NAP (davunetide) rescues neuronal dysfunction in a Drosophila model of tauopathy

Alzheimer’s disease (AD) is a devastating neurodegenerative disease causing irreversible cognitive decline in the elderly. There is no disease-modifying therapy for this condition and the mechanisms underpinning neuronal dysfunction and neurodegeneration are unclear. Compromised cytoskeletal integrity within neurons is reported in AD. This is believed to result from loss-of-function of the microtubule-associated protein tau, which becomes hyper-phosphorylated and deposits into neurofibrillary tangles in AD. We have developed a Drosophila model of tauopathy in which abnormal human tau mediates neuronal dysfunction characterised by microtubule destabilisation, axonal transport disruption, synaptic defects and behavioural impairments. Here we show that a microtubule-stabilising drug, NAPVSIPQ (NAP), prevents as well as reverses these phenotypes even after they have become established. Moreover, it does not alter abnormal tau levels indicating that it by-passes toxic tau altogether. Thus, microtubule stabilisation is a disease-modifying therapeutic strategy protecting against tau-mediated neuronal dysfunction, which holds great promise for tauopathies like AD

Clinical and cost-effectiveness of capecitabine and tegafur with uracil for the treatment of metastatic colorectal cancer: systematic review and economic evaluation

Objectives: To evaluate the clinical and costeffectiveness of capecitabine and tegafur with uracil (UFT/LV) as first-line treatments for patients with metastatic colorectal cancer, as compared with 5- fluorouracil/folinic acid (5-FU/FA) regimens. Data sources: Electronic databases, reference lists of relevant articles and sponsor submissions were also consulted. Review methods: Systematic searches, selection against criteria and quality assessment were performed to obtain data from relevant studies. Costs were estimated through resource-use data taken from the published trials and the unpublished sponsor submissions. Unit costs were taken from published sources, where available. An economic evaluation was undertaken to compare the cost-effectiveness of capecitabine and UFT/LV with three intravenous 5- FU/LV regimens widely used in the UK: the Mayo, the modified de Gramont regimen and the inpatient de Gramont regimens. Results: The evidence suggests that treatment with capecitabine improves overall response rates and has an improved adverse effect profile in comparison with 5-FU/LV treatment with the Mayo regimen, with the exception of hand–foot syndrome. Time to disease progression or death after treatment with UFT/LV in one study appears to be shorter than after treatment with 5-FU/LV with the Mayo regimen, although it also had an improved adverse effect profile. Neither capecitabine nor UFT/LV appeared to improve healthrelated quality of life. Little information on patient preference was available for UFT/LV, but there was indicated a strong preference for this over 5-FU/LV. The total cost of capecitabine and UFT/LV treatments were estimated at £2111 and £3375, respectively, compared with the total treatment cost for the Mayo regimen of £3579. Cost estimates were also presented for the modified de Gramont and inpatient de Gramont regimens. These were £3684 and £6155, respectively. No survival advantage was shown in the RCTs of the oral drugs against the Mayo regimen. Cost savings of capecitabine and UFT/LV over the Mayo regimen were estimated to be £1461 and £209, respectively. Drug acquisition costs were higher for the oral therapies than for the Mayo regimen, but were offset by lower administration costs. Adverse event treatment costs were similar across the three regimens. It was inferred that there was no survival difference between the oral drugs and the de Gramont regimens. Cost savings of capecitabine and UFT/LV over the modified de Gramont regimen were estimated to be £1353 and £101, respectively, and over the inpatient de Gramont regimen were estimated to be £4123 and £2870, respectively. Conclusions: The results show that there are cost savings associated with the use of oral therapies. No survival difference has been proven between the oral drugs and the Mayo regimen. In addition, no evidence of a survival difference between the Mayo regimen and the de Gramont regimens has been identified. However, improved progression-free survival and an improved adverse event profile have been shown for the de Gramont regimen over the Mayo regimen. Further research is recommended into the following areas: quality of life data should be included in trials of colorectal cancer treatments; the place of effective oral treatments in the treatment of colorectal cancer, the safety mechanisms needed to ensure compliance and the monitoring of adverse effects; the optimum duration of treatment; the measurement of patient preference; and a phase III comparative trial of capecitabine and UFT/LV versus modified de Gramont treatment to determine whether there was any survival advantage and to collate the necessary economic data

Charm Meson Mixing: An Experimental Review

We review current experimental results on charm mixing and CP violation. We survey experimental techniques, including time-dependent, time-independent, and quantum-correlated measurements. We review techniques that use a slow pion tag from D*+ --> pi+ D0 + c.c. decays and those that do not, and cover two-body and multi-body D0 decay modes. We provide a summary of D-mixing results to date and comment on future experimental prospects at the LHC and other new or planned facilities.Comment: 53 pages, 29 figures, 8 table

Effects of motion on jet exhaust noise from aircraft

The various problems involved in the evaluation of the jet noise field prevailing between an observer on the ground and an aircraft in flight in a typical takeoff or landing approach pattern were studied. Areas examined include: (1) literature survey and preliminary investigation, (2) propagation effects, (3) source alteration effects, and (4) investigation of verification techniques. Sixteen problem areas were identified and studied. Six follow-up programs were recommended for further work. The results and the proposed follow-on programs provide a practical general technique for predicting flyover jet noise for conventional jet nozzles

Inflation Targeting in Financially Stable Economies: Has it been Flexible Enough?

The events surrounding the financial crisis and recession of 2008-2009 required significant policy responses by central banks. For formal inflation targeters (IT) a natural question arises about whether IT frameworks were flexible enough to address this unprecedented policy environment. In this paper we tackle this question by assessing the policy responses to the crisis of nine IT central banks that did not face systemic problems in their banking or financial systems. We first document substantial deviations of actual policy responses from prescriptions of conventional monetary policy reaction functions, beginning in the second half of 2008. Although several explanations for the deviations are offered, highlighting the extreme challenges at the time, we can more easily reconcile the findings with a decline in the persistence of monetary policy, again, in all cases. Second, we document the banks’ non-monetary-policy measures adopted at the time, and estimate their impact on local money markets (both in local currency and US dollars) and on exchange rates. While these measures helped broadly to normalize markets, firm conclusions on the effectiveness of specific measures are elusive, owing to the difficulty in comparing the different mix of measures adopted across countries and the significant heterogeneity in specific economies’ responses to these non-monetary policy measures.

Spin-Current Relaxation Time in Spin-Polarized Heisenberg Paramagnets

We study the spatial Fourier transform of the spin correlation function G_q(t) in paramagnetic quantum crystals by direct simulation of a 1d lattice of atoms interacting via a nearest-neighbor Heisenberg exchange Hamiltonian. Since it is not practical to diagonalize the s=1/2 exchange Hamiltonian for a lattice which is of sufficient size to study long-wavelength (hydrodynamic) fluctuations, we instead study the s -> infinity limit and treat each spin as a vector with a classical equation of motion. The simulations give a detailed picture of the correlation function G_q(t) and its time derivatives. At high polarization, there seems to be a hierarchy of frequency scales: the local exchange frequency, a wavelength-independent relaxation rate 1/tau that vanishes at large polarization P ->1, and a wavelength-dependent spin-wave frequency proportional to q^2. This suggests a form for the correlation function which modifies the spin diffusion coefficients obtained in a moments calculation by Cowan and Mullin, who used a standard Gaussian ansatz for the second derivative of the correlation function.Comment: 6 pages, 3 figure

Diverse hypolithic refuge communities in the McMurdo Dry Valleys

Hyper-arid deserts present extreme challenges to life. The environmental buffering provided by quartz and other translucent rocks allows hypolithic microbial communities to develop on sub-soil surfaces of such rocks. These refuge communities have been reported, for many locations worldwide, to be predominantly cyanobacterial in nature. Here we report the discovery in Antarctica’s hyper-arid McMurdo Dry Valleys of three clearly distinguishable types of hypolithic community. Based on gross colonization morphology and identification of dominant taxa, we have classified hypolithic communities as Type I (cyanobacterial dominated), Type II (fungal dominated) and Type III (moss dominated). This discovery supports a growing awareness of the high biocomplexity in Antarctic deserts, emphasizes the possible importance of cryptic microbial communities in nutrient cycling and provides evidence for possible successional community processes within a cold arid landscape