Metformin regulates global DNA methylation via mitochondrial one-carbon metabolism.

The anti-diabetic biguanide metformin may exert health-promoting effects via metabolic regulation of the epigenome. Here we show that metformin promotes global DNA methylation in non-cancerous, cancer-prone and metastatic cancer cells by decreasing S-adenosylhomocysteine (SAH), a strong feedback inhibitor of S-adenosylmethionine (SAM)-dependent DNA methyltransferases, while promoting the accumulation of SAM, the universal methyl donor for cellular methylation. Using metformin and a mitochondria/complex I (mCI)-targeted analog of metformin (norMitoMet) in experimental pairs of wild-type and AMP-activated protein kinase (AMPK)-, serine hydroxymethyltransferase 2 (SHMT2)- and mCI-null cells, we provide evidence that metformin increases the SAM:SAH ratio-related methylation capacity by targeting the coupling between serine mitochondrial one-carbon flux and CI activity. By increasing the contribution of one-carbon units to the SAM from folate stores while decreasing SAH in response to AMPK-sensed energetic crisis, metformin can operate as a metabolo-epigenetic regulator capable of reprogramming one of the key conduits linking cellular metabolism to the DNA methylation machinery.

Imaging of transfection and intracellular release of intact, non-labeled DNA using fluorescent nanodiamonds.

Efficient delivery of stabilized nucleic acids (NAs) into cells and release of the NA payload are crucial points in the transfection process. Here we report on the fabrication of a nanoscopic cellular delivery carrier that is additionally combined with a label-free intracellular sensor device, based on biocompatible fluorescent nanodiamond particles. The sensing function is engineered into nanodiamonds by using nitrogen-vacancy color centers, providing stable non-blinking luminescence. The device is used for monitoring NA transfection and the payload release in cells. The unpacking of NAs from a poly(ethyleneimine)-terminated nanodiamond surface is monitored using the color shift of nitrogen-vacancy centers in the diamond, which serve as a nanoscopic electric charge sensor. The proposed device innovates the strategies for NA imaging and delivery, by providing detection of the intracellular release of non-labeled NAs without affecting cellular processing of the NAs. Our system highlights the potential of nanodiamonds to act not merely as labels but also as non-toxic and non-photobleachable fluorescent biosensors reporting complex molecular events.

Charge-sensitive fluorescent nanosensors created from nanodiamonds.

We show that fluorescent nanodiamonds (FNDs) are among the few types of nanosensors that enable direct optical reading of noncovalent molecular events. The unique sensing mechanism is based on switching between the negatively charged and neutral states of NV centers which is induced by the interaction of the FND surface with charged molecules.

A new internal target system for production of (211)At on the cyclotron U-120M.

The alpha emitter (211)At is a radionuclide with good potential for use in the therapy of smaller tumours and metastases. However, limited availability of this radionuclide hinders development of this application and the research of astatine chemistry in general. In this general context we have designed and tested a new internal target system. A thin bismuth layer (3-5 microm) was evaporated onto a light target backing (7.5 g) and irradiated at 0.5-1.5 degrees angles with 29.5 MeV alpha particles beam of intensity up to 30 microA. The backing was then released from the target holder and used directly for astatine separation via dry distillation. Astatine condensed on the Teflon capillary walls was then eluted into 150-250 microl of methanol. The saturation yield was found to be ca. 400 MBq/microA, and the radionuclidic purity of (211)At acceptable for medical applications (activity ratio (210)At/(211)At<10(-3) at EOB). The overall separation yield was 65-75%.

Spurious signals in direct digital frequency synthesizers due to the phase truncation.

Direct digital frequency synthesizers (DDS or DDFS) are widely used in modern communications and measurement devices. Their advantages are small size and power consumption together with excellent frequency stability, high frequency resolution, and short switching times. The difficulties are rather low output frequencies (500 MHz at the present state of the art) and a large set of the spurious signals very often above the -80 dB level. One source of spurious signals in DDS is the use of smaller number, W, of the most significant bits (MSB) applied for the output sine wave reconstruction from all R bits stored in the accumulator. The result is a phase modulation of the output signal. The problem was first solved in a rather complicated way with the result that the level of the largest spurious signal is about -6 W dB below the carrier with an increase of 3.9 dB in some instances. A simpler solution of the problem of spurious signal level due to the phase truncation in DDS was found earlier. However, no attention was paid to the validity of the corrections suggested. In this paper we will be concerned with this problem and investigate the validity and correctness of these generally cited results and provide a simple way for finding positions, levels, and numbers of these spurious signals generated by truncation to W bits of the phase information stored in the DDS accumulator memory of R bits (W