Identification and evaluation of small-molecule inhibitors against the dNTPase SAMHD1 via a comprehensive screening funnel.

SAMHD1 is a dNTP triphosphohydrolase governing nucleotide pool homeostasis and can detoxify chemotherapy metabolites controlling their clinical responses. To understand SAMHD1 biology and investigate the potential of targeting SAMHD1 as neoadjuvant to current chemotherapies, we set out to discover selective small-molecule inhibitors. Here, we report a discovery pipeline encompassing a biochemical screening campaign and a set of complementary biochemical, biophysical, and cell-based readouts for rigorous characterization of the screen output.

Investigation of a Model-based Time-over-threshold Technique for Phoswich Crystal Discrimination.

The best crystal identification (CI) algorithms proposed so far for phoswich detectors are based on adaptive filtering and pulse shape discrimination (PSD). However, these techniques require free running analog to digital converters, which is no longer possible with the ever increasing pixelization of new detectors. We propose to explore the dual-threshold time-over-threshold (ToT) technique, used to measure events energy and time of occurence, as a more robust solution for crystal identification with broad energy windows in phoswich detectors.

Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress.

The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells.

Transient Receptor Potential-Vanilloid (TRPV1-TRPV4) Channels in the Atlantic Salmon, . A Focus on the Pineal Gland and Melatonin Production.

Fish are ectotherm, which rely on the external temperature to regulate their internal body temperature, although some may perform partial endothermy. Together with photoperiod, temperature oscillations, contribute to synchronizing the daily and seasonal variations of fish metabolism, physiology and behavior. Recent studies are shedding light on the mechanisms of temperature sensing and behavioral thermoregulation in fish.

Performance evaluation of the mouse version of the LabPET II PET scanner.

The LabPET II is a new positron emission tomography technology platform designed to achieve submillimetric spatial resolution imaging using fully pixelated avalanche photodiodes-based detectors and highly integrated parallel front-end processing electronics. The detector was designed as a generic building block to develop devices for preclinical imaging of small to mid-sized animals and for clinical imaging of the human brain. The aim of this work is to assess the physical characteristics and imaging performance of the mouse version of LabPET II scanner following the NEMA NU4-2008 standard and using high resolution phantoms and in vivo imaging applications.