Severe hearing loss and outer hair cell death in homozygous Foxo3 knockout mice after moderate noise exposure

Noise induced hearing loss (NIHL) is a disease that affects millions of Americans. Identifying genetic pathways that influence recovery from noise exposure is an important step forward in understanding NIHL. The transcription factor Foxo3 integrates the cellular response to oxidative stress and plays a role in extending lifespan in many organisms, including humans. Here we show that Foxo3 is required for auditory function after noise exposure in a mouse model system, measured by ABR. Absent Foxo3, outer hair cells are lost throughout the middle and higher frequencies. SEM reveals persistent damage to some surviving outer hair cell stereocilia. However, DPOAE analysis reveals that some function is preserved in low frequency outer hair cells, despite concomitant profound hearing loss. Inner hair cells, auditory synapses and spiral ganglion neurons are all present after noise exposure in the Foxo3KO/KO fourteen days post noise (DPN). We also report anti-Foxo3 immunofluorescence in adult human outer hair cells. Taken together, these data implicate Foxo3 and its transcriptional targets in outer hair cell survival after noise damage. An additional role for Foxo3 in preserving hearing is likely, as low frequency auditory function is absent in noise exposed Foxo3KO/KOs even though all cells and structures are present

The neural basis of unconditional love

Functional neuroimaging studies have shown that romantic love and maternal love are mediated by regions specific to each, as well as overlapping regions in the brain's reward system. Nothing is known yet regarding the neural underpinnings of unconditional love. The main goal of this functional magnetic resonance imaging study was to identify the brain regions supporting this form of love. Participants were scanned during a control condition and an experimental condition. In the control condition, participants were instructed to simply look at a series of pictures depicting individuals with intellectual disabilities. In the experimental condition, participants were instructed to feel unconditional love towards the individuals depicted in a series of similar pictures. Significant loci of activation were found, in the experimental condition compared with the control condition, in the middle insula, superior parietal lobule, right periaqueductal gray, right globus pallidus (medial), right caudate nucleus (dorsal head), left ventral tegmental area and left rostro-dorsal anterior cingulate cortex. These results suggest that unconditional love is mediated by a distinct neural network relative to that mediating other emotions. This network contains cerebral structures known to be involved in romantic love or maternal love. Some of these structures represent key components of the brain's reward system

Towards novel difluorinated sugar mimetrics; syntheses and conformational analyses of highly-functionalised difluorinated cyclooctenones

Highly-functionalised difluorinated cyclooctenones were synthesised from trifluoroethanol using either metallated difluoroenol acetal or carbamate chemistry, followed by a [2,3]-Wittig rearrangement or aldol reaction. Efficient RCM reactions afforded the title compounds which showed rather restricted fluxional behaviour by VT 19F NMR. Topological characterisation by molecular modelling and NOESY/ROESY experiments offered a number of challenges, but allowed the identification of two favoured boat-chair conformers which interconverted by pseudorotation with relatively large activation barriers

Non local spatial and angular matching : enabling higher spatial resolution diffusion MRI datasets through adaptive denoising

Diffusion magnetic resonance imaging (MRI) datasets suffer from low Signal-to-Noise Ratio (SNR), especially at high b-values. Acquiring data at high b-values contains relevant information and is now of great interest for microstructural and connectomics studies. High noise levels bias the measurements due to the non-Gaussian nature of the noise, which in turn can lead to a false and biased estimation of the diffusion parameters. Additionally, the usage of in-plane acceleration techniques during the acquisition leads to a spatially varying noise distribution, which depends on the parallel acceleration method implemented on the scanner. This paper proposes a novel diffusion MRI denoising technique that can be used on all existing data, without adding to the scanning time. We first apply a statistical framework to convert both stationary and non stationary Rician and non central Chi distributed noise to Gaussian distributed noise, effectively removing the bias. We then introduce a spatially and angular adaptive denoising technique, the Non Local Spatial and Angular Matching (NLSAM) algorithm. Each volume is first decomposed in small 4D overlapping patches, thus capturing the spatial and angular structure of the diffusion data, and a dictionary of atoms is learned on those patches. A local sparse decomposition is then found by bounding the reconstruction error with the local noise variance. We compare against three other state-of-the-art denoising methods and show quantitative local and connectivity results on a synthetic phantom and on an in-vivo high resolution dataset. Overall, our method restores perceptual information, removes the noise bias in common diffusion metrics, restores the extracted peaks coherence and improves reproducibility of tractography on the synthetic dataset. On the 1.2 mm high resolution in-vivo dataset, our denoising improves the visual quality of the data and reduces the number of spurious tracts when compared to the noisy acquisition. Our work paves the way for higher spatial resolution acquisition of diffusion MRI datasets, which could in turn reveal new anatomical details that are not discernible at the spatial resolution currently used by the diffusion MRI community

Early-onset Amyloid Deposition and Cognitive Deficits in Transgenic Mice Expressing a Double Mutant Form of Amyloid Precursor Protein 695

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Full Mouth Rehabilitation with Implant-Supported Prostheses for Severe Periodontitis: A Case Report

Oral rehabilitation for a patient with severe loss of alveolar bone and soft tissue resulting from severe periodontitis presents a challenge to clinicians. Replacing loosening natural teeth with fixed prostheses supported by dental implants often requires either gingival surgery or bone grafting. The outcome of the bone grafting is sometimes unpredictable and requires longer healing time and/ or multiple surgeries. The presence of periodontal inflammation and periapical lesions often delay the placement of bone grafts as well as dental implants. Here we present a clinical case of a patient undergone full mouth reconstruction with implant-supported fixed prostheses. We demonstrated that early placement of implants (three weeks after extractions) with minimal bone grafting may be an alternative to conventional bone grafting followed by implant placement. We believe that primary stability during implant placement may contribute to our success. In addition, composite resin gingival material may be indicated in cases of large fixed implant prostheses as an alternative to pink porcelain

Thyroid Hormone May Regulate mRNA Abundance in Liver by Acting on MicroRNAs

MicroRNAs (miRNAs) are extensively involved in diverse biological processes. However, very little is known about the role of miRNAs in mediating the action of thyroid hormones (TH). Appropriate TH levels are known to be critically important for development, differentiation and maintenance of metabolic balance in mammals. We induced transient hypothyroidism in juvenile mice by short-term exposure to methimazole and perchlorate from post natal day (PND) 12 to 15. The expression of miRNAs in the liver was analyzed using Taqman Low Density Arrays (containing up to 600 rodent miRNAs). We found the expression of 40 miRNAs was significantly altered in the livers of hypothyroid mice compared to euthyroid controls. Among the miRNAs, miRs-1, 206, 133a and 133b exhibited a massive increase in expression (50- to 500-fold). The regulation of TH on the expression of miRs-1, 206, 133a and 133b was confirmed in various mouse models including: chronic hypothyroid, short-term hyperthyroid and short-term hypothyroid followed by TH supplementation. TH regulation of these miRNAs was also confirmed in mouse hepatocyte AML 12 cells. The expression of precursors of miRs-1, 206, 133a and 133b were examined in AML 12 cells and shown to decrease after TH treatment, only pre-mir-206 and pre-mir-133b reached statistical significance. To identify the targets of these miRNAs, DNA microarrays were used to examine hepatic mRNA levels in the short-term hypothyroid mouse model relative to controls. We found transcripts from 92 known genes were significantly altered in these hypothyroid mice. Web-based target predication software (TargetScan and Microcosm) identified 14 of these transcripts as targets of miRs-1, 206, 133a and 133b. The vast majority of these mRNA targets were significantly down-regulated in hypothyroid mice, corresponding with the up-regulation of miRs-1, 206, 133a and 133b in hypothyroid mouse liver. To further investigate target genes, miR-206 was over-expressed in AML 12 cells. TH treatment of cells over-expressing miR-206 resulted in decreased miR-206 expression, and a significant increase in two predicted target genes, Mup1 and Gpd2. The results suggest that TH regulation of these genes may occur secondarily via miR-206. These studies provide new insight into the role of miRNAs in mediating TH regulation of gene expression

Rare Exonic Minisatellite Alleles in MUC2 Influence Susceptibility to Gastric Carcinoma

BACKGROUND: Mucins are the major components of mucus and their genes share a common, centrally-located region of sequence that encodes tandem repeats. Mucins are well known genes with respect to their specific expression levels; however, their genomic levels are unclear because of complex genomic properties. In this study, we identified eight novel minisatellites from the entire MUC2 region and investigated how allelic variation in these minisatellites may affect susceptibility to gastrointestinal cancer. METHODOLOGY/PRINCIPLE FINDINGS: We analyzed genomic DNA from the blood of normal healthy individuals and multi-generational family groups. Six of the eight minisatellites exhibited polymorphism and were transmitted meiotically in seven families, following Mendelian inheritance. Furthermore, a case-control study was performed that compared genomic DNA from 457 cancer-free controls with DNA from individuals with gastric (455), colon (192) and rectal (271) cancers. A statistically significant association was identified between rare exonic MUC2-MS6 alleles and the occurrence of gastric cancer: odds ratio (OR), 2.56; 95% confidence interval (CI), 1.31-5.04; and p = 0.0047. We focused on an association between rare alleles and gastric cancer. Rare alleles were divided into short (40, 43 and 44) and long (47, 50 and 54), according to their TR (tandem repeats) lengths. Interestingly, short rare alleles were associated with gastric cancer (OR = 5.6, 95% CI: 1.93-16.42; p = 0.00036). Moreover, hypervariable MUC2 minisatellites were analyzed in matched blood and cancer tissue from 28 patients with gastric cancer and in 4 cases of MUC2-MS2, minisatellites were found to have undergone rearrangement. CONCLUSIONS/SIGNIFICANCE: Our observations suggest that the short rare MUC2-MS6 alleles could function as identifiers for risk of gastric cancer. Additionally, we suggest that minisatellite instability might be associated with MUC2 function in cancer cells

Latent class analysis of sexual health markers among men and women participating in a British probability sample survey.

BACKGROUND: Despite known associations between different aspects of sexual health, it is not clear how patterning of adverse sexual health varies across the general population. A better understanding should contribute towards more effective problem identification, prevention and treatment. We sought to identify different clusters of sexual health markers in a general population, along with their socio-demographic, health and lifestyle correlates. METHODS: Data came from men (N = 5113) and women (N = 7019) aged 16-74 who reported partnered sexual activity in the past year in Britain's third National Survey of Sexual Attitudes and Lifestyles, undertaken in 2010-2012. Latent class analysis used 18 self-reported variables relating to adverse sexual health outcomes (STI and unplanned pregnancy, non-volitional sex, and sexual function problems). Correlates included socio-demographics, early debut, alcohol/drug use, depression, and satisfaction/distress with sex life. RESULTS: Four classes were found for men (labelled Good Sexual Health 83%, Wary Risk-takers 4%, Unwary Risk-takers 4%, Sexual Function Problems 9%); six for women (Good Sexual Health 52%, Wary Risk-takers 2%, Unwary Risk-takers 7%, Low Interest 29%, Sexual Function Problems 7%, Highly Vulnerable 2%). Regardless of gender, Unwary Risk-takers reported lower STI/HIV risk perception and more condomless sex than Wary Risk-takers, but both were more likely to report STI diagnosis than Good Sexual Health classes. Highly Vulnerable women reported abortion, STIs and functional problems, and more sexual coercion than other women. Distinct socio-demographic profiles differentiated higher-risk classes from Good Sexual Health classes, with depression, alcohol/drug use, and early sexual debut widely-shared correlates of higher-risk classes. Females in higher-risk classes, and men with functional problems, evaluated their sex lives more negatively than those with Good Sexual Health. CONCLUSIONS: A greater prevalence and diversity of poor sexual health appears to exist among women than men in Britain, with more consistent effects on women's subjective sexual well-being. Shared health and lifestyle characteristics of higher-risk groups suggest widespread benefits of upstream interventions. Several groups could benefit from tailored interventions: men and women who underestimate their STI/HIV risk exposure, women distressed by low interest in sex, and women experiencing multiple adverse outcomes. Distinctive socio-demographic profiles should assist with identification and targeting