Mody, M. | bioRxiv Science

bioRxiv2026

Signal-to-noise ratio of event-related fields in on-scalp and off-scalp MEG

Abstract Optically pumped magnetometer (OPM) sensors can be placed closer to the scalp than conventional superconducting quantum interference devices (SQUID), resulting in larger magnetoencephalography (MEG) signals from neuronal activity. For event-related sensor data, such as epileptogenic activity or sensory and motor evoked responses, however, OPMs and SQUIDs often differ less in signal-to-noise ratio (SNR) than in signal magnitude. We examined two factors contributing to the relative SNR: the dependence of the signal magnitude on source depth and the effect of scalp-to-sensor distance on the noise level. Simulated MEG data for a current dipole in a spherical head model confirmed that on-scalp sensor placement delivers the largest SNR gain for superficial sources. Depending on the relative overall noise level, there may be a crossover source depth at which SNR is equal for on-scalp and off-scalp sensors and beyond which off-scalp sensors achieve higher SNR. Analysis of the equal-SNR source depth in different-sized spherical head models indicated that, for a given relative noise level, the proportion of the brain where SNR is higher in OPM than in SQUID was larger in small head models, supporting the benefits of OPMs in pediatric studies. To experimentally evaluate noise contributions of brain and non-brain origin to the SNR, we recorded somatosensory evoked fields (SEFs) at varying scalp-to-sensor distances. Generally, both the evoked response magnitude and the noise level were lower when the sensors were further away from the scalp; consequently, the SNR depended less than the signal magnitude on the scalp-to-sensor distance. Comparison of power spectral densities (PSDs) at different sensor-to-scalp distances allowed us to identify whether the dominant noise source was of brain or non-brain origin at different frequency bands. Overall, the results highlight complementary properties of OPMs vs. SQUIDs in terms of SNR, which is of interest when optimizing MEG experiments for specific subject populations and brain regions.

neuroscience↗

bioRxiv2025

Toward pharmacologic therapy for glioblastoma: Identifying inhibitors of very long-chain acyl-CoA synthetase 3 (ACSVL3)

Brain tumors, in particular glioblastoma multiforme (GBM), are among the most aggressive and difficult to treat human neoplasms. Even with combined surgery, radiation and chemotherapy, the 5-year survival rate for GBM is only [~]7%. Thus, new treatment approaches are needed. We previously found that the fatty acid metabolism enzyme "very long-chain acyl-CoA synthetase 3" (ACSVL3) is overproduced in human glioma tissue and in glioblastoma cell lines such as U87MG cells. These cells exhibited malignant growth properties in culture and were tumorigenic in nude mice. When either knockdown or knockout strategies were used to deplete U87MG cells of ACSVL3, they adopted a more normal growth rate and produced significantly fewer, slower growing tumors in mice. An inhibitor of ACSVL3, if identified, could prove to be a valuable pharmacotherapeutic agent in GBM. Therefore, we sought to identify small molecule compounds that decrease or block the enzyme activity of ACSVL3, as measured by the formation of stearoyl-CoA from the 18-carbon saturated fatty acid stearic acid, a preferred substrate for ACSVL3. We approached this in two ways. First, we tested several compounds that were previously shown to inhibit the activity of a structurally and functionally related enzyme, ACSVL1. Several compounds tested showed inhibition of stearoyl-CoA formation in U87MG cells when added to an in vitro enzyme assay. These included drugs triflupromazine, phenazopyridine, chlorpromazine, emodin, and perphenazine which are approved for treating other conditions. Also inhibitory to stearoyl-CoA production were several compounds from a ChemBridge Corporation library designated CB2, CB5, CB6 and CB 16.2. One caveat regarding interpretation of these results is that in addition to ACSVL3, all cells including U87MG contain other acyl-CoA synthetases capable of using stearic acid as substrate. Therefore, we also measured stearoyl-CoA synthetase activity in ACSVL3-deficient U87MG cells (U87-KO). If a drug or compound is an ACSVL3 inhibitor, it should decrease total conversion of stearate to stearoyl-CoA more in U87MG than in U87-KO cells. By this criterion, most of the tested compounds showed some ACSVL3-specific inhibition. At the screening concentration of 80M drug, CB5 and CB16.2 showed the greatest potency to inhibit ACSVL3 enzyme activity; at 10 M, CB5 still showed significant inhibition but CB16.2 did not. We conclude that these compounds are worthy of further investigation as potential therapeutic agents in GBM, but additional drugs that have greater specificity and are effective at significantly lower concentrations must also be identified. Therefore, our second strategy was to develop a high-throughput library screening assay. For this, we took advantage of the fatty acid transport capability of some ACSVL family members. ACSVL1, when heterologously expressed in COS-1 cells, promotes cellular uptake of the fluorescent fatty acid analog C1-BODIPY-C12; in contrast, overexpressed ACSVL3 does not. We used a domain-swapping strategy to replace the N-terminal 210 amino acids of ACSVL3 with the N-terminal 100 amino acids of ACSVL1, producing ACSVL1/3. Unlike ACSVL3, ACSVL1/3 robustly promoted C1-BODIPY-C12 uptake while retaining the catalytically active C-terminus of ACSVL3. Most of the drugs and compounds that decreased stearoyl-CoA synthetase inhibition also inhibited C1-BODIPY-C12 uptake in a concentration-dependent manner. Catalytically defective ACSVL1/3 mutants lost their ability to promote C1-BODIPY-C12 uptake. Thus, we conclude that chimeric ACSVL1/3 gained the fatty acid transport function of ACSVL1 while retaining the catalytic properties of ACSVL3. A pilot screening study of >1280 drugs from an approved drug library and >880 compounds from a library of drugs predicted to cross the blood-brain barrier detected more than 50 molecules that lowered C1-BODIPY-C12 by more than 3 standard deviations. Although secondary screening will likely exclude many or all of these, our findings support the notion that we have developed a viable method for detecting potential ACSVL3 inhibitors. Further characterization may reveal candidate pharmacologic agents for treatment of GBM and other cancers.

biochemistry↗

bioRxiv2017

An Essential Role for Argonaute 2 in EGFR-KRAS Signaling in Pancreatic Cancer Development

KRAS and EGFR are known essential mediators of pancreatic cancer development. In addition, KRAS and EGFR have both been shown to interact with and perturb the function of Argonaute 2 (AGO2), a key regulator of RNA-mediated gene silencing. Here, we employed a genetically engineered mouse model of pancreatic cancer to define the effects of conditional loss of AGO2 in KRASG12D-driven pancreatic cancer. Genetic ablation of AGO2 does not interfere with development of the normal pancreas or KRASG12D-driven early precursor pancreatic intraepithelial neoplasia (PanIN) lesions. Remarkably, however, AGO2 is required for progression from early to late PanIN lesions, development of pancreatic ductal adenocarcinoma (PDAC), and metastasis. AGO2 ablation permits PanIN initiation driven by the EGFR-RAS axis, but rather than progressing to PDAC, these lesions undergo profound oncogene-induced senescence (OIS). Loss of Trp53 (p53) in this model obviates the requirement of AGO2 for PDAC development. In mouse and human pancreatic tissues, increased expression of AGO2 and elevated co-localization with RAS at the plasma membrane is associated with PDAC progression. Furthermore, phosphorylation of AGO2Y393 by EGFR disrupts the interaction of wild-type RAS with AGO2 at the membrane, but does not affect the interaction of mutant KRAS with AGO2. ARS-1620, a G12C-specific inhibitor, disrupts the KRASG12C-AGO2 interaction specifically in pancreatic cancer cells harboring this mutant, demonstrating that the oncogenic KRAS-AGO2 interaction can be pharmacologically targeted. Taken together, our study supports a biphasic model of pancreatic cancer development: an AGO2-independent early phase of PanIN formation reliant on EGFR-RAS signaling, and an AGO2-dependent phase wherein the mutant KRAS-AGO2 interaction is critical to prevent OIS in PanINs and allow progression to PDAC.

cancer biology↗