Selective inhibition of phosphodiesterases 4, 5 and 9 induces HSP20 phosphorylation and attenuates amyloid beta 1-42 mediated cytotoxicity

Phosphodiesterase (PDE) inhibitors are currently under evaluation as agents that may facilitate the improvement of cognitive impairment associated with Alzheimer's disease. Our aim was to determine whether inhibitors of PDEs 4,5 and 9 could alleviate the cytotoxic effects of amyloid beta 1–42 (Aβ1-42) via a mechanism involving the small heatshock protein HSP20. We show that inhibition of PDEs 4,5 and 9 but not 3 induces the phosphorylation of HSP20 which, in turn, increases the co-localisation between the chaperone and Aβ1-42 to significantly decrease the toxic effect of the peptide. We conclude that inhibition of PDE9 is most effective to combat Aβ1-42 cytotoxicity in our cell model

Age and size at maturity: sex, environmental variability and developmental thresholds

In most organisms, transitions between different life-history stages occur later and at smaller sizes as growth conditions deteriorate. Day and Rowe recently proposed that this pattern could be explained by the existence of developmental thresholds (minimum sizes or levels of condition below which transitions are unable to proceed). The developmental-threshold model predicts that the reaction norm of age and size at maturity will rotate in an anticlockwise manner from positive to a shallow negative slope if: (i) initial body size or condition is reduced; and/or (ii) some individuals encounter poor growth conditions at increasingly early developmental stages. We tested these predictions by rearing replicated populations of soil mites Sancassania berlesei (Michael) under different growth conditions. High-food environments produced a vertical relationship between age and size at maturity. The slope became increasingly shallow as food was reduced. By contrast, high food in the maternal environment reduced the slope of the reaction norm of age and size at maturity, whereas low food increased it. Overall, the reaction norm of age and size at maturity in S. berlesei was significantly nonlinear and differed for males and females. We describe how growth conditions, mother's environment and sex determine age and size at maturity in S. berlesei

Cooking Vessels, Volumes, and Venues: Evidence from LM IIIC Kavousi Vronda and Karphi

Glowacki, K.T., and L.P. Day. “Cooking Vessels, Volumes, and Venues: Evidence from LM IIIC Kavousi Vronda and Karphi.” Abstract of paper read at Διατροφικές συνήθειες και πρακτικές στην Κρήτη διαχρονικά [Dietary Habits and Practices in Crete over Time], Museum of Cretan Ethnology, Voroi, Crete, Greece, September 9–10, 2017.Our understanding of diet and culinary practices at the Late Minoan IIIC settlement sites of Kavousi Vronda and Karphi is based upon several different types of physical evidence that have been recovered through excavation. These include the botanical and faunal remains of plants and animals available to and consumed by the inhabitants; ceramic vessels used for the cooking and consumption of food and drink; built and fixed cooking installations, such as hearths and ovens; and the architectural spaces within the settlements where food preparation and consumption most likely took place. Each type of evidence is, by itself, incomplete and dependent upon differential preservation resulting from site formation processes specific to each archaeological context. Taken together, however, they allow us to gain important insights into key aspects of food cultivation, provisioning, processing, preparation, and convivial practices on Crete in the 12th and 11th centuries BC. In this paper, we will compare and contrast the evidence for food preparation and dining at each site, paying special attention to the forms and sizes of ceramic vessels used for cooking and consumption

Cooking Vessels, Volumes, and Venues: Evidence from LM IIIC Kavousi Vronda and Karphi

Glowacki, K.T., and L.P. Day. “Cooking Vessels, Volumes, and Venues: Evidence from LM IIIC Kavousi Vronda and Karphi.” Abstract of paper read at Διατροφικές συνήθειες και πρακτικές στην Κρήτη διαχρονικά [Dietary Habits and Practices in Crete over Time], Museum of Cretan Ethnology, Voroi, Crete, Greece, September 9–10, 2017.Our understanding of diet and culinary practices at the Late Minoan IIIC settlement sites of Kavousi Vronda and Karphi is based upon several different types of physical evidence that have been recovered through excavation. These include the botanical and faunal remains of plants and animals available to and consumed by the inhabitants; ceramic vessels used for the cooking and consumption of food and drink; built and fixed cooking installations, such as hearths and ovens; and the architectural spaces within the settlements where food preparation and consumption most likely took place. Each type of evidence is, by itself, incomplete and dependent upon differential preservation resulting from site formation processes specific to each archaeological context. Taken together, however, they allow us to gain important insights into key aspects of food cultivation, provisioning, processing, preparation, and convivial practices on Crete in the 12th and 11th centuries BC. In this paper, we will compare and contrast the evidence for food preparation and dining at each site, paying special attention to the forms and sizes of ceramic vessels used for cooking and consumption

Detoxification in rehabilitation in England: effective continuity of care or unhappy bedfellows?

There is evidence that residential detoxification alone does not provide satisfactory treatment outcomes and that outcomes are significantly enhanced when clients completing residential detoxification attend rehabilitation services (Gossop, Marsden, Stewart, & Rolfe, 1999; Ghodse, Reynolds, Baldacchino, et al., 2002). One way of increasing the likelihood of this continuity of treatment is by providing detoxification and rehabilitation within the same treatment facility to prevent drop-out, while the client awaits a rehabilitation bed or in the transition process. However, there is little research evidence available on the facilities that offer both medical detoxification and residential rehabilitation. The current study compares self-reported treatment provision in 87 residential rehabilitation services in England, 34 of whom (39.1%) reported that they offered detoxification services within their treatment programmes. Although there were no differences in self-reported treatment philosophies, residential rehabilitation services that offered detoxification were typically of shorter duration overall, had significantly more beds and reported offering more group work than residential rehabilitation services that did not offer detoxification. Outcomes were also different, with twice as many clients discharged on disciplinary grounds from residential rehabilitation services without detoxification facilities. The paper questions the UK classification of residential drug treatment services as either detoxification or rehabilitation and suggests the need for greater research focus on the aims, processes and outcomes of this group of treatment providers

Investigating the role of Hedgehog/GLI1 signaling in glioblastoma cell response to temozolomide.

Resistance to chemotherapy substantially hinders successful glioblastoma (GBM) treatment, contributing to an almost 100% mortality rate. Resistance to the frontline chemotherapy, temozolomide (TMZ), arises from numerous signaling pathways that are deregulated in GBM, including Hedgehog (Hh) signaling. Here, we investigate suppression of Hh signaling as an adjuvant to TMZ using U87-MG and T98G cell lines as in vitro models of GBM. We found that silencing GLI1 with siRNA reduces cell metabolic activity by up to 30% in combination with TMZ and reduces multidrug efflux activity by 2.5-fold. Additionally, pharmacological GLI inhibition modulates nuclear p53 levels and decreases MGMT expression in combination with TMZ. While we surprisingly found that silencing GLI1 does not induce apoptosis in the absence of TMZ co-treatment, we discovered silencing GLI1 without TMZ co-treatment induces senescence as evidenced by a significant 2.3-fold increase in senescence associated β-galactosidase staining, and this occurs in a loss of PTEN-dependent manner. Finally, we show that GLI inhibition increases apoptosis in glioma stem-like cells by up to 6.8-fold in combination with TMZ, and this reduces the size and number of neurospheres grown from glioma stem-like cells. In aggregate, our data warrant the continued investigation of Hh pathway inhibitors as adjuvants to TMZ chemotherapy and highlight the importance of identifying signaling pathways that determine whether co-treatment will be successful

Is the Yb2Ti2O7 pyrochlore a quantum spin ice?

We use numerical linked cluster (NLC) expansions to compute the specific heat, C(T), and entropy, S(T), of a quantum spin ice model of Yb2Ti2O7 using anisotropic exchange interactions recently determined from inelastic neutron scattering measurements and find good agreement with experimental calorimetric data. In the perturbative weak quantum regime, this model has a ferrimagnetic ordered ground state, with two peaks in C(T): a Schottky anomaly signalling the paramagnetic to spin ice crossover followed at lower temperature by a sharp peak accompanying a first order phase transition to the ferrimagnetic state. We suggest that the two C(T) features observed in Yb2Ti2O7 are associated with the same physics. Spin excitations in this regime consist of weakly confined spinon-antispinon pairs. We suggest that conventional ground state with exotic quantum dynamics will prove a prevalent characteristic of many real quantum spin ice materials.Comment: 8 pages (two-column), 9 figure

Universality of residence-time distributions in non-adiabatic stochastic resonance

We present mathematically rigorous expressions for the residence-time and first-passage-time distributions of a periodically forced Brownian particle in a bistable potential. For a broad range of forcing frequencies and amplitudes, the distributions are close to periodically modulated exponential ones. Remarkably, the periodic modulations are governed by universal functions, depending on a single parameter related to the forcing period. The behaviour of the distributions and their moments is analysed, in particular in the low- and high-frequency limits.Comment: 8 pages, 1 figure New version includes distinction between first-passage-time and residence-time distribution

Superscaling in inclusive electron-nucleus scattering

We investigate the degree to which the scaling functions $F(\psi')$ derived from cross sections for inclusive electron-nucleus quasi-elastic scattering define the same function for different nuclei. In the region where the scaling variable $\psi'< 0$, we find that this superscaling is experimentally realized to a high degree.Comment: Corrected previously mislabeled figures and cross references; 9 pages, 4 color figures, using BoxedEPS and REVTeX; email correspondence to [email protected]