Population genetic structure associated with a landscape barrier in the Western Grasswren (Amytornis textilis textilis)

Dispersal patterns can dictate genetic population structure and, ultimately, population resilience, through maintaining gene flow and genetic diversity. However, geographical landforms, such as peninsulas, can impact dispersal patterns and thus be a barrier to gene flow. Here, we use 13 375 genome-wide single-nucleotide polymorphisms (SNPs) to evaluate genetic population structure and infer dispersal patterns of the Western Grasswren Amytornis textilis textilis (WGW, n = 140) in the Shark Bay region of Western Australia. We found high levels of genetic divergence between subpopulations on the mainland (Hamelin) and narrow peninsula (Peron). In addition, we found evidence of further genetic sub-structuring within the Hamelin subpopulation, with individuals collected from the western and eastern regions of a conservation reserve forming separate genetic clusters. Spatial autocorrelation analysis within each subpopulation revealed significant local-scale genetic structure up to 35 km at Hamelin and 20 km at Peron. In addition, there was evidence of male philopatry in both subpopulations. Our results suggest a narrow strip of land may be acting as a geographical barrier in the WGW, limiting dispersal between a peninsula and mainland subpopulation. In addition, heterogeneous habitat within Hamelin may be restricting dispersal at the local scale. Furthermore, there is evidence to suggest that the limited gene flow is asymmetrical, with directional dispersal occurring from the bounded peninsula subpopulation to the mainland. This study highlights the genetic structure existing within and between some of the few remaining WGW subpopulations, and shows a need to place equal importance on conservation efforts to maintain them in the future

Oxalate-Induced Damage to Renal Tubular Cells

Our own studies and those of others have shown that the incidence of calcium oxalate stones and plaques is markedly increased by nephrotoxins. The possible role of oxalate as a nephrotoxin has not been fully appreciated. However, recent studies in experimental animals and in cultured cells support this possibility. The results of these studies led us to hypothesize that hyperoxaluria promotes stone formation in several ways: by providing a substrate for the formation of the most common form of renal stones, calcium oxalate stones, and by inducing damage to renal epithelial cells. Damaged cells in turn would produce an environment favorable for crystal retention and provide membranous debris that promotes crystal nucleation, aggregation and adherence. The present report summarizes evidence for oxalate nephrotoxicity and discusses the potential importance of oxalate toxicity in the pathogenesis of stone disease

Safe and Efficient Silencing with a Pol II, but not a Pol lII, Promoter Expressing an Artificial miRNA Targeting Human Huntingtin

Huntington\u27s disease is a devastating, incurable neurodegenerative disease affecting up to 12 per 100,000 patients worldwide. The disease is caused by a mutation in the Huntingtin (Htt) gene. There is interest in reducing mutant Huntingtin by targeting it at the mRNA level, but the maximum tolerable dose and long-term effects of such a treatment are unknown. Using a self-complementary AAV9 vector, we delivered a mir-155-based artificial miRNA under the control of the chicken β-actin or human U6 promoter. In mouse brain, the artificial miRNA reduced the human huntingtin mRNA by 50%. The U6, but not the CβA promoter, produced the artificial miRNA at supraphysiologic levels. Embedding the antisense strand in a U6-mir-30 scaffold reduced expression of the antisense strand but increased the sense strand. In mice treated with scAAV9-U6-mir-155-HTT or scAAV9-CβA-mir-155-HTT, activated microglia were present around the injection site 1 month post-injection. Six months post-injection, mice treated with scAAV9-CβA-mir-155-HTT were indistinguishable from controls. Those that received scAAV9-U6-mir-155-HTT showed behavioral abnormalities and striatal damage. In conclusion, miRNA backbone and promoter can be used together to modulate expression levels and strand selection of artificial miRNAs, and in brain, the CβA promoter can provide an effective and safe dose of a human huntingtin miRNA

Temperature

KEY HEADLINES: • The first MCCIP ARC in 2006 reported following what was then the warmest year globally in 2005 (0.26°C higher than the 1981-2010 average). • Since 2005, new global record temperatures have been set in 2010 and then in each successive year 2014, 2015 and 2016. In these last three record years the global average temperature anomaly was 0.31,0.44, 0.56°C higher than the 1981-2010 average. • 2014 was a record warm year for coastal air and sea temperatures around the UK. Between 1984 and 2014 coastal water temperatures rose around the UK at an average rate of 0.28 °C/decade. The rate varies between regions, the slowest warming was in the Celtic Sea at 0.17 °C/decade and the maximum rate was in the Southern North Sea at 0.45 °C/decade. • There is also variability over shorter time periods. In all regions of UK seas there was a negative trend in the 10-year period between 2003 and 2013. This is due to variability within the ocean /atmosphere system which is natural. • There is a trend towards fewer in-situ observations, and this will ultimately influence the confidence in future assessments. • Some gridded datasets can offer alternatives to single point observations, but to understand the patterns of ocean variability, the quality information from ocean timeseries cannot yet be replaced by surface observations or autonomous data collection. • The first MCCIP report card in 2006 used the UKCIP projections from 2002 which had a very limited representation of the SST. • The latest updates to the UK Climate Projections shelf seas models were published in 2016 and projected increases in sea surface temperature for 2069-89 relative to 1960-89 of over 3 °C for most of the North Sea, English Channel, Irish and Celtic Seas. For the deeper areas to the north and west of Scotland out towards Rockall and in the Faroe Shetland Channel the increase in temperature is projected to be closer to 2 °C. • Over the last 10 years there has been a steady improvement in the scientific basis underlying centennial sea temperature projections for the seas around the UK, and significant progress in the field of seasonal and decadal projections. • The scientific basis to such projections and predictions will continue to improve over the next 10 years, with increasing resolution, treatment of climate uncertainties, and methodology. Over the centennial scale the difference between emissions scenarios are still the source of the largest uncertainties. • Development of North West European Shelf (NWS) modelling systems driven by seasonal forecasting systems may allow NWS temperature prediction over the monthly to decadal period

Allele-Selective Suppression of Mutant Huntingtin in Primary Human Blood Cells

Post-transcriptional gene silencing is a promising therapy for the monogenic, autosomal dominant, Huntington\u27s disease (HD). However, wild-type huntingtin (HTT) has important cellular functions, so the ideal strategy would selectively lower mutant HTT while sparing wild-type. HD patients were genotyped for heterozygosity at three SNP sites, before phasing each SNP allele to wild-type or mutant HTT. Primary ex vivo myeloid cells were isolated from heterozygous patients and transfected with SNP-targeted siRNA, using glucan particles taken up by phagocytosis. Highly selective mRNA knockdown was achieved when targeting each allele of rs362331 in exon 50 of the HTT transcript; this selectivity was also present on protein studies. However, similar selectivity was not observed when targeting rs362273 or rs362307. Furthermore, HD myeloid cells are hyper-reactive compared to control. Allele-selective suppression of either wild-type or mutant HTT produced a significant, equivalent reduction in the cytokine response of HD myeloid cells to LPS, suggesting that wild-type HTT has a novel immune function. We demonstrate a sequential therapeutic process comprising genotyping and mutant HTT-linkage of SNPs, followed by personalised allele-selective suppression in a small patient cohort. We further show that allele-selectivity in ex vivo patient cells is highly SNP-dependent, with implications for clinical trial target selection

Impacts of climate change on harmful algal blooms

High biomass Harmful Algal Blooms (HABs) such as Karenia mikimotoi and shellfish toxin producing HAB species continue to be observed in UK and Republic of Ireland waters. Regional differences continue to be seen in the distribution of HABs in UK and RoI waters with impacts mainly observed in the south and west coast of Ireland and regions in the UK with a strong Atlantic influence, e.g. Regions 1, 3, 4, 6 and 7. There is little monitoring aside from the continuous plankton recorder (CPR) in Region 8. The impacts from HABs in Wales, Northern Ireland and the Isle of Man are generally low. Since the last MCCIP report card was issued, blooms of Karenia mikimotoi have caused problems in Ayrshire, Scotland, and also in the north-west coast of Ireland where concerns about the quantity of dead wild fish washing on shore during an event in Ireland in 2012 resulted in two beaches being closed to the public. No clear trend that can be attributed to climate change can be observed in the incidence of shellfish toxin producing HABs since the last report card was issued. During the last two years the incidence of some shellfish toxins has continued to decrease (e.g. paralytic shellfish poisoning toxins in Scotland). High concentrations of yessotoxins (YTX) and azaspiracids (AZAs) have been recorded for the first time in Scotland. Northern Ireland enforced its first shellfish harvesting closure for high concentrations of domoic acid (the toxin responsible for amnesic shellfish poisoning, ASP) in 2012. A recent survey in Scottish waters (Regions 1, 6 and 7) has revealed the presence of domoic acid in the urine and faeces of harbour seals (Phoca vitulina). The impacts of these toxins on the health of marine mammals are unknown and a more detailed study is currently being undertaken. Many of the future impacts of climate change are unknown. Increasing sea surface temperatures as a result of climate change may increase the potential for blooms of species that are not currently found in UK and RoI waters through range expansion or human mediated introduction. There is evidence that no new HAB species have become established during the last two years. An increase in the duration of stratification of the water column may influence the abundance of HABs in UK and RoI waters. This is particularly relevant in shelf areas and Region 8, an area where offshore high biomass K. mikimotoi blooms have been hypothesized to initiate and impact coastal areas along the west of Ireland and Regions 6, 7 and 1. Conversely, an increase in wind speed and duration may reduce the duration of stratification in the water column. This may result in a decrease of some HAB dinoflagellate species and an increase in HAB diatom species. Little is known about the impacts of ocean acidification or changes in offshore circulation on the incidence of HABs. The role of offshore blooms in seeding coastal blooms (e.g. of K. mikimotoi) remains unknown and the lack of monitoring in Region 8 and on the shelf edge compounds this knowledge gap

Confirmation of a new resonance in 26Si and contribution of classical novae to the galactic abundance of 26Al

© 2023 The Author(s). Published by the American Physical Society. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/The 25Al(p ,γ ) reaction has long been highlighted as a possible means to bypass the production of 26Al cosmic γ rays in classical nova explosions. However, uncertainties in the properties of key resonant states in 26Si have hindered our ability to accurately model the influence of this reaction in such environments. We report on a detailed γ -ray spectroscopy study of 26Si and present evidence for the existence of a new, likely ℓ =1 , resonance in the 25Al + p system at Er=153.9 (15 ) keV. This state is now expected to provide the dominant contribution to the 25Al(p ,γ ) stellar reaction rate over the temperature range, T ≈0.1 −0.2 GK. Despite a significant increase in the rate at low temperatures, we find that the final ejected abundance of 26Al from classical novae remains largely unaffected even if the reaction rate is artificially increased by a factor of 10. Based on new, galactic chemical evolution calculations, we estimate that the maximum contribution of novae to the observed galactic abundance of 26Al is ≈0.2 M⊙ . Finally, we briefly highlight the important role that super-asymptotic giant branch stars may play in the production of 26Al.Peer reviewe

Identification of polymorphic inversions from genotypes

Background: Polymorphic inversions are a source of genetic variability with a direct impact on recombination frequencies. Given the difficulty of their experimental study, computational methods have been developed to infer their existence in a large number of individuals using genome-wide data of nucleotide variation. Methods based on haplotype tagging of known inversions attempt to classify individuals as having a normal or inverted allele. Other methods that measure differences between linkage disequilibrium attempt to identify regions with inversions but unable to classify subjects accurately, an essential requirement for association studies. Results: We present a novel method to both identify polymorphic inversions from genome-wide genotype data and classify individuals as containing a normal or inverted allele. Our method, a generalization of a published method for haplotype data [1], utilizes linkage between groups of SNPs to partition a set of individuals into normal and inverted subpopulations. We employ a sliding window scan to identify regions likely to have an inversion, and accumulation of evidence from neighboring SNPs is used to accurately determine the inversion status of each subject. Further, our approach detects inversions directly from genotype data, thus increasing its usability to current genome-wide association studies (GWAS). Conclusions: We demonstrate the accuracy of our method to detect inversions and classify individuals on principled-simulated genotypes, produced by the evolution of an inversion event within a coalescent model [2]. We applied our method to real genotype data from HapMap Phase III to characterize the inversion status of two known inversions within the regions 17q21 and 8p23 across 1184 individuals. Finally, we scan the full genomes of the European Origin (CEU) and Yoruba (YRI) HapMap samples. We find population-based evidence for 9 out of 15 well-established autosomic inversions, and for 52 regions previously predicted by independent experimental methods in ten (9+1) individuals [3,4]. We provide efficient implementations of both genotype and haplotype methods as a unified R package inveRsion

Artificial miRNAs Reduce Human Mutant Huntingtin Throughout the Striatum in a Transgenic Sheep Model of Huntington's Disease.

Huntington's disease (HD) is a fatal neurodegenerative disease caused by a genetic expansion of the CAG repeat region in the huntingtin (HTT) gene. Studies in HD mouse models have shown that artificial miRNAs can reduce mutant HTT, but evidence for their effectiveness and safety in larger animals is lacking. HD transgenic sheep express the full-length human HTT with 73 CAG repeats. AAV9 was used to deliver unilaterally to HD sheep striatum an artificial miRNA targeting exon 48 of the human HTT mRNA under control of two alternative promoters: U6 or CβA. The treatment reduced human mutant (m) HTT mRNA and protein 50-80% in the striatum at 1 and 6 months post injection. Silencing was detectable in both the caudate and putamen. Levels of endogenous sheep HTT protein were not affected. There was no significant loss of neurons labeled by DARPP32 or NeuN at 6 months after treatment, and Iba1-positive microglia were detected at control levels. It is concluded that safe and effective silencing of human mHTT protein can be achieved and sustained in a large-animal brain by direct delivery of an AAV carrying an artificial miRNA