Biology subjects

Garfinkel, A.

Publications and source records attributed to Garfinkel, A..

4 recordsLinked to original sources

bioRxiv2025

Life in the fast lane: Functional consequences of male-female dynamic differences in the renal autoregulation of flow

Tubuloglomerular feedback (TGF) is essential for the renal auto-regulation of flow. TGF is known to induce spontaneous oscillations in single-nephron tubular fluid flow in male kidneys. However, male-female differences in this dynamic behavior have not been studied. Leveraging intravital two-photon microscopy, resting-state magnetic resonance imaging, ultrasound-based and transdermal recordings, we found TGF-mediated oscillations across spatial scales in the rodent kidney, from single-nephron to whole-organ levels, and that male kidneys exhibited higher operating frequencies than females. To understand the mechanisms involved, we developed a dynamical systems model of TGF that agrees with physiological observations. Analysis of the mathematical model indicated that higher reabsorption rate and fluid flow efficiency in male proximal tubules not only result in higher frequencies, but also render male nephrons more susceptible to lose TGF-mediated oscillations. Furosemide abolished TGF-mediated oscillations in male kidneys and upregulated tubular injury marker KIM-1, suggesting that the propensity to lose TGF-mediated oscillations underlies the heightened risk for injury in males. Our analysis also indicated that SGLT-2 inhibition confers renoprotection by preserving TGF-mediated oscillations in hyperglycemia. Combining quantitative imaging and mathematical modeling, this study provides mechanistic insights into the transition from normal physiology to pathophysiology in the kidney.

physiology↗

bioRxiv2025

Methadone blockade of IK1 promotes both long QT and Brugada-like arrhythmias: Mechanistic insights from computational modeling

BackgroundMethadone is widely used for chronic pain relief and in the maintenance therapy of opioid use disorder, however, it also increases the risk of ventricular arrhythmias and sudden cardiac death. Methadone blocks several ionic currents with different half-maximal inhibitory concentrations (IC50), including the rapid component of the delayed rectifier potassium current (IKr), the inward rectifier potassium current (IK1), the L-type calcium current (ICa,L), and the late component of the sodium current (INaL). Despite the well-known proarrhythmic effect of IKr blockade, the effects of blocking other ionic currents on arrhythmogenesis remain less well understood. MethodsComputer simulations were used to explore the proarrhythmic effects of methadone by investigating how its blocking effects on ionic currents act alone or together in arrhythmogenesis. ResultsThe major findings are: 1) blocking IK1 potentiates QT prolongation-related arrhythmogenesis by enhancing a tissue-scale dynamical instability for the spontaneous genesis of ectopic excitations. Blocking IK1 and IKr together results in a synergistic effect, greatly increasing the arrhythmia propensity, much larger than that of blocking either one alone; 2) blocking IK1 in combination with lowering ICa,L potentiates phase-2 reentry caused by spike-and-dome action potential morphology, an arrhythmia mechanism of Brugada syndrome. Blocking IKr exhibits little effect for this mechanism of arrhythmias; and 3) hypoxia, often comorbid in methadone populations, can potentiate QT prolongation-related arrhythmias at high sympathetic activity and phase-2 reentry at low or basal sympathetic activity, mainly via its effect on ICa,L. ConclusionsThese simulation results provide mechanistic insights into the genesis of QT prolongation-related Torsades de Pointes and Brugada-like ECG related arrhythmias caused by methadone use.

pharmacology and toxicology↗

bioRxiv2022

Human iPSC-CMs and in-silico technologies define mechanisms and accelerate targeted pharmacogenetics in hypertrophic cardiomyopathy

Cardiomyopathies have unresolved genotype-phenotype relationships and lack disease-specific treatments. Here we identify genotype-specific pathomechanisms and therapeutic targets combining experimental hiPSC-CM modelling and human-based cardiac electromechanical in-silico modelling and simulation bridging from specific mutations to clinical biomarkers. We select hypertrophic cardiomyopathy as a challenge for this approach and study genetic variations that mutate proteins of the thick (MYH7R403Q/+) and thin filaments (TNNT2R92Q/+, TNNI3R21C/+) of the cardiac sarcomere. We show that destabilisation of myosin super relaxation drives disease in MYH7R403Q/+ with secondary effects on thin filament activation, which are corrected by Mavacamten. Thin filament variants TNNT2R92Q/+ and TNNI3R21C/+ share calcium regulation-related pathomechanisms, for which Mavacamten provides incomplete salvage. We define the ideal characteristics of a novel thin filament-targeting compound and show its efficacy in-silico. We demonstrate that hybrid human-based hiPSC-CM and in-silico studies accelerate pathomechanism discovery and classification testing, improving clinical interpretation of genetic variants, and directing rational therapeutic targeting and design.

bioengineering↗

bioRxiv2021

Oncogenic alterations in the p53 pathway abolish oscillatory competence

The tumor suppressor p53 displays concentration oscillations in response to DNA damage, a behavior that has been suggested to be essential to its anti-cancer function. Many genetic alterations in the p53 pathway have been shown to be oncogenic, whether by experiment or by clinical associations with various cancers. These oncogenic alterations include somatic mutations, copy number variations and inherited polymorphisms. Using a differential equation model of p53-Mdm2 dynamics, we employ Hopf bifurcation analysis to show that all of the oncogenic perturbations have a common effect, to abolish the oscillatory competence of p53, thereby impairing its tumor suppressor function. In this analysis, these diverse genetic alterations, widely observed in human cancers, have a unified mechanistic explanation. SignificanceIn human cancers, the p53 tumor suppressor pathway is frequently altered by diverse genetic changes. An integrated understanding of these oncogenic alterations is currently lacking. We show that all oncogenic alterations in the p53 pathway abolish the oscillatory competence of p53, a property that is essential for cell cycle arrest upon stress, for effective DNA damage response and for maintaining genome integrity. This unified dynamical explanation of distinct cancer driver events that converge on a key cancer hallmark pathway has practical implications for anti-cancer therapies.

systems biology↗