bluuebunny/crossref_metadata_2025_split huggingface dataset:
Residues in the pore region of Drosophila transient receptor potential A1 dictate sensitivity to thermal stimuli
Authors: Wang Hong , Schupp Melanie , Zurborg Sandra , Heppenstall Paul A. 
Published: October 2012

Key points
Transient receptor potential (TRP) A ion channels are evolutionarily conserved and play a fundamental role in thermal, chemical and mechanical transduction.
In this study, we characterized Drosophila TRPA1 as a non‐selective cation channel that can be activated by heat, voltage and chemicals.
By constructing the chimeric channel between Drosophila TRPA1 and its cold‐sensitive human orthologue, we identified key residues in the transmembrane domain that confer heat sensitivity.
Perturbation of the putative voltage‐sensing module increased the threshold for heat activation.
Single channel recordings revealed the reaction schemes of wild‐type and mutant channels.
Abstract  The capacity to sense temperature is essential for the survival of all animals. At the molecular level, ion channels belonging to the transient receptor potential (TRP) family of channels function as temperature sensors in animals across several phyla. TRP channels are opened directly by changes in temperature and show pronounced sensitivity at their activation range. To determine how temperature activates these channels, we analysed channels belonging to the TRPA family, which detect heat in insects and cold in mammals. By constructing chimeric proteins consisting of human and Drosophila TRPA1 channels, we mapped regions that regulate thermal activation and identified residues in the pore helix that invert temperature sensitivity of TRPA1. From analysis of individual channels we defined the gating reaction of Drosophila TRPA1 and determined how mutagenesis alters the energy landscape for channel opening. Our results reveal specific molecular requirements for thermal activation of TRPA1 and provide mechanistic insight into this process.
Therapeutic Drug Monitoring of Posaconazole in Patients with Acute Myeloid Leukemia or Myelodysplastic Syndrome
Authors: Vaes M. , Hites M. , Cotton F. , Bourguignon A. M. , Csergö M. , Rasson C. , Ameye L. , Bron D. , Jacobs F. , Aoun M. 
Published: October 2012

ABSTRACT

Posaconazole is a broad-spectrum triazole antifungal available as an oral suspension. Pharmacokinetic data showed a high variability of plasma posaconazole concentrations (PPCs) in patients, suggesting a potential interest in drug monitoring. The aim of our prospective study was to measure the PPCs in prophylactically treated patients to evaluate the impact of different factors on these concentrations. In 40 patients treated prophylactically with posaconazole for acute myeloid leukemia or myelodysplastic syndrome between February 2009 and August 2010, PPCs were measured at day 7 of treatment and then twice weekly. Demographic data, clinical data (including gastrointestinal disorders, comedications, and treatment compliance), caloric and fat intake, and biological data were collected and evaluated. We obtained 275 measurements of PPCs, with a median of 430 ng/ml. PPCs were significantly lower in patients with mucositis (
P
< 0.001), nausea (
P
= 0.03), diarrhea (
P
= 0.03), or vomiting (
P
= 0.05). PPCs were higher in patients with a higher caloric intake (
P
= 0.02), while the proportion of fat intake had no influence on PPCs (
P
= 0.84). The concomitant use of proton pump inhibitors decreased the PPCs (
P
= 0.02), while the use of tacrolimus increased the PPC (
P
= 0.03). In the multivariate analysis, the factors influencing the PPCs independently were the concomitant use of tacrolimus (
P
< 0.001), the presence of mucositis (
P
= 0.01), and food intake (
P
= 0.02). Our study confirmed the high variability of posaconazole bioavailability and showed the significant influence of gastrointestinal disorders, food intake, and concomitant medication on the PPCs. However, the optimal PPCs still remain to be defined and correlated with clinical efficacy.
A Case of Daptomycin-Induced Immune Thrombocytopenia
Authors: Grégoire Charles , Brumpt Caren , Loirat Delphine , Lau Nicolas , Bruel Cedric , Philippart Francois , Couzigou Carine , Garrouste-Orgeas Maité , Misset Benoit 
Published: October 2012

ABSTRACTWe report a case of severe daptomycin-induced immune thrombocytopenia in a patient treated for methicillin-resistantStaphylococcus epidermidisand ampicillin-resistantEnterococcus faecalisbacteremia acquired in an intensive care unit. Serum antibodies bound to platelets in the presence of daptomycin on flow cytometry. There was no evidence of other causes of thrombocytopenia. The patient died of brain herniation complicating extensive cerebral hemorrhage. To our knowledge, this is the first described case of daptomycin-induced thrombocytopenia.
Ceftaroline versus Isolates from Animal Bite Wounds: Comparative
In Vitro
Activities against 243 Isolates, Including 156 Pasteurella Species Isolates
Authors: Goldstein Ellie J. C. , Citron Diane M. , Merriam C. Vreni , Tyrrell Kerin L. 
Published: October 2012

ABSTRACT

More than 5 million Americans are bitten by animals, usually dogs, annually. Bite patients comprise ∼1% of all patients who visit emergency departments (300,000/year), and approximately 10,000 require hospitalization and intravenous antibiotics. Ceftaroline is the bioactive component of the prodrug ceftaroline fosamil, which is FDA approved for the treatment of acute bacterial skin and skin structure infections (ABSSSIs), including those containing methicillin-resistant
Staphylococcus aureus
(MRSA). There are no
in vitro
data about the activity of ceftaroline against
Pasteurella multocida
subsp.
multocida
and
Pasteurella multocida
subsp.
septica
, other
Pasteurella
spp., or other bite wound isolates. We therefore studied the
in vitro
activity of ceftaroline against 243 animal bite isolates. MICs were determined using the broth microdilution method according to CLSI guidelines. Comparator drugs included cefazolin, ceftriaxone, ertapenem, ampicillin-sulbactam, azithromycin, doxycycline, and sulfamethoxazole-trimethoprim (SMX-TMP). Ceftaroline was the most active agent against all 5
Pasteurella
species, including
P. multocida
subsp.
multocida
and
P. multocida
subsp.
septica
, with a maximum MIC of ≤0.008 μg/ml; more active than ceftriaxone and ertapenem (MIC
90
s, ≤0.015 μg/ml); and more active than cefazolin (MIC
90
, 0.5 μg/ml) doxycycline (MIC
90
, 0.125 μg/ml), azithromycin (MIC
90
, 0.5 μg/ml), ampicillin-sulbactam (MIC
90
, 0.125 μg/ml), and SMX-TMP (MIC
90
, 0.125 μg/ml). Ceftaroline was also very active against all
S. aureus
isolates (MIC
90
, 0.125 μg/ml) and other
Staphylococcus
and
Streptococcus
species, with a maximum MIC of 0.125 μg/ml against all bite isolates tested. Ceftaroline has potential clinical utility against infections involving
P. multocida
, other
Pasteurella
species, and aerobic Gram-positive isolates, including
S. aureus
.
Impaired Innate Immunity in Mice Deficient in Interleukin-1 Receptor-Associated Kinase 4 Leads to Defective Type 1 T Cell Responses, B Cell Expansion, and Enhanced Susceptibility to Infection with Toxoplasma gondii
Authors: Béla Samantha R. , Dutra Míriam S. , Mui Ernest , Montpetit Alexandre , Oliveira Fernanda S. , Oliveira Sérgio C. , Arantes Rosa M. E. , Antonelli Lis R. , McLeod Rima , Gazzinelli Ricardo T. 
Published: October 2012

ABSTRACTInterleukin-1 receptor (IL1R)-associated kinase 4 (IRAK4) is a member of the IRAK family and has an important role in inducing the production of inflammatory mediators. This kinase is downstream of MyD88, an adaptor protein essential for Toll-like receptor (TLR) function. We investigated the role of this kinase in IRAK4-deficient mice orally infected with the cystogenic ME49 strain ofToxoplasma gondii. IRAK4−/−mice displayed higher morbidity, tissue parasitism, and accelerated mortality than the control mice. The lymphoid follicles and germinal centers from infected IRAK4−/−mice were significantly smaller. We consistently found that IRAK4−/−mice showed a defect in splenic B cell activation and expansion as well as diminished production of gamma interferon (IFN-γ) by T lymphocytes. The myeloid compartment was also affected. Both the frequency and ability of dendritic cells (DCs) and monocytes/macrophages to produce IL-12 were significantly decreased, and resistance to infection withToxoplasmawas rescued by treating IRAK4−/−mice with recombinant IL-12 (rIL-12). Additionally, we report the association of IRAK4 haplotype-tagging single nucleotide polymorphisms (tag-SNPs) with congenital toxoplasmosis in infected individuals (rs1461567 and rs4251513,P< 0.023 andP< 0.045, respectively). Thus, signaling via IRAK4 is essential for the activation of innate immune cells, development of parasite-specific acquired immunity, and host resistance to infection withT. gondii.
Systemic Macrophage Depletion Inhibits Helicobacter bilis-Induced Proinflammatory Cytokine-Mediated Typhlocolitis and Impairs Bacterial Colonization Dynamics in a BALB/c
Rag2
−/−
Mouse Model of Inflammatory Bowel Disease
Authors: Muthupalani Sureshkumar , Ge Zhongming , Feng Yan , Rickman Barry , Mobley Melissa , McCabe Amanda , Van Rooijen Nico , Fox James G. 
Published: October 2012

ABSTRACT

Helicobacter bilis
, an enterohepatic helicobacter, is associated with chronic hepatitis in aged immunocompetent inbred mice and inflammatory bowel disease (IBD) in immunodeficient mice. To evaluate the role of macrophages in
H. bilis
-induced IBD,
Rag2
−/−
BALB/c or wild-type (WT) BALB/c mice were either sham dosed or infected with
H. bilis
Missouri strain under specific-pathogen-free conditions, followed by an intravenous injection of a 0.2-ml suspension of liposomes coated with either phosphate-buffered saline (control) or clodronate (a macrophage depleting drug) at 15 weeks postinfection (wpi). At 16 wpi, the ceca of
H. bilis
-infected
Rag2
−/−
mice treated with control liposomes had significantly higher histopathological lesional scores (for cumulative typhlitis index, inflammation, edema, epithelial defects, and hyperplasia) and higher counts of F4/80
+
macrophages and MPO
+
neutrophils compared to
H. bilis
-infected
Rag2
−/−
mice treated with clodronate liposomes. In addition, cecal quantitative PCR analyses revealed a significant suppression in the expression of macrophage-related cytokine genes, namely,
Tnfa
,
Il-1
β,
Il-10
,
Cxcl1
, and
iNos
, in the clodronate-treated
H. bilis
-infected
Rag2
−/−
mice compared to the
H. bilis
-infected
Rag
2
−/−
control mice. Finally, cecal quantitative PCR analyses also revealed a significant reduction in bacterial colonization in the clodronate-treated
Rag2
−/−
mice. Taken together, our results suggest that macrophages are critical inflammatory cellular mediators for promoting
H. bilis
-induced typhlocolitis in mice.
Microbial Amyloids Induce Interleukin 17A (IL-17A) and IL-22 Responses via Toll-Like Receptor 2 Activation in the Intestinal Mucosa
Authors: Nishimori Jessalyn H. , Newman Tiffanny N. , Oppong Gertrude O. , Rapsinski Glenn J. , Yen Jui-Hung , Biesecker Steven G. , Wilson R. Paul , Butler Brian P. , Winter Maria G. , Tsolis Renee M. , Ganea Doina , Tükel Çagla 
Published: October 2012

ABSTRACTThe Toll-like receptor 2 (TLR2)/TLR1 receptor complex responds to amyloid fibrils, a common component of biofilm material produced by members of the phylaFirmicutes,Bacteroidetes, andProteobacteria. To determine whether this TLR2/TLR1 ligand stimulates inflammatory responses when bacteria enter intestinal tissue, we investigated whether expression of curli amyloid fibrils by the invasive enteric pathogenSalmonella entericaserotype Typhimurium contributes to T helper 1 and T helper 17 responses by measuring cytokine production in the mouse colitis model. AcsgBAmutant, deficient in curli production, elicited decreased expression of interleukin 17A (IL-17A) and IL-22 in the cecal mucosa compared to theS. Typhimurium wild type. In TLR2-deficient mice, IL-17A and IL-22 expression was blunted duringS. Typhimurium infection, suggesting that activation of the TLR2 signaling pathway contributes to the expression of these cytokines. T cells incubated with supernatants from bone marrow-derived dendritic cells (BMDCs) treated with curli fibrils released IL-17A in a TLR2-dependent mannerin vitro. Lower levels of IL-6 and IL-23 production were detected in the supernatants of the TLR2-deficient BMDCs treated with curli fibrils. Consistent with this, three distinct T-cell populations—CD4+T helper cells, cytotoxic CD8+T cells, and γδ T cells—produced IL-17A in response to curli fibrils in the intestinal mucosa duringS. Typhimurium infection. Notably, decreased IL-6 expression by the dendritic cells and decreased IL-23 expression by the dendritic cells and macrophages were observed in the cecal mucosa of mice infected with the curli mutant. We conclude that TLR2 recognition of bacterial amyloid fibrils in the intestinal mucosa represents a novel mechanism of immunoregulation, which contributes to the generation of inflammatory responses, including production of IL-17A and IL-22, in response to bacterial entry into the intestinal mucosa.
Haemophilus ducreyi-Induced Interleukin-10 Promotes a Mixed M1 and M2 Activation Program in Human Macrophages
Authors: Li Wei , Katz Barry P. , Spinola Stanley M. 
Published: October 2012

ABSTRACTDuring microbial infection, macrophages are polarized to classically activated (M1) or alternatively activated (M2) cells in response to microbial components and host immune mediators. Proper polarization of macrophages is critical for bacterial clearance. To study the role of macrophage polarization duringHaemophilus ducreyiinfection, we analyzed a panel of macrophage surface markers in skin biopsy specimens of pustules obtained from experimentally infected volunteers. Lesional macrophages expressed markers characteristic of both M1 and M2 polarization. Monocyte-derived macrophages (MDM) also expressed a mixed M1 and M2 profile of surface markers and cytokines/chemokines upon infection withH. ducreyiin vitro. Endogenous interleukin 10 (IL-10) produced by infected MDM downregulated and enhanced expression of several M1 and M2 markers, respectively. Bacterial uptake, mediated mainly by class A scavenger receptors, and activation of mitogen-activated protein kinase and phosphoinositide 3-kinase signaling pathways were required forH. ducreyi-induced IL-10 production in MDM. Compared to M1 cells, IL-10-polarized M2 cells displayed enhanced phagocytic activity againstH. ducreyiand similar bacterial killing. Thus, IL-10-modulated macrophage polarization may contribute toH. ducreyiclearance during human infection.
In Vivo
Sequence Variation in HopZ, a Phase-Variable Outer Membrane Protein of Helicobacter pylori
Authors: Kennemann Lynn , Brenneke Birgit , Andres Sönke , Engstrand Lars , Meyer Thomas F. , Aebischer Toni , Josenhans Christine , Suerbaum Sebastian 
Published: October 2012

ABSTRACT

The
Helicobacter pylori
outer membrane protein HopZ is regulated by a phase-variable CT repeat and occurs in two distinct allelic variants. Whole-genome comparisons of isolates from one human volunteer recently provided evidence for
in vivo
selection for the
hopZ
ON status. We explored the frequency of sequence variation in
hopZ
during acute and chronic human infection and studied the association of
hopZ
with the phylogeographic population structure of
H. pylori. hopZ
ON variants were cultured from 24 out of 33 volunteers challenged with the
hopZ
OFF strain BCS 100. Transmission of
H. pylori
within families was also frequently associated with a status change of
hopZ
. In contrast,
hopZ
sequences obtained from 26 sets of sequential isolates from chronically infected individuals showed no changes of status, suggesting that the
hopZ
status selected during early infection is subsequently stable. Mutations leading to amino acid changes in HopZ occurred more frequently in ON than in OFF status isolates during chronic infection, indicating that sequence changes are more likely the result of positive selection in ON isolates than of a loss of negative selection pressure in OFF isolates. Analysis of 63 isolates from chronically infected individuals revealed no significant correlation of
hopZ
status with chronic atrophic gastritis.
hopZ
sequences were obtained from a globally representative collection of 54
H. pylori
strains. All
H. pylori
populations contained
hopZ
-positive isolates. The data suggest that
hopZ
has been acquired and split into the two variants before the human migration out of Africa.
Estimate of HIV prevalence and number of people living with HIV in India 2008–2009
Authors: Pandey Arvind , Sahu Damodar , Bakkali Taoufi , Reddy DCS , Venkatesh S , Kant Shashi , Bhattacharya M , Raj Yujwal , Haldar Partha , Bhardwaj Deepak , Chandra Nalini 
Published: October 2012

ObjectivesTo update the estimation of the adult HIV prevalence and number of people living with HIV (PLHIV) in India for the year 2008−2009 with the combination of improved data and methods.DesignBased on HIV sentinel surveillance (HSS) data and a set of epidemiological assumptions, estimates of HIV prevalence and burden in India have been derived.SettingHSS sites spread over all the States of India.ParticipantsSecondary data from HSS sites which include attendees of antenatal clinics and sites under targeted interventions of high-risk groups, namely, female sex workers (FSW), intravenous drug users (IDU) and men having sex with men (MSM).Primary and secondary outcome measuresEstimates of adult HIV prevalence and PLHIV in India and its states.ResultsThe adult HIV prevalence in India has declined to an estimated 0.31% (0.25–0.39%) in 2009 against 0.36% (0.29–0.45%) in 2006. Among the high prevalence states, the HIV prevalence has declined in Tamil Nadu to 0.33% in 2009 and other states show either a plateau or a slightly declining trend over the time period 2006–2009. There are states in the low prevalence states where the adult HIV prevalence has risen over the last 4 years. The estimated number of PLHIV in India is 2.4 million (1.93–3.04 million) in 2009. Of which, 39% are women, children under 15 years of age account for 4.4% of all infections, while people aged 15–49 years account for 82.4% of all infections.ConclusionsThe estimated adult prevalence has declined in few states, a plateau or a slightly declining trend over the time. In future, efforts may be made to examine the implications of the emerging trend of the HIV prevalence on the recent infections in the study population.
What we talk about when we talk about cloud network performance
Authors: Mogul Jeffrey C. , Popa Lucian 
Published: October 2012

Infrastructure-as-a-Service ("Cloud") data-centers intrinsically depend on high-performance networks to connect servers within the data-center and to the rest of the world. Cloud providers typically offer different service levels, and associated prices, for different sizes of virtual machine, memory, and disk storage. However, while all cloud providers provide network connectivity to tenant VMs, they seldom make any promises about network performance, and so cloud tenants suffer from highly-variable, unpredictable network performance.
Many cloud customers do want to be able to rely on network performance guarantees, and many cloud providers would like to offer (and charge for) these guarantees. But nobody really agrees on how to define these guarantees, and it turns out to be challenging to define "network performance" in a way that is useful to both customers and providers. We attempt to bring some clarity to this question.
An Insertion/Deletion Polymorphism within RERT-lncRNA Modulates Hepatocellular Carcinoma Risk
Authors: Zhu Zhansheng , Gao Xueren , He Yan , Zhao Hua , Yu Qiang , Jiang Deke , Zhang Pingzhao , Ma Xiaopin , Huang Huixing , Dong Dong , Wan Jiao , Gu Zhenyong , Jiang Xinghong , Yu Long , Gao Yuzhen 
Published: October 2012

Abstract
The Prolyl hydroxylase 1 (EGLN2) is known to affect tumorigenesis by regulating the degradation of hypoxia-inducible factor. Polymorphisms in EGLN2 may facilitate cancer cell survival under hypoxic conditions and directly associate with cancer susceptibility. Here, we examined the contribution of a 4-bp insertion/deletion polymorphism (rs10680577) within the distal promoter of EGLN2 to the risk of hepatocelluar carcinoma (HCC) in Chinese populations. The contribution of rs10680577 to HCC risk was investigated in 623 HCC cases and 1,242 controls and replicated in an independent case–control study consisting of 444 HCC cases and 450 controls. Logistic regression analysis showed that the deletion allele of rs10680577 was significantly associated with increased risk for HCC occurrence in both case–control studies [OR = 1.40; 95% confidence interval (CI) = 1.18–1.66, P &lt; 0.0001; OR = 1.49; 95% CI = 1.18–1.88, P = 0.0007]. Such positive association was more pronounced in current smokers (OR = 3.49, 95% CI = 2.24–5.45) than nonsmokers (OR = 1.24, 95% CI = 1.03–1.50; heterogeneity P = 0.0002). Genotype–phenotype correlation studies showed that the deletion allele was significantly correlated with higher expression of both EGLN2 and RERT-lncRNA [a long noncoding RNA whose sequence overlaps with Ras-related GTP-binding protein 4b (RAB4B) and EGLN2)] in vivo and in vitro. Furthermore, RERT-lncRNA expression was also significantly correlated with EGLN2 expression in vivo, consistent with in vitro gain-of-function study that showed overexpressing RERT-lncRNA upregulated EGLN2. Finally, in silico prediction suggested that the insertion allele could disrupt the structure of RERT-lncRNA. Taken together, our findings provided strong evidence for the hypothesis that rs10680577 contributes to hepatocarcinogenesis, possibly by affecting RERT-lncRNA structure and subsequently EGLN2 expression, making it a promising biomarker for early diagnosis of HCC. Cancer Res; 72(23); 6163–72. ©2012 AACR.
ICOS-Ligand Expression on Plasmacytoid Dendritic Cells Supports Breast Cancer Progression by Promoting the Accumulation of Immunosuppressive CD4+ T Cells
Authors: Faget Julien , Bendriss-Vermare Nathalie , Gobert Michael , Durand Isabelle , Olive Daniel , Biota Cathy , Bachelot Thomas , Treilleux Isabelle , Goddard-Leon Sophie , Lavergne Emilie , Chabaud Sylvie , Blay Jean Yves , Caux Christophe , Ménétrier-Caux Christine 
Published: October 2012

Abstract
Human breast tumors are infiltrated by memory CD4+ T cells along with increased numbers of regulatory T cells (Treg) and plasmacytoid dendritic cells (pDC) that facilitate immune escape and correlate with poor prognosis. Here, we report that inducible costimulatory molecule (ICOS), a T cell costimulatory molecule of the CTLA4/PD1/CD28 family, is expressed mostly by tumor-associated Treg in primary breast tumors. A large proportion of these ICOS+ Treg were Ki67+ and this evident proliferative expansion was found to rely on interactions with tumor-associated pDC. Indeed, tumor-associated Treg highly expanded in presence of pDC but failed to proliferate under CD3/CD28 signal. In vitro experiments revealed that the addition of a neutralizing anti-ICOS antibody blocked pDC-induced Treg expansion and interleukin-10 secretion by memory CD4+ T cells, establishing a pivotal role for ICOS in this process. Supporting these findings, the presence of ICOS+ cells in clinical specimens of breast cancer correlated with a poor prognosis. Together, our results highlight an important relationship between Treg and pDC in breast tumors, and show that ICOS/ICOS-L interaction is a central event in immunosuppression of tumor-associated memory CD4+ T cells. These findings strongly rationalize antibody-mediated ICOS blockade as a powerful clinical strategy to correct immune escape and promote therapeutic responses in breast cancer. Cancer Res; 72(23); 6130–41. ©2012 AACR.