MI(R,)G(R) and British Covert Operations, 1939-42

The Military Intelligence (Research) Department of the British War Office was tasked in 1940 with encouraging and supporting armed resistance in occupied Europe and the Axis-controlled Middle East. The major contention of this paper is that, in doing so, MI(R) performed a key role in British strategy in 1940-42 and in the development of what are now known as covert operations. MI(R) developed an organic, but coherent doctrine for such activity which was influential upon the Special Operations Executive (SOE) and its own sub-branch, G(R), which applied this doctrine in practice in East Africa and the Middle East in 1940-41. It was also here that a number of key figures in the development of covert operations and special forces first cut their teeth, the most notable being Major Generals Colin Gubbins and Orde Wingate.

Heme oxygenase-1 protects against Alzheimer’s amyloid-β1-42 induced toxicity via carbon monoxide production

Heme oxygenase-1 (HO-1), an inducible enzyme up-regulated in Alzheimer‟s disease (AD), catabolises heme to biliverdin, Fe2+ and carbon monoxide (CO). CO can protect neurones from oxidative stress-induced apoptosis by inhibiting Kv2.1 channels, which mediate cellular K+ efflux as an early step in the apoptotic cascade. Since apoptosis contributes to the neuronal loss associated with amyloid β peptide (Aβ) toxicity in AD, we investigated the protective effects of HO-1 and CO against Aβ1-42 toxicity in SH-SY5Y cells, employing cells stably transfected with empty vector or expressing the cellular prion protein, PrPc, and rat primary hippocampal neurons. Aβ1-42 (containing protofibrils) caused a concentrationdependent decrease in cell viability, attributable at least in part to induction of apoptosis, with the PrPc expressing cells showing greater susceptibility to Aβ1-42 toxicity. Pharmacological induction or genetic over-expression of HO-1 significantly ameliorated the effects of Aβ1-42. The CO-donor CORM-2 protected cells against Aβ1-42 toxicity in a concentration-dependent manner. Electrophysiological studies revealed no differences in the outward current pre- and post-Aβ1-42 treatment suggesting that K+ channel activity is unaffected in these cells. Instead, Aβ toxicity was reduced by the L-type Ca2+ channel blocker nifedipine, and by the CaMKKII inhibitor, STO-609. Aβ also activated the downstream kinase, AMP-dependent protein kinase (AMPK). CO prevented this activation of AMPK. Our findings indicate that HO-1 protects against Aβ toxicity via production of CO. Protection does not arise from inhibition of apoptosis-associated K+ efflux, but rather by inhibition of AMPK activation, which has been recently implicated in the toxic effects of Aβ. These data provide a novel, beneficial effect of CO which adds to its growing potential as a therapeutic agent.

Surface behaviour and lipid interaction of Alzheimer beta-amyloid peptide 1-42: a membrane-disrupting peptide

Amyloid aggregates, found in patients that suffer from Alzheimer's disease, are composed of fibril-forming peptides in a β-sheet conformation. One of the most abundant components in amyloid aggregates is the β-amyloid peptide 1–42 (Aβ 1–42). Membrane alterations may proceed to cell death by either an oxidative stress mechanism, caused by the peptide and synergized by transition metal ions, or through formation of ion channels by peptide interfacial self-aggregation. Here we demonstrate that Langmuir films of Aβ 1–42, either in pure form or mixed with lipids, develop stable monomolecular arrays with a high surface stability. By using micropipette aspiration technique and confocal microscopy we show that Aβ 1–42 induces a strong membrane destabilization in giant unilamellar vesicles composed of palmitoyloleoyl-phosphatidylcholine, sphingomyelin, and cholesterol, lowering the critical tension of vesicle rupture. Additionally, Aβ 1–42 triggers the induction of a sequential leakage of low- and high-molecular-weight markers trapped inside the giant unilamellar vesicles, but preserving the vesicle shape. Consequently, the Aβ 1–42 sequence confers particular molecular properties to the peptide that, in turn, influence supramolecular properties associated to membranes that may result in toxicity, including: 1), an ability of the peptide to strongly associate with the membrane; 2), a reduction of lateral membrane cohesive forces; and 3), a capacity to break the transbilayer gradient and puncture sealed vesicles.

a7-Nicotinic acetylcholine receptors mediate an A71-42-induced increase in the level of acetylcholinesterase in primary cortical neurones

The β-amyloid protein (Aβ) is the major protein component of amyloid plaques found in the Alzheimer brain. Although there is a loss of acetylcholinesterase (AChE) from both cholinergic and non-cholinergic neurones in the brain of Alzheimer patients, the level of AChE is increased around amyloid plaques. Previous studies using P19 cells in culture and transgenic mice which overexpress human Aβ have suggested that this increase may be due to a direct action of Aβ on AChE expression in cells adjacent to amyloid plaques. The aim of the present study was to examine the mechanism by which Aβ increases levels of AChE in primary cortical neurones. Aβ₁₋₄₂ was more potent than Aβ₁₋₄₀ in its ability to increase AChE in primary cortical neurones. The increase in AChE was unrelated to the toxic effects of the Aβ peptides. The effect of Aβ₁₋₄₂ on AChE was blocked by inhibitors of α7 nicotinic acetylcholine receptors (α7 nAChRs) as well as by inhibitors of L- or N-type voltage-dependent calcium channels (VDCCs), whereas agonists of α7 nAChRs (choline, nicotine) increased the level of AChE. The results demonstrate that the effect of Aβ₁₋₄₂ on AChE is due to an agonist effect of Aβ₁₋₄₂ on the α7 nAChR.

Baltic winter 42 seconds ethereal sweeping and haunting with female vocals

Baltic Winter Shorts 03 - a Slavic mermaid rests upon a rock on the edge of the Baltic Sea. It is night time during the depths of winter. She risks not being able to return to the sea as it could freeze in the time that she drapes the snow crested pine trees with her ethereal calls. Her voice travels through the Medieval forest in search of her nymph . . . will he hear her? Or will her calls only serve to sing her loneliness?

OK . . . now for the technical . . . I wrote this with a documentary in mind. I have used a sampled Finnish/Estonian Kantele, a touch of an acoustic guitar, female vocals, percussion, and a couple of synths.

Impaired neuronal insulin signaling precedes Aβ42 accumulation in female AβPPsw/PS1ΔE9 mice

Reduced glucose utilization is likely to precede the onset of cognitive deficits in Alzheimer's disease (AD). Similar aberrant glucose metabolism can also be detected in the brain of several AD mouse models. Although the cause of this metabolic defect is not well understood, it could be related to impaired insulin signaling that is increasingly being reported in AD brain. However, the temporal relationship between insulin impairment and amyloid-β (Aβ) biogenesis is unclear. In this study using female AβPPsw/PS1ΔE9 mice, we found that the level of Aβ40 was fairly constant in 6- to 15-month-old brains, whereas Aβ42 was only significantly increased in the 15-month-old brain. In contrast, increased levels of IRβ, IGF-1R, IRS1, and IRS-2, along with reduced glucose and insulin content, were detected earlier in the 12-month-old brains of AβPPsw/PS1ΔE9 mice. The reduction in brain glucose content was accompanied by increased GLUT3 and GLUT4 levels. Importantly, these changes precede the significant upregulation of Aβ42 level in the 15-month-old brain. Interestingly, reduction in the p85 subunit of PI3K was only apparent in the 15-month-old AβPPsw/PS1ΔE9 mouse brain. Furthermore, the expression profile of IRβ, IRS-2, and p85/PI3K in AβPPsw/PS1ΔE9 was distinct in wild-type mice of a similar age. Although the exact mechanisms underlining this connection remain unclear, our results suggest a possible early role for insulin signaling impairment leading to amyloid accumulation in AβPPsw/PS1ΔE9 mice.