Biology subjects

Isaac, G.

Publications and source records attributed to Isaac, G..

5 recordsLinked to original sources

bioRxiv2025

HSD17B13 Couples Hepatocyte Lipid Metabolism to Stellate Cell Activation via TGFb-1 Signaling

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease driven by hepatocellular lipid overload, immune activation, and hepatic stellate cell (HSC)-driven fibrogenesis. Human genetic studies reveal that loss-of-function (LoF) variants in 17 beta-hydroxysteroid dehydrogenase 13 (HSD17B13) confer robust protection against advanced fibrosis and cirrhosis, establishing HSD17B13 as a critical genetic modifier of MASH severity. Yet the mechanisms linking HSD17B13 activity to fibrogenic progression remain poorly understood. Here, we show that both wild-type and catalytically deficient HSD17B13 (mHSD) localize to lipid droplets (LDs) in cultured human hepatocytes, but only catalytically active HSD17B13 enhances hepatocellular lipid accumulation and markedly upregulates the lipogenic transcriptional regulator carbohydrate-responsive element-binding protein (ChREBP). This HSD17B13-driven lipogenic axis elicits potent paracrine activation of LX2 stellate cells, both in hepatocyte-HSC co-culture and in response to hepatocyte-conditioned medium (CM). Screening of candidate signaling mediators revealed that transforming growth factor beta-1 (TGFb-1) is uniquely and strongly upregulated by active HSD17B13, with minimal induction by mHSD. Remarkably, siRNA-mediated knockdown of TGFB1 or neutralization of active TGFb-1 protein abolishes CM-induced LX2 activation and collagen synthesis. Collectively, these findings identify HSD17B13 as a dual metabolic and profibrotic effector that drives TGFb-1-dependent HSC activation, thereby linking hepatocellular lipid dysregulation to fibrogenic progression and providing a mechanistic framework for understanding how HSD17B13 contributes to MASH pathogenesis.

cell biology↗

bioRxiv2025

Acoustic Coupling for Double-Blind Human Low-Intensity Focused Ultrasound Neuromodulation

ObjectiveLow-intensity focused ultrasound (LIFU) is a non-invasive neuromodulation technique with the potential for precise targeting of small and deep human brain circuitry. To ensure rigorous and reproducible effects, it is necessary to implement double-blinding to mitigate potential experimental biases. This study innovates on previous ultrasound coupling methods by embedding a 3D-printed thermoplastic disc in a high-density gel-polymer matrix to create identical gel-plastic coupling devices that either transmit (verum) or block (sham) ultrasound. MethodsWe evaluated varying thicknesses (1.5 mm, 2,0 mm, 2.5 mm) and infill densities (25%, 50%, 75%, and 100%) of Acrylonitrile Butadiene Styrene (ABS) for insertion loss and effects on beam characteristics across relevant human neuromodulation frequencies from 0.2 - 1 MHz. ResultsABS at 1.5 mm thickness and 50 % infill had the lowest insertion loss at 0.50 MHz of 0.9 {+/-} 0.04 dB demonstrating acoustic transparency suitable for a verum device. For the sham device, we introduced an internal air gap that produced 31 dB insertion loss at 0.50 MHz. The verum device demonstrated minimal effects on the beam shape with a radial peak shift of 0.3 {+/-} 0.2 mm and an average axial shift of 0.5 mm. DiscussionThis novel gel-plastic coupling device can be tailored to most LIFU transducer shapes and is designed to support double-blind protocols by maintaining visual and tactile indistinguishability while controlling transmitted energy. This method provides a cost-effective and easily implementable solution for double-blinding in human LIFU studies to improve the reliability and rigor of experimental outcomes.

neuroscience↗

bioRxiv2024

Examination of low-intensity focused ultrasound parameters for human neuromodulation

BackgroundLow-intensity focused ultrasound (LIFU) is a promising form of non-invasive neuromodulation characterized by a rich parameter space that includes intensity, duration, duty cycle and pulsing strategy. The effect and interaction of these parameters to affect human brain activity is poorly understood. A better understanding of how parameters interact is critical to advance LIFU as a potential therapeutic. Objective/HypothesisTo determine how different parameters, including intensity, duration, and duty cycle interact to produce neuromodulation effects in the human brain. Further, this study assesses the effect of pulsing versus continuous ultrasound. We hypothesize that higher duty cycles will confer excitation. Increasing intensity or duration will increase the magnitude of effect. Pulsing LIFU will not be more effective than continuous wave ultrasound. MethodsN = 18 healthy human volunteers underwent 20 different parameter combinations that included a fully parametrized set of two intensities (ISPPA: 6 & 24 W/cm2), five duty cycles (1, 10, 30, 50, 70%) and two durations (100, 500 msec) with a constant pulse repetition frequency of 1 kHz delivered concurrently with transcranial magnetic stimulation (TMS) to the primary motor cortex (M1). Four of these parameter combinations were also delivered continuously, matched on the number of cycles. Motor-evoked potential (MEP) amplitude was the primary outcome measure. All parameter combinations were collected time-locked to MEP generation. ResultsThere was no evidence of excitation from any parameter combination. 3 of the 24 parameter sets resulted in inhibition. The parameter set that resulted in the greatest inhibition ([~] 30%) was an intensity of 6W/cm2 with a duty cycle of 30% and a duration of 500 msec. A three-way ANOVA revealed an interaction of intensity and duty cycle. The analysis of continuous versus pulsed ultrasound revealed a 3-way interaction of intensity, pulsing, and the number of cycles such that under the 6W/cm2 condition higher cycles of pulsed ultrasound resulted in inhibition whereas lower number of cycles using continuous LIFU resulted in inhibition. ConclusionsLIFU to M1 in humans, in the range employed, either conferred inhibition or had no effect. Significant excitation was not observed. In general, lower intensity looks to be more efficacious for inhibition that depends on duration. Finally, pulsed ultrasound looks to be more effective for inhibition as compared to continuous wave after controlling for total energy delivered.

neuroscience↗

bioRxiv2024

Low-intensity focused ultrasound to the human insular cortex differentially modulates the heartbeat-evoked potential: a proof-of-concept study

BackgroundThe heartbeat evoked potential (HEP) is a brain response time-locked to the heartbeat and a potential marker of interoceptive processing. The insula and dorsal anterior cingulate cortex (dACC) are brain regions that may be involved in generating the HEP. Low-intensity focused ultrasound (LIFU) is a non-invasive neuromodulation technique that can selectively target sub-regions of the insula and dACC to better understand their contributions to the HEP. ObjectiveProof-of-concept study to determine whether LIFU modulation of the anterior insula (AI), posterior insula (PI), and dACC influences the HEP. MethodsIn a within-subject, repeated-measures design, healthy human participants (n=16) received 10 minutes of stereotaxically targeted LIFU to the AI, PI, dACC or Sham at rest during continuous electroencephalography (EEG) and electrocardiography (ECG) recording on separate days. Primary outcome was change in HEP amplitudes. Relationships between LIFU pressure and HEP changes were examined using linear mixed modelling. Peripheral indices of visceromotor output including heart rate and heart rate variability (HRV) were explored between conditions. ResultsRelative to sham, LIFU to the PI, but not AI or dACC, decreased HEP amplitudes; this was partially explained by increased LIFU pressure. LIFU did not affect time or frequency dependent measures of HRV. ConclusionsThese results demonstrate the ability to modulate HEP amplitudes via non-invasive targeting of key interoceptive brain regions. Our findings have implications for the causal role of these areas in bottom-up heart-brain communication that could guide future work investigating the HEP as a marker of interoceptive processing in healthy and clinical populations.

neuroscience↗

bioRxiv2019

Feature-based Molecular Networking in the GNPS Analysis Environment

Molecular networking has become a key method used to visualize and annotate the chemical space in non-targeted mass spectrometry-based experiments. However, distinguishing isomeric compounds and quantitative interpretation are currently limited. Therefore, we created Feature-based Molecular Networking (FBMN) as a new analysis method in the Global Natural Products Social Molecular Networking (GNPS) infrastructure. FBMN leverages feature detection and alignment tools to enhance quantitative analyses and isomer distinction, including from ion-mobility spectrometry experiments, in molecular networks.

bioinformatics↗