Biology subjects

Rahman, S.

Publications and source records attributed to Rahman, S..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Mechanism of USP21 autoinhibition and histone H2AK119 deubiquitination

Monoubiquitinated histone H2A lysine 119 (H2AK119ub) is a signature modification associated with transcriptional silencing and heterochromatin formation. Ubiquitin-specific protease 21 (USP21), one of four major deubiquitinating enzymes (DUBs) that target H2AK119ub, plays critical roles in diverse cellular processes1-4. The molecular mechanisms by which USP21 specifically deubiquitinates H2AK119ub and is regulated is unknown. USP21 contains a C-terminal USP catalytic domain, preceded by an N-terminal intrinsically disordered region (IDR). We determined the cryo-EM structure of the USP21 catalytic domain bound to an H2AK119ub nucleosome, which reveals a recognition mode that differs from that of two other H2AK119-specific DUBs, Polycomb repressive complex5 and USP166. We unexpectedly discovered that the N-terminal intrinsically disordered region (IDR) of USP21 inhibits the enzymes activity. Using AlphaFold-Multimer to perform a virtual screen of USP21 interactors, we identified kinases that phosphorylate the USP21 IDR and thereby relieve autoinhibition. Modeling of USP21 using AlphaFold3 suggests a structural model explaining the mechanism of autoinhibition. AlphaFold analysis of other ubiquitin-specific proteases suggests that phosphorylation-regulated autoinhibition may be a feature of multiple USP enzymes. These findings shed light on the molecular mechanisms of H2AK119 deubiquitination and reveal a novel mode of phosphorylation-dependent DUB autoregulation.

biophysics↗

bioRxiv2024

High-Throughput Screening Reveals Potential Inhibitors Targeting Trimethoprim-Resistant DfrA1 Protein in Klebsiella pneumoniae and Escherichia coli

The DfrA1 protein provides trimethoprim resistance in bacteria, especially Klebsiella pneumoniae and Escherichia coli, by modifying dihydrofolate reductase, which reduces the binding efficacy of the antibiotic. Thus, this study aimed to identify inhibitors of the trimethoprim-resistant DfrA1 protein through high-throughput computational screening of 3,601 newly synthesized chemical compounds sourced from the ChemDiv database. We conducted high-throughput computational optimization and screening of a library containing 3,601 compounds against the DfrA1 protein from K. pneumoniae and E. coli to identify potential drug candidates (DCs). Through this extensive approach, we identified six promising DCs, labeled DC1 to DC6, as potential inhibitors of DfrA1. Each DC demonstrated strong initial binding affinity and favorable chemical interactions with the DfrA1 binding sites when compared to the effective drug Iclaprim (effective antibiotic against DfrA1), used as a control. To validate these findings, we further investigated the molecular mechanisms of inhibition, focusing on the thermodynamic properties of the promising DCs. Furthermore, molecular dynamics simulation (MDS) validated the inhibitory efficacy of these six DCs against the DfrA1 protein. Our results showed that DC4 (an organoflourinated compound) and DC6 (a benzimidazol compound) showed superior efficacy against the DfrA1 protein than the control drug, particularly regarding stability, solvent-accessible surface area, solvent exposure, polarity, and binding site interactions, which influence their residence time and efficacy. Overall, findings of this study suggest that DC4 and DC6 have the potential to act as inhibitors against the DfrA1, offering promising prospects for the treatment and management of infections caused by trimethoprim-resistant K. pneumoniae and E. coli in both humans and animals.

bioinformatics↗

bioRxiv2024

In silico Identification of Novel Common Drug Targets Against Four Infectious Acinetobacter Species

The global emergence of multidrug-resistant Acinetobacter species has become a major concern in the management of hospital-acquired infections. Moreover, misdiagnosis of one species of Acinetobacter with another has been reported, making it difficult to choose appropriate treatment. World Health Organization emphasizes the urgent need to develop new antibiotics to combat Acinetobacter infections. This study aimed to discover novel common drug targets that will be effective against Acinetobacter nosocomialis, Acinetobacter baumannii, Acinetobacter pittii, and Acinetobacter haemolyticus. We utilized a cluster-based subtractive genomics approach to identify potential drug targets. The main focus was to find drug targets that are absent in humans and essential for pathogens. We also performed metabolic pathway and subcellular localization analyses. Furthermore, protein structure-based studies and druggability analyses were conducted to identify viable therapeutic options. Out of 1245 protein clusters (minimum 4 proteins/cluster), 204 clusters were human non-homologous and essential for bacteria. Among them, 39 clusters were cytoplasmic and involved in unique metabolic pathways which are specific to the pathogens. After analyzing the drug target sequences of DrugBank database, 12 clusters were found to be novel drug targets. Eventually, proteins of one cluster were identified as advantageous drug targets having drug-binding pockets at very similar regions with high druggability scores. These proteins can be inhibited to disrupt the Lysine/DAP biosynthetic pathway of Acinetobacter. Our research might open up a new possibility for drug discovery against these pathogens.

bioinformatics↗

bioRxiv2024

Loss of Calcitonin gene-related Related Receptor component protein (RCP) in nervous system can bias gepant antagonism

We examined calcitonin gene-related peptide (CGRP)s effects on behavioral surrogates for motion-induced nausea and static imbalance in the nestinRCP (-/-), a novel mouse model that loses expression of receptor component protein (RCP) in the nervous system after tamoxifen induction. The assays used were the motion-induced thermoregulation and center of pressure (CoP) assays. Findings suggest CGRPs affects behavioral measures in the nestinRCP (-/-) similarly to littermate controls, since CGRP was observed to increase female sway and diminishes tail vasodilations to provocative motion in both sexes. However, the CGRP-receptor antagonist olcegepant did not antagonize CGRPs effects in the nestinRCP (-/-), whereas it was effective in littermate controls. Findings suggest RCP loss may change the sensitivity of the CGRP receptor and affect the efficacy of receptor antagonists. Significance StatementResearch in calcitonin gene-related peptide (CGRP) has primarily focused on ligand- receptor interactions at the calcitonin-like receptor (CLR) and receptor activity-modifying unit 1 (RAMP1) subunits. However, the role of receptor component protein (RCP), which mediates signaling via the G-stimulatory pathway, is less understood. A novel tamoxifen-inducible mouse model, nestinRCP (-/-), was generated to study loss of RCP in CGRP signaling in the nervous system, and behavioral changes to motion-induced nausea and postural sway were studied after systemic injections of CGRP or CGRP co-delivered with migraine drugs. Findings from this study suggest the loss of CGRP-RCP can bias "gepant" antagonists like olcegepant, and may promote development of therapies to inhibit the RCP-CLR interactions.

neuroscience↗

bioRxiv2024

Subtractive proteomics unravel the potency of D-Alanine-D-Alanine Ligase as the drug target for Burkholderia pseudomallei

Melioidosis, also known as Whitmores disease, is caused by the deadly pathogen Burkholderia pseudomallei and remains a significant global health concern, particularly in South Asia. The disease is contracted through exposure to contaminated soil, water, air, and food. Infected individuals often present with abscesses in internal organs such as the lungs, spleen, and liver, and in soft tissues, with severe cases leading to septic shock and acute pneumonia. The rising incidence and mortality rates, coupled with B. pseudomalleis ability to form biofilms and develop resistance to antibiotics like cephalosporins, make treatment increasingly challenging. This highlights the urgent need for novel therapeutic approaches. D-Alanine-D-Alanine ligase (Ddl), a crucial enzyme involved in the final stage of bacterial cell wall synthesis, which protects the pathogen from the hostile cellular environment of the host. While many bacteria have two isoforms of this enzyme, B. pseudomallei possesses only the DdlB isoform, presenting a significant vulnerability. Our study represents the first successful attempt to target DdlB through a combination of molecular docking and molecular dynamics simulations. These investigations provide strong evidence that Conivaptan acts as an effective inhibitor of DdlB, offering a novel therapeutic approach for combating melioidosis.

bioinformatics↗

bioRxiv2024

Effects of fasting on heat-stressed broiler chickens: part I- growth performance, meat quality, gut histomorphological and microbial responses

The current study aimed to optimize the fasting duration in order to mitigate the detrimental effects of heat stress on broilers raised in hot and humid climatic environments. A total of 500 broiler DOCs were assigned to five distinct treatment groups: T= Non-fasted controlled temperature (24-26) (NF-CT), T1= Non-fasted heat stressed (30-38) (NF-HS), T2= 6 hours fasted heat stressed (6-h FHS), T3= 8 hours fasted heat stressed (8-h FHS), and T4= 10 hours fasted heat stressed (10-h FHS). Each treatment was replicated five times, with 20 birds in each replicate group. As expected, the birds in NF-CT group showed significantly better performances for all the growth parameters, although birds who fasted for 8-h under heat stress exerted better growth and FCR in comparison to the other HS groups. Fasting of birds under heat stress significantly showed the lowest mortality. Like the NF-CT group, birds in 8-h FHS achieved significantly higher dressing percentage, breast meat, liver yields, and the lowest abdominal fat. Fasting for 8- and 10-h significantly increased breast meat pH and water holding capacity and thus reduced cooking loss. Fasting also improved the breast meat color quality by increasing redness (a*) and reducing the hue angle values comparable with the NF-CT group. A significantly upward trend in villi height (VH), width (VW) and crypt depth (CD) of gut segments was also observed in the birds of the 8-h FHS group. Total bacterial and coliform counts in cecum contents were reduced significantly with the increase in the fasting period. Benefit-cost analysis showed better profitability in the 8-h FHS group than other HS groups. Taken altogether, it can be concluded that broiler chicken exposed to 8-h fasting period is an effective approach to mitigate heat stress under hot and humid climatic conditions.

zoology↗

bioRxiv2024

Transcriptomic Insights into the Virulence of Acinetobacter baumannii During Infection: Role of Iron Uptake and Siderophore Production Genes

Acinetobacter baumannii is a top-priority pathogen as classified by the World Health Organisation. It causes life-threatening infections in immunocompromised patients, resulting in prolonged hospitalisation and high mortality. Increasing cases of community-acquired A. baumannii infections with rapid progression and severe infections have been reported. This study used the previously described Galleria mellonella infection model to investigate the virulence mechanisms of the community strain C98 (Ab-C98) via transcriptomic analysis using direct RNA sequencing. This strain showed greater killing and more rapid colonisation in the larvae than a clinical reference strain (ATCC BAA1605). Differential gene expression analysis revealed the significant upregulation of three major iron clusters: the acinetobactin and baumannoferrin clusters for siderophore production and the Feo system for ferrous iron uptake. Targeted knockout of siderophore production genes (basC, bfnD and isochorismatase family protein) significantly attenuated virulence in mutants with minimal impact on the bacterial growth in vivo. Overall, this study highlights the virulence of basC, isochorismatase family protein and bfnD in the pathogenicity of A. baumannii. As these targets are highly conserved in A. baumannii and the closely related A. pittii and A. lactucae, they could serve as potential therapeutic targets for developing new antivirulence agents to combat these pathogens.

microbiology↗

bioRxiv2024

Designing a novel Scaffold-Based Multi-Epitope Vaccine to Combat Melioidosis Caused by Burkholderia pseudomallei: An In-silico and Immunoinformatics approach

Burkholderia pseudomallei, the gram-negative bacteria causing melioidosis, is becoming a serious threat to healthcare settings. In recent years, B. pseudomallei has been identified as an emerging and significant etiological agent responsible for localized pyogenic infections primarily observed in India and South Asia. At present, no vaccine against melioidosis is available in the treatment system. This study has undertaken an in-silico reverse vaccinology approach to design a novel multi-epitope vaccine for treating B. pseudomallei-mediated infections. B-cell and T-cell epitopes have been predicted and stitched to develop a multi-epitope vaccine. The predicted vaccine is found to be non-toxic, non-allergic, and immunogenic in nature. Immune simulation results indicate that the designed vaccine can generate an immune response resembling a real-life scenario. The 610 amino-acid long vaccine construct has been codon-optimized and could be cloned in the E. coli K12 system. These findings from this immunoinformatics study offer a foundation for developing a tailored, safe, and potent vaccine targeting B. pseudomallei.

bioinformatics↗

bioRxiv2024

VASCilia (Vision Analysis StereoCilia): A Napari Plugin for Deep Learning-Based 3D Analysis of Cochlear Hair Cell Stereocilia Bundles

Cochlear hair cells are essential for hearing, and their stereocilia bundles are critical for mechanotransduction. However, analyzing the 3D morphology of these bundles can be challenging due to their complex organization and the presence of other cellular structures in the tissue. To address this, we developed VASCilia (Vision Analysis StereoCilia), a Napari plugin suite that automates the analysis of 3D confocal microscopy datasets of phalloidin-stained cochlear hair cell bundles. VASCilia includes five deep learning-based models that streamline the analysis process, including: (1) Z-Focus Tracker (ZFT) for selecting relevant slices in a 3D image stack; (2) PCPAlignNet (Planar Cell Polarity Alignment Network) for automated orientation of image stacks; (3) a segmentation model for identifying and delineating stereocilia bundles; (4) a tonotopic Position Prediction tool; and (5) a classification tool for identifying hair cell subtypes. In addition, VASCilia provides automated computational tools and measurement capabilities. Using VASCilia, we demonstrate its utility on challenging datasets, including neonatal wildtype and Eps8 KO 5-day old mice), revealing that total actin content does not necessarily scale with bundle height. We further showcase its power by quantifying complex bundle disorganization in Cdh23-/- cochleae via texture analysis, which revealed systematically more heterogeneous and less regular bundles than in controls. These novel biological findings demonstrate the power of VASCilia in facilitating detailed quantitative analysis of stereocilia. VASCilia also provides a user-friendly interface that allows researchers to easily navigate and use the tool, with the added capability to reload all their analyses for review or sharing purposes. We believe that VASCilia will be a valuable resource for researchers studying cochlear hair cell development and function, addressing a longstanding need in the hair cell research community for specialized deep learning-based tools capable of high-throughput image quantitation. We have released our code along with a manually annotated dataset that includes approximately 55 3D stacks featuring instance segmentation (https://github.com/ucsdmanorlab/Napari-VASCilia). This dataset comprises a total of 502 inner and 1,703 outer hair cell bundles annotated in 3D. As the first open-source dataset of its kind, we aim to establish a foundational resource for constructing a comprehensive atlas of cochlea hair cell images. Ultimately, this initiative will support the development of foundational models adaptable to various species, markers, and imaging scales to accelerate advances within the hearing research community.

bioinformatics↗

bioRxiv2024

A Novel Artificial Intelligence (AI) Method to Classify and Predict the Progression of Alzheimers Disease

PurposeThe objective of this study was to develop a novel AI-ensembled network based on the most important features and affected brain regions to accurately classify and exhibit the pattern of progression of the stages of Cognitive Impairment (CI). MethodsWe proposed a novel ensembled architecture, 3D ResNet-18 - RF (Random Forest), and used this network to categorize the stages of Alzheimers disease (AD). The residual unit (blocks of ResNet) was introduced to the 3D Convolutional Neural network (CNN) to solve the degradation problem. It was considered an innovative strategy since the combination with fine-tuning resulted in higher accuracy. This network was trained on selected features and affected brain regions. The structured magnetic resonance images (MRI) were collected from the Alzheimers Disease Neuroimaging Initiative (ADNI) dataset, and the random forest was used for determining the importance of the features and affected regions from the parcellated 170 regions of interest (ROIs) using Atlas, automated anatomical labeling 3(AAL-3). This framework classified five categories of AD and detected the progression pattern. ResultsThe proposed network showed promising results with a 66% F-1 score, 76% sensitivity, and 93.5% specificity, which outperformed the performance of conventional methods for categorizing five categories. Ventral Posterolateral and Pulvinar lateral regions were the regions most affected, indicating the progression from early MCI to AD. The five-fold validation accuracy for the developed model was 60.02%. ConclusionThe results showed that the gray matter to white matter ratio was the most significant feature, which also accurately predicted the progression pattern. The performance metrics fluctuated with different hyperparameters, but they never exceeded 0.05% of the estimated results, indicating the validity and originality of the suggested methodology.

bioinformatics↗

bioRxiv2024

Haspin kinase binds to a nucleosomal DNA supergroove

Phosphorylation of histone H3 threonine 3 (H3T3) by Haspin recruits the chromosomal passenger complex to the inner centromere and ensures proper cell cycle progression through mitosis. The mechanism by which Haspin binds to nucleosomes to phosphorylate H3T3 is not known. We report here cryo-EM structures of the Haspin kinase domain bound to a nucleosome. In contrast with previous structures of histone-modifying enzymes, Haspin solely contacts the nucleosomal DNA, inserting into a supergroove formed by apposing major grooves of two DNA gyres. This unique binding mode provides a plausible mechanism by which Haspin can bind to nucleosomes in a condensed chromatin environment to phosphorylate H3T3. We identify key basic residues in the Haspin kinase domain that are essential for phosphorylation of nucleosomal histone H3 and binding to mitotic chromatin. Our structure is the first of a kinase domain bound to a nucleosome and is the first example of a histone-modifying enzyme that binds to nucleosomes solely through DNA contacts.

biophysics↗

bioRxiv2024

GENE THERAPY PREVENTS HEPATIC MITOCHONDRIAL DYSFUNCTION IN MURINE DEOXYGUANOSINE KINASE DEFICIENCY

Primary mitochondrial disorders are an uncommon cause of neonatal hepatic failure. Biallelic pathogenic variants of the gene encoding the mitochondrial localising enzyme deoxyguanosine kinase (DGUOK) cause hepatocerebral mitochondrial DNA depletion syndrome leading to acute neonatal liver failure and early mortality. There are currently no effective disease-modifying therapies. In this study, we developed an adeno-associated virus 9 (AAV9) gene therapy approach to treat a mouse model of DGUOK deficiency that recapitulates human disease. We delivered AAV9-hDGUOK gene therapy intravenously to newborn Dguok knock-out mice and showed that liver dysfunction was prevented in a dose dependent manner. Unexpectedly for neonatal delivery, durable and long-lasting liver transduction and RNA expression were demonstrated. Liver mitochondrial DNA depletion, deficiencies of oxidative phosphorylation complexes I, III and IV and liver transaminitis and survival were ameliorated in a dose-dependent manner.

genetics↗

bioRxiv2024

An optical aptamer-based cytokine nanosensor detects macrophage activation by bacterial toxins

Overactive or dysregulated cytokine expression is hallmark of many acute and chronic inflammatory diseases. This is true for acute or chronic infection, neurodegenerative diseases, autoimmune diseases, cardiovascular disease, cancer, and others. Cytokines such as interleukin-6 (IL-6) are known therapeutic targets and biomarkers for such inflammatory diseases. Platforms for cytokine detection are therefore desirable tools for both research and clinical applications. Single-walled carbon nanotubes (SWCNT) are versatile nanomaterials with near-infrared fluorescence that can serve as transducers for optical sensors. When functionalized with an analyte-specific recognition element, SWCNT emission may become sensitive and selective towards the desired target. SWCNT-aptamer sensors are easily assembled, inexpensive, and biocompatible. In this work, we introduced a nanosensor design based on SWCNT and a DNA aptamer specific to IL-6. We first evaluated several SWCNT-aptamer constructs based on this simple direct complexation method, wherein the aptamer both solubilizes the SWCNT and confers sensitivity to IL-6. The sensor limit of detection, 105 ng/mL, lies in the relevant range for pathological IL-6 levels. Upon investigation of sensor kinetics, we found rapid response within seconds of antigen addition which continued over the course of three hours. We found that this sensor construct is stable, and the aptamer is not displaced from the nanotube surface during IL-6 detection. Finally, we investigated the ability of this sensor construct to detect macrophage activation caused by bacterial lipopolysaccharides (LPS) in an in vitro model of disease, finding rapid and sensitive detection of macrophage-expressed IL-6. We are confident further development of this sensor will have novel implications for diagnosis of acute and chronic inflammatory diseases, in addition to contributing to the understanding of the role of cytokines in these diseases.

bioengineering↗

bioRxiv2024

Investigating the Structural Impact and Conformational Dynamics of a Sequence Variant (c.242G>A) in TMIE Gene Provoking Usher Syndrome

Usher syndrome (USH) is a retinal autosomal recessive genetic disorder, characterized by congenital severe-to-profound sensorineural hearing loss, retinitis pigmentosa (RP), and rarely vestibular dysfunction. A transmembrane inner ear gene TMIE causing autosomal recessive usher syndrome hearing loss, which may open up interesting perspectives into the function of this protein in inner ear. This disease is linked with mutations in TMIE gene. In this study delineates the pathogenic association, miss-fold aggregation, and conformational paradigm of a missense variant (c.242G>A) resulting into (p.Arg81His) in TMIE gene segregating usher syndrome through a molecular dynamics simulations approach. The transmembrane inner ear expressed protein assumes a critical role as its helices actively engage in binding with specific target DNA base pairs. The alteration observed in the mutant protein, characterized by an outward repositioning of the proximal helical portion, which is attributed to the absence of preceding beta-hairpins in the C-terminal region. This structural modification results in the loss of hydrogen bonds, exposure of hydrophobic residues to the solvent, and a consequential transformation of helices into loops, ultimately leading to functional impairment in the TMIE protein. These notable modifications in the stability and conformation of the mutant protein were verified through essential dynamics analysis, revealing that a point mutation induces distinct overall motions and correlations between proteins, ultimately resulting in usher syndrome. The current study provides insilico evidences of Usher syndrome hearing loss disease as protein folding disorder. The energy calculation also revealed that there is a difference of -251.211Kj/mol which also indicates that the SNP has significantly decreased the stability of protein consequently folding into Usher syndrome. This study contributes molecular insights into the structural correlation between the TMIE protein and usher syndrome. The docking analysis highlight various interaction between wild and mutant structure emphasizing key residues involved in hydrogen and hydrophobic interaction.

bioinformatics↗

bioRxiv2024

Designing a Novel 3D Scaffold for Multiepitope Vaccine Development: Engineering Ag85a Protein for Enhanced Stability and Antigenicity

Designing multi epitope vaccine (MEV) by reverse vaccinology has become immensely important in the area of vaccine research due to the emergence of new pathogens as well as rise of multi drug resistant old evils like tuberculosis. Administering a vaccine may have the best possibility to save mankind from these unforeseeable events. The strategy of designing a MEV in-silico lies in a few basic steps, including procuring the amino acid sequence of the B cell and T cell epitopes from literature search, bioinformatics approach to construct a potent immunogen capable of eliciting both humoral and cell mediated response. But the challenge lies in the construction of a stable protein with a compact tertiary structure. Merely joining the epitopes one after another, may not be sufficient to achieve this. In this study, a methodology has been detailed to tackle this great challenge using a simple approach of protein engineering. A scaffold based MEV has been designed for the very first time against Mtb by converting a vaccine candidate protein, Ag85A into a scaffold by truncating its non-immunogenic regions so the gaps could be filled by the highly immunogenic epitopes. The stability of the MEV was estimated by molecular dynamics simulation.

biochemistry↗

bioRxiv2024

Ubiquitinated histone H2B as gatekeeper of the nucleosome acidic patch

Monoubiquitination of histones H2B-K120 (H2BK120ub) and H2A-K119 (H2AK119ub) play opposing roles in regulating transcription and chromatin compaction. H2BK120ub is a hallmark of actively transcribed euchromatin, while H2AK119ub is highly enriched in transcriptionally repressed heterochromatin. Whereas H2BK120ub is known to stimulate the binding or activity of various chromatin-modifying enzymes, this post-translational modification (PTM) also interferes with the binding of several proteins to the nucleosome H2A/H2B acidic patch via an unknown mechanism. Here we report cryoEM structures of an H2BK120ub nucleosome showing that ubiquitin adopts discrete positions that occlude the acidic patch. Molecular dynamics simulations show that ubiquitin remains stably positioned over this nucleosome region. By contrast, our cryoEM structures of H2AK119ub nucleosomes show ubiquitin adopting discrete positions that minimally occlude the acidic patch. Consistent with these observations, H2BK120ub, but not H2AK119ub, abrogates nucleosome interactions with acidic patch-binding proteins RCC1 and LANA, and single-domain antibodies specific to this region. Our results suggest a mechanism by which H2BK120ub serves as a gatekeeper to the acidic patch and point to distinct roles for histone H2AK119 and H2BK120 ubiquitination in regulating protein binding to nucleosomes.

biophysics↗

bioRxiv2024

Focal Deletions of a Promoter Tether Activate the IRX3 Oncogene in T Cell Acute Lymphoblastic Leukemia

Oncogenes can be activated in cis through multiple mechanisms including enhancer hijacking events and noncoding mutations that create enhancers or promoters de novo. These paradigms have helped parse somatic variation of noncoding cancer genomes, thereby providing a rationale to identify noncanonical mechanisms of gene activation. Here we describe a novel mechanism of oncogene activation whereby focal copy number loss of an intronic element within the FTO gene leads to aberrant expression of IRX3, an oncogene in T cell acute lymphoblastic leukemia (T-ALL). Loss of this CTCF bound element downstream to IRX3 (+224 kb) leads to enhancer hijack of an upstream developmentally active super-enhancer of the CRNDE long noncoding RNA (-644 kb). Unexpectedly, the CRNDE super-enhancer interacts with the IRX3 promoter with no transcriptional output until it is untethered from the FTO intronic site. We propose that promoter tethering of oncogenes to inert regions of the genome is a previously unappreciated biological mechanism preventing tumorigenesis.

cancer biology↗

bioRxiv2023

Noninvasive Injectable Optical Nanosensor-Hydrogel Hybrids Detect Doxorubicin in Living Mice

While the tissue-transparent fluorescence of single-walled carbon nanotubes (SWCNTs) imparts substantial potential for use in non-invasive biosensors, development of non-invasive systems is yet to be realized. Here, we investigated the functionality of a SWCNT-based nanosensor in several injectable SWCNT-hydrogel systems, ultimately finding SWCNT encapsulation in a sulfonated methylcellulose hydrogel optimal for detection of ions, small molecules, and proteins. We found that the hydrogel system and nanosensor signal were stable for several weeks in live mice. We then found that this system successfully detects local injections of the chemotherapeutic agent doxorubicin in mice. We anticipate future studies to adapt this device for detection of other analytes in animals and, ultimately, patients.

bioengineering↗