Modeling and Rescue of RP2 Retinitis Pigmentosa Using iPSC-Derived Retinal Organoids

RP2 mutations cause a severe form of X-linked retinitis pigmentosa (XLRP). The mechanism of RP2-associated retinal degeneration in humans is unclear, and animal models of RP2 XLRP do not recapitulate this severe phenotype. Here, we developed gene-edited isogenic RP2 knockout (RP2 KO) induced pluripotent stem cells (iPSCs) and RP2 patient-derived iPSC to produce 3D retinal organoids as a human retinal disease model. Strikingly, the RP2 KO and RP2 patient-derived organoids showed a peak in rod photoreceptor cell death at day 150 (D150) with subsequent thinning of the organoid outer nuclear layer (ONL) by D180 of culture. Adeno-associated virus-mediated gene augmentation with human RP2 rescued the degeneration phenotype of the RP2 KO organoids, to prevent ONL thinning and restore rhodopsin expression. Notably, these data show that 3D retinal organoids can be used to model photoreceptor degeneration and test potential therapies to prevent photoreceptor cell death

Retrieval of the Alzheimer's amyloid precursor protein from the endosome to the TGN is S655 phosphorylation state-dependent and retromer-mediated

Background: Retrograde transport of several transmembrane proteins from endosomes to the trans-Golgi network (TGN) occurs via Rab 5-containing endosomes, mediated by clathrin and the recently characterized retromer complex. This complex and one of its putative sorting receptor components, SorLA, were reported to be associated to late onset Alzheimer's disease (AD). The pathogenesis of this neurodegenerative disorder is still elusive, although accumulation of amyloidogenic Abeta is a hallmark. This peptide is generated from the sucessive β- and γ- secretase proteolysis of the Alzheimer's amyloid precursor protein (APP), events which are associated with endocytic pathway compartments. Therefore, APP targeting and time of residence in endosomes would be predicted to modulate Abeta levels. However, the formation of an APP- and retromer-containing protein complex with potential functions in retrieval of APP from the endosome to the TGN had, to date, not been demonstrated directly. Further, the motif(s) in APP that regulate its sorting to the TGN have not been characterized. Results: Through the use of APP-GFP constructs, we show that APP containing endocytic vesicles targeted for the TGN, are also immunoreactive for clathrin-, Rab 5- and VPS35. Further, they frequently generate protruding tubules near the TGN, supporting an association with a retromer-mediated pathway. Importantly, we show for the first time, that mimicking APP phosphorylation at S655, within the APP 653YTSI656 basolateral motif, enhances APP retrieval via a retromer-mediated process. The phosphomimetic APP S655E displays decreased APP lysosomal targeting, enhanced mature half-life, and decreased tendency towards Abeta production. VPS35 downregulation impairs the phosphorylation dependent APP retrieval to the TGN, and decreases APP half-life. Conclusions: We reported for the first time the importance of APP phosphorylation on S655 in regulating its retromer-mediated sorting to the TGN or lysosomes. Significantly, the data are consistent with known interactions involving the retromer, SorLA and APP. Further, these findings add to our understanding of APP targeting and potentially contribute to our knowledge of sporadic AD pathogenesis representing putative new targets for AD therapeutic strategies

Neanderthals on the Lower Danube: Middle Palaeolithic evidence in the Danube Gorges of the Balkans

The article presents evidence about the Middle Palaeolithic and Middle to Upper Palaeolithic transition interval in the karst area of the Danube Gorges in the Lower Danube Basin. We review the extant data and present new evidence from two recently investigated sites found on the Serbian side of the Danube River – Tabula Traiana and Dubočka-Kozja caves. The two sites have yielded layers dating to both the Middle and Upper Palaeolithic and have been investigated by the application of modern standards of excavation and recovery along with a suite of state-of-the-art analytical procedures. The presentation focuses on micromorphological analyses of the caves’ sediments, characterisation of cryptotephra, a suite of new radiometric dates (accelerator mass spectrometry and optically stimulated luminescence) as well as proteomics (zooarchaeology by mass spectrometry) and stable isotope data in discerning patterns of human occupation of these locales over the long term

Neanderthals on the Lower Danube: Middle Palaeolithic evidence in the Danube Gorges of the Balkans

The article presents evidence about the Middle Palaeolithic and Middle to Upper Palaeolithic transition interval in the karst area of the Danube Gorges in the Lower Danube Basin. We review the extant data and present new evidence from two recently investigated sites found on the Serbian side of the Danube River – Tabula Traiana and Dubočka-Kozja caves. The two sites have yielded layers dating to both the Middle and Upper Palaeolithic and have been investigated by the application of modern standards of excavation and recovery along with a suite of state-of-the-art analytical procedures. The presentation focuses on micromorphological analyses of the caves’ sediments, characterisation of cryptotephra, a suite of new radiometric dates (accelerator mass spectrometry and optically stimulated luminescence) as well as proteomics (zooarchaeology by mass spectrometry) and stable isotope data in discerning patterns of human occupation of these locales over the long term

Contemporary accuracy of death certificates for coding prostate cancer as a cause of death : Is reliance on death certification good enough? A comparison with blinded review by an independent cause of death evaluation committee

BACKGROUND: Accurate cause of death assignment is crucial for prostate cancer epidemiology and trials reporting prostate cancer-specific mortality outcomes. METHODS: We compared death certificate information with independent cause of death evaluation by an expert committee within a prostate cancer trial (2002-2015). RESULTS: Of 1236 deaths assessed, expert committee evaluation attributed 523 (42%) to prostate cancer, agreeing with death certificate cause of death in 1134 cases (92%, 95% CI: 90%, 93%). The sensitivity of death certificates in identifying prostate cancer deaths as classified by the committee was 91% (95% CI: 89%, 94%); specificity was 92% (95% CI: 90%, 94%). Sensitivity and specificity were lower where death occurred within 1 year of diagnosis, and where there was another primary cancer diagnosis. CONCLUSIONS: UK death certificates accurately identify cause of death in men with prostate cancer, supporting their use in routine statistics. Possible differential misattribution by trial arm supports independent evaluation in randomised trials

A note on the pricing of multivariate contingent claims under a transformed-gamma distribution

We develop a framework for pricing multivariate European-style contingent claims in a discrete-time economy based on a multivariate transformed-gamma distribution. In our model, each transformed-gamma distributed underlying asset depends on two terms: a idiosyncratic term and a systematic term, where the latter is the same for all underlying assets and has a direct impact on their correlation structure. Given our distributional assumptions and the existence of a representative agent with a standard utility function, we apply equilibrium arguments and provide sufficient conditions for obtaining preference-free contingent claim pricing equations. We illustrate the applicability of our framework by providing examples of preference-free contingent claim pricing models. Multivariate pricing models are of particular interest when payoffs depend on two or more underlying assets, such as crack and crush spread options, options to exchange one asset for another, and options with a stochastic strike price in general

Linking habitat quality with genetic diversity: a lesson from great bustards in Spain

P. 411-419The effects of habitat loss and fragmentation on the genetic structure and variability of wild populations have received wide empirical support and theoretical formalization. By contrast, the effects of habitat quality seem largely underinvestigated, partly due to technical difficulties in properly assessing habitat quality. In this study, we combine geographic information system (GIS)-based habitat-quality modelling with a landscape genetics approach based on mitochondrial DNA markers to evaluate the possible influence of habitat quality on the levels and distribution of genetic diversity in a range of natural populations (n = 15) of Otis tarda throughout Spain. Ninety-three percent of the population represented by our countrywide sample lives in good-quality habitats, while 4.5% and 2.5% occur respectively in intermediate and poor habitats. Habitat quality was highly correlated with patch size, population size and population density, indicating the reliability and predictive power of the habitat suitability model. Genetic diversity was significantly correlated with habitat quality, size and density of the population, but not with patch size. Three of a total of 20 existing matrilineages from the species’ current genetic pool are restricted to poor-quality habitats. This study therefore highlights the importance of considering both population genetics and habitat quality in a species of high conservation priority.S

Elevated extinction rates as a trigger for diversification rate shifts: early amniotes as a case study

Tree shape analyses are frequently used to infer the location of shifts in diversification rate within the Tree of Life. Many studies have supported a causal relationship between shifts and temporally coincident events such as the evolution of “key innovations”. However, the evidence for such relationships is circumstantial. We investigated patterns of diversification during the early evolution of Amniota from the Carboniferous to the Triassic, subjecting a new supertree to analyses of tree balance in order to infer the timing and location of diversification shifts. We investigated how uneven origination and extinction rates drive diversification shifts, and use two case studies (herbivory and an aquatic lifestyle) to examine whether shifts tend to be contemporaneous with evolutionary novelties. Shifts within amniotes tend to occur during periods of elevated extinction, with mass extinctions coinciding with numerous and larger shifts. Diversification shifts occurring in clades that possess evolutionary innovations do not coincide temporally with the appearance of those innovations, but are instead deferred to periods of high extinction rate. We suggest such innovations did not cause increases in the rate of cladogenesis, but allowed clades to survive extinction events. We highlight the importance of examining general patterns of diversification before interpreting specific shifts

Asteroseismology and Interferometry

Asteroseismology provides us with a unique opportunity to improve our understanding of stellar structure and evolution. Recent developments, including the first systematic studies of solar-like pulsators, have boosted the impact of this field of research within Astrophysics and have led to a significant increase in the size of the research community. In the present paper we start by reviewing the basic observational and theoretical properties of classical and solar-like pulsators and present results from some of the most recent and outstanding studies of these stars. We centre our review on those classes of pulsators for which interferometric studies are expected to provide a significant input. We discuss current limitations to asteroseismic studies, including difficulties in mode identification and in the accurate determination of global parameters of pulsating stars, and, after a brief review of those aspects of interferometry that are most relevant in this context, anticipate how interferometric observations may contribute to overcome these limitations. Moreover, we present results of recent pilot studies of pulsating stars involving both asteroseismic and interferometric constraints and look into the future, summarizing ongoing efforts concerning the development of future instruments and satellite missions which are expected to have an impact in this field of research.Comment: Version as published in The Astronomy and Astrophysics Review, Volume 14, Issue 3-4, pp. 217-36

Improved precision on the experimental E0 decay branching ratio of the Hoyle state

Stellar carbon synthesis occurs exclusively via the $3\alpha$ process, in which three $\alpha$ particles fuse to form $^{12}$C in the excited Hoyle state, followed by electromagnetic decay to the ground state. The Hoyle state is above the $\alpha$ threshold, and the rate of stellar carbon production depends on the radiative width of this state. The radiative width cannot be measured directly, and must instead be deduced by combining three separately measured quantities. One of these quantities is the $E0$ decay branching ratio of the Hoyle state, and the current $10$\% uncertainty on the radiative width stems mainly from the uncertainty on this ratio. The $E0$ branching ratio was deduced from a series of pair conversion measurements of the $E0$ and $E2$ transitions depopulating the $0^+_2$ Hoyle state and $2^+_1$ state in $^{12}$C, respectively. The excited states were populated by the $^{12}$C$(p,p^\prime)$ reaction at 10.5 MeV beam energy, and the pairs were detected with the electron-positron pair spectrometer, Super-e, at the Australian National University. The deduced branching ratio required knowledge of the proton population of the two states, as well as the alignment of the $2^+_1$ state in the reaction. For this purpose, proton scattering and $\gamma$-ray angular distribution experiments were also performed. An $E0$ branching ratio of $\Gamma^{E0}_{\pi}/\Gamma=8.2(5)\times10^{-6}$ was deduced in the current work, and an adopted value of $\Gamma^{E0}_{\pi}/\Gamma=7.6(4)\times10^{-6}$ is recommended based on a weighted average of previous literature values and the new result. The new recommended value for the $E0$ branching ratio is about 14% larger than the previous adopted value of $\Gamma^{E0}_{\pi}/\Gamma=6.7(6)\times10^{-6}$, while the uncertainty has been reduced from 9% to 5%.Comment: Accepted for publication as a Regular Article in Phys. Rev. C on July 29 202