Biology subjects

Haddad, S.

Publications and source records attributed to Haddad, S..

7 recordsLinked to original sources

bioRxiv2026

Mosaic selection and gene flow at the onset of grain beetle domestication

Domestication is an evolutionary process that can begin before deliberate breeding, when association with humans reshapes gene flow and selection. The yellow mealworm, Tenebrio molitor, is undergoing this transition from a synanthropic pest of stored grain to farmed species. We asked whether gene flow between farmed populations contributes to adaptation to captivity and whether selection extends to production traits. We combined population genomics of 320 beetles from eight farmed and wild populations with genetic mapping of 15 production traits from 3,575 individuals. Farm stocks retained high diversity and weak differentiation, with Netherlands-related ancestry connecting populations across Europe and Canada. Farm-restricted sweep-like signatures were 2.06-fold enriched within regions of excess allele sharing, suggesting local selection on introgressed variation. Across 305 production-trait QTLs, overlaps with selection and introgression signals showed no significant enrichment or depletion, suggesting that adaptive gene flow may primarily contribute to adaptation to captivity rather than broadly shaping growth, development and fertility. Nevertheless, egg-hatching-rate and development-time QTLs overlapped regions of reduced nucleotide diversity and low Tajima's D. These findings support a model in which gene flow supplies variation for unintended selection under intensive rearing. Crowding and physiological stress may favour adaptation to captive environments before sustained breeding establishes a broad genomic response at production loci.

evolutionary biology↗

bioRxiv2025

The expression level of CACNA1C-encoded CaV1.2 is a tipping point between promotion and inhibition of dendritic growth in neurons

The CACNA1C gene encodes the CaV1.2 L-type voltage-gated calcium channel, which plays a crucial role in neuronal signaling. CACNA1C is a risk gene for psychiatric conditions involving disruption of neuronal connectivity such as schizophrenia, autism, and bipolar disorders. While genomic studies are consistently reinforcing the notion of CACNA1C as an important locus related to these diseases, the role of CaV1.2 channels in determining neuronal architecture is incompletely understood. Several studies pinpoint the L-type current (ICaL) as regulator of dendritic arborization development. ICaL lays upstream of competing cellular mechanisms leading to both inhibition and promotion of dendritic growth. How signal selectivity is achieved remains an open question. Here, we report that ICaL-dependent dendritic development of murine cultured hippocampal neurons relies on CaV1.2 and is determined by an equilibrium between the level of CaV1.2 protein expression and ICaL activity. Indeed, increasing ICaL enhances dendritic complexity only when CaV1.2 expression level is reduced. In contrast, when channel levels are at baseline, the CaV1.2-dependent growing signal is overcome by the elevation of the dendritic growth inhibiting CaMKII signaling beyond basal conditions. These findings suggest that CaV1.2 expression level acts as a molecular switch between dendritic growing and inhibiting signals. Consequently, altered CaV1.2 expression during early development may alter neuronal structure, potentially impairing neural network formation and increasing susceptibility to psychiatric disorders. SIGNIFICANCE STATEMENTL-type voltage-gated calcium channels (L-VGCCs) allow calcium influx upon membrane depolarization. In neurons, L-VGCCs play a crucial role in regulating gene transcription, synaptic plasticity, and membrane excitability. Our data demonstrate that the L-VGCCs CaV1.2 isoform is a key regulator of early dendritic development. Calcium influx via CaV1.2 is necessary for proper dendritic growth under basal conditions. However, enhanced calcium currents boost dendritic growth only when channel expression levels are reduced. When the amount of CaV1.2 is at baseline, current stimulation antagonizes the growing process by upregulating the CaMKII signaling. Our findings suggest that the number of CaV1.2 available determines whether channel activity leads to aberrant dendritic arborization by sizing the recruitment of growth inhibiting CaMKII cascade.

neuroscience↗

bioRxiv2025

Temporal evolution of hemodynamics in murine arteriovenous fistula: a micro-CT based computational fluid dynamics study

In this study, we investigated the hemodynamic characteristics of arteriovenous fistulae (AVF) in murine models using micro-CT based computational fluid dynamics (CFD). By combining high-resolution micro-CT imaging with ultrasound flow measurements, our methodology offers a cost-effective and efficient alternative to traditional MRI-based approaches. CFD simulations performed at 7 and 21 days post-surgery revealed significant temporal changes in both geometry and hemodynamics. Geometric analysis showed that: the proximal artery diameter increased from 0.29 mm to 0.38 mm, while the initial 2 mm fistula segment showed a 21.6% decrease (0.74 mm to 0.58 mm). Blood flow through the AVF nearly doubled from 1.33 mL/min to 2.57 mL/min. Time-averaged wall shear stress (TAWSS) peak values increased from 142 Pa (day 7) within the proximal artery to 200 Pa (day 21), in the stenotic region. The oscillatory shear index (OSI) showed marked elevation at the anastomosis (increasing from 0.22 to 0.48), indicating disturbed flow development. An inverse relationship between TAWSS and OSI was identified consistent with previous studies. Our methodology demonstrates the capability to analyze relationships between early hemodynamics and subsequent geometric changes. This approach could enable identification of regions susceptible to stenosis development and monitoring of AVF maturation, which could ultimately lead to quantitative metrics to evaluate surgical outcomes and early therapeutic interventions.

bioengineering↗

bioRxiv2023

Utilizing Heteroatom Types and Numbers from Extensive Ligand Libraries to Develop Novel hERG Blocker QSAR Models Using Machine Learning-based Classifiers

The human Ether-a-go-go Related Gene (hERG) channel plays a crucial role in membrane repolarization. Any disruptions in its function can lead to severe cardiovascular disorders like long QT syndrome (LQTS), which increases the risk of serious cardiovascular problems such as tachyarrhythmia and sudden cardiac death. Drug-induced LQTS is a significant concern and has resulted in drug withdrawals in the past. The main objective of this research study is to pinpoint crucial heteroatoms present in ligands that initiate interactions leading to effective blocking of the hERG channel. To achieve this aim, ligand-based quantitative structure-activity relationships (QSAR) models were constructed using extensive ligand libraries, considering the heteroatom types and numbers, and their associated hERG channel blockage pIC50 values. Machine learning-assisted QSAR models were developed to analyze the key structural components influencing compound activity. Among various methods, the KPLS method proved to be the most efficient, allowing the construction of models based on eight distinct fingerprints. The study delved into investigating the influence of heteroatoms on the activity of hERG blockers, revealing their significant role. Furthermore, by quantifying the effect of heteroatom types and numbers on ligand activity at the hERG channel, six compound pairs were selected for molecular docking. Subsequent molecular dynamics (MD) simulations and MM/GBSA calculations per residue were performed to comprehensively analyze the interactions of the selected pair compounds.

bioinformatics↗

bioRxiv2023

A Template for Translational Bioinformatics: Facilitating Multimodal Data Analyses in Preclinical Models of Neurological Injury

BackgroundPediatric neurological injury and disease is a critical public health issue due to increasing rates of survival from primary injuries (e.g., cardiac arrest, traumatic brain injury) and a lack of monitoring technologies and therapeutics for the treatment of secondary neurological injury. Translational, preclinical research facilitates the development of solutions to address this growing issue but is hindered by a lack of available data frameworks and standards for the management, processing, and analysis of multimodal data sets. MethodsHere, we present a generalizable data framework that was implemented for large animal research at the Childrens Hospital of Philadelphia to address this technological gap. The presented framework culminates in an interactive dashboard for exploratory analysis and filtered data set download. ResultsCompared with existing clinical and preclinical data management solutions, the presented framework accommodates heterogeneous data types (single measure, repeated measures, time series, and imaging), integrates data sets across various experimental models, and facilitates dynamic visualization of integrated data sets. We present a use case of this framework for predictive model development for intra-arrest prediction of cardiopulmonary resuscitation outcome. ConclusionsThe described preclinical data framework may serve as a template to aid in data management efforts in other translational research labs that generate heterogeneous data sets and require a dynamic platform that can easily evolve alongside their research.

bioinformatics↗

bioRxiv2023

CETP inhibitor evacetrapib enters mouse brain tissue

High levels of plasma cholesterol, especially high levels of low-density lipoprotein-cholesterol (LDL-C), have been associated with an increased risk of Alzheimers disease. The cholesteryl ester transfer protein (CETP) in plasma distributes cholesteryl esters between lipoproteins and increases LDL-C in plasma. Epidemiologically, decreased CETP activity has been associated with sustained cognitive performance during aging, longevity, and a lower risk of Alzheimers disease. Thus, pharmacological CETP inhibitors could potentially be repurposed for the treatment of Alzheimers disease as they are safe and effective at lowering CETP activity and LDL-C. While CETP is mostly expressed by the liver and secreted into the bloodstream, CETP is also expressed by astrocytes in the brain. It is therefore important to determine if CETP inhibitors can enter the brain. Here, we describe pharmacokinetic parameters of the CETP inhibitor evacetrapib in plasma, liver, and brain tissues in CETP transgenic mice. We show that evacetrapib crosses the blood-brain barrier and is detectable in brain tissue 0.5 h after a 40 mg/kg i.v. injection in a nonlinear function. We conclude that evacetrapib may prove to be a good candidate to treat CETP-mediated cholesterol dysregulation in Alzheimers disease.

pharmacology and toxicology↗

bioRxiv2020

Coupling between fast and slow oscillator circuits in Cancer borealis is temperature compensated

Coupled oscillatory circuits are ubiquitous in nervous systems. Given that most biological processes are temperature sensitive, it is remarkable that the neuronal circuits of poikilothermic animals can maintain coupling across a wide range of temperatures. Within the stomatogastric ganglion (STG) of the crab, Cancer borealis, the fast pyloric rhythm (~1Hz) and the slow gastric mill rhythm (~0.1Hz) are precisely coordinated at ~11{degrees}C such that there is an integer number of pyloric cycles per gastric mill cycle (integer coupling). Upon increasing temperature from 7-23{degrees}C, both oscillators showed similar temperature-dependent increases in cycle frequency, and integer coupling between the circuits was conserved. Thus, although both rhythms show temperature dependent changes in rhythm frequency, the processes that couple these circuits maintain their coordination over a wide range of temperature. Such robustness to temperature changes could be part of a toolbox of processes that enables neural circuits to maintain function despite global perturbations.

neuroscience↗