bluuebunny/crossref_metadata_2025 huggingface dataset:
The Source of Our Morality
Moral Origins
The Evolution of Virtue, Altruism, and Shame

by Christopher Boehm

Basic Books, New York, 2012. 426 pp. $28.99, C$33.50, £18.99. ISBN 9780465020485.
Authors: Zhao Buyun
Published: August 2012

Drawing on studies of primates and human hunter-gatherer populations, Boehm offers a naturalistic explanation for the development of morality.
Spare the (Elastic) Rod
Authors: Nelson Philip C.
Published: August 2012

Experiments show that at biologically relevant length scales and under conditions resembling those in cells, DNA does not behave like an elastic rod.
Bad News for Soil Carbon Sequestration?
Authors: Kowalchuk George A.
Published: August 2012

Arbuscular mycorrhizal fungi may stimulate additional decomposition of organic carbon in the soil, resulting in a net source of carbon dioxide.
A Crystal-Clear View of an Extinct Girl's Genome
Authors: Gibbons Ann
Published: August 2012

Researchers report online in
Science
this week that they have sequenced the genome of an archaic Siberian girl 31 times over, using a new method that amplifies single strands of DNA.
LIFE SCIENCE TECHNOLOGIES: Panning the Proteome for Biomarker Gold
Authors: Harding Anne
Published: August 2012

Targeted proteomics is homing in on promising biomarkers to help screen for cancer and guide patient treatment, but much work still needs to be done to validate these biomarkers and develop technology capable of bringing them to the clinic.
Evaluation of Methods for Identification and Determination of the Taxonomic Status of Strains Belonging to the Streptococcus porcinus-Streptococcus pseudoporcinus Complex Isolated from Animal, Human, and Dairy Sources
Authors: Shewmaker Patricia Lynn , Steigerwalt Arnold G. , Whitney Anne M. , Morey Roger E. , Graziano James C. , Facklam Richard R. , Musser Kimberlee A. , Merquior Vânia L. C. , Teixeira Lucia M.
Published: August 2012

Ninety-seven animal, human, and dairy
Streptococcus porcinus
or
Streptococcus pseudoporcinus
isolates in the CDC
Streptococcus
strain collection were evaluated on the basis of DNA-DNA reassociation, 16S rRNA and
rpoB
gene sequencing, conventional biochemical and Rapid ID 32 Strep identification methods, and antimicrobial susceptibility testing to determine their taxonomic status, characteristics for species differentiation, antimicrobial susceptibility, and relevance of clinical source. Nineteen of the 97 isolates (1 human, 18 swine) were identified as
S. porcinus
. The remaining 72 human isolates and 6 dairy isolates were identified as
S. pseudoporcinus.
The use of 16S rRNA or
rpoB
gene sequencing was required to differentiate
S. porcinus
from
S. pseudoporcinus
. The human and dairy
S. pseudoporcinus
isolates were biochemically distinct from each other as well as distinct by 16S rRNA and
rpoB
gene sequencing. Therefore, we propose the subspecies denominations
S. pseudoporcinus
subsp
. hominis
subsp. nov. for the human isolates and
S. pseudoporcinus
subsp.
lactis
subsp. nov. for the dairy isolates. Most strains were susceptible to the antimicrobials tested, with the exception of tetracycline. Two strains of each species were also resistant to clindamycin and erythromycin and carried the
erm
(A) (
S. pseudoporcinus
) or the
erm
(B) (
S. porcinus
) gene.
S. porcinus
was identified from a single human isolate recovered from a wound in an abattoir worker.
S. pseudoporcinus
was primarily isolated from the genitourinary tract of women but was also associated with blood, placental, and wound infections. Isolates reacting with group B antiserum and demonstrating wide beta-hemolysis should be suspected of being
S. pseudoporcinus
and not
S. agalactiae
.
Rapid Determination of Lymphogranuloma Venereum Serovars of Chlamydia trachomatis by Quantitative High-Resolution Melt Analysis (HRMA)
Authors: Twin Jimmy , Stevens Matthew P. , Garland Suzanne M. , Zaia Angelo M. , Tabrizi Sepehr N.
Published: August 2012

A quantitative high-resolution melt analysis assay was developed to differentiate lymphogranuloma venereum-causing serovars of
Chlamydia trachomatis
(L1 to L3) from other
C. trachomatis
serovars (D to K). The detection limit of this assay is approximately 10 copies per reaction, comparable to the limits of other quantitative-PCR-based methods.
Comparative Evaluation of Tigecycline Susceptibility Testing Methods for Expanded-Spectrum Cephalosporin- and Carbapenem-Resistant Gram-Negative Pathogens
Authors: Zarkotou Olympia , Pournaras Spyros , Altouvas George , Pitiriga Vassiliki , Tziraki Maria , Mamali Vassiliki , Themeli-Digalaki Katerina , Tsakris Athanassios
Published: August 2012

We evaluated the Vitek2, Etest, and MIC Test Strip (MTS) methods of tigecycline susceptibility testing with 241 expanded-spectrum cephalosporin-resistant and/or carbapenem-resistant
Enterobacteriaceae
and
Acinetobacter baumannii
clinical isolates by using dry-form broth microdilution (BMD) as the reference method. The MIC
50/90
s were as follows: BMD, 1/4 μg/ml; Vitek2, 4/≥8 μg/ml; Etest, 2/4 μg/ml; MTS, 0.5/2 μg/ml. Vitek2 produced 9.1/21.2% major errors, Etest produced 0.4/0.8% major errors, and MTS produced no major errors but 0.4/3.3% very major errors (FDA/EUCAST breakpoints). Vitek2 tigecycline results require confirmation by BMD or Etest for multidrug-resistant pathogens.
Genetic Heterogeneity and Recombination in Human Type 2 Astroviruses
Authors: De Grazia S. , Medici M. C. , Pinto P. , Moschidou P. , Tummolo F. , Calderaro A. , Bonura F. , Banyai K. , Giammanco G. M. , Martella V.
Published: August 2012

Novel lineages of human astrovirus (HAstV) types 2, 2c, and 2d have been identified. Upon sequencing of the 3′ end of the genome, the type 2c and 2d HAstVs were found to be open reading frame 1b (ORF1b)-ORF2 recombinant, with ORF1b being derived from type 3 and type 1 HAstVs, respectively. An ORF2 interlineage recombinant strain, 2c/2b, was also identified.
Antibody-Independent Thrombocytopenia in Lactate Dehydrogenase-Elevating Virus-Infected Mice
Authors: Su Dan , Musaji Andrei , Legrain Sarah , Detalle Laurent , van der Kaa Jos , Verbeek J. Sjef , Ryffel Bernhard , Coutelier Jean-Paul
Published: August 2012

Previously we demonstrated that antibody-mediated thrombocytopenia is strongly enhanced by lactate dehydrogenase-elevating virus (LDV) infection. Here we report that mice infected with LDV develop a moderate thrombocytopenia, even in the absence of immunoglobulins or Fc receptors. A similar decrease of platelet counts was observed after mouse hepatitis virus infection. LDV-induced type I interferon-independent thrombocytopenia was partly suppressed by treatment with clodronate-containing liposomes. Therefore, we conclude that the thrombocytopenia results from increased phagocytosis of nonopsonized platelets by macrophages.
p33-Independent Activation of a Truncated p92 RNA-Dependent RNA Polymerase of Tomato Bushy Stunt Virus in Yeast Cell-Free Extract
Authors: Pogany Judit , Nagy Peter D.
Published: August 2012

Plus-stranded RNA viruses replicate in membrane-bound structures containing the viral replicase complex (VRC). A key component of the VRC is the virally encoded RNA-dependent RNA polymerase (RdRp), which should be activated and incorporated into the VRC after its translation. To study the activation of the RdRp of
Tomato bushy stunt virus
(TBSV), a small tombusvirus of plants, we used N-terminal truncated recombinant RdRp, which supported RNA synthesis in a cell-free yeast extract-based assay. The truncated RdRp required a
cis
-acting RNA replication element and soluble host factors, while unlike the full-length TBSV RdRp, the truncated RdRp did not need the viral p33 replication cofactor or cellular membranes for RNA synthesis. Interestingly, the truncated RdRp used 3′-terminal extension for initiation and terminated prematurely at an internal
cis
-acting element. However, the truncated RdRp could perform
de novo
initiation on a TBSV plus-strand RNA template in the presence of the p33 replication cofactor, cellular membranes, and soluble host proteins. Altogether, the data obtained with the truncated RdRp indicate that this RdRp still requires activation, but with the participation of fewer components than with the full-length RdRp, making it suitable for future studies on dissection of the RdRp activation mechanism.
Maintenance of the Flip Sequence Orientation of the Ears in the Parvoviral Left-End Hairpin Is a Nonessential Consequence of the Critical Asymmetry in the Hairpin Stem
Authors: Li Lei , Cotmore Susan F. , Tattersall Peter
Published: August 2012

Parvoviral terminal hairpins are essential for viral DNA amplification but are also implicated in multiple additional steps in the viral life cycle. The palindromes at the two ends of the minute virus of mice (MVM) genome are dissimilar and are processed by different resolution mechanisms that selectively direct encapsidation of predominantly negative-sense progeny genomes and conserve a single Flip sequence orientation at the 3′ (left) end of such progeny. The sequence and predicted structure of these 3′ hairpins are highly conserved within the genus
Parvovirus
, exemplified by the 121-nucleotide left-end sequence of MVM, which folds into a Y-shaped hairpin containing small internal palindromes that form the “ears” of the Y. To explore the potential role(s) of this hairpin in the viral life cycle, we constructed infectious clones with the ear sequences either inverted, to give the antiparallel Flop orientation, or with multiple transversions, conserving their base composition but changing their sequence. These were compared with a “bubble” mutant, designed to activate the normally silent origin in the inboard arm of the hairpin, thus potentially rendering symmetric the otherwise asymmetric junction resolution mechanism that drives maintenance of Flip. This mutant exhibited a major defect in viral duplex and single-strand DNA replication, characterized by the accumulation of covalently closed turnaround forms of the left end, and was rapidly supplanted by revertants that restored asymmetry. In contrast, both sequence and orientation changes in the hairpin ears were tolerated, suggesting that maintaining the Flip orientation of these structures is a consequence of, but not the reason for, asymmetric left-end processing.
A Novel Assay for Antibody-Dependent Cell-Mediated Cytotoxicity against HIV-1- or SIV-Infected Cells Reveals Incomplete Overlap with Antibodies Measured by Neutralization and Binding Assays
Authors: Alpert Michael D. , Heyer Lisa N. , Williams David E. J. , Harvey Jackson D. , Greenough Thomas , Allhorn Maria , Evans David T.
Published: August 2012

The resistance of human immunodeficiency virus type 1 (HIV-1) to antibody-mediated immunity often prevents the detection of antibodies that neutralize primary isolates of HIV-1. However, conventional assays for antibody functions other than neutralization are suboptimal. Current methods for measuring the killing of virus-infected cells by antibody-dependent cell-mediated cytotoxicity (ADCC) are limited by the number of natural killer (NK) cells obtainable from individual donors, donor-to-donor variation, and the use of nonphysiological targets. We therefore developed an ADCC assay based on NK cell lines that express human or macaque CD16 and a CD4+T-cell line that expresses luciferase from a Tat-inducible promoter upon HIV-1 or simian immunodeficiency virus (SIV) infection. NK cells and virus-infected targets are mixed in the presence of serial plasma dilutions, and ADCC is measured as the dose-dependent loss of luciferase activity. Using this approach, ADCC titers were measured in plasma samples from HIV-infected human donors and SIV-infected macaques. For the same plasma samples paired with the same test viruses, this assay was approximately 2 orders of magnitude more sensitive than optimized assays for neutralizing antibodies—frequently allowing the measurement of ADCC in the absence of detectable neutralization. Although ADCC correlated with other measures of Env-specific antibodies, neutralizing and gp120 binding titers did not consistently predict ADCC activity. Hence, this assay affords a sensitive method for measuring antibodies capable of directing ADCC against HIV- or SIV-infected cells expressing native conformations of the viral envelope glycoprotein and reveals incomplete overlap of the antibodies that direct ADCC and those measured in neutralization and binding assays.
Evidence thatIn VitroSusceptibility of CD3+T Lymphocytes to Equine Arteritis Virus Infection Reflects Genetic Predisposition of Naturally Infected Stallions To Become Carriers of the Virus
Authors: Go Yun Young , Bailey Ernest , Timoney Peter J. , Shuck Kathleen M. , Balasuriya Udeni B. R.
Published: August 2012

We investigated the correlation betweenin vitrosusceptibility of CD3+T lymphocytes to equine arteritis virus (EAV) infection and establishment of persistent infection among 14 stallions following natural infections. The data showed that carrier stallions with a CD3+T lymphocyte susceptibility phenotype toin vitroEAV infection may be at higher risk of becoming carriers than those that lack this phenotype (P= 0.0002).
Visualization of the Two-Step Fusion Process of the Retrovirus Avian Sarcoma/Leukosis Virus by Cryo-Electron Tomography
Authors: Cardone Giovanni , Brecher Matthew , Fontana Juan , Winkler Dennis C. , Butan Carmen , White Judith M. , Steven Alasdair C.
Published: August 2012

Retrovirus infection starts with the binding of envelope glycoproteins to host cell receptors. Subsequently, conformational changes in the glycoproteins trigger fusion of the viral and cellular membranes. Some retroviruses, such as avian sarcoma/leukosis virus (ASLV), employ a two-step mechanism in which receptor binding precedes low-pH activation and fusion. We used cryo-electron tomography to study virion/receptor/liposome complexes that simulate the interactions of ASLV virions with cells. Binding the soluble receptor at neutral pH resulted in virions capable of binding liposomes tightly enough to alter their curvature. At virion-liposome interfaces, the glycoproteins are ∼3-fold more concentrated than elsewhere in the viral envelope, indicating specific recruitment to these sites. Subtomogram averaging showed that the oblate globular domain in the prehairpin intermediate (presumably the receptor-binding domain) is connected to both the target and the viral membrane by 2.5-nm-long stalks and is partially disordered, compared with its native conformation. Upon lowering the pH, fusion took place. Fusion is a stochastic process that, once initiated, must be rapid, as only final (postfusion) products were observed. These fusion products showed glycoprotein spikes on their surface, with their interiors occupied by patches of dense material but without capsids, implying their disassembly. In addition, some of the products presented a density layer underlying and resolved from the viral membrane, which may represent detachment of the matrix protein to facilitate the fusion process.
Human CRM1 Augments Production of Infectious Human and Feline Immunodeficiency Viruses from Murine Cells
Authors: Elinav Hila , Wu Yuanfei , Coskun Ayse , Hryckiewicz Katarzyna , Kemler Iris , Hu Yani , Rogers Hilary , Hao Bing , Ben Mamoun Choukri , Poeschla Eric , Sutton Richard
Published: August 2012

Productive replication of human immunodeficiency virus type 1 (HIV-1) occurs efficiently only in humans. The posttranscriptional stages of the HIV-1 life cycle proceed poorly in mouse cells, with a resulting defect in viral assembly and release. Previous work has shown that the presence of human chromosome 2 increases HIV-1 production in mouse cells. Recent studies have shown that human chromosome region maintenance 1 (hCRM1) stimulates Gag release from rodent cells. Here we report that expressions of hCRM1 in murine cells resulted in marked increases in the production of infectious HIV-1 and feline immunodeficiency virus (FIV). HIV-1 production was also increased by hSRp40, and a combination of hCRM1 and hSRp40 resulted in a more-than-additive effect on HIV-1 release. In contrast, the overexpression of mouse CRM1 (mCRM1) minimally affected HIV-1 and FIV production and did not antagonize hCRM1. In the presence of hCRM1 there were large increases in the amounts of released capsid, which paralleled the increases in the infectious titers. Consistent with this finding, the ratios of unspliced to spliced HIV-1 mRNAs in mouse cells expressing hCRM1 and SRp40 became similar to those of human cells. Furthermore, imaging of intron-containing FIV RNA showed that hCRM1 increased RNA export to the cytoplasm.By testing chimeras between mCRM1 and hCRM1 and comparing those sequences to feline CRM1, we mapped the functional domain to HEAT (Huntingtin, elongation factor 3, protein phosphatase 2A, and the yeast kinase TOR1) repeats 4A to 9A and a triple point mutant in repeat 9A, which showed a loss of function. Structural analysis suggested that this region of hCRM1 may serve as a binding site for viral or cellular factors to facilitate lentiviral RNA nuclear export.
Frequent expression of fibroblast growth factor-23 (FGF23) mRNA in aneurysmal bone cysts and chondromyxoid fibromas
Authors: Graham Rondell , Krishnamurthy Smita , Oliveira Andre , Inwards Carrie , Folpe Andrew L
Published: August 2012

Osteomalacia has multiple aetiologies including the least common, tumour-induced osteomalacia (TIO). Recently, most cases of TIO have been confirmed to be due to phosphaturic mesenchymal tumour of mixed connective tissue type (PMTMCT). Most cases of TIO are the result of production of the fibroblast growth factor-23 (FGF-23) by the tumour. The authors recently showed reverse transcriptase PCR (RT-PCR) for FGF-23 to be valuable in the diagnosis of PMTMCT. However, the authors also noted FGF-23 expression in some cases of aneurysmal bone cyst (ABC) and chondromyxoid fibroma (CMF). For the present study, the authors studied FGF-23 expression by RT-PCR in 19 cases of ABC and eight cases of CMF, all with typical clinical and radiographic features and without evidence of TIO. Seven of 16 (44%) ABC and two of seven (29%) CMF were positive for FGF-23. These results confirm that ABC and CMF not uncommonly express FGF-23. These results strongly suggest caution and careful integration with all other clinical and radiographic data in the use of FGF-23 RT-PCR for the diagnosis of PMTMCT.
GRAPH-THEORY INDUCED GRAVITY AND STRONGLY-DEGENERATE FERMIONS IN A SELF-CONSISTENT EINSTEIN UNIVERSE
Authors: KAN NAHOMI , KOBAYASHI KOICHIRO , SHIRAISHI KIYOSHI
Published: August 2012

We study UV-finite theory of induced gravity. We use scalar fields, Dirac fields and vector fields as matter fields whose one-loop effects induce the gravitational action. To obtain the mass spectrum that satisfies the UV-finiteness condition, we use a graph-based construction of mass matrices. The existence of a self-consistent static solution for an Einstein universe is shown in the presence of degenerate fermions.
INTRA-LEFT VENTRICULAR FLOW DISTRIBUTIONS IN DIASTOLIC AND SYSTOLIC PHASES, BASED ON ECHO VELOCITY FLOW MAPPING OF NORMAL SUBJECTS AND HEART FAILURE PATIENTS, TO CHARACTERIZE LEFT VENTRICULAR PERFORMANCE OUTCOMES OF HEART FAILURE
Authors: LE THU-THAO , TAN RU-SAN , HUANG FEIQIONG , ZHONG LIANG , IDAPALAPATI SRIDHAR , GHISTA DHANJOO
Published: August 2012

Heart failure (HF), one of the most common diseases in the world, causes left ventricular dysfunction (LV) and high mortality. HF patients are stratified into two groups based on their LV ejection fraction (EF) — HF with normal EF (HFNEF) and with reduced EF (HFREF). EF is a commonly used measure of LV contractile performance. Despite preserved EF, a complex mixture of systolic and diastolic dysfunction and variable degrees of LV remodelling underlying HFNEF poses challenges to diagnose and provide pharmacological treatment for HFNEF. In recent years, the velocity flow mapping (VFM) technique has been developed to generate flow velocity vector fields by post-processing color Doppler echocardiographic (echo) images. We aim to obtain the intra-LV blood flow patterns for patients with HFNEF, HFREF, and normal subjects, in order to characterize the LV performance outcomes of normal subjects and HF patients.

Two subjects from each group of HFNEF, HFREF, and normal underwent echo scans. Velocity vector distributions throughout the cardiac cycle were then analysed using the VFM technique. In each subject, the outflow rate during systole, inflow rate during diastole, as well as wall stress-based pressure-normalized contractility index, dσ*/dtmax, were computed and compared among the groups.

This study demonstrated the use of VFM to visualize LV blood flow patterns in HF patients and normal subjects. Different patterns of flow distributions were observed in these subjects. In HFREF patients, dσ*/dtmax, the peak outflow rate and peak inflow rate during early filling were markedly reduced. In HFNEF patients, peak outflow rates were increased compared to those of normal subjects.
WHAT ARE THE LIMITS ON COMMERCIAL BANK LENDING?
Authors: MALLETT JACKY
Published: August 2012

Analysis of the 2007–2008 credit crisis has concentrated on issues of relaxed lending standards, and the perception of irrational behavior by speculative investors in real estate and other assets. Asset backed securities have been extensively criticized for creating a moral hazard in loan issuance and an associated increase in default risk, by removing the immediate lender's incentive to ensure that the underlying loans could be repaid. However significant monetary issues can accompany any form of increased commercial bank lending, and these appear to have been overlooked by this analysis. In this paper we propose a general explanation for credit crises based on an examination of the mechanics of the banking system, and in particular its internal controls on the supply of credit. We suggest that the current credit crisis is the result of multiple failures in the Basel regulatory framework, including the removal of central bank reserve requirements from some classes of deposit accounts within the banking system, allowing financial instruments representing debt to be used as regulatory capital, and in particular the introduction of securitized lending which effectively removed a previously implicit control over the total quantity of lending originating from the banking system. We further argue that the interaction of these problems has led to a destabilizing imbalance between total money and loan supply growth, in that total lending sourced from the commercial bank sector increased at a faster rate than accompanying growth in the money supply. This not only created a multi-decade macro-economic debt spiral, but by increasing the ratio of debt to money within the monetary system acted to increase the risk of loan defaults, and consequentially reduce the overall stability of the banking system.
AN IMPROVED QSPR STUDY OF REVERSE FACTOR OF NANOPARTICLES IN ROADSIDE ATMOSPHERE ON KERNEL PARTIAL LEAST SQUARES AND GENETIC ALGORITHM
Authors: MEHDIKHANI ALI , LOTFIZADEH HAMID REZA , ARMAN KAMYAR , NOORIZADEH HADI
Published: August 2012

Thermal desorption-comprehensive two-dimensional gas chromatography high-resolution time-of-flight mass spectrometry (TD–GC × GC–HRTOF-MS) is one of the most powerful tools in analytical nanoparticle compounds. Genetic algorithm and partial least square (GA-PLS) and kernel PLS (GA-KPLS) models were used to investigate the correlation between reverse factor (RF) and descriptors for 50 nanoparticles fraction with a diameter of 29–58 nm in roadside atmosphere which obtained by TD–GC×GC–HRTOF-MS. The correlation coefficient leave-group-out cross validation (LGO-CV (Q2)) of prediction for the GA-PLS and GA-KPLS models for training and test sets were (0.761 and 0.718) and (0.825 and 0.814), respectively, revealing the reliability of these models. This is the first research on the quantitative structure-property relationship (QSPR) of the nanoparticles in roadside atmosphere using the GA-PLS and GA-KPLS.
A COMPUTATIONAL METHOD FOR FUZZY TIME SERIES FORECASTING BASED ON DIFFERENCE PARAMETERS
Authors: JOSHI BHAGAWATI P. , KUMAR SANJAY
Published: August 2012

Present study proposes a method for fuzzy time series forecasting based on difference parameters. The developed method has been presented in a form of simple computational algorithm. It utilizes various difference parameters being implemented on current state for forecasting the next state values to accommodate the possible vagueness in the data in an efficient way. The developed model has been simulated on the historical student enrollments data of University of Alabama and the obtained forecasted values have been compared with the existing methods to show its superiority. Further, the developed model has also been implemented in forecasting the movement of market prices of share of State Bank of India (SBI) at Bombay Stock Exchange (BSE), India.
Estimation of Dynamic Term Structure Models
Authors: Duffee Gregory R. , Stanton Richard H.
Published: August 2012

We study the finite-sample properties of some of the standard techniques used to estimate modern term structure models. For sample sizes and models similar to those used in most empirical work, we reach three surprising conclusions. First, while maximum likelihood works well for simple models, it produces strongly biased parameter estimates when the model includes a flexible specification of the dynamics of interest rate risk. Second, despite having the same asymptotic efficiency as maximum likelihood, the small-sample performance of Efficient Method of Moments (a commonly used method for estimating complicated models) is unacceptable even in the simplest term structure settings. Third, the linearized Kalman filter is a tractable and reasonably accurate estimation technique, which we recommend in settings where maximum likelihood is impractical.
The Importance of Angel Investing in Financing the Growth of Entrepreneurial Ventures
Authors: Shane Scott
Published: August 2012

Investigation of the role of angel investing in financing private businesses in the US is important. Many observers consider angel investments to be one of the key drivers behind the startup and growth of new businesses (Council on Competitiveness, 2007), despite a paucity of information to confirm whether or not this is true. Unlike venture capital investments, angel investments are made by individual investors who do not make up a known population. Therefore, much of what is reported about angel investing comes from anecdotes and surveys of convenience samples, which are prone to biases and inaccuracies. Moreover, research on this topic is plagued by definitional confusion, in which different investigators confound informal investors, friends and family who invest in startups, accredited and unaccredited angel investors, and individual and group investing; this confusion makes it difficult to compare findings across studies. This report seeks to provide an accurate understanding of the role of angel investing in the entrepreneurial finance system. It defines angel investing and reviews the current state of understanding of the phenomenon, focusing on answering four questions: (1) How large is the angel capital market? (2) How much demand is there for angel capital? (3) What are the primary characteristics of angel investments? (4) What do the companies that receive angel financing look like? It answers these questions by reviewing the literature, providing a statistical evaluation of data sources drawn from representative samples of known populations, examining new non-representative surveys of angel investors, and comparing the results of these new analyses to previous studies of non-representative samples of business angels.
PERFECT ALLOYS FOR SPIN HALL CURRENT-INDUCED MAGNETIZATION SWITCHING
Authors: GRADHAND MARTIN , FEDOROV DMITRY V. , ZAHN PETER , MERTIG INGRID , OTANI YOSHICHIKA , NIIMI YASUHIRO , VILA LAURENT , FERT ALBERT
Published: August 2012

We propose a device that allows for magnetization switching in nanomagnets by means of a pure spin current induced by the spin Hall effect. For this purpose we combine the ideas of magnetization switching of a ferromagnet by a spin current produced via the spin accumulation at a ferromagnet/nonmagnet interface with the electronic measurement of the direct spin Hall effect, and the theoretical material design to identify systems with a large spin Hall angle and an appropriate spin diffusion length. We will discuss the device design with respect to the size of the charge and spin currents. Based on ab initio calculations, we predict dilute alloys ideally suited for this application. Noble metals with single-sheeted Fermi surfaces, doped with either heavy impurities like Bi and Pb in Cu or Bi in Ag and light impurities like C and N in Au , seem to be the best candidates for a spin Hall angle larger than 5%.
Mutation Load: The Fitness of Individuals in Populations Where Deleterious Alleles Are Abundant
Authors: Agrawal Aneil F. , Whitlock Michael C.
Published: August 2012

Many multicellular eukaryotes have reasonably high per-generation mutation rates. Consequently, most populations harbor an abundance of segregating deleterious alleles. These alleles, most of which are of small effect individually, collectively can reduce substantially the fitness of individuals relative to what it would be otherwise; this is mutation load. Mutation load can be lessened by any factor that causes more mutations to be removed per selective death, such as inbreeding, synergistic epistasis, population structure, or harsh environments. The ecological effects of load are not clear-cut because some conditions (such as selection early in life, sexual selection, reproductive compensation, and intraspecific competition) reduce the effects of load on population size and persistence, but other conditions (such as interspecific competition and load on resource use efficiency) can cause small amounts of load to have strong effects on the population, even extinction. We suggest a series of studies to improve our understanding of the effects of mutation load.
From Animalcules to an Ecosystem: Application of Ecological Concepts to the Human Microbiome
Authors: Fierer Noah , Ferrenberg Scott , Flores Gilberto E. , González Antonio , Kueneman Jordan , Legg Teresa , Lynch Ryan C. , McDonald Daniel , Mihaljevic Joseph R. , O'Neill Sean P. , Rhodes Matthew E. , Song Se Jin , Walters William A.
Published: August 2012

The human body is inhabited by billions of microbial cells and these microbial symbionts play critical roles in human health. Human-associated microbial communities are diverse, and the structure of these communities is variable across body habitats, through time, and between individuals. We can apply concepts developed by plant and animal ecologists to better understand and predict the spatial and temporal patterns in these communities. Due to methodological limitations and the largely unknown natural history of most microbial taxa, this integration of ecology into research on the human microbiome is still in its infancy. However, such integration will yield a deeper understanding of the role of the microbiome in human health and an improved ability to test ecological concepts that are more difficult to test in plant and animal systems.
Recurrent Evolution of Dependent Colony Foundation Across Eusocial Insects
Authors: Cronin Adam L. , Molet Mathieu , Doums Claudie , Monnin Thibaud , Peeters Christian
Published: August 2012

The spectacular success of eusocial insects can be attributed to their sophisticated cooperation, yet cooperation is conspicuously absent during colony foundation when queens are alone. Selection against this solitary stage has led to a dramatically different strategy in thousands of eusocial insect species in which colonies are started by groups of nestmates and the benefits of sociality are retained continuously. Dependent colony foundation (DCF) evolved recurrently multiple times across the ants, bees, and wasps, though its prevalence in termites remains unclear. We review adaptations at both the colony level (reproductive investment shifts from sexuals to workers) and the individual level (wingless queens evolve in ants), and other consequences for life history (invasiveness, parasite transmission). Although few studies have focused on DCF, the accumulated data from anecdotal reports, supported by indirect information including morphology, population genetics, and colony demographics, make it clear that this strategy is more diverse and widespread than is usually recognized.
Chromosome Replication and Segregation in Bacteria
Authors: Reyes-Lamothe Rodrigo , Nicolas Emilien , Sherratt David J.
Published: August 2012

In dividing cells, chromosome duplication once per generation must be coordinated with faithful segregation of newly replicated chromosomes and with cell growth and division. Many of the mechanistic details of bacterial replication elongation are well established. However, an understanding of the complexities of how replication initiation is controlled and coordinated with other cellular processes is emerging only slowly. In contrast to eukaryotes, in which replication and segregation are separate in time, the segregation of most newly replicated bacterial genetic loci occurs sequentially soon after replication. We compare the strategies used by chromosomes and plasmids to ensure their accurate duplication and segregation and discuss how these processes are coordinated spatially and temporally with growth and cell division. We also describe what is known about the three conserved families of ATP-binding proteins that contribute to chromosome segregation and discuss their inter-relationships in a range of disparate bacteria.
Disentangling the Many Layers of Eukaryotic Transcriptional Regulation
Authors: Lelli Katherine M. , Slattery Matthew , Mann Richard S.
Published: August 2012

Regulation of gene expression in eukaryotes is an extremely complex process. In this review, we break down several critical steps, emphasizing new data and techniques that have expanded current gene regulatory models. We begin at the level of DNA sequence where cis-regulatory modules (CRMs) provide important regulatory information in the form of transcription factor (TF) binding sites. In this respect, CRMs function as instructional platforms for the assembly of gene regulatory complexes. We discuss multiple mechanisms controlling complex assembly, including cooperative DNA binding, combinatorial codes, and CRM architecture. The second section of this review places CRM assembly in the context of nucleosomes and condensed chromatin. We discuss how DNA accessibility and histone modifications contribute to TF function. Lastly, new advances in chromosomal mapping techniques have provided increased understanding of intra- and interchromosomal interactions. We discuss how these topological maps influence gene regulatory models.
Regeneration and Transdetermination in Drosophila Imaginal Discs
Authors: Worley Melanie I. , Setiawan Linda , Hariharan Iswar K.
Published: August 2012

The study of regeneration in Drosophila imaginal discs provides an opportunity to use powerful genetic tools to address fundamental problems pertaining to tissue regeneration and cell plasticity. We present a historical overview of the field and describe how the application of modern methods has made the study of disc regeneration amenable to genetic analysis. Discs respond to tissue damage in several ways: (a) Removal of part of the disc elicits localized cell proliferation and regeneration of the missing tissue. (b) Damage at specific locations in the disc can cause cells to generate disc-inappropriate structures (e.g., wing instead of leg), a phenomenon known as transdetermination. (c) Diffuse damage to imaginal discs, results in compensatory proliferation of surviving cells. Candidate-gene approaches have implicated the JNK, Wingless, and Hippo pathways in regeneration. Recently developed systems will enable extensive genetic screens that could provide new insights into tissue regeneration, transdetermination and compensatory proliferation.
Empirical Studies of Contract
Authors: Eigen Zev J.
Published: August 2012

Since the mid-2000s, a cottage industry has slowly blossomed of empirical research dedicated to advancing our knowledge of contracts on the books—accounting for what contracts tend to purportedly obligate signers to do—and contracts in action—accounting for how contracting parties tend to behave. This article reviews this literature, focusing on the past seven years, and identifies eight questions organized by two propositions that span across disciplines that have most contributed empirical research on contracts, such as law, economics, and management. The article highlights key findings and points of consensus in this research and notes areas most pressingly in need of additional research.
Legacies of Legal Realism: The Sociology of Criminal Law and Criminal Justice
Authors: Skolnick Jerome H.
Published: August 2012

In this article, I trace the history of the sociology of law from its roots at Yale Law School to the present. The legal realists, situated at Yale Law in the 1930s, saw the law as an instrument of policy. Building on this foundation, the Yale Law faculty pioneered the sociology of law in the 1950s, and the Russell Sage Foundation supported the then-emerging field's development in the 1960s. Philip Selznick was a major theorist and institution builder in the field, and my own writing has stressed how the sociology of law has challenged American ideology regarding economic, gender, and social equality. Nowhere is this more evident today than in the current racial distribution of the prison population. The legal realist vision first developed at Yale Law—of constitutional law as an instrument of social policy—was also confirmed by the most recent 2012 US Supreme Court decisions on immigration and health care.
Vitamin D improves the angiogenic properties of endothelial progenitor cells
Authors: Grundmann M. , Haidar M. , Placzko S. , Niendorf R. , Darashchonak N. , Hubel C. A. , von Versen-Höynck F.
Published: August 2012

The main pathogenic feature of preeclampsia is maternal endothelial dysfunction that results from impaired angiogenesis and reduced endothelial repair capacity. In addition, preeclampsia risk is associated with vitamin D deficiency. We hypothesized that vitamin D3 stimulates proangiogenic properties of endothelial colony-forming cells (ECFCs). ECFCs were obtained and cultured from cord blood and characterized by immunocytochemistry and flow cytometry. Proliferation, total length of tubule formation on Matrigel, expression of VEGF mRNA, and pro-matrix metalloproteinases (MMP)-2 activity were assessed after treatment of ECFCs with vitamin D3. Specificity of the observed effects was tested by blocking the vitamin D receptor (VDR) or the VEGF signaling pathway. ECFCs treated with 10 nM vitamin D3 showed a 1.27 times higher tubule formation compared with vehicle-treated controls (1.27 ± 0.19) as well as a 1.36 times higher proliferation rate (1.36 ± 0.06). Vitamin D3 induced pro-MMP-2 activity (1.29 ± 0.17) and VEGF mRNA levels (1.74 ± 0.73) in ECFCs. VDR blocking by pyridoxal-5-phosphate (0.73 ± 0.19) or small interfering RNA (0.75 ± 0.17) and VEGF inhibition by Su5416 (0.56 ± 0.16) or soluble fms-like tyrosine kinase-1 (0.7 ± 0.14) reduced tubule formation and pro-MMP-2 activity (pyridoxal-5-phosphate: 0.84 ± 0.09; Su5416: 0.79 ± 0.11; or sFlt: 0.88 ± 0.13). This effect was neutralized by vitamin D3. Consequently, vitamin D3 significantly promoted angiogenesis in ECFCs in vitro possibly due to an increase in VEGF expression and pro-MMP-2 activity. Since angiogenesis is a crucial feature in the pathophysiology of preeclampsia these findings could explain the positive influence of vitamin D3 in reducing preeclampsia risk.
Apolipoprotein E does not cross the blood-cerebrospinal fluid barrier, as revealed by an improved technique for sampling CSF from mice
Authors: Liu Min , Kuhel David G. , Shen Ling , Hui David Y. , Woods Stephen C.
Published: August 2012

Apolipoprotein E (apoE) is a 34-kDa glycoprotein that is important in lipoprotein metabolism both peripherally and centrally. Because it is primarily produced in the liver, apoE observed in the brain or cerebrospinal fluid (CSF) could have originated in the periphery; i.e., circulating apoE may cross the blood-brain barrier (BBB) and/or enter CSF and be taken up by brain cells. To determine whether this occurs, a second-generation adenovirus encoding human apoE3 was administered intravenously (iv) to C57BL/6J mice, and the detection of human apoE3 in the CSF was used as a surrogate measure of central availability of this protein utilizing an improved method for sampling CSF from mice. This improved technique collects mouse CSF samples with a 92% success rate and consistently yields relatively large volumes of CSF with a very low rate of blood contamination, as determined by molecular assessment of apolipoprotein B, a plasma-derived protein that is absent in the central nervous system. Through this improved method, we demonstrated that in mice receiving the administered apoE3 adenovirus, human apoE3 was expressed at high levels in the liver, leading to high levels of human apoE3 in mouse plasma. In contrast, human apoE3 levels in the CSF, as assessed by a sensitive ELISA, were essentially undetectable in human apoE3 adenovirus-treated mice, and comparable to levels in LacZ adenovirus-treated control mice. These data indicate that apoE in the CSF cannot be derived from the plasma pool and, therefore, must be synthesized locally in the brain.
A physiological increase in insulin suppresses gluconeogenic gene activation in fetal sheep with sustained hypoglycemia
Authors: Thorn Stephanie R. , Sekar Satya M. , Lavezzi Jinny R. , O'Meara Meghan C. , Brown Laura D. , Hay William W. , Rozance Paul J.
Published: August 2012

Reduced maternal glucose supply to the fetus and resulting fetal hypoglycemia and hypoinsulinemia activate fetal glucose production as a means to maintain cellular glucose uptake. However, this early activation of fetal glucose production may be accompanied by hepatic insulin resistance. We tested the capacity of a physiological increase in insulin to suppress fetal hepatic gluconeogenic gene activation following sustained hypoglycemia to determine whether hepatic insulin sensitivity is maintained. Control fetuses (CON), hypoglycemic fetuses induced by maternal insulin infusion for 8 wk (HG), and 8 wk HG fetuses that received an isoglycemic insulin infusion for the final 7 days (HG+INS) were studied. Glucose and insulin concentrations were 60% lower in HG compared with CON fetuses. Insulin was 50% higher in HG+INS compared with CON and four-fold higher compared with HG fetuses. Expression of the hepatic gluconeogenic genes, PCK1, G6PC, FBP1, GLUT2, and PGC1A was increased in the HG and reduced in the HG+INS liver. Expression of the insulin-regulated glycolytic and lipogenic genes, PFKL and FAS, was increased in the HG+INS liver. Total FOXO1 protein expression, a gluconeogenic activator, was 60% higher in the HG liver. Despite low glucose, insulin, and IGF1 concentrations, phosphorylation of AKT and ERK was higher in the HG liver. Thus, a physiological increase in fetal insulin is sufficient for suppression of gluconeogenic genes and activation of glycolytic and lipogenic genes in the HG fetal liver. These results demonstrate that fetuses exposed to sustained hypoglycemia have maintained hepatic insulin action in contrast to fetuses exposed to placental insufficiency.
Evidence for an interaction of neuronostatin with the orphan G protein-coupled receptor, GPR107
Authors: Yosten Gina L. C. , Redlinger Lauren J. , Samson Willis K.
Published: August 2012

Neuronostatin, derived from the somatostatin preprohormone, is a recently described peptide that is produced by several tissues involved in cardiovascular regulation and metabolism, including the hypothalamus. Injection of neuronostatin into the lateral cerebroventricle led to a dose-related increase in mean arterial pressure (MAP) in rats. Any attempt to inhibit the production of neuronostatin would alter somatostatin production as well, making determination of the physiological relevance of the peptide's pharmacologic effects by compromise of production approaches impossible. Therefore, we employed an alternative approach to identify and compromise the production of the neuronostatin receptor. Because neuronostatin was shown to signal via a PKA-dependent mechanism, we hypothesized that the neuronostatin receptor was a G protein-coupled receptor (GPCR), in particular, one of the orphan GPCRs for which the ligand is unknown. Therefore, we screened neuronostatin-responsive tissues, including hypothalamus, heart, pancreatic α-cells, and the gastric tumor cell line KATOIII, for expression of orphan GPCRs. Four orphan GPCRs were expressed by all cell types, including GPR56 and GPR107. Knockdown of GPR107, but not GPR56 or GPR146, led to a loss of responsiveness to neuronostatin by KATOIII cells. Rats injected with siRNA directed against GPR107 (2 μg/day for 2 days) into the lateral cerebroventricle did not exhibit an increase in MAP in response to neuronostatin treatment. Rats with compromised GPR107 expression also displayed blunted reactivity in a baroreflex sensitivity test, indicating that GPR107 and neuronostatin may be important regulators of cardiovascular function. Thus, GPR107 is a promising candidate receptor for neuronostatin, and neuronostatin, interacting with GPR107, may play an important role in the central control of cardiovascular function.
Prostaglandin E2mediates proliferation and chloride secretion in ADPKD cystic renal epithelia
Authors: Liu Yu , Rajagopal Madhumitha , Lee Kim , Battini Lorenzo , Flores Daniel , Gusella G. Luca , Pao Alan C. , Rohatgi Rajeev
Published: August 2012

Prostaglandin E2(PGE2) contributes to cystogenesis in genetically nonorthologous models of autosomal dominant polycystic kidney disease (ADPKD). However, it remains unknown whether PGE2induces the classic features of cystic epithelia in genetically orthologous models of ADPKD. We hypothesized that, in ADPKD epithelia, PGE2induces proliferation and chloride (Cl−) secretion, two archetypal phenotypic features of ADPKD. To test this hypothesis, proliferation and Cl−secretion were measured in renal epithelial cells deficient in polycystin-1 (PC-1). PC-1-deficient cells increased in cell number (proliferated) faster than PC-1-replete cells, and this proliferative advantage was abrogated by cyclooxygenase inhibition, indicating a role for PGE2in cell proliferation. Exogenous administration of PGE2increased proliferation of PC-1-deficient cells by 38.8 ± 5.2% ( P < 0.05) but inhibited the growth of PC-1-replete control cells by 49.4 ± 1.9% ( P < 0.05). Next, we tested whether PGE2-specific E prostanoid (EP) receptor agonists induce intracellular cAMP and downstream β-catenin activation. PGE2and EP4 receptor agonism (TCS 2510) increased intracellular cAMP concentration and the abundance of active β-catenin in PC-1-deficient cells, suggesting a mechanism for PGE2-mediated proliferation. Consistent with this hypothesis, antagonizing EP4 receptors reverted the growth advantage of PC-1-deficient cells, implicating a central role for the EP4 receptor in proliferation. To test whether PGE2-dependent Cl−secretion is also enhanced in PC-1-deficient cells, we used an Ussing chamber to measure short-circuit current ( Isc). Addition of PGE2induced a fivefold higher increase in Iscin PC-1-deficient cells compared with PC-1-replete cells. This PGE2-induced increase in Iscin PC-1-deficient cells was blocked by CFTR-172 and flufenamic acid, indicating that PGE2activates CFTR and calcium-activated Cl−channels. In conclusion, PGE2activates aberrant signaling pathways in PC-1-deficient epithelia that contribute to the proliferative and secretory phenotype characteristic of ADPKD and suggests a therapeutic role for PGE2inhibition and EP4 receptor antagonism.