bluuebunny/crossref_metadata_2025_split huggingface dataset:
Down‐regulation of CaV1.2 channels during hypertension: how fewer CaV1.2 channels allow more Ca2+ into hypertensive arterial smooth muscle
Authors: Tajada Sendoa , Cidad Pilar , Colinas Olaia , Santana L. Fernando , López‐López José R. , Pérez‐García M. Teresa 
Published: October 2013

Key points
A hallmark of essential hypertension is an anomalous vascular tone due to the increase in intracellular Ca2+ ([Ca2+]i) and/or Ca2+ sensitivity in vascular smooth muscle. Down‐regulation of K+ channels together with increased CaV1.2 channel function has been proposed as one pathogenic mechanism.
Using a mouse model of essential hypertension (BPH line), we found a decrease in the global smooth muscle Ca2+ influx due to fewer CaV1.2 channels. However, these CaV1.2 channels are hyperactive, allowing a larger local Ca2+ influx at rest that triggers an increased Ca2+ release from intracellular stores (sparks).
Large conductance, Ca2+‐activated K+ (BK) channels of BPH myocytes show reduced Ca2+ sensitivity, so that its activation by the increased [Ca2+]i is impaired.
Our results suggest that changes in the molecular composition of both CaV1.2 and BK channels could explain vascular dysfunction during hypertension in BPH mice.
Abstract  Hypertension is a clinical syndrome characterized by increased arterial tone. Although the mechanisms are varied, the generally accepted view is that increased CaV1.2 channel function is a common feature of this pathological condition. Here, we investigated the mechanisms underlying vascular dysfunction in a mouse model of genetic hypertension. Contrary to expectation, we found that whole‐cell CaV1.2 currents (ICa) were lower in hypertensive (BPH line) than normotensive (BPN line) myocytes. However, local CaV1.2 sparklet activity was higher in BPH cells, suggesting that the relatively low ICa in these cells was produced by a few hyperactive CaV1.2 channels. Furthermore, our data suggest that while the lower expression of the pore‐forming α1c subunit of CaV1.2 currents underlies the lower ICa in BPH myocytes, the increased sparklet activity was due to a different composition in the auxiliary subunits of the CaV1.2 complexes. ICa currents in BPN cells were produced by channels composed of α1c/α2δ/β3 subunits, while in BPH myocytes currents were probably generated by the opening of channels formed by α1c/α2δ/β2 subunits. In addition, Ca2+ sparks evoked large conductance, Ca2+‐activated K+ (BK) currents of lower magnitude in BPH than in BPN myocytes, because BK channels were less sensitive to Ca2+. Our data are consistent with a model in which a decrease in the global number of CaV1.2 currents coexist with the existence of a subpopulation of highly active channels that dominate the resting Ca2+ influx. The decrease in BK channel activity makes the hyperpolarizing brake ineffective and leads BPH myocytes to a more contracted resting state.
Evaluating Aziridinyl Nitrobenzamide Compounds as Leishmanicidal Prodrugs
Authors: Voak Andrew A. , Seifert Karin , Helsby Nuala A. , Wilkinson Shane R. 
Published: October 2013

ABSTRACT

Many of the nitroaromatic agents used in medicine function as prodrugs and must undergo activation before exerting their toxic effects. In most cases, this is catalyzed by flavin mononucleotide (FMN)-dependent type I nitroreductases (NTRs), a class of enzyme absent from higher eukaryotes but expressed by bacteria and several eukaryotic microbes, including trypanosomes and
Leishmania
. Here, we utilize this difference to evaluate whether members of a library of aziridinyl nitrobenzamides have activity against
Leishmania major
. Biochemical screens using purified
L. major
NTR (LmNTR) revealed that compounds containing an aziridinyl-2,4-dinitrobenzyl core were effective substrates for the enzyme and showed that the 4-nitro group was important for this activity. To facilitate drug screening against intracellular amastigote parasites, we generated leishmanial cells that expressed the luciferase reporter gene and optimized a mammalian infection model in a 96-well plate format. A subset of aziridinyl-2,4-dinitrobenzyl compounds possessing a 5-amide substituent displayed significant growth-inhibitory properties against the parasite, with the most potent agents generating 50% inhibitory concentrations of <100 nM for the intracellular form. This antimicrobial activity was shown to be LmNTR specific since
L. major NTR
+/−
heterozygote parasites were slightly resistance to most aziridinyl dinitrobenzyl agents tested. When the most potent leishmanicidal agents were screened against the mammalian cells in which the amastigote parasites were propagated, no growth-inhibitory effect was observed at concentrations of up to 100 μM. We conclude that the aziridinyl nitrobenzamides represent a new lead structure that may have the potential to treat leishmanial infections.
HLA Class II (DR0401) Molecules Induce Foxp3+Regulatory T Cell Suppression of B Cells in Plasmodium yoelii Strain 17XNL Malaria
Authors: Wijayalath Wathsala , Danner Rebecca , Kleschenko Yuliya , Majji Sai , Villasante Eileen Franke , Richie Thomas L. , Brumeanu Teodor-Doru , David Chella S. , Casares Sofia 
Published: October 2013

ABSTRACTUnlike human malaria parasites that induce persistent infection, some rodent malaria parasites, likePlasmodium yoeliistrain 17XNL (Py17XNL), induce a transient (self-curing) malaria infection. Cooperation between CD4 T cells and B cells to produce antibodies is thought to be critical for clearance of Py17XNL parasites from the blood, with major histocompatibility complex (MHC) class II molecules being required for activation of CD4 T cells. In order to better understand the correspondence between murine malaria models and human malaria, and in particular the role of MHC (HLA) class II molecules, we studied the ability of humanized mice expressing human HLA class II molecules to clear Py17XNL infection. We showed that humanized mice expressing HLA-DR4 (DR0401) molecules and lacking mouse MHC class II molecules (EA0) have impaired production of specific antibodies to Py17XNL and cannot cure the infection. In contrast, mice expressing HLA-DR4 (DR0402), HLA-DQ6 (DQ0601), HLA-DQ8 (DQ0302), or HLA-DR3 (DR0301) molecules in an EA0background were able to elicit specific antibodies and self-cure the infection. In a series of experiments, we determined that the inability of humanized DR0401.EA0mice to elicit specific antibodies was due to expansion and activation of regulatory CD4+Foxp3+T cells (Tregs) that suppressed B cells to secrete antibodies through cell-cell interactions. Treg depletion allowed the DR0401.EA0mice to elicit specific antibodies and self-cure the infection. Our results demonstrated a differential role of MHC (HLA) class II molecules in supporting antibody responses to Py17XNL malaria and revealed a new mechanism by which malaria parasites stimulate B cell-suppressogenic Tregs that prevent clearance of infection.
Serogroup-Specific Interaction of Neisseria meningitidis Capsular Polysaccharide with Host Cell Microtubules and Effects on Tubulin Polymerization
Authors: Talà Adelfia , Cogli Laura , De Stefano Mario , Cammarota Marcella , Spinosa Maria Rita , Bucci Cecilia , Alifano Pietro 
Published: October 2013

ABSTRACT

We have previously shown that during late stages of the infectious process, serogroup B meningococci (MenB) are able to escape the phagosome of
in vitro
-infected human epithelial cells. They then multiply in the cytosolic environment and spread intracellularly and to surrounding cells by exploiting the microtubule cytoskeleton, as suggested by results of infections in the presence of microtubule inhibitors and evidence of nanotubes connecting neighboring cells. In this study, by using microtubule binding assays with purified microtubule asters and bundles and microtubule bundles synthesized
in vitro
, we demonstrate that the MenB capsule directly mediates the interaction between bacteria and microtubules. The direct interaction between the microtubules and the MenB capsular polysaccharide was confirmed by coimmunoprecipitation experiments. Unexpectedly, serogroup C meningococci (MenC), which have a capsular polysaccharide that differs from that of MenB only by its anomeric linkage, α(2→9) instead of α(2→8), were not able to interact with the microtubules, and the lack of interaction was not due to capsular polysaccharide
O
-acetylation that takes place in most MenC strains but not in MenB strains. Moreover, we demonstrate that the MenB capsular polysaccharide inhibits tubulin polymerization
in vitro
. Thus, at variance with MenC, MenB may interfere with microtubule dynamics during cell infection.
Human Lung Tissue Explants Reveal Novel Interactions during Legionella pneumophila Infections
Authors: Jäger Jens , Marwitz Sebastian , Tiefenau Jana , Rasch Janine , Shevchuk Olga , Kugler Christian , Goldmann Torsten , Steinert Michael 
Published: October 2013

ABSTRACT

Histological and clinical investigations describe late stages of Legionnaires' disease but cannot characterize early events of human infection. Cellular or rodent infection models lack the complexity of tissue or have nonhuman backgrounds. Therefore, we developed and applied a novel model for
Legionella pneumophila
infection comprising living human lung tissue. We stimulated lung explants with
L. pneumophila
strains and outer membrane vesicles (OMVs) to analyze tissue damage, bacterial replication, and localization as well as the transcriptional response of infected tissue. Interestingly, we found that extracellular adhesion of
L. pneumophila
to the entire alveolar lining precedes bacterial invasion and replication in recruited macrophages. In contrast, OMVs predominantly bound to alveolar macrophages. Specific damage to septa and epithelia increased over 48 h and was stronger in wild-type-infected and OMV-treated samples than in samples infected with the replication-deficient, type IVB secretion-deficient DotA
−
strain. Transcriptome analysis of lung tissue explants revealed a differential regulation of 2,499 genes after infection. The transcriptional response included the upregulation of uteroglobin and the downregulation of the macrophage receptor with collagenous structure (MARCO). Immunohistochemistry confirmed the downregulation of MARCO at sites of pathogen-induced tissue destruction. Neither host factor has ever been described in the context of
L. pneumophila
infections. This work demonstrates that the tissue explant model reproduces realistic features of Legionnaires' disease and reveals new functions for bacterial OMVs during infection. Our model allows us to characterize early steps of human infection which otherwise are not feasible for investigations.
Role of Leptin-Mediated Colonic Inflammation in Defense against Clostridium difficile Colitis
Authors: Madan Rajat , Guo Xiaoti , Naylor Caitlin , Buonomo Erica L. , Mackay Donald , Noor Zannatun , Concannon Patrick , Scully Kenneth W. , Pramoonjago Patcharin , Kolling Glynis L. , Warren Cirle A. , Duggal Priya , Petri William A. 
Published: October 2013

ABSTRACTThe role of leptin in the mucosal immune response toClostridium difficilecolitis, a leading cause of nosocomial infection, was studied in humans and in a murine model. Previously, a mutation in the receptor for leptin (LEPR) was shown to be associated with susceptibility to infectious colitis and liver abscess due toEntamoeba histolyticaas well as to bacterial peritonitis. Here we discovered that European Americans homozygous for the sameLEPRQ223R mutation (rs1137101), known to result in decreased STAT3 signaling, were at increased risk ofC. difficileinfection (odds ratio, 3.03;P= 0.015). The mechanism of increased susceptibility was studied in a murine model. Mice lacking a functional leptin receptor (db/db) had decreased clearance ofC. difficilefrom the gut lumen and diminished inflammation. Mutation of tyrosine 1138 in the intracellular domain of LepRb that mediates signaling through the STAT3/SOCS3 pathway also resulted in decreased mucosal chemokine and cell recruitment. Collectively, these data support a protective mucosal immune function for leptin inC. difficilecolitis partially mediated by a leptin-STAT3 inflammatory pathway that is defective in theLEPRQ223R mutation. Identification of the role of leptin in protection fromC. difficileoffers the potential for host-directed therapy and demonstrates a connection between metabolism and immunity.
Deficiency of the Myeloid Differentiation Primary Response Molecule MyD88 Leads to an Early and Rapid Development of Helicobacter-Induced Gastric Malignancy
Authors: Banerjee Anirban , Thamphiwatana Soracha , Carmona Ellese M. , Rickman Barry , Doran Kelly S. , Obonyo Marygorret 
Published: October 2013

ABSTRACT

Approximately 50% of the world's population is infected with
Helicobacter pylori
, leading to chronic inflammation, which increases the risk for gastric adenocarcinoma. MyD88 is a key adaptor molecule in inflammatory pathways involved in interleukin 1 (IL-1)/IL-18/Toll-like receptor signaling and has been shown to have divergent effects in carcinogenesis. The role of MyD88 in
Helicobacter
-induced gastric malignancy is unknown. Using a mouse model of
Helicobacter
-induced gastric cancer, we assessed the role of MyD88 in cancer development by evaluating gastric histopathology, apoptosis, proliferation, and cytokine expression. Infection of MyD88-deficient (
Myd88
−/−
) mice with
Helicobacter
resulted in early and rapid advancement to gastric dysplasia as early as 25 weeks postinfection. The progression of
Helicobacter
-induced disease to precancerous and cancerous lesions in the absence of MyD88 signaling was accompanied by increased gastric epithelial apoptosis and proliferation. In addition, inflammatory cytokines, including tumor necrosis factor alpha (TNF-α), gamma interferon (IFN-γ), IL-6, and IL-1β were highly expressed in association with the development of gastric dysplasia. These data suggest that MyD88 signaling retards development and progression to cancer during
Helicobacter
infection. This is the first study to show evidence of MyD88 protection in an infection-driven inflammation-associated cancer model.
Ten years of progress—improved hysterectomy outcomes in Finland 1996–2006: a longitudinal observation study
Authors: Mäkinen Juha , Brummer Tea , Jalkanen Jyrki , Heikkinen Anna-Mari , Fraser Jaana , Tomás Eija , Härkki Päivi , Sjöberg Jari 
Published: October 2013

ObjectivesTo study the outcome of various hysterectomies in 2 years 1996 (N =10110) and 2006 (N=5279). The hypothesis was that the change in operative practices in 10 years has resulted in improvements.Design2 prospective nationwide cohort evaluations with the same questionnaire.SettingAll national operative hospitals in Finland.ParticipantsPatients scheduled to either abdominal hysterectomy (AH), vaginal hysterectomy (VH) or laparoscopic hysterectomy (LH) for benign disease.Outcome measuresPatients’ characteristics, surgery-related details and complications (organ injury, infection, venous thromboembolism and haemorrhage).ResultsThe overall complication rates fell in LH and markedly in VH (from 22.2% to 11.7%, p<0.001). The overall surgery-related infectious morbidity decreased in all groups and significantly in VH (from 12.3% to 5.2%, p<0.001) and AH (from 9.9% to 7.7%, p<0.05). The incidence of bowel lesions in VH sank from 0.5% to 0.1% and of ureter lesions in LH from 1.1% to 0.3%. In 2006 there were no deaths compared with three in 1996.ConclusionsThe rate of postoperative complications fell markedly in the decade from 1996 to 2006. This parallels with the recommendation of the recent meta-analyses by Cochrane collaboration; the order of preference of hysterectomies was for the first time precisely followed in this nationwide study.Trial registrationThe 2006 study was registered in the Clinical Trials of Protocol Registration System Data (NCT00744172).
No Link between Breast Cancer and Meningioma: Results from a Large Monoinstitutional Retrospective Analysis
Authors: Criscitiello Carmen , Disalvatore Davide , Santangelo Michele , Rotmensz Nicole , Bazolli Barbara , Maisonneuve Patrick , Goldhirsch Aron , Curigliano Giuseppe 
Published: October 2013

Abstract
Background: The etiology of meningioma is largely unknown, although breast cancer has been suggested to play a role.
Methods: A monoinstitutional, retrospective analysis was performed at European Institute of Oncology on 12,330 patients with breast cancer. The cumulative incidence of meningioma was estimated using the Kaplan–Meier method and the log-rank test was used to assess differences between groups.
Results: In total, 33 patients with meningioma were identified from a study population of 12,330, with a 10-year cumulative incidence of meningioma of 0.37%. We did not find a significantly increased risk of meningioma among patients with breast cancer or an association between the hormonal receptor status and the risk of meningioma (P = 0.65).
Conclusions: Our results do not support a role of breast cancer or endocrine treatments in meningioma development.
Impact: This analysis adds new information on a debated topic. Cancer Epidemiol Biomarkers Prev; 23(1); 215–7. ©2013 AACR.
Resting State Correlates of Subdimensions of Anxious Affect
Authors: Bijsterbosch Janine , Smith Stephen , Forster Sophie , John Oliver P. , Bishop Sonia J. 
Published: October 2013

Abstract
Resting state fMRI may help identify markers of risk for affective disorder. Given the comorbidity of anxiety and depressive disorders and the heterogeneity of these disorders as defined by DSM, an important challenge is to identify alterations in resting state brain connectivity uniquely associated with distinct profiles of negative affect. The current study aimed to address this by identifying differences in brain connectivity specifically linked to cognitive and physiological profiles of anxiety, controlling for depressed affect. We adopted a two-stage multivariate approach. Hierarchical clustering was used to independently identify dimensions of negative affective style and resting state brain networks. Combining the clustering results, we examined individual differences in resting state connectivity uniquely associated with subdimensions of anxious affect, controlling for depressed affect. Physiological and cognitive subdimensions of anxious affect were identified. Physiological anxiety was associated with widespread alterations in insula connectivity, including decreased connectivity between insula subregions and between the insula and other medial frontal and subcortical networks. This is consistent with the insula facilitating communication between medial frontal and subcortical regions to enable control of physiological affective states. Meanwhile, increased connectivity within a frontoparietal–posterior cingulate cortex–precunous network was specifically associated with cognitive anxiety, potentially reflecting increased spontaneous negative cognition (e.g., worry). These findings suggest that physiological and cognitive anxiety comprise subdimensions of anxiety-related affect and reveal associated alterations in brain connectivity.
South Pacific Ocean Dipole: A Predictable Mode on Multiseasonal Time Scales
Authors: Guan Yuanhong , Zhu Jieshun , Huang Bohua , Hu Zeng-Zhen , Kinter III James L. 
Published: October 2013

Abstract
Evaluating the climate hindcasts for 1982–2009 from the NCEP CFS Reanalysis and Reforecast (CFSRR) project using the Climate Forecast System, version 2 (CFSv2), this study identifies substantial areas of high prediction skill of the sea surface temperature (SST) in the South Pacific. The skill is the highest in the extratropical oceans on seasonal-to-interannual time scales, and it is only slightly lower than that for the El Niño–Southern Oscillation (ENSO). Two regions with the highest prediction skills in the South Pacific in both the CFSv2 and persistence hindcasts coincide with the active centers of opposite signs in the South Pacific Ocean dipole (SPOD) mode, a seesaw between the subtropical and extratropical SST in the South Pacific with a strong phase locking to austral summer. Interestingly, the CFSv2 prediction exhibits skillful predictions made three seasons ahead, more superior to the persistence forecast, suggesting significant dynamical predictability of the SPOD. An austral “spring predictability barrier” is noted in both the dynamical and persistence hindcasts. An analysis of the observational and model data suggests that the SPOD mode is significantly associated with ENSO, as an oceanic response to the atmospheric planetary wave trains forced by the anomalous atmospheric heating in the western Pacific. Although previous studies have demonstrated that the pattern of subtropical SST dipole is ubiquitous in the Southern Ocean, the SPOD has been least known and studied, compared with its counterparts in the south Indian and Atlantic Oceans. Since the SPOD is the most predictable oceanic mode in the whole Southern Hemisphere, its climate effects for local and remote regions should be further studied.
Clinical Outcomes After Cell-Seeded Autologous Chondrocyte Implantation of the Knee
Authors: Pestka Jan M. , Bode Gerrit , Salzmann Gian , Steinwachs Mathias , Schmal Hagen , Südkamp Norbert P. , Niemeyer Philipp 
Published: October 2013

Background: Autologous chondrocyte implantation (ACI) has been associated with satisfying results. Still, it remains unclear when success or failure after ACI can be estimated. Purpose: To evaluate the clinical outcomes of cell-seeded collagen matrix–supported ACI (ACI-Cs) for the treatment of cartilage defects of the knee at 36 months and to determine a time point after ACI-Cs at which success or failure can be estimated. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 80 patients with isolated full-thickness cartilage defects of the knee joint treated with ACI-Cs were prospectively assessed before surgery as well as postoperatively by use of the International Knee Documentation Committee (IKDC) score and Lysholm knee score. Results: Preoperative IKDC and Lysholm scores increased from 49.6 and 59.5, respectively, to 79.1 and 83.5, respectively, at 36 months. Only half the patients (46.6%) with poor IKDC scores (ie, <70) at 6 months postoperatively showed continued poor or fair scores at 36 months’ follow-up. The probability of poor scores at 36 months after surgery further increased to 0.61 and 0.81, respectively, when scores were persistent at 12 and 24 months. All 3 patients (100%) with good IKDC scores (ie, 81-90) at 6 months after surgery showed constant or even improved scores at 36 months’ follow-up. Ninety-one percent of patients with good and excellent scores at 12 months and 83% of patients with good and excellent scores at 24 months (a total of 23 and 37 patients, respectively) were able to maintain these scores at 36 months’ follow-up. Similar results were obtained for the Lysholm score. Conclusion: With regard to the improvements in functional outcomes after ACI-Cs at 36 months after surgery, the technique described here appears to lead to satisfying and stable clinical results. This study helps the treating physician to predict the likeliness of further clinical improvements or constant unsatisfactory results after ACI. In patients with good/excellent scores shortly after surgery, deterioration of the knee’s condition is rarely found. For patients with poor and fair postoperative scores, clinical outcomes are more difficult to predict, especially during the first year after the procedure.