Biology subjects

Hussain, K.

Publications and source records attributed to Hussain, K..

9 recordsLinked to original sources

bioRxiv2026

A foundation model for brain organoid network dynamics uncovers intrinsic computation and convergent disease phenotypes

Brain organoids develop self-organizing neural networks that can be used to model neurodevelopment and disease. Here we introduce PULSE, a foundation model developed using over 900 hours of high-density microelectrode array recordings of in vitro and ex vivo neural tissue. We show that this single model can address two open questions: how disease-associated variants alter network development, and how naive circuits encode information. PULSE revealed accelerated network maturation in held-out human 16p11.2-deletion organoids. It also revealed a change in network coordination shared with SHANK3 deficiency. Because organoids develop without sensory input, they let us ask how circuits encode information before any representation is learned. Closed-loop control of a virtual inverted pendulum engaged existing spontaneous activity patterns rather than creating new ones. PULSE provides a common reference frame for neural circuits across genotypes, protocols and tasks.

neuroscience↗

bioRxiv2026

SpikeLab: Agentic tools for spike data analysis

Large language models have the potential to transform scientific research and analysis, but without domain-specific structure they produce silent methodological errors, unreported decisions, and irreproducible results. Here we present SpikeLab, a text-to-analysis framework for neural spike data that combines composable data structures with a skill-based agentic system enforcing bounded autonomy: mandatory use of expert-vetted methods, correctness over efficiency, and clarification-seeking on ambiguous requests. In a controlled benchmark on electrophysiology data, Sonnet 4.6 with SpikeLab produced correct and reproducible results across all tasks, outperforming both the unassisted Sonnet and the more capable Opus 4.6, which exhibited deterministic failures including ad hoc method invention, silent data reduction, and inconsistent experimental designs. We demonstrate versatility across in vivo mouse, human, and in vitro brain organoid recordings, and apply the framework to a pharmacological dose-response study spanning single-unit dynamics, pairwise network structure, burst-level temporal sequences, and latent population states, all through natural language prompts without writing analysis code.

neuroscience↗

bioRxiv2025

Inhibition of lagging strand replication by G-rich telomeric DNA and the shelterin subunit POT1

Telomeres preserve stable eukaryotic chromosomes by protecting the natural chromosome ends from DNA repair but pose a persistent challenge to the replication machinery and an endogenous source of replication stress. Different features have been implicated in causing this effect but how the canonical replication process is altered at telomeres in mechanistic terms remains poorly understood. To address this question, we have reconstituted telomere replication with purified human proteins. This system reveals that while G-rich telomeric DNA directly and specifically blocks lagging strand replication in a manner counteracted by BLM helicase, shelterin unexpectedly acts as an additional lagging strand barrier. Biochemical experiments and electron microscopy imaging show that POT1-containing shelterin complexes induce Okazaki fragment skipping by binding the lagging strand template, generating large single-stranded gaps that remain unreplicated. Our study defines how the core components of telomeres interfere with the canonical replication process, identifying several potential sources of replication stress.

molecular biology↗

bioRxiv2025

Divergent photosynthesis and leaf respiration responses of four common subtropical tree species to modest warming

Subtropical forests are vital to global carbon pools, and their responses to increasing warming may significantly influence carbon sequestration. However, how subtropical tree species adjust the photosynthesis and respiration process in response to climatic warming through phenotypic plasticity is still unclear which is critical for predicting future forest carbon dynamics. In this study we investigate the effects of controlled warming experiment (1.5 {+/-} 0.5) on growth and leaf economic traits especially photosynthesis and respiration in four common subtropical tree species. Our findings reveal that modest warming enhanced photosynthesis, stomatal conductance, and night respiration, leaf anatomical traits as well as growth in Schima superba, Ormosia pinnata, and Pinus massoniana, of those species under warming. In contrast, Castanopsis hystrix demonstrated reduced performance in all measured traits because it may lack adaptive traits critical for warming resilience, indicating a divergent response to the same environmental condition. Our findings highlight the species-specific variation in how subtropical trees adjust traits associated with trees capacity to acclimate to increased temperatures. Specifically, Ormosia pinnata, Pinus massoniana, and Schima superba may exhibit beneficial responses to warming, whereas Castanopsis hystrix may experience negative effects in future climatic conditions which alters future carbon storage and tree diversity. Thus, our study offers new insights for further research on common trees under warming to improve predictions of forest dynamics under climate change, aiding conservation efforts to address environmental pressures.

ecology↗

bioRxiv2025

ATRX safeguards cellular identity during C. elegans development

ATRX is a member of the SWI/SNF family of ATP-dependent chromatin remodellers. In humans, loss of ATRX function leads to ATRX syndrome, a neurodevelopmental disorder. ATRX mutation in human cell lines is associated with multiple phenotypes including activation of the alternative lengthening of telomere (ALT) pathway, upregulation of retrotransposons and increased sensitivity to replication stress. However, the principal role of ATRX and the reason why its mutation causes such diverse phenotypes is currently unclear. To address this, we studied the role of ATRX in the model organism Caenorhabditis elegans. We find that loss of XNP-1, the C. elegans homologue of ATRX, recapitulates many human phenotypes. Loss of XNP-1 causes ectopic activation of germline genes in somatic cells, indicating a loss of cellular identity control. Strikingly, mutation of the germline transcription factor gsox-1 suppresses both this misexpression and multiple xnp-1 phenotypes, including developmental delay and telomeric defects. These findings suggest that ectopic germline gene expression underlies the majority of XNP-1-dependent phenotypes, consistent with a role for XNP-1 in maintaining cellular identity, offering insights into the functions of ATRX in humans.

molecular biology↗

bioRxiv2024

The Chemokine Receptor CCR8 is Not a High-affinity Receptor for the Human Chemokine CCL18

The primate-specific chemokine CCL18 is a potent chemoattractant for T cells and is expressed at elevated levels in several inflammatory diseases. However, the cognate receptor for CCL18 remains unconfirmed. Here, we describe attempts to validate a previous report that the chemokine receptor CCR8 is the human CCL18 receptor (Islam et al. J Exp Med. 2013, 210:1889-98). Two mouse pre-B cell lines (4DE4 and L1.2) exogenously expressing CCR8 exhibited robust migration in response to the known CCR8 ligand CCL1 but not to CCL18. Similarly, CCL1 but not CCL18 induced internalization of CCR8 on 4DE4 cells. CCR8 expressed on Chinese hamster ovarian (CHO) cells mediated robust G protein activation, inhibition of cAMP synthesis and {beta}-arrestin2 recruitment in response to CCL1 but not CCL18. Several N- and C-terminal variants of CCL18 also failed to stimulate CCR8 activation. On the other hand, and as previously reported, CCL18 inhibited CCL11-stimulated migration of 4DE4 cells expressing the receptor CCR3. These data suggest that CCR8, at least in the absence of unidentified cofactors, does not function as a high affinity receptor for CCL18.

immunology↗

bioRxiv2020

Virome-wide serological profiling reveals association of herpesviruses with obesity

The relationship between viral infection and obesity has been known for several decades but epidemiological data related to obesity is limited to only a few viral pathogens. To identify associations between viral infections and obesity, a high-throughput virome-wide serological profiling tool, VirScan, was used to measure antibody responses to a wide range of viruses. Serum specimens from 457 Qatari adults (lean=184;obese=273) and 231 Qatari children (lean=111;obese=120) were assessed by VirScan. Pediatric specimens were simultaneously tested by conventional serology for several herpesviruses to validate VirScan results. Viral association with obesity was determined by calculation of odds ratio (OR) and p-values from Fisher test, and by multivariate regression analysis to adjust for age and gender, with Bonferroni correction for multiple testing. Comprehensive serological profiling of Qatari adult population with VirScan revealed positive and negative associations (p<0.05) of antibody responses to members of Herpesviridae and Picornaviridae families, respectively, with obesity. After adjusting p-values for multiple comparisons, only herpes simplex virus 1 (HSV-1) and Rhinovirus A were positively (OR=3.3; 95%CI 2.15-4.99; p=2.787E-08) and negatively (OR=0.4; 95%CI 0.26-0.65; p=1.175E-03) associated with obesity. At the peptide level, higher prevalence of antibodies against several peptide epitopes of HSV-1/2 was positively (OR=2.35-3.82; p[≤]3.981E-05) associated with obesity. No such associations were seen at the species or peptide levels in the pediatric population. By multivariate regression analysis, HSV-1 was independently associated with obesity irrespective of age and gender. These findings are in agreement with limited data on the adipogenic properties of HSV-1 observed in vitro. ImportanceThe state of Qatar has one of the highest rates of obesity and associated morbidities in the world. Although obesity is predominantly caused by the intake of high calorie diet and reduced physical activities, other factors including infections with certain viruses have been reported. Among these viruses, human adenoviruses were widely studied but epidemiological data for other viruses in relation to human obesity are limited. Here, we studied the association of obesity in Qatari adults and children with a wide range of viral pathogens using VirScan, a virome-wide serological profiling tool. Our results indicate significant association HSV-1 with obesity in the adult population only. Furthermore, we have identified a set of HSV peptides as candidate obesogenic factors for future studies.

microbiology↗

bioRxiv2020

Domain Binding and Isotype Dictate the Activity of Anti-human OX40 Antibodies

Previous data suggests that anti-OX40 mAb can elicit anti-tumour effects in mice through deletion of Tregs. However, OX40 also has powerful costimulatory effects on T cells which could evoke therapeutic responses. The contributions of these different effector mechanisms has not previously been systematically evaluated, particularly for mAb directed to human OX40. Therefore, we generated a novel human OX40 knock-in (KI) mouse to evaluate a panel of anti-hOX40 mAb and show that their activities relate directly to two key properties: 1) isotype – with mIgG1 mAb evoking receptor agonism and CD8+ T cell expansion and mIgG2a mAb evoking deletion of Treg and; 2) epitope - with membrane-proximal mAb delivering more powerful agonism. Intriguingly, both isotypes acted therapeutically in tumour models by engaging these different mechanisms. These findings highlight the significant impact of isotype and epitope on the modulation of anti-hOX40 mAb therapy, and indicate that CD8+ T cell expansion or Treg depletion might be preferable according to the composition of different tumours.Summary Human trials with anti-OX40 antibodies have been disappointing indicating that optimal reagents have not yet been developed. Here, using a new panel of antibodies, we show that isotype and epitope combine to determine agonistic and therapeutic activity.Competing Interest StatementMSC is a retained consultant for BioInvent International and has performed educational and advisory roles for Baxalta and Boehringer Ingleheim. He has received research funding from Roche, Gilead, Bioinvent International and GSK. BF, IT, LM and MS are employees of Bioinvent International.View Full Text

immunology↗

bioRxiv2018

Comprehensive screening shows that mutations in the known syndromic genes are rare in individuals presenting with hyperinsulinaemic hypoglycaemia

ObjectiveHyperinsulinaemic hypoglycaemia (HH) can occur in isolation or more rarely feature as part of a syndrome. Screening for mutations in the syndromic HH genes is guided by phenotype with genetic testing used to confirm the clinical diagnosis. As HH can be the presenting feature of a syndrome it is possible that mutations will be missed as these genes are not routinely screened in all newly diagnosed individuals. We investigated the frequency of pathogenic variants in syndromic genes in individuals with HH who had not been clinically diagnosed with a syndromic disorder at referral for genetic testing.\n\nDesignWe used genome sequencing data to assess the prevalence of mutations in syndromic HH genes in an international cohort of patients with HH of unknown genetic cause.\n\nMethodsWe undertook genome sequencing in 82 individuals with HH without a clinical diagnosis of a known syndrome at referral for genetic testing. Within this cohort we searched for the genetic aetiologies causing 20 different syndromes where HH had been reported as a feature.\n\nResultsWe identified a pathogenic KMT2D variant in a patient with HH diagnosed at birth, confirming a genetic diagnosis of Kabuki syndrome. Clinical data received following the identification of the mutation highlighted additional features consistent with the genetic diagnosis. Pathogenic variants were not identified in the remainder of the cohort.\n\nConclusionsPathogenic variants in the syndromic HH genes are rare but should be considered in newly diagnosed individuals as HH may be the presenting feature.

genetics↗