Biology subjects

Ali, A.

Publications and source records attributed to Ali, A..

At least 73 records · Page 4Linked to original sources

bioRxiv2024

Genomic characterization of a unique population of Leishmania tropica in a new emerging focus of cutaneous leishmaniasis in Somali region of Ethiopia

We sequenced Leishmania tropica genomes directly from eight human skin samples collected in a newly emerging focus of cutaneous leishmaniasis in Somali region, Ethiopia. We found a new variant with unique genomic signatures of drug resistance. Genomic homogeneity in the sampled population demonstrates the occurrence of a L. tropica outbreak.

microbiology↗

bioRxiv2024

Identification of functional rare coding variants in IGF-1 gene in humans with exceptional longevity

Diminished signaling via insulin/insulin-like growth factor-1 (IGF-1) axis is associated with longevity in different model organisms. IGF-1 gene is highly conserved across species, with only few evolutionary changes identified in it. Despite its potential role in regulating life span, no coding variants in IGF-1 have been reported in human longevity cohorts to date. This study investigated the whole exome sequencing data from 2,487 individuals in a cohort of Ashkenazi Jewish centenarians, their offspring, and controls without familial longevity to identify functional IGF-1 coding variants. We identified two likely functional coding variants IGF-1:p.Ile91Leu and IGF-1:p.Ala118Thr in our longevity cohort. Notably, a centenarian specific novel variant IGF-1:p.Ile91Leu was located at the binding interface of IGF-1 - IGF-1R, whereas IGF-1:p.Ala118Thr was significantly associated with lower circulating levels of IGF-1. We performed extended all-atom molecular dynamics simulations to evaluate the impact of Ile91Leu on stability, binding dynamics and energetics of IGF-1 bound to IGF-1R. The IGF-1:p.Ile91Leu formed less stable interactions with IGF-1Rs critical binding pocket residues and demonstrated lower binding affinity at the extracellular binding site compared to wild-type IGF-1. Our findings suggest that IGF-1:p.Ile91Leu and IGF-1:p.Ala118Thr variants attenuate IGF-1R activity by impairing IGF-1 binding and diminishing the circulatory levels of IGF-1, respectively. Consequently, diminished IGF-1 signaling resulting from these variants may contribute to exceptional longevity in humans.

biophysics↗

bioRxiv2024

Engineered Age-Mimetic Breast Cancer Models Reveal Differential Drug Responses in Young and Aged Microenvironments

Aging is one of the most significant risk factors for breast cancer. With the growing interests in the alterations of the aging breast tissue microenvironment, it has been identified that aging is related to tumorigenesis, invasion, and drug resistance. However, current pre-clinical disease models often neglect the impact of aging and sometimes result in worse clinical outcomes. In this study, we utilized aged animal-generated materials to create and validate a novel age-mimetic breast cancer model that generates an aging microenvironment for cells and alters cells towards a phenotype found in the aged environment. Furthermore, we utilized the age-mimetic models for 3D breast cancer invasion assessment and high-throughput screening of over 700 drugs in the FDA-approved drug library. We identified 36 potential effective drug targets and 34 potential drug targets with different drug responses in different age groups, demonstrating the potential of this age-mimetic breast cancer model for further in-depth breast cancer studies and drug development.

bioengineering↗

bioRxiv2024

Evidence that Dmrta2 acts as a transcriptional repressor of Pax6 in murine cortical progenitors and identification of a mutation crucial for DNA recognition associated with microcephaly in human

Dmrta2 (also designated Dmrt5) is a transcriptional regulator expressed in cortical progenitors in a caudomedialhigh/rostrolaterallow gradient with important roles at different steps of cortical development. Dmrta2 has been suggested to act in cortex development mainly by differential suppression of Pax6 and other homeobox transcription factors such as the ventral telencephalic regulator Gsx2, which remains to be fully demonstrated. Here we have addressed the epistatic relation between Pax6 and Dmrta2 by comparing phenotypes in mutant embryos or embryos overexpressing both genes in various allelic combinations. We showed that Dmrta2 cooperates with Pax6 in the maintenance of cortical identity in dorsal telencephalic progenitors and that it acts as a transcriptional repressor of Pax6 to control cortical patterning. Mechanistically, we show that in P19 cells, Dmrta2 can act as a DNA-binding dependent repressor on the Pax6 E60 enhancer and that a point mutation that affects its DNA binding properties leads to agenesis of the corpus callosum, pachygyria, and the absence of the cingulate gyrus. Finally, we provide evidence that Dmrta2 binds to the Zfp423 zinc finger protein and that it enhances its ability to recruit the NurD repressor complex. Together, our results highlight the importance and conserved function of Dmrta2 in cortical development and provide novel insights into its mechanism of action. SIGNIFICANCE STATEMENTCorticogenesis is controlled by an array of transcription factors that coordinate neural progenitor self-renewal and differentiation to generate correct cortical cell number and diversity. However, how this complex array of transcription factors works in concert to regulate this delicate process remains largely unknown. Here we provide important insights into the mechanism of action of Dmrta2 by demonstrating that it cooperates with the transcription factor Pax6 to define the pallium-subpallium boundary and that it acts by repressing it, likely via the recruitment of Zfp423 and the NurD repressor complex, to control cortical patterning. Our data also reveal that a point mutation that affects its DNA binding causes cortical abnormalities in human, further highlighting its importance in cortex development.

neuroscience↗

bioRxiv2024

The global spectrum of tree crown architecture

Trees can differ enormously in their crown architectural traits, such as the scaling relationships that link their height and crown size to their stem diameter. Yet despite the importance of crown architecture in shaping the structure and function of woody ecosystems, we lack a complete picture of what drives this incredible diversity in crown shapes. Using data from >500,000 globally distributed trees, we explored how climate, disturbance, competition, functional traits, and evolutionary history constrain the height, crown size and shape of the worlds tree species. We found that variation in height scaling relationships was primarily controlled by water availability and light competition. Conversely, crown width was predominantly shaped by exposure to wind and fire, while also covarying with other functional traits related to mechanical stability and photosynthesis. Additionally, several plant lineages had crown architectures that defy their environments, such as the exceedingly slender dipterocarps of Southeast Asia, or the extremely wide crowns of legumes in African savannas. Our study charts the global spectrum of tree crown architectural types. It provides a roadmap for integrating crown architecture with vegetation models and remote sensing observations, so that we may better understand the processes that shape the 3D structure of woody ecosystems.

ecology↗

bioRxiv2024

Rapid and Sensitive Detection of Fusarium oxysporum f. sp. cubense Tropical Race 4 Using a RPA-DETECTR Assay

Early and prompt detection of banana wilt pathogen Fusarium oxysporum f. sp. cubense (Foc), tropical race 4 (Foc TR4), causing global banana crop losses is crucial to curtail the disease spread, minimize damage and implement quarantine measures. We report the first successfully developed DNA Endonuclease Targeted CRISPR Trans Reporter (DETECTR) assay for the highly sensitive and specific detection of Foc TR4, validated across several isolates. Notably, specific crRNA spacer sequences and recombinant polymerase amplification (RPA) primers designed and evaluated for the DETECTR assay exhibited exceptional sensitivity, detecting Foc TR4 with genomic DNA as low as 0.005 ng, and demonstrated a very high specificity, and reproducibility. The RPA-DETECTR assay was validated using a diverse panel of samples, including both target and non-target pathogens confirming its robustness and reliability across different types of samples, ensuring practical application under varied conditions. In terms of throughput, the RPA-DETECTR assays enabled faster detection of Foc TR4 than other molecular diagnostics including PCR, quantitative PCR (qPCR) and droplet digital PCR (ddPCR) analyses, making this assay suitable for point-of-care (POC) detection of Foc TR4, and facilitating rapid decision-making and immediate response. This rapid detection capability is crucial in restricting any potential transboundary movement as part of ongoing disease management efforts.

pathology↗

bioRxiv2024

Efficient De Novo Assembly and Recovery of Microbial Genomes from Complex Metagenomes Using a Reduced Set of k-mers

In recent years, the analysis of metagenomic data to recover unculturable microbes has revolutionized microbial genomics by rapidly expanding the reference genome catalog. Central to this, are the computational approaches of de novo assembly and genome binning that enable large-scale reference-independent recovery of microbial genomes from the metagenomic sequencing data. Despite the advancements in bioinformatics approaches to address the computational challenges inherent to these tasks, the limitation of computational resources continues to be a significant barrier to harvesting the full potential of these techniques. Consequently, there is a stressed need to devise strategies involving the fine-tuning of the employed parameters for the effective utilization of the available metagenomic tools. As most of the available metagenome assembly tools are based on the de Bruijn graph framework that relies on a parameter k, selecting an appropriate subset of k-mers has become a common approach in bioinformatics for efficient computations. In this study, we propose a reduced set of k-mers, optimized to strike a balance between computational efficiency and the quality of the high- and low-complexity metagenome assemblies. Utilizing this set of k-mers with MEGAHIT reduces the metagenome assembly time by half compared to the default set, thus greatly reducing the associated computational cost. In addition, it also brings the promise to improve large-scale genome binning studies that adopt this set in the future as we observed an increase in the total number of the recovered genomes as well as obtained higher proportions of high- and medium-quality genomes recovered from the reduced k-mers-based metagenome assemblies.

bioinformatics↗

bioRxiv2024

Centromeres are Hotspots for Chromosomal Inversions and Breeding Traits in Mango

Chromosomal inversions can preserve combinations of favorable alleles by suppressing recombination. Simultaneously, they reduce the effectiveness of purifying selection enabling deleterious alleles to accumulate. This study explores how areas of low recombination, including centromeric regions and chromosomal inversions, contribute to the accumulation of deleterious and favorable loci in 225 Mangifera indica genomes from the Australian Mango Breeding Program. Here, we identify 17 chromosomal inversions that cover 7.7% (29.7Mb) of the M. indica genome: eight pericentric (inversion includes the centromere) and nine paracentric (inversion is on one arm of the chromosome). Our results show that these large pericentric inversions are accumulating deleterious loci, while the paracentric inversions show deleterious levels above and below the genome wide average. We find that despite their deleterious load, chromosomal inversions contain small effect loci linked to variation in crucial breeding traits, indicating that chromosomal inversions have likely facilitated their selection. The results from this study have important implications for selective breeding of favorable combinations of alleles in regions of low recombination. Significance StatementChromosomal inversions and other low recombination regions of the genome can drive trait evolution. Fewer recombination events can assist in maintaining favorable combinations of alleles, but it can also make disentangling favorable and deleterious alleles difficult. Understanding whether these low recombination regions contain favorable or deleterious loci could drive our decision to increase or decrease the frequency of these regions in target breeding populations. Breeding for large segments of the genome based on presence or absence of an inversion can rapidly drive large trait differences within few generations. Harnessing the impact of large low recombination regions of the genome could have major implications for future genetic improvement in breeding.

genomics↗

bioRxiv2024

Population growth poses a significant threat to forest ecosystems: a case study from the Hindukush-Himalayas of Pakistan

Human population growth and associated increases in anthropogenic activities pose a significant threat to forest ecosystems by diminishing the natural ecosystem services these systems provide. Malam Jabba is located in District Swat Pakistans Hindukush-Himalayan temperate zone, which is renowned for ecotourism and skiing and is rich in timber-producing tree species, medicinal plants, and unique biodiversity; however, the majority of Swat Valleys population relies on Malam Jabba forests for their timber & fuelwood requirements. We examined how the deforestation rate increased with increasing human population density in Pakistans Malam Jabba area of the Hindukush-Himalayas. To identify the forest cover, remote sensing, and geographic information systems were used (RS & GIS). The study areas vegetation was analyzed with the Normalized Divergence Vegetation Index (NDVI) using multitemporal satellite images for the years 1980, 2000, and 2020. The deforestation rate from 1980 to 2020 was then determined using the decay model, and the MATLAB program was used to predict the deforestation rate for the following two decades in relation to the anticipated growth in the human population. Our result revealed that, in the last two decades, the average rate of deforestation increased from 0.7% to 1.93% per year, while the human population of District Swat increased from 1.2 to 2.3 million at a rate of 9% per year. The decay model predicts that the study areas deforestation rate will increase to 2.5% per year over the next two decades due to the forecasted 11.6% per year population growth rate. Human population growth in District Swat, Pakistan has seriously threatened the nearby forest ecosystems, and a future increase in human population will further accelerate anthropogenic activities like unsustanible tourism, fuel and timber wood collection and urbanization. Based on our results, we recommend that: (i) in addition to reforestation programs and sustainable use of forest resources, the government should implement a long-term forest management plan (ii) where the density of forest cover can be sustained at an equilibrium level dependent of population growth pressure (iii) and areas with extreme human pressure should be designated as most important for in situ conservation approach.

ecology↗

bioRxiv2024

In-Vivo and In-Vitro Toxicity Evaluation of 2,3-Dimethylquinoxaline: an Antimicrobial Found in a Traditional Herbal Medicine

2,3-dimethylquinoxaline (DMQ) is a broad-spectrum antimicrobial phytochemical. This study aims to assess its toxicological profile. In vitro studies conducted in appropriate cell cultures, included assessment of cardiotoxicity, nephrotoxicity, and hepatotoxicity. An in vivo study was conducted in mice to determine acute oral toxicity (AOT), and subacute oral toxicity (SAOT). Acute dermal toxicity (ADT) was conducted in rats. All in-vitro toxicity studies of DMQ had negative results at concentrations [≤]100 {micro}M except for a non-significant reduction in the ATP in human hepatocellular carcinoma cell culture. The median lethal dose of DMQ was higher than 2000 mg/kg. All animals survived the scheduled necropsy and none showed any alteration in clinical signs. Biochemistry analysis revealed a significant difference between the satellite and control groups, showing an increase in platelet counts and white blood cell counts by 99.8% and 188.8%, respectively. Histology revealed enlargement of renal corpuscles; hyperplasia of testosterone-secreting cells; and dilatation of coronaries and capillaries. The present data suggests an acceptable safety profile of DMQ in rodents except for thrombocytosis, leukocytosis, and histological changes in high doses that need further investigation.

pathology↗

bioRxiv2023

Metabolite profiling of human renal cell carcinoma reveals tissue-origin dominance in nutrient availability

The tumor microenvironment is a determinant of cancer progression and therapeutic efficacy, with nutrient availability playing an important role. Although it is established that the local abundance of specific nutrients defines the metabolic parameters for tumor growth, the factors guiding nutrient availability in tumor compared to normal tissue and blood remain poorly understood. To define these factors in renal cell carcinoma (RCC), we performed quantitative metabolomic and comprehensive lipidomic analyses of tumor interstitial fluid (TIF), adjacent normal kidney interstitial fluid (KIF), and plasma samples collected from patients. TIF nutrient composition closely resembles KIF, suggesting that tissue-specific factors unrelated to the presence of cancer exert a stronger influence on nutrient levels than tumor-driven alterations. Notably, select metabolite changes consistent with known features of RCC metabolism are found in RCC TIF, while glucose levels in TIF are not depleted to levels that are lower than those found in KIF. These findings inform tissue nutrient dynamics in RCC, highlighting a dominant role of non-cancer driven tissue factors in shaping nutrient availability in these tumors.

cancer biology↗

bioRxiv2023

Epigenomic signatures as circulating and predictive biomarkers in sarcomatoid renal cell carcinoma

Renal cell carcinoma with sarcomatoid differentiation (sRCC) is associated with poor survival and heightened response to immune checkpoint inhibitors (ICIs). Two major barriers to improving outcomes for sRCC are (1) a limited understanding of its gene regulatory programs and (2) difficulty identifying sarcomatoid differentiation on tumor biopsies due to spatial heterogeneity. To address these challenges, we characterized the epigenomic landscape of sRCC by profiling 107 epigenomic libraries in tissue and plasma samples from 50 patients with RCC and healthy volunteers. We identified highly recurrent epigenomic reprogramming, as assessed by histone modifications and DNA methylation, that distinguishes sRCC from non-sarcomatoid RCC. Computational analysis of RCC epigenomic profiles and CRISPRa experiments implicated the transcription factor FOSL1 in activating sRCC-associated gene regulatory programs. Analysis of two randomized clinical trials identified FOSL1 expression as a predictive biomarker of response to ICIs in RCC. Finally, we demonstrate that epigenomic signatures of sRCC are detectable in patient plasma, establishing an approach for blood-based diagnosis of this clinically important phenotype. These findings provide a framework for the discovery and non-invasive detection of epigenomic correlates of tumor histology via liquid biopsy.

genomics↗

bioRxiv2023

Beneficial effects of intermittent fasting in NASH and subsequent HCC development are executed by concerted PPAR alpha and PCK1 action in hepatocytes

The role and molecular mechanisms of intermittent fasting (IF) in non-alcoholic steatohepatitis (NASH) and its transition to hepatocellular carcinoma (HCC) are unknown. Here, we identified that an IF 5:2 regimen (two non-consecutive days of food deprivation per week), initiated in the active phase of mice, prevents/ameliorates NASH and fibrosis as well as reduces subsequent HCC development without affecting total calorie intake. The timing, length and number of fasting cycles as well as the type of NASH diet were all critical parameters determining the effectiveness of the fasting benefits. Combined proteomic, transcriptomic and metabolomic analyses identified that PPAR and glucocorticoid receptor (GR)-PCK1 act co-operatively as hepatic executors of the fasting response by promoting fatty acid catabolism and gluconeogenesis whilst suppressing anabolic lipogenesis. In line, PPAR targets and PCK1 were reduced in human NASH. Additionally, dynamic [18F]FDG-PET analysis in vivo revealed increased [18F]FDG uptake/retention and enhanced gluconeogenesis in the liver upon fasting (in accordance with PPAR and GR-PCK1 activation) when assessed by compartmental modelling. Hepatocyte-specific GR deletion only partially abrogated the hepatic fasting response. In contrast, the combined knockdown of Ppara and Pck1 in vivo abolished the beneficial outcomes of fasting against inflammation and fibrosis, confirming their causal relationship in integrating systemic signalling in hepatocytes. Notably, PPAR agonist pemafibrate recapitulated key aspects of hepatic fasting signalling at a molecular level. Therefore, IF or pharmacological mimetics of the PPAR and/or GR-PCK1 axis could be a viable intervention against NASH and subsequent liver cancer. One-Sentence SummaryIntermittent fasting protects against fatty liver disease and liver cancer through concerted PPAR and GR-PCK1 action in hepatocytes.

cancer biology↗

bioRxiv2023

Inhibiting the GPI Transamidase Subunit GPAA1 Abolishes CD24 Surface Localization and Enhances Macrophage-Mediated Phagocytosis of Ovarian Cancer Cells

The CD24-Siglec10 signaling axis is an immune checkpoint pathway that shields ovarian cancer cells from phagocytosis by tumor-associated macrophages (TAMs), making it an appealing immunotherapeutic target. Here, we investigate factors influencing CD24 cell surface expression and assess their suitability as drug targets. Using a CRISPR-based knockout screen, we identify GPAA1 (glycosylphosphatidylinositol anchor attachment-1) as a positive regulator of CD24 cell surface expression. GPAA1 is a crucial component of the multi-subunit GPI transamidase complex, which facilitates the attachment of GPI lipid anchor to the C-terminus of CD24, enabling its surface localization. Reducing the activity of GPAA1 in ovarian cancer cells, either by genetic ablation or targeting with an aminopeptidase inhibitor bestatin, disrupts GPI attachment to CD24. This disruption impairs CD24 cell surface localization, enhances phagocytosis by TAMs, and suppresses tumor growth in mice. Our study highlights the potential of GPAA1 targeting as a therapeutic approach for CD24-positive ovarian cancers.

cancer biology↗

bioRxiv2023

CellPie: a fast spatial transcriptomics topic discovery method via joint factorization of gene expression and imaging data

Spatially resolved transcriptomics has enabled the study of expression of genes within tissues while retaining their spatial identity. Most spatial transcriptomics technologies generate a matched histopathological image as part of the standard pipeline, providing morphological information that can complement the transcriptomics data. Here we present CellPie, a fast, unsupervised factor discovery method, based on joint non-negative matrix factorisation of spatial RNA transcripts and histological image features.CellPie employs the accelerated hierarchical least squares method to significantly reduce the computational time, enabling efficient application to high-dimensional spatial transcriptomics datasets. We assessed CellPie on two different human cancer types and spatial resolutions, showing an improved performance against published factorisation methods. Additionally, we applied CellPie to a highly resolved Visium HD dataset, demonstrating its high computational efficiency compared to standard non-negative matrix factorisation and other existing methods. Availabilityhttps://github.com/ManchesterBioinference/CellPie

bioinformatics↗

bioRxiv2023

Notch signalling plays a critical role in patterning the ventral mesoderm during early embryogenesis in Drosophila melanogaster

Notch signalling is a critical regulator of multiple developmental processes through its ability to control gene expression and thereby influence cell fate specification and cell proliferation through direct cell-cell communication. Although Notch signalling has been implicated in myogenesis during late embryogenesis, its role in early mesoderm development has been largely unexplored. Endocytosis of the Notch ligand Delta and the Notch receptor extracellular domain, a critical step in Notch pathway activation, has been extensively observed in the ventral mesoderm of the early Drosophila embryo, indicating a potential for Notch signalling activity in this early germ layer. Here we present evidence that genes critical to mesoderm development require and are responsive to Notch signalling activity. Using a novel light-inducible Optogenetic variant of the Notch intracellular domain (OptoNotch), which affords precise spatial and temporal control over ectopic activation of Notch signalling, in combination with high-resolution fluorescent RNA in situ hybridization and qPCR, we identified a set of mesodermal genes whose expression is directly regulated by Notch signalling. We also provide evidence that Notch signalling indirectly regulates the dorsal-ventral patterning program mediated by the Toll signalling pathway through the Dorsal/ Twist/ Snail gene network. Our findings demonstrate that Notch signalling regulates ventral mesoderm patterning and is critical for establishing the mesoderm-mesectoderm-ectoderm boundary by regulating gene expression patterns and providing negative feedback on the upstream patterning network.

developmental biology↗

bioRxiv2023

The HOMEODOMAIN-Like protein HDL mediates chromatin organization and rewires leaf epidermal patterning

The Arabidopsis leaf epidermis is comprised of trichomes, pavement cells, and stomata, originating from versatile precursor cells capable of dividing or differentiating to create unique epidermal patterns. The mechanism governing these transitions and the maintenance of cell heterogeneity remains unclear. In this study, we identified a novel homeodomain-like superfamily protein, HDL, localized in chromocenters and playing a role in chromatin organization. HDL interacts with histone deacetylase 6 (HDA6) and methyltransferases, indicating its function in modulating chromatin accessibility. In hdl mutants, we observed moderately increased chromatin accessibility in the promoter region of protein-coding genes, along with reduced stomatal density and elevated trichome numbers on leaf surfaces. Corresponding to these phenotypes, stomatal-related gene expression decreased, while a transcriptional reporter for GLABRA2, a trichome initiation gene, exhibited higher and more variable expression levels. These findings highlight how HDL-mediated chromatin organization influences epidermal cell fate by modulating gene expression and enhancing cell heterogeneity within the leaf epidermis. One Sentence SummaryA homeodomain-like protein functions with histone modifiers to regulate chromatin and influence cell fate decisions.

plant biology↗

bioRxiv2023

Wiskott-Aldrich Syndrome Protein Regulates Nucleolar Organization and Function in Innate Immune Response

Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency disorder caused by the dysfunction of the WAS protein (WASP). Using an isogenic macrophage model derived from genome edited induced pluripotent stem cells we demonstrated that WASP functions in the nucleolus, which plays important roles in immune regulation. The absence of WASP resulted in smaller and misshapen nucleoli, decreased fibrillar center territory, and impaired ribosomal RNA (rRNA) transcription. The nucleolar and rRNA phenotypes were confirmed in WAS patient samples. Furthermore, WASP interacts with nucleolar proteins, including nucleophosmin 1 (NPM1) and fibrillarin (FBL). NPM1 deficiency is known to cause elevated cytokine expression following lipopolysaccharide (LPS) stimulation. Consistently, WASP deficient cells displayed lower levels of NPM1 and a heightened inflammatory cytokine response to LPS, which was rescued by overexpressing NPM1. Together, our research provides novel insights into the critical role of WASP in nucleolar function and the modulation of inflammatory cytokine production.

cell biology↗