bluuebunny/crossref_metadata_2025 huggingface dataset:
Using Damage Delocalization to Model Localization Phenomena in Bammann-Chiesa-Johnson Metals
Authors: Enakoutsa Koffi , Ahad Fazle R. , Solanki Kiran N. , Tjiptowidjojo Yustianto , Bammann Douglas J.
Published: September 2012

The Bammann, Chiesa, and Johnson (BCJ) material model predicts unlimited localization of strain and damage, resulting in a zero dissipation energy at failure. This difficulty resolves when the BCJ model is modified to incorporate a nonlocal evolution equation for the damage, as proposed by Pijaudier-Cabot and Bazant (1987, “Nonlocal Damage Theory,” ASCE J. Eng. Mech., 113, pp. 1512–1533.). In this work, we theoretically assess the ability of such a modified BCJ model to prevent unlimited localization of strain and damage. To that end, we investigate two localization problems in nonlocal BCJ metals: appearance of a spatial discontinuity of the velocity gradient in any finite, inhomogeneous body, and localization of the dissipation energy into finite bands. We show that in spite of the softening arising from the damage, no spatial discontinuity occurs in the velocity gradient. Also, we find that the dissipation energy is continuously distributed in nonlocal BCJ metals and therefore cannot localize into zones of vanishing volume. As a result, the appearance of any vanishing width adiabatic shear band is impossible in a nonlocal BCJ metal. Finally, we study the finite element (FE) solution of shear banding in a rectangular plate, deformed in plane strain tension and containing an imperfection, thereby illustrating the effects of imperfections and finite size on the localization of strain and damage.
Rad51 Is an Accessory Factor for Dmc1-Mediated Joint Molecule Formation During Meiosis
Authors: Cloud Veronica , Chan Yuen-Ling , Grubb Jennifer , Budke Brian , Bishop Douglas K.
Published: September 2012

Relegated to Accessory

Critical aspects of meiosis, the specialized cell division that makes haploid gametes and spores, evolved from those of the normal mitotic cell cycle. In mitosis, the RecA homolog Rad51 is required for the homology-mediated repair of DNA double-strand breaks (DSBs). DSBs play a critical role in chromosome segregation in meiosis.

Cloud
et al.

(p.
1222
) show that the strand-exchange activity of Rad51 is not required in meiosis. Rather, a second meiosis-specific RecA homolog, Dmc1, carries out the homology search and strand-exchange function that Rad51 performs in mitosis, with Rad51 relegated to enhancing the strand-exchange activity of Dmc1. It appears after the gene duplication event that created Dmc1 from an ancestral Rad51. Rad51 took on an accessory role to Dmc1 in meiosis.
Massive Trials to Test Inflammation Hypothesis
Authors: Couzin-Frankel Jennifer
Published: September 2012

The idea that inflammation is deeply intertwined with cardiovascular disease is being put to the test in a pair of massive clinical trials.
Development of an Inhalational Bacillus anthracis Exposure Therapeutic Model in Cynomolgus Macaques
Authors: Henning Lisa N. , Comer Jason E. , Stark Gregory V. , Ray Bryan D. , Tordoff Kevin P. , Knostman Katherine A. B. , Meister Gabriel T.
Published: September 2012

Appropriate animal models are required to test medical countermeasures to bioterrorist threats. To that end, we characterized a nonhuman primate (NHP) inhalational anthrax therapeutic model for use in testing anthrax therapeutic medical countermeasures according to the U.S. Food and Drug Administration Animal Rule. A clinical profile was recorded for each NHP exposed to a lethal dose ofBacillus anthracisAmes spores. Specific diagnostic parameters were detected relatively early in disease progression, i.e., by blood culture (∼37 h postchallenge) and the presence of circulating protective antigen (PA) detected by electrochemiluminescence (ECL) ∼38 h postchallenge, whereas nonspecific clinical signs of disease, i.e., changes in body temperature, hematologic parameters (ca. 52 to 66 h), and clinical observations, were delayed. To determine whether the presentation of antigenemia (PA in the blood) was an appropriate trigger for therapeutic intervention, a monoclonal antibody specific for PA was administered to 12 additional animals after the circulating levels of PA were detected by ECL. Seventy-five percent of the monoclonal antibody-treated animals survived compared to 17% of the untreated controls, suggesting that intervention at the onset of antigenemia is an appropriate treatment trigger for this model. Moreover, the onset of antigenemia correlated with bacteremia, and NHPs were treated in a therapeutic manner. Interestingly, brain lesions were observed by histopathology in the treated nonsurviving animals, whereas this observation was absent from 90% of the nonsurviving untreated animals. Our results support the use of the cynomolgus macaque as an appropriate therapeutic animal model for assessing the efficacy of medical countermeasures developed against anthrax when administered after a confirmation of infection.
Antibody Responses to Individual Bordetella pertussis Fimbrial Antigen Fim2 or Fim3 following Immunization with the Five-Component Acellular Pertussis Vaccine or to Pertussis Disease
Authors: Alexander Frances , Matheson Mary , Fry Norman K. , Labram Briony , Gorringe Andrew R.
Published: September 2012

Bordetella pertussisexpresses two serologically distinct fimbriae (Fim2 and Fim3) which are included in the Sanofi Pasteur 5-component acellular pertussis vaccine, and antibody responses to these antigens have been shown to be associated with protection. Studies to date have assessed the IgG response to this vaccine using a copurified mixture of Fim2 and Fim3, and the response to the individual antigens has not been characterized. We have purified separate Fim2 and Fim3 from strains that express either Fim2 or Fim3 and have used these antigens in an enzyme-linked immunosorbent assay (ELISA) to quantify IgG responses following immunization with 5-component acellular pertussis vaccine in 15-month-old, 4- to 6-year-old, and 11- to 18-year-old subjects. All individuals showed increases in Fim2 and Fim3 IgG concentrations following immunization, with 3-fold-greater Fim2 than Fim3 IgG concentrations seen in the younger two age groups. Fim2 IgG concentrations were 1.5-fold greater than Fim3 IgG concentrations in the 11- to 18-year-olds. We have also compared Fim2 and Fim3 IgG concentrations in individuals with prolonged cough who were diagnosed as having recent pertussis using a pertussis toxin (Ptx) IgG ELISA with individuals with prolonged cough but without elevated Ptx IgG concentrations. Individuals with evidence of recent pertussis had greater Fim3 IgG concentrations, consistent with the predominant serotype of isolates obtained in the United Kingdom. However, a surprising number of individuals had moderate Fim2 IgG concentrations despite very few isolates of that serotype obtained in the sampling period.
Ten Years of External Quality Assessment of Human Immunodeficiency Virus Type 1 RNA Quantification
Authors: Senechal Brigitte , James Vivienne L. A.
Published: September 2012

Viral load testing is an essential parameter in guiding antiretroviral therapy for individuals infected with human immunodeficiency virus type 1 (HIV-1). An external quality assessment scheme for the molecular quantification of HIV-1 RNA was introduced by the United Kingdom National External Quality Assessment Service for Microbiology in 2000. Specimen pairs of freeze-dried plasma were distributed to a median of 141 participants three times a year. The aim of this study was to analyze the quantification of HIV-1 RNA results between 2000 and 2010. Overall variability, measured by the standard deviations of all viral load results for each specimen, was below 0.5 log copy/ml (
n
= 48). When we compared assay results, the medians of the viral load by assay were within a range of 0.25 to 1.08 log copies/ml, with the lowest median values being consistently reported with the Siemens branched-chain DNA assay. The spread of participant results and, hence, differences between assay medians were greater when quantifying non-B subtypes. Laboratories were scored on the proximity of their reported log difference for the specimen pair to the median log difference reported by all laboratories. The overall level of performance with the HIV-1 RNA specimens over the past 10 years has been consistently good, with more than 90% of the participants reporting in the accepted range (median difference, ±0.5 log unit). Future distributions may result in tightening the acceptance levels of quantification and the use of more challenging specimens, including a variety of subtypes, with developments focusing on maintaining the clinical relevance and educational value of the scheme.
Distribution and Phosphorylation of the Basic Protein P6.9 of Autographa californica Nucleopolyhedrovirus
Authors: Liu XiaoXiao , Zhao Haizhou , Fang Zhixin , Yuan Meijin , Yang Kai , Pang Yi
Published: September 2012

A protamine-like protein named P6.9 is thought to play a role in the condensation of genomes of the baculovirus
Autographa californica
multiple nucleopolyhedrovirus (AcMNPV) during an infection. Previous studies have shown that P6.9 is phosphorylated immediately upon synthesis and dephosphorylated upon the entry of the P6.9-DNA complex into the capsid. Here, we investigate the dynamic distribution of P6.9 in AcMNPV-infected
Spodoptera frugiperda
cells using an influenza virus hemagglutinin (HA)-tagged P6.9. Although a portion of P6.9-HA localized to the virogenic stroma, which is the center of viral DNA replication, transcription, and nucleocapsid assembly, the majority of P6.9-HA was distributed near the inner nuclear membrane throughout the course of infection. Antiserum against P6.9 detected specific phosphorylated forms of P6.9 at the edge of, but not within, the electron-dense matte regions of the virogenic stroma. Further analysis using immunoblotting revealed that at least 11 different phosphorylated forms of P6.9, as well as dephosphorylated P6.9, were present in association with occlusion-derived virions, although only dephosphorylated P6.9 was associated with budded virions.
Zinc Finger Antiviral Protein Inhibits Murine Gammaherpesvirus 68 M2 Expression and Regulates Viral Latency in Cultured Cells
Authors: Xuan Yifang , Liu Ling , Shen Sheng , Deng Hongyu , Gao Guangxia
Published: September 2012

Zinc finger antiviral protein (ZAP) is a host factor that specifically inhibits the replication of certain viruses by binding to specific viral mRNAs and repressing mRNA expression. Here we report that ZAP inhibits expression of murine gammaherpesvirus 68 (MHV-68) M2, which plays important roles in establishment and maintenance of viral latency. Downregulation of endogenous ZAP in cells harboring latent MHV-68 promoted lytic replication of the virus. These results suggest that ZAP inhibits M2 expression and regulates the maintenance of MHV-68 latency.
Structure of Crimean-Congo Hemorrhagic Fever Virus Nucleoprotein: Superhelical Homo-Oligomers and the Role of Caspase-3 Cleavage
Authors: Wang Yi , Dutta Sujit , Karlberg Helen , Devignot Stéphanie , Weber Friedemann , Hao Quan , Tan Yee Joo , Mirazimi Ali , Kotaka Masayo
Published: September 2012

Crimean-Congo hemorrhagic fever, a severe hemorrhagic disease found throughout Africa, Europe, and Asia, is caused by the tick-borne Crimean-Congo hemorrhagic fever virus (CCHFV). CCHFV is a negative-sense single-stranded RNA (ssRNA) virus belonging to theNairovirusgenus of theBunyaviridaefamily. Its genome of three single-stranded RNA segments is encapsidated by the nucleocapsid protein (CCHFV N) to form the ribonucleoprotein complex. This ribonucleoprotein complex is required during replication and transcription of the viral genomic RNA. Here, we present the crystal structures of the CCHFV N in two distinct forms, an oligomeric form comprised of double antiparallel superhelices and a monomeric form. The head-to-tail interaction of the stalk region of one CCHFV N subunit with the base of the globular body of the adjacent subunit stabilizes the helical organization of the oligomeric form of CCHFV N. It also masks the conserved caspase-3 cleavage site present at the tip of the stalk region from host cell caspase-3 interaction and cleavage. By incubation with primer-length ssRNAs, we also obtained the crystal structure of CCHFV N in its monomeric form, which is similar to a recently published structure. The conformational change of CCHFV N upon deoligomerization results in the exposure of the caspase-3 cleavage site and subjects CCHFV N to caspase-3 cleavage. Mutations of this cleavage site inhibit cleavage by caspase-3 and result in enhanced viral polymerase activity. Thus, cleavage of CCHFV N by host cell caspase-3 appears to be crucial for controlling viral RNA synthesis and represents an important host defense mechanism against CCHFV infection.
In Vitro
Quantification of the Relative Packaging Efficiencies of Single-Stranded RNA Molecules by Viral Capsid Protein
Authors: Comas-Garcia Mauricio , Cadena-Nava Ruben D. , Rao A. L. N. , Knobler Charles M. , Gelbart William M.
Published: September 2012

While most T=3 single-stranded RNA (ssRNA) viruses package
in vivo
about 3,000 nucleotides (nt),
in vitro
experiments have demonstrated that a broad range of RNA lengths can be packaged. Under the right solution conditions, for example, cowpea chlorotic mottle viru
s
(CCMV) capsid protein (CP) has been shown to package RNA molecules whose lengths range from 100 to 10,000 nt. Furthermore, in each case it can package the RNA completely, as long as the mass ratio of CP to nucleic acid in the assembly mixture is 6:1 or higher. Yet the packaging efficiencies of the RNAs can differ widely, as we demonstrate by measurements in which two RNAs compete head-to-head for a limited amount of CP. We show that the relative efficiency depends nonmonotonically on the RNA length, with 3,200 nt being optimum for packaging by the T=3 capsids preferred by CCMV CP. When two RNAs of the same length—and hence the same charge—compete for CP, differences in packaging efficiency are necessarily due to differences in their secondary structures and/or three-dimensional (3D) sizes. For example, the heterologous RNA1 of brome mosaic virus (BMV) is packaged three times more efficiently by CCMV CP than is RNA1 of CCMV, even though the two RNAs have virtually identical lengths. Finally, we show that in an assembly mixture at neutral pH, CP binds reversibly to the RNA and there is a reversible equilibrium between all the various RNA/CP complexes. At acidic pH, excess protein unbinds from RNA/CP complexes and nucleocapsids form irreversibly.
Persistence of Epstein-Barr Virus in Self-Reactive Memory B Cells
Authors: Tracy Sean I. , Kakalacheva Kristina , Lünemann Jan D. , Luzuriaga Katherine , Middeldorp Jaap , Thorley-Lawson David A.
Published: September 2012

Epstein-Barr virus infection has been epidemiologically associated with the development of multiple autoimmune diseases, particularly systemic lupus erythematosus and multiple sclerosis. Currently, there is no known mechanism that can account for these associations. The germinal-center (GC) model of EBV infection and persistence proposes that EBV gains access to the memory B cell compartment via GC reactions by driving infected cells to differentiate using the virus-encoded LMP1 and LMP2a proteins, which act as functional homologues of CD40 and the B cell receptor, respectively. The ability of LMP2a, when expressed in mice, to allow escape of autoreactive B cells suggests that it could perform a similar role in infected GC B cells, permitting the survival of potentially pathogenic autoreactive B cells. To test this hypothesis, we cloned and expressed antibodies from EBV
+
and EBV
−
memory B cells present during acute infection and profiled their self- and polyreactivity. We find that EBV does persist within self- and polyreactive B cells but find no evidence that it favors the survival of pathogenic autoreactive B cells. On the contrary, EBV
+
memory B cells express lower levels of self-reactive and especially polyreactive antibodies than their uninfected counterparts do. Our work suggests that EBV has only a modest effect on the GC process, which allows it to access and persist within a subtly unique niche of the memory compartment characterized by relatively low levels of self- and polyreactivity. We suggest that this might reflect an active process where EBV and its human host have coevolved so as to minimize the virus's potential to contribute to autoimmune disease.
Deletion of the Herpes Simplex Virus 1 U
L
49 Gene Results in mRNA and Protein Translation Defects That Are Complemented by Secondary Mutations in U
L
41
Authors: Mbong Ekaette F. , Woodley Lucille , Dunkerley Eric , Schrimpf Jane E. , Morrison Lynda A. , Duffy Carol
Published: September 2012

Herpes simplex virus 1 (HSV-1) virions, like those of all herpesviruses, contain a protein layer termed the tegument localized between the capsid and the envelope. VP22, encoded by the U
L
49 gene, is one of the most abundant tegument proteins in HSV-1 virions. Studies with a U
L
49-null mutant showed that the absence of VP22 resulted in decreased protein synthesis at late times in infection. VP22 is known to form a tripartite complex with VP16 and vhs through direct interactions with VP16. Given that U
L
49-null mutants have been shown to acquire spontaneous secondary mutations in the U
L
41 gene, which encodes vhs, we hypothesized that VP22 and vhs may play antagonistic roles during HSV-1 infections. In the present study, we show that the protein synthesis defect observed in U
L
49-null virus infections was rescued by a secondary, compensatory frameshift mutation in U
L
41. A double mutant bearing a deletion of U
L
49 and a point mutation in vhs previously shown to specifically abrogate vhs's RNase activity also resulted in a rescue of protein synthesis. To determine whether the U
L
49
−
protein synthesis defect, and the rescue by secondary mutations in vhs, occurred at the mRNA and/or translational levels, quantitative reverse transcriptase PCR (qRT-PCR) and polysome analyses were performed. We found that the absence of VP22 caused a small decrease in mRNA levels as well as a defect in polysome assembly that was independent of mRNA abundance. Both defects were complemented by the secondary mutations in vhs, indicating functional interplay between VP22 and vhs in both accumulation and translation of viral mRNAs.
Pathways to a rising caesarean section rate: a population-based cohort study
Authors: Roberts Christine L , Algert Charles S , Ford Jane B , Todd Angela L , Morris Jonathan M
Published: September 2012

Objectives

To determine whether the obstetric pathways leading to caesarean section changed from one decade to another. We also aimed to explore how much of the increase in caesarean rate could be attributed to maternal and pregnancy factors including a shift towards delivery in private hospitals.

Design

Population-based record linkage cohort study.

Setting

New South Wales, Australia.

Participants

For annual rates, all women giving birth in NSW during 1994 to 2009 were included. To examine changes in obstetric pathways two cohorts were compared: all women with a first-birth during either 1994–1997 (82 988 women) or 2001–2004 (85 859 women) and who had a second (sequential) birth within 5 years of their first-birth.

Primary outcome measures

Caesarean section rates, by parity and onset of labour.

Results

For first-births, prelabour and intrapartum caesarean rates increased from 1994 to 2009, with intrapartum rates rising from 6.5% to 11.7%. This fed into repeat caesarean rates; from 2003, over 18% of all multiparous births were prelabour repeat caesareans. In the 1994–1997 cohort, 17.7% of women had a caesarean delivery for their first-birth. For their second birth, the vaginal birth after caesarean (VBAC) rate was 28%. In the 2001–2004 cohort, 26.1% of women had a caesarean delivery for their first-birth and the VBAC rate was 16%. Among women with a first-birth, maternal and pregnancy factors and increasing deliveries in private hospitals, only explained 24% of the rise in caesarean rates from 1994 to 2009.

Conclusions

Rising first-birth caesarean rates drove the overall increase. Maternal factors and changes in public/private care could explain only a quarter of the increase. Changes in the perceived risks of vaginal birth versus caesarean delivery may be influencing the pregnancy management decisions of clinicians and/or mothers.
Easternmost Mediterranean evidence of the Zanclean flooding event and subsequent surface uplift: Adana Basin, southern Turkey
Authors: Cipollari Paola , Cosentino Domenico , Radeff Giuditta , Schildgen Taylor F. , Faranda Costanza , Grossi Francesco , Gliozzi Elsa , Smedile Alessandra , Gennari Rocco , Darbaş Güldemin , Dudas Francis Ö. , Gürbüz Kemal , Nazik Atike , Echtler Helmut
Published: September 2012

According to the literature, the Adana Basin, at the easternmost part of the Mediterranean Basin in southern Turkey, records the Pliocene stage with shallow-marine to fluvial deposits. Our micropalaeontological analysis of samples from the Adana Basin reveal Late Lago–Mare biofacies with Paratethyan ostracod assemblages pertaining to the
Loxocorniculina djafarovi
zone. Grey clays rich in planktonic foraminifera lie above the Lago–Mare deposits. Within the grey clays, the continuous occurrence of the calcareous nannofossil
Reticulofenestra zancleana
and the base of the
Reticulofenestra pseudoumbilicus
paracme points to an Early Zanclean age (5.332–5.199 Ma). Both ostracod and benthic foraminifera indicate epibathyal and bathyal environments.
87
Sr/
86
Sr measurements on planktonic and benthic foraminifera fall below the mean global ocean value for the Early Zanclean, indicating potentially insufficient mixing of low
87
Sr/
86
Sr Mediterranean brackish ‘Lago–Mare’ water with the global ocean in the earliest Pliocene. We utilize the ages and palaeodepths of the marine sediments together with their modern elevations to determine uplift rates of the Adana Basin of 0.06 to 0.13 mm a
−1
since 5.2–5.3 Ma (total uplift of 350–650 m) from surface data, and 0.02–0.13 mm a
−1
since
c.
1.8 Ma (total uplift of 30–230 m) from subsurface data.

Supplementary material:

Microphotographs of foraminifers, ostracods, and calcareous nannofossils, plots of the calcareous nannofossil frequencies, occurrence of foraminifers and ostracods in the study sections, results of Sr isotopic analysis, and a complete list of fossils are available at
www.geolsoc.org.uk/SUP18535
.
Upper Miocene–Pleistocene deformation of the Girne (Kyrenia) Range and Dar Dere (Ovgos) lineaments, northern Cyprus: role in collision and tectonic escape in the easternmost Mediterranean region
Authors: McCay G. A. , Robertson A. H. F.
Published: September 2012

During Late Cretaceous–Mid-Eocene the Girne (Kyrenia) Range formed part of the northerly active continental margin of the southern Neotethys. Following Late Eocene–Late Miocene mainly deep-marine clastic deposition, the range was thrust southwards in a convergent (transpressional) stress regime during Late Miocene (Messinian)–earliest Pliocene time. Sinistral transpression is most evident near the front of the range in the east and in several segments, implying strain compartmentalization. The range was relatively quiescent during Early–Mid Pliocene, followed by strong
c.
east–west-trending uplift during Late Pliocene–Pleistocene. Further south, the east–west Dar Dere (Ovgos) lineament was active as a north-down extensional (or transtensional) fault zone during Oligocene–Mid-Miocene. Sinistral strike-slip/transpression followed during Late Miocene, followed by strike-slip at least during Late Pliocene–Pleistocene. The latest Miocene–earliest Pliocene thrusting/oblique convergence reflects closure of the southern Neotethys and tightening of the suture between the Arabian (North African) and Turkish (Eurasian) continents. Collision-related uplift of the Girne (Kyrenia) Range and the Troodos Massif further south took place from Late Pliocene time onwards. The Dar Dere (Ovgos) lineament is interpreted as a terrane boundary that was reactivated related to westward tectonic escape of Anatolia during Neogene–Recent time. The structure as a whole reflects regional diachronous continental collision.

Supplementary material:

Detailed geological maps of key areas to the south and north of the Girne (Kyrenia) Range based on regional mapping and field observations are available at
www.geolsoc.org.uk/SUP18534
.
What can we learn from high-resolution numerical simulations of single- and multi-phase fluid flow in fractured outcrop analogues?
Authors: Geiger Sebastian , Matthäi Stephan
Published: September 2012

Naturally fractured reservoirs (NFR), such as the large carbonate reservoirs in the Middle East, contain a major part of the world's remaining conventional oil reserves, but recovering these is especially challenging as the fractures only constitute fluid conduits while the oil is trapped in a low-permeability rock matrix. Recovery factors are therefore difficult to estimate, permeability anisotropy is high, size and shape of drainage areas are difficult to constrain, early water breakthrough is likely to be associated with a high and irreversible water cut, and secondary recovery behaviour is unusual. Outcrop-analogue model-based discrete fracture and matrix (DFM) simulations have emerged recently, helping us to disentangle and rationalize this erratic production behaviour. They allow us to understand the emergent flow behaviour and resulting saturation patterns in NFRs. Thus, classical simulation approaches, such as dual-continua conceptualizations, can be critically evaluated and improved where they fail to capture the flow behaviour of interest.

This paper discusses recent advances in DFM simulation of single- and multi-phase flow processes in geologically realistic outcrop-analogue models, and solved with finite-element (FE) and finite-volume (FV) methods. It also reviews key results from recent DFM simulation studies, in particular how new measures such as the fracture–matrix flux ratio and velocity spectra can provide new means to analyse flow behaviour in heterogeneous domains or how results from outcrop-based simulations can be used to test the suitability of conventional upscaling approaches for NFR and guide the development of new ones. We close by enlisting outstanding challenges in outcrop-based flow simulations such as the need to capture the fracture–matrix transfer processes due to capillary, gravity and viscous forces accurately, which often implies detailed grid refinement at the fracture–matrix interface and small time-steps to resolve the physical processes adequately. Thus, we explore how outcrop-based flow simulation could be applied more routinely in NFR reservoir characterization and simulation workflows.
Mesenchymal stem cell therapy promotes renal repair by limiting glomerular podocyte and progenitor cell dysfunction in adriamycin-induced nephropathy
Authors: Zoja Carla , Garcia Pablo Bautista , Rota Cinzia , Conti Sara , Gagliardini Elena , Corna Daniela , Zanchi Cristina , Bigini Paolo , Benigni Ariela , Remuzzi Giuseppe , Morigi Marina
Published: September 2012

We previously reported that in a model of spontaneously progressive glomerular injury with early podocyte loss, abnormal migration, and proliferation of glomerular parietal epithelial progenitor cells contributed to the formation of synechiae and crescentic lesions. Here we first investigated whether a similar sequence of events could be extended to rats with adriamycin (ADR)-induced nephropathy. As a second aim, the regenerative potential of therapy with bone marrow-derived mesenchymal stem cells (MSCs) on glomerular resident cells was evaluated. In ADR-treated rats, decrease of WT1+podocyte number due to apoptosis was associated with reduced glomerular expression of nephrin and CD2AP. As a consequence of podocyte injury, glomerular adhesions of the capillary tuft to the Bowman's capsule were observed, followed by crescent-like lesions and glomerulosclerosis. Cellular components of synechiae were either NCAM+parietal progenitor cells or nestin+podocytes. In ADR rats, repeated injections of MSCs limited podocyte loss and apoptosis and partially preserved nephrin and CD2AP. MSCs attenuated the formation of glomerular podocyte-parietal epithelial cell bridges and normalized the distribution of NCAM+progenitor cells along the Bowman's capsule, thereby reducing glomerulosclerosis. Finding that MSCs increased glomerular VEGF expression and limited microvascular rarefaction may explain the prosurvival effect by stem cell therapy. MSCs also displayed anti-inflammatory activity. Coculture of MSCs with ADR-damaged podocytes showed a functional role of stem cell-derived VEGF on prosurvival pathways. These data suggest that MSCs by virtue of their tropism for damaged kidney and ability to provide a local prosurvival environment may represent a useful strategy to preserve podocyte viability and reduce glomerular inflammation and sclerosis.
Calmodulin-sensitive adenylyl cyclases mediate AVP-dependent cAMP production and Cl−secretion by human autosomal dominant polycystic kidney cells
Authors: Pinto Cibele S. , Reif Gail A. , Nivens Emily , White Corey , Wallace Darren P.
Published: September 2012

In autosomal dominant polycystic kidney disease (ADPKD), binding of AVP to the V2 receptor (V2R) increases cAMP and accelerates cyst growth by stimulating cell proliferation and Cl−-dependent fluid secretion. Basal cAMP is elevated in human ADPKD cells compared with normal human kidney (NHK) cells. V2R mRNA levels are elevated in ADPKD cells; however, AVP caused a greater increase in global cAMP in NHK cells, suggesting an intrinsic difference in cAMP regulation. Expression, regulatory properties, and receptor coupling of specific adenylyl cyclases (ACs) provide temporal and spatial regulation of the cAMP signal. ADPKD and NHK cells express mRNAs for all nine ACs. Ca2+-inhibited ACs 5 and 6 are increased in ADPKD cells, while Ca2+/CaM-stimulated ACs 1 and 3 are downregulated. ACs 1, 3, 5, and 6 were detected in cyst cells in situ, and codistribution with aquaporin-2 suggests that these cysts were derived from collecting ducts. To determine the contribution of CaM-sensitive ACs to AVP signaling, cells were treated with W-7, a CaM inhibitor. W-7 decreased AVP-induced cAMP production and Cl−secretion by ADPKD cells. CaMKII inhibition increased AVP-induced cAMP, suggesting that cAMP synthesis is mediated by AC3. In contrast, CaM and CaMKII inhibition in NHK cells did not affect AVP-induced cAMP production. Restriction of intracellular Ca2+switched the response in NHK cells, such that CaM inhibition decreased AVP-induced cAMP production. We suggest that a compensatory response to decreased Ca2+in ADPKD cells switches V2R coupling from Ca2+-inhibited ACs 5/6 to Ca2+/CaM-stimulated AC3, to mitigate high cAMP levels in response to continuous AVP stimulation.
Pain-facilitating medullary neurons contribute to opioid-induced respiratory depression
Authors: Phillips Ryan S. , Cleary Daniel R. , Nalwalk Julia W. , Arttamangkul Seksiri , Hough Lindsay B. , Heinricher Mary M.
Published: September 2012

Respiratory depression is a therapy-limiting side effect of opioid analgesics, yet our understanding of the brain circuits mediating this potentially lethal outcome remains incomplete. Here we studied the contribution of the rostral ventromedial medulla (RVM), a region long implicated in pain modulation and homeostatic regulation, to opioid-induced respiratory depression. Microinjection of the μ-opioid agonist DAMGO in the RVM of lightly anesthetized rats produced both analgesia and respiratory depression, showing that neurons in this region can modulate breathing. Blocking opioid action in the RVM by microinjecting the opioid antagonist naltrexone reversed the analgesic and respiratory effects of systemically administered morphine, showing that this region plays a role in both the analgesic and respiratory-depressant properties of systemically administered morphine. The distribution of neurons directly inhibited by RVM opioid microinjection was determined with a fluorescent opioid peptide, dermorphin-Alexa 594, and found to be concentrated in and around the RVM. The non-opioid analgesic improgan, like DAMGO, produced antinociception but, unlike DAMGO, stimulated breathing when microinjected into the RVM. Concurrent recording of RVM neurons during improgan microinjection showed that this agent activated RVM ON-cells, OFF-cells, and NEUTRAL-cells. Since opioids are known to activate OFF-cells but suppress ON-cell firing, the differential respiratory response to these two analgesic drugs is best explained by their opposing effects on the activity of RVM ON-cells. These findings show that pain relief can be separated pharmacologically from respiratory depression and identify RVM OFF-cells as important central targets for continued development of potent analgesics with fewer side effects.
Response variability of frontal eye field neurons modulates with sensory input and saccade preparation but not visual search salience
Authors: Purcell Braden A. , Heitz Richard P. , Cohen Jeremiah Y. , Schall Jeffrey D.
Published: September 2012

Discharge rate modulation of frontal eye field (FEF) neurons has been identified with a representation of visual search salience (physical conspicuity and behavioral relevance) and saccade preparation. We tested whether salience or saccade preparation are evident in the trial-to-trial variability of discharge rate. We quantified response variability via the Fano factor in FEF neurons recorded in monkeys performing efficient and inefficient visual search tasks. Response variability declined following stimulus presentation in most neurons, but despite clear discharge rate modulation, variability did not change with target salience. Instead, we found that response variability was modulated by stimulus luminance and the number of items in the visual field independently of attentional demands. Response variability declined to a minimum before saccade initiation, and presaccadic response variability was directionally tuned. In addition, response variability was correlated with the response time of memory-guided saccades. These results indicate that the trial-by-trial response variability of FEF neurons reflects saccade preparation and the strength of sensory input, but not visual search salience or attentional allocation.
A New Approach in the Simplification of a Multiple-Beam Forming Network Based on CORPS Using Compressive Arrays
Authors: Arce Armando , Yepes Leonardo F. , Covarrubias David H. , Panduro Marco A.
Published: September 2012

This research paper deals with a innovative way to simplify the design of beam-forming networks (BFNs) for multibeam steerable antenna arrays based on coherently radiating periodic structures (CORPS) technology using the noniterative matrix pencil method (MPM). This design approach is based on the application of the MPM to linear arrays fed by CORPS-BFN configurations to further reduce the complexity of the beam-forming network. Two 2-beam design configurations of CORPS-BFN for a steerable linear array are analyzed and compared using this compressive method. Simulation results show the effectiveness and advantages of applying the MPM on BFNs based on CORPS exploiting the nonuniformity of the antenna elements. Furthermore, final results show that the integration of CORPS-BFN and MPM reduces the entire antenna system including the antenna array and the beam-forming network subsystem resulting in a substantial simplification in such systems.
Some Properties of the (p, q)‐Fibonacci and (p, q)‐Lucas Polynomials
Authors: Lee GwangYeon , Asci Mustafa
Published: September 2012

Riordan arrays are useful for solving the combinatorial sums by the help of generating functions. Many theorems can be easily proved by Riordan arrays. In this paper we consider the Pascal matrix and define a new generalization of Fibonacci polynomials called (p, q)‐Fibonacci polynomials. We obtain combinatorial identities and by using Riordan method we get factorizations of Pascal matrix involving (p, q)‐Fibonacci polynomials.
Design and Analysis of a Novel Compact Wideband Antenna with Two Excited Modes
Authors: Li Li , Zhou Zhi-Li , Hong Jing-Song
Published: September 2012

A novel planar compact wideband antenna with coplanar waveguide (CPW) feeding configuration is presented in this paper. The proposed antenna is fed and coupled by the CPW feeding line at the same time. Therefore, two distinct excited modes are realized. Besides, detail investigation is presented as well to demonstrate the properties of the proposed antenna. Eventually, the prototype of the proposed antenna with optimal design is fabricated and tested. The proposed antenna, with a fairly compact size of 24 mm × 18 mm × 1 mm, has a measured 10 dB impedance bandwidth spanning from 3.05 GHz to 6 GHz, about 65.2%. Moreover, stable radiation patterns over the operating band are obtained. Furthermore, time-domain characteristics of the proposed antenna are also investigated.
Ballroom Music Spillover into a Beluga Whale Aquarium Exhibit
Authors: Scheifele Peter M. , Clark John Greer , Sonstrom Kristine , Kim Huikwan , Potty Gopu , Miller James H. , Gaglione Eric
Published: September 2012

It is not uncommon for modern aquaria to be built with special entertainment areas. There are no known measurements of sound spillover from such entertainment areas into underwater animal exhibits. Entertainment organizations typically prefer to play music for events at 95 and 100 dBA in a ballroom at Georgia Aquarium. Concern over the potential effects of the music and noise on animals in adjacent exhibits inspired an initial project to monitor and compare sound levels in the adjacent underwater exhibits against the typical in-air sound levels of the ballroom. Measured underwater noise levels were compared to modeled levels based on finite element analysis and plane wave transmission loss calculations through the acrylic viewing window. Results were compared with the model to determine how, if at all, the ambient noise level in the Cold Water Quest exhibit changed as a result of music played in the ballroom.
Public Knowledge about and Detection of Canine Visceral Leishmaniasis in Urban Divinópolis, Brazil
Authors: Margonari Carina , Menezes Júlia Alves , Rocha Marcele Neves , Maia Kamila Nunes , Éder de Oliveira Michael , Luisa Fonseca Amanda , Furtado de Sousa Fabrizio , Ferreira Eduardo de Castro , Madureira Ana Paula , Melo Maria Norma , Soares Rodrigo Pedro
Published: September 2012

Background. Leishmaniases are diseases with a wide spectrum of clinical manifestations including cutaneous (CL) and visceral (VL) forms. Many factors may affect their occurrence and expansion including environmental, geographic, and social conditions. In the past two decades, Divinópolis, Minas Gerais State, Brazil, has exhibited the potential for a disease outbreak, with the appearance of CL, and VL cases (human and canine). Hence, this study was initiated to monitor public knowledge of the disease. Questionnaires were administered in four neighborhoods (Jardim Belvedere, Esplanada, Danilo Passos I and II) where most of the human and canine cases have been reported. The analyses demonstrated that public knowledge of the disease is sparse and fragmented. A strong perception of the dog as the main reservoir was observed. Five veterinary clinics were evaluated for the presence of canine VL using serological (RIFI and ELISA) and molecular (PCR-RFLP) techniques. This is the first study demonstrating the occurrence ofLeishmania infantumin Divinópolis, suggesting a possible urbanization of VL.
Dysregulation of Dicer1 in Beta Cells Impairs Islet Architecture and Glucose Metabolism
Authors: Mandelbaum Amitai D. , Melkman-Zehavi Tal , Oren Roni , Kredo-Russo Sharon , Nir Tomer , Dor Yuval , Hornstein Eran
Published: September 2012

microRNAs (miRNAs) play important roles in pancreas development and in regulation of insulin expression in the adult. Here we show that loss of miRNAs activity in beta-cells during embryonic development results in lower beta-cell mass and in impaired glucose tolerance. Dicer1-null cells initially constitute a significant portion of the total beta-cell population. However, during postnatal development, Dicer1-null cells are depleted. Furthermore, wild-type beta cells are repopulating the islets in complex compensatory dynamics. Because loss of Dicer1 is also associated with changes in the distribution of membranous E-cadherin, we hypothesized that E-cadherin activity may play a role in beta cell survival or islet architecture. However, genetic loss of E-cadherin function does not impair islet architecture, suggesting that miRNAs likely function through other or redundant effectors in the endocrine pancreas.
Recent Advances in Chemical Modification of Peptide Nucleic Acids
Authors: Rozners Eriks
Published: September 2012

Peptide nucleic acid (PNA) has become an extremely powerful tool in chemistry and biology. Although PNA recognizes single-stranded nucleic acids with exceptionally high affinity and sequence selectivity, there is considerable ongoing effort to further improve properties of PNA for both fundamental science and practical applications. The present paper discusses selected recent studies that improve on cellular uptake and binding of PNA to double-stranded DNA and RNA. The focus is on chemical modifications of PNA's backbone and heterocyclic nucleobases. The paper selects representative recent studies and does not attempt to provide comprehensive coverage of the broad and vibrant field of PNA modification.
Endocrine-Disrupting Chemicals: Associated Disorders and Mechanisms of Action
Authors: De Coster Sam , van Larebeke Nicolas
Published: September 2012

The incidence and/or prevalence of health problems associated with endocrine-disruption have increased. Many chemicals have endocrine-disrupting properties, including bisphenol A, some organochlorines, polybrominated flame retardants, perfluorinated substances, alkylphenols, phthalates, pesticides, polycyclic aromatic hydrocarbons, alkylphenols, solvents, and some household products including some cleaning products, air fresheners, hair dyes, cosmetics, and sunscreens. Even some metals were shown to have endocrine-disrupting properties. Many observations suggesting that endocrine disruptors do contribute to cancer, diabetes, obesity, the metabolic syndrome, and infertility are listed in this paper. An overview is presented of mechanisms contributing to endocrine disruption. Endocrine disruptors can act through classical nuclear receptors, but also through estrogen-related receptors, membrane-bound estrogen-receptors, and interaction with targets in the cytosol resulting in activation of the Src/Ras/Erk pathway or modulation of nitric oxide. In addition, changes in metabolism of endogenous hormones, cross-talk between genomic and nongenomic pathways, cross talk with estrogen receptors after binding on other receptors, interference with feedback regulation and neuroendocrine cells, changes in DNA methylation or histone modifications, and genomic instability by interference with the spindle figure can play a role. Also it was found that effects of receptor activation can differ in function of the ligand.
CFD Simulation of Annular Centrifugal Extractors
Authors: Vedantam S. , Wardle K. E. , Tamhane T. V. , Ranade V. V. , Joshi J. B.
Published: September 2012

Annular centrifugal extractors (ACE), also called annular centrifugal contactors offer several advantages over the other conventional process equipment such as low hold-up, high process throughput, low residence time, low solvent inventory and high turn down ratio. The equipment provides a very high value of mass transfer coefficient and interfacial area in the annular zone because of the high level of power consumption per unit volume and separation inside the rotor due to the high g of centrifugal field. For the development of rational and reliable design procedures, it is important to understand the flow patterns in the mixer and settler zones. Computational Fluid Dynamics (CFD) has played a major role in the constant evolution and improvements of this device. During the past thirty years, a large number of investigators have undertaken CFD simulations. All these publications have been carefully and critically analyzed and a coherent picture of the present status has been presented in this review paper. Initially, review of the single phase studies in the annular region has been presented, followed by the separator region. In continuation, the two-phase CFD simulations involving liquid-liquid and gas-liquid flow in the annular as well as separator regions have been reviewed. Suggestions have been made for the future work for bridging the existing knowledge gaps. In particular, emphasis has been given to the application of CFD simulations for the design of this equipment.
A Note on the Second Order of Accuracy Stable Difference Schemes for the Nonlocal Boundary Value Hyperbolic Problem
Authors: Ashyralyev Allaberen , Yildirim Ozgur
Published: September 2012

The second order of accuracy absolutely stable difference schemes are presented for the nonlocal boundary value hyperbolic problem for the differential equations in a Hilbert space H with the self‐adjoint positive definite operator A. The stability estimates for the solutions of these difference schemes are established. In practice, one‐dimensional hyperbolic equation with nonlocal boundary conditions and multidimensional hyperbolic equation with Dirichlet conditions are considered. The stability estimates for the solutions of these difference schemes for the nonlocal boundary value hyperbolic problem are established. Finally, a numerical method proposed and numerical experiments, analysis of the errors, and related execution times are presented in order to verify theoretical statements.
Lipoprotein(a): Cellular Effects and Molecular Mechanisms
Authors: Riches Kirsten , Porter Karen E.
Published: September 2012

Lipoprotein(a) (Lp(a)) is an independent risk factor for the development of cardiovascular disease (CVD). Indeed, individuals with plasma concentrations >20 mg/dL carry a 2-fold increased risk of developing CVD, accounting for~25% of the population. Circulating levels of Lp(a) are remarkably resistant to common lipid lowering therapies, and there are currently no robust treatments available for reduction of Lp(a) apart from plasma apheresis, which is costly and labour intensive. The Lp(a) molecule is composed of two parts, an LDL/apoB-100 core and a unique glycoprotein, apolipoprotein(a) (apo(a)), both of which can interact with components of the coagulation cascade, inflammatory pathways, and cells of the blood vessel wall (smooth muscle cells (SMC) and endothelial cells (EC)). Therefore, it is of key importance to determine the molecular pathways by which Lp(a) exerts its influence on the vascular system in order to design therapeutics to target its cellular effects. This paper will summarise the role of Lp(a) in modulating cell behaviour in all aspects of the vascular system including platelets, monocytes, SMC, and EC.
Existence of Three Solutions for a Nonlinear Fractional BoundaryValue Problem via a Critical Points Theorem
Authors: Bai Chuanzhi
Published: September 2012

This paper is concerned with the existence of three solutions to a nonlinear fractional boundary value problem as follows: u(0) = u(T) = 0, where α ∈ (1/2,1], and λ is a positive real parameter. The approach is based on a critical‐points theorem established by G. Bonanno.