Biology subjects

Ibrahim, K.

Publications and source records attributed to Ibrahim, K..

10 recordsLinked to original sources

bioRxiv2026

Multimodal Connectome Markers of Disruptive Behavior Problems in Youth: Distinct Patterns of Concurrent Severity and Prospective Symptom Change

Disruptive behaviors problems, such as irritability/anger and maladaptive aggression, are associated with altered connectivity across networks supporting emotion regulation. However, multimodal connectome markers of concurrent severity and prospective symptom change, including sex-specific patterns, remain unclear. Using a large, sex-balanced sample from the Adolescent Brain Cognitive Development (ABCD) Study, we applied multimodal connectome-based predictive modelling (CPM) to test whether resting-state functional (n = 7,556; 49.3% female) and structural (N = 8,978; 48.4%) connectivity predicted baseline disruptive behavior severity (at ages 9-10) and 2-year symptom change (from ages 9-10 to 11-12). Models were adjusted for covariates, permutation-tested, and FDR corrected. Secondary analyses tested sex-stratified models separately in males and females. In models emerging as significant, follow-up analyses tested for distinct vs shared predictive edges. Functional and structural connectomes predicted baseline severity ({rho} = 0.087 and {rho} = 0.071, respectively). Functional connectivity also predicted prospective symptom change ({rho} = 0.038), whereas prospective structural prediction was predominately with negative edges ({rho} = 0.026). Functional connectivity models were significant in both sexes, while prospective structural connectivity models were significant in males, but not females. Frontoparietal, medial frontal, sensorimotor, salience, cerebellar, and visual networks contributed across models. Cross-sectional models showed a more distributed pattern while prospective models showed a more focal pattern. These findings identify complementary, largely distinct functional and structural connectome patterns associated with current disruptive behavior risk and subsequent symptom change, supporting the importance of developmental timing, sex, and imaging modality in developing brain-based biomarkers of disruptive behavior risk in youth.

neuroscience↗

bioRxiv2026

Generative Design of New-to-nature Biosynthetic Assembly Lines with Genomic Language Modeling

Reprogramming biosynthetic assembly lines can extend biosynthesis beyond the chemical space explored by nature. However, this remains difficult because assembly-line function depends on coordinated interactions across large multidomain enzymes. Here, we couple gLM2, a genomic language model trained on metagenomic sequences, with discrete diffusion and domain-level conditioning to enable generative design and optimization of biosynthetic gene clusters. We apply this approach to a chimeric type I polyketide synthase (PKS) engineered to produce {delta}-valerolactam, a molecule not naturally synthesized by PKSs. Through iterative redesign of two multi-domain regions in the context of the full PKS sequence, gLM2 progressively improved {delta}-valerolactam production, yielding variants with up to 9.4-fold higher titer than the starting enzyme. Together, these results demonstrate that evolutionary sequence information can be learned and applied to complex, multi-domain enzyme design problems, expanding biosynthetic assembly lines to produce molecules outside their natural biosynthetic repertoire.

bioengineering↗

bioRxiv2026

Programming protein shape as an explicit design layer via CAD blueprint-guided diffusion

In engineering, industrial design principles link geometric form with function. In nature, global protein shape, curvature, and chirality similarly drive critical processes like membrane remodeling and cellular motility. However, explicitly programming these global features remains a challenge for generative AI. Here, we integrate computer-aided design (CAD) blueprints with diffusion models, establishing protein shape as an explicit, programmable layer. We engineered diverse, tunable architectures, including single-chain shapes, scaffolds with unusual twist handedness, and superhelical assemblies, structurally validating 31 of 59 designs via X-ray crystallography or electron microscopy. To demonstrate shape-encoded function, we coupled fluid-flow-optimized helical propellers to an F1-ATPase rotor, yielding a prototype ATP-dependent molecular swimmer. This framework translates industrial design principles to the molecular scale, enabling the programmable engineering of biomimetic architecture with emergent functions. One-sentence summaryIntegrating CAD blueprints with diffusion-based AI translates industrial design principles to the molecular scale, enabling the explicit programming of protein shapes with emergent functions.

bioengineering↗

bioRxiv2026

Mitochondrial genomes of individual microfilariae: Undescribed Dirofilaria-like filariae from Malaysian cats and two filaria species related to Dirofilaria and Mansonella from Indonesian macaques

Three molecularly undescribed filarial species were co-detected, while screening animals for Brugia malayi, the agent of lymphatic filariasis. Single microfilariae (Mf) isolated from blood samples of crab-eating macaques (Macaca fascicularis) from Belitung, Indonesia, and from pet dogs and cats in Sabah, Malaysia, were analyzed. Among 163 macaques, 33 (20.2%) were positive for large Mf (mean length 498.9 {micro}m) similar to Dirofilaria ( Belitung I). One macaque was infected with small Mf (mean length 150.4 {micro}m) ( Belitung II), with a high density of 17,150 Mf/mL. In two cats co-infected with B. malayi, Mf of a Dirofilaria species ( Sabah) with an average length of 299.1 {micro}m were detected. Morphometric analysis of Mf showed distinct differences between these three species and other Mf described in the area. Whole genome amplification and genome sequencing of 24 individual Mf enabled phylogenetic analysis of mitochondrial genomes, and analysis of specific mitochondrial and nuclear barcode regions. The three Mf groups formed distinct clusters and did not match any currently available reference sequence. Cluster Belitung I from macaques formed a sister group to all other Dirofilaria. Cluster Belitung II included bird filariae and primate filariae of the genus Mansonella as close relatives. The cluster Sabah formed a monophyletic group with the zoonotic species D. asiatica and Dirofilaria sp. Thailand. DNA of Wolbachia endobacteria was detected in Mf of Belitung I and Sabah, but not in Belitung II. These findings highlight the limited understanding of filarial diversity in macaques and cats in Asia and underscore the need for a more comprehensive approach that combines morphological and molecular data to identify and assess the pathogenicity and zoonotic potential of these parasites. Author summaryFilarial worms are parasitic nematodes that infect humans and animals and are often transmitted by the same vector mosquito. We identified three molecularly undescribed filarial species while investigating animals as reservoirs for the agent of lymphatic filariasis, Brugia malayi on Belitung Island, Indonesia, and in Sabah, Malaysia. Blood samples were collected from Indonesian macaques and Malaysian pet cats. Out of 163 macaques, 20.2% tested positive for exceptionally large microfilariae (Mf) of an unclassified Dirofilaria-like species (Belitung I). Another filarial species ( Belitung II) with very small Mf, but with a remarkably high density of 17,150 Mf/mL was detected in one macaque. Two cats harbored medium sized Mf of a Dirofilaria species (Sabah). Genetic analysis revealed unique phylogenetic clusters that did not match any reference sequence. Dirofilaria sp. Sabah was closely related to the zoonotic D. asiatica complex, whereas Belitung I clustered as a sister group to Dirofilaria. Belitung II Mf clustered next to but not within the Mansonella spp. cluster. DNA of Wolbachia endobacteria was only detected in Mf of Belitung I and Sabah. These findings highlight the limited understanding of filarial diversity in animals and underscore the need for a comprehensive approach that combines morphological and molecular data to identify and assess the pathogenicity and zoonotic potential of these parasites.

microbiology↗

bioRxiv2025

Dynamic Resting-State Network Markers of Disruptive Behavior Problems in Youth

BackgroundChildhood disruptive behavior problems are linked to aberrant integrity within large-scale cognitive control networks. However, it is unclear if transitory or dynamic variation in the functional brain architecture is a marker of disruptive behavior problems. The current study tested whether functional connectivity across dynamic networks is distinctly associated with the transdiagnostic symptom domain of disruptive behavior problems in children. MethodsParticipants were aged 9-10 years from the Adolescent Brain Cognitive Development (ABCD) Study, who completed resting-state fMRI (N=877). We employed a dynamic connectivity approach leveraging a hidden semi-Markov model (HSMM) to identify transient properties of brain networks and states. Models estimated the time spent in each state (occupancy time) and the number of consecutive timepoints in a state (dwell time) for each participant. Linear regression models were utilized to identify distinct associations between dynamic properties (occupancy and sojourn times) and severity of disruptive behavior problems, accounting for other commonly co-occurring symptoms. ResultsDynamic network markers of disruptive behavior problems included increased time in network states characterized by globally aberrant connectivity patterns in circuitry involved in cognitive control including frontoparietal and dorsal attention networks. Replication of findings was found in a held-out sample of resting-state fMRI runs in which greater severity of disruptive behavior problems was uniquely linked to greater occupancy time in similarly characterized brain states. ConclusionTransdiagnostic, dynamic resting-state markers of disruptive behavior problems in youth may assist in the development of brain-based biomarkers for monitoring treatment outcomes, assessing circuit target engagement and informing clinical decisions.

neuroscience↗

bioRxiv2025

In vivo generation of chimeric antigen receptor T cells using optimally retargeted and functionalized lentiviral vectors with reduced immune clearance

Despite striking efficacy against hematologic malignancies, the cost and complexity of CAR T manufacturing present significant barriers to broader patient access. Beyond manufacturing challenges, ex vivo expansion of T cells may be detrimental for their function and persistence. Thus, delivery of CARs to reprogram host cells in vivo would represent a significant advance toward "off-the-shelf" therapy but has been limited by low efficiency, low specificity, and immunogenicity of viral vectors. Here we describe the design of pseudotyped lentiviral vectors (LV) with superior functionality and high target specificity. We show that LV pseudotyped with chimeric envelope glycoproteins from dolphin morbillivirus (DMV) can be engineered to selectively infect human T cells and evade neutralizing antibody responses in measles-vaccinated human serum. We further demonstrate that camelid-derived nanobodies are a superior retargeting domain, overcoming limitations inherent to the use of single chain variable fragment antibodies. Using a chimeric DMV-pseudotyped virus targeting the CD7 receptor, we demonstrate efficient and highly specific infection of T cells both in vitro and in vivo, generating functional CAR T cells and inducing therapeutic efficacy in a preclinical B cell lymphoma model.

bioengineering↗

bioRxiv2024

Transdiagnostic Symptom Domains are Associated with Head Motion During Multimodal Imaging in Children

BackgroundHead motion is a challenge for neuroimaging research in developmental populations. However, it is unclear how transdiagnostic symptom domains including attention, disruptive behavior (e.g., externalizing behavior), and internalizing problems are linked to scanner motion in children, particularly across structural and functional MRI. The current study examined whether transdiagnostic domains of attention, disruptive behavior, and internalizing symptoms are associated with scanner motion in children during multimodal imaging. MethodsIn a sample of 9,045 children aged 9-10 years in the Adolescent Brain Cognitive Development (ABCD) Study, logistic regression and linear mixed-effects models were used to examine associations between motion and behavior. Motion was indexed using ABCD Study quality control metrics and mean framewise displacement for the following: T1-weighted structural, resting-state fMRI, diffusion MRI, Stop-Signal Task, Monetary Incentive Delay task, and Emotional n-Back task. The Child Behavior Checklist was used as a continuous measure of symptom severity. ResultsGreater attention and disruptive behavior problem severity was associated with a lower likelihood of passing motion quality control across several imaging modalities. In contrast, increased internalizing severity was associated with a higher likelihood of passing motion quality control. Increased attention and disruptive behavior problem severity was also associated with increased mean motion, whereas increased internalizing problem severity was associated with decreased mean motion. ConclusionTransdiagnostic domains emerged as predictors of motion in youths. These findings have implications for advancing development of generalizable and robust brain-based biomarkers, computational approaches for mitigating motion effects, and enhancing accessibility of imaging protocols for children with varying symptom severities.

neuroscience↗

bioRxiv2022

Hippocampal microstructure, but not macrostructure, mediates age differences in episodic memory

Separate unimodal magnetic resonance imaging (MRI) literatures have shown that hippocampal gray matter macrostructure (volume) and microstructure (diffusion) decline in aging and relate to episodic memory performance, with multimodal MRI studies reporting that episodic memory may be better explained by a combination of these metrics. However, these effects are often assessed independent of age or only within older adults and therefore do not address whether these distinct modalities mediate the effect of age on episodic memory. Here, we simultaneously examined the unique and joint contribution of hippocampal volume and diffusion to age-related differences in episodic memory in 83 younger and 61 older adults who underwent a T1-and diffusion-weighted MRI and completed the Rey Auditory Verbal Learning Test. As expected, older age was significantly related to smaller volume and higher diffusion (intracellular, dispersion, and free) in bilateral hippocampus and to worse episodic memory performance (immediate and delayed free recall, recognition). Structural equation modelling revealed that the age-memory relationship was significantly mediated by hippocampal diffusion, but not volume. A non-significant influential indirect effect further revealed that the structural metrics did not jointly mediate the age-memory relationship. Together, these findings indicate that hippocampal microstructure uniquely contributes to age-related differences in episodic memory and suggest that volume and diffusion capture distinct neurobiological properties of hippocampal gray matter.

neuroscience↗

bioRxiv2020

Spritz: A Proteogenomic Database Engine

Proteoforms are the workhorses of the cell, and subtle differences between their amino acid sequence or post-translational modifications (PTMs) can change their biological function. To most effectively identify and quantify proteoforms in genetically diverse samples by mass spectrometry (MS), it is advantageous to search the MS data against a sample-specific protein database that is tailored to the sample being analyzed, in that it contains the correct amino acid sequences and relevant PTMs for that sample. To this end, we have developed Spritz (https://smith-chem-wisc.github.io/Spritz/), an open-source software tool for generating protein databases annotated with sequence variations and PTMs. We provide a simple graphical user interface (GUI) for Windows and scripts that can be run on any operating system. Spritz automatically sets up and executes approximately 20 tools, which enable construction of a proteogenomic database from only raw RNA sequencing data. Sequence variations that are discovered in RNA sequencing data upon comparison to the Ensembl reference genome are annotated on proteins in these databases, and PTM annotations are transferred from UniProt. Modifications can also be discovered and added to the database using bottom-up mass spectrometry data and global PTM discovery in MetaMorpheus. We demonstrate that such sample-specific databases allow the identification of variant peptides, modified variant peptides, and variant proteoforms by searching bottom-up and top-down proteomic data from the Jurkat human T lymphocyte cell line and demonstrate the identification of phosphorylated variant sites with phosphoproteomic data from the U2OS human osteosarcoma cell line.

bioinformatics↗

bioRxiv2018

Drosophila small ovary gene ensures germline stem cell maintenance and differentiation by silencing transposons and organising heterochromatin

Self-renewal and differentiation of stem cells is one of the fundamental biological phenomena relying on proper chromatin organisation. In our study, we describe a novel chromatin regulator encoded by the Drosophila small ovary (sov) gene. We demonstrate that sov is required in both the germline stem cells (GSCs) and the surrounding somatic niche cells to ensure GSC survival and differentiation. Sov maintains niche integrity and function by repressing transposon mobility, not only in the germline, but also in the soma. Protein interactome analysis of Sov revealed a physical interaction between Sov and HP1a. In the germ cell nuclei, Sov co-localises with HP1a, suggesting that Sov affects transposon repression as a component of the heterochromatin. In a position effect variegation assay, we found a dominant genetic interaction between sov and HP1a, indicating their functional cooperation in promoting the spread of heterochromatin. An in vivo tethering assay and FRAP analysis revealed that Sov enhances heterochromatin formation by supporting the recruitment of HP1a to the chromatin. We propose a model in which sov maintains GSC niche integrity by regulating piRNA-mediated transposon silencing as a heterochromatin regulator.\n\nSummary statementSmall ovary maintains the integrity of the stem cell niche by regulating piRNA-mediated transposon silencing acting as a key component of the heterochromatin.

developmental biology↗