ABSTRACT
We present a temporal and spectral analysis of the gamma-ray flux from nine of the brightest flat-spectrum radio quasars (FSRQs) detected with the Fermi Large Area Telescope during its first ...8 yr of operation, with the aim of constraining the location of the emission region. Using the increased photon statistics obtained from the two brightest flares of each source, we find evidence of sub-hour variability from B2 1520+31, PKS 1502+106, and PKS 1424−41, with the remaining sources showing variability on time-scales of a few hours. These indicate gamma-ray emission from extremely compact regions in the jet, potentially compatible with emission from within the broad-line region (BLR). The flare spectra show evidence of a spectral cut-off in 7 of the 18 flares studied, further supporting the argument for BLR emission in these sources. An investigation into the energy dependence of cooling time-scales finds evidence for both BLR origin and emission from within the molecular torus (MT). However, Monte Carlo simulations show that the very high energy (Eγ ≥ 20 GeV) emission from all sources except 3C 279, 3C 454.3, and 4C 21.35 is incompatible with a BLR origin. The combined findings of all the approaches used suggest that the gamma-ray emission in the brightest FSRQs originates in multiple compact emission regions throughout the jet, within both the BLR and the MT.
The cytoplasmic mislocalization and aggregation of TAR DNA-binding protein-43 (TDP-43) is a common histopathological hallmark of the amyotrophic lateral sclerosis and frontotemporal dementia disease ...spectrum (ALS/FTD). However, the composition of aggregates and their contribution to the disease process remain unknown. Here we used proximity-dependent biotin identification (BioID) to interrogate the interactome of detergent-insoluble TDP-43 aggregates and found them enriched for components of the nuclear pore complex and nucleocytoplasmic transport machinery. Aggregated and disease-linked mutant TDP-43 triggered the sequestration and/or mislocalization of nucleoporins and transport factors, and interfered with nuclear protein import and RNA export in mouse primary cortical neurons, human fibroblasts and induced pluripotent stem cell-derived neurons. Nuclear pore pathology is present in brain tissue in cases of sporadic ALS and those involving genetic mutations in TARDBP and C9orf72. Our data strongly implicate TDP-43-mediated nucleocytoplasmic transport defects as a common disease mechanism in ALS/FTD.
When learning new movements some people make larger kinematic errors than others, interpreted as a reduction in motor-learning ability. Consider a learning task where error-cancelling strategies ...incur higher effort costs, specifically where subjects reach to targets in a force field. Concluding that those with greater error have learned less has a critical assumption: everyone uses the same error-canceling strategy. Alternatively, it could be that those with greater error may be choosing to sacrifice error reduction in favor of a lower effort movement. Here, we test this hypothesis in a dataset that includes both younger and older adults, where older adults exhibited greater kinematic errors. Utilizing the framework of optimal control theory, we infer subjective costs (i.e., strategies) and internal model accuracy (i.e., proportion of the novel dynamics learned) by fitting a model to each population's trajectory data. Our results demonstrate trajectories are defined by a combination of the amount learned and strategic differences represented by relative cost weights. Based on the model fits, younger adults could have learned between 65-90% of the novel dynamics. Critically, older adults could have learned between 60-85%. Each model fit produces trajectories that match the experimentally observed data, where a lower proportion learned in the model is compensated for by increasing costs on kinematic errors relative to effort. This suggests older and younger adults could be learning to the same extent, but older adults have a higher relative cost on effort compared to younger adults. These results call into question the proposition that older adults learn less than younger adults and provide a potential explanation for the equivocal findings in the literature. Importantly, our findings suggest that the metrics commonly used to probe motor learning paint an incomplete picture, and that to accurately quantify the learning process the subjective costs of movements should be considered.
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share phenotypic and pathologic overlap. Recently, an expansion of GGGGCC repeats in the first intron of C9orf72 was found to be ...a common cause of both illnesses; however, the molecular pathogenesis of this expanded repeat is unknown. Here we developed both Drosophila and mammalian models of this expanded hexanucleotide repeat and showed that expression of the expanded GGGGCC repeat RNA (rGGGGCC) is sufficient to cause neurodegeneration. We further identified Pur α as the RNA-binding protein of rGGGGCC repeats and discovered that Pur α and rGGGGCC repeats interact in vitro and in vivo in a sequence-specific fashion that is conserved between mammals and Drosophila . Furthermore, overexpression of Pur α in mouse neuronal cells and Drosophila mitigates rGGGGCC repeat-mediated neurodegeneration, and Pur α forms inclusions in the fly eye expressing expanded rGGGGCC repeats, as well as in cerebellum of human carriers of expanded GGGGCC repeats. These data suggest that expanded rGGGGCC repeats could sequester specific RNA-binding protein from their normal functions, ultimately leading to cell death. Taken together, these findings suggest that the expanded rGGGGCC repeats could cause neurodegeneration, and that Pur α may play a role in the pathogenesis of amyotrophic lateral sclerosis and frontotemporal dementia.
The Christy Gadget is the informal name for the plutonium device detonated in the Trinity test on July 16, 1945. In September 1944, Robert Christy, working in the theoretical implosion group, ...proposed a novel concept that altered the design of the nuclear core in Fat Man. While scientists originally intended to use a hollow sphere of plutonium, this design entailed substantial risk due to the likelihood of asymmetries resulting from implosion. Christy proposed changing the design to a solid sphere of plutonium with a modulated neutron source, and the design was eventually adopted, tested at Trinity, and used in the attack on Nagasaki. While there is no question regarding the important role that Christy played in demonstrating its feasibility as a reliable design, there is a debate as to who initially proposed the idea; though most sources have attributed this invention to Christy, some historical sources have attributed credit to Christy's group leader, Rudolf Peierls, or indeed other scientists. This paper seeks to outline and resolve this dispute. We present new unclassified evidence extracted from previously unavailable sources (to unclassified audiences) from the National Security Research Center archives at Los Alamos National Laboratory. This evidence consists of 1945-1946 patent documentation, oral history interview tapes of Christy and Peierls, and monthly 1944 progress reports from the Theoretical Division. Though Christy and Peierls share joint credit on the patent, both Christy's and Peierls' words and writings, together with sources from Hans Bethe and Edward Teller, support the traditional view that Christy was indeed the originator of the idea. While Christy does deserve the majority of the credit for the invention and design, we acknowledge the important role Peierls and von Neumann played in its development.
Here, we report proteomic analyses of 129 human cortical tissues to define changes associated with the asymptomatic and symptomatic stages of Alzheimer’s disease (AD). Network analysis revealed 16 ...modules of co-expressed proteins, 10 of which correlated with AD phenotypes. A subset of modules overlapped with RNA co-expression networks, including those associated with neurons and astroglial cell types, showing altered expression in AD, even in the asymptomatic stages. Overlap of RNA and protein networks was otherwise modest, with many modules specific to the proteome, including those linked to microtubule function and inflammation. Proteomic modules were validated in an independent cohort, demonstrating some module expression changes unique to AD and several observed in other neurodegenerative diseases. AD genetic risk loci were concentrated in glial-related modules in the proteome and transcriptome, consistent with their causal role in AD. This multi-network analysis reveals protein- and disease-specific pathways involved in the etiology, initiation, and progression of AD.
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•Protein modules correlated with cognition and Alzheimer’s disease (AD) pathology•Modules associated with brain cell types overlapped in protein and RNA networks•Many protein-based modules were distinct from those in RNA-directed networks•AD risk loci converged in glial-related modules in the proteome and transcriptome
Using label-free “single shot” proteomics, we define changes in the proteome of human brain linked to preclinical and clinical stages of Alzheimer’s disease (AD). These data reveal modules of co-expressed proteins that correlate with AD phenotypes, are distinct from modules identified from gene co-expression data, and highlight non-neuronal drivers of disease.
•Consumers could discern differences in taste that were quantified biochemically.•Ratio of bitter:sweet compounds determines bitterness perception and liking.•8-Deoxylactucin-15-sulphate contributes ...most strongly to bitterness perception.•Glucose was most highly correlated with sweetness perception.•There is a genetic basis to the biochemical composition of lettuce.
Lettuce is an important leafy vegetable, consumed across the world, containing bitter sesquiterpenoid lactone (SL) compounds that may negatively affect consumer acceptance and consumption. We assessed liking of samples with differing absolute abundance and different ratios of bitter:sweet compounds by analysing recombinant inbred lines (RILs) from an interspecific lettuce mapping population derived from a cross between a wild (L. serriola acc. UC96US23) and domesticated lettuce (L. sativa, cv. Salinas). We found that the ratio of bitter:sweet compounds was a key determinant of bitterness perception and liking. We were able to demonstrate that SLs, such as 8-deoxylactucin-15-sulphate, contribute most strongly to bitterness perception, whilst 15-p-hydroxylphenylacetyllactucin-8-sulphate does not contribute to bitter taste. Glucose was the sugar most highly correlated with sweetness perception. There is a genetic basis to the biochemical composition of lettuce. This information will be useful in lettuce breeding programmes in order to produce leaves with more favourable taste profiles.
Gamma-rays from SS433: evidence for periodicity Rasul, Kajwan; Chadwick, Paula M; Graham, Jamie A ...
Monthly notices of the Royal Astronomical Society,
05/2019, Letnik:
485, Številka:
2
Journal Article
Recenzirano
ABSTRACT
In this paper we present our study of the gamma-ray emission from the microquasar SS433. Integrating over 9 yr of Fermi-LAT Pass 8 data, we detect SS433 with a significance of ∼13σ in the ...200 to 500 MeV photon energy range, with evidence for an extension in the direction of the w1 X-ray ‘hotspot’. A temporal analysis reveals evidence for modulation of SS433’s gamma-ray emission with the precession period of its relativistic jet. This suggests that at least some of SS433’s gamma-ray emission originates close to the object rather than from the jet termination regions.
Deposition of insoluble protein aggregates is a hallmark of neurodegenerative diseases. The universal presence of β-amyloid and tau in Alzheimer’s disease (AD) has facilitated advancement of the ...amyloid cascade and tau hypotheses that have dominated AD pathogenesis research and therapeutic development. However, the underlying etiology of the disease remains to be fully elucidated. Here we report a comprehensive study of the human brain-insoluble proteome in AD by mass spectrometry. We identify 4,216 proteins, among which 36 proteins accumulate in the disease, including U1-70K and other U1 small nuclear ribonucleoprotein (U1 snRNP) spliceosome components. Similar accumulations in mild cognitive impairment cases indicate that spliceosome changes occur in early stages of AD. Multiple U1 snRNP subunits form cytoplasmic tangle-like structures in AD but not in other examined neurodegenerative disorders, including Parkinson disease and frontotemporal lobar degeneration. Comparison of RNA from AD and control brains reveals dysregulated RNA processing with accumulation of unspliced RNA species in AD, including myc box-dependent-interacting protein 1, clusterin, and presenilin-1 . U1-70K knockdown or antisense oligonucleotide inhibition of U1 snRNP increases the protein level of amyloid precursor protein. Thus, our results demonstrate unique U1 snRNP pathology and implicate abnormal RNA splicing in AD pathogenesis.
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