Biology subjects

de Jong, B.

Publications and source records attributed to de Jong, B..

5 recordsLinked to original sources

bioRxiv2026

Phase-lag-dependent modulation of interhemispheric β-band functional connectivity by dual-site tACS

Dual-site transcranial alternating current stimulation (ds-tACS) is a promising tool for causally manipulating interhemispheric communication; nevertheless, how different stimulation phase-lags selectively modulate functional connectivity (FC) remains unclear. We recruited 29 healthy participants and included 23 in the final analyses. Participants received 20 Hz ds-tACS over the bilateral primary motor cortices (M1s) using four phase-lags (0, pi/2, pi, 3pi/2) and sham stimulation, combined with recording of high-density EEG before and after stimulation. We quantified the interhemispheric FC using the debiased weighted phase-lag index. No significant differences were found in the average FC changes between overall active stimulation and sham. However, the phase-lag associated with maximum absolute FC changes varied substantially across participants. Accordingly, the assessment of phase-lag-dependency of FC using the Kullback-Leibler distance (DKL) revealed a significant phase-lag-dependent modulation of FC that was transient (limited to the first 5 s after stimulation), restricted to frequencies around the stimulation frequency (18-22 Hz), and occurred without corresponding phase-lag-dependent modulation of the spectral power. In an exploratory analysis, the modulation magnitude showed a quadratic relationship with the individual {beta}-peak FC frequency, where participants with {beta}-peak frequencies farther from the 20 Hz stimulation frequency exhibited stronger effects. These findings indicate that ds-tACS can induce time- and frequency-specific modulation of interhemispheric FC across phase-lags. Given the observed association with individual {beta}-peak connectivity frequency and the variability in the phase-lag associated with maximal FC change, our findings motivate further investigation of personalised neuromodulation protocols.

neuroscience↗

bioRxiv2025

Reduced triacylglycerols and lipid droplets are associated with resilience to Alzheimers disease

IntroductionWhile it has become clear that alterations in lipid metabolism are associated with AD, it is unclear how they contribute to both cognitive decline and the pathophysiology of AD. MethodsWe performed lipidomics and activity-based protein profiling in the frontal cortex of control, AD and resilient donors, i.e. individuals with AD pathology without cognitive decline. Subsequently we integrated these data using multi-omics factor analysis and correlated the multi-omics profiles to disease and clinical parameters. ResultsThe most pronounced alterations in lipids were in the {omega}6-derived oxylipins, which were particularly increased in the AD patients. Both triacylglycerols (TAGs) and lipid droplets were more abundant in the AD donors compared to the resilient donors. Enzyme activities showed a similar direction in the AD and resilient donors, including decreased activity of ABHD6. Multi-omics factor analysis showed that increased oxylipins, loss of inhibitory cells, synaptic genes and genes related to the inflammatory response were associated with A{beta} plaque load in both AD and resilient donors. ConclusionOur multi-omics data show a response associated with A{beta} load shared among AD and resilient donors and, for the first time, reduced lipid droplets in resilient donors.

neuroscience↗

bioRxiv2024

Direct thin-layer agar for bedaquiline-susceptibility testing of Mycobacterium tuberculosis at BSL2 level yields high accuracy in 15 days from sputum processing.

This study evaluated thin-layer agar (TLA) as a faster alternative for both indirect MIC determination of bedaquiline (BDQ) from culture isolates and direct drug-susceptibility testing (DST) from sputum samples. Indirect BDQ-MIC results from TLA were compared to the established 7H11 solid DST. Direct-TLA-DST performance was assessed using 143 baseline sputum samples from rifampicin-resistant TB cases. Direct-TLA tested susceptibility to rifampicin, isoniazid, levofloxacin, and BDQ, with results compared to Lowenstein-Jensen (LJ) and MGIT. For indirect BDQ-MIC determination, TLA demonstrated high accuracy, with MIC values for H37Rv falling within the WHO control range (0.015-0.12g/ml). The incubation conditions (5-10% CO2, standard) and reading time (day 7, 14) significantly affected results, with D7 readings in standard incubator providing optimal accuracy. Direct-TLA-DST detected MTB in 53.8% of samples, compared to 55.9% on LJ and 69.4% in MGIT. Uninterpretable results due to contamination or medium drying were low (4.9%). Median time to result was 15 days for smear-positive and 22 days for smear-negative samples, faster than WHO endorsed methods. Sensitivity was 100% for rifampicin and 87.8% for isoniazid, with a specificity of 100% for all drugs except isoniazid (96.2%). No BDQ nor levofloxacin resistance was detected, thus direct TLA sensitivity could not be assessed. In conclusion, direct-TLA-DST offers a reliable and faster alternative to conventional DST methods for BDQ and other anti-TB drugs. Essentially, this technique can be operated at BioSafety Level 2, allowing decentralization of pDST for managing drug-resistant TB in settings with limited laboratory infrastructure. ImportanceThis paper addresses the critical need for faster direct drug-susceptibility testing (DST) on sputum, especially for bedaquiline (BDQ), which is a key drug in treating drug-resistant TB. Currently, there is a lack of rapid, reliable methods for direct BDQ testing from sputum samples, limiting timely and accurate treatment decisions and monitoring. By demonstrating the potential of thin-layer agar (TLA) for direct BDQ-MIC determination, this study offers a promising solution that could significantly improve patient care.

microbiology↗

bioRxiv2021

Analysis of the H-Ras mobility pattern in vivo shows cellular heterogeneity inside epidermal tissue

Over the last two decades, developments in single-molecule microscopy (SMM) have enabled imaging and tracking of individual, fluorescently labelled proteins in biological systems, and most of these studies have focused on the analysis of protein mobility patterns inside cultured cells. In the present study, SMM was applied in vivo, using the zebrafish embryo model. We studied the protein dynamics of the membrane protein H-Ras, mutants of this protein, and its membrane-anchoring domain, C10H-Ras, in epidermal cells of living two-day-old embryos, using a total internal reflection fluorescence microscopy (TIRFM) setup. For all proteins studied, our results consistently confirm the presence of a fast- and a slow-diffusing subpopulations of molecules, which both confine to microdomains within the plasma membrane. Although the mobility patterns of H-Ras, mutants of this proteins and its membrane-anchoring domain were remarkably similar, the constitutively active H-Ras mutant, H-RasV12, exhibited significantly higher diffusion rates than the wild-type H-Ras and its inactive mutant, H-RasN17. Ultimately, we characterized variability in our data obtained using the zebrafish embryo model and demonstrated that differences between cells within the same embryo are the largest source of variation in our data. Our findings are in line with a model in which the cellular architecture of individual cells within a tissue determine the mobility of H-Ras proteins anchored in the plasma membrane cytoplasmic leaflet. Thereby, our results underline the growing importance of performing SMM imaging in vivo in order to better understand factors influencing the protein dynamics in an intact living organism. SUMMARY STATEMENTBy application of single-molecule microscopy to living zebrafish embryos, factors altering the in vivo dynamics of H-Ras proteins in epidermal cells were analyzed.

biophysics↗

bioRxiv2018

Genome wide association with quantitative resistance phenotypes in Mycobacterium tuberculosis reveals novel resistance genes and regulatory regions

Drug resistance is threatening attempts at tuberculosis epidemic control. Molecular diagnostics for drug resistance that rely on the detection of resistance-related mutations could expedite patient care and accelerate progress in TB eradication. We performed minimum inhibitory concentration testing for 12 anti-TB drugs together with Illumina whole genome sequencing on 1452 clinical Mycobacterium tuberculosis (MTB) isolates. We then used a linear mixed model to evaluate genome wide associations between mutations in MTB genes or noncoding regions and drug resistance, followed by validation of our findings in an independent dataset of 792 patient isolates. Novel associations at 13 genomic loci were confirmed in the validation set, with 2 involving noncoding regions. We found promoter mutations to have smaller average effects on resistance levels than gene body mutations in genes where both can contribute to resistance. Enabled by a quantitative measure of resistance, we estimated the heritability of the resistance phenotype to 11 anti-TB drugs and identify a lower than expected contribution from known resistance genes. We also report the proportion of variation in resistance levels explained by the novel loci identified here. This study highlights the complexity of the genomic mechanisms associated with the MTB resistance phenotype, including the relatively large number of potentially causative or compensatory loci, and emphasizes the contribution of the noncoding portion of the genome.

evolutionary biology↗