Biology subjects

Abbas, F.

Publications and source records attributed to Abbas, F..

6 recordsLinked to original sources

bioRxiv2023

Kinetics and functional consequences of BK Channels activation by N-type Ca2+ channels in the dendrite of mouse neocortical layer-5 pyramidal neurons

The back-propagation of an action potential (AP) from the axon/soma to the dendrites plays a central role in dendritic integration. This process involves an intricate orchestration of various ion channels, but a comprehensive understanding of the contribution of each channel type remains elusive. In this study, we leverage ultrafast membrane potential recordings (Vm) and Ca2+ imaging techniques to shed light on the involvement of N-type voltage-gated Ca2+ channels (VGCCs) in layer-5 neocortical pyramidal neurons apical dendrites. We found a selective interaction between N-type VGCCs and large-conductance Ca2+-activated K+ channels (BK CAKCs). Remarkably, we observe that BK CAKCs are activated within a mere 500 {micro}s after the AP peak, preceding the peak of the Ca2+ current triggered by the AP. Consequently, when N-type VGCCs are inhibited, the early broadening of the AP shape amplifies the activity of other VGCCs, leading to an augmented total Ca2+ influx. A NEURON model, constructed to replicate and support these experimental results, reveals the critical coupling between N-type and BK channels. This study not only redefines the conventional role of N-type VGCCs as primarily involved in presynaptic neurotransmitter release but also establishes their distinct and essential function as activators of BK CAKCs in neuronal dendrites. Furthermore, our results provide original functional validation of a physical interaction between Ca2+ and K+ channels, elucidated through ultrafast kinetic reconstruction. This insight enhances our understanding of the intricate mechanisms governing neuronal signaling and may have far-reaching implications in the field.

neuroscience↗

bioRxiv2023

Analysis of the effect of the scorpion toxin AaH-II on action potential generation in the axon initial segment

The toxin AaH-II, from the scorpion Androctonus australis Hector venom, is a 64 amino acid peptide that targets voltage-gated Na+ channels (VGNCs) and slows their inactivation. While at macroscopic cellular level AaH-II prolongs the action potential (AP), a functional analysis of the effect of the toxin in the axon initial segment (AIS), where VGNCs are highly expressed, was never performed so far. Here, we report an original analysis of the effect of AaH-II on the AP generation in the AIS of neocortical layer-5 pyramidal neurons from mouse brain slices. After determining that AaH-II does not discriminate between Nav1.2 and Nav1.6, i.e. between the two VGNC isoforms expressed in this neuron, we established that 7 nM was the smallest toxin concentration producing a minimal detectable deformation of the somatic AP after local delivery of the toxin. Using membrane potential imaging, we found that, at this minimal concentration, AaH-II substantially widened the AP in the AIS. Using ultrafast Na+ imaging, we found that local application of 7 nM AaH-II caused a large increase in the slower component of the Na+ influx in the AIS. Finally, using ultrafast Ca2+ imaging, we observed that 7 nM AaH-II produces a spurious slow Ca2+ influx via Ca2+-permeable VGNCs. Molecules targeting VGNCs, including peptides, are proposed as potential therapeutic tools. Thus, the present analysis in the AIS can be considered a general proof-of-principle on how high-resolution imaging techniques can disclose drug effects that cannot be observed when tested at the macroscopic level.

neuroscience↗

bioRxiv2023

Highly multiplexed ddPCR-amplicon sequencing reveals strong Plasmodium falciparum population structure and isolated populations amenable to local elimination efforts in Zanzibar

Over the past 15 years, Zanzibar has made great strides towards malaria elimination; yet progress has stalled. Parasite genetic data of Plasmodium falciparum may inform strategies for malaria elimination by helping to identify contributory factors to parasite persistence. Here we elucidate fine-scale parasite population structure and infer relatedness and connectivity of infections using an identity-by-descent (IBD) approach. We sequenced 518 P. falciparum samples from 5 districts covering both main islands using a novel, highly multiplexed droplet digital PCR (ddPCR)-based amplicon deep sequencing method targeting 35 microhaplotypes and drug-resistance loci. Despite high genetic diversity, we observe strong fine-scale spatial and temporal structure of local parasite populations, including isolated populations on Pemba Island and genetically admixed populations on Unguja Island, providing evidence of ongoing local transmission. We observe a high proportion of highly related parasites in individuals living closer together, including between clinical index cases and the mostly asymptomatic cases surrounding them, consistent with isolation-by-distance. We identify a substantial fraction (2.9%) of related parasite pairs between Zanzibar, and mainland Tanzania and Kenya, consistent with recent importation. We identify haplotypes known to confer resistance to known antimalarials in all districts, including multidrug-resistant parasites, but most parasites remain sensitive to current first-line treatments. Our study provides a high-resolution view of parasite genetic structure across the Zanzibar archipelago and reveals actionable patterns, including isolated parasite populations, which may be prioritized for malaria elimination.

genomics↗

bioRxiv2021

TISON: a next-generation multi-scale modeling theatre for in silico systems oncology

Multi-scale models integrating biomolecular data from genetic, transcriptional, and translational levels, coupled with extracellular microenvironments can assist in decoding the complex mechanisms underlying system-level diseases such as cancer. To investigate the emergent properties and clinical translation of such cancer models, we present Theatre for in silico Systems Oncology (TISON, https://tison.lums.edu.pk), a next-generation web-based multi-scale modeling and simulation platform for in silico systems oncology. TISON provides a "zero-code" environment for multi-scale model development by seamlessly coupling scale-specific information from biomolecular networks, microenvironments, cell decision circuits, in silico cell lines, and organoid geometries. To compute the temporal evolution of multi-scale models, a simulation engine and data analysis features are also provided. Furthermore, TISON integrates patient-specific gene expression data to evaluate patient-centric models towards personalized therapeutics. Several literature-based case studies have been developed to exemplify and validate TISONs modeling and analysis capabilities. TISON provides a cutting-edge multi-scale modeling pipeline for scale-specific as well as integrative systems oncology that can assist in drug target discovery, repositioning, and development of personalized therapeutics.

systems biology↗

bioRxiv2020

Revival of light-evoked neuronal signals in the post-mortem mammalian and human retina

The retina, a highly metabolic tissue in the central nervous system, consumes the most oxygen and energy stores in the body by tissue mass/volume. Consequently, it is not surprising that retinal ischemia leads to a rapid loss of retinal light responses and electrical transmission. In this study, we show that despite a swift decline of retinal light responses after circulatory death (decay time constant {tau} = [~]1-2 min), we were able to restore mouse rod and cone photoreceptor light signals from enucleated eyes up to 3 h postmortem with significantly better postmortem recovery of cone versus rod light responses. We also demonstrate that both rod and cone phototransduction are more resistant to postmortem enucleation delay than synaptic transmission to second order neurons (bipolar cells). Encouraged by these analyses and the lack of previously successful postmortem retinal light recordings from human foveal/macular photoreceptors, we attempted to restore light responses in the human macula using donor eyes harvested 0.5 - 5 hours postmortem. Here we show successful recordings of human macular cone photoresponses in samples obtained from eyes enucleated up to 5 hours postmortem. Comparing freshly enucleated non-human primate eyes with human eyes enucleated and reoxygenated at different times after death, we show the exponential decay of the light response amplitudes has a time constant of 74 min. We find that both cause of death and donor age are useful parameters for predicting the recovery of retinal light responses in postmortem human macular tissue. Moreover, we present evidence that hypoxia and secondary acidosis, two modifiable factors, are primary contributors to the rapid loss of retinal light signaling after death. Finally, we show postmortem hypoxia rather than acidosis is the major cause of irreversible decay of the light response amplitudes. The criteria and methodology that we have established here for reviving electrical photoresponses in the postmortem human eye will serve as a new starting point for studying neurophysiology and disease in the human retina.

neuroscience↗

bioRxiv2019

Mitochondrial Ca2+ influences photoresponse recovery, metabolism, and mitochondrial localization in cone photoreceptors

Mitochondrial Ca2+ regulates key cellular processes including cytosolic Ca2+ signals, energy production, and susceptibility to apoptosis. Photoreceptors are specialized neurons that have extraordinarily high energy demands and rely on cytosolic Ca2+ signals for light adaptation and neurotransmission. Here we show that unlike other neurons zebrafish cone photoreceptors express low levels of the mitochondrial Ca2+ uniporter (MCU), the channel that allows mitochondrial Ca2+ entry. To determine why MCU expression is kept low, we overexpressed MCU specifically in cones. This increases mitochondrial [Ca2+], causes faster cytosolic Ca2+ clearance, and accelerates photoresponse recovery. Moreover, flux through the citric acid cycle increases despite dramatic changes in mitochondrial ultrastructure and localization. Remarkably, cones survive this ongoing stress until late adulthood. Our findings demonstrate the importance of tuning mitochondrial Ca2+ influx to modulate physiological and metabolic processes and reveal a novel directed movement of abnormal mitochondria in photoreceptors.

cell biology↗