Zebrafish as a Model for Determining the Mechanisms Causing Deafness in MYH9-Related Disease

Approximately 1 in 500 infants are diagnosed with hearing loss, and about half of these cases can be traced to genetic defects. Several hundred genes have been implicated in deafness, including MYH9, which codes for the conventional motor protein non-muscle myosin IIA (NMIIA). Mutations in MYH9 lead to syndromic MYH9-related diseases, which include deafness as a variable symptom, as well as non-syndromic autosomal deafness DFNA17. Despite its identification as a deafness gene, the functions of MYH9 in ear development and hearing remain unknown. To study this role, we will use zebrafish as a model. Zebrafish offer significant advantages including established genetic tools, large clutch sizes, and transparent embryos that develop externally. In addition, non-muscle myosin genes, including MYH9, are highly conserved from zebrafish to human, and the development and function of the vertebrate ear is also highly conserved. Zebrafish share many inner ear structures with humans including the sensory hair cells and cilia that make vestibular and auditory function possible. We hypothesize that myh9 plays a significant role in the developing zebrafish ear as suggested by myh9 knockdown experiments, which resulted in the phenotype of an abnormal number of otoliths. Because otoliths nucleate from precursor particles distributed in the fluid of the otic vesicle by motile cilia, we further hypothesize that the otolith phenotype is caused by a cilia defect. Our work has demonstrated that NMIIA colocalizes with ciliary basal bodies in the otic vesicle, suggesting a possible role in establishing basal body orientation

Endozoochorous Spread of Nonnative Plant Species by White-Tailed Deer, Odocoileus Virginianus

Movement of plant seeds can be facilitated by endozoochory in white-tailed deer (Odocoileus virginianus) and elk (Cervus elaphus), but at rates that are unknown in natural systems. Spread of planted forage crops into wildlands, or nonnative invasive weeds into food plots would affect ecosystem processes and management costs. To address endozoochory, collections of fecal pellets from both ungulate species were done at the Current River Conservation Area in Southeastern Missouri. Randomly chosen individual pellets collected from nine food plots were planted in a greenhouse setting. After cold stratification of pellets (2°C at 15 days), pellets were either left whole or broken apart to simulate natural decomposition or weathering. Significantly more seeds germinated from pellets which were broken apart, indicating some decomposition may be an important factor for germination from fecal pellets. Data supports studies showing spread of plant species by deer and elk, both nonnative and native. Both species more successfully dispersed viable seed from nonnative species throughout the study; however, no native forage species germinated from elk pellets. Seeds of plants consumed by these wild ungulate species may contribute to same-season growth of invasive plant species, which will certainly result in novel seed banks via this dispersal mechanism

Generation of cloned transgenic pigs rich in omega-3 fatty acids

Meat products are generally low in omega-3 (n-3) fatty acids, which are beneficial to human health. We describe the generation of cloned pigs that express a humanized Caenorhabditis elegans gene, fat-1, encoding an n-3 fatty acid desaturase. The hfat-1 transgenic pigs produce high levels of n-3 fatty acids from n-6 analogs, and their tissues have a significantly reduced ratio of n-6/n-3 fatty acids (P < 0.001). © 2006 Nature Publishing Group

BSQ Conserved Charges in Relativistic Viscous Hydrodynamics solved with Smoothed Particle Hydrodynamics

Conservation laws play a crucial role in the modeling of heavy-ion collisions, including the those for charges such as baryon number (B), strangeness (S), and electric charge (Q). In this study, we present a new 2+1 relativistic viscous hydrodynamic code called CCAKE which uses the Smoothed Particle Hydrodynamics (SPH) formalism to locally conserve BSQ charges, together with an extended description of the multi-dimensional equation of state (EoS) obtained from lattice Quantum Chromodynamics. Initial conditions for CCAKE are supplied by the ICCING model, which samples gluon splittings into quark anti-quark pairs to generate the initial BSQ charge distributions. We study correlations between the BSQ charges and find that local BSQ fluctuations remain finite during the evolution, with corresponding chemical potentials of ($\sim100$--$200 \,\rm MeV$) at freeze-out. We find that our framework produces reasonable multiplicities of identified particles and that ICCING has no significant effect on the collective flow of all charged particles nor of identified particles when only one particle of interest is considered. However, we show specifically for Pb+Pb collisions at the LHC $\sqrt{s_{NN}}=5.02$ TeV that ICCING does have an effect on collective flow of identified particles if two particles of interest are considered.Comment: 51 pages, 28 Figure

Advancing Tau PET Quantification in Alzheimer Disease with Machine Learning: Introducing THETA, a Novel Tau Summary Measure

Alzheimer disease (AD) exhibits spatially heterogeneous 3- or 4-repeat tau deposition across participants. Our overall goal was to develop an automated method to quantify the heterogeneous burden of tau deposition into a single number that would be clinically useful. Methods: We used tau PET scans from 3 independent cohorts: the Mayo Clinic Study of Aging and Alzheimer's Disease Research Center (Mayo, n = 1,290), the Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 831), and the Open Access Series of Imaging Studies (OASIS-3, n = 430). A machine learning binary classification model was trained on Mayo data and validated on ADNI and OASIS-3 with the goal of predicting visual tau positivity (as determined by 3 raters following Food and Drug Administration criteria for 18F-flortaucipir). The machine learning model used region-specific SUV ratios scaled to cerebellar crus uptake. We estimated feature contributions based on an artificial intelligence-explainable method (Shapley additive explanations) and formulated a global tau summary measure, Tau Heterogeneity Evaluation in Alzheimer's Disease (THETA) score, using SUV ratios and Shapley additive explanations for each participant. We compared the performance of THETA with that of commonly used meta-regions of interest (ROIs) using the Mini-Mental State Examination, the Clinical Dementia Rating-Sum of Boxes, clinical diagnosis, and histopathologic staging. Results: The model achieved a balanced accuracy of 95% on the Mayo test set and at least 87% on the validation sets. It classified tau-positive and -negative participants with an AUC of 1.00, 0.96, and 0.94 on the Mayo, ADNI, and OASIS-3 cohorts, respectively. Across all cohorts, THETA showed a better correlation with the Mini-Mental State Examination and the Clinical Dementia Rating-Sum of Boxes (ρ ≥ 0.45, P < 0.05) than did meta-ROIs (ρ < 0.44, P < 0.05) and discriminated between participants who were cognitively unimpaired and those who had mild cognitive impairment with an effect size of 10.09, compared with an effect size of 3.08 for meta-ROIs. Conclusion: Our proposed approach identifies positive tau PET scans and provides a quantitative summary measure, THETA, that effectively captures heterogeneous tau deposition observed in AD. The application of THETA for quantifying tau PET in AD exhibits great potential

Reproductive abnormalities in mice expressing omega-3 fatty acid desaturase in their mammary glands

The Caenorhabditis elegans n-3 fatty acid desaturase (Fat-1) acts on a range of 18- and 20-carbon n-6 fatty acid substrates. Transgenic female mice expressing the Fat-1 gene under transcriptional control of the goat β-casein promoter produce milk phospholipids having elevated levels of n-3 polyunsaturated fatty acids (PUFA). However, females from this line were also observed to have impaired reproductive performance characterized by a smaller litter size (2.7 ± 0.6 vs. 7.2 ± 0.7; P < 0.05) than wildtype controls. While there is a close association between PUFA metabolism, prostaglandin biosynthesis, and fertility; reproductive problems in these mice were unanticipated given that the Fat-1 transgene is primarily expressed in the lactating mammary gland. Using multiple approaches it was found that Fat-1 mice have normal ovulation and fertilization rates; however fewer embryos were present in the uterus prior to implantation. Small litter size was also found to be partly attributable to a high incidence of post-implantation fetal resorptions. Embryo transfer experiments revealed that embryos developing from oocytes derived from transgenic ovaries had an increased rate of post-implantation resorption, regardless of the uterine genotype. Ovary transplantation between Fat-1 and C57BL/6 wildtype females revealed that non-ovarian factors also contributed to the smaller litter size phenotype. Finally, surgical removal of the mammary glands from juvenile Fat-1 mice increased the subsequent number of implantation sites per female, but did not lessen the high rate of post-implantation resorptions. In conclusion, we herein report on a system where an exogenous transgene expressed predominately in the mammary gland detrimentally affects female reproduction, suggesting that in certain circumstances the mammary gland may function as an endocrine regulator of reproductive performance

Potato (Solanum tuberosum L.) tuber ageing induces changes in the proteome and antioxidants associated with the sprouting pattern

During post-harvest storage, potato tubers age as they undergo an evolution of their physiological state influencing their sprouting pattern. In the present study, physiological and biochemical approaches were combined to provide new insights on potato (Solanum tuberosum L. cv. Désirée) tuber ageing. An increase in the physiological age index (PAI) value from 0.14 to 0.83 occurred during storage at 4 °C over 270 d. Using this reference frame, a proteomic approach was followed based on two-dimensional electrophoresis. In the experimental conditions of this study, a marked proteolysis of patatin occurred after the PAI reached a value of 0.6. In parallel, several glycolytic enzymes were up-regulated and cellular components influencing protein conformation and the response to stress were altered. The equilibrium between the 20S and 26S forms of the proteasome was modified, the 20S form that recycles oxidized proteins being up-regulated. Two proteins belonging to the cytoskeleton were also differentially expressed during ageing. As most of these changes are also observed in an oxidative stress context, an approach focused on antioxidant compounds and enzymes as well as oxidative damage on polyunsaturated fatty acids and proteins was conducted. All the changes observed during ageing seemed to allow the potato tubers to maintain their radical scavenging activity until the end of the storage period as no accumulation of oxidative damage was observed. These data are interpreted considering the impact of reactive oxygen species on the development and the behaviour of other plant systems undergoing ageing or senescence processes

Differential sensitivities of plant and animal mitochondria to the herbicide paraquat

Paraquat herbicide is toxic to animals, including humans, via putative toxicity mechanisms associated to microsomal and mitochondrial redox systems. It is also believed to act in plants by generating highly reactive oxygen free radicals from electrons of photosystem I on exposure to light. Paraquat also acts on non-chlorophyllous plant tissues, where mitochondria are candidate targets, as in animal tissues. Therefore, we compared the interaction of paraquat with the mitochondrial bioenergetics of potato tuber, using rat liver mitochondria as a reference. Paraquat depressed succinate-dependent mitochondrial Deltapsi, with simultaneous stimulation of state 4 O2 consumption. It also induced a slow time-dependent effect for respiration of succinate, exogenous NADH, and N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD)/ascorbate, which was more pronounced in rat than in potato mitochondria. However, with potato tuber mitochondria, the Deltapsi promoted by complex-I-dependent respiration is insensitive to this effect, indicating a protection against paraquat radical afforded by complex I redox activity, which was just the reverse of to the findings for rat liver mitochondria. The experimental set up with the tetraphenyl phosphonium (TPP+)-electrode also indivated production of the paraquat radical in mitochondria, also suggesting its accessibility to the outside space. The different activities of protective antioxidant agents can contribute to explain the different sensitivities of both kinds of mitochondria. Values of SOD activity and alpha-tocopherol detected in potato mitochondria were significantly higher than in rat mitochondria, which, in turn, revealed higher values of lipid peroxidation induced by paraquat. © 2001 John Wiley & Sons, Inc. J Biochem Mol Toxicol 15:322-330, 200