Biology subjects

Tariq, A.

Publications and source records attributed to Tariq, A..

9 recordsLinked to original sources

bioRxiv2026

Fluoxetine Hydrochloride Treatment Influences Site-Specific ADAR Editing and Transcriptome Regulation in Arid1b +/- Mice

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by repetitive behavior and impaired social interactions. Recent reports from human postmortem brain samples of ASD show transcriptome-wide dysregulations, including changes in differential gene expression and alternative splicing. An important mechanism regulating transcriptome function is the editing of double-stranded RNA by adenosine deaminases acting on RNA (ADARs), which play regulatory roles in neurodevelopment and innate immunity. We explore the ADAR editing changes associated with the use of Selective Serotonin Reuptake Inhibitors (SSRIs) in Arid1b haploinsufficient mouse models. Our results show dynamic changes in site-specific editing rates in autistic mice. We further demonstrate the transcriptome-wide effects of differential ADAR editing in terms of changes in miRNA-mRNA interactions. Moreover, our findings highlight a site-specific change in editing rates for evolutionarily conserved sites in mammals and ASD associated risk genes, such as Gria2. Our analysis of significant biological processes shows the association of differentially edited genes with processes vital for neurotransmission. Overall, our findings imply that the use of SSRIs can induce distinct ADAR editing signatures, potentially contributing to ASD pathology.

bioinformatics↗

bioRxiv2026

The HMD domain of the PAF complex primes Rad6-Bre1 E3 ligase complexes for H2B ubiquitination

Mono-ubiquitination of histone H2B (H2Bub) is deposited by Bre1-type E3 ubiquitin ligase complexes during transcription elongation and is critical for chromatin organization, DNA repair, and transcription regulation. In S. pombe, this activity is carried out by HULC, a complex of the Bre1 homologs Brl1 and Brl2 with Rhp6 and Shf1. While H2Bub deposition depends on recruitment of HULC to RNA Pol II by the Paf1 complex (PAF1C), the molecular basis for how PAF1C activates HULC has remained unclear. Using AlphaFold modelling, biochemical reconstitution, and functional assays, we define the architecture of HULC as a flexible 1:1:1:1 assembly in which Shf1 stabilizes an elongated coiled-coil hairpin that brings the RING and Rad6-binding domains into proximity. However, for full stimulation of HULC activity, we find that the HMD domain of the PAF1C subunit Prf1 stimulates ubiquitin transfer through a RING-binding region (RBR) that repositions the RING domains adjacent to Rhp6 in a catalytically competent configuration. These findings reveal an activation mechanism in which transcription-associated Prf1 primes HULC for ubiquitin transfer through the Prf1RBR, revealing a critical regulatory interface for H2B ubiquitination.

molecular biology↗

bioRxiv2026

Hair promotion effect of Beta vulgaris L. fruit extracts; physicochemical, and analytical evaluation

Natural products are used frequently for medicinal purposes due to their lower toxicity effect and greater safety than synthetic products. Alopecia is becoming common due to inheritance, hormonal change and environmental factors. The current study evaluates the physicochemical, analytical and hair growth promotion activity of extracts of Beta vulgaris L. Extraction was done by using hexane, chloroform, methanol, ethanol and water in increasing order of their polarity. For the hair growth activity, five groups (positive, negative, untreated, test-group 1 and test-group 2) of albino mice were made and each group has five mice. The hair tonic formulation was applied on their dorsal surface. The analysis revealed that methanolic and ethanolic extracts showed the highest phytochemical content. The average length and diameter were noted. On day 14 and 21 length of different groups were: standard group (7.40{+/-}0.34, 8.15{+/-}0.56), negative group (3.05{+/-}0.65 and 5.65{+/-}0.78), untreated group (3.44{+/-}0.27 and 4.58{+/-}0.61), test group1 5% methanol (5.25{+/-}0.20 and 6.26{+/-}0.10), 10% methanol (5.23{+/-}0.07 and 6.35{+/-}0.33), test group2, 5% ethanol 5.28{+/-}0.50 and 6.30{+/-}0.84, 10% ethanol 5.50{+/-}0.50 and 6.72{+/-}0.75 and the diameter of groups were; standard (3.5{+/-}0.42 and 4{+/-}0.86), negative (1.5{+/-}0.33 and 2{+/-}0.22), untreated (2{+/-}0.34 and 2{+/-}0.24), test group1 5% (2{+/-}0.41 and 2.5{+/-}0.65), 10%(2{+/-}0.65 and 2.5{+/-}0.34), test group2 5%(1.5{+/-}0.67 and 2.5{+/-}0.42), 10% (2{+/-}0.88 and 2.5{+/-}0.54). Both extracts showed significant results, but ethanolic extract is more effective than methanolic. The exact mechanism of hair growth is not known yet, but it might be due to its strong antioxidant and anti-inflammatory effect. hence, this study is useful in treating baldness.

pharmacology and toxicology↗

bioRxiv2024

The role of ADAR editing and nonsense-mediated decay in Parkinson's Disease

Parkinsons Disease (PD) is a multifactorial disease with heterogenous phenotypes that vary across individuals, as well as by age and sex. Therefore, it is likely that multiple interacting factors, such as environmental influences and aging, as well as genetic factors, including dynamic RNA (ADAR, Adenosine Deaminases Acting on RNA) editing, may play a role in PD pathology. In this analysis of 317 transcriptomes of healthy controls, PD and prodromal patients aged 65 years or older, from Parkinsons Project Markers Initiative dataset, we observe differences in ADAR expression, number of putative ADAR edits, editing index, and the number of high and moderate impact edits between control groups and diseased samples, particularly when ADAR editing is associated with nonsense-mediated decay (NMD). Likewise, differentially expressed genes between comparison groups were linked to NMD-related pathways. NMD is an important process in detecting deleterious nonsense sequences in mRNA transcripts and eliminating them from the cell. Thus, NMD regulation serves an important role in neurodevelopment, neural differentiation, and neural maturation. RNA misprocessing, which includes dysregulation of NMD, is known to play an important role in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia. Our results suggest that NMD may also be an important factor in PD physiology.

bioinformatics↗

bioRxiv2024

Reovirus infection induces transcriptome-wide unique A-to-I editing changes in the murine fibroblasts

The conversion of Adenosine (A) to Inosine (I), by Adenosine Deaminases Acting on RNA or ADARs, is an essential post-transcriptional modification that contributes to proteome diversity and regulation in metazoans including humans. In addition to its transcriptome-regulating role, ADARs also play a major part in immune response to viral infection, where an interferon response activates interferon-stimulated genes, such as ADARp150, in turn dynamically regulating host-virus interactions. A previous report has shown that infection from reoviruses, despite strong activation of ADARp150, does not influence the editing of some of the major known editing targets, while likely editing others, suggesting a potentially nuanced editing pattern that may depend on different factors. However, the results were based on a handful of selected editing sites and did not cover the entire transcriptome. Thus, to determine whether and how reovirus infection specifically affects host ADAR editing patterns, we analyzed a publicly available deep-sequenced RNA-seq dataset, from murine fibroblasts infected with wild-type and mutant reovirus strains that allowed us to examine changes in editing patterns on a transcriptome-wide scale. To the best of our knowledge, this is the first transcriptome-wide report on host editing changes after reovirus infection. Our results demonstrate that reovirus infection induces unique nuanced editing changes in the host, including introducing sites uniquely edited in infected samples. Genes with edited sites are overrepresented in pathways related to immune regulation, cellular signaling, metabolism, and growth. Moreover, a shift in editing targets has also been observed, where the same genes are edited in infection and control conditions but at different sites, or where the editing rate is increased for some and decreased for other differential targets, supporting the hypothesis of dynamic and condition-specific editing by ADARs.

bioinformatics↗

bioRxiv2022

Viral burdens are associated with age and viral variant in a population-representative study of SARS-CoV-2 that accounts for time-since-infection related sampling bias.

In this study, we evaluated the impact of viral variant, in addition to other variables, on within-host viral burdens, by analysing cycle threshold (Ct) values derived from nose and throat swabs, collected as part of the UK COVID-19 Infection Survey. Because viral burden distributions determined from community survey data can be biased due to the impact of variant epidemiology on the time-since-infection of samples, we developed a method to explicitly adjust observed Ct value distributions to account for the expected bias. Analysing the adjusted Ct values using partial least squares regression, we found that among unvaccinated individuals with no known prior infection, the average Ct value was 0.94 lower among Alpha variant infections, compared those with the predecessor strain, B.1.177. However, among vaccinated individuals, it was 0.34 lower among Delta variant infections, compared to those with the Alpha variant. In addition, the average Ct value decreased by 0.20 for every 10 year age increment of the infected individual. In summary, within-host viral burdens are associated with age, in addition to the interplay of vaccination status and viral variant.

genetics↗

bioRxiv2020

Tuning Hsp104 specificity to selectively detoxify alpha-synuclein

Hsp104 is an AAA+ protein disaggregase that solubilizes and reactivates proteins trapped in aggregated states. We have engineered potentiated Hsp104 variants to mitigate toxic misfolding of -synuclein, TDP-43, and FUS implicated in fatal neurodegenerative disorders. Though potent disaggregases, these enhanced Hsp104 variants lack substrate specificity, and can have unfavorable off-target effects. Here, to lessen off-target effects, we engineer substrate-specific Hsp104 variants. By altering Hsp104 pore loops that engage substrate, we disambiguate Hsp104 variants that selectively suppress -synuclein toxicity but not TDP-43 or FUS toxicity. Remarkably, -synuclein-specific Hsp104 variants emerge that mitigate -synuclein toxicity via distinct ATPase-dependent mechanisms, involving -synuclein disaggregation or detoxification of -synuclein conformers without disaggregation. Importantly, both types of -synuclein-specific Hsp104 variant reduce dopaminergic neurodegeneration in a C. elegans model of Parkinsons disease more effectively than non-specific variants. We suggest that increasing the substrate specificity of enhanced disaggregases could be applied broadly to tailor therapeutics for neurodegenerative disease.

bioengineering↗

bioRxiv2019

In vitro reconstitution of branched microtubule nucleation

Eukaryotic cell division requires the mitotic spindle, a microtubule (MT)-based structure which accurately aligns and segregates duplicated chromosomes. The dynamics of spindle formation are determined primarily by correctly localising the MT nucleator,{gamma} -Tubulin Ring Complex ({gamma}-TuRC)1-4, within the cell. A conserved MT-associated protein complex, Augmin, recruits{gamma} -TuRC to pre-existing spindle MTs, amplifying their number, in an essential cellular phenomenon termed \"branched\" MT nucleation5-9. Here, we purify endogenous, GFP-tagged Augmin and{gamma} -TuRC from Drosophila embryos to near homogeneity using a novel one-step affinity technique. We demonstrate that, in vitro, while Augmin alone does not affect Tubulin polymerisation dynamics, it stimulates{gamma} -TuRC-dependent MT nucleation in a cell cycle-dependent manner. We also assemble and visualise the MT-Augmin-{gamma}-TuRC-MT junction using light microscopy. Our work therefore conclusively reconstitutes branched MT nucleation. It also provides a powerful synthetic approach with which to investigate the emergence of cellular phenomena, such as mitotic spindle formation, from component parts.

cell biology↗

bioRxiv2019

Vaccination strategies to control Ebola epidemics in the context of variable household inaccessibility levels

Despite a very effective vaccine, active conflict and community distrust during the ongoing DRC Ebola epidemic are undermining control efforts, including a ring vaccination strategy that requires the prompt immunization of close contacts of infected individuals. However, in April 2019, it was reported 20% or more of close contacts cannot be reached or refuse vaccination [1], and it is predicted that the ring vaccination strategy would not be effective with such a high level of inaccessibility [2]. The vaccination strategy is now incorporating a "third ring" community-level vaccination that targets members of communities even if they are not known contacts of Ebola cases. To assess the impact of vaccination strategies for controlling Ebola epidemics in the context of variable levels of community accessibility, we employed an individual-level stochastic transmission model that incorporates four sources of heterogeneity: a proportion of the population is inaccessible for contact tracing and vaccination due to lack of confidence in interventions or geographic inaccessibility, two levels of population mixing resembling household and community transmission, two types of vaccine doses with different time periods until immunity, and transmission rates that depend on spatial distance. Our results indicate that a ring vaccination strategy alone would not be effective for containing the epidemic in the context of significant delays to vaccinating contacts even for low levels of household inaccessibility and affirm the positive impact of a supplemental community vaccination strategy. Our key results are that as levels of inaccessibility increase, there is a qualitative change in the effectiveness of the vaccination strategy. For higher levels of vaccine access, the probability that the epidemic will end steadily increases over time, even if probabilities are lower than they would be otherwise with full community participation. For levels of vaccine access that are too low, however, the vaccination strategies are not expected to be successful in ending the epidemic even though they help lower incidence levels, which saves lives, and makes the epidemic easier to contain and reduces spread to other communities. This qualitative change occurs for both types of vaccination strategies: ring vaccination is effective for containing an outbreak until the levels of inaccessibility exceeds approximately 10% in the context of significant delays to vaccinating contacts, a combined ring and community vaccination strategy is effective until the levels of inaccessibility exceeds approximately 50%. More broadly, our results underscore the need to enhance community engagement to public health interventions in order to enhance the effectiveness of control interventions to ensure outbreak containment. Author summaryIn the context of the ongoing Ebola epidemic in DRC, active conflict and community distrust are undermining control efforts, including vaccination strategies. In this paper, we employed an individual-level stochastic structured transmission model to assess the impact of vaccination strategies on epidemic control in the context of variable levels of household inaccessibility. We found that a ring vaccination strategy of close contacts would not be effective for containing the epidemic in the context of significant delays to vaccinating contacts even for low levels of household inaccessibility and evaluate the impact of a supplemental community vaccination strategy. For lower levels of inaccessibility, the probability of epidemic containment increases over time. For higher levels of inaccessibility, even the combined ring and community vaccination strategies are not expected to contain the epidemic even though they help lower incidence levels, which saves lives, makes the epidemic easier to contain and reduces spread to other communities. We found that ring vaccination is effective for containing an outbreak until the levels of inaccessibility exceeds approximately 10%, a combined ring and community vaccination strategy is effective until the levels of inaccessibility exceeds approximately 50%. Our findings underscore the need to enhance community engagement to public health interventions.

epidemiology↗