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Aggressive periodontitis (AgP) is a multifactorial disease with unknown association to the development and function of peripheral lymphocytes. The aim of this study was to elucidate a connection between the periodontal condition in 10 patients with AgP and their potential state of immunodeficiency. Based on full periodontal examination and radiographs, 10 females (ages 29.8±8.62 years) with established diagnosis of aggressive periodontitis were included in this study. Flow cytometric analysis revealed substantial reduction of switched memory B cells (IgM-, IgD-, CD27+) in 9 of 10 patients, whereas numbers of naïve, IgM+ memory, transitional, and activated B cells were normal. Serum levels of IgM, IgG, IgA, and subclasses were normal. In vitro differentiation of B cells showed normal amounts of secreted IgG and IgA at day 5 of culture. Our results indicate that lowered numbers of switched memory B cells - typically referred to the state of common variable immunodeficiency type I (Freiburg classification) - are unlikely to influence immunoglobulin serum levels or clinical anamnesis of our patients with AgP. Lipopolysaccharide-induced elevated levels of IL-1β and IL-8 and lowering of IL-4 are more likely to trigger a pro-inflammatory circle that attracts lymphocytes to local pockets of aggressive periodontitis. [ABSTRACT FROM AUTHOR]

Background. Although chick embryogenesis has been studied extensively, there has been growing interest in the investigation of skeletogenesis. In addition to improved poultry health and minimized economic loss, a greater understanding of skeletal abnormalities can also have implications for human medicine. True in vivo studies require noninvasive imaging techniques such as high-resolution microCT. However, the manual analysis of acquired images is both time consuming and subjective. Methods. We have developed a system for automated image segmentation that entails object-based image analysis followed by the classification of the extracted image objects. For image segmentation, a rule set was developed using Definiens image analysis software. The classification engine was implemented using the WEKA machine learning tool. Results. Our system reduces analysis time and observer bias while maintaining high accuracy. Applying the system to the quantification of long bone growth has allowed us to present the first true in ovo data for bone length growth recorded in the same chick embryos. Conclusions. The procedures developed represent an innovative approach for the automated segmentation, classification, quantification, and visualization of microCT images. MicroCT offers the possibility of performing longitudinal studies and thereby provides unique insights into the morpho- and embryogenesis of live chick embryos. [ABSTRACT FROM AUTHOR]

Objectives: This in vivo study compared the antibacterial effect of a self-etch adhesive with and without the brominated monomer 12-methacryloyloxydodecyl-pyridinium bromide (MDPB) on carious dentin after selective caries removal., Methods: 10 patients showing deep primary carious lesions at two posterior teeth without pulpal symptoms were included. At visit I, carious tissue was selectively removed and carious dentin was sampled with a sterile roundbur (Komet No. 18). One cavity was restored with composite (SDR, Ceram X; DENTSPLY DeTrey) using an MDPB-containing self-etch adhesive (Clearfil Protect Bond, Kuraray Noritake; PB). The other restoration served as a control (Clearfil SE Bond II, Kuraray Noritake; SE). At visit II after 8 weeks, carious dentin was sampled again. Bacterial growth in carious dentin was differentiated using microbial cultivation. Bacterial DNA from intact cells and cell-free DNA were quantified using 16S rRNA gene-based real-time PCR and the microbial community composition was analyzed by amplicon deep-sequencing. Wilcoxon test was applied for statistical analysis., Results: Both treatments showed a decrease of intact bacterial cells in carious dentin at visit II compared to visit I (PB: visit I: 1.1*10 6 , visit II: 1.7*10 5 (p = 0.03); SE: visit I: 1.1*10 7 , visit II = 2.4*10 5 (p = 0.002)). No statistically significant reduction of cell-free bacterial DNA was detected (PB: visit I: 6.1*10 5 , visit II: 1.6*10 5 (p = 0.08); SE: visit I: 5.3*10 5 , visit II: 2.9*10 5 (p = 0.10)). The decrease of intact cell-derived (p = 0.371) and cell-free DNA (p = 0.455) did not differ significantly between PB and SE. Lactobacillus was most abundant within the microbial community at both visits. Alpha-diversity was not affected by treatment and samples showed high intra- and interindividual diversity., Conclusion and Clinical Significance: Both self-etch adhesives have an antibacterial effect due to a decrease of bacterial DNA after selective caries removal. However, the results do not reveal any additional antibacterial effect by MDPB. The study is registered with the German Clinical Trials Register (DRKS00011532)., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

New phosphorous-containing lead structures against drought stress in crops interacting with RCAR/(PYR/PYL) receptor proteins were identified starting from in-depth SAR studies of related sulfonamide lead structures and protein docking studies. A converging 6-step synthesis via phosphinic chlorides and phosphono chloridates as key intermediates afforded envisaged tetrahydroquinolinyl phosphinamidates and phosphonamidates. Whilst tetrahydroquinolinyl phosphonamidates 13a,b exhibited low to moderate target affinities, the corresponding tetrahydroquinolinyl phosphinamidates 12a,b revealed confirmed strong affinities for RCAR/ (PYR/PYL) receptor proteins in Arabidopsis thaliana on the same level as essential plant hormone abscisic acid (ABA) combined with promising efficacy against drought stress in vivo (broad-acre crops wheat and canola)., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Aim of this study was to describe the characteristics of 1- to 6-year-old children who underwent general anesthesia (GA) in a German specialized pediatric dental institution between 2002 and 2011, and to evaluate the risk factors (age, migration background, nutritional status) for caries experience (dmf-s) in these children., Methods: A cross-sectional study with retrospective data collection was designed. Children who underwent comprehensive dental treatment under GA were enrolled in the study. The data were collected from patient records and included personal background: age, sex, dmf-s, nutritional status, reasons for GA and treatments provided. Mann-Whitney-U test, Chi-square tests, and linear regression modelling were applied for statistical analyses., Results: 652 children (median age: 3 years [IQR: 2-4], 41.6% female) were treated under GA between 2002 and 2011. Of these, 30.8% had migration background, 17.3% were underweight and 14.8% overweight. The median dmf-s was 28 (IQR: 19-43.5). Univariate, only age and migration showed a significant association with dmf-s (p < 0.01) up to the age of 5 years. In the linear regression analysis, this association of dmf-s with age (OR: 4.04/CI: 2.81-5.27; p < 0.01) and migration (OR: 4.26/CI: 0.89-7.62; p = 0.013) was confirmed. At the patient level, tooth extraction was the most chosen option in both time periods, however, more restorative approaches were taken between 2007 and 2011 including pulp therapy and the use of strip and stainless steel crowns compared to 2002-2006., Conclusions: Children aged 1-6 years treated under GA showed a high caries experience (dmf-s), whereby age as well as migration, but not BMI, were relevant risk factors. Although tooth extraction is the first choice in most cases in the first time period, more conservative procedures were performed in the second half of the follow-up period.

Objectives: This study investigated utilisation behaviour of the dentist compared to general practitioners (GP) and medical specialists in a German cohort under consideration of risk indicators for irregular dental attendance., Methods: Analysis of the results of the population-based LIFE-Adult-Study (Leipzig, Germany) was performed. A total of 2231 participants of the LIFE-Adult-Study were randomly selected to complete the relevant questionnaire, considering medical attendance behaviour. Associations of self-reported medical conditions, including dentaland medical attendance, sociodemographic factors, as well as self-reported general health status and oral health complaints were determined., Results: Of the 2231 participants who were included in the analysis, 14.2% reported not to have visited the dentist during the preceding 12 months. There could be shown a more selective utilisation behaviour towards medical services in smokers, men, low socioeconomic status and depression. Women were more likely to attend the dentist than men (OR = 1.8, CI = 1.4-2.3). Smoking (OR = 0.7, CI = 0.6-1.0), low socioeconomic status (OR = 0.6, CI = 0.4-0.8) and depression (OR = 0.6, CI = 0.4-0.9) were related to less dental attendance. Additionally, persons who do not visit the dentist regularly showed less attendance of the GP as well as medical specialists (p <0.05). Depression could be shown to be an additional risk factor for unfavourable utilisation behaviour towards the dentist., Conclusions: The results showed differences in dental and medical attendance, depending on different patient-related factors. Focusing attention towards high-risk groups might improve dental as well as medical utilisation behaviour, and therefore health status as well.

Background: Audience response systems allow to activate the audience and to receive a direct feedback of participants during lectures. Modern systems do not require any proprietary hardware anymore. Students can directly respond on their smartphone. Several studies reported about a high level of satisfaction of students when audience response systems are used, however their impact on learning success is still unclear., Methods: In order to evaluate the impact of an audience response system on the learning success we implemented the audience response system eduVote into a seminar series and performed a controlled crossover study on its impact on assessments. One hundred fifty-four students in nine groups were taught the same content. In four groups, eduVote was integrated for the first topic while five groups were taught this topic without the audience response systems. For a second topic, the groups were switched: Those groups who were taught before using eduVote were now taught without the audience response system and vice versa. We then analysed the impact of the audience response system on the students' performance in a summative assessment and specifically focused on questions dealing with the topic, for which the audience response system was used during teaching. We further assessed the students' perception on the use of eduVote using questionnaires., Results: In our controlled crossover study we could not confirm an impact of the audience response system eduVote on long-term persistence i.e. the students' performance in the summative assessment. Our evaluation revealed that students assessed the use of eduVote very positively, felt stronger engaged and better motivated to deal with the respective topics and would prefer their integration into additional courses as well. In particular we identified that students who feel uncomfortable with answering questions in front of others profit from the use of an audience response system during teaching., Conclusions: Audience response systems motivate and activate students and increase their engagement during classes. However, their impact on long-term persistence and summative assessments may be limited. Audience response systems, however, specifically allow activating students which cannot be reached by the traditional way of asking questions without such an anonymous tool.

Objectives: Selective caries removal in deep lesions means that soft carious affected dentin is left in the center of the cavity. Thus, using a tricalcium silicate cement Biodentine™ (Septodont, Paris) to seal the remaining soft dentin could have an antibacterial effect. This in-vivo study aimed to do quantitative and qualitative analyses on the bacterial composition within carious dentin before and after selective caries removal when applying Biodentine., Methods: Eleven patients with deep primary carious lesions at two posterior teeth without pulpal symptoms were included. Carious dentin was selectively removed and sampled with a sterile round bur (Komet No. 18) at baseline visit and eight weeks later. On the first visit, one lesion per patient, the remaining carious dentin was covered with Biodentine before adhesive restoration. Caries samples were investigated by microbial cultivation, molecular analysis and amplicon deep-sequencing of 16S rRNA genes. Bacterial DNA from intact cells was differentiated from cell-free DNA by DNase degradation prior to DNA isolation., Results: Reduction of cell-derived as well as cell-free bacterial DNA eight weeks after selective caries removal was significantly higher when Biodentine was applied. Lactobacillus was most abundant within the microbial community of deep carious dentin lesions at the first visit. After intervention with Biodentine application, Lactobacillus was diminished to a high degree. In general, the diversity in samples, as well as bacterial composition differed interindividually as well as intraindividually., Conclusion and Clinical Significance: Despite the heterogenous and diversity of microbial composition in patients, Biodentine can have beneficial antibacterial effects when applied to residual carious dentin, offering an alternative and safe treatment option. The study is officially registered with German Clinical Trials Register (DRKS00011067)., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: To investigate the genetic and epigenetic differences between human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) and HPV-negative OPSCC., Methods: Microarray data of HPV-positive and -negative OPSCC were retrieved from NCBI GEO datasets. Differentially expressed genes (DEGs) and differentially expressed miRNAs (DE-miRNAs) were identified by performing differential expression analysis. A functional enrichment analysis was performed to explore the biological processes and signaling pathways that DEGs and DE-miRNAs were involved in, respectively. A protein-protein interaction (PPI) network of DEGs was constructed to identify hub genes. miRNA-target network and miRNA-miRNA functional synergistic network were each constructed in order to identify risk-marker miRNAs. An miRNA-target-pathway network was constructed in order to explore the function of identified risk-marker miRNAs., Results: Microarray data from 3 datasets (GSE39366, GSE40774, and GSE55550) was included and analyzed. The PPI network identified 3 hub genes (VCAM1, UBD, and RPA2). MiR-107 and miR-142-3p were found to play the most significant role in both the DE-miRNA-target network as well as in the miRNA-miRNA functional synergistic network. MiR-107 was involved in HPV-induced tumorigenesis by targeting many genes (CAV1, CDK6, MYB, and SERPINB5) and regulating the p53 signaling pathway, the PI3K-Akt signaling pathway, and the autophagy pathway. In addition, miR-142-3p was implicated in HPV-induced tumorigenesis by targeting the PPFIA1 gene and regulating transcriptional dysregulation and other cancerous pathways., Conclusion: Three genes (VCAM1, UBD, and RPA2), two miRNAs (miR-107 and miR-142-3p), and four pathways (p53, PI3K-Akt, autophagy, and transcription dysregulation in cancer) were identified to play critical roles in distinguishing HPV-positive OPSCC from HPV-negative OPSCC., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The quality of forage plants is a crucial component of animal performance and a limiting factor in pasture based production systems. Key forage attributes that may require improvement include the sugar, lipid, protein and energy contents of the vegetative parts of these plants. The aim of this study was to evaluate the potential capacity of hyperspectral imaging (HSI) for non-invasive assessment of forage chemical composition. Hyperspectral image data within the visible near-infrared range into the extended near-infrared covering 550-1700 nm wavelengths were obtained from 185 accessions of ryegrass ( Lolium perenne ), which were also analysed for 13 forage quality attributes., Results: Medium to high predictive power was observed for the HSI models of total sugars (R 2 validation of 0.58), high molecular weight sugars (R 2 validation of 0.63), %Ash (R 2 validation of 0.50) and %Nitrogen (R 2 validation of 0.70). Significant HSI models with low R 2 validation of 0.1-0.5 were also obtained for low molecular weight sugars, NDF (%), ADF (%), DOMD (% DM), ME (MJ/kg DM), DM (%), Ca (mg/g) and OM (%). We also observed significant differences in the chemical composition between the pseudostems and leaves of the plants for each accession. The power of HSI for prediction of these differences within plants was also demonstrated., Conclusion: This study paves the way for the HSI technology to be used for in-field estimation of forage composition attributes in perennial ryegrass. This will allow more rapid genetic-based selection and breeding for a trait that is normally expensive to measure providing a cheaper, non-destructive and high throughput screening tool., Competing Interests: Competing interestsThe authors declare that they have no competing interests.

Microbial analyzes of carious dentine samples, especially in terms of interventions, represent a challenge due to difficulties in carious dentine sampling particularly with small bacterial DNA contents. Therefore, information about the quantitative reduction of bacterial DNA as well as microbial shifts and differences in diversity correlating with treatment interventions are scarce. In this study, carious dentine samples were collected in a first step in the course of a selective caries excavation at two different deep dentine caries lesions in three patients. Second, after selective caries excavation and sampling of carious dentine, an intervention was performed by applying dental materials onto the remaining carious dentine followed by a restoration of the study teeth with composite fillings. After 8 weeks, remaining carious dentine was sampled and analyzed as described above. The microbial community before and after therapy was analyzed by conventional culture compared to bacterial DNA analyses using 16S rRNA gene based real-time PCR and terminal restriction fragment length polymorphism (T-RFLP) for fingerprinting community changes within carious dentine samples. An ultra-pure workflow allowed the valid comparison of even small carious dentine samples with low DNA contents and the differentiation between intact cell-derived and cell-free bacterial DNA. Intra- and inter-subject related differences in the bacterial DNA content and its composition in deep dentine caries were determined considering the first visits. The ratio of cell-free bacterial DNA and DNA from intact cells decreased in two of three subjects included in the current study from visit 1 to visit 2 with the test substance (1:200 to 1:17) and the control substance (1:82 to 1:7). T-RFLP revealed changes in the bacterial diversity and composition shifts after treatment as well as between cell-free bacterial DNA and DNA derived from intact cells. The approach of differentiation and quantification of cell-free and intact cell-derived bacterial DNA is reasonable within the investigation of carious dentine samples, especially when considering the effect of an intervention. T-RFLP is principally suitable for the analysis of microbial shifts within carious dentine samples., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: The aim of this in vitro study was to evaluate the ability of optical coherence tomography (OCT) to display calculus on root surfaces., Material and Methods: Ten teeth with calculus on the root surface were embedded in resin, omitting the root surface. A region of interest (ROI) was marked by small drill holes coronally and apically of the calculus and imaged by spectral-domain optical coherence tomography ([SD OCT], Telesto SP5, centre wavelength 1310 nm) and light microscopy (LM). To evaluate the impact of different fluids on calculus visualisation, using OCT, root surfaces were covered by a layer of NaCl and blood and displayed by OCT. Subsequently, teeth were completely covered with resin and sectioned for histological evaluation. Within the ROI, lengths of root surface and calculus were measured by LM and OCT, and the ratio [%] was calculated. In addition, at three sites of each ROI, agreement of presence and length of calculus was evaluated. Both methods were compared using Pearson's correlation., Results: Regarding the presence of calculus, agreement between LM and OCT was strong (κ i  = 0.783, p = 0.033), and measurements regarding the length of the calculus were strongly correlated (r i >0.906; p i <0.001). However, the values differed for dry (p = 0.023) and NaCl-covered root surfaces (p = 0.035)., Conclusion: Calculus on the root surface can be displayed by SD-OCT, which therefore may be suited as imaging technology for subgingival calculus in periodontal pockets., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Ataxin-3 is a deubiquitinating enzyme and the affected protein in the neurodegenerative disorder Machado-Joseph disease (MJD). The ATXN3 gene is alternatively spliced, resulting in protein isoforms that differ in the number of ubiquitin-interacting motifs. Additionally, nonsynonymous SNPs in ATXN3 cause amino acid changes in ataxin-3, and one of these polymorphisms introduces a premature stop codon in one isoform. Here, we examined the effects of different ataxin-3 isoforms and of the premature stop codon on ataxin-3's physiological function and on main disease mechanisms. At the physiological level, we show that alternative splicing and the premature stop codon alter ataxin-3 stability and that ataxin-3 isoforms differ in their enzymatic deubiquitination activity, subcellular distribution, and interaction with other proteins. At the pathological level, we found that the expansion of the polyglutamine repeat leads to a stabilization of ataxin-3 and that ataxin-3 isoforms differ in their aggregation properties. Interestingly, we observed a functional interaction between normal and polyglutamine-expanded ATXN3 allelic variants. We found that interactions between different ATXN3 allelic variants modify the physiological and pathophysiological properties of ataxin-3. Our findings indicate that alternative splicing and interactions between different ataxin-3 isoforms affect not only major aspects of ataxin-3 function but also MJD pathogenesis. Our results stress the importance of considering isoforms of disease-causing proteins and their interplay with the normal allelic variant as disease modifiers in MJD and autosomal-dominantly inherited diseases in general., (© 2019 Weishäupl et al.)

Objectives: To analyze bioinformatic datasets for detecting genetic and epigenetic mechanisms shared by chronic periodontitis (CP) and oral squamous cell carcinoma (OSCC)., Materials and Methods: Datasets from GEO and TCGA databases reporting mRNAs, miRNAs or methylation expression in human CP and OSCC tissues were analyzed. Differential expression, functional enrichment and protein-protein interaction (PPI) network analyses were performed. Differentially expressed miRNAs (DEmiRNAs) and genes (DEG) in CP and OSCC were determined. DEmiRNA-target and DEmiRNA-DEG networks were constructed. Directly and indirectly interacting cross-talk genes were screened, and their prediction accuracy and association with OSCC prognosis was determined., Results: 3 DE-miRNAs (miR-375, miR-3609 and miR-3652) expressed in both CP and OSCC critically regulated most DEGs. Among 12 directly interacting cross-talk genes, NCAPH was significantly related with the prognosis of OSCC. NR2F2 had highest differential expression in CP and OSCC. Among 4 cross-talk genes (FN1, MPPED1, NDEL1, and NR2F2) differentially expressed in CP, 3 (FN1, MPPED1, NDEL1) were also expressed in OSCC. Among 12 indirectly interacting cross-talk genes differentially expressed in OSCC, 3 genes (CDCA8, HIST1H3J, and RAD51) were significantly related to its prognosis. Significant pathways involved in CP and OSCC included: chemokine receptors, class I PI3K signaling events, epithelial-to-mesenchymal transition and signaling events by VEGFR1 and VEGFR2, EGF receptor (ErbB1)., Conclusion: Bioinformatic analysis of available datasets implicated 1 directly interacting cross-talk gene (NCAPH), 4 indirectly interacting cross-talk genes (NCAPH, NR2F2, FN1, and MPPED1) and 3 DE-miRNAs (hsa-miR-375, miR-3609 and miR-3652) as shared genetic and epigenetic expression patterns between CP and OSCC., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: Recent literature reveals worse periodontal health condition in ankylosing spondylitis (AS). However, roles of AS-related parameters, periodontal condition, and their association appear unclear. This cross-sectional study aimed at investigating dental and periodontal health as well as potentially periodontal pathogenic bacteria in patients with AS compared to healthy control subjects (HC)., Methods: Dental examination comprised dental findings (DMF-T), periodontal probing depth (PPD), bleeding on probing, clinical attachment loss (CAL), papillary bleeding index, and microbiological analysis based on polymerase chain reaction of selected potentially periodontal pathogenic bacteria. Classification of periodontitis severity was based on PPD and/or CAL and divided into no/mild, moderate, and severe periodontitis., Results: 52 participants with AS and 52 HC were included. 96% of the AS group and 75% of HC had moderate to severe periodontitis (moderate: AS = 26, HC = 34; severe: AS = 23, HC = 5; p < 0.01). Furthermore, a higher number of decayed teeth (D-T) were found in AS compared to HC (p = 0.02). A significant difference between AS und HC was detected for the prevalences of Parvimonas micra (AS = 92%, HC = 71%; p = 0.01), Eubacterium nodatum (AS = 35%, HC = 17%; p = 0.05), and Eikenella corrodens (AS = 96%, HC = 77%; p = 0.01). Bath Ankylosing Spondylitis Metrology Index (BASMI) and disease duration showed significant associations to PPD and CAL (p < 0.01)., Conclusion: Patients with AS show worse dental and periodontal conditions compared to HC. Thereby, prevalence of bacteria related to insufficient oral hygiene was higher in AS. BASMI and duration of AS affect periodontal burden. Accordingly, particular attention considering dental care and oral hygiene in AS patients seems to be reasonable.

Background: The aim of this randomized clinical study was to detect the effect of an instruction within a group using oscillating-rotating (OR), sonic-active (SA), or manual toothbrushes (MTB) in young, oral healthy adults., Methods: One hundred fifty participants were randomly assigned into six groups (n = 25): with (OR-I, SA-I, MTB-I) and without instruction (OR-NI, SA-NI, MTB-NI). Participants in I subgroups received one standardized instruction of the toothbrush system. At baseline (t0), after 2 (t1), 4 (t2), and 12 weeks (t3), plaque indices including modified Quigley-Hein Index (QHI) and Marginal Plaque Index (MPI) as well as inflammation indices including Papilla Bleeding Index (PBI) and Gingival Index (GI) were assessed. Kruskal-Wallis test, Friedman test, and chi-square or Fisher's exact test (p < 0.05) were used for statistical analysis., Results: One hundred thirty-one participants completed the follow-up and were analyzed: OR-I = 21, OR-NI = 22, SA-I = 22, SA-NI = 22, MTB-I = 22, and MTB-NI = 22. Within groups between t0 and t3, OR and SA systems showed a significant plaque reduction, irrespective of instruction (p i  < 0.05). In MTB-I and in SA-NI subgroups, a reduction of GI was detected, while an improvement in PBI within SA-I was found (p i  < 0.05). Thereby, after 12 weeks, gingival inflammation and plaque indices were comparable between all subgroups (p i  > 0.05). Irrespective of the toothbrush system used, only QHI was positively influenced by instruction (p < 0.01)., Conclusion: The used toothbrush as well as the presence or absence of a single brush-specific instruction has no influence on plaque removal and reduction of gingival inflammation in young, oral healthy adults in an observation period of 12 weeks., Clinical Relevance: A single instruction might bring no benefit in this patient group, independently of the used toothbrush system.

Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder caused by a CAG expansion in the ATXN3 gene leading to a polyglutamine expansion in the ataxin-3 protein. The nuclear presence and aggregation of expanded ataxin-3 are critical steps in disease pathogenesis. To identify novel therapeutic targets, we investigated the nucleocytoplasmic transport system by screening a collection of importins and exportins that potentially modulate this nuclear localization. Using cell, Drosophila , and mouse models, we focused on three transport proteins, namely, CRM1, IPO13, KPNA3, and their respective Drosophila orthologs Emb, Cdm, and Kap-α3. While overexpression of CRM1/Emb demonstrated positive effects in Drosophila , KPNA3/Kap-α3 emerged as the most promising target, as knockdown via multiple RNAi lines demonstrated its ability to shuttle both truncated and full-length expanded ataxin-3, rescue neurodegeneration, restore photoreceptor formation, and reduce aggregation. Furthermore, KPNA3 knockout in SCA3 mice resulted in an amelioration of molecular and behavioral disturbances such as total activity, anxiety, and gait. Since KPNA3 is known to function as an import protein and recognize nuclear localization signals (NLSs), this work unites ataxin-3 structure to the nuclear pore machinery and provides a link between karyopherins, NLS signals, and polyglutamine disease, as well as demonstrates that KPNA3 is a key player in the pathogenesis of SCA3., Competing Interests: The authors declare no conflict of interest.

Key Message: Genomic prediction models for multi-year dry matter yield, via genotyping-by-sequencing in a composite training set, demonstrate potential for genetic gain improvement through within-half sibling family selection. Perennial ryegrass (Lolium perenne L.) is a key source of nutrition for ruminant livestock in temperate environments worldwide. Higher seasonal and annual yield of herbage dry matter (DMY) is a principal breeding objective but the historical realised rate of genetic gain for DMY is modest. Genomic selection was investigated as a tool to enhance the rate of genetic gain. Genotyping-by-sequencing (GBS) was undertaken in a multi-population (MP) training set of five populations, phenotyped as half-sibling (HS) families in five environments over 2 years for mean herbage accumulation (HA), a measure of DMY potential. GBS using the ApeKI enzyme yielded 1.02 million single-nucleotide polymorphism (SNP) markers from a training set of n = 517. MP-based genomic prediction models for HA were effective in all five populations, cross-validation-predictive ability (PA) ranging from 0.07 to 0.43, by trait and target population, and 0.40-0.52 for days-to-heading. Best linear unbiased predictor (BLUP)-based prediction methods, including GBLUP with either a standard or a recently developed (KGD) relatedness estimation, were marginally superior or equal to ridge regression and random forest computational approaches. PA was principally an outcome of SNP modelling genetic relationships between training and validation sets, which may limit application for long-term genomic selection, due to PA decay. However, simulation using data from the training experiment indicated a twofold increase in genetic gain for HA, when applying a prediction model with moderate PA in a single selection cycle, by combining among-HS family selection, based on phenotype, with within-HS family selection using genomic prediction.

Deubiquitinating enzymes (DUBs) play important roles in a variety of cellular processes, including regulation of protein homeostasis. The DUB ataxin-3 is an enzyme implicated in protein quality control mechanisms. In the neurodegenerative disease spinocerebellar ataxia type 3 (SCA3), ataxin-3 contains an expanded polyglutamine (polyQ) stretch that leads to aggregation of the protein and neuronal dysfunction. Increasing the understanding of ataxin-3 protein interaction partners could help to elucidate disease mechanisms. Hence, we analyzed the repertoire of proteins interacting with normal and polyQ expanded ataxin-3 by mass spectrometry. This showed that both normal and polyQ expanded ataxin-3 interacted with components of the protein quality control system and mitochondria. Five proteins showed increased interaction with polyQ expanded ataxin-3 relative to normal and three of these were mitochondrial proteins. The analyses underline the role of ataxin-3 in ubiquitin biology and point towards a role in mitochondrial biology., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Animal models are an important tool to study the pathophysiology of Machado-Joseph Disease (MJD). So far, animal models using simple organisms (like the round worm Caenorhabditis elegans or the fruit fly drosophila) but also mammalian models (mouse and even a non-human primate model) have been generated to study MJD. While simple organisms made an important contribution to the identification of pathophysiological mechanisms in MJD and were further used for modifier and screening purposes, mammalian models recapitulate major disease features of MJD in humans and are therefore a highly valuable tool for e.g. the validation of mechanisms or for pre-clinical validation of treatment approaches. Here we give an overview about the strategies which were used to model MJD and about the different models generated so far. We further highlight advantages of specific model organisms and describe the new findings which were made employing these animal models of MJD.

Purpose: Breast cancer patients have the option to choose a breast reconstruction after mastectomy. A range of studies have postulated that patients' individually appraised significance of their breast is an important factor in the decision for or against breast reconstruction. This study explored the individually perceived significance of the breast among patients with and without breast reconstruction and its correlation with postoperative satisfaction., Methods: Ten patients without breast reconstruction, and ten patients with immediate breast reconstruction after mastectomy participated in the study. The perceived importance of the breast and the pre-and postoperative esthetic satisfaction of the patients were obtained using an 11-point Likert scale. Qualitative interviews explored patients' views on the meaning of their breast and their experience after surgery., Results: Patients who had decided for breast reconstruction rated the importance of their breast for femininity (p = 0.004) and attractiveness (p = 0.037) significantly higher than patients without reconstruction. The qualitative data provide evidence that the breast of a woman fulfills a variety of intrapsychic and interactional functions. Difficulties in integrating the reconstructed breast into the body image were reported. A high importance of the breast correlated significantly with a decrease in satisfaction with the breast after reconstruction (rs = -0.652, p = 0.041)., Conclusions: Patients who found their breast to be highly important were more likely to decide for a reconstruction. Mastectomy has an impact on various psychosocial variables but impairments may also occur after breast reconstruction. Patients reporting a high significance of their breast showed the greatest decrease in satisfaction with their breast after reconstruction.

Objectives: This study aims to reveal regulatory network of lncRNAs-miRNAs-mRNAs in oral squamous cell carcinoma (OSCC) through gene expression data., Material and Methods: Differentially expressed lncRNAs, miRNAs and mRNAs (cut-off: False discovery rate (FDR)<0.05 and |fold change|>1.5) were unveiled by package edgeR of R. Cox regression analysis was performed to screen prognostic factors in OSCC related with overall survival (OS) and relapse-free survival (RFS). Protein-protein interaction (PPI) network was constructed for differentially expressed mRNAs using BioGRID, HPRD and DIP. Key hub genes were identified from top 100 differentially expressed mRNAs ranked by betweenness centrality using recursive feature elimination. LncRNA-miRNA and miRNA-mRNA regulatory network were constructed and combined into ceRNAs regulatory network. Gene ontology biological terms and Kyoto Encyclopedia of Genes and Genomes pathways were identified using Fisher's exact test., Results: A total of 929 differentially expressed mRNAs, 23 differentially expressed lncRNAs and 29 differentially expressed miRNAs were identified. 59 mRNAs, 6 miRNAs (hsa-mir-133a-1, hsa-mir-1-2, hsa-mir-486, hsa-mir-135b, hsa-mir-196b, hsa-mir-193b) and 6 lncRNAs (C10orf91, C2orf48, SFTA1P, FLJ41941,PART1,TTTY14) were related with OS; and 52 mRNAs, 4 miRNAs (hsa-mir-133a-1, hsa-mir-135b, hsa-mir-196b, hsa-mir-193b) and 2 lncRNAs (PART1, TTTY14) were associated with RFS. A support vector machine (SVM) classifier containing 37 key hub genes was obtained. A ceRNA regulatory network containing 417 nodes and 696 edges was constructed. ECM-receptor interaction, cytokine-cytokine receptor interaction, focal adhesion, arachidonic acid metabolism, and p53 signaling pathway were significantly enriched in the network., Conclusion: These findings uncover the pathogenesis of OSCC and might provide potential therapeutic targets., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

68 Ga-Glu-urea-Lys-(Ahx)-HBED-CC ( 68 Ga-PSMA-11) represents a successful radiopharmaceutical for PET/CT imaging of prostate cancer. Further optimization of the tumor-to-background contrast might significantly enhance the sensitivity of PET/CT imaging and the probability of detecting recurrent prostate cancer at low PSA values. This study describes the advantage of histidine (H)/glutamic acid (E) and tryptophan (W)/glutamic acid (E) containing linkers on the pharmacokinetic properties of 68 Ga-PSMA-11. The tracers were obtained by a combination of standard Fmoc-based solid-phase synthesis and copper(I)-catalyzed azide-alkyne cycloaddition. Their 68 Ga complexes were compared to the clinical reference 68 Ga-PSMA-11 with respect to cell binding, effective internalization, and tumor targeting properties in LNCaP-bearing balb/c nu/nu mice. The introduction of (HE) i (i = 1-3) or (WE) i (i = 1-3) into PSMA-11 resulted in a significantly changed biodistribution profile. The uptake values in kidneys, spleen, liver, and other background organs were reduced for (HE) 3 while the tumor uptake was not affected. For (HE) 1 the tumor uptake was significantly increased. The introduction of tryptophan-containing linkers also modulated the organ distribution profile. The results clearly indicate that histidine is of essential impact in order to improve the tumor-to-organ contrast. Hence, the histidine/glutamic acid linker modifications considerably improved the pharmacokinetic properties of 68 Ga-PSMA-11 leading to a reduced uptake in dose limiting organs and a significantly enhanced tumor-to-background contrast. Glu-urea-Lys-(HE) 3 -HBED-CC represents a promising 68 Ga complex ligand for PET/CT-imaging of prostate cancer.