Biology subjects

Williams, J. A.

Publications and source records attributed to Williams, J. A..

18 recordsLinked to original sources

bioRxiv2026

Gut-derived serine protease reduces sleep but extends lifespan

Sleep has historically been viewed through a brain-centric lens with little known about the contribution of the periphery. Through a targeted screen of secreted peptides from the fat body, gut, and body wall muscle in Drosophila, we identified CG11037, a trypsin-like serine endopeptidase secreted from midgut enterocytes, as a previously unrecognized regulator of sleep. Loss of CG11037 reduces daily sleep, as well as sleep following injury/infection, although recovery is enhanced suggesting reduced need for sleep during sickness. Proteomic analysis of flies with reduced CG11037 revealed altered oxidative stress response pathways including cytochrome P450-related proteins. Indeed, gut-specific knockdown of Cyp6a2 or Cyp28d1 phenocopies CG11037 sleep defects, and loss of CG11037 or P450 elevates reactive oxygen species (ROS) selectively in the gut without affecting brain ROS. Rescue of sleep by antioxidant treatment demonstrates that peripheral ROS accumulation drives the behavioral phenotype. Strikingly, despite physiological dysfunction and reduced sleep, CG11037 or Cytochrome P450 knockdown extends lifespan in a ROS-dependent manner, suggesting that stress adaptation of these knockdowns allows them to live longer. Together, these findings uncover a mechanism for the unexpected association of reduced sleep and extended lifespan.

genetics↗

bioRxiv2026

Nanovibrational stimulation preferentially enhances osteogenic responses in zebrafish

Mechanical cues are key regulators of bone formation, yet their potential as therapeutic stimuli remains incompletely explored in vivo. Nanovibrational stimulation, which delivers low-amplitude, high-frequency mechanical input, has been shown to promote osteogenic differentiation in vitro, and rodent studies have similarly demonstrated osteogenic effects. However, its impact on other cellular systems at the whole-organism level remains poorly understood. Here, we demonstrate that nanovibrational stimulation enhances myogenic differentiation in vitro before investigating its effects on skeletal development and tissue specificity in zebrafish. Larval zebrafish exposed to nanovibrational stimulation exhibited increased osteoblast numbers and enhanced bone formation relative to controls. In adult zebrafish, nanovibration increased the osteoblast response to a fracture-like injury, indicating enhanced osteogenic activity during repair. To assess tissue specificity, we examined additional cell types and systems relevant to skeletal regeneration, including cartilage, muscle, vasculature and innate immune cells. Although nanovibrational stimulation promoted myogenic differentiation of C2C12 cells in vitro, its effects on muscle and other non-skeletal tissues in zebrafish larvae were comparatively limited. These findings suggest that nanovibrational stimulation exerts a preferential effect on osteogenic processes in vivo. These findings demonstrate that nanovibrational stimulation preferentially enhances osteoblast-mediated bone formation and skeletal injury responses in zebrafish, without causing significant perturbations in other tissues. Our results establish zebrafish as a tractable in vivo model for investigating vibration-induced mechanobiological processes, providing a more physiologically relevant representation of tissue-level mechanotransduction than conventional two-dimensional culture systems. Furthermore, these findings highlight the potential of nanovibrational stimulation as a non-invasive strategy to promote bone regeneration and fracture repair.

physiology↗

bioRxiv2026

Beyond mean trabecular separation: decomposing metaphyseal marrow space into local trabecular spacing and marrow cavity expansion

Micro-computed tomography ({micro}CT) is widely used to assess trabecular bone microarchitecture, with trabecular separation (Tb.Sp) among the core parameters recommended for reporting. Tb.Sp is typically expressed as a single volume-weighted mean derived from maximal sphere fitting, although the underlying distribution of local separation values is rarely examined. Here, we show that Tb.Sp distributions in metaphyseal trabecular bone are frequently non-Gaussian and bimodal or multimodal. Using {micro}CT datasets from three established models of osteoporosis, spinal cord injury (SCI), ovariectomy (OVX), and ageing, we demonstrate that this behaviour is most evident in metaphyseal trabecular bone and is less apparent in epiphyseal trabecular bone or trabecular thickness distributions. We further show that multimodal metaphyseal Tb.Sp distributions correspond to two spatially distinct contributions within the marrow space: lower-diameter local separation within the residual trabecular network, and higher-diameter regions associated with larger contiguous marrow cavities. Based on this observation, we introduce a simple extension to standard morphometric analysis in which Tb.Sp is decomposed into local trabecular separation (Tb.SpL) and marrow cavity separation (Tb.SpM). Tb.Sp decomposition revealed model-specific patterns of trabecular deterioration. SCI was characterised predominantly by increased Tb.SpM, consistent with expansion of larger marrow cavities, whereas OVX showed a more subtle or distributed alteration. Ageing showed changes in both Tb.SpL and Tb.SpM, with the higher-diameter component becoming most prominent in older animals. Together, these findings demonstrate that mean Tb.Sp can mask structurally distinct forms of metaphyseal marrow-space organisation and support reporting distributional descriptors, and where appropriate Tb.SpL and Tb.SpM, alongside conventional Tb.Sp.

bioengineering↗

bioRxiv2025

Disruption of Marrow Microenvironments in Chronic Lymphocytic Leukemia by High-Resolution Synchrotron Micro-Computed Tomography

Chronic lymphocytic leukemia (CLL) is associated with increased fracture risk unexplained by standard bone density scans, suggesting underlying microstructural alterations. To investigate this, we used high-resolution synchrotron micro-computed tomography (SR{micro}CT) on bone marrow biopsies from 17 CLL patients, who were stratified into low and high infiltration groups using objective, data-driven clustering. To our knowledge, this is the first report to quantify these changes. High CLL marrow infiltration was associated with a 40.3% reduction in lacuna density and a 101% increase in the normalized adipose surface area-to-volume ratio, a metric indicating greater structural fragmentation. Both changes correlated with leukemic infiltration percentage and showed partial reversal after therapy in a longitudinal case. Furthermore, high CLL burden significantly altered the morphological distributions of the remaining lacunar osteocyte (p < 0.001). We identify a novel marrow remodeling phenotype in CLL characterized by osteocyte depletion and adipose disruption. These changes likely contribute to skeletal fragility and represent potential microstructural biomarkers for assessing marrow health more accurately than conventional imaging.

physiology↗

bioRxiv2025

Nanovibrational stimulation of osteogenesis engages non-canonical Wnt signalling and NF-κB regulator BCL3 as a mechanotransducer

Enhancing osteogenesis in mesenchymal stromal (stem) cells is essential for advancing cellular therapies that target and alleviate skeletal pathologies. By employing a bespoke bioreactor capable of delivering nano-amplitude vibration (30 nm, 1kHz) to human adipose-derived mesenchymal stromal cells, we observed osteo-specific differentiation. We related this to the mechanotransductive mechanism by showing that inhibition of intracellular tension results in the loss of cytoskeletal organisation and myosin activation driven by nanovibration. Further, we dissect the mechanism of osteogenesis using a panel of Wnt agonists and antagonists and highlight the role of non-canonical Wnt. Then, using Bcl3-/- cells and by stimulating with BCL3 peptide, we show that non-canonical Wnt, osteogenesis-related inflammation and osteogenesis itself are all regulated by BCL3. This is important as nanoscale direct cell-stimulation is gaining interest, and there is an emerging consensus that such signals can be osteogenic. While prior research has only broadly hinted at how nanovibrational signals convert to an osteogenic phenotype, this new work pinpoints critical mechanistic insights, thereby advancing our understanding of this promising avenue in musculoskeletal cell therapy.

bioengineering↗

bioRxiv2025

Music-evoked reactivation during continuous perception is associated with enhanced subsequent recall of naturalistic events

Music is a potent cue for recalling personal experiences, yet the neural basis of music-evoked memory remains elusive. We address this question by using the full-length film Eternal Sunshine of the Spotless Mind to examine how repeated musical themes reactivate previously encoded events in cortex and shape next-day recall. Participants in an fMRI study viewed either the original film (with repeated musical themes) or a no-music version. By comparing neural activity patterns between these groups, we found that music-evoked reactivation of neural patterns linked to earlier scenes in the default mode network was associated with improved subsequent recall. This relationship was specific to the music condition and persisted when we controlled for a proxy measure of initial encoding strength (spatial intersubject correlation), suggesting that music-evoked reactivation may play a role in making event memories stick that is distinct from what happens at initial encoding.

neuroscience↗

bioRxiv2025

Stability and characterization of infectious monkeypox virus extracellular virions in vitro2and vivo; implications for transmission, pathogenesis and treatment

Abstract/SummaryPoxviruses exist as multiple infectious morphogenic forms commonly simplified as mature virions (MV) and extracellular virions (EV). The roles of morphogenic subtypes as related to disease and transmission are enigmatic as EVs can exist both as cell associated (CEV) or released particles (rCEV) each with potentially unique biochemical properties impacting stability and infectivity. In vitro analysis of prototypical poxviruses is commonly utilized to infer larger conclusions about the in vivo function of all EV-like particles. Here we show that infectious EV of MPXV and VACV strains are stable for [≥] 14 weeks and are more sensitive to human or non-human primate complement compared to rabbit-derived complement. We also characterize the levels of EV produced during MPXV infection in NHPs and found temporal differences in production that may influence spread. Also, we present data characterizing and contrasting the EV from monkeypox (MPXV) and vaccinia virus (VACV) strains. Specifically, we quantified infectious EV quantities produced by different cultured cell lines and characterized the infectious properties and composition of the released (extracellular) virions. We conclude that A33 neutralizable cell associated-like virions (CEV-like), a form of EV, can significantly increase, depending on the strain of VACV or MPXV and the cell lines from which they were released. Based on the outcomes of our studies, the importance of understanding specific orthopoxvirus EV roles in a host-specific manner, as it relates to pathogenesis, stability, and transmission, is warranted and requires further study.

microbiology↗

bioRxiv2024

Developing and Investigating a Nanovibration Intervention for the Prevention/Reversal of Bone Loss Following Spinal Cord Injury

Osteoporosis disrupts the fine-tuned balance between bone formation and resorption leading to reductions in bone quantity and quality, ultimately leading to increased fracture risk. Prevention and treatment of osteoporotic fractures is essential, for reductions in mortality, morbidity and the economic burden, particularly considering the ageing global population. Extreme bone loss that mimics time-accelerated osteoporosis develops in the paralysed limbs following complete spinal cord injury (SCI). In vitro nanoscale vibration (1 kHz, 30- or 90 nm amplitude) has been shown to drive differentiation of mesenchymal stem cells towards osteoblast-like phenotypes, enhancing osteogenesis, and inhibiting osteoclastogenesis, simultaneously. Here we develop and characterise a wearable device designed to deliver continuous nano-amplitude vibration to the hindlimb long bones of rats with complete SCI. We investigate whether a clinically feasible dose of nanovibration (4-hours/day, 5-days/week for 6 weeks) is effective at reversing the established SCI-induced osteoporosis. Laser interferometry and finite element analysis confirmed transmission of nanovibration into the bone, and micro-computed tomography and serum bone formation and resorption markers assessed effectiveness. The intervention did not reverse SCI-induced osteoporosis. However, serum analysis indicated an elevated concentration of the bone formation marker procollagen type 1 N-terminal propeptide (P1NP) in rats receiving 40 nm amplitude nanovibration, suggesting increased synthesis of type 1 collagen, the major organic component of bone. Therefore, enhanced doses of nanovibrational stimulus may yet prove beneficial in attenuating/reversing osteoporosis, particularly in less severe forms of osteoporosis.

bioengineering↗

bioRxiv2023

The NFκB Dif is required for behavioral and molecular correlates of sleep homeostasis in Drosophila

The nuclear factor binding the {kappa} light chain in B-cells (NF{kappa}B) is involved in a wide range of cellular processes including development, growth, innate immunity, and sleep. However, efforts have been limited toward understanding how specific NF{kappa}B transcription factors function in sleep. Drosophila fruit flies carry three genes encoding NF{kappa}B transcription factors, Dorsal, Dorsal Immunity Factor (Dif), and Relish. We previously found that loss of the Relish gene from fat body suppressed daily nighttime sleep, and abolished infection-induced sleep. Here we show that Dif regulates daily sleep and recovery sleep following prolonged wakefulness. Mutants of Dif showed reduced daily sleep and suppressed recovery in response to sleep deprivation. Pan-neuronal knockdown of Dif strongly suppressed daily sleep, indicating that in contrast to Relish, Dif functions from the central nervous system to regulate sleep. Based on the distribution of a Dif-associated GAL4 driver, we hypothesized that its effects on sleep were mediated by the pars intercerebralis (PI). While RNAi knock-down of Dif in the PI reduced daily sleep, it had no effect on the recovery response to sleep deprivation. However, recovery sleep was suppressed when RNAi knock-down of Dif was distributed across a wider range of neurons. Induction of the nemuri (nur) antimicrobial peptide by sleep deprivation was suppressed in Dif mutants and pan-neuronal over-expression of nur also suppressed the Dif mutant phenotype. Together, these findings indicate that Dif functions from brain to target nemuri and to promote sleep. Statement of SignificanceNF{kappa}B transcription factors drive inflammatory processes that underly a multitude of human diseases that are accompanied by sleep disturbance. However, genetic studies in mammals that investigate a function of NF{kappa}B in sleep have been limited. Using genetic approaches in the Drosophila fruit fly, we show that the Dif NF{kappa}B, homologous to the Rel family of NF{kappa}Bs in humans, functions from neuronal tissue to regulate daily sleep and to mediate responses to sleep loss. These findings enhance our understanding of the role of a specific NF{kappa}B gene in sleep regulation.

neuroscience↗

bioRxiv2023

Modelling cognitive outcomes in the UK Biobank: education, noradrenaline and frontoparietal networks

Education is often used as a surrogate measure of so called cognitive reserve (CR) benefiting cognitive functioning in later years. In line with Robertsons theory we tested here a hypothesis that education acting on the noradrenergic system strengthen the right fronto-parietal networks to facilitate CR and maintain cognition throughout the lifetime. We used machine learning and mediation analysis to model interactions between neurobiological features (genetic variants in noradrenergic signalling, structural and functional fronto-parietal connectivity) and education (proxy of CR) on cognitive outcomes (general cognitive ability score) in the UK Biobank cohort. We show that: (1) interactions between education and neurobiological variables better explain cognitive outcomes than either factor alone; (2) among the neurobiological features selected using variable importance testing, measures of right fronto-parietal connectivity are the strongest mediators of the effect of education on cognitive outcomes. Our findings offer novel insights into neurobiological basis of CR by pointing to between-networks connectivity, representing connections linking the default mode network with the right fronto-parietal network as the key facilitator of CR.

neuroscience↗

bioRxiv2023

Genetically mediated associations between chronotype and neuroimaging phenotypes in the UK Biobank: a Mendelian randomisation study

Chronotype impacts numerous physiological and disease traits, from metabolic syndrome to schizophrenia. The suprachiasmatic nucleus (SCN) maintains transcriptional-translational feedback loop (TTFL) which acts as a central chronobiological pacemaker, regulating 24-hour cycles throughout the human body. However, each tissue maintains its own peripheral clock, and both endogenous hormones and neurotransmitters and exogenous environmental cues regulate the SCNs central clock. The extent to which brain regions outside the SCN influence the core TTFL is unknown. Here, we investigated how genetic variability affecting brain regions outside the SCN may indirectly influence chronotype, using Mendelian randomization and causal inference. We performed genome wide association studies (GWAS) based on image derived phenotypes (IDPs) from neuroimaging data (grey matter volume, thickness and surface area, microstructural white matter measures; 42,062 participants), and additionally for sleep duration and morning/evening chronotype (361,739 participants). Significant, single nucleotide polymorphisms (SNPs) associating with each phenotype were entered into 2-sample Mendelian randomization performed using inverse-variance weighted methods (exposure versus outcome): 1) chronotype versus each IDP, 2) sleep versus each IDP and 3) each IDP versus chronotype. Subsequently, we investigated genes where significant instrumental SNPs were located for circadian periodic cycling, interaction with TTFL genes in common biological pathways (genetic, physical, or functional interaction), and enrichment of traits from UK Biobank and GWAS Catalogs. We found three associations with chronotype (morning/evening diurnal preference) outside the SCN based on genetically predicted (FAM76B, DENND1A, CDH11) regional differences in brain volume. Specifically, genetically predicted lower inferior temporal gyrus volume linked to morning phenotype, while lower volume of the superior parietal lobule and angular gyrus linked to evening preference. In addition, evening chronotype exposure influenced superior temporal gyrus volume, and both increased sleep duration and evening chronotype influenced thalamic volume. We conclude that genetically mediated associations between chronotype and brain regions outside SCN exist suggesting novel zeitgeber mechanisms.

neuroscience↗

bioRxiv2021

Klarigi: Explanations for Semantic Groupings

BackgroundAnnotation of biomedical entities with ontology classes provides for formal semantic analysis and mobilisation of background knowledge in determining their relationships. To date enrichment analysis has been routinely employed to identify classes that are over-represented in annotations across sets of groups, such as biosample gene expression profiles or patient phenotypes. These approaches, however, usually consider only univariate relationships, make limited use of the semantic features of ontologies, and provide limited information and evaluation of the explanatory power of both singular and grouped candidate classes. Moreover, they do not solve the problem of deriving cohesive, characteristic, and discriminatory sets of classes for entity groups. ResultsWe have developed a new method, Klarigi, which introduces multiple scoring heuristics for identification of classes that are both compositional and discriminatory for groups of entities annotated with ontology classes. The tool includes a novel algorithm for derivation of multivariable semantic explanations for entity groups, makes use of semantic inference through live use of an ontology reasoner, and includes a classification method for identifying the discriminatory power of candidate sets. We describe the design and implementation of Klarigi, and evaluate its use in two test cases, comparing and contrasting methods and results with literature and enrichment analysis methods. ConclusionsWe demonstrate that Klarigi produces characteristic and discriminatory explanations for groups of biomedical entities in two settings. We also show that these explanations recapitulate and extend the knowledge held in existing biomedical databases and literature for several diseases. We conclude that Klarigi provides a distinct and valuable perspective on biomedical datasets when compared with traditional enrichment methods, and therefore constitutes a new method by which biomedical datasets can be explored, contributing to improved insight into semantic data.

bioinformatics↗

bioRxiv2021

Towards Similarity-based Differential Diagnostics For Common Diseases

Ontology-based phenotype profiles have been utilised for the purpose of differential diagnosis of rare genetic diseases, and for decision support in specific disease domains. Particularly, semantic similarity facilitates diagnostic hypothesis generation through comparison with disease phenotype profiles. However, the approach has not been applied for differential diagnosis of common diseases, or generalised clinical diagnostics from uncurated text-derived phenotypes. In this work, we describe the development of an approach for deriving patient phenotype profiles from clinical narrative text, and apply this to text associated with MIMIC-III patient visits. We then explore the use of semantic similarity with those text-derived phenotypes to classify primary patient diagnosis, comparing the use of patient-patient similarity and patient-disease similarity using phenotype-disease profiles previously mined from literature. We also consider a combined approach, in which literature-derived phenotypes are extended with the content of text-derived phenotypes we mined from 500 patients. The results reveal a powerful approach, showing that in one setting, uncurated text phenotypes can be used for differential diagnosis of common diseases, making use of information both inside and outside the setting. While the methods themselves should be explored for further optimisation, they could be be applied to a variety of clinical tasks, such as differential diagnosis, cohort discovery, document and text classification, and outcome prediction.

bioinformatics↗

bioRxiv2021

High-order areas and auditory cortex both represent the high-level event structure of music

Recent fMRI studies of event segmentation have found that default mode regions represent high-level event structure during movie watching. In these regions, neural patterns are relatively stable during events and shift at event boundaries. Music, like narratives, contains hierarchical event structure (e.g., sections are composed of phrases). Here, we tested the hypothesis that brain activity patterns in default mode regions reflect the high-level event structure of music. We used fMRI to record brain activity from 25 participants (male and female) as they listened to a continuous playlist of 16 musical excerpts, and additionally collected annotations for these excerpts by asking a separate group of participants to mark when meaningful changes occurred in each one. We then identified temporal boundaries between stable patterns of brain activity using a hidden Markov model and compared the location of the model boundaries to the location of the human annotations. We identified multiple brain regions with significant matches to the observer-identified boundaries, including auditory cortex, medial prefrontal cortex, parietal cortex, and angular gyrus. From these results, we conclude that both higher-order and sensory areas contain information relating to the high-level event structure of music. Moreover, the higher-order areas in this study overlap with areas found in previous studies of event perception in movies and audio narratives, including regions in the default mode network. Significance StatementListening to music requires the brain to track dynamics at multiple hierarchical timescales. In our study, we had fMRI participants listen to real-world music (classical and jazz pieces) and then used an unsupervised learning algorithm (a hidden Markov model) to model the high-level event structure of music within participants brain data. This approach revealed that default mode brain regions involved in representing the high-level event structure of narratives are also involved in representing the high-level event structure of music. These findings provide converging support for the hypothesis that these regions play a domain-general role in processing events occurring over long timescales.

neuroscience↗

bioRxiv2020

Eastern Equine Encephalitis Virus Rapidly Infects and Disseminates in the Brain and Spinal Cord of Infected Cynomolgus Macaques Following Aerosol Challenge

Eastern equine encephalitis virus (EEEV) is mosquito-borne virus that produces fatal encephalitis in humans. We recently conducted a first of its kind study to investigate EEEV clinical disease course following aerosol challenge in a cynomolgus macaque model utilizing the state of the art telemetry to measure critical physiological parameters. Following challenge, all parameters were rapidly and profoundly altered, and all nonhuman primates (NHPs) met the euthanasia criteria. In this study, we performed the first comprehensive pathology investigation of tissues collected at euthanasia to gain insights into EEEV pathogenesis. Viral RNA and proteins as well as microscopic lesions were absent in the visceral organs. In contrast, viral RNA and proteins were readily detected throughout the brain including autonomic nervous system (ANS) control centers and spinal cord. However, despite presence of viral RNA and proteins, majority of the brain and spinal cord tissues exhibited minimal or no microscopic lesions. The virus tropism was restricted primarily to neurons, and virus particles (~61-68 nm) were present within axons of neurons and throughout the extracellular spaces. However, active virus replication was absent or minimal in majority of the brain and was limited to regions proximal to the olfactory tract. These data suggest that EEEV initially replicates in/near the olfactory bulb following aerosol challenge and is rapidly transported to distal regions of the brain by exploiting the neuronal axonal transport system to facilitate neuron-to-neuron spread. Once within the brain, the virus gains access to the ANS control centers likely leading to disruption and/or dysregulation of critical physiological parameters to produce severe disease. Moreover, the absence of microscopic lesions strongly suggests that the underlying mechanism of EEEV pathogenesis is due to neuronal dysfunction rather than neuronal death. This study is the first comprehensive investigation of EEEV clinical disease course and pathogenesis in a NHP model and will provide significant insights into the evaluation of countermeasure. Author SummaryEEEV is an arbovirus endemic in parts of North America and is able to produce fatal encephalitis in humans and domesticated animals. Despite multiple human outbreaks during the last 80 years, there are still no therapeutic or vaccines to treat or prevent human disease. One critical obstacle in the development of effective countermeasure is the lack of insights into EEEV pathogenesis in a susceptible animal host. We recently conducted a study in cynomolgus macaques to investigate the disease course by measuring clinical parameters relevant to humans. Following infection, these parameters were rapidly and profoundly altered leading to severe disease. In this study, we examined the potential mechanisms that underlie pathogenesis to cause severe disease. The virus was present in many parts of the brain and spinal cord, however, little or no pathological lesions as well as active virus replication were observed. Additionally, neurons were the predominant target of EEEV and virus transport was facilitated by axonal transport system to spread neuron-to-neuron throughout the brain and spinal cord. These data show that EEEV likely hijacks host cell transport system to rapidly spread in the brain and local/global neuronal dysfunction rather than death is the principal cause of severe disease.

microbiology↗

bioRxiv2020

Development of antibody-dependent cell cytotoxicity function in HIV-1 antibodies

A prerequisite for the design of an HIV vaccine that elicits protective antibodies is understanding the developmental pathways that result in desirable antibody features. The development of antibodies that mediate antibody-dependent cellular cytotoxicity (ADCC) is particularly relevant because such antibodies have been associated with HIV protection in humans. We reconstructed the developmental pathways of six human HIV-specific ADCC antibodies using longitudinal antibody sequencing data. Most of the inferred naive antibodies did not mediate detectable ADCC. Gain of antigen binding and ADCC function typically required mutations in complementarity determining regions of one or both chains. Enhancement of ADCC potency often required additional mutations in framework regions. Antigen binding affinity and ADCC activity were correlated, but affinity alone was not sufficient to predict ADCC potency. Thus, elicitation of human ADCC antibodies may require mutations that first enable high affinity antigen recognition, followed by mutations that optimize factors contributing to functional ADCC activity.

immunology↗

bioRxiv2020

Biomarker-guided treatment strategies for ovarian cancer identified from a heterogeneous panel of patient-derived tumor xenografts

Advanced ovarian cancers are a leading cause of cancer-related death in women. Such cancers are currently treated with surgery and chemotherapy which is often temporarily successful but exhibits a high rate of relapse after which treatment options are few. Here we assess the responses of a panel of patient-derived ovarian cancer xenografts (PDXs) to 19 mono and combination therapies, including small molecules and antibody-drug conjugates. The PDX panel aimed to mimic the heterogeneity of disease observed in patients, and exhibited a distribution of responsiveness to standard of care chemotherapy similar to human clinical data. Three monotherapies and one drug combination were found to be active in different subsets of PDXs. By analyzing gene expression data we identified gene expression biomarkers predictive of responsiveness to each of three novel targeted therapy regimens. While no single treatment had as high a response rate as chemotherapy, nearly 90% of PDXs were eligible for and responded to at least one biomarker-guided treatment, including tumors resistant to standard chemotherapy. Biomarker frequency was similar in human patients, suggesting the possibility of a new therapeutic approach to ovarian cancer and demonstrating the potential power of PDX-based trials in broadening the reach of precision cancer medicine.

cancer biology↗

bioRxiv2018

Rapid development of an infant-derived HIV-1 broadly neutralizing antibody lineage

HIV-infected infants develop broadly neutralizing plasma responses with more rapid kinetics than adults, suggesting the ontogeny of infant responses could better inform a path to achievable vaccine targets. We developed computational methods to reconstruct the developmental lineage of BF520.1, the first example of a HIV-specific broadly neutralizing antibody (bnAb) from an infant. The BF520.1 inferred naive precursor binds HIV Env and a bnAb evolved within six months of infection and required only 3% mutation. Mutagenesis and structural analyses revealed that for this infant bnAb, substitutions in the kappa chain were critical for activity, particularly in CDRL1. Overall, the developmental pathway of this infant antibody includes features distinct from adult antibodies, including several that may be amenable to better vaccine responses.

immunology↗