bluuebunny/crossref_metadata_2025_split huggingface dataset:
Postnatal development of electrophysiological properties of principal neurons in the rat basolateral amygdala
Authors: Ehrlich D. E. , Ryan S. J. , Rainnie D. G. 
Published: July 2012

Key points
The amygdala mediates emotional processing, in particular fear learning, and disruption of its function is thought to contribute to the developmental origins of psychiatric disorders like depression, anxiety and autism spectrum disorders.
It is difficult to identify the causes of these disorders or provide effective intervention because most of what is known of amygdala physiology is based on the adult.
Using the whole‐cell patch clamp technique, we show that neurons in the developing rat amygdala undergo drastic changes to their electrophysiology, including passive membrane properties, intrinsic currents and resonance.
This provides the first evidence that amygdala neuron physiology is dynamic before adulthood, and likely to contribute to emotional development.
The results help us better understand the normative development of emotional processing and identify critical periods of maturation that may be sensitive to insult.
Abstract  The basolateral amygdala (BLA) is critically involved in the pathophysiology of psychiatric disorders, which often emerge during brain development. Several studies have characterized postnatal changes to the morphology and biochemistry of BLA neurons, and many more have identified sensitive periods of emotional maturation. However, it is impossible to determine how BLA development contributes to emotional development or the aetiology of psychiatric disorders because no study has characterized the physiological maturation of BLA neurons. We addressed this critical knowledge gap for the first time using whole‐cell patch clamp recording in rat BLA principal neurons to measure electrophysiological properties at postnatal day (P)7, P10, P14, P21, P28 and after P35. We show that intrinsic properties of these neurons undergo significant transitions before P21 and reach maturity around P28. Specifically, we observed significant reductions in input resistance and membrane time constant of nearly 10‐ and 4‐fold, respectively, from P7 to P28. The frequency selectivity of these neurons to input also changed significantly, with peak resonance frequency increasing from 1.0 Hz at P7 to 5.7 Hz at P28. In the same period, maximal firing frequency significantly increased and doublets and triplets of action potentials emerged. Concomitantly, individual action potentials became significantly faster, firing threshold hyperpolarized 6.7 mV, the medium AHP became faster and shallower, and a fast AHP emerged. These results demonstrate neurons of the BLA undergo vast change throughout postnatal development, and studies of emotional development and treatments for juvenile psychiatric disorders should consider the dynamic physiology of the immature BLA.
Chemical Inhibitors of the Type Three Secretion System: Disarming Bacterial Pathogens
Authors: Duncan Miles C. , Linington Roger G. , Auerbuch Victoria 
Published: July 2012

ABSTRACT
The recent and dramatic rise of antibiotic resistance among bacterial pathogens underlies the fear that standard treatments for infectious disease will soon be largely ineffective. Resistance has evolved against nearly every clinically used antibiotic, and in the near future, we may be hard-pressed to treat bacterial infections previously conquered by “magic bullet” drugs. While traditional antibiotics kill or slow bacterial growth, an important emerging strategy to combat pathogens seeks to block the ability of bacteria to harm the host by inhibiting bacterial virulence factors. One such virulence factor, the type three secretion system (T3SS), is found in over two dozen Gram-negative pathogens and functions by injecting effector proteins directly into the cytosol of host cells. Without T3SSs, many pathogenic bacteria are unable to cause disease, making the T3SS an attractive target for novel antimicrobial drugs. Interdisciplinary efforts between chemists and microbiologists have yielded several T3SS inhibitors, including the relatively well-studied salicylidene acylhydrazides. This review highlights the discovery and characterization of T3SS inhibitors in the primary literature over the past 10 years and discusses the future of these drugs as both research tools and a new class of therapeutic agents.
Cobicistat Boosts the Intestinal Absorption of Transport Substrates, Including HIV Protease Inhibitors and GS-7340,
In Vitro
Authors: Lepist Eve-Irene , Phan Truc K. , Roy Anupma , Tong Leah , MacLennan Kelly , Murray Bernard , Ray Adrian S. 
Published: July 2012

ABSTRACT

The experimental pharmacoenhancer cobicistat (COBI), a potent mechanism-based inhibitor of cytochrome P450 3A enzymes, was found to inhibit the intestinal efflux transporters P-glycoprotein and breast cancer resistance protein. Consistent with its transporter inhibition, COBI significantly increased the absorptive flux of potential candidates for clinical coadministration, including the HIV protease inhibitors atazanavir and darunavir and the lymphoid cell- and tissue-targeted prodrug of the nucleotide analog tenofovir, GS-7340, through monolayers of Caco-2 cells
in vitro
.
Effect on Hepatitis C Virus Replication of Combinations of Direct-Acting Antivirals, Including NS5A Inhibitor Daclatasvir
Authors: Pelosi Lenore A. , Voss Stacey , Liu Mengping , Gao Min , Lemm Julie A. 
Published: July 2012

ABSTRACT
Three hepatitis C virus (HCV) inhibitors, asunaprevir (ASV; BMS-650032), daclatasvir (DCV; BMS-790052), and BMS-791325, each targeting a different nonstructural protein of the virus (NS3, NS5A, and NS5B, respectively), have independently demonstrated encouraging preclinical profiles and are currently undergoing clinical evaluation. Since drug-resistant variants have rapidly developed in response to monotherapy with almost all direct-acting antiviral agents (DAAs) for HCV, the need for combination therapies to effectively eradicate the virus from infected patients is clear. These studies demonstrated the additive-synergistic effects on replicon inhibition and clearance of combining NS3 protease or NS5B RNA polymerase inhibitors with the first-in-class, NS5A replication complex inhibitor daclatasvir (DCV) and reveal new resistance pathways for combinations of two small-molecule inhibitors that differ from those that develop during monotherapy. The results suggest that under a specific selective pressure, a balance must be reached in the fitness costs of substitutions in one target gene when substitutions are also present in another target gene. Further synergies and additional novel resistance substitutions were observed during triple-combination treatment relative to dual-drug therapy, indicating that, in combination, HCV inhibitors can exert cross-target influences on resistance development. Enhanced synergies in replicon inhibition and a reduced frequency of resistance together lend strong support to the utility of combinations of DAAs for the treatment of HCV, and the identification of altered resistance profiles during combination treatment provides useful information for monitoring resistance in the clinic.
Infection with Toxoplasma gondii Alters Lymphotoxin Expression Associated with Changes in Splenic Architecture
Authors: Glatman Zaretsky Arielle , Silver Jonathan S. , Siwicki Marie , Durham Amy , Ware Carl F. , Hunter Christopher A. 
Published: July 2012

ABSTRACTB cell responses are required for resistance toToxoplasma gondii; however, the events that lead to production of class-switched antibodies duringT. gondiiinfection have not been defined. Indeed, mice challenged with the parasite exhibited an expansion of T follicular helper cells and germinal center B cells in the spleen. Unexpectedly, this was not associated with germinal center formation and was instead accompanied by profound changes in splenic organization. This phenomenon was transient and was correlated with a decrease in expression of effector proteins that contribute to splenic organization, including lymphotoxins α and β. The importance of lymphotoxin was confirmed, as the use of a lymphotoxin β receptor agonist results in partial restoration of splenic structure. Splenectomized mice were used to test the splenic contribution to the antibody response duringT. gondiiinfection. Analysis of splenectomized mice revealed delayed kinetics in the production of parasite-specific antibody, but the mice did eventually develop normal levels of parasite-specific antibody. Together, these studies provide a better understanding of how infection withT. gondiiimpacts the customized structures required for the optimal humoral responses to the parasite and the role of lymphotoxin in these events.
Roles of Chaperone/Usher Pathways of Yersinia pestis in a Murine Model of Plague and Adhesion to Host Cells
Authors: Hatkoff Matthew , Runco Lisa M. , Pujol Celine , Jayatilaka Indralatha , Furie Martha B. , Bliska James B. , Thanassi David G. 
Published: July 2012

ABSTRACT

Yersinia pestis
and many other Gram-negative pathogenic bacteria use the chaperone/usher (CU) pathway to assemble virulence-associated surface fibers termed pili or fimbriae.
Y. pestis
has two well-characterized CU pathways: the
caf
genes coding for the F1 capsule and the
psa
genes coding for the pH 6 antigen. The
Y. pestis
genome contains additional CU pathways that are capable of assembling pilus fibers, but the roles of these pathways in the pathogenesis of plague are not understood. We constructed deletion mutations in the usher genes for six of the additional
Y. pestis
CU pathways. The wild-type (WT) and usher deletion strains were compared in the murine bubonic (subcutaneous) and pneumonic (intranasal) plague infection models.
Y. pestis
strains containing deletions in CU pathways
y0348-0352
,
y1858-1862
, and
y1869-1873
were attenuated for virulence compared to the WT strain by the intranasal, but not subcutaneous, routes of infection, suggesting specific roles for these pathways during pneumonic plague. We examined binding of the
Y. pestis
WT and usher deletion strains to A549 human lung epithelial cells, HEp-2 human cervical epithelial cells, and primary human and murine macrophages.
Y. pestis
CU pathways
y0348-0352
and
y1858-1862
were found to contribute to adhesion to all host cells tested, whereas pathway
y1869-1873
was specific for binding to macrophages. The correlation between the virulence attenuation and host cell binding phenotypes of the usher deletion mutants identifies three of the additional CU pathways of
Y. pestis
as mediating interactions with host cells that are important for the pathogenesis of plague.
Type 2 Innate Immunity in Helminth Infection Is Induced Redundantly and Acts Autonomously following CD11c+Cell Depletion
Authors: Smith Katherine A. , Harcus Yvonne , Garbi Natalio , Hämmerling Günter J , MacDonald Andrew S. , Maizels Rick M. 
Published: July 2012

ABSTRACTInfection with gastrointestinal helminths generates a dominant type 2 response among both adaptive (Th2) and innate (macrophage, eosinophil, and innate lymphoid) immune cell types. Two additional innate cell types, CD11chighdendritic cells (DCs) and basophils, have been implicated in the genesis of type 2 immunity. Investigating the type 2 response to intestinal nematode parasites, includingHeligmosomoides polygyrusandNippostrongylus brasiliensis, we first confirmed the requirement for DCs in stimulating Th2 adaptive immunity against these helminths through depletion of CD11chighcells by administration of diphtheria toxin to CD11c.DOG mice. In contrast, responsiveness was intact in mice depleted of basophils by antibody treatment. Th2 responses can be induced by adoptive transfer of DCs, but not basophils, exposed to soluble excretory-secretory products from these helminths. However, innate type 2 responses arose equally strongly in the presence or absence of CD11chighcells or basophils; thus, in CD11c.DOG mice, the alternative activation of macrophages, as measured by expression of arginase-1, RELM-α, and Ym-1 (Chi3L3) in the intestine followingH. polygyrusinfection or in the lung followingN. brasiliensisinfection, was unaltered by depletion of CD11c-expressing DCs and alveolar macrophages or by antibody-mediated basophil depletion. Similarly, goblet cell-associated RELM-β in lung and intestinal tissues, lung eosinophilia, and expansion of innate lymphoid (“nuocyte”) populations all proceeded irrespective of depletion of CD11chighcells or basophils. Thus, while CD11chighDCs initiate helminth-specific adaptive immunity, innate type 2 cells are able to mount an autonomous response to the challenge of parasite infection.
A Variability-Aware Robust Design Space Exploration Methodology for On-Chip Multiprocessors Subject to Application-Specific Constraints
Authors: Palermo Gianluca , Silvano Cristina , Zaccaria Vittorio 
Published: July 2012

Manufacturing process variation is dramatically becoming one of the most important challenges related to power and performance optimization for sub-90nm CMOS technologies. Process variability impacts the optimization of the target system metrics, that is, performance and energy consumption by introducing fluctuations and unpredictability. Besides, it impacts the parametric yield of the chip with respect to application level constraints by reducing the number of devices working within normal operating conditions.
The impact of variability on systems with stringent application-specific requirements (such as portable multimedia and critical embedded systems) is much greater than on general-purpose systems given the emphasis on predictability and reduced operating margins. In this market segment, failing to address such a problem within the early design stages of the chip may lead to missing market deadlines and suffering greater economic losses.

In the context of a design space exploration framework for supporting the platform-based design approach, we address the problem of robustness with respect to manufacturing process variations. First, we apply
Response Surface Modeling
(RSM) techniques to enable an efficient evaluation of the statistical measures of execution time and energy consumption for each system configuration. Then, we apply a robust design space exploration framework to afford the problem of the impact of manufacturing process variations onto the system-level metrics and consequently onto the application-level constraints. We finally provide a comparison of our design space exploration technique with conventional approaches on two different case studies.
Generating Invariant-Based Certificates for Embedded Systems
Authors: Blech Jan Olaf , Périn Michaël 
Published: July 2012

Automatic verification tools, such as model checkers and tools based on static analysis or on abstract interpretation, have become popular in software and hardware development. They increase confidence and potentially provide rich feedback. However, with increasing complexity, verification tools themselves are more likely to contain errors.
In contrast to automatic verification tools, higher-order theorem provers use mathematically founded proof strategies checked by a small proof checker to guarantee selected properties. Thus, they enjoy a high level of trustability. Properties of software and hardware systems and their justifications can be encapsulated into a certificate, thereby guaranteeing correctness of the systems, with respect to the properties. These results offer a much higher degree of confidence than results achieved by verification tools. However, higher-order theorem provers are usually slow, due to their general and minimalistic nature. Even for small systems, a lot of human interaction is required for establishing a certificate.
In this work, we combine the advantages of automatic verification tools (i.e., speed and automation) with those of higher-order theorem provers (i.e., high level of trustability). The verification tool generates a certificate for each invocation. This is checked by the higher-order theorem prover, thereby guaranteeing the desired property. The generation of certificates is much easier than producing the analysis results of the verification tool in the first place. In our work, we are able to create certificates that come with an algorithmic description of the proof of the desired property as justification. We concentrate on verification tools that generate invariants of systems and certify automatically that these do indeed hold. Our approach is applied to the certification of the verdicts of a deadlock-detection tool for an asynchronous component-based language.
PKCδ Regulates Death Receptor 5 Expression Induced by PS-341 through ATF4–ATF3/CHOP Axis in Human Lung Cancer Cells
Authors: Xu Linyan , Su Ling , Liu Xiangguo 
Published: July 2012

Abstract
PS-341 (bortezomib), a proteasome inhibitor, has been approved for the treatment of multiple myeloma. Our previous work has shown that PS-341 induces death receptor 5 (DR5)–dependent apoptosis and enhances the TNF-related apoptosis-inducing ligand–induced apoptosis in human non–small cell lung cancer cells. However, the definite mechanism remains undefined. In the present study, we reveal that PKCδ and RSK2 mediate PS-341–induced DR5 upregulation, involving coactivation of endoplasmic reticulum (ER) stress. We discovered that PS-341 activated ER stress through elevating the expression of BiP, p-eIF2α, IRE1α, ATF4, ATF3, and CCAAT/enhancer-binding protein homologous protein (CHOP). Further study showed that DR5 upregulation was dependent on ATF4, ATF3, and CHOP expression. Silencing either one of the ATF4, ATF3, and CHOP expression decreased DR5 upregulation and subsequent apoptosis. We determined that ATF4 regulated ATF3 and CHOP expression. Thereafter, ATF3 and CHOP formed a complex and regulated DR5 expression. In addition, we discovered that the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and RSK2 were elevated after PS-341 treatment and inhibition of their phosphorylation using MAP-ERK kinase 1/2 inhibitor decreased the DR5 level, indicating that ERK/RSK2 signaling is involved in DR5 upregulation. Furthermore, we detected the cleavage of PKCδ, and the blockage of PKCδ expression cut down DR5 upregulation and apoptosis. Importantly, knockdown of PKCδ expression decreased the induction of ER stress and the phosphorylation of ERK1/2 and RSK2, suggesting that PKCδ regulates DR5 expression through ERK/RSK2 signaling and ATF4–CHOP/ATF3 axis. Collectively, we show that PS-341 induces PKCδ-dependent DR5 expression through activation of ERK/RSK2 and ER stress signaling pathway. Mol Cancer Ther; 11(10); 2174–82. ©2012 AACR.
Working Memory Capacity and Visual–Verbal Cognitive Load Modulate Auditory–Sensory Gating in the Brainstem: Toward a Unified View of Attention
Authors: Sörqvist Patrik , Stenfelt Stefan , Rönnberg Jerker 
Published: July 2012

Abstract
Two fundamental research questions have driven attention research in the past: One concerns whether selection of relevant information among competing, irrelevant, information takes place at an early or at a late processing stage; the other concerns whether the capacity of attention is limited by a central, domain-general pool of resources or by independent, modality-specific pools. In this article, we contribute to these debates by showing that the auditory-evoked brainstem response (an early stage of auditory processing) to task-irrelevant sound decreases as a function of central working memory load (manipulated with a visual–verbal version of the n-back task). Furthermore, individual differences in central/domain-general working memory capacity modulated the magnitude of the auditory-evoked brainstem response, but only in the high working memory load condition. The results support a unified view of attention whereby the capacity of a late/central mechanism (working memory) modulates early precortical sensory processing.
A functional equation related to inner product spaces in non-Archimedean "Equation missing" -random normed spaces
Authors: Vahidi Javad , Park Choonkil , Saadati Reza 
Published: July 2012

Abstract
In this paper, we prove the stability of a functional equation related to inner product spaces in non-Archimedean

L

-random normed spaces.

MSC: 46S10, 39B52, 47S10, 26E30, 12J25.
Whole blood-derived microRNA signatures in mice exposed to lipopolysaccharides
Authors: Hsieh Ching-Hua , Rau Cheng-Shyuan , Jeng Jonathan Chris , Chen Yi-Chun , Lu Tsu-Hsiang , Wu Chia-Jung , Wu Yi-Chan , Tzeng Siou-Ling , Yang Johnson Chia-Shen 
Published: July 2012

Abstract

Background
Lipopolysaccharide (LPS) is recognized as the most potent microbial mediator presaging the threat of invasion of Gram-negative bacteria that implicated in the pathogenesis of sepsis and septic shock. This study was designed to examine the microRNA (miRNA) expression in whole blood from mice injected with intraperitoneal LPS.

Methods
C57BL/6 mice received intraperitoneal injections of varying concentrations (range, 10–1000 μg) of LPS from different bacteria, including Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa, Salmonella enterica, and Serratia marcescens and were killed 2, 6, 24, and 72 h after LPS injection. Whole blood samples were obtained and tissues, including lung, brain, liver, and spleen, were harvested for miRNA expression analysis using an miRNA array (Phalanx miRNA OneArray® 1.0). Upregulated expression of miRNA targets in the whole blood of C57BL/6 and Tlr4

−/−
mice injected with LPS was quantified using real-time RT-PCR and compared with that in the whole blood of C57BL/6 mice injected with lipoteichoic acid (LTA) from Staphylococcus aureus.

Results
Following LPS injection, a significant increase of 15 miRNAs was observed in the whole blood. Among them, only 3 miRNAs showed up-regulated expression in the lung, but no miRNAs showed a high expression level in the other examined tissues. Upregulated expression of the miRNA targets (let-7d, miR-15b, miR-16, miR-25, miR-92a, miR-103, miR-107 and miR-451) following LPS injection on real-time RT-PCR was dose- and time-dependent. miRNA induction occurred after 2 h and persisted for at least 6 h. Exposure to LPS from different bacteria did not induce significantly different expression of these miRNA targets. Additionally, significantly lower expression levels of let-7d, miR-25, miR-92a, miR-103, and miR-107 were observed in whole blood of Tlr4
−/− mice. In contrast, LTA exposure induced moderate expression of miR-451 but not of the other 7 miRNA targets.

Conclusions
We identified a specific whole blood–derived miRNA signature in mice exposed to LPS, but not to LTA, from different gram-negative bacteria. These whole blood-derived miRNAs are promising as biomarkers for LPS exposure.