bluuebunny/crossref_metadata_2025_split huggingface dataset:
Insights into the preclinical treatment of blood‐stage malaria by the antibiotic borrelidin
Authors: Azcárate IG , Marín‐García P , Camacho N , Pérez‐Benavente S , Puyet A , Diez A , Ribas de Pouplana L , Bautista JM 
Published: March 2013

Background and PurposeBlood‐stage Plasmodium parasites cause morbidity and mortality from malaria. Parasite resistance to drugs makes development of new chemotherapies an urgency. Aminoacyl‐tRNA synthetases have been validated as antimalarial drug targets. We explored long‐term effects of borrelidin and mupirocin in lethal P. yoelii murine malaria.Experimental ApproachLong‐term (up to 340 days) immunological responses to borrelidin or mupirocin were measured after an initial 4 day suppressive test. Prophylaxis and cure were evaluated and the inhibitory effect on the parasites analysed.Key ResultsBorrelidin protected against lethal malaria at 0.25 mg·kg−1·day−1. Antimalarial activity of borrelidin correlated with accumulation of trophozoites in peripheral blood. All infected mice treated with borrelidin survived and subsequently developed immunity protecting them from re‐infection on further challenges, 75 and 340 days after the initial infection. This long‐term immunity in borrelidin‐treated mice resulted in negligible parasitaemia after re‐infections and marked increases in total serum levels of antiparasite IgGs with augmented avidity. Long‐term memory IgGs mainly reacted against high and low molecular weight parasite antigens. Immunofluorescence microscopy showed that circulating IgGs bound predominantly to late intracellular stage parasites, mainly schizonts.Conclusions and ImplicationsLow borrelidin doses protected mice from lethal malaria infections and induced protective immune responses after treatment. Development of combination therapies with borrelidin and selective modifications of the borrelidin molecule to specifically inhibit plasmodial threonyl tRNA synthetase should improve therapeutic strategies for malaria.
β1‐Adrenoceptor stimulation suppresses endothelial IKCa‐channel hyperpolarization and associated dilatation in resistance arteries
Authors: Yarova PL , Smirnov SV , Dora KA , Garland CJ 
Published: March 2013

Background and PurposeIn small arteries, small conductance Ca2+‐activated K+ channels (SKCa) and intermediate conductance Ca2+‐activated K+ channels (IKCa) restricted to the vascular endothelium generate hyperpolarization that underpins the NO‐ and PGI2‐independent, endothelium‐derived hyperpolarizing factor response that is the predominate endothelial mechanism for vasodilatation. As neuronal IKCa channels can be negatively regulated by PKA, we investigated whether β‐adrenoceptor stimulation, which signals through cAMP/PKA, might influence endothelial cell hyperpolarization and as a result modify the associated vasodilatation.Experimental ApproachRat isolated small mesenteric arteries were pressurized to measure vasodilatation and endothelial cell [Ca2+]i, mounted in a wire myograph to measure smooth muscle membrane potential or dispersed into endothelial cell sheets for membrane potential recording.Key ResultsIntraluminal perfusion of β‐adrenoceptor agonists inhibited endothelium‐dependent dilatation to ACh (1 nM–10 μM) without modifying the associated changes in endothelial cell [Ca2+]i. The inhibitory effect of β‐adrenoceptor agonists was mimicked by direct activation of adenylyl cyclase with forskolin, blocked by the β‐adrenoceptor antagonists propranolol (non‐selective), atenolol (β1) or the PKA inhibitor KT‐5720, but remained unaffected by ICI 118 551 (β2) or glibenclamide (ATP‐sensitive K+ channels channel blocker). Endothelium‐dependent hyperpolarization to ACh was also inhibited by β‐adrenoceptor stimulation in both intact arteries and in endothelial cells sheets. Blocking IKCa {with 1 μM 1‐[(2‐chlorophenyl)diphenylmethyl]‐1H‐pyrazole (TRAM‐34)}, but not SKCa (50 nM apamin) channels prevented β‐adrenoceptor agonists from suppressing either hyperpolarization or vasodilatation to ACh.Conclusions and ImplicationsIn resistance arteries, endothelial cell β1‐adrenoceptors link to inhibit endothelium‐dependent hyperpolarization and the resulting vasodilatation to ACh. This effect appears to reflect inhibition of endothelial IKCa channels and may be one consequence of raised circulating catecholamines.
Evidence for involvement of central vasopressin V1b and V2 receptors in stress‐induced baroreflex desensitization
Authors: Milutinović‐Smiljanić Sanja , Šarenac Olivera , Lozić‐Djurić Maja , Murphy David , Japundžić‐Žigon Nina 
Published: March 2013

Background and PurposeIt is well recognized that vasopressin modulates the neurogenic control of the circulation. Here, we report the central mechanisms by which vasopressin modulates cardiovascular response to stress induced by immobilization.Experimental ApproachExperiments were performed in conscious male Wistar rats equipped with radiotelemetric device for continuous measurement of haemodynamic parameters: systolic and diastolic BP and heart rate (HR). The functioning of the spontaneous baro‐receptor reflex (BRR) was evaluated using the sequence method and the following parameters were evaluated: BRR sensitivity (BRS) and BRR effectiveness index (BEI).Key ResultsUnder baseline physiological conditions intracerebroventricular injection of 100 and 500 ng of selective non‐peptide V1a or V1b or V2 receptor antagonist did not modify BP, HR and BRR. Rats exposed to 15 min long stress by immobilization exhibited increase of BP, HR, reduction of BRS and no change in BEI. Pretreatment of rats with V1a receptor antagonist did not modulate the BP, HR, BRS and BEI response to stress. Pretreatment of rats with V1b receptor and V2 receptor antagonist, at both doses, prevented BRR desensitization and tachycardia, but failed to modulate stress‐induced hypertension.Conclusions and ImplicationsVasopressin by the stimulation of central V1b‐ and V2‐like receptors mediates stress‐induced tachycardia and BRR desensitization. If these mechanisms are involved, BRR desensitization in heart failure and hypertension associated with poor outcome, they could be considered as novel targets for cardiovascular drug development.
Metabotropic glutamate receptor 5 positive allosteric modulators are neuroprotective in a mouse model of Huntington's disease
Authors: Doria JG , Silva FR , de Souza JM , Vieira LB , Carvalho TG , Reis HJ , Pereira GS , Dobransky T , Ribeiro FM 
Published: March 2013

Background and PurposeHuntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin protein. We have previously demonstrated that the cell signalling of the metabotropic glutamate receptor 5 (mGluR5) is altered in a mouse model of HD. Although mGluR5‐dependent protective pathways are more activated in HD neurons, intracellular Ca2+ release is also more pronounced, which could contribute to excitotoxicity. In the present study, we aim to investigate whether mGluR5 positive allosteric modulators (PAMs) could activate protective pathways without triggering high levels of Ca2+ release and be neuroprotective in HD.Experimental ApproachWe performed a neuronal cell death assay to determine which drugs are neuroprotective, Western blot and Ca2+ release experiments to investigate the molecular mechanisms involved in this neuroprotection, and object recognition task to determine whether the tested drugs could ameliorate HD memory deficit.Key ResultsWe find that mGluR5 PAMs can protect striatal neurons from the excitotoxic neuronal cell death promoted by elevated concentrations of glutamate and NMDA. mGluR5 PAMs are capable of activating Akt without triggering increased intracellular Ca2+ concentration ([Ca2+]i); and Akt blockage leads to loss of PAM‐mediated neuroprotection. Importantly, PAMs' potential as drugs that may be used to treat neurodegenerative diseases is highlighted by the neuroprotection exerted by mGluR5 PAMs on striatal neurons from a mouse model of HD, BACHD. Moreover, mGluR5 PAMs can activate neuroprotective pathways more robustly in BACHD mice and ameliorate HD memory deficit.Conclusions and ImplicationsmGluR5 PAMs are potential drugs that may be used to treat neurodegenerative diseases, especially HD.
Short‐term treatment with the GABAA receptor antagonist pentylenetetrazole produces a sustained pro‐cognitive benefit in a mouse model of Down's syndrome
Authors: Colas D , Chuluun B , Warrier D , Blank M , Wetmore D Z , Buckmaster P , Garner C C , Heller H C 
Published: March 2013

Background and PurposeDown's syndrome is a common genetic cause of intellectual disability, for which there are no drug therapies. Mechanistic studies in a model of Down's syndrome [Ts65Dn (TS) mice] demonstrated that impaired cognitive function was due to excessive neuronal inhibitory tone. These deficits were normalized by low doses of GABAA receptor antagonists in adult animals. In this study, we explore the therapeutic potential of pentylenetetrazole, a GABAA receptor antagonist with a history of safe use in humans.Experimental ApproachLong‐term memory was assessed by the novel object recognition test in different cohorts of TS mice after a delay following a short‐term chronic treatment with pentylenetetrazole. Seizure susceptibility, an index of treatment safety, was studied by means of EEG, behaviour and hippocampus morphology. EEG spectral analysis was used as a bio‐marker of the treatment.Key ResultsPTZ has a wide therapeutic window (0.03–3 mg·kg−1) that is >10–1000‐fold below its seizure threshold and chronic pentylenetetrazole treatment did not lower the seizure threshold. Short‐term, low, chronic dose regimens of pentylenetetrazole elicited long‐lasting (>1 week) normalization of cognitive function in young and aged mice. Pentylenetetrazole effectiveness was dependent on the time of treatment; cognitive performance improved after treatment during the light (inactive) phase, but not during the dark (active) phase. Chronic pentylenetetrazole treatment normalized EEG power spectra in TS mice.Conclusions and ImplicationsLow doses of pentylenetetrazole were safe, produced long‐lasting cognitive improvements and have the potential of fulfilling an unmet therapeutic need in Down's syndrome.
Selectivity of commonly used pharmacological inhibitors for cystathionine β synthase (CBS) and cystathionine γ lyase (CSE)
Authors: Asimakopoulou Antonia , Panopoulos Panagiotis , Chasapis Christos T , Coletta Ciro , Zhou Zongmin , Cirino Giuseppe , Giannis Athanassios , Szabo Csaba , Spyroulias Georgios A , Papapetropoulos Andreas 
Published: March 2013

Background and PurposeHydrogen sulfide (H2S) is a signalling molecule that belongs to the gasotransmitter family. Two major sources for endogenous enzymatic production of H2S are cystathionine β synthase (CBS) and cystathionine γ lyase (CSE). In the present study, we examined the selectivity of commonly used pharmacological inhibitors of H2S biosynthesis towards CSE and CBS.Experimental ApproachTo address this question, human CSE or CBS enzymes were expressed and purified from Escherichia coli as fusion proteins with GSH‐S‐transferase. After purification, the activity of the recombinant enzymes was tested using the methylene blue method.Key Resultsβ‐cyanoalanine (BCA) was more potent in inhibiting CSE than propargylglycine (PAG) (IC50 14 ± 0.2 μM vs. 40 ± 8 μM respectively). Similar to PAG, L‐aminoethoxyvinylglycine (AVG) only inhibited CSE, but did so at much lower concentrations. On the other hand, aminooxyacetic acid (AOAA), a frequently used CBS inhibitor, was more potent in inhibiting CSE compared with BCA and PAG (IC50 1.1 ± 0.1 μM); the IC50 for AOAA for inhibiting CBS was 8.5 ± 0.7 μM. In line with our biochemical observations, relaxation to L‐cysteine was blocked by AOAA in aortic rings that lacked CBS expression. Trifluoroalanine and hydroxylamine, two compounds that have also been used to block H2S biosynthesis, blocked the activity of CBS and CSE. Trifluoroalanine had a fourfold lower IC50 for CBS versus CSE, while hydroxylamine was 60‐fold more selective against CSE.Conclusions and ImplicationsIn conclusion, although PAG, AVG and BCA exhibit selectivity in inhibiting CSE versus CBS, no selective pharmacological CBS inhibitor is currently available.
Dynamics of giant mass transport in deep submarine environments: the Matakaoa Debris Flow, New Zealand
Authors: Joanne C. , Lamarche G. , Collot J.‐Y. 
Published: March 2013

AbstractThe Matakaoa Debris Flow (MDF) is a 200‐km‐long mass‐transport deposit resulting from the failure of the Matakaoa continental margin, northeast New Zealand, ca. 38–100 ky ago. In this study, high‐quality bathymetric and seismic reflection data are used to identify the morpho‐structural characters that reflect the kinematics of the MDF, as well as its interactions with basin sediments. We demonstrate how the transport energy, together with the local topography led to the present geometry and complex structure of the MDF deposits. The remarkable transport energy of the MDF is demonstrated by its dynamic impact on adjacent sedimentary series, including erosion of the substratum, shearing and compressional deformation. In the proximal zone of transport, momentous substratum erosion, demonstrated by giant tool marks and truncated sediments at the base of the debrite, triggered the excavation of a large volume (>200 km3) of basin sediments. The size of transported blocks (up to 3‐km long) is used to estimate the matrix yield strength in an early stage of transport. In the distal zone of transport, 100 km north of the source, seismic profiles show the propagation of thrust structures from the MDF into adjacent basin sediments. This study highlights that the remarkable volume of 2000 km3 of deposits partly resulted from the propagation of compressive structures within the basin sedimentary series to the front of the debrite.
Can bayesian models play a role in dental caries epidemiology? Evidence from an application to theBELCAPdata set
Authors: Matranga Domenica , Firenze Alberto , Vullo Angela 
Published: March 2013

AbstractObjectivesThe aim of this study was to show the potential ofBayesian analysis in statistical modelling of dental caries data. Because of the bounded nature of the dmft (DMFT) index, zero‐inflated binomial (ZIB) and beta‐binomial (ZIBB) models were considered. The effects of incorporating prior information available about the parameters of models were also shown.MethodsThe data set used in this study was theBeloHorizonteCariesPrevention (BELCAP) study (Böhning et al. (1999)), consisting of five variables collected among 797Brazilian school children designed to evaluate four programmes for reducing caries. Only the eight primary molar teeth were considered in the data set. A data augmentation algorithm was used for estimation. Firstly, noninformative priors were used to express our lack of knowledge about the regression parameters. Secondly, prior information about the probability of being a structural zero dmft and the probability of being caries affected in the subpopulation of susceptible children was incorporated.ResultsWith noninformative priors, the best fitting model was theZIBB. Education (OR = 0.76, 95% CrI: 0.59, 0.99), all interventions (OR = 0.46, 95% CrI: 0.35, 0.62), rinsing (OR = 0.61, 95% CrI: 0.47, 0.80) and hygiene (OR = 0.65, 95% CrI: 0.49, 0.86) were demonstrated to be factors protecting children from being caries affected. Being male increased the probability of being caries diseased (OR = 1.19, 95% CrI: 1.01, 1.42). However, after incorporating informative priors,ZIBmodels' estimates were not influenced, whileZIBBmodels reduced deviance and confirmed the association with all interventions and rinsing only.DiscussionIn our application,Bayesian estimates showed a similar accuracy and precision than likelihood‐based estimates, although they offered many computational advantages and the possibility of expressing all forms of uncertainty in terms of probability. The overdispersion parameter could expound why the introduction of prior information had significant effects on the parameters of theZIBBmodel, whileZIBestimates remained unchanged. Finally, the best performance ofZIBBcompared to theZIBmodel was shown to catch overdispersion in data.
Patients treated with high-dose intravenous immunoglobulin show selective activation of regulatory T cells
Authors: Tjon A S W , Tha-In T , Metselaar H J , van Gent R , van der Laan L J W , Groothuismink Z M A , te Boekhorst P A W , van Hagen P M , Kwekkeboom J 
Published: March 2013

Summary
Intravenous immunoglobulin (IVIg) is used to treat autoimmune and systemic inflammatory diseases caused by derailment of humoral and cellular immunity. In this study we investigated whether IVIg treatment can modulate regulatory T cells (Tregs) in humans in vivo. Blood was collected from IVIg-treated patients with immunodeficiency or autoimmune disease who were treated with low-dose (n = 12) or high-dose (n = 15) IVIg before, immediately after and at 7 days after treatment. Percentages and activation status of circulating CD4+CD25+forkhead box protein 3 (FoxP3+) Tregs and of conventional CD4+FoxP3− T-helper cells (Tconv) were measured. The suppressive capacity of Tregs purified from blood collected at the time-points indicated was determined in an ex-vivo assay. High-dose, but not low-dose, IVIg treatment enhanced the activation status of circulating Tregs, as shown by increased FoxP3 and human leucocyte antigen D-related (HLA-DR) expression, while numbers of circulating Tregs remained unchanged. The enhanced activation was sustained for at least 7 days after infusion, and the suppressive capacity of purified Tregs was increased from 41 to 70% at day 7 after IVIg treatment. The activation status of Tconv was not affected by IVIg. We conclude that high-dose IVIg treatment activates Tregs selectively and enhances their suppressive function in humans in vivo. This effect may be one of the mechanisms by which IVIg restores imbalanced immune homeostasis in patients with autoimmune and systemic inflammatory disorders.
The Influence of Platform Switching on Clinical, Laboratory, and Image‐Based Measures: A Prospective Clinical Study
Authors: Dursun Erhan , Tulunoglu Ibrahim , Ozbek S. Murat , Uysal Serdar , Akalın F. Alev , Kilinc Kamer , Karabulut Erdem , Tözüm Tolga F. 
Published: March 2013

AbstractPurposeThis prospective study was conducted to compare the marginal bone level alterations, stability/mobility measurements, and volume of myeloperoxidase (MPO) and nitric oxide (NO) of peri‐implant sulcus fluid (PISF) between platform‐switched (PS) and standard platform (SP) implants inserted to mandibular premolar/molar regions with a single‐stage protocol.Materials and MethodsThirty‐two (16 PS and 16 SP) implants restorated with fixed prosthesis were included in the study. For both implant systems standard implant dimensions were used. Implant abutment connections and final restorations were made after 3 months of osseointegration. Standard parallel periapical radiographs were used to measure marginal bone loss in over time. Resonance frequency analysis (RFA) and mobility measuring (MM) device were used to determine implant stability/mobility. PISF samples were derived with paper strips and PISF MPO and nitrite level analysis were done spectrophotometrically. Peri‐implant parameters were assessed by periodontal indices and all parameters were evaluated at baseline, 1, 3, 6, and 12 months follow‐up.ResultsNo healing problems were recorded for all implants at the end of the study period. At 12 months, mean bone loss measures were 0.84 and 0.76 mm, and mean implant stability quotient (ISQ) values were 74.04 and 76 for PS and SP implants, respectively. Mean MM values were found as −4.82 for PS and −6.26 for SP implants. There were no significant differences between implant types according to PISF volume and laboratory biochemical measures including MPO and NO, and clinical peri‐ implant indices at any time point.ConclusionPlatform switching seems not to affect the marginal bone level, clinical peri‐implant parameters and MPO and NO metabolism around implants inserted to mandibular premolar/molar regions when using a single‐stage protocol.
The Disturbance of Hippocampal CaMKII/PKA/PKC Phosphorylation in Early Experimental Diabetes Mellitus
Authors: Liao Mei‐Hua , Xiang Ying‐Chun , Huang Ji‐Yun , Tao Rong‐Rong , Tian Yun , Ye Wei‐Feng , Zhang Gen‐Sheng , Lu Ying‐Mei , Ahmed Muhammad M. , Liu Zhi‐Rong , Fukunaga Kohji , Han Feng 
Published: March 2013

SummaryBackgroundDefining the impact of diabetes and related risk factors on brain cognitive function is critically important for patients with diabetes.AimsTo investigate the alterations in hippocampal serine/threonine kinases signaling in the early phase of type 1 and type 2 diabetic rats.MethodsEarly experimental diabetes mellitus was induced in rats with streptozotocin or streptozotocin/high fat. Changes in the phosphorylation of proteins were determined by immunoblotting and immunohistochemistry.ResultsOur data showed a pronounced decrease in the phosphorylation of Ca2+/calmodulin‐dependent protein kinase II (CaMKII) in the hippocampi of both type 1 and type 2 diabetic rats compared with age‐matched control rats. Unexpectedly, we found a significant increase in the phosphorylation of synapsin I (Ser 603) and GluR1 (Ser 831) in the same experiment. In addition, aberrant changes in hippocampal protein kinase C (PKC) and protein kinase A (PKA) signaling in type 1 and type 2 diabetic rats were also found. Moreover, PP1α and PP2A protein levels were decreased in the hippocampus of type 1 diabetic rats, but significantly up‐regulated in type 2 diabetic rats.ConclusionsThe disturbance of CaMKII/PKA/PKC phosphorylation in the hippocampus is an early change that may be associated with the development and progression of diabetes‐related cognitive dysfunction.
Prognostic and diagnostic significance of annexin A2 in colorectal cancer
Authors: Yang T. , Peng H. , Wang J. , Yang J. , Nice E. C. , Xie K. , Huang C. 
Published: March 2013

AbstractAimAnnexin A2 (ANXA2) is known to be a tumourigenic molecule and is highly expressed in colorectal cancer (CRC). Its diagnostic and prognostic value is not fully understood. This study was designed to investigate the relationship between ANXA2 expression, clinicopathological characteristics, tumour recurrence and survival.MethodImmunohistochemical staining was used to evaluate ANXA2 expression in 150 matched samples from patients with CRC. Overall survival and recurrence were determined by Kaplan–Meier analysis. The Cox proportional hazards model was used to determine independent factors contributing to survival and recurrence. Receiver operating characteristic (ROC) curve and liner correlation analysis were used to estimate the sensitivity and specificity of ANXA2 expression for clinical diagnosis.ResultsANXA2 was found to be strongly expressed in poorly differentiated tumours (P < 0.001), late stage (P = 0.020) and lymph node positivity (P = 0.002). ANXA2 expression was significantly related to recurrence (P < 0.001) and survival (P = 0.002). The Cox proportional hazards model indicated that ANXA2 expression [P < 0.001, hazard ratio (HR) = 1.366, 95% CI 1.232–1.515] and tumour location (P = 0.039, HR = 1.891, 95% CI 1.034–3.456) were independent factors in predicting overall survival while ANXA2 expression (P < 0.001, HR = 1.445, 95% CI 1.222–1.709) were independent factors predicting recurrence. Receiver operating characteristic (ROC) (AUC = 0.768, 95% CI = 0.642–0.894) and liner correlation analysis suggested that ANXA2 was suitable for the clinical diagnosis of CRC.ConclusionThese results indicate that ANXA2 is a biomarker with diagnostic and prognostic potential for patients with CRC.