Wide-Scale Analysis of Human Functional Transcription Factor Binding Reveals a Strong Bias towards the Transcription Start Site

We introduce a novel method to screen the promoters of a set of genes with shared biological function, against a precompiled library of motifs, and find those motifs which are statistically over-represented in the gene set. The gene sets were obtained from the functional Gene Ontology (GO) classification; for each set and motif we optimized the sequence similarity score threshold, independently for every location window (measured with respect to the TSS), taking into account the location dependent nucleotide heterogeneity along the promoters of the target genes. We performed a high throughput analysis, searching the promoters (from 200bp downstream to 1000bp upstream the TSS), of more than 8000 human and 23,000 mouse genes, for 134 functional Gene Ontology classes and for 412 known DNA motifs. When combined with binding site and location conservation between human and mouse, the method identifies with high probability functional binding sites that regulate groups of biologically related genes. We found many location-sensitive functional binding events and showed that they clustered close to the TSS. Our method and findings were put to several experimental tests. By allowing a "flexible" threshold and combining our functional class and location specific search method with conservation between human and mouse, we are able to identify reliably functional TF binding sites. This is an essential step towards constructing regulatory networks and elucidating the design principles that govern transcriptional regulation of expression. The promoter region proximal to the TSS appears to be of central importance for regulation of transcription in human and mouse, just as it is in bacteria and yeast.Comment: 31 pages, including Supplementary Information and figure

Fear expression is suppressed by tyrosine administration

Animal studies have demonstrated that catecholamines regulate several aspects of fear conditioning. In humans, however, pharmacological manipulations of the catecholaminergic system have been scarce, and their primary focus has been to interfering with catecholaminergic activity after fear acquisition or expression had taken place, using L-Dopa, primarily, as catecholaminergic precursor. Here, we sought to determine if putative increases in presynaptic dopamine and norepinephrine by tyrosine administered before conditioning could affect fear expression. Electrodermal activity (EDA) of 46 healthy participants (24 placebo, 22 tyrosine) was measured in a fear instructed task. Results showed that tyrosine abolished fear expression compared to placebo. Importantly, tyrosine did not affect EDA responses to the aversive stimulus (UCS) or alter participants' mood. Therefore, the effect of tyrosine on fear expression cannot be attributed to these factors. Taken together, these findings provide evidence that the catecholaminergic system influences fear expression in humans

A dopaminergic switch for fear to safety transitions

Overcoming aversive emotional memories requires neural systems that detect when fear responses are no longer appropriate. The midbrain ventral tegmental area (VTA) dopamine system has been implicated in reward and more broadly in signalling when a better than expected outcome has occurred. This suggests that it may be important in guiding fear to safety transitions. We report that when an expected aversive outcome does not occur, activity in midbrain dopamine neurons is necessary to extinguish behavioral fear responses and engage molecular signalling events in extinction learning circuits. Furthermore, a specific dopamine projection to the nucleus accumbens medial shell is partially responsible for this effect. By contrast, a separate dopamine projection to the medial prefrontal cortex opposes extinction learning. This demonstrates a novel function for the canonical VTA-dopamine reward system and reveals opposing behavioural roles for different dopamine neuron projections in fear extinction learning

Evaluation of the accuracy of different transfer impression techniques for multiple implants

The aim of this study was to evaluate the accuracy of three implant transfer impression techniques. Four groups (n = 5) were defined, according to the technique: TC - tapered copings without splint; SC - square copings without splint; SCS - square copings splinted with dental floss and acrylic resin, and CG (control group) - master model with four external hexagonal implants and a superstructure. Individual trays and polyether were used for the impression. All casts were checked for their fit into the master superstructure; for this, all four screws were placed in the implants. Digital photos were taken and images were analyzed using UTHSCSA ImageTool software. Statistical analyses were performed using one-way analysis of variance and Student’s t test (p < 0.05). The means and standard deviation were (µm): CG = 2.03 ± 0.00, TC = 14.74 ± 3.41, SC = 12.08 ± 2.56, and SCS = 6.51 ± 0.09. The control group was found to be statistically different from the TC and SC groups. Within the limitations of this study, all groups presented clinically acceptable standard gap values, and the SCS group showed no statistical difference in relation to the CG (control group), demonstrating more accuracy and fidelity to transfer implants

Comparison of the fracture resistance of endodontically treated teeth restored with prefabricated posts and composite resin cores with different post lenghts

OBJECTIVE: This study evaluated the fracture strengths of endodontically treated teeth restored with prefabricated posts with different post lengths. MATERIAL AND METHODS: Thirty freshly extracted canines were endodontically treated. They were randomly divided into groups of 10 teeth and prepared according to 3 experimental protocols, as follows; Group 1/3 PP: teeth restored with prefabricated post and composite resin core (Z250) with post length of 5.0mm; Group 1/2 PP and Group 2/3 PP: teeth restored with prefabricated post and composite resin core (Z250) with different combinations of post length of 7.5mm and 10mm, respectively. All teeth were restored with full metal crowns. The fracture resistance (N) was measured in a universal testing machine (crosshead speed 0.5mm/min) at 45 degrees to the tooth long axis until failure. Data were analyzed by one-way analysis of variance (alpha=.05). RESULTS: The one-way analysis of variance demonstrated no significant difference among the different post lengths (P>;.05) (Groups 1/3 PP = 405.4 N, 1/2 PP = 395.6 N, 2/3 PP = 393.8 N). Failures occurred mainly due to core fracture. CONCLUSIONS: The results of this study showed that an increased post length in teeth restored with prefabricated posts did not significantly increase the fracture resistance of endodontically treated teeth

Association between intra-radicular posts and periapical lesions in endodontically treated teeth

Introduction: A significant number of endodontically treated teeth restored with posts have associated periapical lesions, and several authors have discussed the probable causes of the development of these. Attention has been focused on restorative procedures performed after endodontic treatment and their association with the prognosis of endodontic therapy because a number of root-filled teeth will require post- and core-retained restorations. Purpose: The purpose of this study was to evaluate, by examination of periapical radiographs, whether the placement of intra-radicular posts in endodontically treated teeth may act as a risk factor for development of periapical lesions. Material and Methods: This case-control study analyzed periapical radiographs of 72 endodontically treated teeth with coronal restorations. All radiographs were obtained from a single private practice. Specimens were assigned to 2 groups: Group 1 (control) was composed of teeth without periapical lesions and Group 2 (case) was composed of teeth with periapical lesions. The number of teeth with and without posts in each group was recorded. Three calibrated examiners analyzed the radiographs visually under X4 magnification. Results: In Group 1, 28 (65.1%) out of 43 teeth were restored with posts. In Group 2, 24 (82.8%) out of 29 teeth had intra-radicular posts. The interpretation of chi-square test showed that these percentages were not significantly different (x²=2.687; p=0.101). Odds ratio was 2.571 (0.815-8.118), which indicates that there was no statistically significant association between periapical lesions and posts. Conclusion: Intra-radicular posts placed in endodontically treated teeth were not a significant risk factor for development of periapical lesions in the practice where the cohort of patients was treated

Machined and plastic copings in three-element prostheses with different types of implantabutment joints: a strain gauge comparative analysis

OBJECTIVE: Using strain gauge (SG) analysis, the aim of this in vitro study was quantify the strain development during the fixation of three-unit screw implant-supported fixed partial dentures, varying the types of implant-abutment joints and the type of prosthetic coping. The hypotheses were that the type of hexagonal connection would generate different microstrains and the type of copings would produce similar microstrains after prosthetic screws had been tightened onto microunit abutments. MATERIALS AND METHODS: Three dental implants with external (EH) and internal (IH) hexagonal configurations were inserted into two polyurethane blocks. Microunit abutments were screwed onto their respective implant groups, applying a torque of 20 Ncm. Machined Co-Cr copings (M) and plastic prosthetic copings (P) were screwed onto the abutments, which received standard wax patterns. The wax patterns were cast in Co-Cr alloy (n=5), forming four groups: G1) EH/M; G2) EH/P; G3) IH/M and G4) IH/P. Four SGs were bonded onto the surface of the block tangentially to the implants, SG 1 mesially to implant 1, SG 2 and SG 3 mesially and distally to implant 2, respectively, and SG 4 distally to implant 3. The superstructure's occlusal screws were tightened onto microunit abutments with 10 Ncm torque using a manual torque driver. The magnitude of microstrain on each SG was recorded in units of microstrain (µ&#949;). The data were analyzed statistically by ANOVA and Tukey's test (p0.05). The hypotheses were partially accepted. CONCLUSIONS: It was concluded that the type of hexagonal connection and coping presented similar mechanical behavior under tightening conditions