Three-Dimensional Quantitative Structure-Activity Relationship Study of Antitumor 2-Formylpyridine Thiosemicarbazones Derivatives as Inhibitors of Ribonucleotide Reductase

In order to extend previous SAR and QSAR studies, 3D-QSAR analysis has been performed using CoMFA and CoMSIA approaches applied to a set of 39 alpha-(N)-heterocyclic carboxaldehydes thiosemicarbazones with their inhibitory activity values (IC(50)) evaluated against ribonucleotide reductase (RNR) of H.Ep.-2 cells (human epidermoid carcinoma), taken from selected literature. Both rigid and field alignment methods, taking the unsubstituted 2-formylpyridine thiosemicarbazone in its syn conformation as template, have been used to generate multiple predictive CoMFA and CoMSIA models derived from training sets and validated with the corresponding test sets. Acceptable predictive correlation coefficients (Q(cv)(2) from 0.360 to 0.609 for CoMFA and Q(cv)(2) from 0.394 to 0.580 for CoMSIA models) with high fitted correlation coefficients (r` from 0.881 to 0.981 for CoMFA and r(2) from 0.938 to 0.993 for CoMSIA models) and low standard errors (s from 0.135 to 0.383 for CoMFA and s from 0.098 to 0.240 for CoMSIA models) were obtained. More precise CoMFA and CoMSIA models have been derived considering the subset of thiosemicarbazones (TSC) substituted only at 5-position of the pyridine ring (n=22). Reasonable predictive correlation coefficients (Q(cv)(2) from 0.486 to 0.683 for CoMFA and Q(cv)(2) from 0.565 to 0.791 for CoMSIA models) with high fitted correlation coefficients (r(2) from 0.896 to 0.997 for CoMFA and r(2) from 0.991 to 0.998 for CoMSIA models) and very low standard errors (s from 0.040 to 0.179 for CoMFA and s from 0.029 to 0.068 for CoMSIA models) were obtained. The stability of each CoMFA and CoMSIA models was further assessed by performing bootstrapping analysis. For the two sets the generated CoMSIA models showed, in general, better statistics than the corresponding CoMFA models. The analysis of CoMFA and CoMSIA contour maps suggest that a hydrogen bond acceptor near the nitrogen of the pyridine ring can enhance inhibitory activity values. This observation agrees with literature data, which suggests that the nitrogen pyridine lone pairs can complex with the iron ion leading to species that inhibits RNR. The derived CoMFA and CoMSIA models contribute to understand the structural features of this class of TSC as antitumor agents in terms of steric, electrostatic, hydrophobic and hydrogen bond donor and hydrogen bond acceptor fields as well as to the rational design of this key enzyme inhibitors.

Phase-only optical encryption based on the zeroth-order phase-contrast technique

A phase-only encryption/decryption scheme with the readout based on the zeroth-order phase-contrast technique (ZOPCT), without the use of a phase-changing plate on the Fourier plane of an optical system based on the 4f optical correlator, is proposed. The encryption of a gray-level image is achieved by multiplying the phase distribution obtained directly from the gray-level image by a random phase distribution. The robustness of the encoding is assured by the nonlinearity intrinsic to the proposed phase-contrast method and the random phase distribution used in the encryption process. The experimental system has been implemented with liquid-crystal spatial modulators to generate phase-encrypted masks and a decrypting key. The advantage of this method is the easy scheme to recover the gray-level information from the decrypted phase-only mask applying the ZOPCT. An analysis of this decryption method was performed against brute force attacks. (C) 2009 Society of Photo-Optical Instrumentation Engineers. [DOI: 10.1117/1.3223629]

Topology Optimized Design, Microfabrication and Characterization of Electro-Thermally Driven Microgripper

This article presents a systematic and logical study of the topology optimized design, microfabrication, and static/dynamic performance characterization of an electro-thermo-mechanical microgripper. The microgripper is designed using a topology optimization algorithm based on a spatial filtering technique and considering different penalization coefficients for different material properties during the optimization cycle. The microgripper design has a symmetric monolithic 2D structure which consists of a complex combination of rigid links integrating both the actuating and gripping mechanisms. The numerical simulation is performed by studying the effects of convective heat transfer, thermal boundary conditions at the fixed anchors, and microgripper performance considering temperature-dependent and independent material properties. The microgripper is fabricated from a 25 mm thick nickel foil using laser microfabrication technology and its static/dynamic performance is experimentally evaluated. The static and dynamic electro-mechanical characteristics are analyzed as step response functions with respect to tweezing/actuating displacements, applied current/power, and actual electric resistance. A microgripper prototype having overall dimensions of 1mm (L) X 2.5mm (W) is able to deliver the maximum tweezing and actuating displacements of 25.5 mm and 33.2 mm along X and Y axes, respectively, under an applied power of 2.32 W. Experimental performance is compared with finite element modeling simulation results.

Reconstruction of large cranial defects in nonimmunosuppressed experimental design with human dental pulp stem cells

The main aim of this study is to evaluate the capacity of human dental pulp stem cells (hDPSC), isolated from deciduous teeth, to reconstruct large-sized cranial bone defects in nonimmunosuppressed (NIS) rats. To our knowledge, these cells were not used before in similar experiments. We performed two symmetric full-thickness cranial defects (5 x 8 mm) on each parietal region of eight NIS rats. In six of them, the left side was supplied with collagen membrane only and the right side (RS) with collagen membrane and hDPSC. In two rats, the RS had collagen membrane only and nothing was added at the left side (controls). Cells were used after in vitro characterization as mesenchymal cells. Animals were euthanized at 7, 20, 30, 60, and 120 days postoperatively and cranial tissue samples were taken from the defects for histologic analysis. Analysis of the presence of human cells in the new bone was confirmed by molecular analysis. The hDPSC lineage was positive for the four mesenchymal cell markers tested and showed osteogenic, adipogenic, and myogenic in vitro differentiation. We observed bone formation 1 month after surgery in both sides, but a more mature bone was present in the RS. Human DNA was polymerase chain reaction-amplified only at the RS, indicating that this new bone had human cells. The us e of hDPSC in NIS rats did not cause any graft. rejection. Our findings suggest that hDPSC is an additional cell resource for correcting large cranial defects in rats and constitutes a promising model for reconstruction of human large cranial defects in craniofacial surgery.

Hyrax appliance opening and pattern of skeletal maxillary expansion after surgically assisted rapid palatal expansion: a computed tomography evaluation

Objective. The objective of this study was to evaluate, using computed tomography, correlations between Hyrax appliance opening and post-SARPE skeletal changes. Study design. Fifteen patients underwent SARPE according to a specific protocol and were followed. Linear and angular measurements of the anterior, intermediate, and posterior portions of the maxilla were evaluated. The correlation between maxillary expansion and appliance opening was investigated. Results. Significant overall expansion was observed. In the anterior and intermediate portions of the maxilla, the increase in maxillary width was greater than that observed in the posterior portion. The degree of appliance opening was significantly greater than that of the skeletal expansion. Also, no linear correlation between appliance opening and regional maxillary expansion was established. Conclusion. The transverse expansion of the maxilla was less than uniform. The lack of linear correlation between appliance opening and skeletal expansion is attributable to multiple factors, including those related to the device, the surgical technique, and the craniofacial deformity itself. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008; 106: 812-819)

The Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRA.CER) trial: study design and rationale

Background The protease-activated receptor 1 (PAR-1), the main platelet receptor for thrombin, represents a novel target for treatment of arterial thrombosis, and SCH 530348 is an orally active, selective, competitive PAR-1 antagonist. We designed TRA.CER to evaluate the efficacy and safety of SCH 530348 compared with placebo in addition to standard of care in patients with non-ST-segment elevation (NSTE) acute coronary syndromes (ACS) and high-risk features. Trial design TRA.CER is a prospective, randomized, double-blind, multicenter, phase III trial with an original estimated sample size of 10,000 subjects. Our primary objective is to demonstrate that SCH 530348 in addition to standard of care will reduce the incidence of the composite of cardiovascular death, myocardial infarction (MI), stroke, recurrent ischemia with rehospitalization, and urgent coronary revascularization compared with standard of care alone. Our key secondary objective is to determine whether SCH 530348 will reduce the composite of cardiovascular death, MI, or stroke compared with standard of care alone. Secondary objectives related to safety are the composite of moderate and severe GUSTO bleeding and clinically significant TIMI bleeding. The trial will continue until a predetermined minimum number of centrally adjudicated primary and key secondary end point events have occurred and all subjects have participated in the study for at least I year. The TRA.CER trial is part of the large phase III SCH 530348 development program that includes a concomitant evaluation in secondary prevention. Conclusion TRA.CER will define efficacy and safety of the novel platelet PAR-1 inhibitor SCH 530348 in the treatment of high-risk patients with NSTE ACS in the setting of current treatment strategies. (Am Heart J 2009; 158:327-34.)

Cigarette smoke inhalation modulates gene expression in sites of bone healing: a study in rats

Objective. The aim of this study was to assess the effect of cigarette smoke inhalation (CSI) on gene expression in alveolar bone healing sites. Study design. Wistar rats were randomly assigned to the groups: control [animals not exposed to CSI (n = 20)] and test [animals exposed to CSI, starting 3 days before teeth extraction and maintained until killing them (n = 20)]. First mandibular molars were bilaterally extracted, and the expression of alkaline phosphatase, bone morphogenetic protein (BMP) 2 and 7, receptor activator of nuclear factor kappa B ligand, osteoprotegerin, and d2 isoform of vacuolar adenosine triphosphatase V(o) domain were assessed by quantitative polymerase chain reaction in the newly formed tissue in the sockets. Results. Overall, data analysis demonstrated that CSI significantly affected the expression pattern of all of the studied genes except BMP-7. Conclusion. The expression of key genes for bone healing may be affected by CSI in tooth extraction sites. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010;110:447-452)

Expression of bone resorption regulators (RANK, RANKL, and OPG) in odontogenic tumors

Objective. To investigate the expression of bone resorption regulators (receptor activator of nuclear factor kappa B [RANK], RANK ligand [RANKL], and osteoprotegerin [OPG]) in calcifying cystic odontogenic tumor (CCOT), adenomatoid odontogenic tumor (AOT), calcifying epithelial odontogenic tumor (CEOT), odontogenic myxoma (OM), and ameloblastic fibroma (AF). Study design. The expression of these mediators was evaluated by means of immunohistochemistry. Results. All specimens demonstrated positive immunoreactivity to RANK, RANKL, and OPG. The quantification of these mediators in epithelium revealed a similar pattern of expression for RANKL and OPG in CCOT, AOT, CEOT, and AF. With regard to stromal/mesenchymal cells, the majority of AOT and CCOT cases showed a higher content of OPG than RANKL, whereas CEOT, OM, and especially AF had a tendency to present a greater content of RANKL than OPG. Conclusion. Our data indicate that the CCOT, AOT, CEOT, OM, and AF cell constituents express key regulators of bone metabolism that might locally modulate tumor-associated bone resorption. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;106:548-55)

Clock Genes, Melanopsins, Melatonin, and Dopamine Key Enzymes and Their Modulation by Light and Glutamate in Chicken Embryonic Retinal Cells

The avian circadian system is composed of the retina, the mammalian homolog region of the suprachiasmatic nucleus (SNC), and the pineal gland. The retina, itself, displays many rhythmic physiological events, such as movements of photoreceptor cells, opsin expression, retinal reisomerization, and melatonin and dopamine production and secretion. Altogether, these rhythmic events are coordinated to predict environmental changes in light conditions during the day, optimizing retina function. The authors investigated the expression pattern of the melanopsin genes Opn4x and Opn4m, the clock genes Clock and Per2, and the genes for the key enzymes N-Acetyltransferase and Tyrosine Hidroxylase in chicken embryo dispersed retinal cells. Primary cultures of chicken retina from 8-day-old embryos were kept in constant dark (DD), in 12-h light/12-h dark (12L:12D), in 12L:12D followed by DD, or in DD in the absence or presence of 100 mu M glutamate for 12 h. Total RNA was extracted throughout a 24-h span, every 3 h starting at zeitgeber time 0 (ZT0) of the 6th day, and submitted to reverse transcriptase-polymerase chain reaction (RT-PCR) followed by quantitative PCR (qPCR) for mRNA quantification. The data showed no rhythmic pattern of transcription for any gene in cells kept in DD. However under a light-dark cycle, Clock, Per2, Opn4m, N-Acetyltransferase, and Tyrosine Hydroxylase exhibited rhythmic patterns of transcription. In DD, 100 mu M glutamate was able to induce rhythmic expression of Clock, strongly inhibited the expression of Tyrosine Hydroxylase, and, only at some ZTs, of Opn4x and Opn4m. The neurotransmitter had no effect on Per2 and N-Acetyltransferase transcription. The authors confirmed the expression of the protein OPN4x by immunocytochemistry. These results suggest that chicken embryonic retinal cells contain a functional circadian clock, whose synchronization requires light-dark cycle or glutamate stimuli. (Author correspondence: amdlcast@ib.usp.br).

Mannose-binding lectin complement pathway plays a key role in complement activation by Paracoccidioides brasiliensis

Paracoccidioides brasiliensis (Pb) is a dimorphic fungal pathogen that causes paracoccidioidomycosis the most severe deep mycosis from South America Although cell mediated immunity is considered the most efficient protective mechanism against Pb infection mechanisms of innate immunity are poorly defined Herein we investigated the interaction of the complement system with high and low virulence isolates of Pb We demonstrated that Pb18 a high virulence Pb Isolate when incubated with normal human serum (NHS) induces consumption of hemolytic complement and when immobilized promotes binding of C4b C3b and C5b-C9 Both low virulence (Pb265) and high virulence (Pb18) isolates consumed C4 C3 and mannose-binding learn (MBL) of MBL-sufficient but not of MBL-deficient serum as revealed by deposition of residual C4 C3 and MBL on immune complexes and mannan However higher complement components consumption was observed with Pb265 as compared with Pb18 The suggested relationship between low virulence and significant complement activation properties of Pb isolates was confirmed by the demonstration that virulence attenuation of Pb 18 results in acquisition of the ability to activate complement Conversely reactivation of attenuated Pb18 results in loss of the ability to activate complement Our results demonstrate for the first time that Pb yeasts activate the complement system by the lectin pathway and there is an Inverse correlation between complement activating ability and Pb virulence These differences could exert an influence on Innate immunity and severity of the disease developed by infected hosts (C) 2010 Elsevier Ltd All rights reserved

Design of associative memories using cellular neural networks

Cellular neural networks (CNNs) have locally connected neurons. This characteristic makes CNNs adequate for hardware implementation and, consequently, for their employment on a variety of applications as real-time image processing and construction of efficient associative memories. Adjustments of CNN parameters is a complex problem involved in the configuration of CNN for associative memories. This paper reviews methods of associative memory design based on CNNs, and provides comparative performance analysis of these approaches.

From Rational Design of Drug Crystals to Understanding of Nucleic Acid Structures: Lamivudine Duplex

A DNA-like duplex of nucleosides is probable to exist even without the 5`-phosphate groups needed to assemble the chain backbone. However, double-stranded helical structures of nucleosides are unknown. Here, we report a duplex of nucleoside analogs that is spontaneously assembled due to stacking of the neutral and protonated molecules of lamivudine, a nucleoside reverse transcriptase inhibitor (NTRI) widely used in anti-HIV drug combinatory medication. The left-handed lamivudine duplex has features similar to those of i-motif DNA, as the face-to-face base stacking and the helix rise per base pair. Furthermore, the protonation pattern on alternate bases expected for it DNA-like duplex stabilized by pairing of neutral and protonated cytosine fragments was observed for the first time in the lamivudine double-stranded helix. This structure demonstrates that hydrogen bonds can substitute for covalent phosphodiester linkage in the stabilization of the duplex backbone. This interesting example of spontaneous molecular self-organization indicates that the 5`-phosphate group could not be a requirement for duplex assembly.

An Information Theory framework for two-stage binary image operator design

The design of translation invariant and locally defined binary image operators over large windows is made difficult by decreased statistical precision and increased training time. We present a complete framework for the application of stacked design, a recently proposed technique to create two-stage operators that circumvents that difficulty. We propose a novel algorithm, based on Information Theory, to find groups of pixels that should be used together to predict the Output Value. We employ this algorithm to automate the process of creating a set of first-level operators that are later combined in a global operator. We also propose a principled way to guide this combination, by using feature selection and model comparison. Experimental results Show that the proposed framework leads to better results than single stage design. (C) 2009 Elsevier B.V. All rights reserved.

Effect of different ferrule designs on the fracture resistance and failure pattern of endodontically treated teeth restored with fiber posts and all-ceramic crowns

OBJECTIVE: This study investigated the effect of different ferrule heights on endodontically treated premolars. MATERIAL AND METHODS: Fifty sound mandibular first premolars were endodontically treated and then restored with 7-mm fiber post (FRC Postec Plus #1 Ivoclar-Vivadent) luted with self-polymerized resin cement (Multilink, Ivoclar Vivadent) while the coronal section was restored with hybrid composite core build-up material (Tetric Ceram, Ivoclar-Vivadent), which received all-ceramic crown. Different ferrule heights were investigated: 1-mm circumferential ferrule without post and core (group 1 used as control), a circumferential 1-mm ferrule (group 2), non-uniform ferrule 2-mm buccally and 1-mm lingually (group 3), non-uniform ferrule 3-mm buccally and 2-mm lingually (group 4), and finally no ferrule preparation (group 5). The fracture load and failure pattern of the tested groups were investigated by applying axial load to the ceramic crowns (n=10). Data were analyzed statistically by one-way ANOVA and Tukey's post-hoc test was used for pair-wise comparisons (α=0.05). RESULTS: There were no significant differences among the failure load of all tested groups (P<0.780). The control group had the lowest fracture resistance (891.43±202.22 N) and the highest catastrophic failure rate (P<0.05). Compared to the control group, the use of fiber post reduced the percentage of catastrophic failure while increasing the ferrule height did not influence the fracture resistance of the restored specimens. CONCLUSIONS: Within the limitations of this study, increasing the ferrule length did not influence the fracture resistance of endodontically treated teeth restored with glass ceramic crowns. Insertion of a fiber post could reduce the percentage of catastrophic failure of these restorations under function.

Effectiveness of a new toothbrush design versus a conventional tongue scraper in improving breath odor and reducing tongue microbiota

For centuries, specific instruments or regular toothbrushes have routinely been used to remove tongue biofilm and improve breath odor. Toothbrushes with a tongue scraper on the back of their head have recently been introduced to the market. The present study compared the effectiveness of a manual toothbrush with this new design, i.e., possessing a tongue scraper, and a commercial tongue scraper in improving breath odor and reducing the aerobic and anaerobic microbiota of tongue surface. The evaluations occurred at 4 moments, when the participants (n=30) had their halitosis quantified with a halimeter and scored according to a 4-point scoring system corresponding to different levels of intensity. Saliva was collected for counts of aerobic and anaerobic microorganisms. Data were analyzed statistically by Friedman's test (p<0.05). When differences were detected, the Wilcoxon test adjusted for Bonferroni correction was used for multiple comparisons (group to group). The results confirmed the importance of mechanical cleaning of the tongue, since this procedure provided an improvement in halitosis and reduction of aerobe and anaerobe counts. Regarding the evaluated methods, the toothbrush's tongue scraper and conventional tongue scraper had a similar performance in terms of breath improvement and reduction of tongue microbiota, and may be indicated as effective methods for tongue cleaning.