p63-microRNA feedback in keratinocyte senescence

We investigated the expression of microRNAs (miRNAs) associated with replicative senescence in human primary keratinocytes. A cohort of miRNAs up-regulated in senescence was identified by genome-wide miRNA profiling, and their change in expression was validated in proliferative versus senescent cells. Among these, miRNA (miR)-138, -181a, -181b, and -130b expression increased with serial passages. miR-138, -181a, and -181b, but not miR-130b, overexpression in proliferating cells was sufficient per se to induce senescence, as evaluated by inhibition of BrdU incorporation and quantification of senescence-activated β-galactosidase staining. We identified Sirt1 as a direct target of miR-138, -181a, and -181b, whereas ΔNp63 expression was inhibited by miR-130b. We also found that ΔNp63α inhibits miR-138, -181a, -181b, and -130b expression by binding directly to p63-responsive elements located in close proximity to the genomic loci of these miRNAs in primary keratinocytes. These findings suggest that changes in miRNA expression, by modulating the levels of regulatory proteins such as p63 and Sirt1, strongly contribute to induction of senescence in primary human keratinocytes, thus linking these two proteins. Our data also indicate that suppression of miR-138, -181a, -181b, and -130b expression is part of a growth-promoting strategy of ΔNp63α in epidermal proliferating cells.     

The folliculin-FNIP1 pathway deleted in human Birt-Hogg-Dube syndrome is required for murine B-cell development

Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder characterized by cutaneous fibrofolliculomas, pulmonary cysts, and kidney malignancies. Affected individuals carry germ line mutations in folliculin (FLCN), a tumor suppressor gene that becomes biallelically inactivated in kidney tumors by second-hit mutations. Similar to other factors implicated in kidney cancer, FLCN has been shown to modulate activation of mammalian target of rapamycin (mTOR). However, its precise in vivo function is largely unknown because germ line deletion of Flcn results in early embryonic lethality in animal models. Here, we describe mice deficient in the newly characterized folliculin-interacting protein 1 (Fnip1). In contrast to Flcn, Fnip1(-/-) mice develop normally, are not susceptible to kidney neoplasia, but display a striking pro-B cell block that is entirely independent of mTOR activity. We show that this developmental arrest results from rapid caspase-induced pre-B cell death, and that a Bcl2 transgene reconstitutes mature B-cell populations, respectively. We also demonstrate that conditional deletion of Flcn recapitulates the pro-B cell arrest of Fnip1(-/-) mice. Our studies thus demonstrate that the FLCN-FNIP complex deregulated in BHD syndrome is absolutely required for B-cell differentiation, and that it functions through both mTOR-dependent and independent pathways.     

Genetic variability at the TREX1 locus is not associated with natural resistance to HIV-1 infection

Three prime repair exonuclease 1 (TREX1) degrades excess HIV-1 DNA, thereby preventing recognition by innate immunity receptors and type I interferon responses. Analyses performed in two HIV-exposed seronegative (HESN) cohorts did not show any differences in TREX1 sequence, single nucleotide polymorphisms frequency, or expression in HESN compared to controls, suggesting that, despite its central role in the HIV-1 infection process, genetic diversity at TREX1 is not a major determinant of susceptibility to infection in humans.     

The Val66Met Polymorphism at the BDNF Gene does not Influence Wisconsin Card Sorting Test Results in Children and Adolescents with Bipolar Disorder

ObjectivesTo assess the role of the Val66Met polymorphism at the brain-derived neurotrophic factor (BDNF) gene on the performance of children and adolescents with bipolar disorder [juvenile bipolar disorder (JBD)] on the Wisconsin Card Sorting Test (WCST).MethodsChildren and adolescents were assessed by the K-SADS-PL and a clinical evaluation for BD and comorbid conditions. Manic and depressive symptoms were assessed with the Young Mania Rating Scale and the Children Depression Rating Scale – Reviewed. The Val66Met polymorphism at the BDNF was genotyped from a blood sample. Patients’ IQ and executive functions were assessed by a standard cognitive flexibility test (WCST).ResultsFifty-three subjects were included in the study. No significant difference was observed between the Val/Val and Val/Met+Met/Met groups on any WCST scores in the MANCOVA (F48,5 = .76; p = .59; Perseverative Errors, p = .66; Nonperseverative Errors, p = .58; Categories Completed, p = .34; Attempts to Reach First Category, p=.64; and Percentage of Conceptual Level Responses, p = .99).ConclusionsOur findings from this sample of children and adolescents with BD do not replicate results from studies of adults and suggest the existence of differences in the neurobiology of this disorder across the life cycle. Investigations of larger samples are necessary to confirm these data.     

Does chlorhexidine in different formulations interfere with the force of orthodontic elastics

Objective:To evaluate the effects of different concentrations of chlorhexidine on the decline in force of orthodontic elastics.Materials and Methods:In a laboratory study, five groups of samples were tested, with one control group represented by distilled water (group 1) and four experimental groups: 0.12% manipulated chlorhexidine (group 2), 0.2% manipulated chlorhexidine (group 3), 0.12% chlorhexidine gluconate–based oral solution (0.12% Periogard; group 4), and 0.2% Cleanform mouthwash (formula and action; group 5). The test groups were submersed in artificial saliva at 37°C. Templates were used and submerged in the chlorhexidine solutions for 30 seconds twice a day. Force was measured with a digital dynamometer at six different time intervals: 0, 1, 7, 14, 21, and 28 days.Results:No statistical differences were found among the groups in the initial period, at 24 hours, and at 7 days (P > .05). There were statistical differences between groups 2 and 5 at 14 days of the experiment and between group 1 and the others at 28 days. In the initial period, the force was statistically higher than it was at any of the other periods of the experiment (P < .05).Conclusion:In the present study, chlorhexidine showed no significant influence on the force degradation of the chain elastics tested.     

Displacement of Dental Implants in Trabecular Bone under a Static Lateral Load in Fresh Bovine Bone

Aim: The study aims to provide objective data for the displacement of titanium screw implants in trabecular bone specimens. One hundred Semados implants (Bego, Bremen, Germany) were inserted in bovine type IV bone specimens. All implants had a diameter of 3.75 mm; 50 implants had a length of 8.5 mm and 50 implants had a length of 15 mm. Insertion torque was determined at intervals of 10, 20, and 30 Ncm. Implants were loaded horizontally with 10, 20, and 30 N for 2 seconds. An indicator strip was attached to the implant abutment to allow direct observation of implant movement relative to the bone surface. Horizontal displacement was assessed with an accuracy of measurement of 10 µm. Seven implants got lost by visible loosening. Degree of displacement was subject to evaluation with all others. Those implants showed a mean displacement of 59 µm for 10 N (n = 100), 173 µm for 20 N (n = 99), and 211 µm for 30 N (n = 93). The mean displacement of 15‐mm implants (16, 37, 51 µm) was significantly lower compared with 8.5‐mm implants (103, 311, 396 µm) corresponding to 10, 20, and 30 N as lateral loads. Conclusions: Displacement of screw implants in trabecular bone can be detected and visualized using commercially available endoscopes with a high magnification. A lateral load of 20 N indicates a mean displacement of over 100 µm and therefore results in a critical displacement.