Molecular basis for the interplay of apoptosis and proliferation mediated by Bcl-xL:Bim interactions in pancreatic cancer cells

A major mechanism through which cancer cells avoid apoptosis is by promoting the association of anti-apoptotic members of the pro-survival Bcl-2 protein family (like Bcl-2 and Bcl-xL) with BH3 domain-only proteins (like Bim and Bid). Apoptosis and cell proliferation have been shown to be linked for many cancers but the molecular basis for this link is far from understood. We have identified the Bcl-xL:Bim protein–protein interface as a direct regulator of proliferation and apoptosis in pancreatic cancer cells. We were able to predict and subsequently verify experimentally the effect of various Bcl-xL single-point mutants (at the position A142) on binding to Bim by structural analysis and computational modeling of the inter-residue interactions at the Bcl-xL:Bim protein–protein interface. The mutants A142N, A142Q, and A142Y decreased binding of Bim to Bcl-xL and A142S increased this binding. The Bcl-xL mutants, with decreased affinity for Bim, caused an increase in apoptosis and a corresponding decrease in cell proliferation. However, we could prevent these effects by introducing a small interfering RNA (siRNA) targeted at Bim. These results show a novel role played by the Bcl-xL:Bim interaction in regulating proliferation of pancreatic cancer cells at the expense of apoptosis. This study presents a physiologically relevant model of the Bcl-xL:Bim interface that can be used for rational therapeutic design for the inhibition of proliferation and cancer cell resistance to apoptosis

Superconformal Coset Equivalence from Level-Rank Duality

We construct a one-to-one map between the primary fields of the N=2 superconformal Kazama-Suzuki models G(m,n,k) and G(k,n,m) based on complex Grassmannian cosets, using level-rank duality of Wess-Zumino-Witten models. We then show that conformal weights, superconformal U(1) charges, modular transformation matrices, and fusion rules are preserved under this map, providing strong evidence for the equivalence of these coset models.Comment: 25 pages, harvmac, no figures, added referenc

Structure and lithium-ion dynamics in fluoride-doped cubic Li7La3Zr2O12 (LLZO) garnet for Li solid-state battery applications

The lithium-stuffed garnet Li7La3Zr2O12 (LLZO), when suitably doped, is a promising candidate material for use as a solid-state electrolyte within advanced Li-ion batteries. It possesses the thermal and mechanical stability of many inorganic ceramics, while exhibiting high Li+ ionic conductivities often associated with conventional liquid electrolytes, making it an ideal component for large-scale energy storage. However, only the high-temperature cubic phase has any meaningful Li-ion conductivity. Typically the formation of this phase is achieved through cation doping (e.g., Al3+ on the Li site) to lower the Li content and so disrupt Li ordering. However, Li-site doping, in particular, may potentially lead to some disruption of the Li-ion conduction pathways and suboptimal ionic conductivities. Consequently, other novel doping strategies involving the anion site are gaining traction, for example, F– for O2– as an alternative strategy to lower the Li content without directly blocking the lithium-diffusion pathways. For the first time, classical potential-based simulations have been employed to simulate the incorporation of fluoride anions into LLZO. Low incorporation energies have been calculated, suggesting fluoride anions are stable on the oxygen sites with a compensating lithium-ion vacancy defect. Molecular dynamics calculations suggest a definitive phase transition to the more desirable cubic phase of LLZO when doped with fluoride at temperature significantly lower than that for the tetragonal–cubic phase transition found for pure LLZO. Remarkably, the lithium-ion transport properties are shown to improve in the fluoride-doped samples particularly at low temperatures due to the stabilization of the cubic phase, suggesting anion doping of garnet systems may be a compelling alternative route to optimize the ionic conductivity

An analytically solvable model of the effect of magnetic breakdown on angle-dependent magnetoresistance in a quasi-two-dimensional metal

We have developed an analytical model of angle-dependent magnetoresistance oscillations (AMROs) in a quasi-two-dimensional metal in which magnetic breakdown occurs. The model takes account of all the contributions from quasiparticles undergoing both magnetic breakdown and Bragg reflection at each junction and allows extremely efficient simulation of data which can be compared with recent experimental results on the organic metal kappa-ET2Cu(NCS)2. AMROs resulting from both closed and open orbits emerge naturally at low field, and the model enables the transition to breakdown-AMROs with increasing field to be described in detail.Comment: 4 pages, 3 figure

Current Approaches to Seasonal to Interannual Climate Predictions

This review paper presents an assessment of the current state of knowledge and capability in seasonal climate prediction at the end of the 20th century. The discussion covers the full range of issues involved in climate forecasting, including (1) the theory and empirical evidence for predictability; (2) predictions of surface boundary conditions, such as sea surface temperatures (SSTs) that drive the predictable part of the climate; (3) predictions of the climate; and (4) a brief consideration of the application of climate forecasts. Within this context, the research of the coming decades that seeks to address shortcomings in each area is described

Current approaches to season-to-interannual climate prediction

This review paper presents an assessment of the current state of knowledge and capability in seasonal climate prediction at the end of the 20th century. The discussion covers the full range of issues involved in climate forecasting, including (1) the theory and empirical evidence for predictability; (2) predictions of surface boundary conditions, such as sea surface temperatures (SSTs) that drive the predictable part of the climate; (3) predictions of the climate; and (4) a brief consideration of the application of climate forecasts. Within this context, the research of the coming decades that seeks to address shortcomings in each area is described

Spatial distribution of organic carbon contents of Langkawi island coastal waters, Malaysia

The distribution of total organic carbon content (TOC) in surface sediments of 5 zones in the area of Langkawi Island coastal waters were analysed by using wet oxidation dichromate method. A total of 51 samples were obtained using Ekman Grab from Kuah coastal area (Zone A), Cenang coastal area (Zone B), Datai River (Zone E), Kilim River (Zone D) and Pulau Tuba waters (Zone E). In this study, the highest mean of organic carbon was found in zone A (2.27±0.59), followed by zone C (2.09±0.14), zone D (2.01±0.15), zone E (1.89±0.28) and the lowest is in zone B (1.72±0.38). A relatively weak positive relationship was also found between the organic carbon content and the sediments grain size

Controlling magnetic order and quantum disorder in molecule-based magnets

We investigate the structural and magnetic properties of two molecule-based magnets synthesized from the same starting components. Their different structural motifs promote contrasting exchange pathways and consequently lead to markedly different magnetic ground states. Through examination of their structural and magnetic properties we show that [Cu(pyz)(H2O)(gly)2](ClO4)2 may be considered a quasi-one-dimensional quantum Heisenberg antiferromagnet whereas the related compound [Cu(pyz)(gly)](ClO4), which is formed from dimers of antiferromagnetically interacting Cu2+ spins, remains disordered down to at least 0.03 K in zero field but shows a field-temperature phase diagram reminiscent of that seen in materials showing a Bose-Einstein condensation of magnons

Seasonal Comparison of the Response of CCM3.6, ECHAM4.5 and COLA2.0 Atmospheric Models to Observed SSTs

The main features of three atmospheric general circulation models forced with monthly-mean, observed sea surface temperature for the 1979-1995 period are analyzed and compared with observational data. The ensemble means and intra-ensemble standard deviations of several variables were investigated for the two seasons December-January-February and June-July-August. Correlations of the ensemble mean anomalies with observational data and with the indices Nino-3 and the Atlantic Dipole were also calculated. The probability distribution function of the precipitation at different regions was also examined, as well as the internal and external variance of the precipitation in the three models. No model has uniformly better characteristics than the others. On the contrary, each model has strengths and weaknesses that depend on the region and season

An evaluation of a pilot of daily testing of SARS-CoV-2 contacts in acute hospital and ambulance trusts in England

OBJECTIVES: Healthcare worker (HCW) SARS-CoV-2 contacts in England have been required to quarantine, creating staff shortages. We piloted daily contact testing (DCT) to assess its feasibility as an alternative. STUDY DESIGN: Observational service evaluation. METHODS: We conducted an observational service evaluation of seven-day daily contact testing using antigen lateral flow devices, (LFDs) at four acute hospital trusts and one ambulance trust in England. Mixed methods were employed, utilising aggregate and individual-level test monitoring data, semi-structured interviews, and a survey of eligible contacts. RESULTS: In total, 138 HCWs were identified as contacts of a confirmed SARS-CoV-2 case. Of these, 111 (80%) consented to daily LFD testing, of whom 82 (74%) completed the required programme without interruption, and 12 (11%) completed with interruption. Fifty-eight (52%) participants and two (7·4%) non-participants completed the survey. In total, 28 interviews were conducted with participants, site and infection control leads, and union representatives. One participant tested positive on LFD and polymerase chain reaction (PCR) test. Three participants tested positive on PCR but not LFD. DCT was well-accepted by trusts and staff. Participants reported no relaxation of their infection prevention and control behaviours. No incidents of transmission were detected. An estimated 729 potential days of work absence were averted. CONCLUSIONS: DCT can be acceptably operated in a healthcare setting, averting quarantine-related work absences in HCW SARS-CoV-2 contacts