bluuebunny/crossref_metadata_2025 huggingface dataset:
Simple fabrication of ultrahigh aspect ratio nanostructures for enhanced antireflectivity
Authors: Dominguez Sagrario , Cornago Ignacio , Bravo Javier , Pérez-Conde Jesus , Choi Hyungryul J. , Kim Jeong-Gil , Barbastathis George
Published: March 2014

In this work, the authors present a novel fabrication process to create periodic nanostructures with aspect ratio as high as 9.6. These nanostructures reduce spectral reflectance of silicon to less than 4% over the broad wavelength region from 200 to 2000 nm. At the visible range of the spectrum, from 200 to 650 nm, reflectivity is reduced to less than 0.1%. The aspect ratio and reflectance performance that the authors achieved have never been reported before for ordered tapered nanostructures, to our knowledge.
Self-rolled-up InGaAs/GaAs microtubes fabricated directly on Si (100) substrates
Authors: Wang Qi , Wang Eryang , Pan Zhihong , Gao Yunxia , Li Bochang , Jia Zhigang , Wang Yifan , Li Xiaoyi , Zhang Xia , Ren Xiaomin , Huang Yongqing
Published: March 2014

The authors have fabricated the high-performance smooth-walled InGaAs/GaAs microtubes directly on Si (100) substrates. All the strained In0.2Ga0.8As (15 nm)/GaAs (35 nm) bilayers metamorphically grown on Si have rolled up into microtubes from the long-side of rectangular patterns. The average diameter of Si-based microtubes is ∼4.2 μm, which is slightly bigger than that of their GaAs-based counterparts. Scanning electron microscopy and atomic force microscopy measurements show that the structural properties of the Si-based InGaAs/GaAs microtubes have been quite good and nearly consistent with the GaAs-based counterparts except for very slight surface undulation.
Radioactive Decay and Penetration Depth – Why Should There Be an e?
Authors: Baird Bill
Published: March 2014

When students are first introduced to the idea of radioactive decay, a large conceptual hurdle must be overcome. The thought that an object's age has no bearing on the chance it will “die” (decay in this case) on a particular day is completely at odds with biological notions of life and death. Through the use of a simple spreadsheet, students are shown that something analogous to coin flips will yield the exponential curve describing decay. A similar spreadsheet is then used to show that the exponential curve associated with the penetration depth of radiation is produced through the use of the same kind of random process applied to slices of matter rather than slices of time. The spreadsheets model two common introductory laboratory experiments but avoid the need for Geiger counters, radioactive sources, and sheets of absorbing material.
Simulating the Phases of the Moon Shortly After Its Formation
Authors: Noordeh Emil , Hall Patrick , Cuk Matija
Published: March 2014

The leading theory for the origin of the Moon is the giant impact hypothesis, in which the Moon was formed out of the debris left over from the collision of a Marssized body with the Earth.1 Soon after its formation, the orbit of the Moon may have been very different than it is today. We have simulated the phases of the Moon in a model for its formation wherein the Moon develops a highly elliptical orbit with its major axis tangential to the Earth's orbit. This note describes these simulations and their pedagogical value.
A Non–Cell Autonomous Role of E
(
z
)
to Prevent Germ Cells from Turning on a Somatic Cell Marker
Authors: Eun Suk Ho , Shi Zhen , Cui Kairong , Zhao Keji , Chen Xin
Published: March 2014

Keeping Germ Cells Special

Germ cells separate from the somatic lineage during early metazoan development.

Eun
et al.

(p.
1513
) found that
Drosophila
germ cells lose their identity and turn on somatic cell–specific marker expression in adult testes when a Polycomb group component E(z) is inactivated in somatic cells. However, only early-stage germ cells, including germline stem cells, retain this plasticity. Thus, one role for somatic cells in male gonads is to antagonize somatic identity in germ cells.
Early Childhood Investments Substantially Boost Adult Health
Authors: Campbell Frances , Conti Gabriella , Heckman James J. , Moon Seong Hyeok , Pinto Rodrigo , Pungello Elizabeth , Pan Yi
Published: March 2014

Look After the Child

Investing in children has been demonstrated to improve their lives, both during the school-age years and afterward, as assessed by outcomes such as employment and income; furthermore, these investments often help those in the most need.

Campbell
et al.

(p.
1478
) report that these investments can also lead to improved adult health. Results from a randomized and intensive intervention that involved 122 children in four cohorts recruited in the 1970s suggest that full-day child care for the first 5 years of life has produced adults in their 30s with better metabolic and cardiovascular health measures.
Quantifying Global International Migration Flows
Authors: Abel Guy J. , Sander Nikola
Published: March 2014

Monitoring Migration

Migrant “stock” data—the number of people living in a country other than the one in which they were born—are frequently used to understand contemporary trends in international migration, but the data are severely limited.Abel and Sander(p.1520) present a set of global bilateral migration flows estimated from sequential stock data in 5-year intervals. The percentage of the world population moving over 5-year periods has not shown dramatic changes between 1995 and 2010. People from individual African countries tended to move within the continent, whereas people from Europe tended to move to very diverse locations.
Optical Broadband Angular Selectivity
Authors: Shen Yichen , Ye Dexin , Celanovic Ivan , Johnson Steven G. , Joannopoulos John D. , Soljačić Marin
Published: March 2014

Optical Angular Selection

A monochromatic electromagnetic plane wave is typically characterized by three properties: its frequency, its polarization, and its propagation direction. While the selection of light signals based on the first two properties has been studied in depth, selection based on direction is relatively unexplored but equally important.

Shen
et al.

(p.
1499
) demonstrate a simple approach that provides narrow-angle selectivity over a broad range of wavelengths using heterostructured photonic crystals that act as a mirror for all but a narrow range of viewing angles where the crystals are transparent. Such angular selection should find a number of applications in, for example, high efficiency solar energy conversion, privacy protection systems, or high signal-to-noise detectors.
Why Mineral Interfaces Matter
Authors: Putnis Andrew
Published: March 2014

Reactions at mineral-fluid interfaces play a key role in processes ranging from the deep Earth to materials synthesis and nuclear waste storage.
Tracking Subatomic Physicists

Particle Fever
Mark Levinson, director

Anthos Media, USA, 2014. 99 minutes. http://particlefever.com/
Authors: Reece Matthew
Published: March 2014

Levinson's film presents the search for the Higgs with the Large Hadron Collider in the form of a compelling, personality-driven narrative.
“The Race” to Clone
BRCA1
Authors: King Mary-Claire
Published: March 2014

The existence of
BRCA1
was proven in 1990 by mapping predisposition to young-onset breast cancer in families to chromosome 17q21. Knowing that such a gene existed and approximately where it lay triggered efforts by public and private groups to clone and sequence it. The press baptized the competition “the race” and reported on it in detail for the next 4 years.
BRCA1
was positionally cloned in September 1994. Twenty years later, I reflect on “the race” and its consequences for breast cancer prevention and treatment.
Breast Cancer—Thinking Globally
Authors: Anderson Benjamin O.
Published: March 2014

Few diseases have seen more rapid scientific progress over the past three decades than breast cancer. Beginning in the 1980s, screening mammography led to sweeping improvements in early cancer detection. At the same time, endocrine treatment and systemic chemotherapy proved life-saving. The development of drugs that target hormone receptor and
HER2/neu
oncogene signaling pathways, coupled with biomarker-based subclassification of the disease, have helped make breast cancer therapy a more precise science. Cloning of the
BRCA
genes provided insight into inherited predisposition and the opportunity for genetic testing. As a result of these advances, breast cancer death rates in the United States dropped by 34% between 1990 and 2014.
China Gets Serious About Its Pollutant-Laden Soil
Authors: Larson Christina
Published: March 2014

Last week, China's environment ministry reportedly began hammering out a plan to curb all sources of soil pollution by 2020 and to begin remediating filthy areas.
Oldest
Homo sapiens
Genome Pinpoints Neandertal Input
Authors: Gibbons Ann
Published: March 2014

The genome sequence of an ancient modern human man from Siberia helps show when early
Homo sapiens
and Neandertals interbred.
Potential Impact of Different Cytomegalovirus (CMV) IgM Assays on an Algorithm Requiring IgM Reactivity as a Criterion for Measuring CMV IgG Avidity
Authors: Prince Harry E. , Lapé-Nixon Mary , Brenner Andrew , Pitstick Nancy , Couturier Marc Roger
Published: March 2014

The measurement of cytomegalovirus (CMV) IgG avidity is a powerful tool for identifying individuals with recent CMV infection. Because such patients are expected to be positive for CMV IgM, several investigators have suggested that CMV IgG-positive sera first be screened for CMV IgM and then only the IgM-reactive sera be tested for avidity. We investigated the impact of different CMV IgM assays on such a reflexing algorithm using a panel of 369 consecutive IgG-positive serum samples submitted for avidity testing. A bead-based immunofluorescent assay (BIFA) identified 105 IgM-positive serum samples, whereas an IgM-capture enzyme immunoassay (EIA) identified 48 IgM-positive serum samples; this marked difference led us to evaluate additional CMV IgM assays. An enzyme-linked immunofluorescent assay (ELFA) and a chemiluminescent immunoassay (CIA) were used to test all sera with discordant BIFA/EIA results, all sera with concordant positive results, and selected sera with concordant negative results. The findings indicated that the ELFA would identify 74 CMV IgM-positive samples and the CIA would identify 64. Of the 23 low-avidity serum samples, 2 were IgM negative by BIFA, 3 by ELFA and CIA, and 4 by EIA; of the 23 intermediate-avidity serum samples, 6 were IgM negative by BIFA, 10 by ELFA, and 15 by EIA and CIA. In both these avidity groups, BIFA IgM-negative sera were also negative by the other 3 assays. These findings demonstrate that an algorithm requiring CMV IgM reactivity as a criterion for CMV IgG avidity testing does not identify all low-avidity sera and thus misses some cases of acute CMV infection.
A Burkholderia pseudomallei Outer Membrane Vesicle Vaccine Provides Protection against Lethal Sepsis
Authors: Nieves Wildaliz , Petersen Hailey , Judy Barbara M. , Blumentritt Carla A. , Russell-Lodrigue Kasi , Roy Chad J. , Torres Alfredo G. , Morici Lisa A.
Published: March 2014

The environmental Gram-negative encapsulated bacillusBurkholderia pseudomalleiis the causative agent of melioidosis, a disease associated with high morbidity and mortality rates in areas of Southeast Asia and northern Australia in which the disease is endemic.B. pseudomalleiis also classified as a tier I select agent due to the high level of lethality of the bacterium and its innate resistance to antibiotics, as well as the lack of an effective vaccine. Gram-negative bacteria, includingB. pseudomallei, secrete outer membrane vesicles (OMVs) which are enriched with multiple protein, lipid, and polysaccharide antigens. Previously, we demonstrated that immunization with multivalentB. pseudomallei-derived OMVs protects highly susceptible BALB/c mice against an otherwise lethal aerosol challenge. In this work, we evaluated the protective efficacy of OMV immunization against intraperitoneal challenge with a heterologous strain because systemic infection with phenotypically diverse environmentalB. pseudomalleistrains poses another hazard and a challenge to vaccine development. We demonstrated thatB. pseudomalleiOMVs derived from strain 1026b afforded significant protection against septicemic infection withB. pseudomalleistrain K96243. OMV immunization induced robust OMV-, lipopolysaccharide-, and capsular polysaccharide-specific serum IgG (IgG1, IgG2a, and IgG3) and IgM antibody responses. OMV-immune serum promoted bacterial killingin vitro, and passive transfer ofB. pseudomalleiOMV immune sera protected naive mice against a subsequent challenge. These results indicate that OMV immunization provides antibody-mediated protection against acute, rapidly lethal sepsis in mice.B. pseudomallei-derived OMVs may represent an efficacious multivalent vaccine strategy against melioidosis.
Serological Identification and Prevalence of a Novel O-Antigen Epitope Linked to 3- and 4-
O
-Acetylated Rhamnose III of Lipopolysaccharide in Shigella flexneri
Authors: Wang Jianping , Lan Ruiting , Knirel Yuriy A. , Luo Xia , Senchenkova Sof'ya N. , Shashkov Alexander S. , Xu Jianguo , Sun Qiangzheng
Published: March 2014

Shigella flexneri
is the major cause of shigellosis in developing countries. All serotypes except for serotype 6 share an O-antigen backbone composed of a →2)-α-
l
-Rha
p
III
-(1→2)-α-
l
-Rha
p
II
-(1→3)-α-
l
-Rha
p
I
-(1→3)-β-
d
-Glc
p
NAc-(1→ tetrasaccharide repeat. It can be modified by the addition of a glucosyl group to one or more sugar residues and/or an
O
-acetyl group to Rha
I
and/or a phosphoethanolamine to Rha
II
and/or Rha
III
. These modifications give rise to type I-, IC-, II-, IV-, and V- and to group 6-, 7,8-, and MASF IV-1-specific antigenic determinants, which comprise the current serotyping scheme of
S. flexneri
. Recently, another O-antigen modification created by adding an
O
-acetyl group to Rha
III
at position 3 or 4 (3/4-
O
-acetylation) has been found in
S. flexneri
serotypes 1a, 1b, 2a, 5a, Y, and 6. A new
O
-acyltransferase gene named
oacB
has been shown to mediate the 3/4-
O
-acetylation in serotypes 1a, 1b, 2a, 5a, and Y but not in 6. In this work, we studied the distribution of the 3/4-
O
-acetylation in
S. flexneri
and the antigenicity that resulted from this modification. PCR screening of the
oacB
gene in clinical isolates of
S. flexneri
demonstrated that the
oacB
-mediated 3/4-
O
-acetylation is widespread in serotypes 1a, 1b, 2a, 5a, and Y. Serological analysis indicated that this modification confers the host with a novel antigenic determinant that is provisionally named group O factor 9. These findings enhance our understanding of the varieties of O-antigenic determinants related to O-antigen modification in
S. flexneri
and will assist epidemiological studies and vaccine development.
First Report of Emerging Zoonotic Pathogen Wohlfahrtiimonas chitiniclastica in the United States
Authors: Thaiwong Tuddow , Kettler Niesa M. , Lim Ailam , Dirkse Heidi , Kiupel Matti
Published: March 2014

Wohlfahrtiimonas chitiniclastica
is an emerging human pathogen that has been identified as the cause of septicemia in humans in Europe and South America. Here we report the first case of a unique disease manifestation of
Wohlfahrtiimonas chitiniclastica
-induced bacterial septicemia secondary to wound myiasis in a deer in Michigan in the United States.
Performance of Galactomannan, Beta-
d
-Glucan, Aspergillus Lateral-Flow Device, Conventional Culture, and PCR Tests with Bronchoalveolar Lavage Fluid for Diagnosis of Invasive Pulmonary Aspergillosis
Authors: Hoenigl M. , Prattes J. , Spiess B. , Wagner J. , Prueller F. , Raggam R. B. , Posch V. , Duettmann W. , Hoenigl K. , Wölfler A. , Koidl C. , Buzina W. , Reinwald M. , Thornton C. R. , Krause R. , Buchheidt D.
Published: March 2014

Galactomannan detection in bronchoalveolar lavage (BAL) fluid samples (GM test) is currently considered the gold standard test for diagnosing invasive pulmonary aspergillosis (IPA). The limitations, however, are the various turnaround times and availability of testing. We compared the performance of GM testing with that of conventional culture, an
Aspergillus
lateral-flow-device (LFD) test, a beta-
d
-glucan (BDG) test, and an
Aspergillus
PCR assay by using BAL fluid samples from immunocompromised patients. A total of 78 BAL fluid samples from 78 patients at risk for IPA (74 samples from Graz and 4 from Mannheim) collected between December 2012 and May 2013 at two university hospitals in Austria and Germany were included. Three patients had proven IPA, 14 probable IPA, and 17 possible IPA, and 44 patients had no IPA. The diagnostic accuracies of the different methods for probable/proven IPA were evaluated. The diagnostic odds ratios were the highest for the GM, PCR, and LFD tests. The sensitivities for the four methods (except culture) were between 70 and 88%. The combination of the GM (cutoff optical density index [ODI], >1.0) and LFD tests increased the sensitivity to 94%, while the combination of the GM test (>1.0) and PCR resulted in 100% sensitivity (specificity for probable/proven IPA, 95 to 98%). The performance of conventional culture was limited by low sensitivity, while that of the BDG test was limited by low specificity. We evaluated established and novel diagnostic methods for IPA and found that the
Aspergillus
PCR, LFD, and GM tests were the most useful methods for diagnosing the disease by using BAL fluid samples. In particular, the combination of the GM test and PCR or, if PCR is not available, the LFD test, allows for sensitive and specific diagnosis of IPA.
Cytomegalovirus in Bone Marrow Cells Correlates with Cytomegalovirus in Peripheral Blood Leukocytes
Authors: Capobianchi Angela , Iori Anna Paola , Micozzi Alessandra , Torelli Giovanni Fernando , Testi Anna Maria , Girmenia Corrado , Santilli Stefania , Barberi Walter , Antonelli Guido , Foà Robin , Gentile Giuseppe
Published: March 2014

In allogeneic hematopoietic stem cell transplant recipients with bone marrow (BM) suppression, cytomegalovirus (CMV) pp65 antigenemia and DNA were detectable in peripheral blood leukocytes (PBL) and BM cells. A relationship between CMV infection of PBL and BM cells has been found.
Significantly Higher Cytokine and Chemokine Levels in Patients with Japanese Spotted Fever than in Those with Tsutsugamushi Disease
Authors: Tai Katsunori , Iwasaki Hiromichi , Ikegaya Satoshi , Takada Nobuhiro , Tamaki Yukiko , Tabara Kenji , Ueda Takanori
Published: March 2014

Tetracyclines are administered to cure Japanese spotted fever (JSF) and tsutsugamushi disease (TD). It is generally said that the clinical course of JSF is worse than that of TD despite antibiotic treatment. The precise mechanism underlying the more severe clinical course of JSF is not fully understood. We therefore examined whether the differential cytokine profile between these two infectious diseases contributes to the difference in clinical severity. The serum concentrations of various cytokines (tumor necrosis factor alpha [TNF-α], interleukin-6 [IL-6], and gamma interferon [IFN-γ]) and chemokines (IL-8, interferon-inducible protein 10 [IP-10], monocyte chemoattractant protein 1 [MCP-1], macrophage inflammatory protein 1α [MIP-1α], MIP-1β, and eotaxin) were measured in 32 TD and 21 JSF patients. The results showed that serum levels of TNF-α in the acute phases of TD and JSF were significantly increased, with a higher concentration of TNF-α in patients with JSF (mean, 39.9 pg/ml) than in those with TD (mean, 13.8 pg/ml). Comparatively higher levels of other cytokines and chemokines (IL-6, IFN-γ, IL-8, IP-10, MCP-1, MIP-1α, and MIP-1β) were also observed in the acute phase of JSF. The clinical severity score (3.67 ± 1.71) of JSF patients was higher than that of TD patients (1.47 ± 0.77). Our findings revealed that the cytokine and chemokine levels in the acute phase of JSF were significantly higher than those in the acute phase of TD. The differential cytokine levels may be related to the difference in clinical severity between JSF and TD.
Optimal Positive Cutoff Points for careHPV Testing of Clinician- and Self-Collected Specimens in Primary Cervical Cancer Screening: an Analysis from Rural China
Authors: Kang Le-Ni , Jeronimo Jose , Qiao You-Lin , Zhao Fang-Hui , Chen Wen , Valdez Melissa , Zhang Xun , Bansil Pooja , Paul Proma , Bai Ping , Peck Roger , Li Jing , Chen Feng , Stoler Mark H. , Castle Philip E.
Published: March 2014

careHPV, a lower-cost DNA test for human papillomavirus (HPV), is being considered for cervical cancer screening in low- and middle-income countries. However, not a single large-scaled study exists to investigate the optimal positive cutoff point of careHPV test. We pooled data for 9,785 women participating in two individual studies conducted from 2007 to 2011 in rural China. Woman underwent multiple screening tests, including careHPV on clinician-collected specimens (careHPV-C) and self-collected specimens (careHPV-S), and Hybrid Capture 2 on clinician-collected specimens (HC2-C) as a reference standard. The primary endpoint was cervical intraepithelial neoplasia grade 3 or more severe (CIN3+) (
n
= 127), and secondary endpoint was CIN2+ (
n
= 213). The area under the curves (AUCs) for HC2-C and careHPV-C were similar (0.954 versus 0.948,
P
= 0.166), and better than careHPV-S (0.878;
P
< 0.001 versus both). The optimal positive cutoff points for HC2-C, careHPV-C, and careHPV-S were 1.40, 1.74, and 0.85, respectively. At the same cutoff point, careHPV-C was not significantly less sensitive and more specific for CIN3+ than HC2-C, and careHPV-S was significantly less sensitive for CIN3+ than careHPV-C and HC2-C. Raising the cutoff point of careHPV-C from 1.0 to 2.0 could result in nonsignificantly lower sensitivity but significantly higher specificity. Similar results were observed using CIN2+ endpoint. careHPV using either clinician- or self-collected specimens performed well in detecting cervical precancer and cancer. We found that the optimal cutoff points of careHPV were 2.0 on clinician-collected specimens and 1.0 on self-collected specimens.
Human Metapneumovirus Virus-Like Particles Induce Protective B and T Cell Responses in a Mouse Model
Authors: Cox Reagan G. , Erickson John J. , Hastings Andrew K. , Becker Jennifer C. , Johnson Monika , Craven Ryan E. , Tollefson Sharon J. , Boyd Kelli L. , Williams John V.
Published: March 2014

Human metapneumovirus (HMPV) is a leading cause of respiratory disease in infants, children, and the elderly worldwide, yet no licensed vaccines exist. Live-attenuated vaccines present safety challenges, and protein subunit vaccines induce primarily antibody responses. Virus-like particles (VLPs) are an attractive alternative vaccine approach because of reduced safety concerns compared with live vaccines. We generated HMPV VLPs by expressing viral proteins in suspension-adapted human embryonic kidney epithelial (293-F) cells and found that the viral matrix (M) and fusion (F) proteins were sufficient to form VLPs. We previously reported that the VLPs resemble virus morphology and incorporate fusion-competent F protein (R. G. Cox, S. B. Livesay, M. Johnson, M. D. Ohi, and J. V. Williams, J. Virol. 86:12148–12160, 2012), which we hypothesized would elicit F-specific antibody and T cell responses. In this study, we tested whether VLP immunization could induce protective immunity to HMPV by using a mouse model. C57BL/6 mice were injected twice intraperitoneally with VLPs alone or with adjuvant and subsequently challenged with HMPV. Mice were euthanized 5 days postinfection, and virus titers, levels of neutralizing antibodies, and numbers of CD3+T cells were quantified. Mice immunized with VLPs mounted an F-specific antibody response and generated CD8+T cells recognizing an F protein-derived epitope. VLP immunization induced a neutralizing-antibody response that was enhanced by the addition of either TiterMax Gold or α-galactosylceramide adjuvant, though adjuvant reduced cellular immune responses. Two doses of VLPs conferred complete protection from HMPV replication in the lungs of mice and were not associated with a Th2-skewed cytokine response. These results suggest that nonreplicating VLPs are a promising vaccine candidate for HMPV.

IMPORTANCEHuman metapneumovirus (HMPV) is a leading cause of acute respiratory infection in infants, children, and the elderly worldwide, yet no licensed vaccines exist. Live-attenuated vaccines present safety challenges, and protein subunit vaccines induce primarily antibody responses. Virus-like particles (VLPs) are an attractive alternative vaccine approach. We generated HMPV VLPs by expressing the viral matrix (M) and fusion (F) proteins in mammalian cells. We found that mice immunized with VLPs mounted an F-specific antibody response and generated CD8+T cells recognizing an F protein-derived epitope. VLP immunization induced a neutralizing-antibody response that was enhanced by the addition of either TiterMax Gold or α-galactosylceramide adjuvant. Two doses of VLPs conferred complete protection against HMPV replication in the lungs of mice and were not associated with a Th2-skewed cytokine response. These results suggest that nonreplicating VLPs are a promising vaccine candidate for HMPV.
Animal Model of Respiratory Syncytial Virus: CD8
+
T Cells Cause a Cytokine Storm That Is Chemically Tractable by Sphingosine-1-Phosphate 1 Receptor Agonist Therapy
Authors: Walsh Kevin B. , Teijaro John R. , Brock Linda G. , Fremgen Daniel M. , Collins Peter L. , Rosen Hugh , Oldstone Michael B. A.
Published: March 2014

The cytokine storm is an intensified, dysregulated, tissue-injurious inflammatory response driven by cytokine and immune cell components. The cytokine storm during influenza virus infection, whereby the amplified innate immune response is primarily responsible for pulmonary damage, has been well characterized. Now we describe a novel event where virus-specific T cells induce a cytokine storm. The paramyxovirus pneumonia virus of mice (PVM) is a model of human respiratory syncytial virus (hRSV). Unexpectedly, when C57BL/6 mice were infected with PVM, the innate inflammatory response was undetectable until day 5 postinfection, at which time CD8
+
T cells infiltrated into the lung, initiating a cytokine storm by their production of gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α). Administration of an immunomodulatory sphingosine-1-phosphate (S1P) receptor 1 (S1P1R) agonist significantly inhibited PVM-elicited cytokine storm by blunting the PVM-specific CD8
+
T cell response, resulting in diminished pulmonary disease and enhanced survival.

IMPORTANCE
A dysregulated overly exuberant immune response, termed a “cytokine storm,” accompanies virus-induced acute respiratory diseases (VARV), is primarily responsible for the accompanying high morbidity and mortality, and can be controlled therapeutically in influenza virus infection of mice and ferrets by administration of sphingosine-1-phosphate 1 receptor (S1P1R) agonists. Here, two novel findings are recorded. First, in contrast to influenza infection, where the cytokine storm is initiated early by the innate immune system, for pneumonia virus of mice (PVM), a model of RSV, the cytokine storm is initiated late in infection by the adaptive immune response: specifically, by virus-specific CD8 T cells via their release of IFN-γ and TNF-α. Blockading these cytokines with neutralizing antibodies blunts the cytokine storm and protects the host. Second, PVM infection is controlled by administration of an S1P1R agonist.
Enterovirus 68 3C Protease Cleaves TRIF To Attenuate Antiviral Responses Mediated by Toll-Like Receptor 3
Authors: Xiang Zichun , Li Linlin , Lei Xiaobo , Zhou Hongli , Zhou Zhuo , He Bin , Wang Jianwei
Published: March 2014

Human enterovirus 68 (EV68) is a member of the EV-D species, which belongs to the EV genus of the
Picornaviridae
family. Over the past several years, there have been increasingly documented outbreaks of respiratory disease associated with EV68. As a globally emerging pathogen, EV68 infects both adults and children. However, the molecular basis of EV68 pathogenesis is unknown. Here we report that EV68 inhibits Toll-like receptor 3 (TLR3)-mediated innate immune responses by targeting the TIR domain-containing adaptor inducing beta interferon (TRIF). In infected HeLa cells, EV68 inhibits poly(I·C)-induced interferon regulatory factor 3 (IRF3) activation and beta interferon (IFN-β) expression. Further investigations revealed that TRIF, a critical adaptor downstream of TLR3, is targeted by EV68. When expressed alone, 3C
pro
, an EV68-encoded protease, cleaves TRIF. 3C
pro
mediates TRIF cleavage at Q312 and Q653, which are sites in the amino- and carboxyl-terminal domains, respectively. This cleavage relies on 3C
pro
's cysteine protease activity. Cleavage of TRIF abolishes the capacity of TRIF to activate NF-κB and IFN-β signaling. These results suggest that control of TRIF by 3C
pro
may be a mechanism by which EV68 subverts host innate immune responses.

IMPORTANCE
EV68 is a globally emerging pathogen, but the molecular basis of EV68 pathogenesis is unclear. Here we report that EV68 inhibits TLR3-mediated innate immune responses by targeting TRIF. Further investigations revealed that TRIF is cleaved by 3C
pro
. These results suggest that control of TRIF by 3C
pro
may be a mechanism by which EV68 impairs type I IFN production in response to TLR3 activation.
Investments in respiratory infectious disease research 1997–2010: a systematic analysis of UK funding
Authors: Head Michael G , Fitchett Joseph R , Cooke Mary K , Wurie Fatima B , Hayward Andrew C , Lipman Marc C , Atun Rifat
Published: March 2014

Objectives

Respiratory infections are responsible for a large global burden of disease. We assessed the public and philanthropic investments awarded to UK institutions for respiratory infectious disease research to identify areas of underinvestment. We aimed to identify projects and categorise them by pathogen, disease and position along the research and development value chain.

Setting

The UK.

Participants

Institutions that host and carry out infectious disease research.

Primary and secondary outcome measures

The total amount spent and number of studies with a focus on several different respiratory pathogens or diseases, and to correlate these against the global burden of disease; also the total amount spent and number of studies relating to the type of science, the predominant funder in each category and the mean and median award size.

Results

We identified 6165 infectious disease studies with a total investment of £2·6 billion. Respiratory research received £419 million (16.1%) across 1192 (19.3%) studies. The Wellcome Trust provided greatest investment (£135.2 million; 32.3%). Tuberculosis received £155 million (37.1%), influenza £80 million (19.1%) and pneumonia £27.8 million (6.6%). Despite high burden, there was relatively little investment in vaccine-preventable diseases including diphtheria (£0.1 million, 0.03%), measles (£5.0 million, 1.2%) and drug-resistant tuberculosis. There were 802 preclinical studies (67.3%) receiving £273 million (65.2%), while implementation research received £81 million (19.3%) across 274 studies (23%). There were comparatively few phase I–IV trials or product development studies. Global health research received £68.3 million (16.3%). Relative investment was strongly correlated with 2010 disease burden.

Conclusions

The UK predominantly funds preclinical science. Tuberculosis is the most studied respiratory disease. The high global burden of pneumonia-related disease warrants greater investment than it has historically received. Other priority areas include antimicrobial resistance (particularly within tuberculosis), economics and proactive investments for emerging infectious threats.
Veterinary anaesthesia and analgesia: from chloroform to designer drugs
Authors: Taylor Polly
Published: March 2014

In 2013, to celebrate its 125th anniversary, Veterinary Record published a series of articles exploring developments in veterinary medicine since the journal was launched. According to an online poll in which over 1000 readers voted, the most important innovation in that time was anaesthesia and analgesia. Here, Polly Taylor explains why advancements in this field have made such a crucial impact on animal health and welfare and clinical practice. Veterinary anaesthesia and analgesia: from chloroform to designer drugs
Dynamics of WD-repeat containing proteins in SSU processome components
Authors: Wada Kouko , Sato Manae , Araki Nanase , Kumeta Masahiro , Hirai Yuya , Takeyasu Kunio , Furukawa Kazuhiro , Horigome Tsuneyoshi
Published: March 2014

Nine WD-repeat containing proteins in human SSU processome components have been found in a HeLa cell nuclear matrix fraction. In these proteins, t-UTP sub-complex components, i.e., CIRH1A, UTP15, and WDR43, were shown to be immobilized in the fibrillar centers of nucleoli in living cells. In this study, the dynamics of the remaining six proteins fused with green fluorescent protein (GFP), i.e., PWP2-GFP, TBL3-GFP, GFP-UTP18, GFP-NOL10, GFP-WDR46, and GFP-WDSOF1, were examined in living cells. The findings were as follows. (i) The majority of UTP-B sub-complex components, i.e., PWP2-GFP, TBL3-GFP, and GFP-UTP18, are localized to the dense fibrillar component and granular component regions in nucleoli; (ii) When rRNA transcription is suppressed, the majority of GFP-fused UTP-B sub-complex components are localized in the cap and body regions of nucleoli. (iii) The mobility of these proteins except for GFP-WDSOF1, and half of GFP-UTP18 and GFP-WDR46, respectively, is very low in living cells. (iv) When rRNA transcription is suppressed, the mobility of these proteins except for GFP-WDSOF1 is accelerated but still slow. These findings and others suggest that these WD-repeat proteins other than GFP-WDSOF1 found in the nuclear matrix fraction bind tightly to some macro-protein complexes and act as a scaffold or a core for the complexes in nucleoli.
AN NHPP SOFTWARE RELIABILITY GROWTH MODEL WITH IMPERFECT DEBUGGING AND ERROR GENERATION
Authors: ROY P. , MAHAPATRA G. S. , DEY K. N.
Published: March 2014

In this paper, we propose a non-homogeneous Poisson process (NHPP) based software reliability growth model (SRGM) in the presence of modified imperfect debugging and fault generation phenomenon. The testing team may not be able to remove a fault perfectly on observation of a failure due to the complexity of software systems and incomplete understanding of software, and the original fault may remain, or get replaced by another fault causing error generation. We have proposed an exponentially increasing fault content function and constant fault detection rate. The total fault content of the software for our proposed model increases rapidly at the beginning of the testing process. It grows gradually at the end of the testing process because of increasing efficiency of the testing team with testing time. We use the maximum likelihood estimation method to estimate the unknown parameters of the proposed model. The applicability of our proposed model and comparisons with established models in terms of goodness of fit and predictive validity have been presented using five known software failure data sets. Experimental results show that the proposed model gives a better fit to the real failure data sets and predicts the future behavior of software development more accurately than the traditional SRGMs.
SIGNATURE AND RELIABILITY OF CONDITIONAL THREE-DIMENSIONAL CONSECUTIVE-(s, s, s)-OUT-OF-(s, s, m):F SYSTEM
Authors: KULKARNI MADHURI G. , KASHIKAR AKANKSHA S.
Published: March 2014

A three-dimensional consecutive (r1, r2, r3)-out-of-(m1, m2, m3):F system was introduced by Akiba et al. [J. Qual. Mainten. Eng.11(3) (2005) 254–266]. They computed upper and lower bounds on the reliability of this system. Habib et al. [Appl. Math. Model.34 (2010) 531–538] introduced a conditional type of two-dimensional consecutive-(r, s)-out-of-(m, n):F system, where the number of failed components in the system at the moment of system failure cannot be more than 2rs. We extend this concept to three dimension and introduce a conditional three-dimensional consecutive (s, s, s)-out-of-(s, s, m):F system. It is an arrangement of ms2 components like a cuboid and it fails if it contains either a cube of failed components of size (s, s, s) or 2s3 failed components. We derive an expression for the signature of this system and also obtain reliability of this system using system signature.
RELIABILITY ANALYSIS OF HYBRID ENERGY SYSTEM
Authors: TIAN ZHIGANG , SEIFI AMIR AHMAD
Published: March 2014

A hybrid energy system integrates renewable energy sources like wind, solar, micro-hydro and biomass, fossil fuel power generators such as diesel generators and energy storage. Hybrid energy system is an excellent option for providing electricity for remote and rural locations where access to grid is not feasible or economical. Reliability and cost-effectiveness are the two most important objectives when designing a hybrid energy system. One challenge is that the existing methods do not consider the time-varying characteristics of the renewable sources and the energy demand over a year, while the distributions of a power source or demand are different over the period, and multiple power sources can often times complement one another. In this paper, a reliability analysis method is developed to address this challenge, where wind and solar are the two renewable energy sources that are considered. The cost evaluation of hybrid energy systems is presented. A numerical example is used to demonstrate the proposed method.
A CUBIC ARRANGED SPHERICAL DISCRETE ELEMENT MODEL
Authors: GAO WEI , TAN YUANQIANG , ZANG MENGYAN
Published: March 2014

A 3D discrete element model (DEM model) named cubic arranged discrete element model is proposed. The model treats the interaction between two connective discrete elements as an equivalent "beam" element. The spring constants between two connective elements are obtained based on the equivalence of strain energy stored in a unit volume of elastic continuum. Following that, the discrete element model proposed and its algorithm are implemented into the in-house developed code. To test the accuracy of the DEM model and its algorithm, the vibration process of the block, a homogeneous plate and laminated plate under impact loading are simulated in elastic range. By comparing the results with that calculated by using LS-DYNA, it is found that they agree with each other very well. The accuracy of the DEM model and its algorithm proposed in this paper is proved.
Features of structure of external layer of murine hair at different stages of malignant tumor development
Authors: Maryakhina Valeriya S. , Scheglova Larisa S. , Anenkova Ksenia A.
Published: March 2014

In the paper, the results of experimental investigations on the differences of wool structure of healthy mice and mice with malignant tumor(s) are represented. It is shown that destruction of wool structure happens during pathology development. Quantity of cells of external wool layer and their thickness decrease when the tumor capsule enlarges. Difference is seen even when the tumor is small. The obtained results can be used to improve optical techniques of biomedical diagnostics of cancer diseases.
Effect of osmotic stress on the expression of TRPV4 and BKCa channels and possible interaction with ERK1/2 and p38 in cultured equine chondrocytes
Authors: Hdud Ismail M. , Mobasheri Ali , Loughna Paul T.
Published: March 2014

The metabolic activity of articular chondrocytes is influenced by osmotic alterations that occur in articular cartilage secondary to mechanical load. The mechanisms that sense and transduce mechanical signals from cell swelling and initiate volume regulation are poorly understood. The purpose of this study was to investigate how the expression of two putative osmolyte channels [transient receptor potential vanilloid 4 (TRPV4) and large-conductance Ca2+-activated K+ (BKCa)] in chondrocytes is modulated in different osmotic conditions and to examine a potential role for MAPKs in this process. Isolated equine articular chondrocytes were subjected to anisosmotic conditions, and TRPV4 and BKCa channel expression and ERK1/2 and p38 MAPK protein phosphorylation were investigated using Western blotting. Results indicate that the TRPV4 channel contributes to the early stages of hypo-osmotic stress, while the BKCa channel is involved in responding to elevated intracellular Ca2+ and mediating regulatory volume decrease. ERK1/2 is phosphorylated by hypo-osmotic stress ( P < 0.001), and p38 MAPK is phosphorylated by hyperosmotic stress ( P < 0.001). In addition, this study demonstrates the importance of endogenous ERK1/2 phosphorylation in TRPV4 channel expression, where blocking ERK1/2 by a specific inhibitor (PD98059) prevented increased levels of the TRPV4 channel in cells exposed to hypo-osmotic stress and decreased TRPV4 channel expression to below control levels in iso-osmotic conditions ( P < 0.001).
Optical mapping of the electrical activity of isolated adult zebrafish hearts: acute effects of temperature
Authors: Lin Eric , Ribeiro Amanda , Ding Weiguang , Hove-Madsen Leif , Sarunic Marinko V. , Beg Mirza Faisal , Tibbits Glen F.
Published: March 2014

The zebrafish ( Danio rerio) has emerged as an important model for developmental cardiovascular (CV) biology; however, little is known about the cardiac function of the adult zebrafish enabling it to be used as a model of teleost CV biology. Here, we describe electrophysiological parameters, such as heart rate (HR), action potential duration (APD), and atrioventricular (AV) delay, in the zebrafish heart over a range of physiological temperatures (18–28°C). Hearts were isolated and incubated in a potentiometric dye, RH-237, enabling electrical activity assessment in several distinct regions of the heart simultaneously. Integration of a rapid thermoelectric cooling system facilitated the investigation of acute changes in temperature on critical electrophysiological parameters in the zebrafish heart. While intrinsic HR varied considerably between fish, the ex vivo preparation exhibited impressively stable HRs and sinus rhythm for more than 5 h, with a mean HR of 158 ± 9 bpm (means ± SE; n = 20) at 28°C. Atrial and ventricular APDs at 50% repolarization (APD50) were 33 ± 1 ms and 98 ± 2 ms, respectively. Excitation originated in the atrium, and there was an AV delay of 61 ± 3 ms prior to activation of the ventricle at 28°C. APD and AV delay varied between hearts beating at unique HRs; however, APD and AV delay did not appear to be statistically dependent on intrinsic basal HR, likely due to the innate beat-to-beat variability within each heart. As hearts were cooled to 18°C (by 1°C increments), HR decreased by ∼40%, and atrial and ventricular APD50increased by a factor of ∼3 and 2, respectively. The increase in APD with cooling was disproportionate at different levels of repolarization, indicating unique temperature sensitivities for ion currents at different phases of the action potential. The effect of temperature was more apparent at lower levels of repolarization and, as a whole, the atrial APD was the cardiac parameter most affected by acute temperature change. In conclusion, this study describes a preparation enabling the in-depth analysis of transmembrane potential dynamics in whole zebrafish hearts. Because the zebrafish offers some critical advantages over the murine model for cardiac electrophysiology, optical mapping studies utilizing zebrafish offer insightful information into the understanding and treatment of human cardiac arrhythmias, as well as serving as a model for other teleosts.
An acute method to test leptin responsiveness in rats
Authors: Desai Bhavna N. , Harris Ruth B. S.
Published: March 2014

Continuous subcutaneous administration of leptin normalizes blood glucose levels in rodent models of Type 1 and Type 2 diabetes independent of changes in food intake, body weight, and plasma insulin. We tested whether an acute intravenous leptin infusion changed blood glucose in normal and diet-induced leptin-resistant rats to determine whether this measure could be used as a marker of leptin sensitivity. Leptin-responsive chow-fed rats and diet-induced leptin-resistant male Sprague-Dawley rats were fitted with thoracic jugular vein catheters. Four days after surgery, conscious rats were infused intravenously with either saline for 32 min, low-dose (LD) leptin (1.9 μg·kg−1·min−1) followed by high-dose (HD) leptin (3.8 μg·kg−1·min−1) for 16 min each, or only HD leptin for 16 min. There was no change in blood glucose after an acute intravenous infusion of either LD leptin or HD leptin alone for 16 min. An intravenous infusion of LD followed by HD leptin for 16 min each significantly decreased serum glucose in leptin-responsive rats but not in leptin-resistant rats. Leptin infusions increased serum leptin in all rat groups but had no effect on plasma glucagon or 12-h weight gain and energy intake in any group of rats. These results show that leptin has an acute glucose-lowering effect that reflects the leptin responsiveness of the rat. This effect is consistent across controls and different leptin-resistant rat models, and the acute nonlethal test provides a novel method of testing leptin responsiveness in rats.
Sensory convergence in the parieto-insular vestibular cortex
Authors: Shinder Michael E. , Newlands Shawn D.
Published: March 2014

Vestibular signals are pervasive throughout the central nervous system, including the cortex, where they likely play different roles than they do in the better studied brainstem. Little is known about the parieto-insular vestibular cortex (PIVC), an area of the cortex with prominent vestibular inputs. Neural activity was recorded in the PIVC of rhesus macaques during combinations of head, body, and visual target rotations. Activity of many PIVC neurons was correlated with the motion of the head in space (vestibular), the twist of the neck (proprioceptive), and the motion of a visual target, but was not associated with eye movement. PIVC neurons responded most commonly to more than one stimulus, and responses to combined movements could often be approximated by a combination of the individual sensitivities to head, neck, and target motion. The pattern of visual, vestibular, and somatic sensitivities on PIVC neurons displayed a continuous range, with some cells strongly responding to one or two of the stimulus modalities while other cells responded to any type of motion equivalently. The PIVC contains multisensory convergence of self-motion cues with external visual object motion information, such that neurons do not represent a specific transformation of any one sensory input. Instead, the PIVC neuron population may define the movement of head, body, and external visual objects in space and relative to one another. This comparison of self and external movement is consistent with insular cortex functions related to monitoring and explains many disparate findings of previous studies.