
Published: April 2011

Human cytomegalovirus (HCMV) induces extensive remodeling of the secretory apparatus to form the cytoplasmic virion assembly compartment (cVAC), where virion tegumentation and envelopment take place. We studied the structure of the cVAC by confocal microscopy to assess the three-dimensional distribution of proteins specifically associated with individual secretory organelles. In infected cells, early endosome antigen 1 (EEA1)-positive vesicles are concentrated at the center of the cVAC and, as previously seen, are distinct from structures visualized by markers for the endoplasmic reticulum, Golgi apparatus, and
trans
-Golgi network (TGN). EEA1-positive vesicles can be strongly associated with markers for recycling endosomes, to a lesser extent with markers associated with components of the endosomal sorting complex required for transport III (ESCRT III) machinery, and then with markers of late endosomes. In comparisons of uninfected and infected cells, we found significant changes in the structural associations and colocalization of organelle markers, as well as in net organelle volumes. These results provide new evidence that the HCMV-induced remodeling of the membrane transport apparatus involves much more than simple relocation and expansion of preexisting structures and are consistent with the hypothesis that the shift in identity of secretory organelles in HCMV-infected cells results in new functional profiles.
A Pre-Immediate-Early Role for Tegument ICP0 in the Proteasome-Dependent Entry of Herpes Simplex Virus
Authors: Delboy Mark G. , Nicola Anthony V.
Published: April 2011

Herpes simplex virus (HSV) entry requires host cell 26S proteasomal degradation activity at a postpenetration step. When expressed in the infected cell, the HSV immediate-early protein ICP0 has E3 ubiquitin ligase activity and interacts with the proteasome. The cell is first exposed to ICP0 during viral entry, since ICP0 is a component of the inner tegument layer of the virion. The function of tegument ICP0 is unknown. Deletion of ICP0 or mutations in the N-terminal RING finger domain of ICP0 results in the absence of ICP0 from the tegument. We show here that these mutations negatively influenced the targeting of incoming capsids to the nucleus. Inhibitors of the chymotrypsin-like activity of the proteasome the blocked entry of virions containing tegument ICP0, including ICP0 mutants that are defective in USP7 binding. However, ICP0-deficient virions were not blocked by proteasomal inhibitors and entered cells via a proteasome-independent mechanism. ICP0 appeared to play a postpenetration role in cells that supported either endocytosis or nonendosomal entry pathways for HSV. The results suggest that ICP0 mutant virions are defective upstream of viral gene expression at a pre-immediate-early step in infection. We propose that proteasome-mediated degradation of a virion or host protein is regulated by ICP0 to allow efficient delivery of entering HSV capsids to the nuclear periphery.
Common HIV-1 Peptide Variants Mediate Differential Binding of KIR3DL1 to HLA-Bw4 Molecules
Authors: Fadda Lena , O'Connor Geraldine M. , Kumar Swati , Piechocka-Trocha Alicja , Gardiner Clair M. , Carrington Mary , McVicar Daniel W. , Altfeld Marcus
Published: April 2011

Epidemiological studies have shown the protective effect of KIR3DL1/HLA-Bw4 genotypes in human immunodeficiency virus type 1 (HIV-1) infection; however, the functional correlates for the protective effect remain unknown. We investigated whether human leukocyte antigen (HLA)-Bw4-presented HIV-1 peptides could affect the interaction between the inhibitory natural killer (NK) cell receptor KIR3DL1 and its ligand HLA-Bw4. Distinct HIV-1 epitopes differentially modulated the binding of KIR3DL1 to HLA-Bw4. Furthermore, cytotoxic T lymphocyte (CTL) escape mutations within the immunodominant HLA-B57 (Bw4)-restricted Gag epitope TSTLQEQIGW abrogated KIR3DL1 binding to HLA-B57, suggesting that sensing of CTL escape variants by NK cells can contribute to the protective effect of the KIR3DL1/HLA-Bw4 compound genotype.
Disulfiram Reactivates Latent HIV-1 in a Bcl-2-Transduced Primary CD4
+
T Cell Model without Inducing Global T Cell Activation
Authors: Xing Sifei , Bullen Cynthia K. , Shroff Neeta S. , Shan Liang , Yang Hung-Chih , Manucci Jordyn L. , Bhat Shridhar , Zhang Hao , Margolick Joseph B. , Quinn Thomas C. , Margolis David M. , Siliciano Janet D. , Siliciano Robert F.
Published: April 2011

Highly active antiretroviral therapy (HAART) can reduce plasma HIV-1 levels to below the detection limit. However, due to the latent reservoir in resting CD4
+
cells, HAART is not curative. Elimination of this reservoir is critical to curing HIV-1 infection. Agents that reactivate latent HIV-1 through nonspecific T cell activation are toxic. Here we demonstrate in a primary CD4
+
T cell model that the FDA-approved drug disulfiram reactivates latent HIV-1 without global T cell activation. The extent to which disulfiram reactivates latent HIV-1 in patient cells is unclear, but the drug alone or in combination may be useful in future eradication strategies.
Broadly Cross-Neutralizing Antibodies in HIV-1 Patients with Undetectable Viremia
Authors: Medina-Ramírez M. , Sánchez-Merino V. , Sánchez-Palomino S. , Merino-Mansilla A. , Ferreira C. B. , Pérez I. , González N. , Alvarez A. , Alcocer-González J. M. , García F. , Gatell J. M. , Alcamí J. , Yuste E.
Published: April 2011

Several recent studies have identified HIV-infected patients able to produce a broad neutralizing response, and the detailed analyses of their sera have provided valuable information to improve future vaccine design. All these studies have excluded patients on antiretroviral treatment and with undetectable viral loads, who have an improved B cell profile compared to untreated patients. To better understand the induction of neutralizing antibodies in patients on antiretroviral treatment with undetectable viremia, we have screened 508 serum samples from 364 patients (173 treated and 191 untreated) for a broadly neutralizing antibody (bNAb) response using a new strategy based on the use of recombinant viruses. Sera able to neutralize a minipanel of 6 recombinant viruses, including envelopes from 5 different subtypes, were found in both groups. After IgG purification, we were able to confirm the presence of IgG-associated broadly neutralizing activity in 3.7% (7 of 191) of untreated patients with detectable viremia and 1.7% (3 of 174) of aviremic patients receiving antiretroviral treatment. We thus confirm the possibility of induction of a broad IgG-associated neutralizing response in patients on antiretroviral treatment, despite having undetectable viremia. This observation is in stark contrast to the data obtained from long-term nonprogressors, whose little neutralizing activity has been attributed to the low levels of viral replication.
Human Cytomegalovirus Induces the Activity and Expression of Acetyl-Coenzyme A Carboxylase, a Fatty Acid Biosynthetic Enzyme Whose Inhibition Attenuates Viral Replication
Authors: Spencer Cody M. , Schafer Xenia L. , Moorman Nathaniel J. , Munger Joshua
Published: April 2011

We have previously reported that human cytomegalovirus (HCMV) infection induces large-scale changes to host cell glycolytic, nucleic acid, and phospholipid metabolism. Here we explore the viral mechanisms involved in fatty acid biosynthetic activation. Our results indicate that HCMV targets ACC1, the rate-limiting enzyme of fatty acid biosynthesis, through multiple mechanisms. HCMV infection was found to activate ACC1 expression, increasing the abundance of both ACC1 mRNA and protein. Viral gene expression but not viral DNA replication was found to be necessary for HCMV-mediated induction of ACC1 levels. HCMV infection was also found to increase the proteolytic processing of SREBP-2, a transcription factor whose proteolytic cleavage is known to activate a variety of phospholipid metabolic genes. Processing of SREBP-2 was found to be dependent on mTOR activity; pharmaceutical inhibition of mTOR blocked HCMV-induced SREBP-2 processing and prevented the induction of fatty acid biosynthesis and ACC1 expression. Independent of the increases in ACC1 expression, HCMV infection also induced ACC1's enzymatic activity. Inhibition of ACC1 through either RNA interference (RNAi) or inhibitor treatment was found to attenuate HCMV replication, and HCMV replication was sensitive to ACC1 inhibition even at the later stages of infection, suggesting a late role for fatty acid biosynthesis during HCMV replication. These findings indicate that HCMV infection actively modulates numerous functional aspects of a key metabolic regulatory enzyme that is important for high-titer viral replication.
Verification of the mutual consistency and reliability of thermodynamic data of inorganic electrolytes
Authors: Balej Jan
Published: April 2011

The mutual consistency and reliability of the published thermodynamic quantities ΔfG°cr, ΔfG°aq, solubility ms, mean activity coefficient γs and water activity aw,s of the saturated solutions of alkali metal nitrites and selected bi-univalent compounds of Ni, Co, Zn, Cd, Pb, Cu, Mn and U at 25 °C have been checked and the obtained results discussed. The method has also been used for the calculation of lacking data ΔfG°cr of the following substances at 25 °C: CsNO2, Ni(NO3)2·6H2O, CoBr2·6H2O, CoI2·6H2O, Pb(ClO4)2·3H2O, Cu(NO3)2·6H2O and Pb(NO3)2.
Feasibility of using routinely collected inpatient data to monitor quality and inform choice: a case study using the UK inflammatory bowel disease audit
Authors: Roberts Stephen E , Williams John G , Cohen David R , Akbari Ashley , Groves Sam , Button Lori A
Published: April 2011

Objective

To assess the utility and cost of using routinely collected inpatient data for large-scale audit.

Design

Comparison of audit data items collected nationally in a designed audit of inflammatory bowel disease (UK IBD audit) with routinely collected inpatient data; surveys of audit sites to compare costs.

Setting

National Health Service hospitals across England, Wales and Northern Ireland that participated in the UK IBD audit.

Patients

Patients in the UK IBD audit.

Interventions

None.

Main outcome measures

Percentage agreement between designed audit data items collected for the UK IBD audit and routine inpatient data items; costs of conducting the designed UK IBD audit and the routine data audit.

Results

There were very high matching rates between the designed audit data and routine data for a small subset of basic important information collected in the UK IBD audit, including mortality; major surgery; dates of admission, surgery, discharge and death; principal diagnoses; and sociodemographic patient characteristics. There were lower matching rates for other items, including source of admission, primary reason for admission, most comorbidities, colonoscopy and sigmoidoscopy. Routine data did not cover most detailed information collected in the UK IBD audit. Using routine data was much less costly than collecting designed audit data.

Conclusion

Although valuable for large population-based studies, and less costly than designed data, routine inpatient data are not suitable for the evaluation of individual patient care within a designed audit.
Bone-marrow plasma cell burden correlates with IgM paraprotein concentration in Waldenström macroglobulinaemia
Authors: Pasricha Sant-Rayn , Juneja Surender K , Westerman David A , Came Neil A
Published: April 2011

Aims

Correlations between the marrow histopathology and clinical findings in Waldenström macroglobulinaemia (WM) are not well defined, and the pathophysiology of the plasma cell involvement is poorly understood. The authors used a standardised immunohistological approach to the enumeration of B lymphocyte and plasma cell compartments in the bone-marrow trephine to investigate associations between bone-marrow morphology and clinical/laboratory indices.

Methods

In 80 newly diagnosed, untreated cases of WM, the authors determined the degree and pattern of B lymphocyte (CD20+) and plasma cell (CD138+) infiltration in the bone-marrow trephine, as defined by immunohistochemistry, and correlated the disease in the marrow with components of the international scoring system for WM (age, serum IgM paraprotein level, haemoglobin, platelet count and β2microglobulin). Plasma cell clonality was assessed by κ and λ staining.

Results

Serum IgM paraprotein concentration was related to the plasma cell burden in the bone marrow (coefficient 0.231, p<0.005), but not the B lymphocytic infiltrate. Overall lymphoplasmacytic disease burden weakly correlated with severity of anaemia (coefficient 0.236, p=0.055). In 28/28 evaluated cases, plasma cells exhibited light chain restriction that was concordant with both that of the B lymphocytic infiltrate and paraprotein.

Conclusions

Bone-marrow features, in particular the degree of plasma cell infiltration, correlate with IgM paraprotein concentration at diagnosis in WM. The plasma cell compartment in this condition appears to be part of the neoplastic clone. In WM, specific evaluation of the plasma cell compartment in the bone marrow at baseline and following therapy may be valuable.
Microbial diversity of active layer and permafrost in an acidic wetland from the Canadian High Arctic
Authors: Wilhelm Roland C. , Niederberger Thomas D. , Greer Charles , Whyte Lyle G.
Published: April 2011

The abundance and structure of archaeal and bacterial communities from the active layer and the associated permafrost of a moderately acidic (pH < 5.0) High Arctic wetland (Axel Heiberg Island, Nunavut, Canada) were investigated using culture- and molecular-based methods. Aerobic viable cell counts from the active layer were ∼100-fold greater than those from the permafrost (2.5 × 105 CFU·(g soil dry mass)–1); however, a greater diversity of isolates were cultured from permafrost, as determined by 16S rRNA gene sequencing. Isolates from both layers demonstrated growth characteristics of a psychrotolerant, halotolerant, and acidotolerant community. Archaea constituted 0.1% of the total 16S rRNA gene copy number and, in the 16S rRNA gene clone library, predominantly (71% and 95%) consisted of Crenarchaeota related to Group I. 1b. In contrast, bacterial communities were diverse (Shannon’s diversity index, H = ∼4), with Acidobacteria constituting the largest division of active layer clones (30%) and Actinobacteria most abundant in permafrost (28%). Direct comparisons of 16S rRNA gene sequence data highlighted significant differences between the bacterial communities of each layer, with the greatest differences occurring within Actinobacteria. Comparisons of 16S rRNA gene sequences with those from other Arctic permafrost and cold-temperature wetlands revealed commonly occurring taxa within the phyla Chloroflexi, Acidobacteria, and Actinobacteria (families Intrasporangiaceae and Rubrobacteraceae).
The Fluorescence Theatre: a cost-effective device using theatre gels for fluorescent protein and dye screening
Authors: Heil John R. , Nordeste Ricardo F. , Charles Trevor C.
Published: April 2011

Here we report a simple cost-effective device for screening colonies on plates for expression of the monomeric red fluorescent protein mRFP1 and the fluorescent dye Nile red. This device can be built from any simple light source, in our case a Quebec Colony Counter, and cost-effective theatre gels. The device can be assembled in as little as 20 min, and it produces excellent results when screening a large number of colonies.
Isolation of transcripts overexpressed in the human pathogenTrichophyton rubrumgrown in lipid as carbon source
Authors: Maranhão Fernanda C.A. , Silveira Henrique C.S. , Rossi Antonio , Martinez-Rossi Nilce M.
Published: April 2011

Trichophyton rubrum is the most common etiological agent of human dermatophytosis. Despite the incidence and medical importance of this dermatophyte, little is known about the mechanisms of host invasion and pathogenicity. Host invasion depends on the adaptive cellular responses of the pathogen that allow it to penetrate the skin layers, which are mainly composed of proteins and lipids. In this study, we used suppression subtractive hybridization to identify transcripts overexpressed in T. rubrum cultured in lipid as carbon source. Among the subtractive cDNA clones isolated, 85 clones were positively screened by cDNA array dot blotting and were sequenced. The putative proteins encoded by the isolated transcripts showed similarities to fungal proteins involved in metabolism, signaling, defense, and virulence, such as the MDR/ABC transporter, glucan 1,3-β-glucosidase, chitin synthase B, copper-sulfate-regulated protein, and serine/threonine phosphatase (calcineurin A). These results provide the first molecular insight into the genes differentially expressed during the adaptation of T. rubrum to a lipidic carbon source.
NICKEL AND LEAD ZIRCONIUM TITANATE MULTI-LAYERED MAGNETOELECTRIC COMPOSITES PREPARED BY ELECTROLESS DEPOSITION
Authors: BI KE , WANG YIN-GANG , PAN DE-AN , WU WEI
Published: April 2011

Magnetoelectric (ME) nickel and lead zirconium titanate multi-layers with neither electrodes nor bonding layers was developed by electroless deposition. Scanning electron microscopy reveals that the Ni layer is in direct contact with the PZT layer without inter-layer not only in Ni /PZT/ Ni trilayer but also in Ni /PZT/ Ni /PZT/ Ni multi-layer. The in-plane parallel magnetostriction has been measured for electroless deposited Ni . The saturation magnetostriction is 32.6 × 10-6. When the total thickness of multi-layers is the same, the ME voltage coefficient α E,31 decreases with increasing the stacking periodicity. On condition that the thickness of each layer is the same, the ME voltage coefficient V E,31 of the Ni /PZT/ Ni /PZT/ Ni multi-layer is nearly twice higher than that of the Ni /PZT/ Ni tri-layer at the resonance frequency, which provides a new choice to obtain higher ME voltage coefficient.
ANISOTROPIC MAGNETORESISTANCE IN PEROVSKITE MANGANITES
Authors: EGILMEZ M. , CHOW K. H. , JUNG J. A.
Published: April 2011

We have summarized some important results of the anisotropic transport properties of the prototypical manganite La 1-x Ca x MnO 3 as well as a few others. The temperature dependence of anisotropic magnetoresistance in manganites exhibits a peak near the magnetic ordering temperature which differs dramatically from the ones in 3d ferromagnetic metals and alloys. Depending on the strain-driven orbital state, the AMR in manganites could be enhanced dramatically. The AMR in manganites is much larger than in ferromagnetic metals, where its magnitude is only of the order of a few percent. At low fields (below few kG) the intrinsic magnetocrystalline anisotropy becomes important and the dependence of resistance on angle changes to a more switching-like behavior. The magnitude of the switching is sufficiently large such that this phenomenon could be useful in spintronics for magnetic field sensing and nonvolatile memory applications. Moreover, at temperatures far below the metal insulator transition temperatures, the AMR in LCMO/LAO also flips and changes a sign in contrast to LCMO/STO films. Also sign flip takes place in charge and orbital ordered manganites exhibiting field induced ferromagnetism. Polycrystalline manganite samples also exhibit strong AMR. At lower temperatures the dependence of the AMR on temperature is dramatically different in polycrystalline samples than the epitaxial or single crystal samples. The behavior in the the polycrystalline samples could be governed by spin-polarized transport across the grain boundaries.
Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy: understanding weight loss and improvements in type 2 diabetes after bariatric surgery
Authors: Scott William R. , Batterham Rachel L.
Published: April 2011

Obesity increases the likelihood of diseases like type 2 diabetes (T2D), heart disease, and cancer, and is one of the most serious public health problems of this century. In contrast to ineffectual prevention strategies, lifestyle modifications, and pharmacological therapies, bariatric surgery is a very effective treatment for morbid obesity and also markedly improves associated comorbidities like T2D. However, weight loss and resolution of T2D after bariatric surgery is heterogeneous and specific to type of bariatric procedure performed. Conventional mechanisms like intestinal malabsorption and gastric restriction do not fully explain this, and potent changes in appetite and the enteroinsular axis, as a result of anatomical reorganization and altered hormonal, neuronal, and nutrient signaling, are the portended cause. Uniquely these signaling changes appear to override vigorous homeostatic defenses of stable body weight and compelling self-gratifying motivations to eat and to reverse defects in beta-cell function and insulin sensitivity. Here we review mechanisms of weight loss and T2D resolution after Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy bariatric surgery, two markedly different procedures with robust clinical outcomes.
Cation-independent mannose 6-phosphate receptor inhibitor (PXS25) inhibits fibrosis in human proximal tubular cells by inhibiting conversion of latent to active TGF-β1
Authors: Wong Muh Geot , Panchapakesan Usha , Qi Weier , Silva Diego G. , Chen Xin-Ming , Pollock Carol A.
Published: April 2011

Hyperglycemia and hypoxia have independent and convergent roles in the development of renal disease. Transforming growth factor-β1(TGF-β1) is a key cytokine promoting the production of extracellular matrix proteins. The cationic-independent mannose 6-phosphate receptor (CI-M6PR) is a membrane protein that binds M6P-containing proteins. A key role is to activate latent TGF-β1. PXS25, a novel CI-MPR inhibitor, has antifibrotic properties in skin fibroblasts, but its role in renal fibrosis is unclear. The aim was to study the role of PXS25 in matrix protein production under high glucose ± hypoxic conditions in human proximal tubule (HK-2) cells. HK-2 cells were exposed to high glucose (30 mM) ± 100 μM PXS25 in both normoxic (20% O2) and hypoxic (1% O2) conditions for 72 h. Cellular fibronectin, collagen IV, and matrix metalloproteinase-2 (MMP-2) and MMP-9 were assessed. Total and active TGF-β1were measured by ELISA. High glucose and hypoxia independently induced TGF-β1production. Active TGF-β1, but not total TGF-β1was reduced with concurrent PXS25 in the presence of high glucose, but not in hyperglycemia+hypoxia conditions. Hyperglycemia induced fibronectin and collagen IV production ( P < 0.05), as did hypoxia, but only hyperglycemia-induced increases in matrix proteins were suppressed by concurrent PXS25 exposure. High glucose induced MMP-2 and -9 in normoxic and hypoxic conditions, which was not modified in the presence of PXS25. High glucose and hypoxia can independently induce endogenous active TGF-β1production in human proximal tubular cells. PXS25 inhibits conversion of high glucose-induced release of active TGF-β1, only in the absence of hypoxia.
Mineralocorticoid receptor activation: a major contributor to salt-induced renal injury and hypertension in young rats
Authors: Kawarazaki Hiroo , Ando Katsuyuki , Fujita Megumi , Matsui Hiromitsu , Nagae Ai , Muraoka Kazuhiko , Kawarasaki Chiaki , Fujita Toshiro
Published: April 2011

Excessive salt intake is known to preferentially increase blood pressure (BP) and promote kidney damage in young, salt-sensitive hypertensive human and animal models. We have suggested that mineralocorticoid receptor (MR) activation plays a major role in kidney injury in young rats. BP and urinary protein were compared in young (3-wk-old) and adult (10-wk-old) uninephrectomized (UNx) Sprague-Dawley rats fed a high (8.0%)-salt diet for 4 wk. The effects of the MR blocker eplerenone on BP and renal injury were examined in the high-salt diet-fed young UNx rats. Renal expression of renin-angiotensin-aldosterone (RAA) system components and of inflammatory and oxidative stress markers was also measured. The effects of the angiotensin receptor blocker olmesartan with or without low-dose aldosterone infusion, the aldosterone synthase inhibitor FAD286, and the antioxidant tempol were also studied. Excessive salt intake induced greater hypertension and proteinuria in young rats than in adult rats. The kidneys of young salt-loaded rats showed marked histological injury, overexpression of RAA system components, and an increase in inflammatory and oxidative stress markers. These changes were markedly ameliorated by eplerenone treatment. Olmesartan also ameliorated salt-induced renal injury but failed to do so when combined with low-dose aldosterone infusion. FAD286 and tempol also markedly reduced urinary protein. UNx rats exposed to excessive salt at a young age showed severe hypertension and renal injury, likely primarily due to MR activation and secondarily due to angiotensin receptor activation, which may be mediated by inflammation and oxidative stress.
NMDA receptor activation enhances inhibitory GABAergic transmission onto hippocampal pyramidal neurons via presynaptic and postsynaptic mechanisms
Authors: Xue Jiu-Gang , Masuoka Takayoshi , Gong Xian-Di , Chen Ken-Shiung , Yanagawa Yuchio , Law S. K. Alex , Konishi Shiro
Published: April 2011

N-methyl-d-aspartate (NMDA) receptors (NMDARs) are implicated in synaptic plasticity and modulation of glutamatergic excitatory transmission. Effect of NMDAR activation on inhibitory GABAergic transmission remains largely unknown. Here, we report that a brief application of NMDA could induce two distinct actions in CA1 pyramidal neurons in mouse hippocampal slices: 1) an inward current attributed to activation of postsynaptic NMDARs; and 2) fast phasic synaptic currents, namely spontaneous inhibitory postsynaptic currents (sIPSCs), mediated by GABAA receptors in pyramidal neurons. The mean amplitude of sIPSCs was also increased by NMDA. This profound increase in the sIPSC frequency and amplitude was markedly suppressed by the sodium channel blocker TTX, whereas the frequency and mean amplitude of miniature IPSCs were not significantly affected by NMDA, suggesting that NMDA elicits repetitive firing in GABAergic interneurons, thereby leading to GABA release from multiple synaptic sites of single GABAergic axons. We found that the NMDAR open-channel blocker MK-801 injected into recorded pyramidal neurons suppressed the NMDA-induced increase of sIPSCs, which raises the possibility that the firing of interneurons may not be the sole factor and certain retrograde messengers may also be involved in the NMDA-mediated enhancement of GABAergic transmission. Our results from pharmacological tests suggest that the nitric oxide signaling pathway is mobilized by NMDAR activation in CA1 pyramidal neurons, which in turn retrogradely facilitates GABA release from the presynaptic terminals. Thus NMDARs at glutamatergic synapses on both CA1 pyramidal neurons and interneurons appear to exert feedback and feedforward inhibition for determining the spike timing of the hippocampal microcircuit.
Sparse coding in striate and extrastriate visual cortex
Authors: Willmore Ben D. B. , Mazer James A. , Gallant Jack L.
Published: April 2011

Theoretical studies of mammalian cortex argue that efficient neural codes should be sparse. However, theoretical and experimental studies have used different definitions of the term “sparse” leading to three assumptions about the nature of sparse codes. First, codes that have high lifetime sparseness require few action potentials. Second, lifetime-sparse codes are also population-sparse. Third, neural codes are optimized to maximize lifetime sparseness. Here, we examine these assumptions in detail and test their validity in primate visual cortex. We show that lifetime and population sparseness are not necessarily correlated and that a code may have high lifetime sparseness regardless of how many action potentials it uses. We measure lifetime sparseness during presentation of natural images in three areas of macaque visual cortex, V1, V2, and V4. We find that lifetime sparseness does not increase across the visual hierarchy. This suggests that the neural code is not simply optimized to maximize lifetime sparseness. We also find that firing rates during a challenging visual task are higher than theoretical values based on metabolic limits and that responses in V1, V2, and V4 are well-described by exponential distributions. These findings are consistent with the hypothesis that neurons are optimized to maximize information transmission subject to metabolic constraints on mean firing rate.
Ataxia telangiectasia: a “disease model” to understand the cerebellar control of vestibular reflexes
Authors: Shaikh Aasef G. , Marti Sarah , Tarnutzer Alexander A. , Palla Antonella , Crawford Thomas O. , Straumann Dominik , Carey John P. , Nguyen Kimanh D. , Zee David S.
Published: April 2011

Experimental animal models have suggested that the modulation of the amplitude and direction of vestibular reflexes are important functions of the vestibulocerebellum and contribute to the control of gaze and balance. These critical vestibular functions have been infrequently quantified in human cerebellar disease. In 13 subjects with ataxia telangiectasia (A-T), a disease associated with profound cerebellar cortical degeneration, we found abnormalities of several key vestibular reflexes. The vestibuloocular reflex (VOR) was measured by eye movement responses to changes in head rotation. The vestibulocollic reflex (VCR) was assessed with cervical vestibular-evoked myogenic potentials (cVEMPs), in which auditory clicks led to electromyographic activity of the sternocleidomastoid muscle. The VOR gain (eye velocity/head velocity) was increased in all subjects with A-T. An increase of the VCR, paralleling that of the VOR, was indirectly suggested by an increase in cVEMP amplitude. In A-T subjects, alignment of the axis of eye rotation was not with that of head rotation. Subjects with A-T thus manifested VOR cross-coupling, abnormal eye movements directed along axes orthogonal to that of head rotation. Degeneration of the Purkinje neurons in the vestibulocerebellum probably underlie these deficits. This study offers insights into how the vestibulocerebellum functions in healthy humans. It may also be of value to the design of treatment trials as a surrogate biomarker of cerebellar function that does not require controlling for motivation or occult changes in motor strategy on the part of experimental subjects.
Skin Needling to Enhance Depigmenting Serum Penetration in the Treatment of Melasma
Authors: Fabbrocini G. , De Vita V. , Fardella N. , Pastore F. , Annunziata M. C. , Mauriello M. C. , Monfrecola A. , Cameli N.
Published: April 2011

Melasma is a common hypermelanotic disorder affecting the facial area which has a considerable psychological impact on the patient. Managing melasma is a difficult challenge that requires long-term treatment with a number of topical agents, such as rucinol and sophora-alpha. Aims. We aim to compare the combined treatment of skin needling and depigmenting serum with that using depigmenting serum alone in the treatment of melasma, in order to evaluate the use of microneedles as a means to enhance the drug’s transdermal penetration. Methods. Twenty patients were treated with combined skin needling and depigmenting serum on one side of the face and with depigmenting serum alone on the other side. The outcome was evaluated periodically for up to two months using the Melasma Area Severity Index score and the Spectrocolorimeter X-Rite 968. Results. The side with combined treatment (skin needling + depigmenting serum) presented a statistically significant reduction in MASI score and luminosity index (L) levels compared to the side treated with depigmenting serum alone, and clinical symptoms were significantly improved. Conclusions. Our study suggests the potential use of combining skin needling with rucinol and sophora-alpha compounds to achieve better results in melasma treatment compared to rucinol and sophora-alpha alone.
Short-Time Intermittent Preexposure of Living Human Donors to Hyperoxia Improves Renal Function in Early Posttransplant Period: A Double-Blind Randomized Clinical Trial
Authors: Montazeri Kamran , Vakily Mohammadali , Honarmand Azim , Kashefi Parviz , Safavi Mohammadreza , Taheri Shahram , Rasoulian Bahram
Published: April 2011

The purpose of this human study was to investigate the effect of oxygen pretreatment in living kidney donors on early renal function of transplanted kidney. Sixty living kidney donor individuals were assigned to receive either 8–10 L/min oxygen (Group I) by a non-rebreather mask with reservoir bag intermittently for one hour at four times (20, 16, 12, and 1 hours before transplantation) or air (Group II). After kidney transplantation, urine output, blood urea nitrogen (BUN), serum creatinine, need to additional diuretics (NTADs) in the first 24 hours after transplantation, delayed graft function (DGF), the creatinine clearance (CrCL) on 10th day, and duration of hospital stay from the first posttransplant day till normalization of renal function was recorded and compared in two groups. Mean CrCL in posttransplant day 10, NTAD after 24 hours of transplantation, and urine output during 6 hours after operation were significantly better in Group I compared with Group II (). Also, DGF during the first week after operation and duration of hospital stay was less in Group I compared with Group II. Intermittent exposure of human living kidney donor to hyperoxic environment may improve renal function following kidney transplantation.
Electrospun Collagen: A Tissue Engineering Scaffold with Unique Functional Properties in a Wide Variety of Applications
Authors: Jha Balendu Shekhar , Ayres Chantal E. , Bowman James R. , Telemeco Todd A. , Sell Scott A. , Bowlin Gary L. , Simpson David G.
Published: April 2011

Type I collagen and gelatin, a derivative of Type I collagen that has been denatured, can each be electrospun into tissue engineering scaffolds composed of nano- to micron-scale diameter fibers. We characterize the biological activity of these materials in a variety of tissue engineering applications, including endothelial cell-scaffold interactions, the onset of bone mineralization, dermal reconstruction, and the fabrication of skeletal muscle prosthetics. Electrospun collgen (esC) consistently exhibited unique biological properties in these functional assays. Even though gelatin can be spun into fibrillar scaffolds that resemble scaffolds of esC, our assays reveal that electrospun gelatin (esG) lacks intact α chains and is composed of proinflammatory peptide fragments. In contrast, esC retains intact α chains and is enriched in the α 2(I) subunit. The distinct fundamental properties of the constituent subunits that make up esC and esG appear to define their biological and functional properties.
A Stochastic Analysis of Hard Disk Drives
Authors: Cady Field , Zhuang Yi , Harchol-Balter Mor
Published: April 2011

We provide a stochastic analysis of hard disk performance, including a closed
form solution for the average access time of a memory request. The model we use
covers a wide range of types and applications of disks, and in particular it captures
modern innovations like zone bit recording. The derivation is based on an analytical
technique we call “shuffling”, which greatly simplifies the analysis relative to
previous work and provides a simple, easy-to-use formula for the average access
time.
Our analysis can predict performance of single disks for a wide range of disk
types and workloads. Furthermore, it can predict the performance benefits of several
optimizations, including short stroking and mirroring, which are common in
disk arrays.
Clinical Characteristics of Patients with Isolated Calf Vein Thrombosis in a Large Teaching Hospital
Authors: Brian Santin , Fries Richard B. , Bhagwan Satiani
Published: April 2011

Objective. To identify the clinical characteristics of a patient population newly diagnosed with acute isolated calf deep venous thrombosis (ICDVT) by duplex ultrasound scan (DUS).Methods. A retrospective review of the records of 100 consecutive patients diagnosed with ICDVT by DUS was conducted.Results. Patients (59% male) were predominantly Caucasian (86%) and inpatients (69%) with an average age of 53 years. The most frequent risk factors were malignancy (22%), immobility (18%), and previous DVT (13%). Thrombus was present in named tibial veins in 58% and muscular branches in 42%. The peroneal vein was most frequently involved (39/117, 33%) followed by the gastrocnemius veins (29/117, 22%) and muscular calf tributaries (14%).Conclusions. Our patient population with ICDVT was predominantly symptomatic, in-patient cohort with a high incidence of risk factors such as malignancy, immobility, previous DVT, trauma, and postoperative status. Partial or complete resolution was documented by DUS in 53%.
Mechanisms of Cellular Uptake of Cell-Penetrating Peptides
Authors: Madani Fatemeh , Lindberg Staffan , Langel Ülo , Futaki Shiroh , Gräslund Astrid
Published: April 2011

Recently, much attention has been given to the problem of drug delivery through the cell-membrane in order to treat and manage several diseases. The discovery of cell penetrating peptides (CPPs) represents a major breakthrough for the transport of large-cargo molecules that may be useful in clinical applications. CPPs are rich in basic amino acids such as arginine and lysine and are able to translocate over membranes and gain access to the cell interior. They can deliver large-cargo molecules, such as oligonucleotides, into cells. Endocytosis and direct penetration have been suggested as the two major uptake mechanisms, a subject still under debate. Unresolved questions include the detailed molecular uptake mechanism(s), reasons for cell toxicity, and the delivery efficiency of CPPs for different cargoes. Here, we give a review focused on uptake mechanisms used by CPPs for membrane translocation and certain experimental factors that affect the mechanism(s).
Pyrazolo Derivatives as Potent Adenosine Receptor Antagonists: An Overview on the Structure-Activity Relationships
Authors: Cheong Siew Lee , Venkatesan Gopalakrishnan , Paira Priyankar , Jothibasu Ramasamy , Mandel Alexander Laurence , Federico Stephanie , Spalluto Giampiero , Pastorin Giorgia
Published: April 2011

In the past few decades, medicinal chemistry research towards potent and selective antagonists of human adenosine receptors (namely, A1, A2A, A2B, and A3) has been evolving rapidly. These antagonists are deemed therapeutically beneficial in several pathological conditions including neurological and renal disorders, cancer, inflammation, and glaucoma. Up to this point, many classes of compounds have been successfully synthesized and identified as potent human adenosine receptor antagonists. In this paper, an overview of the structure-activity relationship (SAR) profiles of promising nonxanthine pyrazolo derivatives is reported and discussed. We have emphasized the SAR for some representative structures such as pyrazolo-[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidines; pyrazolo-[3,4-c] or -[4,3-c]quinolines; pyrazolo-[4,3-d]pyrimidinones; pyrazolo-[3,4-d]pyrimidines and pyrazolo-[1,5-a]pyridines. This overview not only clarifies the structural requirements deemed essential for affinity towards individual adenosine receptor subtypes, but it also sheds light on the rational design and optimization of existing structural templates to allow us to conceive new, more potent adenosine receptor antagonists.
Two Immigrants with Tuberculosis of the Ear, Nose, and Throat Region with Skull Base and Cranial Nerve Involvement
Authors: Richardus Renate A. , Jansen Jeroen C. , Steens Stefan C. A. , Arend Sandra M.
Published: April 2011

We report two immigrants with tuberculosis of the skull base and a review of the literature. A Somalian man presented with bilateral otitis media, hearing loss, and facial and abducens palsy. Imaging showed involvement of both mastoid and petrous bones, extending via the skull base to the nasopharynx, suggesting tuberculosis which was confirmed by characteristic histology and positive auramine staining, while Ziehl-Neelsen staining and PCR were negative. A Sudanese man presented with torticollis and deviation of the uvula due to paresis of N. IX and XI. Imaging showed a retropharyngeal abscess and lysis of the clivus. Histology, acid-fast staining, and PCR were negative. Both patients had a positive Quantiferon TB Gold in-tube result and improved rapidly after empiric treatment for tuberculosis. Cultures eventually yieldedM. tuberculosis. These unusual cases exemplify the many faces of tuberculosis and the importance to include tuberculosis in the differential diagnosis of unexplained problems.
Erk in Kidney Diseases
Authors: Feliers Denis , Kasinath Balakuntalam S.
Published: April 2011

Acute or chronic kidney injury results from various insults and pathological conditions, and is accompanied by activation of compensatory repair mechanisms. Both insults and repair mechanisms are initiated by circulating factors, whose cellular effects are mediated by activation selective signal transduction pathways. Two main signal transduction pathways are activated during these processes, the phosphatidylinositol 3′kinase (PI-3K)/mammalian target of rapamycin (mTOR) and the mitogen-activated protein kinase (MAPK) cascades. This review will focus on the latter, and more specifically on the role of extracellular signal-regulated kinase (ERK) cascade in kidney injury and repair.
Metabolism, Genomics, and DNA Repair in the Mouse Aging Liver
Authors: Lebel Michel , de Souza-Pinto Nadja C. , Bohr Vilhelm A.
Published: April 2011

The liver plays a pivotal role in the metabolism of nutrients, drugs, hormones, and metabolic waste products, thereby maintaining body homeostasis. The liver undergoes substantial changes in structure and function within old age. Such changes are associated with significant impairment of many hepatic metabolic and detoxification activities, with implications for systemic aging and age-related disease. It has become clear, using rodent models as biological tools, that genetic instability in the form of gross DNA rearrangements or point mutations accumulate in the liver with age. DNA lesions, such as oxidized bases or persistent breaks, increase with age and correlate well with the presence of senescent hepatocytes. The level of DNA damage and/or mutation can be affected by changes in carcinogen activation, decreased ability to repair DNA, or a combination of these factors. This paper covers some of the DNA repair pathways affecting liver homeostasis with age using rodents as model systems.