Engineering synucleinopathy‐resistant human dopaminergic neurons by CRISPR‐mediated deletion of the SNCA gene

An emerging treatment for Parkinson's disease (PD) is cell replacement therapy. Authentic midbrain dopaminergic (mDA) neuronal precursors can be differentiated from human embryonic stem cells (hESCs) and human induced pluripotent stem cells (iPSCs). These laboratory‐generated mDA cells have been demonstrated to mature into functional dopaminergic neurons upon transplantation into preclinical models of PD. However, clinical trials with human fetal mesenchephalic cells have shown that cell replacement grafts in PD are susceptible to Lewy body formation suggesting host‐to‐graft transfer of α‐synuclein pathology. Here, we have used CRISPR/Cas9n technology to delete the endogenous SNCA gene, encoding for α‐synuclein, in a clinical‐grade hESC line to generate SNCA+/− and SNCA−/− cell lines. These hESC lines were first differentiated into mDA neurons, and then challenged with recombinant α‐synuclein preformed fibrils (PFFs) to seed the formation for Lewy‐like pathology as measured by phosphorylation of serine‐129 of α‐synuclein (pS129‐αSyn). Wild‐type neurons were fully susceptible to the formation of protein aggregates positive for pS129‐αSyn, while SNCA+/− and SNCA−/− neurons exhibited significant resistance to the formation of this pathological mark. This work demonstrates that reducing or completely removing SNCA alleles by CRISPR/Cas9n‐mediated gene editing confers a measure of resistance to Lewy pathology

Changing Significance of Landslide Hazard and Risk After The 2015 Mw 7.8 Gorkha, Nepal Earthquake

The 2015 Mw 7.8 Gorkha, Nepal Earthquake triggered in excess of 20,000 landslides across 14 districts of Central and Western Nepal. Whilst the instantaneous impact of these landslides was significant, the ongoing effect of the earthquake on changing the potential for rainfall-triggered landsliding in the months and years that followed has remained poorly understood and challenging to predict. To provide insight into how landsliding has evolved since the earthquake, and how it has impacted those living in the affected area, a detailed time-series landslide mapping campaign was undertaken to monitor the evolution of coseismic landslides and the initiation of new post-seismic landslides. This was supplemented by numerical modelling to simulate the future potential reactivation and runout of landslides as debris flows under monsoon rainfall, identifying locations potentially at risk. This analysis shows that landslide hazard was higher in November 2019 as compared to immediately after the 2015 earthquake, with a considerable portion of the landscape being impacted by landsliding. We show that, while pre-existing landslides continued to pose the majority of hazard in the aftermath of the earthquake, a significant number of landslides also occurred in new locations. We discuss the value of this type of analysis in informing the reconstruction and management of settlements at risk by summarizing how this work was integrated into the project Durable Solutions II, that supported communities at risk from landslides. Finally, we consider how such data could be used in future to inform risk sensitive land-use planning and disaster recovery, and to mitigate the impacts of future landsliding in Nepal and beyond

The diversification of Heliconius butterflies: what have we learned in 150 years?

Research into Heliconius butterflies has made a significant contribution to evolutionary biology. Here, we review our understanding of the diversification of these butterflies, covering recent advances and a vast foundation of earlier work. Whereas no single group of organisms can be sufficient for understanding life's diversity, after years of intensive study, research into Heliconius has addressed a wide variety of evolutionary questions. We first discuss evidence for widespread gene flow between Heliconius species and what this reveals about the nature of species. We then address the evolution and diversity of warning patterns, both as the target of selection and with respect to their underlying genetic basis. The identification of major genes involved in mimetic shifts, and homology at these loci between distantly related taxa, has revealed a surprising predictability in the genetic basis of evolution. In the final sections, we consider the evolution of warning patterns, and Heliconius diversity more generally, within a broader context of ecological and sexual selection. We consider how different traits and modes of selection can interact and influence the evolution of reproductive isolation.RMM is funded by a Junior Research Fellowship at King’s College, Cambridge. KMK is supported by the Balfour Studentship, University of Cambridge, SHMa by a Research Fellowship at St John's College, Cambridge, and SHMo by a Research Fellowship from the Royal Commission for the Exhibition of 1851. Our work on Heliconius has been additionally supported by the Agence Nationale de la Recherche (France), the Biology and Biotechnology Research Council (UK), the British Ecological Society, the European Research Council, the Natural Environment Research Council (UK), and the Smithsonian Tropical Research Institute.This is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1111/jeb.1267

Molecular fingerprinting of radiation resistant tumors: Can we apprehend and rehabilitate the suspects?

Radiation therapy continues to be one of the more popular treatment options for localized prostate cancer. One major obstacle to radiation therapy is that there is a limit to the amount of radiation that can be safely delivered to the target organ. Emerging evidence suggests that therapeutic agents targeting specific molecules might be combined with radiation therapy for more effective treatment of tumors. Recent studies suggest that modulation of these molecules by a variety of mechanisms (e.g., gene therapy, antisense oligonucleotides, small interfering RNA) may enhance the efficacy of radiation therapy by modifying the activity of key cell proliferation and survival pathways such as those controlled by Bcl-2, p53, Akt/PTEN and cyclooxygenase-2. In this article, we summarize the findings of recent investigations of radiosensitizing agents in the treatment of prostate cancer

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Adaptive Introgression across Species Boundaries in Heliconius Butterflies

It is widely documented that hybridisation occurs between many closely related species, but the importance of introgression in adaptive evolution remains unclear, especially in animals. Here, we have examined the role of introgressive hybridisation in transferring adaptations between mimetic Heliconius butterflies, taking advantage of the recent identification of a gene regulating red wing patterns in this genus. By sequencing regions both linked and unlinked to the red colour locus, we found a region that displays an almost perfect genotype by phenotype association across four species, H. melpomene, H. cydno, H. timareta, and H. heurippa. This particular segment is located 70 kb downstream of the red colour specification gene optix, and coalescent analysis indicates repeated introgression of adaptive alleles from H. melpomene into the H. cydno species clade. Our analytical methods complement recent genome scale data for the same region and suggest adaptive introgression has a crucial role in generating adaptive wing colour diversity in this group of butterflies