bluuebunny/crossref_metadata_2025 huggingface dataset:
Enhanced Recognition and Neutralization of HIV-1 by Antibody-Derived CCR5-Mimetic Peptide Variants
Authors: Chiang Jessica J. , Gardner Matthew R. , Quinlan Brian D. , Dorfman Tatyana , Choe Hyeryun , Farzan Michael
Published: August 2012

A tyrosine-sulfated CCR5-mimetic peptide, CCR5mim1, inhibits HIV-1 infection more efficiently than sulfopeptides based on the CCR5 amino terminus. Here we characterized sulfopeptide chimeras of CCR5mim1 and the heavy-chain CDR3 of the antibody PG16. Two chimeras bound a range of envelope glycoproteins and neutralized HIV-1 more efficiently than CCR5mim1. An immunoadhesin form of one of these, CCR5mim2-Ig, synergized with CD4-Ig to neutralize HIV-1. These sulfopeptides are among the broadest and most potent CCR5-mimetic peptides described to date.
Identification of a Varicella-Zoster Virus Replication Inhibitor That Blocks Capsid Assembly by Interacting with the Floor Domain of the Major Capsid Protein
Authors: Inoue Naoki , Matsushita Misato , Fukui Yoshiko , Yamada Souichi , Tsuda Mihoko , Higashi Chizuka , Kaneko Keiko , Hasegawa Hideki , Yamaguchi Toyofumi
Published: August 2012

A novel anti-varicella-zoster virus compound, a derivative of pyrazolo[1,5-
c
]1,3,5-triazin-4-one (coded as 35B2), was identified from a library of 9,600 random compounds. This compound inhibited both acyclovir (ACV)-resistant and -sensitive strains. In a plaque reduction assay under conditions in which the 50% effective concentration of ACV against the vaccine Oka strain (V-Oka) in human fibroblasts was 4.25 μM, the 50% effective concentration of 35B2 was 0.75 μM. The selective index of the compound was more than 200. Treatment with 35B2 inhibited neither immediate-early gene expression nor viral DNA synthesis. Twenty-four virus clones resistant to 35B2 were isolated, all of which had a mutation(s) in the amino acid sequence of open reading frame 40 (ORF40), which encodes the major capsid protein (MCP). Most of the mutations were located in the regions corresponding to the “floor” domain of the MCP of herpes simplex virus 1. Treatment with 35B2 changed the localization of MCP in the fibroblasts infected with V-Oka but not in the fibroblasts infected with the resistant clones, although it did not affect steady-state levels of MCP. Overexpression of the scaffold proteins restored the normal MCP localization in the 35B2-treated infected cells. The compound did not inhibit the scaffold protein-mediated translocation of MCP from the cytoplasm to the nucleus. Electron microscopic analysis demonstrated the lack of capsid formation in the 35B2-treated infected cells. These data indicate the feasibility of developing a new class of antivirals that target the herpesvirus MCPs and inhibit normal capsid formation by a mechanism that differs from those of the known protease and encapsidation inhibitors. Further biochemical studies are required to clarify the precise antiviral mechanism.
Recent Transmission of a Novel Alphacoronavirus, Bat Coronavirus HKU10, from Leschenault's Rousettes to Pomona Leaf-Nosed Bats: First Evidence of Interspecies Transmission of Coronavirus between Bats of Different Suborders
Authors: Lau Susanna K. P. , Li Kenneth S. M. , Tsang Alan K. L. , Shek Chung-Tong , Wang Ming , Choi Garnet K. Y. , Guo Rongtong , Wong Beatrice H. L. , Poon Rosana W. S. , Lam Carol S. F. , Wang Sylvia Y. H. , Fan Rachel Y. Y. , Chan Kwok-Hung , Zheng Bo-Jian , Woo Patrick C. Y. , Yuen Kwok-Yung
Published: August 2012

Although coronaviruses are known to infect various animals by adapting to new hosts, interspecies transmission events are still poorly understood. During a surveillance study from 2005 to 2010, a novel alphacoronavirus, BatCoV HKU10, was detected in two very different bat species, Ro-BatCoV HKU10 in Leschenault's rousettes (
Rousettus leschenaulti
) (fruit bats in the suborder Megachiroptera) in Guangdong and Hi-BatCoV HKU10 in Pomona leaf-nosed bats (
Hipposideros pomona
) (insectivorous bats in the suborder Microchiroptera) in Hong Kong. Although infected bats appeared to be healthy, Pomona leaf-nosed bats carrying Hi-BatCoV HKU10 had lower body weights than uninfected bats. To investigate possible interspecies transmission between the two bat species, the complete genomes of two Ro-BatCoV HKU10 and six Hi-BatCoV HKU10 strains were sequenced. Genome and phylogenetic analyses showed that Ro-BatCoV HKU10 and Hi-BatCoV HKU10 represented a novel alphacoronavirus species, sharing highly similar genomes except in the genes encoding spike proteins, which had only 60.5% amino acid identities. Evolution of the spike protein was also rapid in Hi-BatCoV HKU10 strains from 2005 to 2006 but stabilized thereafter. Molecular-clock analysis dated the most recent common ancestor of all BatCoV HKU10 strains to 1959 (highest posterior density regions at 95% [HPDs], 1886 to 2002) and that of Hi-BatCoV HKU10 to 1986 (HPDs, 1956 to 2004). The data suggested recent interspecies transmission from Leschenault's rousettes to Pomona leaf-nosed bats in southern China. Notably, the rapid adaptive genetic change in BatCoV HKU10 spike protein by ∼40% amino acid divergence after recent interspecies transmission was even greater than the ∼20% amino acid divergence between spike proteins of severe acute respiratory syndrome-related
Rhinolophus
bat coronavirus (SARSr-CoV) in bats and civets. This study provided the first evidence for interspecies transmission of coronavirus between bats of different suborders.
Sequences in Glycoprotein gp41, the CD4 Binding Site, and the V2 Domain Regulate Sensitivity and Resistance of HIV-1 to Broadly Neutralizing Antibodies
Authors: O'Rourke Sara M. , Schweighardt Becky , Phung Pham , Mesa Kathryn A. , Vollrath Aaron L. , Tatsuno Gwen P. , To Briana , Sinangil Faruk , Limoli Kay , Wrin Terri , Berman Phillip W.
Published: August 2012

The swarm of quasispecies that evolves in each HIV-1-infected individual represents a source of closely related Env protein variants that can be used to explore various aspects of HIV-1 biology. In this study, we made use of these variants to identify mutations that confer sensitivity and resistance to the broadly neutralizing antibodies found in the sera of selected HIV-1-infected individuals. For these studies, libraries of Env proteins were cloned from infected subjects and screened for infectivity and neutralization sensitivity. The nucleotide sequences of the Env proteins were then compared for pairs of neutralization-sensitive and -resistant viruses.
In vitro
mutagenesis was used to identify the specific amino acids responsible for the neutralization phenotype. All of the mutations altering neutralization sensitivity/resistance appeared to induce conformational changes that simultaneously enhanced the exposure of two or more epitopes located in different regions of gp160. These mutations appeared to occur at unique positions required to maintain the quaternary structure of the gp160 trimer, as well as conformational masking of epitopes targeted by neutralizing antibodies. Our results show that sequences in gp41, the CD4 binding site, and the V2 domain all have the ability to act as global regulators of neutralization sensitivity. Our results also suggest that neutralization assays designed to support the development of vaccines and therapeutics targeting the HIV-1 Env protein should consider virus variation within individuals as well as virus variation between individuals.
Probing, by Self-Assembly, the Number of Potential Binding Sites for Minor Protein Subunits in the Procapsid of Double-Stranded RNA Bacteriophage φ6
Authors: Sun Xiaoyu , Bamford Dennis H. , Poranen Minna M.
Published: August 2012

The double-stranded RNA bacteriophage ϕ6 is an extensively studied prokaryotic model system for virus assembly. There are established
in vitro
assembly protocols available for the ϕ6 system for obtaining infectious particles from purified protein and RNA constituents. The polymerase complex is a multifunctional nanomachine that replicates, transcribes, and translocates viral RNA molecules in a highly specific manner. The complex is composed of (i) the major structural protein (P1), forming a T=1 icosahedral lattice with two protein subunits in the icosahedral asymmetric unit; (ii) the RNA-dependent RNA polymerase (P2); (iii) the hexameric packaging nucleoside triphosphatase (NTPase) (P4); and (iv) the assembly cofactor (P7). In this study, we analyzed several ϕ6 virions and recombinant polymerase complexes to investigate the relative copy numbers of P2, P4, and P7, and we applied saturated concentrations of these proteins in the self-assembly system to probe their maximal numbers of binding sites in the P1 shell. Biochemical quantitation confirmed that the composition of the recombinant particles was similar to that of the virion cores. By including a high concentration of P2 or P7 in the self-assembly reaction mix, we observed that the numbers of these proteins in the resulting particles could be increased beyond those observed in the virion. Our results also suggest a previously unidentified P2-P7 dependency in the assembly reaction. Furthermore, it appeared that P4 must initially be incorporated at each, or a majority, of the 5-fold symmetry positions of the P1 shell for particle assembly. Although required for nucleation, excess P4 resulted in slower assembly kinetics.
Differential Roles of Hsp70 and Hsp90 in the Assembly of the Replicase Complex of a Positive-Strand RNA Plant Virus
Authors: Mine Akira , Hyodo Kiwamu , Tajima Yuri , Kusumanegara Kusumawaty , Taniguchi Takako , Kaido Masanori , Mise Kazuyuki , Taniguchi Hisaaki , Okuno Tetsuro
Published: August 2012

Assembly of viral replicase complexes of eukaryotic positive-strand RNA viruses is a regulated process: multiple viral and host components must be assembled on intracellular membranes and ordered into quaternary complexes capable of synthesizing viral RNAs. However, the molecular mechanisms underlying this process are poorly understood. In this study, we used a model virus,
Red clover necrotic mosaic virus
(RCNMV), whose replicase complex can be detected readily as the 480-kDa functional protein complex. We found that host heat shock proteins Hsp70 and Hsp90 are required for RCNMV RNA replication and that they interact with p27, a virus-encoded component of the 480-kDa replicase complex, on the endoplasmic reticulum membrane. Using a cell-free viral translation/replication system in combination with specific inhibitors of Hsp70 and Hsp90, we found that inhibition of p27-Hsp70 interaction inhibits the formation of the 480-kDa complex but instead induces the accumulation of large complexes that are nonfunctional in viral RNA synthesis. In contrast, inhibition of p27-Hsp90 interaction did not induce such large complexes but rendered p27 incapable of binding to a specific viral RNA element, which is a critical step for the assembly of the 480-kDa replicase complex and viral RNA replication. Together, our results suggest that Hsp70 and Hsp90 regulate different steps in the assembly of the RCNMV replicase complex.
The
ac53
,
ac78
,
ac101
, and
ac103
Genes Are Newly Discovered Core Genes in the Family Baculoviridae
Authors: Garavaglia Matías Javier , Miele Solange Ana Belén , Iserte Javier Alonso , Belaich Mariano Nicolás , Ghiringhelli Pablo Daniel
Published: August 2012

The family
Baculoviridae
is a large group of insect viruses containing circular double-stranded DNA genomes of 80 to 180 kbp, which have broad biotechnological applications. A key feature to understand and manipulate them is the recognition of orthology. However, the differences in gene contents and evolutionary distances among the known members of this family make it difficult to assign sequence orthology. In this study, the genome sequences of 58 baculoviruses were analyzed, with the aim to detect previously undescribed core genes because of their remote homology. A routine based on Multi PSI-Blast/tBlastN and Multi HaMStR allowed us to detect 31 of 33 accepted core genes and 4 orthologous sequences in the
Baculoviridae
which were not described previously. Our results show that the
ac53
,
ac78
,
ac101
(
p40
), and
ac103
(
p48
) genes have orthologs in all genomes and should be considered core genes. Accordingly, there are 37 orthologous genes in the family
Baculoviridae
.
Epstein-Barr Virus BGLF4 Kinase Downregulates NF-κB Transactivation through Phosphorylation of Coactivator UXT
Authors: Chang Ling-Shih , Wang Jiin-Tarng , Doong Shin-Lian , Lee Chung-Pei , Chang Chou-Wei , Tsai Ching-Hwa , Yeh Sheng-Wen , Hsieh Ching-Yueh , Chen Mei-Ru
Published: August 2012

Epstein-Barr virus (EBV) BGLF4 is a member of the conserved herpesvirus kinases that regulate multiple cellular and viral substrates and play an important role in the viral lytic cycles. BGLF4 has been found to phosphorylate several cellular and viral transcription factors, modulate their activities, and regulate downstream events. In this study, we identify an NF-κB coactivator, UXT, as a substrate of BGLF4. BGLF4 downregulates not only NF-κB transactivation in reporter assays in response to tumor necrosis factor alpha (TNF-α) and poly(I·C) stimulation, but also NF-κB-regulated cellular gene expression. Furthermore, BGLF4 attenuates NF-κB-mediated repression of the EBV lytic transactivators, Zta and Rta. In EBV-positive NA cells, knockdown of BGLF4 during lytic progression elevates NF-κB activity and downregulates the activity of the EBV oriLyt
BHLF1
promoter, which is the first promoter activated upon lytic switch. We show that BGLF4 phosphorylates UXT at the Thr3 residue. This modification interferes with the interaction between UXT and NF-κB. The data also indicate that BGLF4 reduces the interaction between UXT and NF-κB and attenuates NF-κB enhanceosome activity. Upon infection with short hairpin RNA (shRNA) lentivirus to knock down UXT, a spontaneous lytic cycle was observed in NA cells, suggesting UXT is required for maintenance of EBV latency. Overexpression of wild-type, but not phosphorylation-deficient, UXT enhances the expression of lytic proteins both in control and UXT knockdown cells. Taking the data together, transcription involving UXT may also be important for EBV lytic protein expression, whereas BGLF4-mediated phosphorylation of UXT at Thr3 plays a critical role in promoting the lytic cycle.
Ultrasensitive Allele-Specific PCR Reveals Rare Preexisting Drug-Resistant Variants and a Large Replicating Virus Population in Macaques Infected with a Simian Immunodeficiency Virus Containing Human Immunodeficiency Virus Reverse Transcriptase
Authors: Boltz Valerie F. , Ambrose Zandrea , Kearney Mary F. , Shao Wei , KewalRamani Vineet N. , Maldarelli Frank , Mellors John W. , Coffin John M.
Published: August 2012

It has been proposed that most drug-resistant mutants, resulting from a single-nucleotide change, exist at low frequency in human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) populations
in vivo
prior to the initiation of antiretroviral therapy (ART). To test this hypothesis and to investigate the emergence of resistant mutants with drug selection, we developed a new ultrasensitive allele-specific PCR (UsASP) assay, which can detect drug resistance mutations at a frequency of ≥0.001% of the virus population. We applied this assay to plasma samples obtained from macaques infected with an SIV variant containing HIV-1 reverse transcriptase (RT) (RT-simian-human immunodeficiency [SHIV]
mne
), before and after they were exposed to a short course of efavirenz (EFV) monotherapy. We detected RT inhibitor (RTI) resistance mutations K65R and M184I but not K103N in 2 of 2 RT-SHIV-infected macaques prior to EFV exposure. After three doses over 4 days of EFV monotherapy, 103N mutations (AAC and AAT) rapidly emerged and increased in the population to levels of ∼20%, indicating that they were present prior to EFV exposure. The rapid increase of 103N mutations from <0.001% to 20% of the viral population indicates that the replicating virus population size in RT-SHIV-infected macaques must be 10
6
or more infected cells per replication cycle.
Modelling the role of highly unsaturated fatty acids in planktonic food web processes: a mechanistic approach
Authors: Perhar Gurbir , Arhonditsis George B. , Brett Michael T.
Published: August 2012

Highly unsaturated fatty acids (HUFAs) are a subgroup of fatty acids characterized by chains of 20 or more carbon atoms with multiple double bonds, which potentially limit the growth of zooplankton. Zooplankton require high HUFA concentrations during periods of rapid growth, but co-limitation with nutrients is also likely to occur. Recent modelling results suggest food webs with high quality (nutritional and biochemical) primary producers can attain inverted biomass distributions with efficient energy transfer between trophic levels. In this study, our objective is to highlight the recent advances in studying the role of HUFAs in aquatic food webs. We take a first-principles approach to investigate the chemical nature of HUFAs, and the role they play in zooplankton ecology. To this end, we introduce a novel zooplankton growth sub model that tracks the interplay between nitrogen, phosphorus, and HUFAs in plankton population models. Our aim is to produce a sub model that incorporates the knowledge gained from decades of biochemical research into management-oriented predictive tools.
Role of ambient light in structuring north-temperate fish communities: potential effects of increasing dissolved organic carbon concentration with a changing climate
Authors: Stasko Ashley D. , Gunn John M. , Johnston Tom A.
Published: August 2012

The vertical light environment in freshwater lakes is sensitive to changes in dissolved organic carbon (DOC) concentrations, and DOC concentrations in most boreal lakes appear to be increasing as the climate changes. Understanding how DOC dynamics in lakes and watersheds are then linked to fish habitat is therefore critical to assessing the effects of climate change on fish communities. This paper reviews the evidence for climate-induced alterations to DOC in north-temperate watersheds and assesses the potential consequences of the resultant decreases in water clarity on fish production and community structure in small boreal lakes (<500 ha). Although DOC increases are forecast for most boreal lakes, complex interactions between local climate, rates of terrestrial organic matter decomposition and runoff, existing water quality, species shifts in forest communities, and changing season lengths can all combine to affect the magnitude of water clarity declines that will occur in individual lakes. Elevated DOC concentrations will affect the availability of coldwater versus warmwater habitat and niche characteristics that are dependent on lake depth, water clarity, and the preferences and physiological tolerances of the individual species. The shifts in availability of suitable thermal habitat will in turn affect fish growth, production, and community composition. Range expansions for warmwater species and range reductions for coldwater species will likely occur in warmer, darker environments, with adverse consequences for some native species and likely advantages for invasive species such as smallmouth bass. Likewise, major shifts in trophic dynamics would accompany the darkening of boreal lakes as species-specific feeding efficiencies change and primary and secondary production are altered. From a beneficial perspective, elevated DOC concentrations will likely relieve some physiological stress in biota via protection against contaminant toxicity and ultraviolet radiation (UVR) exposure. As with many other disturbances, we need to view climate change impacts on fish communities as a multiple stressor problem and the potential impacts of the changing light environment needs to be given as much prominence as the study of stressors such as eutrophication and trace contaminants.
MODELING AND CHARACTERIZATION OF OSCILLATOR CIRCUITS BY VAN DER POL MODEL USING PARAMETER ESTIMATION
Authors: DUMITRESCU IULIA , BACHIR SMAIL , CORDEAU DAVID , PAILLOT JEAN-MARIE , IORDACHE MIHAI
Published: August 2012

In this paper, we present a new method for the modeling and characterization of oscillator circuit with a Van Der Pol (VDP) model using parameter identification. We also discussed and investigated the problem of estimation in nonlinear system based on time domain data. The approach is based on an appropriate state space representation of Van der Pol oscillator that allows an optimal parameter estimation. Using sampled output voltage signal, model parameters are obtained by an iterative identification algorithm based on Output Error method. Normalization issues are fixed by an appropriate transformation allowing a quickly global minimum search. Finally, the proposed estimation method is tested and validated using simulation data from a 1 GHz oscillator circuit in GaAs technology.
THE IMPACT OF BANK ACTIVITIES ON CONTAGION RISK IN INTERBANK NETWORKS
Authors: LI SHOUWEI , HE JIANMIN
Published: August 2012

In this paper, we investigate how contagion risk is affected by bank activities in four types of interbank network structures, that is, random, small-world, scale-free and tiered networks. We vary the key parameters that define bank activities in the interbank market — including the size of interbank exposures, the size of liquid assets, the heterogeneity of the size of credit lending and the heterogeneity of banks — and analyze the impact of these parameters on contagion risk. First, we find that the size of interbank exposures is the main factor in determining the effect of contagion risk, that increases in the size of interbank exposures may lead to an increase in the threat of contagion risk, that after the size of interbank exposures rises beyond a threshold, the effect of contagion risk in small-world networks is the most significant, followed by that in tiered, random and scale-free networks, respectively. Second, increases in the size of liquid assets can decrease the effect of contagion risk. Third, the impact of the heterogeneity of the size of credit lending on contagion risk varies with interbank network structures. Finally, the effect of contagion risk among heterogeneous banks is stronger than that among homogeneous banks, and there is a positive relationship between the effect of contagion risk and the heterogeneity of banks.
1-BIT FULL ADDER IMPLEMENTATION USING SINGLE SPIN LOGIC PARADIGM
Authors: SHUKLA SOUMITRA , GHOSH BAHNIMAN , AKRAM MOHAMMAD WASEEM
Published: August 2012

This paper presents the implementation of important full adder circuits using quantum dots (QDs) and Spin Polarized Scanning Tunneling Microscopy (SPSTM) in Single Spin Logic (SSL) paradigm. A fair comparison among these adders shows that the mirror adder implementation in SSL paradigm does not carry any advantage over the CMOS adder in terms of complexity and number of QDs, opposite to the trend observed in their charge-based counterparts. On the contrary, the transmission gate adder, static and dynamic Manchester carry gate adders in SSL reduces the complexity and number of QDs, in harmony with the trend shown in transistor adders.
Adaptive Genetic Variation on the Landscape: Methods and Cases
Authors: Schoville Sean D. , Bonin Aurélie , François Olivier , Lobreaux Stéphane , Melodelima Christelle , Manel Stéphanie
Published: August 2012

There is a growing interest in identifying ecological factors that influence adaptive genetic diversity patterns in both model and nonmodel species. The emergence of large genomic and environmental data sets, as well as the increasing sophistication of population genetics methods, provides an opportunity to characterize these patterns in relation to the environment. Landscape genetics has emerged as a flexible analytical framework that connects patterns of adaptive genetic variation to environmental heterogeneity in a spatially explicit context. Recent growth in this field has led to the development of numerous spatial statistical methods, prompting a discussion of the current benefits and limitations of these approaches. Here we provide a review of the design of landscape genetics studies, the different statistical tools, some important case studies, and perspectives on how future advances in this field are likely to shed light on important processes in evolution and ecology.
Coextinction and Persistence of Dependent Species in a Changing World
Authors: Colwell Robert K. , Dunn Robert R. , Harris Nyeema C.
Published: August 2012

The extinction of a single species is rarely an isolated event. Instead, dependent parasites, commensals, and mutualist partners (affiliates) face the risk of coextinction as their hosts or partners decline and fail. Species interactions in ecological networks can transmit the effects of primary extinctions within and between trophic levels, causing secondary extinctions and extinction cascades. Documenting coextinctions is complicated by ignorance of host specificity, limitations of historical collections, incomplete systematics of affiliate taxa, and lack of experimental studies. Host shifts may reduce the rate of coextinctions, but they are poorly understood. In the absence of better empirical records of coextinctions, statistical models estimate the rates of past and future coextinctions, and based on primary extinctions and interactions among species, network models explore extinction cascades. Models predict and historical evidence reveals that the threat of coextinction is influenced by both host and affiliate traits and is exacerbated by other threats, including habitat loss, climate change, and invasive species.
Rethinking Community Assembly through the Lens of Coexistence Theory
Authors: HilleRisLambers J. , Adler P.B. , Harpole W.S. , Levine J.M. , Mayfield M.M.
Published: August 2012

Although research on the role of competitive interactions during community assembly began decades ago, a recent revival of interest has led to new discoveries and research opportunities. Using contemporary coexistence theory that emphasizes stabilizing niche differences and relative fitness differences, we evaluate three empirical approaches for studying community assembly. We show that experimental manipulations of the abiotic or biotic environment, assessments of trait-phylogeny-environment relationships, and investigations of frequency-dependent population growth all suggest strong influences of stabilizing niche differences and fitness differences on the outcome of plant community assembly. Nonetheless, due to the limitations of these approaches applied in isolation, we still have a poor understanding of which niche axes and which traits determine the outcome of competition and community structure. Combining current approaches represents our best chance of achieving this goal, which is fundamental to conceptual ecology and to the management of plant communities under global change.
Sovereign and Financial-Sector Risk: Measurement and Interactions
Authors: Gray Dale F. , Malone Samuel W.
Published: August 2012

The complex spillover effects between sectors observed during the global financial crisis and recent European crisis make clear the importance of improving our understanding of the interactions and feedback mechanisms between sovereign and banking-sector risks. To that end, this paper presents a conceptual framework for analyzing the sovereign, banks, and their interlinkages based on contingent claims analysis (CCA). Our bank-by-bank framework uses balance-sheet data plus high-frequency market data in a way that measures risk exposures and can capture key risk transmission and feedbacks with the sovereign in real time. Risk transmission between banks and sovereigns can arise in the framework from several important sources: (a) bank holdings of risky sovereign debt, (b) explicit and implicit guarantees from sovereigns to banks, and (c) spillovers from sovereign spreads into bank borrowing costs. We illustrate the framework with several examples and ways forward to analyze multicountry sovereign and banking interactions.
Available Potential Energy and Exergy in Stratified Fluids
Authors: Tailleux Rémi
Published: August 2012

Lorenz's theory of available potential energy (APE) remains the main framework for studying the atmospheric and oceanic energy cycles. Because the APE generation rate is the volume integral of a thermodynamic efficiency times the local diabatic heating/cooling rate, APE theory is often regarded as an extension of the theory of heat engines. Available energetics in classical thermodynamics, however, usually relies on the concept of exergy and is usually measured relative to a reference-state maximizing entropy at constant energy, whereas APE's reference state minimizes potential energy at constant entropy. This review seeks to shed light on the two concepts; it covers local formulations of available energetics, alternative views of the dynamics/thermodynamics coupling, APE theory and the second law of thermodynamics, APE production/dissipation, extensions to binary fluids, mean/eddy decompositions, APE in incompressible fluids, APE and irreversible turbulent mixing, and the role of mechanical forcing on APE production.
Evolutionary Implications of Horizontal Gene Transfer
Authors: Syvanen Michael
Published: August 2012

The flow of genes between different species represents a form of genetic variation whose implications have not been fully appreciated. Here I examine some key findings on the extent of horizontal gene transfer (HGT) revealed by comparative genome analysis and their theoretical implications. In theoretical terms, HGT affects ideas pertaining to the tree of life, the notion of a last universal common ancestor, and the biological unities, as well as the rules of taxonomic nomenclature. This review discusses the emergence of the eukaryotic cell and the occurrence of HGT among metazoan phyla involving both transposable elements and structural genes for normal housekeeping functions. I also discuss the bacterial pangenome, which provides an important case study on the permeability of species boundaries. An interesting observation about bdelloid rotifers and their reversion to asexual reproduction as it pertains to HGT is included.
Plant Virus Metagenomics: Biodiversity and Ecology
Authors: Roossinck Marilyn J.
Published: August 2012

Viral metagenomics is the study of viruses in environmental samples, using next generation sequencing that produces very large data sets. For plant viruses, these studies are still relatively new, but are already indicating that our current knowledge grossly underestimates the diversity of these viruses. Some plant virus studies are using thousands of individual plants so that each sequence can be traced back to its precise host. These studies should allow for deeper ecological and evolutionary analyses. The finding of so many new plant viruses that do not cause any obvious symptoms in wild plant hosts certainly changes our perception of viruses and how they interact with their hosts. The major difficulty in these (as in all) metagenomic studies continues to be the need for better bioinformatics tools to decipher the large data sets. The implications of this new information on plant viruses for international agriculture remain to be addressed.
The Unfolded Protein Response in Secretory Cell Function
Authors: Moore Kristin A. , Hollien Julie
Published: August 2012

The endoplasmic reticulum (ER) controls many important aspects of cellular function, including processing of secreted and membrane proteins, synthesis of membranes, and calcium storage. Maintenance of ER function is controlled through a network of signaling pathways collectively known as the unfolded protein response (UPR). The UPR balances the load of incoming proteins with the folding capacity of the ER and allows cells to adapt to situations that disrupt this balance. This disruption is referred to as ER stress. Although ER stress often arises in pathological situations, the UPR plays a central role in the normal development and function of cells specializing in secretion. Many aspects of this response are conserved broadly across eukaryotes; most organisms use some subset of a group of ER transmembrane proteins to signal to the nucleus and induce a broad transcriptional upregulation of genes involved in ER function. However, new developments in metazoans, plants, and fungi illustrate interesting variations on this theme. Here, we summarize mechanisms for detecting and counteracting ER stress, the role of the UPR in normal secretory cell function, and how these pathways vary across organisms and among different tissues and cell types.
Systems biology in physiology: the vasopressin signaling network in kidney
Authors: Knepper Mark A.
Published: August 2012

Over the past 80 years, physiological research has moved progressively in a reductionist direction, providing mechanistic information on a smaller and smaller scale. This trend has culminated in the present focus on “molecular physiology,” which deals with the function of single molecules responsible for cellular function. There is a need to assemble the information from the molecular level into models that explain physiological function at cellular, tissue, organ, and whole organism levels. Such integration is the major focus of an approach called “systems biology.” The genome sequencing projects provide a basis for a new kind of systems biology called “data-rich” systems biology that is based on large-scale data acquisition methods including protein mass spectrometry, DNA microarrays, and deep sequencing of nucleic acids. These techniques allow investigators to measure thousands of variables simultaneously in response to an external stimulus. My laboratory is applying such an approach to the question: “How does the peptide hormone vasopressin regulate water permeability in the renal collecting duct?” We are using protein mass spectrometry to identify and quantify the phosphoproteome of collecting duct cells. The response to vasopressin, presented in the form of a network model, includes a general downregulation of proline-directed kinases (MAP kinases and cyclin-dependent kinases) and upregulation of basophilic kinases (ACG kinases and calmodulin-dependent kinases). Further progress depends on characterization and localization of candidate protein kinases in these families. The ultimate goal is to use multivariate statistical techniques and differential equations to obtain predictive models describing vasopressin signaling in the renal collecting duct.
Enrichment of neonatal rat cardiomyocytes in primary culture facilitates long-term maintenance of contractility in vitro
Authors: Nguyen Phong D. , Hsiao Sarah T. , Sivakumaran Priyadharshini , Lim Shiang Y. , Dilley Rodney J.
Published: August 2012

Long-term culture of primary neonatal rat cardiomyocytes is limited by the loss of spontaneous contractile phenotype within weeks in culture. This may be due to loss of contractile cardiomyocytes from the culture or overgrowth of the non-cardiomyocyte population. Using the mitochondria specific fluorescent dye, tetramethylrhodamine methyl ester perchlorate (TMRM), we showed that neonatal rat cardiomyocytes enriched by fluorescence-activated cell sorting can be maintained as contractile cultures for long periods (24-wk culture vs. 2 wk for unsorted cardiomyocytes). Long-term culture of this purified cardiomyocyte (TMRM high) population retained the expression of cardiomyocyte markers, continued calcium cycling, and displayed cyclic electrical activity that could be regulated pharmacologically. These findings suggest that non-cardiomyocyte populations can negatively influence contractility of cardiomyocytes in culture and that by purifying cardiomyocytes, the cultures retain potential as an experimental model for longitudinal studies of cardiomyocyte biology in vitro.
Stanniocalcin-1 in the subfornical organ inhibits the dipsogenic response to angiotensin II
Authors: Moreau Jason M. , Iqbal Waseem , Turner Jeffrey K. , Wagner Graham F. , Ciriello John
Published: August 2012

Recently, receptors for the calcium-regulating glycoprotein hormone stanniocalcin-1 (STC-1) have been found within subfornical organ (SFO), a central structure involved in the regulation of electrolyte and body fluid homeostasis. However, whether SFO neurons produce STC-1 and how STC-1 may function in fluid homeostasis are not known. Two series of experiments were done in Sprague-Dawley rats to investigate whether STC-1 is expressed within SFO and whether it exerts an effect on water intake. In the first series, experiments were done to determine whether STC-1 was expressed within cells in SFO using immunohistochemistry, and whether protein and gene expression for STC-1 existed in SFO using Western blot and quantitative RT-PCR, respectively. Cells containing STC-1 immunoreactivity were found throughout the rostrocaudal extent of SFO. STC-1 protein expression within SFO was confirmed with Western blot, and SFO was also found to express STC-1 mRNA. In the second series, microinjections (200 nl) of STC-1, ANG II, a combination of the two or the vehicle were made into SFO in conscious, unrestrained rats. Water intake was measured at 0700 for a 1-h period after each injection in animals. Microinjections of STC-1 (17.6 or 176 nM) alone had no effect on water intake compared with controls. However, STC-1 not only attenuated the drinking responses to ANG II for about 30 min, but also decreased the total water intake over the 1-h period. These data suggest that STC-1 within the SFO may act in a paracrine/autocrine manner to modulate the neuronal responses to blood-borne ANG II. These findings also provide the first direct evidence of a physiological role for STC-1 in central regulation of body fluid homeostasis.
Remodeling of intrinsic cardiac neurons: effects of β-adrenergic receptor blockade in guinea pig models of chronic heart disease
Authors: Hardwick Jean C. , Southerland E. Marie , Girasole Allison E. , Ryan Shannon E. , Negrotto Sara , Ardell Jeffrey L.
Published: August 2012

Chronic heart disease induces remodeling of cardiac tissue and associated neuronal components. Treatment of chronic heart disease often involves pharmacological blockade of adrenergic receptors. This study examined the specific changes in neuronal sensitivity of guinea pig intrinsic cardiac neurons to autonomic modulators in animals with chronic cardiac disease, in the presence or absence of adrenergic blockage. Myocardial infarction (MI) was produced by ligature of the coronary artery and associated vein on the dorsal surface of the heart. Pressure overload (PO) was induced by a banding of the descending dorsal aorta (∼20% constriction). Animals were allowed to recover for 2 wk and then implanted with an osmotic pump (Alzet) containing either timolol (2 mg·kg−1·day−1) or vehicle, for a total of 6–7 wk of drug treatment. At termination, intracellular recordings from individual neurons in whole mounts of the cardiac plexus were used to assess changes in physiological responses. Timolol treatment did not inhibit the increased sensitivity to norepinephrine seen in both MI and PO animals, but it did inhibit the stimulatory effects of angiotensin II on the norepinephrine-induced increases in neuronal excitability. Timolol treatment also inhibited the increase in synaptically evoked action potentials observed in PO animals with stimulation of fiber tract bundles. These results demonstrate that β-adrenergic blockade can inhibit specific aspects of remodeling within the intrinsic cardiac plexus. In addition, this effect was preferentially observed with active cardiac disease states, indicating that the β-receptors were more influential on remodeling during dynamic disease progression.
Epicatechin limits renal injury by mitochondrial protection in cisplatin nephropathy
Authors: Tanabe Katsuyuki , Tamura Yoshifuru , Lanaspa Miguel A. , Miyazaki Makoto , Suzuki Norihiko , Sato Waichi , Maeshima Yohei , Schreiner George F. , Villarreal Francisco J. , Johnson Richard J. , Nakagawa Takahiko
Published: August 2012

Cisplatin nephropathy can be regarded as a mitochondrial disease. Intervention to halt such deleterious injury is under investigation. Recently, the flavanol (–)-epicatechin emerges as a novel compound to protect the cardiovascular system, owing in part to mitochondrial protection. Here, we have hypothesized that epicatechin prevents the progression of cisplatin-induced kidney injury by protecting mitochondria. Epicatechin was administered 8 h after cisplatin injury was induced in the mouse kidney. Cisplatin significantly induced renal dysfunction and tubular injury along with an increase in oxidative stress. Mitochondrial damages were also evident as a decrease in loss of mitochondrial mass with a reduction in the oxidative phosphorylation complexes and low levels of MnSOD. The renal damages and mitochondrial injuries were significantly prevented by epicatechin treatment. Consistent with these observations, an in vitro study using cultured mouse proximal tubular cells demonstrated that cisplatin-induced mitochondrial injury, as revealed by a decrease in mitochondrial succinate dehydrogenase activity, an induction of cytochrome c release, mitochondrial fragmentation, and a reduction in complex IV protein, was prevented by epicatechin. Such a protective effect of epicatechin might be attributed to decreased oxidative stress and reduced ERK activity. Finally, we confirmed that epicatechin did not perturb the anticancer effect of cisplatin in HeLa cells. In conclusion, epicatechin exhibits protective effects due in part to its ability to prevent the progression of mitochondrial injury in mouse cisplatin nephropathy. Epicatechin may be a novel option to treat renal disorders associated with mitochondrial dysfunction.
Spatiotemporal structure of visual receptive fields in macaque superior colliculus
Authors: Churan Jan , Guitton Daniel , Pack Christopher C.
Published: August 2012

Saccades are useful for directing the high-acuity fovea to visual targets that are of behavioral relevance. The selection of visual targets for eye movements involves the superior colliculus (SC), where many neurons respond to visual stimuli. Many of these neurons are also activated before and during saccades of specific directions and amplitudes. Although the role of the SC in controlling eye movements has been thoroughly examined, far less is known about the nature of the visual responses in this area. We have, therefore, recorded from neurons in the intermediate layers of the macaque SC, while using a sparse-noise mapping procedure to obtain a detailed characterization of the spatiotemporal structure of visual receptive fields. We find that SC responses to flashed visual stimuli start roughly 50 ms after the onset of the stimulus and last for on average ∼70 ms. About 50% of these neurons are strongly suppressed by visual stimuli flashed at certain locations flanking the excitatory center, and the spatiotemporal pattern of suppression exerts a predictable influence on the timing of saccades. This suppression may, therefore, contribute to the filtering of distractor stimuli during target selection. We also find that saccades affect the processing of visual stimuli by SC neurons in a manner that is quite similar to the saccadic suppression and postsaccadic enhancement that has been observed in the cortex and in perception. However, in contrast to what has been observed in the cortex, decreased visual sensitivity was generally associated with increased firing rates, while increased sensitivity was associated with decreased firing rates. Overall, these results suggest that the processing of visual stimuli by SC receptive fields can influence oculomotor behavior and that oculomotor signals originating in the SC can shape perisaccadic visual perception.
Activity-dependent changes in intrinsic excitability of human spinal motoneurones produced by natural activity
Authors: Rossi Alessandro , Rossi Simone , Ginanneschi Federica
Published: August 2012

The current study was designed to evaluate activity-dependent changes intrinsic to the spinal motoneurones (MNs) associated with sustained contractions. The excitability of spinal MNs (reflected by the antidromically evoked F-wave) innervating the abductor digiti minimi muscle (ADM) was measured in 12 healthy subjects following maximum voluntary contractions (MVCs) of ADM lasting 5 s, 15 s, 30 s, and 60 s. Upon cessation of the contractions, F-waves showed a depression, which increased in depth and duration with increasing duration of contraction. Following a 5-s contraction, there was a 20% decrease, which waned in 2 min, whereas a 60-s contraction produced a 40% decrease and waned in over 15 min. The changes in excitability of peripheral motor axons produced by the MVCs were measured by recording an ADM compound muscle action potential (CMAP) of ∼50% of maximum to a constant ulnar nerve electrical stimulation. On cessation of the contractions, there was a prominent decrease in size of the CMAP: following a 5-s MVC, it produced a 10% decrease in the size of the test CMAP, which recovered in 2 min, whereas following a 60-s MVC, it produced a 30% decrease, which recovered in over 15 min. Statistical analysis (correntropy) showed a high-order mutual dependence between F-wave and CMAP, and both were significantly dependent on MVC duration. Because of the parallel excitability changes in peripheral axons and spinal MNs, our interpretation is that intrinsic excitability of the axon initial segment (i.e., where the action potential is generated) and peripheral axon segments changed in a similar, activity-dependent manner.
Cross inhibition from ON to OFF pathway improves the efficiency of contrast encoding in the mammalian retina
Authors: Liang Zhiyin , Freed Michael A.
Published: August 2012

The retina is divided into parallel and mostly independent ON and OFF pathways, but the ON pathway “cross” inhibits the OFF pathway. Cross inhibition was thought to improve signal processing by the OFF pathway, but its effect on contrast encoding had not been tested experimentally. To quantify the effect of cross inhibition on the encoding of contrast, we presented a dark flash to an in vitro preparation of the mammalian retina. We then recorded excitatory currents, inhibitory currents, membrane voltages, and spikes from OFF α-ganglion cells. The recordings were subjected to an ideal observer analysis that used Bayesian methods to determine how accurately the recordings detected the dark flash. We found that cross inhibition increases the detection accuracy of currents and membrane voltages. Yet these improvements in encoding do not fully reach the spike train, because cross inhibition also hyperpolarizes the OFF α-cell below spike threshold, preventing small signals in the membrane voltages at low contrast from reaching the spike train. The ultimate effect of cross inhibition is to increase the accuracy with which the spike train detects moderate contrast, but reduce the accuracy with which it detects low contrast. In apparent compensation for the loss of accuracy at low contrast, cross inhibition, by hyperpolarizing the OFF α-cell, reduces the number of spikes required to detect the dark flash and thereby increases encoding efficiency.