bluuebunny/crossref_metadata_2025 huggingface dataset:
Oxytocin-Mediated GABA Inhibition During Delivery Attenuates Autism Pathogenesis in Rodent Offspring
Authors: Tyzio Roman , Nardou Romain , Ferrari Diana C. , Tsintsadze Timur , Shahrokhi Amene , Eftekhari Sanaz , Khalilov Ilgam , Tsintsadze Vera , Brouchoud Corinne , Chazal Genevieve , Lemonnier Eric , Lozovaya Natalia , Burnashev Nail , Ben-Ari Yehezkel
Published: February 2014

The Switch That Doesn't

In mammals, a class of neurons in the brain normally switches from excitatory to inhibitory functions at birth.

Tyzio
et al.

(p.
675
; see the Perspective by

Zimmerman and Connors

) studied how these neurons function in rat and mouse models of autism. The results show that oxytocin normally accelerates the switch in function, but in these two animal models, the switch fails. The dysfunction could be replicated in normal animals using an oxytocin receptor antagonist.
Janet Rowley (1925–2013)
Authors: Greaves Mel
Published: February 2014

The landmark studies of a brilliant but modest geneticist connected chromosomal translocations with cancer causation.
Pulmonary Mycobacterium bovis BCG Vaccination Confers Dose-Dependent Superior Protection Compared to That of Subcutaneous Vaccination
Authors: Aguilo Nacho , Toledo Ana Maria , Lopez-Roman Eva Maria , Perez-Herran Esther , Gormley Eamonn , Rullas-Trincado Joaquin , Angulo-Barturen Iñigo , Martin Carlos
Published: February 2014

Worldwide, the
Mycobacterium bovis
BCG vaccine is one of the most widely used vaccines. However, it appears to be ineffective in preventing pulmonary tuberculosis. Here, we show that pulmonary BCG vaccination of mice with a broad dose range provides superior protection against
Mycobacterium tuberculosis
challenge compared to that of subcutaneous vaccination.
Immune Responses of Iranian Patients with Visceral Leishmaniasis and Recovered Individuals to LCR1 of Leishmania infantum
Authors: M. Niknam Hamid , Abrishami Firoozeh , Doroudian Mohammad , Rostamian Mosayeb , Moradi Maryam , Khaze Vahid , Iravani Davood
Published: February 2014

Visceral leishmaniasis is a serious public health problem.
Leishmania infantum
is one of its causative agents. LCR1 is an immunogen from
L. infantum
. Antibodies against this protein have been detected in visceral leishmaniasis patients. The aim of this study was to define the antibody and cellular immune responses against LCR1 in Iranian visceral leishmaniasis patients and recovered individuals. The LCR1 protein was produced in recombinant form. Antibody responses against this protein were studied in Iranian individuals with a recent history of visceral leishmaniasis. Responses of peripheral blood mononuclear cells to this protein were studied in Iranian individuals who had recovered from visceral leishmaniasis. Our data show that (i) there was an antibody response to LCR1 in each individual with a recent history of visceral leishmaniasis studied, (ii) there was neither a proliferative response nor production of gamma interferon (IFN-γ) or interleukin 10 in response to LCR1 by mononuclear cells from individuals who had recovered from visceral leishmaniasis, and (iii) individuals who have recovered from visceral leishmaniasis show ongoing immune responses long after recovery from the disease. These data show that there are no detectable cellular memory responses to LCR1 in Iranian individuals who have recovered from visceral leishmaniasis, while there are detectable antibody responses in patients with this disease. Our data suggest that LCR1 has potential applications for the diagnosis of leishmaniasis through antibody detection, while the application of LCR1 alone for induction of IFN-γ in individuals who recovered from this disease is not supported. The presence of long-lasting immune reactivities in individuals who recovered from the disease may show the necessity of extended medical surveillance for these individuals.
Distribution of Nontuberculous Mycobacteria by Multigene Sequence-Based Typing and Clinical Significance of Isolated Strains
Authors: Jang Mi-Ae , Koh Won-Jung , Huh Hee Jae , Kim Su-Young , Jeon Kyeongman , Ki Chang-Seok , Lee Nam Yong
Published: February 2014

Species identification of nontuberculous mycobacteria (NTM) is challenging due to the increasing number of identified NTM species and the lack of standardized testing strategies. The objectives of this study were to investigate the distribution of NTM species recovered from respiratory specimens by multigene sequence-based typing and to evaluate the clinical significance of identified species. Two hundred thirty-two consecutive clinical NTM isolates were subjected to sequencing of multiple genes, including
hsp65
,
rpoB
, and 16S-23S rRNA internal transcribed spacer (ITS) sequence. In addition, clinical data from all patients whose specimens had NTM isolates were analyzed to examine clinical virulence and treatment history. Eighteen strains from 227 isolates from 169 patients were successfully identified at the species level by multigene sequence-based typing.
Mycobacterium avium
complex and
M. abscessus
complex made up the majority of isolated NTM (88%; 199/227), followed by
M. fortuitum
complex (4%; 10/227). The pathogenic potential of NTM differs enormously by species, and
M. avium
complex and
M. abscessus
complex revealed especially high levels of virulence compared with findings for other NTM species. The results from our work support
M. avium
complex and
M. abscessus
complex being the most common NTM species with highly pathogenic potential isolated from clinical respiratory specimens and could be a good resource for molecular epidemiology of NTM species in South Korea.
Prediction of Staphylococcus aureus Antimicrobial Resistance by Whole-Genome Sequencing
Authors: Gordon N. C. , Price J. R. , Cole K. , Everitt R. , Morgan M. , Finney J. , Kearns A. M. , Pichon B. , Young B. , Wilson D. J. , Llewelyn M. J. , Paul J. , Peto T. E. A. , Crook D. W. , Walker A. S. , Golubchik T.
Published: February 2014

Whole-genome sequencing (WGS) could potentially provide a single platform for extracting all the information required to predict an organism's phenotype. However, its ability to provide accurate predictions has not yet been demonstrated in large independent studies of specific organisms. In this study, we aimed to develop a genotypic prediction method for antimicrobial susceptibilities. The whole genomes of 501 unrelated
Staphylococcus aureus
isolates were sequenced, and the assembled genomes were interrogated using BLASTn for a panel of known resistance determinants (chromosomal mutations and genes carried on plasmids). Results were compared with phenotypic susceptibility testing for 12 commonly used antimicrobial agents (penicillin, methicillin, erythromycin, clindamycin, tetracycline, ciprofloxacin, vancomycin, trimethoprim, gentamicin, fusidic acid, rifampin, and mupirocin) performed by the routine clinical laboratory. We investigated discrepancies by repeat susceptibility testing and manual inspection of the sequences and used this information to optimize the resistance determinant panel and BLASTn algorithm. We then tested performance of the optimized tool in an independent validation set of 491 unrelated isolates, with phenotypic results obtained in duplicate by automated broth dilution (BD Phoenix) and disc diffusion. In the validation set, the overall sensitivity and specificity of the genomic prediction method were 0.97 (95% confidence interval [95% CI], 0.95 to 0.98) and 0.99 (95% CI, 0.99 to 1), respectively, compared to standard susceptibility testing methods. The very major error rate was 0.5%, and the major error rate was 0.7%. WGS was as sensitive and specific as routine antimicrobial susceptibility testing methods. WGS is a promising alternative to culture methods for resistance prediction in
S. aureus
and ultimately other major bacterial pathogens.
Multiple-Strain Colonization in Nasal Carriers of Staphylococcus aureus
Authors: Votintseva A. A. , Miller R. R. , Fung R. , Knox K. , Godwin H. , Peto T. E. A. , Crook D. W. , Bowden R. , Walker A. S.
Published: February 2014

Staphylococcus aureus
is a commensal that can also cause invasive infection. Reports suggest that nasal cocolonization occurs rarely, but the resources required to sequence multiple colonies have precluded its large-scale investigation. A staged protocol was developed to maximize detection of mixed-
spa
-type colonization while minimizing laboratory resources using 3,197
S. aureus
-positive samples from a longitudinal study of healthy individuals in Oxfordshire, United Kingdom. Initial typing of pooled material from each sample identified a single unambiguous strain in 89.6% of samples. Twelve single-colony isolates were typed from samples producing ambiguous initial results. All samples could be resolved into one or more
spa
types using the protocol. Cocolonization point prevalence was 3.4 to 5.8% over 24 months of follow-up in 360 recruitment-positives. However, 18% were cocolonized at least once, most only transiently. Cocolonizing
spa
types were completely unrelated in 56% of samples. Of 272 recruitment-positives returning ≥12 swabs, 166 (61%) carried
S. aureus
continuously but only 106 (39%) carried the same single
spa
type without any cocolonization; 31 (11%) switched
spa
type and 29 (11%) had transient cocarriage.
S. aureus
colonization is dynamic even in long-term carriers. New unrelated cocolonizing strains could increase invasive disease risk, and ongoing within-host evolution could increase invasive potential, possibilities that future studies should explore.
Cutaneous Blastomycosis Masquerading as Pyoderma Gangrenosum
Authors: Azar Marwan M. , Relich Ryan F. , Schmitt Bryan H. , Spech Robert W. , Hage Chadi A.
Published: February 2014

Cutaneous blastomycosis (CB) is associated with a variety of skin manifestations. Among other entities, CB may be mistaken for pyoderma gangrenosum due to overlap of findings on histopathologic examination. We report a case of CB, initially diagnosed as pyoderma gangrenosum and treated with steroids, leading to disseminated blastomycosis and acute respiratory distress syndrome (ARDS).
Rapid and Specific Detection, Molecular Epidemiology, and Experimental Virulence of the O16 Subgroup within Escherichia coli Sequence Type 131
Authors: Johnson James R. , Clermont Olivier , Johnston Brian , Clabots Connie , Tchesnokova Veronika , Sokurenko Evgeni , Junka Adam F. , Maczynska Beata , Denamur Erick
Published: February 2014

Escherichia coli
sequence type 131 (ST131), a widely disseminated multidrug-resistant extraintestinal pathogen, typically exhibits serotype O25b:H4. However, certain ST131 isolates exhibit serotype O16:H5 and derive from a phylogenetic clade that is distinct from the classic O25b:H4 ST131 clade. Both clades are assigned to ST131 by the Achtman multilocus sequence typing (MLST) system and a screening PCR assay that targets ST131-specific sequence polymorphisms in the
mdh
and
gyrB
genes. However, they are classified as separate STs by the Pasteur Institute MLST system, and an ST131 PCR method that targets the O25b
rfb
region and an ST131-specific polymorphism in
pabB
detects only the O25b-associated clade. Here, we describe a novel PCR-based method that allows for rapid and specific detection of the O16-associated ST131 clade. The clade members uniformly contained allele 41 of
fimH
(type 1 fimbrial adhesin) and a narrow range of alleles of
gyrA
and
parC
(fluoroquinolone target genes). The virulence genotypes of the clade members resembled those of classic O25b:H4 ST131 isolates; representative isolates were variably lethal in a mouse subcutaneous sepsis model. Several pulsotypes spanned multiple sources (adults, children, pets, and human fecal samples) and locales. An analysis of recent clinical
E. coli
collections showed that the O16 ST131 clade is globally distributed, accounts for 1 to 5% of
E. coli
isolates overall, and, when compared with other ST131 isolates, it is associated with resistance to ampicillin, gentamicin, and trimethoprim-sulfamethoxazole and with susceptibility to fluoroquinolones and extended-spectrum cephalosporins. Attention to this O16-associated ST131 clade, which is facilitated by our novel PCR-based assay, is warranted in future epidemiological studies of ST131 and, conceivably, in clinical applications.
Vaccinia Virus Requires Glutamine but Not Glucose for Efficient Replication
Authors: Fontaine Krystal A. , Camarda Roman , Lagunoff Michael
Published: February 2014

Viruses require host cell metabolism to provide the necessary energy and biosynthetic precursors for successful viral replication. Vaccinia virus (VACV) is a member of the
Poxviridae
family, and its use as a vaccine enabled the eradication of variola virus, the etiologic agent of smallpox. A global metabolic screen of VACV-infected primary human foreskin fibroblasts suggested that glutamine metabolism is altered during infection. Glutamine and glucose represent the two main carbon sources for mammalian cells. Depriving VACV-infected cells of exogenous glutamine led to a substantial decrease in infectious virus production, whereas starving infected cells of exogenous glucose had no significant impact on replication. Viral yield in glutamine-deprived cells or in cells treated with an inhibitor of glutaminolysis, the pathway of glutamine catabolism, could be rescued by the addition of multiple tricarboxylic acid (TCA) cycle intermediates. Thus, VACV infection induces a metabolic alteration to fully rely on glutamine to anaplerotically maintain the TCA cycle. VACV protein synthesis, but not viral transcription, was decreased in glutamine-deprived cells, which corresponded with a dramatic reduction in all VACV morphogenetic intermediates. This study reveals the unique carbon utilization program implemented during poxvirus infection and provides a potential metabolic pathway to target viral replication.

IMPORTANCE
Viruses are dependent on the metabolic machinery of the host cell to supply the energy and molecular building blocks needed for critical processes including genome replication, viral protein synthesis, and membrane production. This study investigates how vaccinia virus (VACV) infection alters global cellular metabolism, providing the first metabolomic analysis for a member of the poxvirus family. Unlike most viruses examined to date, VACV does not activate glycolysis, and exogenous glucose is not required for maximal virus production. Instead, VACV requires exogenous glutamine for efficient replication, and inhibition of glutamine metabolism effectively blocks VACV protein synthesis. This study defines a major metabolic perturbation essential for the replication of a poxvirus and may lead to the discovery of novel antiviral therapies based on metabolic inhibitors.
BAFF Receptor Deficiency Limits Gammaherpesvirus Infection
Authors: Frederico Bruno , May Janet S. , Efstathiou Stacey , Stevenson Philip G.
Published: February 2014

Lymphocyte colonization by gammaherpesviruses (γHVs) is an important target for cancer prevention. However, how it works is not clear. Epstein-Barr virus drives autonomous B cell proliferationin vitrobutin vivomay more subtly exploit the proliferative pathways provided by lymphoid germinal centers (GCs). Murid herpesvirus 4 (MuHV-4), which realistically infects inbred mice, provides a useful tool with which to understand further how a γHV colonizes B cellsin vivo. Not all γHVs necessarily behave the same, but common events can with MuHV-4 be assigned an importance for host colonization and so a potential as therapeutic targets. MuHV-4-driven B cell proliferation depends quantitatively on CD4+T cell help. Here we show that it also depends on T cell-independent survival signals provided by the B cell-activating factor (BAFF) receptor (BAFF-R). B cells could be infected in BAFF-R−/−mice, but virus loads remained low. This corresponded to a BAFF-R-dependent defect in GC colonization. The close parallels between normal, antigen-driven B cell responses and virus-infected B cell proliferation argue thatin vivo, γHVs mostly induce infected B cells into normal GC reactions rather than generating large numbers of autonomously proliferating blasts.

IMPORTANCEγHVs cause cancers by driving the proliferation of infected cells. B cells are a particular target. Thus, we need to know how virus-driven B cell proliferation works. Controversy exists as to whether viral genes drive it directly or less directly orchestrate the engagement of normal, host-driven pathways. Here we show that the B cell proliferation driven by a murid γHV requires BAFF-R. This supports the idea that γHVs exploit host proliferation pathways and suggests that interfering with BAFF-R could more generally reduce γHV-associated B cell proliferation.
Roles of Serine and Threonine Residues of Mumps Virus P Protein in Viral Transcription and Replication
Authors: Pickar Adrian , Xu Pei , Elson Andrew , Li Zhuo , Zengel James , He Biao
Published: February 2014

Mumps virus (MuV), a paramyxovirus containing a negative-sense nonsegmented RNA genome, is a human pathogen that causes an acute infection with symptoms ranging from parotitis to mild meningitis and severe encephalitis. Vaccination against mumps virus has been effective in reducing mumps cases. However, recently large outbreaks have occurred in vaccinated populations. There is no anti-MuV drug. Understanding replication of MuV may lead to novel antiviral strategies. MuV RNA-dependent RNA polymerase minimally consists of the phosphoprotein (P) and the large protein (L). The P protein is heavily phosphorylated. To investigate the roles of serine (S) and threonine (T) residues of P in viral RNA transcription and replication, P was subjected to mass spectrometry and mutational analysis. P, a 392-amino acid residue protein, has 64 S and T residues. We have found that mutating nine S/T residues significantly reduced and mutating residue T at 101 to A (T101A) significantly enhanced activity in a minigenome system. A recombinant virus containing the P-T101A mutation (rMuV-P-T101A) was recovered and analyzed. rMuV-P-T101A grew to higher titers and had increased protein expression at early time points. Together, these results suggest that phosphorylation of MuV-P-T101 plays a negative role in viral RNA synthesis. This is the first time that the P protein of a paramyxovirus has been systematically analyzed for S/T residues that are critical for viral RNA synthesis.

IMPORTANCE
Mumps virus (MuV) is a reemerging paramyxovirus that caused large outbreaks in the United States, where vaccination coverage is very high. There is no anti-MuV drug. In this work, we have systematically analyzed roles of Ser/Thr residues of MuV P in viral RNA synthesis. We have identified S/T residues of P critical for MuV RNA synthesis and phosphorylation sites that are important for viral RNA synthesis. This work leads to a better understanding of viral RNA synthesis as well as to potential novel strategies to control mumps.
Highly Acidic C-Terminal Region of Cytomegalovirus pUL96 Determines Its Functions during Virus Maturation Independently of a Direct pp150 Interaction
Authors: Brechtel Teal M. , Mocarski Edward S. , Tandon Ritesh
Published: February 2014

Tegument proteins pp150 and pUL96 function at a late step in cytomegalovirus (CMV) maturation. Here, we show that pp150 interacts directly with pUL96; however, the N-terminal region of pp150 and the C-terminal region of pUL96, which are critical for these proteins to function, are not required for this interaction. Moreover, the largely dispensable C-terminal region of pp150 is critical for pp150-pUL96 interaction. To further study the role of pUL96, several point and clustered mutations were engineered into the CMV Towne bacterial artificial chromosome (Towne-BAC) genome, replacing the conserved negatively charged C-terminal residues of pUL96. Although individual point mutations (E
122
A, D
124
A, and D
125
A) reduced virus growth slightly, the clustered mutations of
122
EVDDAV
127
significantly reduced virus growth, produced small syncytial plaque phenotypes, and impacted a late stage of virus maturation. When the UL96 C-terminal alanine conversion mutant (B6-BAC) virus was serially passaged in cell culture, it gained a plaque size comparable to that of Towne-BAC, displayed an altered restriction fragment length pattern, and replicated with increased growth kinetics. Whole-genome sequencing of this passaged virus (UL96P10) and the similarly passaged Towne-BAC virus revealed major differences only in the RNA4.9 and UL96 regions. When one of the mutations in the UL96 coding region was engineered into the B6-BAC virus, it significantly increased the plaque size and rescued the virus growth rate. Thus, accumulation of compensatory mutations only in UL96 in this revertant and the specific involvement of functionally dispensable regions of pp150 in the pUL96-pp150 interaction point toward a role for pUL96 in virus maturation that does not depend upon pp150.

IMPORTANCE
Human cytomegalovirus causes significant medical problems in newborns, as well as in people with low immunity. In this study, we investigated the functions of two essential virus proteins, pp150 and pUL96, and determined the impact of their mutual interaction on virus replication. These studies provide valuable information that is critical for the development of targeted antiviral therapies.
Pendular nystagmus associated with venlafaxine overdose: a forme fruste of the serotonin syndrome?
Authors: Varatharaj Aravinthan , Moran James
Published: February 2014

We describe a case of pendular nystagmus as a previously unreported side effect of venlafaxine, and speculate to its importance in the recognition of the serotonin syndrome. In particular, we discuss the importance of identifying incomplete forms of the syndrome, such as those presenting with predominantly ocular manifestations, as is in our case.
Minimally invasive surgery to manage a complicated case of a caesarean scar ectopic pregnancy
Authors: Ong Xiaohui , Mathur Manisha
Published: February 2014

A 30-year-old woman, gravida 3 para 1, presented at 5 weeks of amenorrhoea with vaginal spotting and mild abdominal pain. A transvaginal scan confirmed a caesarean scar pregnancy (CSP). Serum hCG level at presentation was 4357. She declined treatment initially, but eventually underwent laparoscopic-guided suction curettage and excision of CSP. hCG was undetectable at 5 weeks postoperatively. She had an uneventful recovery and was advised to take oral contraceptives.
Associated production of single top quark and W boson through anomalous couplings at LHeC based γp colliders
Authors: Cakir I. T. , Senol A. , Tasci A. T.
Published: February 2014

We consider the production of a single top quark in association with a W boson at LHeC based γp collider. We compute the cross-section for the process γp→WtX with the anomalous Wtb and Wtbγ couplings. We find that the sensitivities to anomalous couplings of top quark are shown to be comparable, even better than the ones obtained from direct searches at hadron colliders.
ASYNCHRONOUS INSTRUCTION CACHE MEMORY FOR AVERAGE-CASE PERFORMANCE
Authors: LEE JE-HOON , CHO HYUN GUG
Published: February 2014

This paper presents an asynchronous instruction cache memory for average-case performance, rather than worst-case performance. Even though the proposed instruction cache design is based on a fixed delay model, it can achieve high throughput by employing a new memory segmentation technique that divides cache memory cell arrays into multiple memory segments. The conventional bit-line memory segmentation divides a whole memory system into multiple segments so that all memory segments have the same size. On the contrary, we propose a new bit-line segmentation technique for the cache memory which consists of multiple segments but all the memory segments have the same delay bound for themselves. We use the resister-capacitor (R-C) modeling of bit-line delay for content addressable memory–random access memory (CAM–RAM) structure in a cache in order to estimate the total bit-line delay. Then, we decide the number of segments to trade-off between the throughput and complexity of a cache system. We synthesized a 128 KB cache memory consisting of various segments from 1 to 16 using Hynix 0.35-μm CMOS process. From the simulation results, our implementation with dividing factor 4 and 16 can reduce the average cache access time to 28% and 35% when compared to the non-segmented counterpart system. It also shows that our implementation can reduce the average cache access time by 11% and 17% when compared to the bit-line segmented cache that consists of the same number of segments that have the same size.
VOLATILITY DERIVATIVES AND MODEL-FREE IMPLIED LEVERAGE
Authors: FUKASAWA MASAAKI
Published: February 2014

We revisit robust replication theory of volatility derivatives and introduce a broader class which may be considered as the second generation of volatility derivatives. One of them is a swap contract on the quadratic covariation between an asset price and the model-free implied variance (MFIV) of the asset. It can be replicated in a model-free manner and its fair strike may be interpreted as a model-free measure for the covariance of the asset price and the realized variance. The fair strike is given in a remarkably simple form, which enable to compute it from the Black–Scholes implied volatility surface. We call it the model-free implied leverage (MFIL) and give several characterizations. In particular, we show its simple relation to the Black–Scholes implied volatility skew by an asymptotic method. Further to get an intuition, we demonstrate some explicit calculations under the Heston model. We report some empirical evidence from the time series of the MFIV and MFIL of the Nikkei stock average.
A simple approach for optimal allocation of dampers in nonsymmetrical 3D multi-storey structures
Authors: Leu L. J. , Chang J. T.
Published: February 2014

A new simple approach is proposed to search for the optimal placement of dampers in nonsymmetrical three-dimensional (3D) structures. Dampers are placed uniformly and initially at each storey of two selected bays of the bare structures and the time-history seismic analysis is performed. The maximal inter-storey drift ratio is chosen as the performance index. Then the inter-storey drift ratio is checked for the locations where dampers were added. The damper in the location with the minimal inter-storey drift ratio is moved to the location having the maximal inter-storey drift ratio. This process is repeated until the prescribed stop criterion is met. Both linear and nonlinear viscous dampers are used in this study. The damping coefficient of added dampers for the initial damper placement is determined by setting the maximal inter-storey drift ratio of the whole structure equal to a certain value when a ground motion is applied. In the proposed relocation process, the maximal inter-storey drift ratio will be reduced significantly. Three examples, including two 10-storey and one 20-storey 3D nonsymmetrical structures, are used to demonstrate the efficiency and accuracy of the proposed approach. The results are compared with those obtained using the simplified sequential search algorithm (SSSA). It is found that the proposed approach requires fewer number of time-history analysis than that using the SSSA while their accuracy is comparable.
Estimating extremes of combined two Gaussian and non-Gaussian response processes
Authors: Gong K. , Chen X. Z.
Published: February 2014

Assessment of structural performance under stochastic dynamic loadings requires estimation of the extremes of stochastic response components and the resultant responses as their linear and nonlinear combinations. This paper addresses the evaluations and combination rules for the extremes of scalar and vectorial resultant responses from two response components that may show non-Gaussian characteristics. The non-Gaussian response process is modeled as a translation process from an underlying Gaussian process. The mean crossing rates and extreme value distributions of resultant responses are calculated following the theory for vector-valued Gaussian processes. An extensive parameter study is conducted concerning the influence of statistical moments of non-Gaussian response components on the extremes of resultant responses. It is revealed that the existing combination rules developed for Gaussian processes are not applicable to the case of non-Gaussian process. New combination rules are suggested that permit predictions of the extremes of resultant responses directly from the extremes of response components.
FINITE ELEMENT ANALYSIS OF THE INTERFACE/SURFACE EFFECT ON THE ELASTIC WAVE BAND STRUCTURE OF TWO-DIMENSIONAL NANOSIZED PHONONIC CRYSTALS
Authors: LIU WEI , LIU YONGQUAN , SU XIANYUE , LI ZHENG
Published: February 2014

In this paper, an interface/surface element is formulated based on the Gurtin–Murdoch interface/surface elasticity theory for accounting the interface/surface effect on the elastic wave propagation in two-dimensional nanosized phononic crystals. The interface/surface element is subsequently incorporated into the finite element procedure for calculating the elastic wave band structure of two-dimensional nanosized phononic crystals with consideration of the interface/surface effect. Elastic wave band structures of two-dimensional phononic crystals comprising a square array of circular or elliptical cylindrical nanoholes embedded in an aluminum matrix are analyzed. Numerical results evidence that the interface/surface effect on the elastic wave band structure can be remarkable when the characteristic size reduces to nanometers.
Paleobiology of Herbivorous Dinosaurs
Authors: Barrett Paul M.
Published: February 2014

Herbivorous dinosaurs were abundant, species-rich components of Late Triassic–Cretaceous terrestrial ecosystems. Obligate high-fiber herbivory evolved independently on several occasions within Dinosauria, through the intermediary step of omnivory. Anatomical character complexes associated with this diet exhibit high levels of convergence and morphological disparity, and may have evolved by correlated progression. Dinosaur faunas changed markedly during the Mesozoic, from early faunas dominated by taxa with simple, uniform feeding mechanics to Cretaceous biomes including diverse sophisticated sympatric herbivores; the environmental and biological drivers causing these changes remain unclear. Isotopic, taphonomic, and anatomical evidence implies that niche partitioning reduced competition between sympatric herbivores, via morphological differentiation, dietary preferences, and habitat selection. Large body size in dinosaur herbivores is associated with low plant productivity, and gave these animals prominent roles as ecosystem engineers. Although dinosaur herbivores lived through several major events in floral evolution, there is currently no evidence for plant-dinosaur coevolutionary interactions.
Heterogeneity and Anisotropy of Earth's Inner Core
Authors: Deuss Arwen
Published: February 2014

Seismic observations provide strong evidence that Earth's inner core is anisotropic, with larger velocity in the polar than in the equatorial direction. The top 60–80 km of the inner core is isotropic; evidence for an innermost inner core is less compelling. The anisotropy is most likely due to alignment of hcp (hexagonal close-packed) iron crystals, aligned either during solidification or by deformation afterward. The existence of hemispherical variations used to be controversial, but there is now strong evidence from both seismic body wave and normal mode observations, showing stronger anisotropy, less attenuation, and a lower isotropic velocity in the western hemisphere. Two mechanisms have been proposed to explain the hemispherical pattern: either (a) inner core translation, wherein one hemisphere is melting and the other is solidifying, or (b) thermochemical convection in the outer core, leading to different solidification conditions at the inner core boundary. Neither is (yet) able to explain all seismically observed features, and a combination of different mechanisms is probably required.
How Did Early Earth Become Our Modern World?
Authors: Carlson Richard W. , Garnero Edward , Harrison T. Mark , Li Jie , Manga Michael , McDonough William F. , Mukhopadhyay Sujoy , Romanowicz Barbara , Rubie David , Williams Quentin , Zhong Shijie
Published: February 2014

Several features of Earth owe their origin to processes occurring during and shortly following Earth formation. Collisions with planetary embryos caused substantial melting of the growing Earth, leading to prolonged core formation, atmosphere outgassing, and deepening of the magma ocean as Earth grew. Mantle noble gas isotopic compositions and the mantle abundance of elements that partition into the core record this very early Earth differentiation. In contrast, the elements that are not involved in either core or atmosphere formation show surprisingly muted evidence of the fractionation expected during magma ocean crystallization, and even this minimal evidence for early intramantle differentiation appears to have been erased by mantle convection within ∼1.5 billion years of Earth formation. By 4.36 Ga, Earth's surface and shallow interior had reached temperatures similar to those of the present Earth, and mantle melting, and perhaps plate subduction, was producing crustal rock types similar to those seen today. Remnants of early Earth differentiation may still exist in the deep mantle and continue to influence patterns of large-scale mantle convection, sequestration of some trace elements, geomagnetic reversals, vertical motions of continents, and hot-spot volcanism.
Models of Caring, or Acting as if One Cared, About the Welfare of Others
Authors: Rotemberg Julio J.
Published: February 2014

This article surveys the theoretical literature in which people are modeled as taking other people’s payoffs into account either because this affects their utility directly or because they wish to impress others with their social-mindedness. Key experimental results that bear on the relevance of these theories are discussed as well. Five types of models are considered. In the first, an individual’s utility function is increasing in the payoffs of other people. The more standard version of these preferences supposes that only consumption leads to payoffs and has trouble explaining prosocial actions such as voting and charitable contributions by poor individuals. If one lets other variables determine happiness as well, this model can explain a much wider set of observations. The second type of model surveyed involves people trying to demonstrate to others that they have prosocial (or altruistic) preferences. In these models, altruistic acts need not have a direct effect on utility. The third class of models includes those of reciprocity in which people’s altruism depends on whether others act kindly or unkindly toward them. In the fourth type of model, inequality has a profound effect on altruism, with individuals being spiteful toward people whose resources exceed their own. Finally, I discuss the fifth type of model, in which specifications of altruism might have to be modified to take into account how people behave when they are able to transfer lotteries to others.
Antigen Presentation in the Autoimmune Diabetes of the NOD Mouse
Authors: Unanue Emil R.
Published: February 2014

This paper reviews the presentation of peptides by major histocompatibility complex (MHC) class II molecules in the autoimmune diabetes of the nonobese diabetic (NOD) mouse. Islets of Langerhans contain antigen-presenting cells that capture the proteins and peptides of the beta cells' secretory granules. Peptides bound to I-Ag7, the unique MHC class II molecule of NOD mice, are presented in islets and in pancreatic lymph nodes. The various beta cell–derived peptides interact with selected CD4 T cells to cause inflammation and beta cell demise. Many autoreactive T cells are found in NOD mice, but not all have a major role in the initiation of the autoimmune process. I emphasize here the evidence pointing to insulin autoreactivity as a seminal component in the diabetogenic process.
Complement and Its Receptors: New Insights into Human Disease
Authors: Holers V. Michael
Published: February 2014

Although new activation and regulatory mechanisms are still being identified, the basic architecture of the complement system has been known for decades. Two major roles of complement are to control certain bacterial infections and to promote clearance of apoptotic cells. In addition, although inappropriate complement activation has long been proposed to cause tissue damage in human inflammatory and autoimmune diseases, whether this is indeed true has been uncertain. However, recent studies in humans, especially those using newly available biological therapeutics, have now clearly demonstrated the pathophysiologic importance of the complement system in several rare diseases. Beyond these conditions, recent genetic studies have strongly supported an injurious role for complement in a wide array of human inflammatory, degenerative, and autoimmune diseases. This review includes an overview of complement activation, regulatory, and effector mechanisms. It then focuses on new understandings gained from genetic studies, ex vivo analyses, therapeutic trials, and animal models as well as on new research opportunities.
Anticytokine Autoantibody–Associated Immunodeficiency
Authors: Browne Sarah K.
Published: February 2014

Anticytokine autoantibodies are an emerging mechanism of disease in previously healthy adults. Patients with these syndromes demonstrate a unique infectious phenotype associated with neutralizing autoantibodies that target a specific cytokine. Examples include anti-interferon (IFN)-γ autoantibodies and disseminated nontuberculous mycobacteria; anti-granulocyte macrophage colony–stimulating factor autoantibodies and cryptococcal meningitis; anti-interleukin (IL)-6 autoantibodies and staphylococcal skin infection; and anti-IL-17A, anti-IL-17F, or anti-IL-22 autoantibodies and mucocutaneous candidiasis in the setting of either APECED (autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy syndrome) or thymoma. Other anticytokine autoantibodies may contribute to an infectious phenotype such as anti-granulocyte colony stimulating factor and anti-IFN-α autoantibodies, although the strength of the association is less clear. Their identification not only affects disease management but also may uncover key mechanisms of host defense against specific organisms. Furthermore, it raises the possibility that currently idiopathic diseases will someday be explained by a yet unidentified anticytokine autoantibody. This review focuses on the current understanding, both clinical and mechanistic, of anticytokine autoantibody-associated immunodeficiency.
Geopolymers and Related Alkali-Activated Materials
Authors: Provis John L. , Bernal Susan A.
Published: February 2014

The development of new, sustainable, low-CO2 construction materials is essential if the global construction industry is to reduce the environmental footprint of its activities, which is incurred particularly through the production of Portland cement. One type of non-Portland cement that is attracting particular attention is based on alkali-aluminosilicate chemistry, including the class of binders that have become known as geopolymers. These materials offer technical properties comparable to those of Portland cement, but with a much lower CO2 footprint and with the potential for performance advantages over traditional cements in certain niche applications. This review discusses the synthesis of alkali-activated binders from blast furnace slag, calcined clay (metakaolin), and fly ash, including analysis of the chemical reaction mechanisms and binder phase assemblages that control the early-age and hardened properties of these materials, in particular initial setting and long-term durability. Perspectives for future research developments are also explored.
PKCδ/midkine pathway drives hypoxia-induced proliferation and differentiation of human lung epithelial cells
Authors: Zhang Hanying , Okamoto Miyako , Panzhinskiy Evgeniy , Zawada W. Michael , Das Mita
Published: February 2014

Epithelial cells are key players in the pathobiology of numerous hypoxia-induced lung diseases. The mechanisms mediating such hypoxic responses of epithelial cells are not well characterized. Earlier studies reported that hypoxia stimulates protein kinase C (PKC)δ activation in renal cancer cells and an increase in expression of a heparin-binding growth factor, midkine (MK), in lung alveolar epithelial cells. We reasoned that hypoxia might regulate MK levels via a PKCδ-dependent pathway and hypothesized that PKCδ-driven MK expression is required for hypoxia-induced lung epithelial cell proliferation and differentiation. Replication of human lung epithelial cells (A549) was significantly increased by chronic hypoxia (1% O2) and was dependent on expression of PKCδ. Hypoxia-induced proliferation of epithelial cells was accompanied by translocation of PKCδ from Golgi into the nuclei. Marked attenuation in MK protein levels by rottlerin, a pharmacological antagonist of PKC, and by small interfering RNA-targeting PKCδ, revealed that PKCδ is required for MK expression in both normoxic and hypoxic lung epithelial cells. Sequestering MK secreted into the culture media with a neutralizing antibody reduced hypoxia-induced proliferation demonstrating that an increase in MK release from cells is linked with epithelial cell division under hypoxia. In addition, recombinant MK accelerated transition of hypoxic epithelial cells to cells of mesenchymal phenotype characterized by elongated morphology and increased expression of mesenchymal markers, α-smooth muscle actin, and vimentin. We conclude that PKCδ/MK axis mediates hypoxic proliferation and differentiation of lung epithelial cells. Manipulation of PKCδ and MK activity in epithelial cells might be beneficial for the treatment of hypoxia-mediated lung diseases.
Maternal high-fat diet during pregnancy and lactation reduces the appetitive behavioral component in female offspring tested in a brief-access taste procedure
Authors: Treesukosol Yada , Sun Bo , Moghadam Alexander A. , Liang Nu-Chu , Tamashiro Kellie L. , Moran Timothy H.
Published: February 2014

Maternal high-fat diet appears to disrupt several energy balance mechanisms in offspring. Here, female offspring from dams fed a high-fat diet (HF) did not significantly differ in body weight compared with those fed chow (CHOW), when weaned onto chow diet. Yet when presented with both a chow and a high-fat diet, high-fat intake was significantly higher in HF compared with CHOW offspring. To assess taste-based responsiveness, offspring (12 wk old) were tested in 30-min sessions (10-s trials) to a sucrose concentration series in a brief-access taste test. Compared with CHOW, the HF offspring initiated significantly fewer trials but did not significantly differ in the amount of concentration-dependent licking. Thus, rather than affect lick response (consummatory), maternal diet affects spout approach (appetitive), which may be attributed to motivation-related mechanisms. Consistent with this possibility, naltrexone, an opioid receptor antagonist, further reduced trial initiation, but not licking in both groups. With naltrexone administration, the group difference in trial initiation was no longer evident, suggesting differences in endogenous opioid activity between the two groups. Relative expression of μ-opioid receptor in the ventral tegmental area was significantly lower in HF rats. When trial initiation was not required in one-bottle intake tests, no main effect of maternal diet on the intake of sucrose and corn oil emulsions was observed. Thus, the maternal high-fat diet-induced difference in diet preference is not likely due to changes in the sensory orosensory component of the taste stimulus but may depend on alterations in satiety signals or absorptive mechanisms.
Downregulation of renal type IIa sodium-dependent phosphate cotransporter during lipopolysaccharide-induced acute inflammation
Authors: Ikeda Shoko , Yamamoto Hironori , Masuda Masashi , Takei Yuichiro , Nakahashi Otoki , Kozai Mina , Tanaka Sarasa , Nakao Mari , Taketani Yutaka , Segawa Hiroko , Iwano Masayuki , Miyamoto Ken-ichi , Takeda Eiji
Published: February 2014

The type IIa sodium-dependent phosphate cotransporter (Npt2a) plays a critical role in reabsorption of inorganic phosphate (Pi) by renal proximal tubular cells. Piabnormalities during early stages of sepsis have been reported, but the mechanisms regulating Pihomeostasis during acute inflammation are poorly understood. We examined the regulation of Pimetabolism and renal Npt2a expression during lipopolysaccharide (LPS)-induced inflammation in mice. Dose-response and time-course studies with LPS showed significant increases of plasma Piand intact parathyroid hormone (iPTH) levels and renal Piexcretion, while renal calcium excretion was significantly decreased. There was no difference in plasma 1,25-dihydroxyvitamin D levels, but the induction of plasma intact fibroblast growth factor 23 levels peaked 3 h after LPS treatment. Western blotting, immunostaining, and quantitative real-time PCR showed that LPS administration significantly decreased Npt2a protein expression in the brush border membrane (BBM) 3 h after injection, but there was no change in renal Npt2a mRNA levels. Moreover, tumor necrosis factor-α injection also increased plasma iPTH and decreased renal BBM Npt2a expression. Importantly, we revealed that parathyroidectomized rats had impaired renal Piexcretion and BBM Npt2a expression in response to LPS. These results suggest that the downregulation of Npt2a expression in renal BBM through induction of plasma iPTH levels alter Pihomeostasis during LPS-induced acute inflammation.
Airway arginase expression and Nω-hydroxy-nor-arginine effect on methacholine-induced bronchoconstriction differentiate Lewis and Fischer rat strains
Authors: Risse Paul-André , Lavoie-Lamoureux Anouk , Jo Taisuke , Tsuchiya Kimitake , Siddiqui Sana , Martin James G.
Published: February 2014

Innate airway hyperresponsiveness (AHR) is well modeled by two strains of rat, the hyperresponsive Fischer 344 rat and the normoresponsive Lewis rat. Arginase has been implicated in AHR associated with allergic asthma models. We addressed the role of arginase in innate AHR using the Fischer-Lewis model. In vivo arginase inhibition with Nω-hydroxy-nor-arginine (nor-NOHA) was evaluated on methacholine-induced bronchoconstriction in the Fischer and the Lewis rats. Arginase activity and mRNA expression were quantified in structural and resident cells of the proximal airway tree. The effect of nor-NOHA was evaluated on cultured tracheal smooth muscle proliferation. Fischer rats exhibited significantly greater changes in respiratory resistance and elastance in response to methacholine compared with Lewis rats. nor-NOHA reduced the methacholine-induced bronchoconstriction in the central airways of Lewis rats, while it did not change the innate AHR of Fischer rats. Lewis rats exhibited greater arginase activity in tracheal smooth muscle but a lower proliferation rate compared with Fischer rats. Smooth muscle proliferation was not affected by nor-NOHA in either strain of rats. The strain-specific arginase expression in the smooth muscle may contribute to the differences in sensitivity of the methacholine challenged airways of Lewis and Fischer rats to inhibition of arginase.