bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reconstruction and Function of Ancestral Center-of-Tree Human Immunodeficiency Virus Type 1 Proteins
Authors: Rolland Morgane , Jensen Mark A. , Nickle David C. , Yan Jian , Learn Gerald H. , Heath Laura , Weiner David , Mullins James I. 
Published: May 2007

ABSTRACT
The extensive diversity of human immunodeficiency virus type 1 (HIV-1) and its capacity to mutate and escape host immune responses are major challenges for AIDS vaccine development. Ancestral sequences, which minimize the genetic distance to circulating strains, provide an opportunity to design immunogens with the potential to elicit broad recognition of HIV epitopes. We developed a phylogenetics-informed algorithm to reconstruct ancestral HIV sequences, called Center of Tree (COT). COT sequences have potentially significant benefits over isolate-based strategies, as they minimize the evolutionary distances to circulating strains. COT sequences are designed to surmount the potential pitfalls stemming from sampling bias with the consensus method and outlier bias with the most-recent-common-ancestor approach. We computationally derived COT sequences from circulating HIV-1 subtype B sequences for the genes encoding the major viral structural protein (Gag) and two regulatory proteins, Tat and Nef. COT genes were synthesized de novo and expressed in mammalian cells, and the proteins were characterized. COT Gag was shown to generate virus-like particles, while COT Tat transactivated gene expression from the HIV-1 long terminal repeat and COT Nef mediated downregulation of cell surface major histocompatibility complex class I. Thus, retrodicted ancestral COT proteins can retain the biological functions of extant HIV-1 proteins. Additionally, COT proteins were immunogenic, as they elicited antigen-specific cytotoxic T-lymphocyte responses in mice. These data support the utility of the COT approach to create novel and biologically active ancestral proteins as a starting point for studies of the structure, function, and biological fitness of highly variable genes, as well as for the rational design of globally relevant vaccine candidates.
p52Shc is required for CXCR4-dependent signaling and chemotaxis in T cells
Authors: Patrussi Laura , Ulivieri Cristina , Lucherini Orso Maria , Paccani Silvia Rossi , Gamberucci Alessandra , Lanfrancone Luisa , Pelicci Pier Giuseppe , Baldari Cosima T. 
Published: May 2007

AbstractShcA is an important mediator of Ras/MAPK activation in PTK-regulated pathways triggered by surface receptors. This function is subserved by the constitutively expressed p52-kDa isoform. Besides activating Ras, p52Shc couples the TCR to Rho GTPases, and thereby participates in actin cytoskeleton remodeling in T cells. Here we have addressed the potential involvement of p52Shc in T-cell chemotaxis and the role of the phosphorylatable tyrosine residues, YY239/240 and Y317, in this process. We show that CXCR4 engagement by the homeostatic chemokine, SDF-1α, results in p52Shc phosphorylation and its assembly into a complex that includes Lck, ZAP-70, and Vav. This process was found to be both Lck and Gi dependent. Expression of p52Shc mutants lacking YY239/240 or Y317, or p52Shc deficiency, resulted in a profound impairment in CXCR4 signaling and SDF-1α–dependent chemotaxis, underscoring a crucial role of p52Shc as an early component of the CXCR4 signaling cascade. p52Shc was also found to be required for ligand-dependent CXCR4 internalization independently of tyrosine phosphorylation. Remarkably, CXCR4 engagement promoted phosphorylation of the ζ chain of the TCR/CD3 complex, which was found to be essential for CXCR4 signaling, as well as for SDF-1α–dependent receptor endocytosis and chemotaxis, indicating that CXCR4 signals by transactivating the TCR.
Pharmacologic inhibition of CDK4/6: mechanistic evidence for selective activity or acquired resistance in acute myeloid leukemia
Authors: Wang Lisheng , Wang Jie , Blaser Bradley W. , Duchemin Anne-Marie , Kusewitt Donna F. , Liu Tom , Caligiuri Michael A. , Briesewitz Roger 
Published: May 2007

AbstractEntry into the cell cycle is mediated by cyclin-dependent kinase 4/6 (CDK4/6) activation, followed by CDK2 activation. We found that pharmacologic inhibition of the Flt3 internal tandem duplication (ITD), a mutated receptor tyrosine kinase commonly found in patients with acute myelogenous leukemia (AML), led to the down-regulation of cyclin D2 and D3 followed by retinoblastoma protein (pRb) dephosphorylation and G1 cell-cycle arrest. This implicated the D-cyclin-CDK4/6 complex as a downstream effector of Flt3 ITD signaling. Indeed, single-agent PD0332991, a selective CDK4/6 inhibitor, caused sustained cell-cycle arrest in Flt3 ITD AML cell lines and prolonged survival in an in vivo model of Flt3 ITD AML. PD0332991 caused an initial cell-cycle arrest in well-established Flt3 wild-type (wt) AML cell lines, but this was overcome by down-regulation of p27Kip and reactivation of CDK2. This acquired resistance was not observed in a Flt3 ITD and a Flt3 wt sample from a patient with primary AML. In summary, the mechanism of cell-cycle arrest after treatment of Flt3 ITD AML with a Flt3 inhibitor involves down-regulation of cyclin D2 and D3. As such, CDK4/6 can be a therapeutic target in Flt3 ITD AML but also in primary Flt3 wt AML. Finally, acquired resistance to CDK4/6 inhibition can arise through activation CDK2.
The low-molecular-weight phosphotyrosine phosphatase is a negative regulator of FcγRIIA-mediated cell activation
Authors: Mancini Francesca , Rigacci Stefania , Berti Andrea , Balduini Cesare , Torti Mauro 
Published: May 2007

AbstractActivation of human platelets by cross-linking of the low-affinity receptor for immunoglobulin G (FcγRIIA) is initiated by Src kinase–mediated phosphorylation of the immunoreceptor tyrosine–based activation motif (ITAM) within the receptor, but the identity of the enzyme responsible for its dephosphorylation and inactivation is unknown. Here we report that the 18-kDa low-molecular-weight phosphotyrosine phosphatase (LMW-PTP) is expressed in human platelets and undergoes subcellular redistribution upon FcγRIIA cross-linking. In vitro, LMW-PTP was found to efficiently dephosphorylate activated FcγRIIA and LAT, but not Syk or phospholipase Cγ2. In the megakaryocytic cell line DAMI, antibody-induced phosphorylation of FcγRIIA was rapid and transient. The late dephosphorylation of FcγRIIA was dramatically delayed upon reduction of LMW-PTP expression by siRNA. Strikingly, overexpression of LMW-PTP resulted in the inhibition of antibody-induced phosphorylation of FcγRIIA, and caused a more rapid dephosphorylation. In addition, overexpression of LMW-PTP inhibited activation of Syk downstream of FcγRIIA and reduced intracellular Ca2+ mobilization. These results demonstrate that LMW-PTP is responsible for FcγRIIA dephosphorylation, and is implicated in the down-regulation of cell activation mediated by this ITAM-bearing immunoreceptor.
Molecular evidence for the role of mycobacteria in sarcoidosis: a meta-analysis
Authors: Gupta D. , Agarwal R. , Aggarwal A. N. , Jindal S. K. 
Published: May 2007

The aetiology of sarcoidosis is currently unknown. Due to the clinical and histological similarities between sarcoidosis and tuberculosis, the role of mycobacteria has been repeatedly investigated as an aetiological agent for sarcoidosis. The current meta-analysis aimed to evaluate the available molecular evidence on the possible role of mycobacteria in the development of sarcoidosis.The MEDLINE, EMBASE, CINAHL, DARE and CENTRAL databases were searched for relevant studies published from 1980 to 2006, and studies evaluating the presence of mycobacteria using molecular techniques in biological samples of patients with sarcoidosis were included in the current analysis. The 95% confidence intervals (CI) were calculated for the expected proportion (of individual studies); the data was then pooled to obtain a summary success rate with 95% CI. The odds ratio (95% CI) was also calculated in order to assess the presence of mycobacteria in samples of patients with sarcoidosisversusthose from nonsarcoidosis control samples.The database search yielded 31 studies. All studies used polymerase chain reaction for nucleic acid amplification followed by identification of nucleic acid sequences specific for different types of mycobacteria. Overall, 231 out of the 874 patients were positive for mycobacteria with a positive signal rate of 26.4 (23.6–29.5%), and the odds of finding mycobacteria in samples of patients with sarcoidosisversuscontrols were 9.67 (4.56–20.5%) using the random effects model and 19.49 (11.21–35.54%) using the exact method. There was methodological and statistical heterogeneity and evidence of publication bias.The results of the current study illustrate a demonstrable mycobacterial presence in sarcoidosis lesions suggesting an association between mycobacteria and some cases of sarcoidosis. To avoid methodological diversity, larger multicentre trials with a central laboratory for sample testing should be designed.
Inhibition of allergen-induced airway remodelling by tiotropium and budesonide: a comparison
Authors: Bos I. S. T. , Gosens R. , Zuidhof A. B. , Schaafsma D. , Halayko A. J. , Meurs H. , Zaagsma J. 
Published: May 2007

Chronic inflammation in asthma and chronic obstructive pulmonary disease drives pathological structural remodelling of the airways. Using tiotropium bromide, acetylcholine was recently identified as playing a major regulatory role in airway smooth muscle remodelling in a guinea pig model of ongoing allergic asthma. The aim of the present study was to investigate other aspects of airway remodelling and to compare the effectiveness of tiotropium to the glucocorticosteroid budesonide.Ovalbumin-sensitised guinea pigs were challenged for 12 weeks with aerosolised ovalbumin.The ovalbumin induced airway smooth muscle thickening, hypercontractility of tracheal smooth muscle, increased pulmonary contractile protein (smooth-muscle myosin) abundance, mucous gland hypertrophy, an increase in mucin 5 subtypes A and C (MUC5AC)-positive goblet cell numbers and eosinophilia. It was reported previously that treatment with tiotropium inhibits airway smooth muscle thickening and contractile protein expression, and prevents tracheal hypercontractility. This study demonstrates that tiotropium also fully prevented allergen-induced mucous gland hypertrophy, and partially reduced the increase in MUC5AC-positive goblet cell numbers and eosinophil infiltration. Treatment with budesonide also prevented airway smooth muscle thickening, contractile protein expression, tracheal hypercontractility and mucous gland hypertrophy, and partially reduced MUC5AC-positive goblet cell numbers and eosinophilia.This study demonstrates that tiotropium and budesonide are similarly effective in inhibiting several aspects of airway remodelling, providing further evidence that the beneficial effects of tiotropium bromide might exceed those of bronchodilation.
Sepsis severity predicts outcome in community-acquired pneumococcal pneumonia
Authors: Schaaf B. , Kruse J. , Rupp J. , Reinert R. R. , Droemann D. , Zabel P. , Ewig S. , Dalhoff K. 
Published: May 2007

Easily performed prognostic rules are helpful for guiding the intensity of monitoring and treatment of patients. The aim of the present study was to compare the predictive value of the sepsis score and the Confusion, Respiratory rate (≥30 breaths·min−1), Blood pressure (systolic value <90 mmHg or diastolic value ≤60 mmHg) and age ≥65 yrs (CRB-65) score in 105 patients with community-acquired pneumococcal pneumonia. In addition, the influence of timing of the antimicrobial treatment on outcome was investigated. The sepsis and the CRB-65 scores were used to allocate patients to subgroups with low, intermediate and high risk.Comparable, highly predictive values for mortality were found for both scores (sepsis scoreversusCRB-65): 1) low-risk group, 0versus0%; 2) intermediate-risk group, 0versus8.6%; 3) high-risk group, 30.6versus40%, with an area under the curve of 0.867versus0.845. Patients with ambulatory antibiotic pre-treatment had less severe disease with a lower acute physiology score, lower white blood cell count and a faster decline of C-reactive protein levels. No pre-treated patient died.In summary, both scores performed equally well in predicting mortality. The prediction of survival in the intermediate-risk group might be more accurate with the sepsis score. Pre-hospital antibiotic treatment was associated with less severe disease.
Quantitative scoring of an interferon-γ assay for differentiating active from latent tuberculosis
Authors: Janssens J-P. , Roux-Lombard P. , Perneger T. , Metzger M. , Vivien R. , Rochat T. 
Published: May 2007

The aim of this study was to assess the contribution of an interferon-γ release assay (T-SPOT.TB) to the differentiation of active tuberculosis (TB) from latent TB infection by quantifying spot-forming units (sfu).The investigation was a prospective study of contacts exposed to a case of contagious TB and cases of HIV-negative culture-proven TB referred over a 16-month period. Tuberculin skin tests (TSTs) and T-SPOT.TBwere performed in 310 contacts 8–12 weeks after exposure. In subjects with culture-proven TB, T-SPOT.TBwas performed within 2 weeks of initiation of treatment. The analysis included all contacts with a positive T-SPOT.TBresult and all subjects with TB.TB contacts (n = 127) and cases (n = 58) were included. Mean±sdT-SPOT.TBresults were 107±56 (range 1–207) sfu for TB, 54±60 (7–239) sfu for contacts with positive T-SPOT.TBresults and a TST induration diameter of >5 mm, and 19±27 (7–143) sfu for contacts with positive T-SPOT.TBresults and a TST induration diameter of ≤5 mm. By receiver operating characteristic curve analysis, a threshold value of 49.5 sfu showed a sensitivity of 83% and specificity of 74% for distinguishing latent TB infection from TB.Although T-SPOT.TBresults were significantly related to disease activity, the test cannot be recommended for the diagnosis of tuberculosis.
The need for macrolides in hospitalised community-acquired pneumonia: propensity analysis
Authors: Paul M. , Nielsen A. D. , Gafter-Gvili A. , Tacconelli E. , Andreassen S. , Almanasreh N. , Goldberg E. , Cauda R. , Frank U. , Leibovici L. 
Published: May 2007

The present study compared β-lactam macrolide (“combination”) therapyversusβ-lactam alone (“monotherapy”) for hospitalised community-acquired pneumonia, using propensity scores to adjust for the differences between patients.A prospective multinational observational study was carried out. Baseline patient and infection characteristics were used to develop a propensity score for combination therapy. Patients were matched by the propensity score (three decimal point precision) and compared with 30-day mortality and hospital stay. The propensity score was used as a covariate in a logistic model for mortality.Patients treated with monotherapy (n = 169) were older (mean±sdage 70.6±17.3versus65.0±19.6 yrs), had a higher chronic diseases score and a different clinical presentation compared with patients treated with combination therapy (n = 282). Unadjusted mortality was significantly higher with monotherapy (37 (22%) out of 169versus21 (7%) out of 282). Only 27 patients in the monotherapy group could be matched to 27 patients in the combination group using the propensity score. The mortality in these groups was identical, with three (11%) demises each. The multivariable odds ratio for mortality associated with combination therapy, adjusted for the propensity score and the Pneumonia Severity Index, was 0.69 (95% confidence interval 0.32–1.48).The benefit of combination therapyversusmonotherapy cannot be reliably assessed in observational studies, since the propensity to prescribe these regimens differs markedly.
Nocturnal melatonin plasma levels in patients with OSAS: the effect of CPAP
Authors: Hernández C. , Abreu J. , Abreu P. , Castro A. , Jiménez A. 
Published: May 2007

Melatonin is a pineal hormone that regulates the human cycle of sleep and wakefulness. Plasma melatonin levels were investigated in patients with obstructive sleep apnoea syndrome (OSAS).In total, 20 patients with OSAS and 11 healthy controls were studied. OSAS patients were tested twice: on the night of diagnostic polysomnography and the night of continuous positive airway pressure (CPAP) titration. Controls were tested on one occasion. Plasma melatonin levels were determined at 23:00 h (light period), at 02:00 h (dark period) and at 06:00 h (light period) in patients and control subjects using the radioimmunoassay method.The control subjects showed a nocturnal melatonin peak value at 02:00 h (70.6±14 pg·mL−1). However, this nocturnal melatonin peak was absent in the OSAS patients. The highest melatonin value was found in OSAS patients on the night of diagnosis, at 06:00 h (49.3±36.8 pg·mL−1). It was found that the melatonin level in OSAS patients at 06:00 h was significantly lower in the night of titration (35.6±37.9 pg·mL−1) than in the diagnosis night. However, the melatonin levels at either 23:00 h or 02:00 h in OSAS patients did not differ significantly when comparing levels in the night of diagnostic polysomnography (23:00 h: 31.6±29.8 pg·mL−1; 02:00 h: 47.4±33.8 pg·mL−1) with levels in the night of CPAP titration (23:00 h: 20.2±10.3 pg·mL−1; 02:00 h: 37.7±27.5 pg·mL−1).Patients with obstructive sleep apnoea syndrome have an abnormal melatonin secretion pattern. The absence of a nocturnal serum melatonin peak could be partially related to the difficulty that these patients have in achieving a normal sleep–wakefulness pattern.
Exacerbations of chronic obstructive pulmonary disease
Authors: Celli B. R. , Barnes P. J. 
Published: May 2007

Exacerbations of chronic obstructive pulmonary disease are of major importance in terms of their prolonged detrimental effects on patients, the acceleration in disease progression and high healthcare costs.There is still debate about how exacerbations should be defined and graded, and their mechanisms are poorly understood. The major causal agents are either bacteria or viral infections, or a combination of the two. Noninfective causes include air pollution and pulmonary embolus but, in some patients, no cause is identified.Exacerbations represent an increase in the inflammation that is present in the stable state, with increased numbers of inflammatory cells (particularly neutrophils), cytokines, chemokines and proteases in the airways, and increased concentrations of certain cytokines and C-reactive protein in the blood. There are presently no reliable biomarkers with which to predict exacerbations.Exacerbations have a long-lasting adverse influence on health status. High doses of bronchodilators are the mainstay of treatment and systemic corticosteroids have some benefit. The routine use of antibiotics remains controversial but they are of benefit with exacerbations of a bacterial origin. Noninvasive ventilation is beneficial in preventing the need for intubation and its important complications but it is not certain whether its use in stable patients prevents exacerbations. Although important advances have been made, more effective treatments are needed in the future for prevention and treatment of exacerbations.
Long-term asthma treatment guided by airway hyperresponsiveness in children: a randomised controlled trial
Authors: Nuijsink M. , Hop W. C. J. , Sterk P. J. , Duiverman E. J. , de Jongste J. C. 
Published: May 2007

Management plans for childhood asthma show limited success in optimising asthma control. The aim of the present study was to assess whether a treatment strategy guided by airway hyperresponsiveness (AHR) increased the number of symptom-free days and improved lung function in asthmatic children, compared with a symptom-driven reference strategy.In a multicentre, double-blind, parallel-group, randomised, 2-yr intervention trial, 210 children (aged 6–16 yrs) with moderate atopic asthma, selected on the basis of symptom scores and/or the presence of AHR, were studied. At 3-monthly visits, symptom scores, forced expiratory volume in one second (FEV1) and methacholine challenge results were obtained, and medication (five levels of fluticasone with or without salmeterol) adjusted according to algorithms based on symptom score (reference strategy, n = 104) or AHR and symptom score (AHR strategy, n = 102).After 2 yrs, no difference was found in the percentage of symptom-free days between treatment strategies. Pre-bronchodilator FEV1was higher in the AHR strategy (2.3% predicted). This was entirely explained by a gradual worsening of FEV1in a subgroup of 91 hyperresponsive children enrolled with low symptom scores (final difference between study arms was 6%).Asthma treatment guided by airway hyperresponsiveness showed no benefits in terms of number of symptom-free days, but produced a better outcome in terms of pre-bronchodilator forced expiratory volume in one second in allergic asthmatic children, especially those characterised by low symptom scores despite airway hyperresponsiveness.
New recommendations for duration of respiratory isolation based on time to detectMycobacterium tuberculosisin liquid culture
Authors: Ritchie S. R. , Harrison A. C. , Vaughan R. H. , Calder L. , Morris A. J. 
Published: May 2007

It was hypothesised that the time to detectMycobacterium tuberculosisin liquid culture of sputum from patients with pulmonary tuberculosis may be a better indicator for the duration of respiratory isolation than sputum smear status.Pre-treatment and during-treatment sputum acid-fast bacilli (AFB) smear and culture results were reviewed in 284 patients with pulmonary tuberculosis. The time to detectM. tuberculosisin liquid culture (TTD-TB) was the number of days from inoculation of the Mycobacterial Growth Indicator Tube to culture detection and visualisation of AFB.The median (interquartile range) TTD-TB for smear group 0 (no bacilli seen) was 14 (12–20) days. This value was used as the standard at which release from isolation could be permitted. In smear group 4 (>9 AFB per high-power field (hpf) in sputum specimens before treatment) patients, the TTD-TB exceeded 14 days after a median of 25 days of treatment.The current authors recommend that patients in smear groups 1 and 2 (1–9 AFB per 100 hpf and 1–9 AFB per 10 hpf in sputum specimens before treatment, respectively) receive treatment in respiratory isolation for 7 days, provided the risk of drug resistance is low. Smear group 3 (1–9 AFB per hpf) and 4 patients should receive treatment in respiratory isolation for 14 and 25 days, respectively. These criteria would have reduced the duration of respiratory isolation by 1,516 days in the 143 study participants with sputum smear-positive pulmonary tuberculosis.Provided clinical and radiographical criteria are satisfactory, use of the time to detectMycobacterium tuberculosisin liquid culture could enable the duration of respiratory isolation to be predicted from the pre-treatment sputum smear grade. The recommendations enable isolation to end well before sputum becomes smear negative, with considerable benefits to patients and healthcare providers.