Unexpected cell type-dependent effects of autophagy on polyglutamine aggregation revealed by natural genetic variation in C. elegans.

BACKGROUND: Monogenic protein aggregation diseases, in addition to cell selectivity, exhibit clinical variation in the age of onset and progression, driven in part by inter-individual genetic variation. While natural genetic variants may pinpoint plastic networks amenable to intervention, the mechanisms by which they impact individual susceptibility to proteotoxicity are still largely unknown. RESULTS: We have previously shown that natural variation modifies polyglutamine (polyQ) aggregation phenotypes in C. elegans muscle cells. Here, we find that a genomic locus from C. elegans wild isolate DR1350 causes two genetically separable aggregation phenotypes, without changing the basal activity of muscle proteostasis pathways known to affect polyQ aggregation. We find that the increased aggregation phenotype was due to regulatory variants in the gene encoding a conserved autophagy protein ATG-5. The atg-5 gene itself conferred dosage-dependent enhancement of aggregation, with the DR1350-derived allele behaving as hypermorph. Surprisingly, increased aggregation in animals carrying the modifier locus was accompanied by enhanced autophagy activation in response to activating treatment. Because autophagy is expected to clear, not increase, protein aggregates, we activated autophagy in three different polyQ models and found a striking tissue-dependent effect: activation of autophagy decreased polyQ aggregation in neurons and intestine, but increased it in the muscle cells. CONCLUSIONS: Our data show that cryptic natural variants in genes encoding proteostasis components, although not causing detectable phenotypes in wild-type individuals, can have profound effects on aggregation-prone proteins. Clinical applications of autophagy activators for aggregation diseases may need to consider the unexpected divergent effects of autophagy in different cell types

Comportamento alimentar do peixe recifal Sargentinho (Abudefduf saxatilis) em Santa Catarina

TCC(graduação) - Universidade Federal de Santa Catarina. Centro de Ciências Biológicas. Biologia.Estudos da ecologia alimentar de peixes recifais são essenciais para compreender o fluxo energético nestes ecossistemas. Diversos estudos abordam o comportamento alimentar das espécies, porém, são poucos os estudos que avaliam esse comportamento ao longo do dia. Visto isso, este estudo busca observar e quantificar o comportamento alimentar do peixe recifal Sargentinho (Abudefduf saxatilis) no litoral de Santa Catarina, Brasil. Foram realizados mergulhos livres e autônomos, nos quais empregou-se busca ativa por indivíduos de A. saxatilis. Utilizando o método de animal focal, um indivíduo era seguido de cada vez por um minuto ou até sua primeira mordida, quando era anotado em qual substrato o mesmo estava mordendo, seu comprimento total e o horário. Para verificar se [1] há diferenças no substrato de forrageio ao longo do dia; e se [2] há diferença no substrato de forrageio entre classes de tamanho, foram utilizados teste-G. Sete substratos foram utilizados pela espécie para forrageio, sendo a coluna d’água o predominante (79,7% dos indivíduos observados), seguido pelos substratos bentônicos: matriz algal epilítica (16,6%), Sargassum sp. (3,3%), alga calcária (0,22%), Palythoa sp. (0,12%) e desova de A. saxatilis (0,06%). As análises sugerem A. saxatilis prefere forragear na coluna d’água durante toda a manhã e no final da tarde, com maior intensidade antes do meio dia, enquanto no começo da tarde preferem o componente bentônico. Estas diferenças podem ser explicadas pelo comportamento oportunista da espécie, que o permite explorar diferentes substratos para forrageio. Também foi demonstrado que as classes de tamanho utilizam diferentes substratos de forrageio, indicando diferenças nas demandas energéticas ao longo de sua ontogenia. Por fim este trabalho revela a grande importância do comportamento alimentar na compreensão geral da ecologia alimentar para a espécie.Reef fish feeding ecology is essential for understating the energy flow of these ecosystems. Many studies approach feeding behaviour, although those approaching the variation of feeding behaviours during the day are scarce. This study aims to observe the feeding behaviour of the reef fish Sargeant major (Abudefduf saxatilis) on the coast of Santa Catarina state, Brazil. For this, free and SCUBA dives were conducted, in which active search for A. saxatilis was performed. Using the focal animal method, an individual was followed each time for one minute or until it’s first bite, when the bitten substrate, total length and time was recorded. To verify if [1] there are differences among the foraging substratum during the day; and if [2] there are differences among foraging substratum between different size classes, a G-test was used. Seven substrata were utilized, being the water column predominant (79,7% of observed individuals), followed by the benthic substrata: epilitic algal matrix (16,6%), Sargassum sp. (3,3%), calcareous algae (0,22%), Palythoa sp. (0,12%) and A. saxatilis eggs (0,06%). The analysis suggests that A. saxatilis prefer to forage on the water column during the morning and end of the evening, with a higher intensity of bites before midday, while at the beginning of the evening benthic substrata are preferred. These differences can be explained by the opportunistic behaviour of the species, that allows the exploration of different substrata. It was also demonstrated that individual size classes use different foraging substrata, indicating different energetic demands according to the species different ontogeny. Lastly, this study verified the important role of feeding behaviour in the general understanding of the species feeding ecology

Healthcare Access for Elderly African American Type 2 Diabetics on Medicare

AbstractPrior research has shown that African Americans have less access to healthcare than do White Americans. The study’s purpose was to determine the association between race/ethnicity and quality care measures in a population of Medicare recipients with Type 2 diabetes, aged 65 75 years and over. Covariates predicted satisfaction with doctor care, compassionate doctor care, and indifferent doctor care using Andersen’s health behavior theory. The Medicare Current Beneficiary Survey (MCBS) sample consisted of 1,716 people with Type 2 diabetes, with most (76.6%) being non-Hispanic Whites, and the remainder non-Hispanic Blacks (10.8%) and Hispanics (12.6%). Race/ethnicity were associated with quality-of-care measures assessed by one-way analysis of variance, with multiple regression showing racial and ethnic differences. Satisfaction with doctor care was higher for Hispanic Americans under 75 years of age, respondents who were male, and those who had fewer than 4.5 chronic conditions, F(7, 1708) = 9.30, p = .001, R² = .037. No racial/ethnic differences were shown on compassionate doctor care, although increased adherence existed for all groups, F(7, 1708) = 3.09, p = .003, R² = .013. Indifferent doctor care revealed racial/ethnic differences between the three groups. Differences were higher for Hispanic respondents and those with more chronic conditions and low adherence frequency, F(7, 1708) = 4.64, p = .001, R² = .019. Differences found that enhance the positive social change imperative of providing care through the patient-centered medical home may compel further research. Policymakers should consider this innovative model to reduce healthcare disparities

Legendre PRF (Multiple) Key Attacks and the Power of Preprocessing

Due to its amazing speed and multiplicative properties the Legendre PRF recently finds widespread applications e.g. in Ethereum 2.0, multiparty computation and in the quantum-secure signature proposal LegRoast. However, its security is not yet extensively studied. The Legendre PRF computes for a key $k$ on input $x$ the Legendre symbol $L_k(x) = \left( \frac {x+k} {p} \right)$ in some finite field \F_p. As standard notion, PRF security is analysed by giving an attacker oracle access to $L_k(\cdot)$. Khovratovich\u27s collision-based algorithm recovers $k$ using $L_k(\cdot)$ in time $\sqrt{p}$ with constant memory. It is a major open problem whether this birthday-bound complexity can be beaten. We show a somewhat surprising wide-ranging analogy between the discrete logarithm problem and Legendre symbol computations. This analogy allows us to adapt various algorithmic ideas from the discrete logarithm setting. More precisely, we present a small memory multiple-key attack on $m$ Legendre keys $k_1, \ldots, k_m$ in time $\sqrt{mp}$, i.e. with amortized cost $\sqrt{p/m}$ per key. This multiple-key attack might be of interest in the Ethereum context, since recovering many keys simultaneously maximizes an attacker\u27s profit. Moreover, we show that the Legendre PRF admits precomputation attacks, where the precomputation depends on the public $p$ only -- and not on a key $k$. Namely, an attacker may compute e.g. in precomputation time $p^{\frac 2 3}$ a hint of size $p^{\frac 1 3}$. On receiving access to $L_k(\cdot)$ in an online phase, the attacker then uses the hint to recover the desired key $k$ in time only $p^{\frac 1 3}$. Thus, the attacker\u27s online complexity again beats the birthday-bound. In addition, our precomputation attack can also be combined with our multiple-key attack. We explicitly give various tradeoffs between precomputation and online phase. E.g. for attacking $m$ keys one may spend time $mp^{\frac 2 3}$ in the precomputation phase for constructing a hint of size $m^2 p^{\frac 1 3}$. In an online phase, one then finds {\em all $m$ keys in total time} only $p^{\frac 1 3}$. Precomputation attacks might again be interesting in the Ethereum 2.0 context, where keys are frequently changed such that a heavy key-independent precomputation pays off

McEliece needs a Break -- Solving McEliece-1284 and Quasi-Cyclic-2918 with Modern ISD

With the recent shift to post-quantum algorithms it becomes increasingly important to provide precise bit-security estimates for code-based cryptography such as McEliece and quasi-cyclic schemes like BIKE and HQC. While there has been significant progress on information set decoding (ISD) algorithms within the last decade, it is still unclear to which extent this affects current cryptographic security estimates. We provide the first concrete implementations for representation-based ISD, such as May-Meurer-Thomae (MMT) or Becker-Joux-May-Meurer (BJMM), that are parameter-optimized for the McEliece and quasi-cyclic setting. Although MMT and BJMM consume more memory than naive ISD algorithms like Prange, we demonstrate that these algorithms lead to significant speedups for practical cryptanalysis on medium-sized instances (around 60 bit). More concretely, we provide data for the record computations of McEliece-1223 and McEliece-1284 (old record: 1161), and for the quasi-cyclic setting up to code length 2918 (before: 1938). Based on our record computations we extrapolate to the bit-security level of the proposed BIKE, HQC and McEliece parameters in NIST\u27s standardization process. For BIKE/HQC, we also show how to transfer the Decoding-One-Out-of-Many (DOOM) technique to MMT/BJMM. Although we achieve significant DOOM speedups, our estimates confirm the bit-security levels of BIKE and HQC. For the proposed McEliece round-3 parameter sets of 192 and 256 bit, however, our extrapolation indicates a security level overestimate by roughly 20 and 10 bits, respectively, i.e., the high-security McEliece instantiations may be a bit less secure than desired

Well-defined hyperstar copolymers based on a thiol–yne hyperbranched core and a poly(2-oxazoline) shell for biomedical applications

Well defined ‘hyperstar’ copolymers were synthesized by combining hyperbranched polymers produced by thiol–yne chemistry with poly(oxazoline)s. The hyperbranched core was prepared using an AB2 monomer and a trifunctional alkene, applying a monomer feeding approach. The degree of branching was high (0.9) while maintaining low dispersities (1.3). Poly(2-ethyl-2-oxazoline) (PEtOx) functionalized with a thiol end group was coupled to the surface of the hyperbranched structure accessing terminal alkyne units. PEtOx-SH was produced by the termination of the living polymerization with ethyl xanthate and subsequent conversion to thiol under alkaline conditions. The degree of polymerization was varied producing PEtOx with 23 or 42 repeating units, respectively with a dispersity of around 1.1. After conjugation of the polymer arms, hyperstar copolymers were characterized by SEC, NMR spectroscopy, light scattering, and AFM. The polymers were able to encapsulate the hydrophobic dye Nile red within the core of the structure with loading efficiencies between 0.3 and 0.9 wt%. Cytotoxicity of the hyperstars was assessed using A2780 human ovarian carcinoma cells resulting in IC50 values of around 0.7 mg ml−1. Successful internalization and colocalization with lysosomal compartments was observed by confocal microscopy studies

Evidence for Intergalactic Absorption in the TeV Gamma-Ray Spectrum of Mkn 501

The recent HEGRA observations of the blazar Mkn 501 show strong curvature in the very high energy gamma-ray spectrum. Applying the gamma-ray opacity derived from an empirically based model of the intergalactic infrared background radiation field (IIRF), to these observations, we find that the intrinsic spectrum of this source is consistent with a power-law: dN/dE~ E^-alpha with alpha=2.00 +/- 0.03 over the range 500 GeV - 20 TeV. Within current synchrotron self-Compton scenarios, the fact that the TeV spectral energy distribution of Mkn 501 does not vary with luminosity, combined with the correlated, spectrally variable emission in X-rays, as observed by the BeppoSAX and RXTE instruments, also independently implies that the intrinsic spectrum must be close to alpha=2. Thus, the observed curvature in the spectrum is most easily understood as resulting from intergalactic absorption.Comment: 7 pages, 1 figure, accepted in ApJ Letters 1999 April

Interactions of ultrahigh-energy cosmic rays with photons in the galactic center

Ultrahigh-energy cosmic rays passing through the central region of the Galaxy interact with starlight and the infrared photons. Both nuclei and protons generate secondary fluxes of photons and neutrinos on their passage through the central region. We compute the fluxes of these secondary particles, the observations of which can be used to improve one's understanding of origin and composition of ultrahigh-energy comic rays, especially if the violation of the Greisen--Zatespin--Kuzmin cutoff is confirmed by the future data.Comment: 8 pages, 2 figure

Effects of Crime Type and Location on Park Use Behavior

Crime and the fear of crime can be a barrier to park use, and locations of crimes can have varied effects. Unsafe areas in or around the park, around the residence, or along the route to the park can alter park use behavior. Our study aimed to examine associations between objective measures of types and location of crimes and park use behaviors. In 2013 we surveyed a sample (N = 230) of residents in Greensboro, North Carolina, about park use, with responses matched to objective crime and spatial measures. We measured all crimes and violent crimes near home, near the closest park, and along the shortest route between home and park. By using ordered and binary logistic modeling, we examined the relationships between the locations of crime and park use and duration of park visit, park rating, and never visiting parks. Additional models included distance to the closest park. Increased crime in parks and near home was associated with fewer park visits. Greater violent crime in all locations was related to fewer park visits. Park ratings were lower for parks with high violent crime rates. Given the importance of parks as settings for outdoor recreation and physical activity, crime may have a detrimental effect on physical activity and, therefore, public health

Chandra Observations of 3C Radio Sources with z<0.3: Nuclei, Diffuse Emission, Jets and Hotspots

We report on our Chandra Cycle 9 program to observe half of the 60 (unobserved by Chandra) 3C radio sources at z<0.3 for 8 ksec each. Here we give the basic data: the X-ray intensity of the nuclei and any features associated with radio structures such as hot spots and knots in jets. We have measured fluxes in soft, medium and hard bands and are thus able to isolate sources with significant intrinsic column density. For the stronger nuclei, we have applied the standard spectral analysis which provides the best fit values of X-ray spectral index and column density. We find evidence for intrinsic absorption exceeding a column density of 10^{22} cm^{-2} for one third of our sources.Comment: 12 pages, 37 figures (the complete version of the paper with all figures is available on line, see appendix for details), ApJ accepte