Pharmacological inhibition of carnitine palmitoyl transferase 1 inhibits and reverses experimental autoimmune encephalitis in rodents

Multiple sclerosis (MS) is a neurodegenerative disease characterized by demyelination and inflammation. Dysregulated lipid metabolism and mitochondrial dysfunction are hypothesized to play a key role in MS. Carnitine Palmitoyl Transferase 1 (CPT1) is a rate-limiting enzyme for beta-oxidation of fatty acids in mitochondria. The therapeutic effect of pharmacological CPT1 inhibition with etomoxir was investigated in rodent models of myelin oligodendrocyte glycoprotein- and myelin basic protein-induced experimental autoimmune encephalitis (EAE). Mice receiving etomoxir showed lower clinical score compared to placebo, however this was not significant. Rats receiving etomoxir revealed significantly lower clinical score and lower body weight compared to placebo group. When comparing etomoxir with interferon-β (IFN-β), IFN-β had no significant therapeutic effects, whereas etomoxir treatment starting at day 1 and 5 significantly improved the clinical scores compared to the IFN-β and the placebo group. Immunohistochemistry and image assessments of brain sections from rats with EAE showed higher myelination intensity and decreased expression of CPT1A in etomoxir-treated rats compared to placebo group. Moreover, etomoxir mediated increased interleukin-4 production and decreased interleukin-17α production in activated T cells. In conclusion, CPT1 is a key protein in the pathogenesis of EAE and MS and a crucial therapeutic target for the treatment

Implementation of the data acquisition system for the Overlap Modular Track Finder in the CMS experiment

The CMS experiment is currently undergoing the upgrade of its trigger, including the Level-1 muon trigger. In the barrel-endcap transition region the Overlap Muon Track Finder (OMTF) combines data from three types of detectors (RPC, DT, and CSC) to find the muon candidates.To monitor the operation of the OMTF, it is important to receive the data which were the basis for the trigger decision. This task must be performed by the Data Acquisition (OMTF DAQ) system.The new MTCA technology applied in the updated trigger allows implementation of the OMTF DAQ together with the OMTF trigger in the MTF7 board. Further concentration of data is performed by standard AMC13 boards.The proposed data concentration methodology assumes parallel filtering and queuing of data arriving from all input links (24 RPC, 30 CSC, and 6 DT). The data are waiting for the trigger decision in the input buffers. The triggered data are then converted into the intermediate 72-bit format and put into the sorter queues. The block responsible for the building of events receives data originating from the particular Bunch Crossing (BX) from the consecutive sorter queues, converts them to the 64-bit AMC payload words, and puts them into the output queue. That block also generates the AMC header at the beginning and the AMC trailer at the end of the event data.The system is implemented in a flexible way, and handling of a new data source requires implementation of two specialized blocks the input data formatter to translate the link data into the sorter queue data and the output data formatter to translate the sorter queue data into the AMC payload. The AMC payload format used by the OMTF DAQ provides bit field allowing the context-free detection of the data source.The system may send data not only from the bunch crossing (BX) in which the L1 trigger was generated but also from a configurable number of BXs before the trigger (up to 3) and after the triger (up to 4). Therefore, according to the current trigger rules, it is possible that the data from a certain BX may belong to two different events. To handle such cases the OMTF DAQ system uses two output queues alternately for assembling the consecutive events. It is easily possible to increase the number of output queues if a single BX may belong to a higher number of events due to the change of the trigger rules or number of BX-es transmitted before or after the trigger.The system in current state handles the RPC data. The data handlers for CSC and DT detectors are being developed. The presented methodology may be reused for other triggered DAQ systems concentrating data from various sources with different formats

Inhibition of carnitine palmitoyl-transferase 1 is a potential target in a mouse model of Parkinson’s disease

Abstract Glucose metabolism is dysregulated in Parkinson’s disease (PD) causing a shift toward the metabolism of lipids. Carnitine palmitoyl-transferase 1A (CPT1A) regulates the key step in the metabolism of long-chain fatty acids. The aim of this study is to evaluate the effect of downregulating CPT1, either genetically with a Cpt1a P479L mutation or medicinally on PD using chronic rotenone mouse models using C57Bl/6J and Park2 knockout mice. We show that Cpt1a P479L mutant mice are resistant to rotenone-induced PD, and that inhibition of CPT1 is capable of restoring neurological function, normal glucose metabolism, and alleviate markers of PD in the midbrain. Furthermore, we show that downregulation of lipid metabolism via CPT1 alleviates pathological motor and non-motor behavior, oxidative stress, and disrupted glucose homeostasis in Park2 knockout mice. Finally, we confirm that rotenone induces gut dysbiosis in C57Bl/6J and, for the first time, in Park2 knockout mice. We show that this dysbiosis is alleviated by the downregulation of the lipid metabolism via CPT1