FARS2 mutations presenting with pure spastic paraplegia and lesions of the dentate nuclei.

Mutations in FARS2, the gene encoding the mitochondrial phenylalanine-tRNA synthetase (mtPheRS), have been linked to a range of phenotypes including epileptic encephalopathy, developmental delay, and motor dysfunction. We report a 9-year-old boy with novel compound heterozygous variants of FARS2, presenting with a pure spastic paraplegia syndrome associated with bilateral signal abnormalities in the dentate nuclei. Exome sequencing identified a paternal nonsense variant (Q216X) lacking the catalytic core and anticodon-binding regions, and a maternal missense variant (P136H) possessing partial enzymatic activity. This case confirms and expands the phenotype related to FARS2 mutations with regards to clinical presentation and neuroimaging findings

Tumor-reactive immune cells protect against metastatic tumor and induce immunoediting of indolent but not quiescent tumor cells

Two major barriers to cancer immunotherapy include tumor-induced immune suppression mediated by myeloid-derived suppressor cells and poor immunogenicity of the tumor-expressing self-antigens. To overcome these barriers, we reprogrammed tumor-immune cell cross-talk by combined use of decitabine and adoptive immunotherapy, containing tumor-sensitized T cells and CD25+ NKT cells. Decitabine functioned to induce the expression of highly immunogenic cancer testis antigens in the tumor, while also reducing the frequency of myeloid-derived suppressor cells and the presence of CD25+ NKT cells rendered T cells, resistant to remaining myeloid-derived suppressor cells. This combinatorial therapy significantly prolonged survival of animals bearing metastatic tumor cells. Adoptive immunotherapy also induced tumor immunoediting, resulting in tumor escape and associated disease-related mortality. To identify a tumor target that is incapable of escape from the immune response, we used dormant tumor cells. We used Adriamycin chemotherapy or radiation therapy, which simultaneously induce tumor cell death and tumor dormancy. Resultant dormant cells became refractory to additional doses of Adriamycin or radiation therapy, but they remained sensitive to tumor-reactive immune cells. Importantly, we discovered that dormant tumor cells contained indolent cells that expressed low levels of Ki67 and quiescent cells that were Ki67 negative. Whereas the former were prone to tumor immunoediting and escape, the latter did not demonstrate immunoediting. Our results suggest that immunotherapy could be highly effective against quiescent dormant tumor cells. The challenge is to develop combinatorial therapies that could establish a quiescent type of tumor dormancy, which would be the best target for immunotherapy

Vaccine Development for Nipah Virus Infection in Pigs

Nipah virus (NiV) causes a severe and often fatal neurological disease in humans. Whilst fruit bats are considered the natural reservoir, NiV also infects pigs and may cause an unapparent or mild disease. Direct pig-to-human transmission was responsible for the first and still most devastating NiV outbreaks in Malaysia and Singapore in 1998–99, with nearly 300 human cases and over 100 fatalities. Pigs can therefore play a key role in the epidemiology of NiV by acting as an “amplifying” host. The outbreak in Singapore ended with the prohibition of pig imports from Malaysia and the Malaysian outbreak was ended by culling 45% of the country's pig population with costs exceeding US$500 million. Despite the importance of NiV as an emerging disease with the potential for pandemic, no vaccines, or therapeutics are currently approved for human or livestock use. In this mini-review, we will discuss current knowledge of NiV infection in pigs; our ongoing work to develop a NiV vaccine for use in pigs; and the pig as a model to support human vaccine development

Small domain estimation of census coverage: A case study in Bayesian analysis of complex survey data

Many countries conduct a full census survey to report official population statistics. As no census survey ever achieves 100 per cent response rate, a post-enumeration survey (PES) is usually conducted and analysed to assess census coverage and produce official population estimates by geographic area and demographic attributes. Considering the usually small size of PES, direct estimation at the desired level of disaggregation is not feasible. Design-based estimation with sampling weight adjustment is a commonly used method but is difficult to implement when survey non-response patterns cannot be fully documented and population benchmarks are not available. We overcome these limitations with a fully model-based Bayesian approach applied to the New Zealand PES. Although theory for the Bayesian treatment of complex surveys has been described, published applications of individual level Bayesian models for complex survey data remain scarce. We provide such an application through a case study of the 2018 census and PES surveys. We implement a multilevel model that accounts for the complex design of PES. We then illustrate how mixed posterior predictive checking and cross-validation can assist with model building and model selection. Finally, we discuss potential methodological improvements to the model and potential solutions to mitigate dependence between the two surveys.Comment: 35 pages, 5 figures This is an author version of a paper accepted for publication in the Journal of Official Statistics. Once published by the Journal of Official Statistics use the Journal citation. This version includes supplementary material and corrected version of Figure

The Helioseismic and Magnetic Imager (HMI) Vector Magnetic Field Pipeline: Overview and Performance

The Helioseismic and Magnetic Imager (HMI) began near-continuous full-disk solar measurements on 1 May 2010 from the Solar Dynamics Observatory (SDO). An automated processing pipeline keeps pace with observations to produce observable quantities, including the photospheric vector magnetic field, from sequences of filtergrams. The primary 720s observables were released in mid 2010, including Stokes polarization parameters measured at six wavelengths as well as intensity, Doppler velocity, and the line-of-sight magnetic field. More advanced products, including the full vector magnetic field, are now available. Automatically identified HMI Active Region Patches (HARPs) track the location and shape of magnetic regions throughout their lifetime. The vector field is computed using the Very Fast Inversion of the Stokes Vector (VFISV) code optimized for the HMI pipeline; the remaining 180 degree azimuth ambiguity is resolved with the Minimum Energy (ME0) code. The Milne-Eddington inversion is performed on all full-disk HMI observations. The disambiguation, until recently run only on HARP regions, is now implemented for the full disk. Vector and scalar quantities in the patches are used to derive active region indices potentially useful for forecasting; the data maps and indices are collected in the SHARP data series, hmi.sharp_720s. Patches are provided in both CCD and heliographic coordinates. HMI provides continuous coverage of the vector field, but has modest spatial, spectral, and temporal resolution. Coupled with limitations of the analysis and interpretation techniques, effects of the orbital velocity, and instrument performance, the resulting measurements have a certain dynamic range and sensitivity and are subject to systematic errors and uncertainties that are characterized in this report.Comment: 42 pages, 19 figures, accepted to Solar Physic

The chromatin architectural proteins HMGD1 and H1 bind reciprocally and have opposite effects on chromatin structure and gene regulation

Background: Chromatin architectural proteins interact with nucleosomes to modulate chromatin accessibility and higher-order chromatin structure. While these proteins are almost certainly important for gene regulation they have been studied far less than the core histone proteins. Results: Here we describe the genomic distributions and functional roles of two chromatin architectural proteins: histone H1 and the high mobility group protein HMGD1 in Drosophila S2 cells. Using ChIP-seq, biochemical and gene specific approaches, we find that HMGD1 binds to highly accessible regulatory chromatin and active promoters. In contrast, H1 is primarily associated with heterochromatic regions marked with repressive histone marks. We find that the ratio of HMGD1 to H1 binding is a better predictor of gene activity than either protein by itself, which suggests that reciprocal binding between these proteins is important for gene regulation. Using knockdown experiments, we show that HMGD1 and H1 affect the occupancy of the other protein, change nucleosome repeat length and modulate gene expression. Conclusion: Collectively, our data suggest that dynamic and mutually exclusive binding of H1 and HMGD1 to nucleosomes and their linker sequences may control the fluid chromatin structure that is required for transcriptional regulation. This study provides a framework to further study the interplay between chromatin architectural proteins and epigenetics in gene regulation

\u3cem\u3eFARS2\u3c/em\u3e Mutations Presenting with Pure Spastic Paraplegia and Lesions of the Dentate Nuclei

Mutations in FARS2, the gene encoding the mitochondrial phenylalanine‐tRNA synthetase (mtPheRS), have been linked to a range of phenotypes including epileptic encephalopathy, developmental delay, and motor dysfunction. We report a 9‐year‐old boy with novel compound heterozygous variants of FARS2, presenting with a pure spastic paraplegia syndrome associated with bilateral signal abnormalities in the dentate nuclei. Exome sequencing identified a paternal nonsense variant (Q216X) lacking the catalytic core and anticodon‐binding regions, and a maternal missense variant (P136H) possessing partial enzymatic activity. This case confirms and expands the phenotype related to FARS mutations with regards to clinical presentation and neuroimaging findings

The effect of ring size on the selective carboxylation of cycloalkene oxides

Carbon dioxide utilisation technology can contribute to the reduction of atmospheric CO2 levels both through its sequestration from flue gases and indirectly by relieving pressure on conventional feedstocks in chemical manufacturing. A promising approach is to employ CO2 to produce valuable cyclic carbonates (CCs) in reaction with suitable epoxides. This also has the advantage that carbon dioxide replaces toxic and hazardous reactants such as phosgene. In earlier work we have investigated the synthesis of epoxides from cycloalkenes using supported gold and gold–palladium nanoparticles as catalysts and oxygen from air as the oxidant under solvent free conditions. A strong dependence of epoxide selectivity on ring size was observed with C5 < C6 < C7 ≪ C8. In this study we extend this work to the investigation of cycloaddition of CO2 to different cycloalkene oxides with the ultimate aim of designing a process in which both epoxidation of an alkene and incorporation of CO2 could be achieved in a single process. However, we have found the opposite trend for the selectivity to carbonates: smaller ring cycloalkene oxides giving the highest carbonate selectivities while large rings do not yield CCs at all. The product distributions suggest that an alternative ring opening of the epoxides to yield alcohols and ketones is preferred under all the experimental conditions explored for larger ring systems. Additionally, the mechanism of the CC synthesis using a quaternary ammonium salt and ZnBr2 as the catalyst system was investigated using DFT methods. The results of the calculations support the experimental findings

Animals can assign novel odours to a known category

The ability to identify a novel stimulus as a member of a known category allows an organism torespond appropriately towards it. Categorisation is thus a fundamental component of cognition andan essential tool for processing and responding to unknown stimuli. Therefore, one might expectto observe it throughout the animal kingdom and across sensory domains. There is much evidenceof visual categorisation in non-human animals, but we currently know little about this process inother modalities. In this experiment, we investigated categorisation in the olfactory domain. Dogswere trained to discriminate between 40 odours; the presence or absence of accelerants formed thecategorical rule. Those in the experimental group were rewarded for responding to substrates withaccelerants (either burnt or un-burnt) and inhibit responses to the same substrates (either burnt or unburnt)without accelerants (S+ counterbalanced). The pseudocategory control group was trained onthe same stimuli without the categorical rule. The experimental group learned the discrimination andanimals were able to generalise to novel stimuli from the same category. None of the control animalswere able to learn the discrimination within the maximum number of trials. This study provides the firstevidence that non-human animals can learn to categorise non-biologically relevant odour information