Biology subjects

Goel, P.

Publications and source records attributed to Goel, P..

13 recordsLinked to original sources

bioRxiv2026

HapSolo2: GPU-accelerated optimization for removing secondary haplotigs from diploid genome assemblies

BackgroundSecondary haplotigs retained in a primary assembly inflate genome size and duplicate gene content, and their removal remains a necessary curation step for heterozygous diploid genomes. HapSolo (Solares et al. 2021) treats this step as an optimization problem: it searches three pairwise alignment thresholds (percent identity, query coverage, and the ratio of aligned query to aligned reference length) to minimize a cost defined over single-copy, duplicated, and missing conserved orthologs. The original implementation depended on a separate BUSCO v3 run for every contig, on Python 2.7 and pandas in its inner loop, on a single randomized forward-walk optimizer, and on OrthoDB v9 lineage datasets that are no longer distributed. ResultsHere we report HapSolo2, a reimplementation that replaces the per-contig BUSCO step with miniprot-based ortholog classification against OrthoDB v9, v10, or v12.2 lineage datasets, adds steepest descent and simulated annealing to the original random forward walk, and evaluates all walkers in batched CuPy array operations on a single GPU. On an avocado assembly of 5,122 contigs scored against 1,440 orthologs, 100,000 iterations of random walk and steepest descent ran 5.6- and 7.6-fold faster on one NVIDIA RTX A6000 than on 10 CPU processes. Across 45 runs on four diploid assemblies (Anopheles funestus, Persea americana, Vitis vinifera, and Amblyraja radi-ata; 212 Mb to 3.2 Gb) and three OrthoDB releases, the three optimizers reached best costs within 1.8% of one another. Independent assessment with BUSCO v6.1 showed that HapSolo2 reduced duplicated orthologs from 52.0% to 5.6% in P. americana, from 17.9% to 10.4% in V. vinifera, and from 7.8% to 2.8% in A. funestus, with completeness decreasing by at most 1.3 percentage points. On the avocado assembly, HapSolo2 reduced the cost reached by the original HapSolo from 0.2200 to 0.1036 and raised contig N50 from 3,366 kb to 4,608 kb. ConclusionsHapSolo2 makes ortholog-guided haplotig removal practical in minutes on a single workstation, independent of a BUSCO installation, and reproducible across OrthoDB releases. It is distributed as an installable Python package with a unified command-line pipeline, an assembly statistics and plotting tool, an Apptainer container, and archived copies of the legacy ortholog datasets.

bioinformatics↗

bioRxiv2026

Fos regulates age-dependent neuroinflammation in VAPBALS

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of motor function. We have developed a Drosophila model of ALS8 (VAPBP58S) using CRISPR/Cas9 genome editing. VAPB is an ER-based adapter protein associated with and regulating intracellular membrane:membrane contact sites. VAPBP58S flies show progressive age-dependent motor deficits and a shortened lifespan, paralleling features of the human disease. VAPBP58S brains exhibit age-dependent neuroinflammation, as measured by whole-transcriptome quantitative mRNA sequencing, suggesting a broad, low-grade enhancement in signalling in multiple (Toll, IMD, Jak-STAT and Jun-kinase) immune pathways. We implicate glial cells in the brain as the site of brain inflammation and identify Drosophila Fos (Kayak) as a key modulator of age-dependent inflammation. In accordance, we find that overexpression of wild-type kayak or its dominant-active variant kayakK357R in glia reduces inflammation and, concomitantly, improves motor function. In contrast, knockdown of glial kayak accelerates age-dependent deterioration of motor function and enhances neuroinflammation. Our study underscores the roles of glial-modulated brain inflammation in dictating ALS8 progression and identifies kayak as a central negative regulator of neuroinflammation in disease. Summary StatementWe uncover definitive evidence for age-dependent neuroinflammation, originating from glial cells and regulated by Fos, as a key mechanism underlying Amyotrophic Lateral Sclerosis 8.

neuroscience↗

bioRxiv2025

Striatal pathology in Spinocerebellar Ataxia Type 1 mice: A comparative study with Huntingtons disease

Spinocerebellar ataxia type 1 (SCA1) and Huntingtons disease (HD), are motor diseases caused by CAG expansions in ATXN1 and HTT, where SCA1 shows prominent cerebellar neurodegeneration and HD shows prominent striatal neurodegeneration, particularly in the Medium Spiny Neurons (MSNs). Since human and mouse studies demonstrate progressive striatal vulnerability in SCA1, we examined age-dependent molecular, cellular and functional striatal attributes in SCA1 (f-ATXN1146Q/2Q) knockin mice, by assessing RNA-sequencing, immunohistochemistry and electrophysiology. Striatal mRNAs are downregulated in SCA1 mice, many in common with HD mice, and specificity in MSNs is supported by the rescue of transcriptomic dysregulation with deletion of mutant Ataxin1 from MSNs. Immunohistochemistry assessed dopamine receptor 1 (D1R) and 2 (D2R) expression in indirect and direct MSNs. In HD mice (HttQ175/Q7), expression of both D1R and D2R proteins in MSNs decreased with age in parallel with their RNA levels. In the SCA1 mouse striatum, D1R protein expression decreased with age as seen in murine HD striatum. In contrast, while D2R protein level was decreased similar to D1R protein at 5-weeks of age, by 40-weeks expression of D2R protein recovered to levels recorded in WT mice. Electrophysiological assessment showed a reduction of excitatory synaptic transmission in SCA1 mouse MSNs, indicating functional deficits early in disease. In contrast to cerebellar and many other aspects of SCA1 pathology known to depend on proper nuclear localization of ATXN1 with an expanded polyglutamine, mutating ATXN1s nuclear localization failed to correct striatal MSN RNA and protein downregulations, indicating a difference in how ATXN1 exerts its pathological effects between the cerebellum and the striatum. Together, these data provide a molecular and cellular basis of striatal pathology in SCA1.

neuroscience↗

bioRxiv2025

A connectomic resource for neural cataloguing and circuit dissection of the larval zebrafish brain

We present a correlated light and electron microscopy (CLEM) dataset from a 7-day-old larval zebrafish, integrating confocal imaging of genetically labeled excitatory (vglut2a) and inhibitory (gad1b) neurons with nanometer-resolution serial section EM. The dataset spans the brain and anterior spinal cord, capturing >180,000 segmented soma, >40,000 molecularly annotated neurons, and 30 million synapses, most of which were classified as excitatory, inhibitory, or modulatory. To characterize the directional flow of activity across the brain, we leverage the synaptic and cell body annotations to compute region-wise input and output drive indices at single cell resolution. We illustrate the datasets utility by dissecting and validating circuits in three distinct systems: water flow direction encoding in the lateral line, recurrent excitation and contralateral inhibition in a hindbrain motion integrator, and functionally relevant targeted long-range projections from a tegmental excitatory nucleus, demonstrating that this resource enables rigorous hypothesis testing as well as exploratory-driven circuit analysis. The dataset is integrated into an open-access platform optimized to facilitate community reconstruction and discovery efforts throughout the larval zebrafish brain.

neuroscience↗

bioRxiv2024

The Ratchet Model of Synovial Flares in Palindromic Rheumatism

Synovial flares in palindromic rheumatism (PR) are aperiodic bursts of inflammation in the joints, which usually self-resolve in a timescale hours or days. PR patients are believed to transit to a chronic auto-immune disease called rheumatoid arthritis (RA) in most cases, however, many patients remain palindromic indefinitely. We utilize and adapt a minimal ODE model of rheumatoid arthritis (RA) developed by Baker et al. to study PR in greater detail. We address questions characterizing the incidence, decay and sustenance of synovial flares in palindromic patients. A key question is to describe the nature of the transition from palindromic to full RA. We show that PR flares ordinarily resolve spontaneously, however, there is a secondary equilibrium in the model into which the trajectory can sometimes get trapped. When this "meta-stable locking" occurs, it initiates an adaptation that helps rescue the flare. Furthermore, this adaptation in turn activates a secondary adaptation in response to fluctuations in the healthy steady state. Finally, we show that if metastable locking occurs frequently enough these adaptation sequences turn maladaptive and the system slowly progresses into fully developed RA.

immunology↗

bioRxiv2022

Excess glutamate release triggers subunit-specific homeostatic receptor scaling

Ionotropic glutamate receptors (GluRs) are targets for modulation in Hebbian and homeostatic synaptic plasticity and are remodeled by development, experience, and disease. Although much is known about activity-dependent mechanisms that regulate GluR composition and abundance, the role of glutamate itself in these processes is unclear. To determine how glutamate sculpts GluR receptive fields, we have manipulated synaptically released glutamate and generated precise CRISPR mutations in the two postsynaptic GluR subtypes at the Drosophila neuromuscular junction, GluRA and GluRB. We first demonstrate that GluRA and GluRB compete to establish postsynaptic receptive fields, and that proper GluR abundance and localization can be orchestrated in the absence of any synaptic glutamate release. However, excess glutamate release adaptively tunes postsynaptic GluR abundance, echoing GluR receptor scaling observed in mammalian systems. Unexpectedly, when GluRA vs GluRB competition is eliminated, excess glutamate homeostatically regulates GluRA abundance, while GluRB abundance is now insensitive to glutamate modulation. Finally, Ca2+ impermeable GluRA receptors are no longer sensitive to homeostatic regulation by glutamate. Thus, excess glutamate, GluR competition, and Ca2+ signaling collaborate to selectively target GluR subtypes for homeostatic regulation at postsynaptic compartments.

neuroscience↗

bioRxiv2022

Botulinum neurotoxin accurately separates tonic vs phasic transmission and reveals heterosynaptic plasticity rules in Drosophila

In developing and mature nervous systems, diverse neuronal subtypes innervate common targets to establish and maintain functional neural circuits. A major challenge towards understanding the structural and functional architecture of neural circuits is to separate these inputs and determine their intrinsic and heterosynaptic relationships. The Drosophila larval neuromuscular junction is a powerful model system to study these questions, where two glutamatergic motor neurons, the strong phasic-like Is and weak tonic-like Ib, co-innervate individual muscle targets to coordinate locomotor behavior. However, complete neurotransmission from each input has never been electrophysiologically separated. We have developed a botulinum neurotoxin, BoNT-C, that eliminates both spontaneous and evoked neurotransmission without perturbing synaptic growth or structure, enabling the first approach that accurately isolates input-specific neurotransmission. Selective expression of BoNT-C in Is or Ib motor inputs disambiguates functional properties of each input. Importantly, the composite values of Is and Ib neurotransmission can be fully recapitulated by isolated physiology from each input. Finally, selective silencing by BoNT-C does not induce heterosynaptic structural or functional plasticity at the convergent input. Thus, BoNT-C establishes the first approach to cleanly separate neurotransmission between tonic vs phasic neurons and defines heterosynaptic plasticity rules in a powerful model glutamatergic circuit.

neuroscience↗

bioRxiv2020

Distinct target-specific mechanisms homeostatically stabilize transmission at pre-and post-synaptic compartments

Neurons must establish and stabilize connections made with diverse targets, each with distinct demands and functional characteristics. At Drosophila neuromuscular junctions, synaptic strength remains stable in a manipulation that simultaneously induces hypo-innervation on one target and hyper-innervation on the other. However, the expression mechanisms that achieve this exquisite target-specific homeostatic control remain enigmatic. Here, we identify the distinct target-specific homeostatic expression mechanisms. On the hypo-innervated target, an increase in postsynaptic glutamate receptor (GluR) abundance is sufficient to compensate for reduced innervation, without any apparent presynaptic adaptations. In contrast, a target-specific reduction in presynaptic neurotransmitter release probability is reflected by a decrease in active zone components restricted to terminals of hyper-innervated targets. Finally, loss of postsynaptic GluRs on one target induces a compartmentalized, homeostatic enhancement of presynaptic neurotransmitter release called presynaptic homeostatic potentiation that can be precisely balanced with the adaptations required for both hypo- and hyper-innervation to maintain stable synaptic strength. Thus, distinct anterograde and retrograde signaling systems operate at pre- and post-synaptic compartments to enable target-specific, homeostatic control of neurotransmission.

neuroscience↗

bioRxiv2019

Presynaptic depression maintains stable synaptic strength in developmentally arrested Drosophila larvae

Positive and negative modes of regulation typically constrain synaptic growth and function within narrow physiological ranges. However, it is unclear how synaptic strength is maintained when both pre- and post-synaptic compartments continue to grow beyond stages imposed by typical developmental programs. To address whether and how synapses can adjust to a novel life stage for which they were never molded by evolution, we have characterized synaptic growth, structure and function at the Drosophila neuromuscular junction (NMJ) under conditions where larvae are terminally arrested at the third instar stage. While wild type larvae transition to pupae after 5 days, arrested third instar (ATI) larvae persist for up to 35 days, during which NMJs exhibit extensive overgrowth in muscle size, presynaptic release sites, and postsynaptic glutamate receptors. Remarkably, despite this exuberant growth of both pre- and post-synaptic structures, stable neurotransmission is maintained throughout the ATI lifespan through a potent homeostatic reduction in presynaptic neurotransmitter release. Arrest of the larval stage in stathmin mutants reveals a degree of progressive instability and neurodegeneration that was not apparent during the typical larval period. Hence, during a period of unconstrained synaptic growth through an extended developmental period, a robust and adaptive form of presynaptic homeostatic depression can stabilize neurotransmission. More generally, the ATI manipulation provides an attractive system for studying neurodegeneration and plasticity across longer time scales. SIGNIFICANCE STATEMENTIt is unclear whether and how synapses adjust to a novel life stage for which they were never molded by evolution. We have characterized synaptic plasticity at the Drosophila neuromuscular junction in third instar larvae arrested in development for over 35 days. This approach has revealed that homeostatic depression stabilizes synaptic strength throughout the life of arrested third instars to compensate for excessive pre- and post-synaptic growth. This system also now opens the way for the study of synapses and degeneration over long time scales in this powerful model synapse.

neuroscience↗

bioRxiv2019

Genome-wide expression analysis identifies core components during iron starvation in hexaploid wheat

Iron is one of essential micronutrient for all organisms. Its deficiency causes a severe loss in crops yield. Nevertheless, our current understanding on major crops response to Fe deficiency remains limited. Herein, we investigated the effect of Fe deprivation at both transcriptomic and metabolic levels in hexaploid wheat. A genome-wide gene expression reprogramming was observed with a total of 5854 genes showing differential expression in roots of wheat subjected to Fe-starved medium. Subsequent, analysis revealed a predominance of strategy-II mode of Fe uptake, with induced genome bias contribution from the A and B genomes. In general, the predominance of genes encoding for nicotianamine synthase, yellow stripe like transporters, metal transporters, ABC transporters and zinc-induced facilitator-like protein was noticed. Our transcriptomic data were in agreement with the GC-MS analysis that showed an enhancement of accumulation of various metabolites such as fumarate, malonate, succinate and xylofuranose, which could be linked for enhancing Fe-mobilization. Interestingly, Fe starvation causes a significant temporal increase of glutathione-S-transferase both at transcriptional and enzymatic activity, which indicate the important role of glutathione in the response to Fe starvation in wheat roots. Taken together, our result provides new insight on wheat response to Fe starvation and lays foundation to design strategies to improve Fe nutrition in crops.

plant biology↗

bioRxiv2018

Rapid active zone remodeling consolidates presynaptic potentiation

Synaptic transmission is mediated by neurotransmitter release at presynaptic active zones (AZs) followed by postsynaptic neurotransmitter detection. Plastic changes in transmission maintain functionality during perturbations and enable memory formation. Postsynaptic plasticity targets neurotransmitter receptors, but presynaptic plasticity mechanisms directly regulating the neurotransmitter release apparatus remain largely enigmatic. Here we describe that AZs consist of nano-modular release site units and identify a molecular sequence adding more modules within minutes of plasticity induction. This requires cognate transport machinery and a discrete subset of AZ scaffold proteins. Structural remodeling is not required for the immediate potentiation of neurotransmitter release, but rather necessary to sustain this potentiation over longer timescales. Finally, mutations in Unc13 that disrupt homeostatic plasticity at the neuromuscular junction also impair shot-term memory when central neurons are targeted, suggesting that both forms of plasticity operate via Unc13. Together, while immediate synaptic potentiation capitalizes on available material, it triggers the coincident incorporation of modular release sites to consolidate stable synapse function.

neuroscience↗

bioRxiv2018

The sleep gene insomniac ubiquitinates targets at postsynaptic densities and is required for retrograde homeostatic signaling

The nervous system confronts challenges during development and experience that can destabilize information processing. To adapt to these perturbations, synapses homeostatically adjust synaptic strength, a process referred to as homeostatic synaptic plasticity. At the Drosophila neuromuscular junction, inhibition of postsynaptic glutamate receptors activates retrograde signaling that precisely increases presynaptic neurotransmitter release to restore baseline synaptic strength. However, the nature of the underlying postsynaptic induction process remains enigmatic. Here, we designed a forward genetic screen to identify factors necessary in the postsynaptic compartment to generate retrograde homeostatic signaling. This approach identified insomniac (inc), a gene that encodes a putative adaptor for the Cullin-3 ubiquitin ligase complex and is essential for normal sleep regulation. Intriguingly, we find that Inc rapidly traffics to postsynaptic densities and is required for increased ubiquitination following acute receptor inhibition. Our study suggests that Inc-dependent ubiquitination, compartmentalized at postsynaptic densities, gates retrograde signaling and provides an intriguing molecular link between the control of sleep behavior and homeostatic plasticity at synapses.

neuroscience↗

bioRxiv2018

A screen for genes that regulate synaptic growth reveals mechanisms that stabilize synaptic strength

Synapses grow, prune, and remodel throughout development, experience, and disease. This structural plasticity can destabilize information transfer in the nervous system. However, neural activity remains remarkably stable throughout life, implying that adaptive countermeasures exist to stabilize neurotransmission. Aberrant synaptic structure and function has been associated with a variety of neural diseases including Fragile X syndrome, autism, and intellectual disability. We have screened disruptions in over 300 genes in Drosophila for defects in synaptic growth at the neuromuscular junction. This effort identified 12 mutants with severe reductions or enhancements in synaptic growth. Remarkably, electrophysiological recordings revealed synaptic strength in all but one of these mutants was unchanged compared to wild type. We utilized a combination of genetic, anatomical, and electrophysiological analyses to illuminate three mechanisms that stabilize synaptic strength in the face of alterations in synaptic growth. These include compensatory changes in 1) postsynaptic receptor abundance; 2) presynaptic morphology; and 3) active zone structure. Together, this analysis identifies new genes that regulate synaptic growth and the adaptive strategies that synapses employ to homeostatically stabilize synaptic strength in response.\n\nAUTHOR SUMMARYThroughout development, maturation, experience, and disease, synapses undergo dramatic changes in growth and remodeling. Although these processes are necessary for learning and memory, they pose major challenges to stable function in the nervous system. However, neurotransmission is typically constrained within narrow physiological ranges, implying the existence of homeostatic mechanisms that maintain stable functionality despite drastic alterations in synapse number. In this study we investigate the relationship between synaptic growth and function across a variety of mutations in neural and synaptic genes in the fruitfly Drosophila melanogaster. Using the neuromuscular junction as a model system, we reveal three adaptive mechanisms that stabilize synaptic strength when synapses are dramatically under- or over-grown. Together, these findings provide insights into the strategies employed at both pre- and post-synaptic compartments to ensure stable functionality while allowing considerable flexibility in overall synapse number.

neuroscience↗