bluuebunny/crossref_metadata_2025 huggingface dataset:
The Changing Shape of Global Inequality 1820–2000; Exploring a New Dataset
Authors: van Zanden Jan Luiten , Baten Joerg , Foldvari Peter , van Leeuwen Bas
Published: January 2013

A new dataset for charting the development of global inequality between 1820 and 2000 is presented, based on a large variety of sources and methods for estimating (gross household) income inequality. On this basis we estimate the evolution of global income inequality over the past two centuries. Two sets of benchmarks about between‐country inequality (the Maddison 1990 benchmark and the recent 2005 ICP round) are taken into account. We find that between 1820 and 1950, increasing per capita income is combined with increasing global inequality. After 1950, global inequality as measured by the Gini coefficient or the Theil index remains more or less constant. It also appears that the global income distribution was uni‐modal in the nineteenth century, became increasingly bi‐modal between 1910 and 1970 with two world wars, a depression and de‐globalization, and was suddenly transformed back into a uni‐modal distribution between 1980 and 2000.
Complexity in Language Acquisition
Authors: Clark Alexander , Lappin Shalom
Published: January 2013

Learning theory has frequently been applied to language acquisition, but discussion has largely focused on information theoretic problems—in particular on the absence of direct negative evidence. Such arguments typically neglect the probabilistic nature of cognition and learning in general. We argue first that these arguments, and analyses based on them, suffer from a major flaw: they systematically conflate the hypothesis class and the learnable concept class. As a result, they do not allow one to draw significant conclusions about the learner. Second, we claim that the real problem for language learning is the computational complexity of constructing a hypothesis from input data. Studying this problem allows for a more direct approach to the object of study—the language acquisition device—rather than the learnable class of languages, which is epiphenomenal and possibly hard to characterize. The learnability results informed by complexity studies are much more insightful. They strongly suggest that target grammars need to be objective, in the sense that the primitive elements of these grammars are based on objectively definable properties of the language itself. These considerations support the view that language acquisition proceeds primarily through data‐driven learning of some form.
What Should Be the Data Sharing Policy of Cognitive Science?
Authors: Pitt Mark A. , Tang Yun
Published: January 2013

There is a growing chorus of voices in the scientific community calling for greater openness in the sharing of raw data that lead to a publication. In this commentary, we discuss the merits of sharing, common concerns that are raised, and practical issues that arise in developing a sharing policy. We suggest that the cognitive science community discuss the topic and establish a data‐sharing policy.
Actively Learning Object Names Across Ambiguous Situations
Authors: Kachergis George , Yu Chen , Shiffrin Richard M.
Published: January 2013

Previous research shows that people can use the co‐occurrence of words and objects in ambiguous situations (i.e., containing multiple words and objects) to learn word meanings during a brief passive training period (Yu & Smith, 2007). However, learners in the world are not completely passive but can affect how their environment is structured by moving their heads, eyes, and even objects. These actions can indicate attention to a language teacher, who may then be more likely to name the attended objects. Using a novel active learning paradigm in which learners choose which four objects they would like to see named on each successive trial, this study asks whether active learning is superior to passive learning in a cross‐situational word learning context. Finding that learners perform better in active learning, we investigate the strategies and discover that most learners use immediate repetition to disambiguate pairings. Unexpectedly, we find that learners who repeat only one pair per trial—an easy way to infer this pair—perform worse than those who repeat multiple pairs per trial. Using a working memory extension to an associative model of word learning with uncertainty and familiarity biases, we investigate individual differences that correlate with these assorted strategies.
Human Semi‐Supervised Learning
Authors: Gibson Bryan R. , Rogers Timothy T. , Zhu Xiaojin
Published: January 2013

Most empirical work in human categorization has studied learning in either fully supervised or fully unsupervised scenarios. Most real‐world learning scenarios, however, are semi‐supervised: Learners receive a great deal of unlabeled information from the world, coupled with occasional experiences in which items are directly labeled by a knowledgeable source. A large body of work in machine learning has investigated how learning can exploit both labeled and unlabeled data provided to a learner. Using equivalences between models found in human categorization and machine learning research, we explain how these semi‐supervised techniques can be applied to human learning. A series of experiments are described which show that semi‐supervised learning models prove useful for explaining human behavior when exposed to both labeled and unlabeled data. We then discuss some machine learning models that do not have familiar human categorization counterparts. Finally, we discuss some challenges yet to be addressed in the use of semi‐supervised models for modeling human categorization.
Bilateral Trade and the Eurozone: Evidence from New Member Countries
Authors: Jagelka Tomáš
Published: January 2013

The question of whether and how much currency unions increase bilateral trade among their members has garnered much attention since Rose’s seminal article. The answer is as pertinent now as ever for both the Eurozone’s existing and future members as the financial crisis shook the very foundations of the European Monetary Union (EMU) and brought its shortcomings into the spotlight. This paper analyses the issue using the gravity equation with country pair and time fixed effects. For a sample of the four new members of the EMU – Slovakia, Slovenia, Malta and Cyprus – which has, to the author’s knowledge, not been studied thus far due to their recent joining, and controls drawn from the European Union, this paper finds a positive relationship between joining the EMU and trade with EMU partners but not with non‐EMU partners.
Mapping procedures can produce non-centered auditory images in bilateral cochlear implantees
Authors: Goupell Matthew J. , Kan Alan , Litovsky Ruth Y.
Published: January 2013

Good localization accuracy depends on an auditory spatial map that provides consistent binaural information across frequency and level. This study investigated whether mapping bilateral cochlear implants (CIs) independently contributes to distorted perceptual spatial maps. In a meta-analysis, interaural level differences necessary to perceptually center sound images were calculated for 127 pitch-matched pairs of electrodes; many needed large current adjustments to be perceptually centered. In a separate experiment, lateralization was also found to be inconsistent across levels. These findings suggest that auditory spatial maps are distorted in the mapping process, which likely reduces localization accuracy and target-noise separation in bilateral CIs.
Coherent processing of shipping noise for ocean monitoring
Authors: Lani Shane W. , Sabra Karim G. , Hodgkiss William S. , Kuperman W. A. , Roux Philippe
Published: January 2013

Ambient noise was recorded on two vertical line arrays (VLAs) separated by 450 m and deployed in shallow water (depth ∼150 m) off San Diego, CA continuously for 6 days. Recordings were dominated by non-stationary and non-uniform broadband shipping noise (250 Hz to 1.5 kHz). Stable coherent noise wavefronts were extracted from ambient noise correlations between the VLAs during all 6 days by mitigating the effect of discrete shipping events and using array beamforming with data-derived steering vectors. This procedure allows the tracking of arrival-time variations of these coherent wavefronts during 6 days and may help in developing future passive acoustic tomography systems.
The internal representation of vowel spectra investigated using behavioral response-triggered averaging
Authors: Owen Brimijoin W. , Akeroyd Michael A. , Tilbury Emily , Porr Bernd
Published: January 2013

Listeners presented with noise were asked to press a key whenever they heard the vowels [a] or [i:]. The noise had a random spectrum, with levels in 60 frequency bins changing every 0.5 s. Reverse correlation was used to average the spectrum of the noise prior to each key press, thus estimating the features of the vowels for which the participants were listening. The formant frequencies of these reverse-correlated vowels were similar to those of their respective whispered vowels. The success of this response-triggered technique suggests that it may prove useful for estimating other internal representations, including perceptual phenomena like tinnitus.
Response to Comment on "Extinction Debt and Windows of Conservation Opportunity in the Brazilian Amazon"
Authors: Wearn Oliver R. , Reuman Daniel C. , Ewers Robert M.
Published: January 2013

Halley
et al
. purport to show a power-law relationship between fragment size and relaxation rates. We use a much more extensive data set to show that area dependence of relaxation rates exists only for very small fragment sizes (<60 hectares), which has limited relevance for our analyses conducted using 250,000-hectare grid squares. We also show that the example of Halley
et al
. is based on an unrealistic fragmentation model with an infinite number of fragments that have average size of zero hectares. A more realistic formulation of the model shows that relaxation is much less dependent on fragmentation than Halley
et al
. present.
GDE2 Promotes Neurogenesis by Glycosylphosphatidylinositol-Anchor Cleavage of RECK
Authors: Park Sungjin , Lee Changhee , Sabharwal Priyanka , Zhang Mei , Meyers Caren L. Freel , Sockanathan Shanthini
Published: January 2013

Signaling Differentiation

The six-transmembrane protein GDE2 promotes differentiation through extracellular glycerophosphodiester phosphodiesterase (GDPD) activity and induces neuronal differentiation through inhibition of Notch signaling—a major pathway that maintains stem or progenitor cell states and is implicated in multiple cancers. How then, does GDPD activity inhibit Notch signaling, given that GDPD enzymes are known to metabolize glycerophosphodiesters into glycerol-3-phosphate and corresponding alcohols?

Park
et al.

(p.
324
) show that the six-transmembrane GDPDs such as GDE2, do not function as conventional GDPD enzymes, but instead cleave the glycosylphosphatidylinositol (GPI) anchors of GPI-anchored proteins. GDE2 GDPD activity cleaves and inactivates the GPI-anchored protein RECK, which normally acts to prevent shedding of the Notch ligand Delta. Accordingly, RECK inactivation stimulates Delta shedding leading to Notch inactivation in progenitors and the initiation of cellular differentiation.
Neutralizing Tumor-Promoting Chronic Inflammation: A Magic Bullet?
Authors: Coussens Lisa M. , Zitvogel Laurence , Palucka A. Karolina
Published: January 2013

A Shift in Cancer's Inflammatory Balance

One of the many factors that contribute to the initiation and progression of cancer is inflammation. Inflammation can support tumor development, both directly and indirectly, and tumors can promote a chronic inflammatory environment that results in immunosuppression, which benefits the tumor.

Coussens
et al.

(p.
286
) review the components of the immune system that contribute to the chronic inflammation seen in tumors. Potential therapies might shift this inflammatory environment toward one more characteristic of an acute, resolving inflammation, similar to what is observed during a pathogenic infection. Such a shift would relieve immunosuppression and drive antitumor immunity that, when combined with other therapies, may ultimately result in tumor cell clearance.
Polymer Rigidity Improves Microporous Membranes
Authors: Guiver Michael D. , Lee Young Moo
Published: January 2013

Microporous membranes with rigid polymer chains have high gas permeability but can separate gas molecules of slightly different sizes.

[Also see Report by

Carta
et al.

]
Re-Engineering Nature's Catalysts
Authors: Narayan Alison R. H. , Sherman David H.
Published: January 2013

An engineered enzyme catalyzes a reaction that is fundamentally different from that catalyzed by the natural enzyme.

[Also see Report by

Coelho
et al.

]
Genetic Types, Gene Repertoire, and Evolution of Isolates of the Salmonella enterica Serovar 4,5,12:i:− Spanish Clone Assigned to Different Phage Types
Authors: García Patricia , Malorny Burkhard , Hauser Elisabeth , Mendoza M. Carmen , Rodicio M. Rosario
Published: January 2013

Salmonella enterica
subsp.
enterica
4,[5],12:i:− is one of the most prevalent serovars associated with human infections worldwide. Two multidrug-resistant clones, designated Spanish and European clones, are recognized as having importance for public health and are subject to control measures in the European Union. In this study, 23 clinical isolates belonging to the Spanish clone were characterized by multilocus sequence typing, multiple-locus variable number tandem repeat analysis (MLVA), PCR amplification and sequencing, and a DNA microarray targeting 263 genes, in order to provide new insights into their origins and further evolution. The derived data were compared with information available from other studies for
S
. 4,[5],12:i:− isolates of both the Spanish and the European clones, to identify differential molecular markers which could be potentially used as surveillance tools in the control of dissemination of this serovar. The isolates analyzed were assigned to sequence type 19 and to 17 MLVA patterns, with 3-13-16-NA-311 being the most prevalent. Highly similar virulence, metabolic, and prophage-associated gene profiles were identified, but DNA mobility markers distinguished five genotypes. Two types of deletions, caused by insertion of IS
26
, presumably donated by pUO-STmR/RV1-like plasmids typically found in the Spanish clone, affected the
fljAB
operon and surrounding DNA. The Spanish and European clones differ in sequence type, MLVA patterns, gene repertoire, and
fljAB
deletion type. The observed variability supports an independent evolution of the two successful monophasic clones from different
Salmonella enterica
serovar Typhimurium ancestors and can be taken into consideration for epidemiological surveillance.
Evaluation of Epstein-Barr Virus, Human Herpesvirus 6 (HHV-6), and HHV-8 Antiviral Drug Susceptibilities by Use of Real-Time-PCR-Based Assays
Authors: Bounaadja Lotfi , Piret Jocelyne , Goyette Nathalie , Boivin Guy
Published: January 2013

Evaluation of candidate antiviral drugs against Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), and HHV-8 is hampered by the lack of convenient laboratory assays. We developed real-time quantitative PCR assays performed on supernatants of lymphoma cell lines and determined the 50% inhibitory concentrations (IC
50
s) of nucleoside, nucleotide, and pyrophosphate analogues against these herpesviruses.
An N-Terminal Amphipathic Helix in Dengue Virus Nonstructural Protein 4A Mediates Oligomerization and Is Essential for Replication
Authors: Stern Omer , Hung Yu-Fu , Valdau Olga , Yaffe Yakey , Harris Eva , Hoffmann Silke , Willbold Dieter , Sklan Ella H.
Published: January 2013

Dengue virus (DENV) causes dengue fever, a major health concern worldwide. We identified an amphipathic helix (AH) in the N-terminal region of the viral nonstructural protein 4A (NS4A). Disruption of its amphipathic nature using mutagenesis reduced homo-oligomerization and abolished viral replication. These data emphasize the significance of NS4A in the life cycle of the dengue virus and demarcate it as a target for the design of novel antiviral therapy.
Timeless-Dependent DNA Replication-Coupled Recombination Promotes Kaposi's Sarcoma-Associated Herpesvirus Episome Maintenance and Terminal Repeat Stability
Authors: Dheekollu Jayaraju , Chen Horng-Shen , Kaye Kenneth M. , Lieberman Paul M.
Published: January 2013

Kaposi's Sarcoma-associated herpesvirus (KSHV) is maintained as a stable episome in latently infected pleural effusion lymphoma (PEL) cells. Episome maintenance is conferred by the binding of the KSHV-encoded LANA protein to the viral terminal repeats (TR). Here, we show that DNA replication in the KSHV TR is coupled with DNA recombination and mediated in part through the cellular replication fork protection factors Timeless (Tim) and Tipin. We show by two-dimensional (2D) agarose gel electrophoresis that replication forks naturally stall and form recombination-like structures at the TR during an unperturbed cell cycle. Chromatin immunoprecipitation (ChIP) assays revealed that Tim and Tipin are selectively enriched at the KSHV TR during S phase and in a LANA-dependent manner. Tim depletion inhibited LANA-dependent TR DNA replication and caused the loss of KSHV episomes from latently infected PEL cells. Tim depletion resulted in the aberrant accumulation of recombination structures and arrested MCM helicase at TR. Tim depletion did not induce the KSHV lytic cycle or apoptotic cell death. We propose that KSHV episome maintenance requires Tim-assisted replication fork protection at the viral terminal repeats and that Tim-dependent recombination-like structures form at TR to promote DNA repeat stability and viral genome maintenance.
T-705 (Favipiravir) Induces Lethal Mutagenesis in Influenza A H1N1 Viruses
In Vitro
Authors: Baranovich Tatiana , Wong Sook-San , Armstrong Jianling , Marjuki Henju , Webby Richard J. , Webster Robert G. , Govorkova Elena A.
Published: January 2013

Several novel anti-influenza compounds are in various phases of clinical development. One of these, T-705 (favipiravir), has a mechanism of action that is not fully understood but is suggested to target influenza virus RNA-dependent RNA polymerase. We investigated the mechanism of T-705 activity against influenza A (H1N1) viruses by applying selective drug pressure over multiple sequential passages in MDCK cells. We found that T-705 treatment did not select specific mutations in potential target proteins, including PB1, PB2, PA, and NP. Phenotypic assays based on cell viability confirmed that no T-705-resistant variants were selected. In the presence of T-705, titers of infectious virus decreased significantly (
P
< 0.0001) during serial passage in MDCK cells inoculated with seasonal influenza A (H1N1) viruses at a low multiplicity of infection (MOI; 0.0001 PFU/cell) or with 2009 pandemic H1N1 viruses at a high MOI (10 PFU/cell). There was no corresponding decrease in the number of viral RNA copies; therefore, specific virus infectivity (the ratio of infectious virus yield to viral RNA copy number) was reduced. Sequence analysis showed enrichment of G→A and C→T transversion mutations, increased mutation frequency, and a shift of the nucleotide profiles of individual NP gene clones under drug selection pressure. Our results demonstrate that T-705 induces a high rate of mutation that generates a nonviable viral phenotype and that lethal mutagenesis is a key antiviral mechanism of T-705. Our findings also explain the broad spectrum of activity of T-705 against viruses of multiple families.
Comparative Proteomic Analysis of HIV-1 Particles Reveals a Role for Ezrin and EHD4 in the Nef-Dependent Increase of Virus Infectivity
Authors: Brégnard Christelle , Zamborlini Alessia , Leduc Marjorie , Chafey Philippe , Camoin Luc , Saïb Ali , Benichou Serge , Danos Olivier , Basmaciogullari Stéphane
Published: January 2013

Nef is a human immunodeficiency virus type 1 (HIV-1) auxiliary protein that plays an important role in virus replication and the onset of acquired immunodeficiency. Although known functions of Nef might explain its contribution to HIV-1-associated pathogenesis, how Nef increases virus infectivity is still an open question.
In vitro
, Nef-deleted viruses have a defect that prevents efficient completion of early steps of replication. We have previously shown that this restriction is not due to the absence of Nef in viral particles. Rather, a loss of function in virus-producing cells accounts for the lower infectivity of
nef
-deleted viruses compared to wild-type (WT) viruses. Here we used DiGE and iTRAQ to identify differences between the proteomes of WT and
nef
-deleted viruses. We observe that glucosidase II is enriched in WT virions, whereas Ezrin, ALG-2, CD81, and EHD4 are enriched in
nef
-deleted virions. Functional analysis shows that glucosidase II, ALG-2, and CD81 have no or only Nef-independent effect on infectivity. In contrast, Ezrin and EHD4 are involved in the ability of Nef to increase virus infectivity (referred to thereafter as Nef potency). Indeed, simultaneous Ezrin and EHD4 depletion in SupT1 and 293T virus-producing cells result in an ∼30 and ∼70% decrease of Nef potency, respectively. Finally, while Ezrin behaves as an inhibitory factor counteracted by Nef, EHD4 should be considered as a cofactors required by Nef to increase virus infectivity.
Simian Immunodeficiency Virus Infects Follicular Helper CD4 T Cells in Lymphoid Tissues during Pathogenic Infection of Pigtail Macaques
Authors: Xu Yin , Weatherall Chris , Bailey Michelle , Alcantara Sheilajen , De Rose Robert , Estaquier Jerome , Wilson Kim , Suzuki Kazuo , Corbeil Jacques , Cooper David A. , Kent Stephen J. , Kelleher Anthony D. , Zaunders John
Published: January 2013

T follicular helper (Tfh) cells are a specialized subset of memory CD4
+
T cells that are found exclusively within the germinal centers of secondary lymphoid tissues and are important for adaptive antibody responses and B cell memory. Tfh cells do not express CCR5, the primary entry coreceptor for both human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV), and therefore, we hypothesized that these cells would avoid infection. We studied lymph nodes and spleens from pigtail macaques infected with pathogenic strain SIVmac239 or SIVmac251, to investigate the susceptibility of Tfh cells to SIV infection. Pigtail macaque PD-1
high
CD127
low
memory CD4
+
T cells have a phenotype comparable to that of human Tfh cells, expressing high levels of CXCR5, interleukin-21 (IL-21), Bcl-6, and inducible T cell costimulator (ICOS). As judged by either proviral DNA or cell-associated viral RNA measurements, macaque Tfh cells were infected with SIV at levels comparable to those in other CD4
+
memory T cells. Infection of macaque Tfh cells was evident within weeks of inoculation, yet we confirmed that Tfh cells do not express CCR5 or either of the well-known alternative SIV coreceptors, CXCR6 and GPR15. Mutations in the SIV envelope gp120 region occurred in chronically infected macaques but were uniform across each T cell subset investigated, indicating that the viruses used the same coreceptors to enter different cell subsets. Early infection of Tfh cells represents an unexpected focus of viral infection. Infection of Tfh cells does not interrupt antibody production but may be a factor that limits the quality of antibody responses and has implications for assessing the size of the viral reservoir.
Toscana Virus NSs Protein Promotes Degradation of Double-Stranded RNA-Dependent Protein Kinase
Authors: Kalveram Birte , Ikegami Tetsuro
Published: January 2013

Toscana virus (TOSV), which is transmitted by
Phlebotomus
spp. sandflies, is a major etiologic agent of aseptic meningitis and encephalitis in the Mediterranean. Like other members of the genus
Phlebovirus
of the family
Bunyaviridae
, TOSV encodes a nonstructural protein (NSs) in its small RNA segment. Although the NSs of Rift Valley fever virus (RVFV) has been identified as an important virulence factor, which suppresses host general transcription, inhibits transcription from the beta interferon promoter, and promotes the proteasomal degradation of double-stranded RNA-dependent protein kinase (PKR), little is known about the functions of NSs proteins encoded by less-pathogenic members of this genus. In this study we report that TOSV is able to downregulate PKR with similar efficiency as RVFV, while infection with the other phleboviruses—i.e., Punta Toro virus, sandfly fever Sicilian virus, or Frijoles virus—has no effect on cellular PKR levels. In contrast to RVFV, however, cellular transcription remains unaffected during TOSV infection. TOSV NSs protein promotes the proteasome-dependent downregulation of PKR and is able to interact with kinase-inactive PKR in infected cells.
PEGylation of Vesicular Stomatitis Virus Extends Virus Persistence in Blood Circulation of Passively Immunized Mice
Authors: Tesfay Mulu Z. , Kirk Amber C. , Hadac Elizabeth M. , Griesmann Guy E. , Federspiel Mark J. , Barber Glen N. , Henry Stephen M. , Peng Kah-Whye , Russell Stephen J.
Published: January 2013

We are developing oncolytic vesicular stomatitis viruses (VSVs) for systemic treatment of multiple myeloma, an incurable malignancy of antibody-secreting plasma cells that are specifically localized in the bone marrow. One of the presumed advantages for using VSV as an oncolytic virus is that human infections are rare and preexisting anti-VSV immunity is typically lacking in cancer patients, which is very important for clinical success. However, our studies show that nonimmune human and mouse serum can neutralize clinical-grade VSV, reducing the titer by up to 4 log units in 60 min. In addition, we show that neutralizing anti-VSV antibodies negate the antitumor efficacy of VSV, a concern for repeat VSV administration. We have investigated the potential use of covalent modification of VSV with polyethylene glycol (PEG) or a function-spacer-lipid (FSL)–PEG construct to inhibit serum neutralization and to limit hepatosplenic sequestration of systemically delivered VSV. We report that in mice passively immunized with neutralizing anti-VSV antibodies, PEGylation of VSV improved the persistence of VSV in the blood circulation, maintaining a more than 1-log-unit increase in VSV genome copies for up to 1 h compared to the genome copy numbers for the non-PEGylated virus, which was mostly cleared within 10 min after intravenous injection. We are currently investigating if this increase in PEGylated VSV circulating half-life can translate to increased virus delivery and better efficacy in mouse models of multiple myeloma.
Characterization of the Bhanja Serogroup Viruses (Bunyaviridae): a Novel Species of the Genus Phlebovirus and Its Relationship with Other Emerging Tick-Borne Phleboviruses
Authors: Matsuno Keita , Weisend Carla , Travassos da Rosa Amelia P. A. , Anzick Sarah L. , Dahlstrom Eric , Porcella Stephen F. , Dorward David W. , Yu Xue-Jie , Tesh Robert B. , Ebihara Hideki
Published: January 2013

Bhanja virus (BHAV) and its antigenically close relatives Forecariah virus (FORV), Kismayo virus (KISV), and Palma virus (PALV) are thought to be members of the family
Bunyaviridae
, but they have not been assigned to a genus or species. Despite their broad geographical distribution and reports that BHAV causes sporadic cases of febrile illness and encephalitis in humans, the public health importance of the Bhanja serogroup viruses remains unclear, due in part to the lack of sequence and biochemical information for the virus proteins. In order to better define the molecular characteristics of this group, we determined the full-length sequences of the L, M, and S genome segments of multiple isolates of BHAV as well as FORV and PALV. The genome structures of these Bhanja viruses are similar to those of viruses belonging to the genus
Phlebovirus
. Functional domains and amino acid motifs in the viral proteins that are conserved among other known phleboviruses were also identified in proteins of the BHAV group. Phylogenetic and serological analyses revealed that the BHAVs are most closely related to the novel emerging tick-borne phleboviruses severe fever with thrombocytopenia syndrome virus and Heartland virus, which have recently been implicated as causing severe acute febrile illnesses associated with thrombocytopenia in humans in China and the United States. Our results indicate that the Bhanja serogroup viruses constitute a single novel species in the genus
Phlebovirus
. The results of this study should facilitate epidemiological surveillance for other, similar tick-borne phleboviruses that may represent unrecognized causes of febrile illness in humans.
Adaptation to the Interferon-Induced Antiviral State by Human and Simian Immunodeficiency Viruses
Authors: Bitzegeio Julia , Sampias Marissa , Bieniasz Paul D. , Hatziioannou Theodora
Published: January 2013

The production of type I interferon (IFN) is an early host response to different infectious agents leading to the induction of hundreds of IFN-stimulated genes (ISGs). The roles of many ISGs in host defense are unknown, but their expression results in the induction of an “antiviral state” that inhibits the replication of many viruses. Here we show that prototype primate lentiviruses human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus of macaques (SIV
MAC
and SIV
MNE
) can replicate in lymphocytes from their usual hosts (humans and macaques, respectively), even when an antiviral state is induced by IFN-α treatment. In contrast, HIV-1 and SIV
MAC
/SIV
MNE
replication was hypersensitive to IFN-α in lymphocytes from unnatural hosts, indicating that the antiviral state can effectively curtail the replication of primate lentiviruses in hosts to which they are not adapted. Most of the members of a panel of naturally occurring HIV-1 and HIV-2 strains behaved like prototype strains and were comparatively insensitive to IFN-α in human lymphocytes. Using chimeric viruses engineered to overcome restriction factors whose antiretroviral specificities vary in a species-dependent manner, we demonstrate that differential HIV-1 and SIV
MAC
sensitivities to IFN-α in lymphocytes from humans and macaques could not be ascribed to TRIM5, APOBEC3, tetherin, or SAMHD1. Single-cycle infection experiments indicated that at least part of this species-specific, IFN-α-induced restriction of primate lentivirus replication occurs early in the retroviral life cycle. Overall, these studies indicate the existence of undiscovered, IFN-α-inducible antiretroviral factors whose spectrum of activity varies in a species-dependent manner and to which at least some HIV/SIV strains have become adapted in their usual hosts.
Allosteric N-acetamide-indole-6-carboxylic acid thumb pocket 1 inhibitors of hepatitis C virus NS5B polymerase — Acylsulfonamides and acylsulfamides as carboxylic acid replacements
Authors: Beaulieu Pierre L. , Coulombe René , Gillard James , Brochu Christian , Duan Jianmin , Garneau Michel , Jolicoeur Eric , Kuhn Peter , Poupart Marc-André , Rancourt Jean , Stammers Timothy A. , Thavonekham Bounkham , Kukolj George
Published: January 2013

Acylsulfonamide and acylsulfamide as surrogates for the carboxylic acid function of N-acetamide-indole-6-carboxylic acids were evaluated as allosteric inhibitors of hepatitis C virus (HCV) NS5B polymerase. Several analogs displayed excellent antiviral potency against both 1a and 1b HCV genotypes in cell-based subgenomic replicon assays. Structure–activity relationships (SAR) are discussed in the context of the crystal structure of an inhibitor − NS5B polymerase complex. Absorption, distribution, metabolism, and excretion pharmacokinetic (ADME-PK) properties of this class of inhibitors are also described.
Continuous-flow synthesis of [11C]raclopride, a positron emission tomography radiotracer, on a microfluidic chip
Authors: Haroun Samar , Sanei Zahra , Jivan Salma , Schaffer Paul , Ruth Thomas J. , Li Paul C.H.
Published: January 2013

11C-labelled radiotracers such as [11C]raclopride are produced in a process that can take between 45 and 60 min to complete. These conventional approaches can consume upwards of 75% of the 11C (t1/2 = 20 min) due to radioactive decay alone, even more if synthesis losses are considered. To compensate, a large starting quantity of radioactive precursors such as [11C]methyl iodide is required to produce an adequate amount of the tracer for injection. In this investigation, a continuous-flow microchip is explored for the purpose of synthesizing 11C radiotracers in a shorter time by exploiting the favorable reaction kinetics of using smaller reaction volumes. To enhance the mixing of reagents within the microchannel, a micromixer “loop” design was used in fabricating various polydimethylsiloxane chip styles. With a loop design implemented in an abacus-style chip for the production of nonradioactive raclopride, shorter reaction times, reduced precursor use, and improved yields were possible when compared with the use of a simple serpentine design (no loop-style chip). However, when performing the equivalent radiochemical reaction, the results were not as favorable. Using the loop design in a full loop-style chip, parameters such as premixing the reagents, reducing flow rate, and varying reagent concentrations were explored to improve the yields of [11C]raclopride (in terms of relative radioactivity) formed. The full loop chip design produced the best results, and future work will see the polydimethylsiloxane prototype chip design translated into a glass chip for further optimization.
Selecting DFT methods for use in optimizations of enzyme active sites: applications to ONIOM treatments of DNA glycosylases
Authors: Kellie Jennifer L. , Wetmore Stacey D.
Published: January 2013

When using a hybrid methodology to treat an enzymatic reaction, many factors contribute to selecting the method for the high-level region, which can be complicated by the presence of dispersion-driven interactions such as π–π stacking. In addition, the proper treatment of the reaction center often requires a large number of heavy atoms to be included in the high-level region, precluding the use of ab initio methods such as MP2 as well as large basis sets, in the optimization step. In the present work, popular DFT methods were tested to identify an appropriate functional for treating the high-level region in ONIOM optimizations of reactions catalyzed by nonmetalloenzymes. Eight different DFT methods (B3LYP, B97-2, MPW1K, MPWB1K, BB1K, B1B95, M06-2X, and ωB97X-D) in combination with four double-ζ quality Pople basis sets were tested for their ability to optimize noncovalent interactions (hydrogen bonding and π–π) and characterize reactions (proton transfer, SN2 hydrolysis, and unimolecular cleavage). Although the primary focus of this study is accurate structure determination, energetics were also examined at both the optimization level of theory, and with triple-ζ quality basis set and select (M06-2X or ωB97X-D) methods. If dispersion-driven interactions exist within the active site, then MPWB1K/6-31G(d,p) or M06-2X/6-31+G(d,p) are recommended for the optimization step with subsequent triple-ζ quality single-point energies. However, since dispersion-corrected functionals (M06-2X and ωB97X-D) generally require diffuse functions to yield appropriate geometries, the possible size of the high-level region is greatly limited with these methods. In contrast, if the model is large enough to recover steric constraints on π–π interactions, then B3LYP with a small basis set performs comparatively well for the optimization step and is significantly less computationally expensive. Interestingly, the functionals that afford the best geometries often do not yield the best energetics, which emphasizes the importance of structural benchmark studies.
A California Current bomb radiocarbon reference chronology and petrale sole (Eopsetta jordani) age validation
Authors: Haltuch Melissa A. , Hamel Owen S. , Piner Kevin R. , McDonald Patrick , Kastelle Craig R. , Field John C.
Published: January 2013

As petrale sole (Eopsetta jordani) is a valuable groundfish harvested in the California Current, proper ageing is important for its assessment and management. This study presents the first bomb radiocarbon reference chronology for the California Current and petrale sole age validation. Break-and-burn and surface ages are negatively biased by approximately 1 year and 2–3 years, respectively. The reference and validation curves are more variable and show a lag in the rate of radiocarbon increase in comparison to most other time series of bomb radiocarbon in marine systems. Upwelling in the California Current produces a lagged rate of increase in radiocarbon levels owing to the introduction and mixing of radiocarbon-depleted deep waters with surface waters that interact with the atmosphere. The variable and lagged rate of radiocarbon increase in the petrale sole data may be due to their spending a substantial portion of their first year of life in areas subject to variable upwelling, illustrating the importance of using reference curves for age validation that are region and species specific when possible.
Maximum survival of eggs as the key parameter of stock–recruit meta-analysis: accounting for parameter and structural uncertainty
Authors: Pulkkinen Henni , Mäntyniemi Samu
Published: January 2013

Despite their name, hierarchical stock–recruit meta-analyses are often parameterized in terms of steepness, which depends not only on the assumed stock–recruitment relationship but also on the recruit–spawner relationship. This parameterization requires assumptions about the reproductive potential of the recruit that are not desirable if the focus of the study is limited to the spawning–recruitment phase instead of the full life cycle. Thus, usage of steepness should be avoided in studies that aim to produce informative priors for the stock–recruit relationship for use in studies of other salmon stocks. An alternative key parameter for stock–recruit models is the maximum survival of eggs, which is the slope at the origin of the stock–recruitment curve when spawning stock size is defined in terms of the number of eggs. Furthermore, the current widely used practices in stock–recruit modeling could be improved by taking into account the stock-specific model uncertainty. We use the method of Bayesian model averaging to build a hierarchical stock–recruit model that allows stock-specific model structures with Beverton–Holt, Ricker, and hockey stick models as alternatives, all of which can be parameterized with the maximum survival of eggs. We illustrate our approach by analyzing nine previously published datasets for Atlantic salmon (Salmo salar).
Stable isotope turnover and variability in tail hairs of captive and free-ranging African elephants (Loxodonta africana) reveal dietary niche differences within populations
Authors: Codron Jacqueline , Kirkman Kevin , Duffy Kevin J. , Sponheimer Matt , Lee-Thorp Julia A. , Ganswindt Andre , Clauss Marcus , Codron Daryl
Published: January 2013

Many herbivore species expand their dietary niche breadths by switching from browse-rich diets in dry seasons to grass-rich diets in rainy seasons, in response to phenological changes in plant availability and quality. We analyzed stable isotope series along tail hairs of captive and free-ranging African elephant (Loxodonta africana (Blumenbach, 1797)) to compare patterns of seasonal dietary variability across individuals. Results from elephants translocated from the wild into captivity, where their diets are semicontrolled, revealed tail hair growth rates of ∼0.34 mm/day, on average, and relatively rapid isotope turnover through the transition from wild into captivity. Sampling hairs at 10 mm increments thus archives dietary chronologies at a resolution suitable for tracking diet switches at seasonal, and even subseasonal, scales. Hairs of free-ranging elephants showed extensive carbon isotopic variability within individuals, consistent with seasonal switches between C3-browsing and C4-grazing. Similarly extensive, but asynchronous, shifts in nitrogen isotope ratios were also observed, suggesting an influence of factors other than seasonality. Across individuals, switching patterns differed across habitats, and across age classes, with older, larger animals including increasing amounts of C3browse into their diets. These results demonstrate how stable isotope approaches characterize complex patterns of resource use in wildlife populations.
FROM BINDING MOTIFS IN CHIP-SEQ DATA TO IMPROVED MODELS OF TRANSCRIPTION FACTOR BINDING SITES
Authors: KULAKOVSKIY IVAN , LEVITSKY VICTOR , OSHCHEPKOV DMITRY , BRYZGALOV LEONID , VORONTSOV ILYA , MAKEEV VSEVOLOD
Published: January 2013

Chromatin immunoprecipitation followed by deep sequencing (ChIP-Seq) became a method of choice to locate DNA segments bound by different regulatory proteins. ChIP-Seq produces extremely valuable information to study transcriptional regulation. The wet-lab workflow is often supported by downstream computational analysis including construction of models of nucleotide sequences of transcription factor binding sites in DNA, which can be used to detect binding sites in ChIP-Seq data at a single base pair resolution. The most popular TFBS model is represented by positional weight matrix (PWM) with statistically independent positional weights of nucleotides in different columns; such PWMs are constructed from a gapless multiple local alignment of sequences containing experimentally identified TFBSs. Modern high-throughput techniques, including ChIP-Seq, provide enough data for careful training of advanced models containing more parameters than PWM. Yet, many suggested multiparametric models often provide only incremental improvement of TFBS recognition quality comparing to traditional PWMs trained on ChIP-Seq data. We present a novel computational tool, diChIPMunk, that constructs TFBS models as optimal dinucleotide PWMs, thus accounting for correlations between nucleotides neighboring in input sequences. diChIPMunk utilizes many advantages of ChIPMunk, its ancestor algorithm, accounting for ChIP-Seq base coverage profiles ("peak shape") and using the effective subsampling-based core procedure which allows processing of large datasets. We demonstrate that diPWMs constructed by diChIPMunk outperform traditional PWMs constructed by ChIPMunk from the same ChIP-Seq data. Software website: http://autosome.ru/dichipmunk/
Shank2 contributes to the apical retention and intracellular redistribution of NaPiIIa in OK cells
Authors: Dobrinskikh Evgenia , Lanzano Luca , Rachelson Joanna , Cranston DeeAnn , Moldovan Radu , Lei Tim , Gratton Enrico , Doctor R. Brian
Published: January 2013

In renal proximal tubule (PT) cells, sodium-phosphate cotransporter IIa (NaPiIIa) is normally concentrated within the apical membrane where it reabsorbs ∼70% of luminal phosphate (Pi). NaPiIIa activity is acutely regulated by moderating its abundance within the apical membrane. Under low-Pi conditions, NaPiIIa is retained within the apical membrane. Under high-Pi conditions, NaPiIIa is retrieved from the apical membrane and trafficked to the lysosomes for degradation. The present study investigates the role of Shank2 in regulating the distribution of NaPiIIa. In opossum kidney cells, a PT cell model, knockdown of Shank2 in cells maintained in low-Pi media resulted in a marked decrease in NaPiIIa abundance. After being transferred into high-Pi media, live-cell imaging showed that mRFP-Shank2E and GFP-NaPiIIa underwent endocytosis and trafficked together through the subapical domain. Fluorescence cross-correlation spectroscopy demonstrated that GFP-NaPiIIa and mRFP-Shank2 have indistinguishable diffusion coefficients and migrated through the subapical domain in temporal synchrony. Raster image cross-correlation spectroscopy demonstrated these two proteins course through the subapical domain in temporal-spatial synchrony. In the microvilli of cells under low-Pi conditions and in the subapical domain of cells under high-Pi conditions, fluorescence lifetime imaging microscopy-Forster resonance energy transfer analysis of Cer-NaPiIIa and EYFP-Shank2E found these fluors reside within 10 nm of each other. Demonstrating a complexity of functions, in cells maintained under low-Pi conditions, Shank2 plays an essential role in the apical retention of NaPiIIa while under high-Pi conditions Shank2 remains associated with NaPiIIa and escorts NaPiIIa through the cell interior.
Substrate specificity of the electrogenic sodium/bicarbonate cotransporter NBCe1-A (SLC4A4, variant A) from humans and rabbits
Authors: Lee Seong-Ki , Boron Walter F. , Parker Mark D.
Published: January 2013

In the basolateral membrane of proximal-tubule cells, NBCe1-A (SLC4A4, variant A), operating with an apparent Na+:HCO3−stoichiometry of 1:3, contributes to the reclamation of HCO3−from the glomerular filtrate, thereby preventing whole body acidosis. Others have reported that NBCe1-like activity in human, rabbit, and rat renal preparations is substantially influenced by lithium, sulfite, oxalate, and harmaline. These data were taken as evidence for the presence of distinct Na+and CO32−binding sites in NBCe1-A, favoring a model of 1 Na+:1 HCO3−:1 CO32−. Here, we reexamine these findings by expressing human or rabbit NBCe1-A clones in Xenopus oocytes. In oocytes, NBCe1-A exhibits a 1:2 stoichiometry and could operate in one of five thermodynamically equivalent transport modes: 1) cotransport of Na++ 2 HCO3−, 2) cotransport of Na++ CO32−, 3) transport of NaCO3−, 4) exchange of Na++ HCO3−for H+, or 5) HCO3−-activated exchange of Na+for 2 H+. In contrast to the behavior of NBCe1-like activity in renal preparations, we find that cloned NBCe1-A is only slightly stimulated by Li+, not at all influenced by sulfite or oxalate, and only weakly inhibited by harmaline. These negative data do not uniquely support any of the five models above. In addition, we find that NBCe1-A mediates a small amount of Na+-independent NO3−transport and that NBCe1-A is somewhat inhibited by extracellular benzamil. We suggest that the features of NBCe1-like activity in renal preparations are influenced by yet-to-be-identified renal factors. Thus the actual ionic substrates of NBCe1 remain to be identified.
Encoding of ultrasonic vocalizations in the auditory cortex
Authors: Carruthers Isaac M. , Natan Ryan G. , Geffen Maria N.
Published: January 2013

One of the central tasks of the mammalian auditory system is to represent information about acoustic communicative signals, such as vocalizations. However, the neuronal computations underlying vocalization encoding in the central auditory system are poorly understood. To learn how the rat auditory cortex encodes information about conspecific vocalizations, we presented a library of natural and temporally transformed ultrasonic vocalizations (USVs) to awake rats while recording neural activity in the primary auditory cortex (A1) with chronically implanted multielectrode probes. Many neurons reliably and selectively responded to USVs. The response strength to USVs correlated strongly with the response strength to frequency-modulated (FM) sweeps and the FM rate tuning index, suggesting that related mechanisms generate responses to USVs as to FM sweeps. The response strength further correlated with the neuron's best frequency, with the strongest responses produced by neurons whose best frequency was in the ultrasonic frequency range. For responses of each neuron to each stimulus group, we fitted a novel predictive model: a reduced generalized linear-nonlinear model (GLNM) that takes the frequency modulation and single-tone amplitude as the only two input parameters. The GLNM accurately predicted neuronal responses to previously unheard USVs, and its prediction accuracy was higher than that of an analogous spectrogram-based linear-nonlinear model. The response strength of neurons and the model prediction accuracy were higher for original, rather than temporally transformed, vocalizations. These results indicate that A1 processes original USVs differentially than transformed USVs, indicating preference for temporal statistics of the original vocalizations.