Mortality and morbidity risks from space radiation exposure are an important concern for astronauts participating in International Space Station (ISS) missions. NASA's radiation limits set a 3% ...cancer fatality probability as the upper bound of acceptable risk and considers uncertainties in risk predictions using the upper 95% confidence level (CL) of the assessment. In addition to risk limitation, an important question arises as to the likelihood of a causal association between a crew-members' radiation exposure in the past and a diagnosis of cancer. For the first time, we report on predictions of age and sex specific cancer risks, expected years of life-loss for specific diseases, and probability of causation (PC) at different post-mission times for participants in 1-year or multiple ISS missions. Risk projections with uncertainty estimates are within NASA acceptable radiation standards for mission lengths of 1-year or less for likely crew demographics. However, for solar minimum conditions upper 95% CL exceed 3% risk of exposure induced death (REID) by 18 months or 24 months for females and males, respectively. Median PC and upper 95%-confidence intervals are found to exceed 50% for several cancers for participation in two or more ISS missions of 18 months or longer total duration near solar minimum, or for longer ISS missions at other phases of the solar cycle. However, current risk models only consider estimates of quantitative differences between high and low linear energy transfer (LET) radiation. We also make predictions of risk and uncertainties that would result from an increase in tumor lethality for highly ionizing radiation reported in animal studies, and the additional risks from circulatory diseases. These additional concerns could further reduce the maximum duration of ISS missions within acceptable risk levels, and will require new knowledge to properly evaluate.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Rab GTPases are highly conserved components of vesicle trafficking pathways that help to ensure the fusion of a vesicle with a specific target organelle membrane. Specific regulatory pathways promote ...kinetic proofreading of membrane surfaces by Rab GTPases, and permit accumulation of active Rabs only at the required sites. Emerging evidence indicates that Rab activation and inactivation are under complex feedback control, suggesting that ultrasensitivity and bistability, principles established for other cellular regulatory networks, may also apply to Rab regulation. Such systems can promote the rapid membrane accumulation and removal of Rabs to create time-limited membrane domains with a unique composition, and can explain how Rabs define the identity of vesicle and organelle membranes.
Mouse embryonic stem (ES) cells grown in serum exhibit greater heterogeneity in morphology and expression of pluripotency factors than ES cells cultured in defined medium with inhibitors of two ...kinases (Mek and GSK3), a condition known as “2i” postulated to establish a naive ground state. We show that the transcriptome and epigenome profiles of serum- and 2i-grown ES cells are distinct. 2i-treated cells exhibit lower expression of lineage-affiliated genes, reduced prevalence at promoters of the repressive histone modification H3K27me3, and fewer bivalent domains, which are thought to mark genes poised for either up- or downregulation. Nonetheless, serum- and 2i-grown ES cells have similar differentiation potential. Precocious transcription of developmental genes in 2i is restrained by RNA polymerase II promoter-proximal pausing. These findings suggest that transcriptional potentiation and a permissive chromatin context characterize the ground state and that exit from it may not require a metastable intermediate or multilineage priming.
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▸ High-resolution genome-wide transcriptome and epigenome of naive pluripotency ▸ Reduced H3K27me3 at promoters and fewer bivalent domains in naive ES cells ▸ Reduced lineage priming and increased RNA polymerase II pausing in the naive state ▸ Naive ES cells show no delay in differentiation
Ground state pluripotency is characterized by a permissive chromatin context, but gene expression is not promiscuous due to the high prevalence of promoter-proximal pausing of transcription.
The genetics of bipolar disorder Gordovez, Francis James A; McMahon, Francis J
Molecular psychiatry,
03/2020, Letnik:
25, Številka:
3
Journal Article
Recenzirano
Bipolar disorder (BD) is one of the most heritable mental illnesses, but the elucidation of its genetic basis has proven to be a very challenging endeavor. Genome-Wide Association Studies (GWAS) have ...transformed our understanding of BD, providing the first reproducible evidence of specific genetic markers and a highly polygenic architecture that overlaps with that of schizophrenia, major depression, and other disorders. Individual GWAS markers appear to confer little risk, but common variants together account for about 25% of the heritability of BD. A few higher-risk associations have also been identified, such as a rare copy number variant on chromosome 16p11.2. Large scale next-generation sequencing studies are actively searching for other alleles that confer substantial risk. As our understanding of the genetics of BD improves, there is growing optimism that some clear biological pathways will emerge, providing a basis for future studies aimed at molecular diagnosis and novel therapeutics.
I conduct an empirical investigation into the pricing of subprime asset-backed collateralized debt obligations (CDOs) and their contagion effects on other markets. Using data for the ABX subprime ...indexes, I find strong evidence of contagion in the financial markets. The results support the hypothesis that financial contagion was propagated primarily through liquidity and risk-premium channels, rather than through a correlated-information channel. Surprisingly, ABX index returns forecast stock returns and Treasury and corporate bond yield changes by as much as three weeks ahead during the subprime crisis. This challenges the popular view that the market prices of these “toxic assets” were unreliable; the results suggest that significant price discovery did in fact occur in the subprime market during the crisis.
Recent boreal winters have exhibited a large-scale seesaw temperature pattern characterized by an unusually warm Arctic and cold continents. Whether there is any physical link between Arctic ...variability and Northern Hemisphere (NH) extreme weather is an active area of research. Using a recently developed index of severe winter weather, we show that the occurrence of severe winter weather in the United States is significantly related to anomalies in pan-Arctic geopotential heights and temperatures. As the Arctic transitions from a relatively cold state to a warmer one, the frequency of severe winter weather in mid-latitudes increases through the transition. However, this relationship is strongest in the eastern US and mixed to even opposite along the western US. We also show that during mid-winter to late-winter of recent decades, when the Arctic warming trend is greatest and extends into the upper troposphere and lower stratosphere, severe winter weather-including both cold spells and heavy snows-became more frequent in the eastern United States.
Hermansky-Pudlak syndrome (HPS) is a human disease characterized by partial loss of pigmentation and impaired blood clotting 1–3. These symptoms are caused by defects in the biogenesis of melanosomes ...and platelet dense granules, often referred to as lysosome-related organelles 2. Genes mutated in HPS encode subunits of the biogenesis of lysosome-related organelles complexes (BLOCs). BLOC-1 and BLOC-2, together with the AP-3 clathrin adaptor complex, act at early endosomes to sort components required for melanin formation and melanosome biogenesis away from the degradative lysosomal pathway toward early stage melanosomes 4–6. However the molecular functions of the Hps1-Hps4 complex BLOC-3 remain mysterious 7–9. Like other trafficking pathways, melanosome biogenesis and transport of enzymes involved in pigmentation involves specific Rab GTPases, in this instance Rab32 and Rab38 10–12. We now demonstrate that BLOC-3 is a Rab32 and Rab38 guanine nucleotide exchange factor (GEF). Silencing of the BLOC-3 subunits Hps1 and Hps4 results in the mislocalization of Rab32 and Rab38 and reduction in pigmentation. In addition, we show that BLOC-3 can promote specific membrane recruitment of Rab32/38. BLOC-3 therefore defines a novel Rab GEF family with a specific function in the biogenesis of lysosome-related organelles.
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► The Hps1-Hps4 complex (BLOC-3) is a guanine nucleotide exchange factor (GEF) ► Purified BLOC-3 has specific GEF activity toward Rab32 and Rab38 ► BLOC-3 can promote recruitment of Rab32 and Rab38 to membranes ► BLOC-3 and its target Rabs act in the biogenesis of melanosomes
The prediction of space radiation induced cancer risk carries large uncertainties with two of the largest uncertainties being radiation quality and dose-rate effects. In risk models the ratio of the ...quality factor (QF) to the dose and dose-rate reduction effectiveness factor (DDREF) parameter is used to scale organ doses for cosmic ray proton and high charge and energy (HZE) particles to a hazard rate for γ-rays derived from human epidemiology data. In previous work, particle track structure concepts were used to formulate a space radiation QF function that is dependent on particle charge number Z, and kinetic energy per atomic mass unit, E. QF uncertainties where represented by subjective probability distribution functions (PDF) for the three QF parameters that described its maximum value and shape parameters for Z and E dependences. Here I report on an analysis of a maximum QF parameter and its uncertainty using mouse tumor induction data. Because experimental data for risks at low doses of γ-rays are highly uncertain which impacts estimates of maximum values of relative biological effectiveness (RBEmax), I developed an alternate QF model, denoted QFγAcute where QFs are defined relative to higher acute γ-ray doses (0.5 to 3 Gy). The alternate model reduces the dependence of risk projections on the DDREF, however a DDREF is still needed for risk estimates for high-energy protons and other primary or secondary sparsely ionizing space radiation components. Risk projections (upper confidence levels (CL)) for space missions show a reduction of about 40% (CL∼50%) using the QFγAcute model compared the QFs based on RBEmax and about 25% (CL∼35%) compared to previous estimates. In addition, I discuss how a possible qualitative difference leading to increased tumor lethality for HZE particles compared to low LET radiation and background tumors remains a large uncertainty in risk estimates.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The TIPS-Treasury Bond Puzzle FLECKENSTEIN, MATTHIAS; LONGSTAFF, FRANCIS A.; LUSTIG, HANNO
The Journal of finance (New York),
October 2014, Letnik:
69, Številka:
5
Journal Article
Recenzirano
We show that the price of a Treasury bond and an inflation-swapped Treasury Inflation-Protected Securities (TIPS) issue exactly replicating the cash flows of the Treasury bond can differ by more than ...$20 per $100 notional. Treasury bonds are almost always overvalued relative to TIPS. Total TIPS-Treasury mispricing has exceeded $56 billion, representing nearly 8% of the total amount of TIPS outstanding. We find direct evidence that the mispricing narrows as additional capital flows into the markets. This provides strong support for the slow-moving-capital explanation of arbitrage persistence.
Systems Chronotherapeutics Ballesta, Annabelle; Innominato, Pasquale F; Dallmann, Robert ...
Pharmacological reviews,
04/2017, Letnik:
69, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Chronotherapeutics aim at treating illnesses according to the endogenous biologic rhythms, which moderate xenobiotic metabolism and cellular drug response. The molecular clocks present in individual ...cells involve approximately fifteen clock genes interconnected in regulatory feedback loops. They are coordinated by the suprachiasmatic nuclei, a hypothalamic pacemaker, which also adjusts the circadian rhythms to environmental cycles. As a result, many mechanisms of diseases and drug effects are controlled by the circadian timing system. Thus, the tolerability of nearly 500 medications varies by up to fivefold according to circadian scheduling, both in experimental models and/or patients. Moreover, treatment itself disrupted, maintained, or improved the circadian timing system as a function of drug timing. Improved patient outcomes on circadian-based treatments (chronotherapy) have been demonstrated in randomized clinical trials, especially for cancer and inflammatory diseases. However, recent technological advances have highlighted large interpatient differences in circadian functions resulting in significant variability in chronotherapy response. Such findings advocate for the advancement of personalized chronotherapeutics through interdisciplinary systems approaches. Thus, the combination of mathematical, statistical, technological, experimental, and clinical expertise is now shaping the development of dedicated devices and diagnostic and delivery algorithms enabling treatment individualization. In particular, multiscale systems chronopharmacology approaches currently combine mathematical modeling based on cellular and whole-body physiology to preclinical and clinical investigations toward the design of patient-tailored chronotherapies. We review recent systems research works aiming to the individualization of disease treatment, with emphasis on both cancer management and circadian timing system-resetting strategies for improving chronic disease control and patient outcomes.
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