Kinase Inhibitor Profile For Human Nek1, Nek6, And Nek7 And Analysis Of The Structural Basis For Inhibitor Specificity.

Human Neks are a conserved protein kinase family related to cell cycle progression and cell division and are considered potential drug targets for the treatment of cancer and other pathologies. We screened the activation loop mutant kinases hNek1 and hNek2, wild-type hNek7, and five hNek6 variants in different activation/phosphorylation statesand compared them against 85 compounds using thermal shift denaturation. We identified three compounds with significant Tm shifts: JNK Inhibitor II for hNek1(Δ262-1258)-(T162A), Isogranulatimide for hNek6(S206A), andGSK-3 Inhibitor XIII for hNek7wt. Each one of these compounds was also validated by reducing the kinases activity by at least 25%. The binding sites for these compounds were identified by in silico docking at the ATP-binding site of the respective hNeks. Potential inhibitors were first screened by thermal shift assays, had their efficiency tested by a kinase assay, and were finally analyzed by molecular docking. Our findings corroborate the idea of ATP-competitive inhibition for hNek1 and hNek6 and suggest a novel non-competitive inhibition for hNek7 in regard to GSK-3 Inhibitor XIII. Our results demonstrate that our approach is useful for finding promising general and specific hNekscandidate inhibitors, which may also function as scaffolds to design more potent and selective inhibitors.

Mechanical And Photoelastic Analysis Of Four Different Fixation Methods For Mandibular Body Fractures.

The aim of the present study was to compare four methods of fixation in mandibular body fractures. Mechanical and photoelastic tests were performed using polyurethane and photoelastic resin mandibles, respectively. The study groups contained the following: (I), two miniplates of 2.0 mm; (II) one 2.0 mm plate and an Erich arch bar; (III) one 2.4 mm plate and an Erich arch bar, and (IV) one 2.0 mm plate and one 2.4 mm plate. The differences between the mean values were analyzed using Tukey's test, the Mann-Whitney test and the Bonferroni correction. Group II recorded the lowest resistance, followed by groups I, IV and III. The photoelastic test confirmed the increase of tension in group II. The 2.4 mm system board in linear mandibular body fractures provided more resistance and the use of only one 2.0 mm plate in the central area of the mandible created higher tension.

Sim-xl: A Powerful And User-friendly Tool For Peptide Cross-linking Analysis.

Chemical cross-linking has emerged as a powerful approach for the structural characterization of proteins and protein complexes. However, the correct identification of covalently linked (cross-linked or XL) peptides analyzed by tandem mass spectrometry is still an open challenge. Here we present SIM-XL, a software tool that can analyze data generated through commonly used cross-linkers (e.g., BS3/DSS). Our software introduces a new paradigm for search-space reduction, which ultimately accounts for its increase in speed and sensitivity. Moreover, our search engine is the first to capitalize on reporter ions for selecting tandem mass spectra derived from cross-linked peptides. It also makes available a 2D interaction map and a spectrum-annotation tool unmatched by any of its kind. We show SIM-XL to be more sensitive and faster than a competing tool when analyzing a data set obtained from the human HSP90. The software is freely available for academic use at http://patternlabforproteomics.org/sim-xl. A video demonstrating the tool is available at http://patternlabforproteomics.org/sim-xl/video. SIM-XL is the first tool to support XL data in the mzIdentML format; all data are thus available from the ProteomeXchange consortium (identifier PXD001677).

Detection Of Explosives On The Surface Of Banknotes By Raman Hyperspectral Imaging And Independent Component Analysis.

The aim of this study was to develop a methodology using Raman hyperspectral imaging and chemometric methods for identification of pre- and post-blast explosive residues on banknote surfaces. The explosives studied were of military, commercial and propellant uses. After the acquisition of the hyperspectral imaging, independent component analysis (ICA) was applied to extract the pure spectra and the distribution of the corresponding image constituents. The performance of the methodology was evaluated by the explained variance and the lack of fit of the models, by comparing the ICA recovered spectra with the reference spectra using correlation coefficients and by the presence of rotational ambiguity in the ICA solutions. The methodology was applied to forensic samples to solve an automated teller machine explosion case. Independent component analysis proved to be a suitable method of resolving curves, achieving equivalent performance with the multivariate curve resolution with alternating least squares (MCR-ALS) method. At low concentrations, MCR-ALS presents some limitations, as it did not provide the correct solution. The detection limit of the methodology presented in this study was 50μgcm(-2).

Surgical Treatment Of Microinvasive Cervical Cancer: Analysis Of Pathologic Features With Implications On Radicality.

To evaluate pathologic features with implications on surgical radicality in women treated with radical hysterectomy and pelvic lymphadenectomy for cervical cancer stage IA1 with lymph vascular space invasion (LVSI) and stage IA2 by correlating findings in conization and hysterectomy specimens. Women with cervical cancer stage IA1 with LVSI and stage IA2 diagnosed by loop electrosurgical excisional procedure or cold knife conization were treated with radical hysterectomy and pelvic lymphadenectomy from January 1999 to December 2011 in 2 institutions. Fifty patients were enrolled: 40 with stage IA2 and 10 with stage IA1 with LVSI. Median age was 43 (30-67) years. All patients underwent cervical conization for diagnosis (45 loop electrosurgical excisional procedure, 5 cold knife). Lymph vascular space invasion was detected in 15 patients (30%). Two patients had positive pelvic nodes. No parametrial involvement was detected in the entire cohort. Positive margins were present in 35 patients, and residual disease was detected in 22 patients (44%). Positive margins predicted residual disease at radical hysterectomy (P = 0.02). Medium follow-up time was 51 months. One patient developed a pelvic recurrence, and there were no disease-related deaths. Patients with positive margins in cone biopsy specimens have an increased risk of residual disease at radical hysterectomy and require careful evaluation before conservative surgery. Pelvic lymph node evaluation is essential because lymph node metastasis may occur even in early stages. The lack of parametrial invasion in this study reinforces the knowledge that the select group of patients with microinvasive cervical carcinoma stages IA1 LVSI and stage IA2 have a very low risk of parametrial infiltration. Less radical surgery can be carefully considered for these patients.

The Geometric Curvature Of The Spine Of Runners During Maximal Incremental Effort Test.

This study sought to analyse the behaviour of the average spinal posture using a novel investigative procedure in a maximal incremental effort test performed on a treadmill. Spine motion was collected via stereo-photogrammetric analysis in thirteen amateur athletes. At each time percentage of the gait cycle, the reconstructed spine points were projected onto the sagittal and frontal planes of the trunk. On each plane, a polynomial was fitted to the data, and the two-dimensional geometric curvature along the longitudinal axis of the trunk was calculated to quantify the geometric shape of the spine. The average posture presented at the gait cycle defined the spine Neutral Curve. This method enabled the lateral deviations, lordosis, and kyphosis of the spine to be quantified noninvasively and in detail. The similarity between each two volunteers was a maximum of 19% on the sagittal plane and 13% on the frontal (p<0.01). The data collected in this study can be considered preliminary evidence that there are subject-specific characteristics in spinal curvatures during running. Changes induced by increases in speed were not sufficient for the Neutral Curve to lose its individual characteristics, instead behaving like a postural signature. The data showed the descriptive capability of a new method to analyse spinal postures during locomotion; however, additional studies, and with larger sample sizes, are necessary for extracting more general information from this novel methodology.

The Conformational Analysis Of 2-halocyclooctanones.

The establishment of the most stable structures of eight membered rings is a challenging task to the field of conformational analysis. In this work, a series of 2-halocyclooctanones were synthesized (including fluorine, chlorine, bromine and iodine derivatives) and submitted to conformational studies using a combination of theoretical calculation and infrared spectroscopy. For each compound, four conformations were identified as the most important ones. These conformations are derived from the chair-boat conformation of cyclooctanone. The pseudo-equatorial (with respect to the halogen) conformer is preferred in vacuum and in low polarity solvents for chlorine, bromine and iodine derivatives. For 2-fluorocyclooctanone, the preferred conformation in vacuum is pseudo-axial. In acetonitrile, the pseudo-axial conformer becomes the most stable for the chlorine derivative. According to NBO calculations, the conformational preference is not dictated by electron delocalization, but by classical electrostatic repulsions.

Modeling The Effects Of Temperature And Ph On The Resistance Of Alicyclobacillus Acidoterrestris In Conventional Heat-treated Fruit Beverages Through A Meta-analysis Approach.

In this work, all publicly-accessible published findings on Alicyclobacillus acidoterrestris heat resistance in fruit beverages as affected by temperature and pH were compiled. Then, study characteristics (protocols, fruit and variety, °Brix, pH, temperature, heating medium, culture medium, inactivation method, strains, etc.) were extracted from the primary studies, and some of them incorporated to a meta-analysis mixed-effects linear model based on the basic Bigelow equation describing the heat resistance parameters of this bacterium. The model estimated mean D* values (time needed for one log reduction at a temperature of 95 °C and a pH of 3.5) of Alicyclobacillus in beverages of different fruits, two different concentration types, with and without bacteriocins, and with and without clarification. The zT (temperature change needed to cause one log reduction in D-values) estimated by the meta-analysis model were compared to those ('observed' zT values) reported in the primary studies, and in all cases they were within the confidence intervals of the model. The model was capable of predicting the heat resistance parameters of Alicyclobacillus in fruit beverages beyond the types available in the meta-analytical data. It is expected that the compilation of the thermal resistance of Alicyclobacillus in fruit beverages, carried out in this study, will be of utility to food quality managers in the determination or validation of the lethality of their current heat treatment processes.

Association Between Unilateral Tonsillar Enlargement And Lymphoma In Children: A Systematic Review And Meta-analysis.

Lymphoma is the most common head and neck malignancy in children, and palatine tonsils asymmetry is the most frequent clinical manifestation of tonsillar lymphoma. However, several studies with children with tonsillar asymmetry found no case of lymphoma, showing that the relationship of tonsillar asymmetry with lymphoma is unclear. In this review, we aimed to identify the association between tonsillar asymmetry and tonsillar lymphoma in children by conducting systematic reviews of the literature on children with palatine tonsil lymphoma and tonsillar asymmetry. Articles comprising the paediatric age group (up to 18 years) with information concerning clinical manifestations of tonsillar lymphoma or the diagnosis of the tonsillar asymmetry were included. The main cause of asymmetry of palatine tonsils was lymphoid hyperplasia, followed by lymphoma and nonspecific benign changes. The asymmetry of tonsils was present in 73.2% of cases of lymphoma. There was an association between asymmetric palatine tonsils and lymphoma, with a likelihood ratio of 43.5 for children with asymmetry of palatine tonsils and 8938.4 for children with asymmetry of tonsils and other signs of suspicion for malignancy. We also provide recommendations on the management of suspicious cases of palatine tonsil lymphoma.

Epilepsias parciais familiares

OBJECTIVE: To investigate the clinical and genetic characteristics of familial partial epilepsies. METHOD: Family history of seizures was questioned in all patients followed in our epilepsy clinics, from October 1997 to December 1998. Those with positive family history were further investigated and detailed pedigrees were obtained. All possibly affected individuals available underwent clinical evaluation. Seizures and epilepsy syndromes were classified according to the ILAE recommendations. Whenever possible, EEG and MRI were performed. RESULTS: Positive family history was identified in 32 unrelated patients. A total of 213 possibly affected individuals were identified, 161 of whom have been evaluated. The number of affected subjects per family ranged from two to 23. Temporal lobe epilepsy (TLE) was identified in 22 families (68%), frontal lobe epilepsy in one family (3%), partial epilepsy with centrotemporal spikes in five families (15%), and other benign partial epilepsies of childhood in four families (12%). Most of the affected individuals in the TLE families (69%) had clinical and/or EEG characteristics of typical TLE. However, the severity of epilepsy was variable, with 76% of patients with spontaneous seizure remission or good control with medication and 24% with refractory seizures, including 7 patients that underwent surgical treatment. In the other 10 families, we identified 39 possibly affected subjects, 23 of whom were evaluated. All had good seizure control (with or without medication) except for one patient with frontal lobe epilepsy. Pedigree analysis suggested autosomal dominant inheritance with incomplete penetrance in all families. CONCLUSION: Family history of seizures is frequent among patients with partial epilepsies. The majority of our families had TLE and its expression was not different from that observed in sporadic cases. The identification of genes involved in partial epilepsies may be usefull in classification of syndromes, to stablish prognosis and optimal treatment.

Fases estacionárias monolíticas para separações cromatográficas

Monolithic stationary phases represent a new generation of chromatographic separation media. These phases consist of a continuous separation bed prepared by in situ polymerization or consolidation inside the column tubing. In recent years, their simple preparation procedure, unique properties and excellent performance have attracted quite remarkable attention in liquid chromatography and capillary electrochromatography. This review summarizes the preparation, characterization and applications of monolithic stationary phases. The analytical potential of these columns is demonstrated with separations involving various families of compounds in different separation modes.

Flow injection green method for the quantitative analysis of ketoconazole in pharmaceutical preparations

A flow injection method for the quantitative analysis of ketoconazole in tablets, based on the reaction with iron (III) ions, is presented. Ketoconazole forms a red complex with iron ions in an acid medium, with maximum absorbance at 495 nm. The detection limit was estimated to be 1×10--4 mol L-1; the quantitation limit is about 3×10--4 mol L-1 and approximately 30 determinations can be performed in an hour. The results were compared with those obtained with a reference HPLC method. Statistical comparisons were done using the Student's t procedure and the F test. Complete agreement was found at the 0.95 significance level between the proposed flow injection and the HPLC procedures. The two methods present similar precision, i.e., for HPLC the mean relative standard deviation was ca. 1.2% and for FIA ca. 1.6%.

Cromatografia líquida capilar: estado da arte e aplicações

This review describes the advantages and disadvantages of using capillary liquid chromatography (CLC), which is considered the newest member in the analytical separation science arsenal. Although CLC has tremendous potential for being the next major innovation in separatory analysis, it has not yet obtained great popularity compared to conventional high performance (and ultra-high performance) liquid chromatography. Comparisons are made between these techniques and some of the reasons that CLC has not yet reached its potential will be advanced.

A motivação de alunos no contexto da progressão continuada

This study investigated the intrinsic and extrinsic motivacional orientations of students in the context of the educational continuous progression. The sample was composed of 160 subjects of second, fourth, sixth and eighth grades of the elementary school. Data was collected by means of the presentation of histories involving the intrinsic, extrinsic motivation and the educational continuous progression system. Subjects were interviewed individually. Their answers were transcribed verbatim and submitted to content analysis. Results indicated that a expressive percentage of students did not know the educational system of continuous progression. Students revealed a predominantly intrinsic motivation orientation with advances in age and in school grade level, even though knowing that they will not repeat any school grade. This study pointed out the importance of deepening our knowledge concerning the impact of the educational continuous progression in students' motivation to learn.

Comparative analysis of adverse events between infliximab and adalimumab in Crohn's disease management: a Brazilian single-centre experience

INTRODUCTION: Data is scarce regarding adverse events (AE) of biological therapy used in the management of Crohn's Disease (CD) among Brazilian patients. OBJECTIVES: To analyse AE prevalence and profile in patients with CD treated with Infliximab (IFX) or Adalimumab (ADA) and to verify whether there are differences between the two drugs. METHOD: Retrospective observational single-centre study of CD patients on biological therapy. Variables analysed: Demographic data, Montreal classification, biological agent administered, treatment duration, presence and type of AE and the need for treatment interruption. RESULTS: Forty-nine patients were analysed, 25 treated with ADA and 24 with IFX. The groups were homogeneous in relation to the variables studied. The average follow-up period for the group treated with ADA was 19.3 months and 21.8 months for the IFX group (p = 0.585). Overall, 40% (n = 10) of patients taking ADA had AE compared with 50% (n = 12) of IFX users (p = 0.571). There was a tendency towards higher incidence of cutaneous and infusion reactions in the IFX group and higher incidence of infections in the ADA treated group, although without significant difference. CONCLUSIONS: No difference was found in the AE prevalence and profile between ADA and IFX CD patients in the population studied.