Microphthalmia in Texel Sheep Is Associated with a Missense Mutation in the Paired-Like Homeodomain 3 (PITX3) Gene

Microphthalmia in sheep is an autosomal recessive inherited congenital anomaly found within the Texel breed. It is characterized by extremely small or absent eyes and affected lambs are absolutely blind. For the first time, we use a genome-wide ovine SNP array for positional cloning of a Mendelian trait in sheep. Genotyping 23 cases and 23 controls using Illumina's OvineSNP50 BeadChip allowed us to localize the causative mutation for microphthalmia to a 2.4 Mb interval on sheep chromosome 22 by association and homozygosity mapping. The PITX3 gene is located within this interval and encodes a homeodomain-containing transcription factor involved in vertebrate lens formation. An abnormal development of the lens vesicle was shown to be the primary event in ovine microphthalmia. Therefore, we considered PITX3 a positional and functional candidate gene. An ovine BAC clone was sequenced, and after full-length cDNA cloning the PITX3 gene was annotated. Here we show that the ovine microphthalmia phenotype is perfectly associated with a missense mutation (c.338G>C, p.R113P) in the evolutionary conserved homeodomain of PITX3. Selection against this candidate causative mutation can now be used to eliminate microphthalmia from Texel sheep in production systems. Furthermore, the identification of a naturally occurring PITX3 mutation offers the opportunity to use the Texel as a genetically characterized large animal model for human microphthalmia

Long-term experience of the thermo-active ground source system at the metro station Taborstrasse in Vienna

Four of the stations newly opened during the underground extension of the U2 line in Vienna in 2008 have been covering a large part of their heating and cooling needs for now almost one and a half decades by using geothermal energy, which is generated by means of energy diaphragm walls, energy piles and energy bottom slabs of the station buildings. As this was the first infrastructure building of this type and scale worldwide at the time of construction, one of the diaphragm walls of the Taborstraße station was equipped with numerous sensors to obtain data sets for the thermo-mechanical long-term behavior of these wall elements for the very first time. Continuous measurements with automatic data recording were initially carried out from April 2008 until May 2011. In October 2020, the measurements were resumed with the existing sensors, this time manually and once a month, in order to carry out a long-term comparison of the measurement data and to create a basis for assessing the effects of the geothermal operation on its structural components. This paper gives an overview of the Taborstraße station with a focus on the thermally activated geostructures and their instrumentation. A comparison of the recorded generated energy with the predicted heating and cooling demand is discussed in the context of the energy data. In addition, the temperature and the strain behavior of the observed energy diaphragm wall is discussed based on the measurement data collected over a period of around 14 years of operational experience

A Missense Mutation in the SERPINH1 Gene in Dachshunds with Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a hereditary disease occurring in humans and dogs. It is characterized by extremely fragile bones and teeth. Most human and some canine OI cases are caused by mutations in the COL1A1 and COL1A2 genes encoding the subunits of collagen I. Recently, mutations in the CRTAP and LEPRE1 genes were found to cause some rare forms of human OI. Many OI cases exist where the causative mutation has not yet been found. We investigated Dachshunds with an autosomal recessive form of OI. Genotyping only five affected dogs on the 50 k canine SNP chip allowed us to localize the causative mutation to a 5.82 Mb interval on chromosome 21 by homozygosity mapping. Haplotype analysis of five additional carriers narrowed the interval further down to 4.74 Mb. The SERPINH1 gene is located within this interval and encodes an essential chaperone involved in the correct folding of the collagen triple helix. Therefore, we considered SERPINH1 a positional and functional candidate gene and performed mutation analysis in affected and control Dachshunds. A missense mutation (c.977C>T, p.L326P) located in an evolutionary conserved domain was perfectly associated with the OI phenotype. We thus have identified a candidate causative mutation for OI in Dachshunds and identified a fifth OI gene

Prospective longitudinal study of immune checkpoint molecule (ICM) expression in immune cell subsets during curative conventional therapy of head and neck squamous cell carcinoma (HNSCC)

Programmed-death-1 (PD1) antibodies are approved for recurrent and metastatic head and neck squamous cell carcinoma. Multiple drugs targeting costimulatory and coinhibitory immune checkpoint molecules (ICM) have been discovered. However, it remains unknown how these ICM are affected by curative conventional therapy on different immune cell subsets during the course of treatment. In the prospective noninterventional clinical study titled “Immune Response Evaluation to Curative conventional Therapy” (NCT03053661), 22 patients were prospectively enrolled. Blood samples were drawn at defined time points throughout curative conventional treatment and follow-up. Immune cells (IC) from the different time points were assessed by multicolor flow cytometry. The following ICM were measured by flow cytometry: PD1, CTLA4, BTLA, CD137, CD27, GITR, OX40, LAG3 and TIM3. Dynamics of ICM expression were assessed using nonparametric paired samples tests. Significant changes were noted for PD1, BTLA and CD27 on multiple IC types during or after radiotherapy. Nonsignificant trends for increased expression of OX40 and GITR from baseline until the end of RT were observed on CD4 T cells and CD4+ CD39+ T cells. In patients with samples at recurrence of disease, a nonsignificant increase of TIM3 and LAG3 positive CD4+ CD39+ T cells was evident, accompanied by an increase of double positive cells for TIM3/LAG3. Potential future targets to be combined with RT in the conventional treatment and anti-PD1/PD-L could be BTLA agonists, or agonistic antibodies to costimulatory ICM like CD137, OX40 or GITR. The combination of cetuximab with CD27 agonistic antibodies enhancing ADCC or the targeting of TIM3/LAG3 may be another promising strategy

Protein-based oncopanel as addition to target sequencing in head and neck squamous cell carcinoma to individualize treatment decisions

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of cancers and patients have limited therapy options if primary treatment fails. Therefore, additional information about the biology of the tumor is essential. Here we performed a feasibility study of concurrently applying two precision diagnostic tools in a consecutive series of HNSCC patients. We analyzed tumor samples of 31 patients using a genomic (oncomine) and a proteomic, immunohistochemical approach (oncopanel) and compared the result, also in the focus on their overlapping therapeutical targets. We found no strong correlation between the two approaches and observed a higher proportion of marker expression for the immunohistochemical panel. However, both panels show in our HNSCC cohort distinct patterns with druggable targets. The data suggest that both approaches complement one another and can be applied side-by-side to identify the best targets for the development of individual treatment options for HNSCC patients

Non-canonical BIM-regulated energy metabolism determines drug-induced liver necrosis.

Paracetamol (acetaminophen, APAP) overdose severely damages mitochondria and triggers several apoptotic processes in hepatocytes, but the final outcome is fulminant necrotic cell death, resulting in acute liver failure and mortality. Here, we studied this switch of cell death modes and demonstrate a non-canonical role of the apoptosis-regulating BCL-2 homolog BIM/Bcl2l11 in promoting necrosis by regulating cellular bioenergetics. BIM deficiency enhanced total ATP production and shifted the bioenergetic profile towards glycolysis, resulting in persistent protection from APAP-induced liver injury. Modulation of glucose levels and deletion of Mitofusins confirmed that severe APAP toxicity occurs only in cells dependent on oxidative phosphorylation. Glycolytic hepatocytes maintained elevated ATP levels and reduced ROS, which enabled lysosomal recycling of damaged mitochondria by mitophagy. The present study highlights how metabolism and bioenergetics affect drug-induced liver toxicity, and identifies BIM as important regulator of glycolysis, mitochondrial respiration, and oxidative stress signaling

Mock galaxy redshift catalogues from simulations: implications for Pan-STARRS1

We describe a method for constructing mock galaxy catalogues which are well suited for use in conjunction with large photometric surveys. We use the semi-analytic galaxy formation model of Bower et al. implemented in the Millennium simulation. We apply our method to the specific case of the surveys soon to commence with PS1, the first of 4 telescopes planned for the Pan-STARRS system. PS1 has 5 photometric bands (grizy), and will carry out an all-sky 3pi survey and a medium deep survey (MDS) over 84 sq.deg. We calculate the expected magnitude limits for extended sources in the two surveys. We find that, after 3 years, the 3pi survey will have detected over 10^8 galaxies in all 5 bands, 10 million of which will lie at redshift z>0.9, while the MDS will have detected over 10^7 galaxies with 0.5 million lying at z>2. These numbers at least double if detection in the shallowest band, y is not required. We then evaluate the accuracy of photometric redshifts estimated using an off-the-shelf photo-z code. With the grizy bands alone it is possible to achieve an accuracy in the 3pi survey of Delta z/(1+z)~0.06 for 0.25<z<0.8, which could be reduced by about 15% using near infrared photometry from the UKIDDS survey, but would increase by about 25% for the deeper sample without the y band photometry. For the MDS an accuracy of Delta z/(1+z)~0.05 is achievable for 0.02<z<1.5 using grizy. A dramatic improvement in accuracy is possible by selecting only red galaxies. In this case, Delta z/(1+z)~0.02-0.04 is achievable for ~100 million galaxies at 0.4<z<1.1 in the 3pi survey and for 30 million galaxies in the MDS at 0.4<z<2. We investigate the effect of using photo-z in the estimate of the baryonic acoustic oscillation scale. We find that PS1 will achieve a similar accuracy in this estimate as a spectroscopic survey of 20 million galaxies.Comment: 23 pages, 18 figures, accepted by MNRA

Peripheral cytokine levels differ by HPV status and change treatment-dependently in patients with head and neck squamous cell carcinoma

Cytokines and immune mediators play an important role in the communication between immune cells guiding their response to infectious diseases or cancer. In this study, a comprehensive longitudinal analysis of serum cytokines and immune mediators in head and neck squamous cell carcinoma (HNSCC) patients was performed. In a prospective, non-interventional, longitudinal study, blood samples from 22 HNSCC patients were taken at defined time points (TP) before, during, and every 3 months after completion of (chemo)radio)therapy (CRT/RT) until 12 months after treatment. Serum concentrations of 17 cytokines/immune mediators and High-Mobility-Group-Protein B1 (HMGB1) were measured by fluorescent bead array and ELISA. Concentrations of sFas were significantly elevated during and after CRT/RT, whereas perforin levels were significantly decreased after CRT/RT. Levels of MIP-1β and Granzyme B differed significantly during CRT/RT by HPV status. Increased HMGB1 levels were observed at recurrence, accompanied by high levels of IL-4 and IL-10. The sFas increase and simultaneous perforin decrease may indicate an impaired immune cell function during adjuvant radiotherapy. Increased levels of pro-inflammatory cytokines in HPV+ compared to HPV− patients seem to reflect the elevated immunogenicity of HPV-positive tumors. High levels of HMGB1 and anti-inflammatory cytokines at recurrence may be interpreted as a sign of immune evasion

A specific case in the classification of woods by FTIR and chemometric: discrimination of Fagales from Malpighiales

Fourier transform infrared (FTIR) spectroscopic data was used to classify wood samples from nine species within the Fagales and Malpighiales using a range of multivariate statistical methods. Taxonomic classification of the family Fagaceae and Betulaceae from Angiosperm Phylogenetic System Classification (APG II System) was successfully performed using supervised pattern recognition techniques. A methodology for wood sample discrimination was developed using both sapwood and heartwood samples. Ten and eight biomarkers emerged from the dataset to discriminate order and family, respectively. In the species studied FTIR in combination with multivariate analysis highlighted significant chemical differences in hemicelluloses, cellulose and guaiacyl (lignin) and shows promise as a suitable approach for wood sample classification