Biology subjects

Manning, J.

Publications and source records attributed to Manning, J..

14 recordsLinked to original sources

bioRxiv2026

Developmental and molecular features shaping broad and synergistic actions of human autoantibodies targeting interferon-α

Neutralizing autoantibodies against interferon- (IFN) are associated with severe viral infections but may improve outcomes in IFN-driven autoimmunity. How these antibodies emerge, mature, and function at the molecular level remains unclear. Here, we tracked development of plasma neutralizing activity against all 12 IFNs in multiple human donors over years. Plasma neutralization frequently initiates with narrow IFN specificity, often IFN8, but increases in breadth and potency with individual kinetics. Monoclonal antibody analyses reveal that affinity maturation generates epitope-specific antibody classes, highlighting parallel emergence of subtype-restricted and broadly-reactive antibodies. Biophysical and structural characterization of human antibody-IFN complexes uncovers determinants of initial specificity and breadth development. Strikingly, antibodies engaging non-competing, neutralizing epitopes can act co-operatively to block IFN signaling, and some combinations trigger Fc-effector functions via cell surface IFN:IFNAR2 interactions that may eliminate IFN-responsive cells. Our findings reveal features shaping anti-IFN autoantibody repertoires and unappreciated synergistic mechanisms that amplify their potency and pathogenic potential.

immunology↗

bioRxiv2026

Scientific computing in the age of agentic AI: an exploratory field report

Scientific computing has become a central component of modern scientific discovery. Yet many computational tools are developed by small, specialized teams under incentives that encourage the release of rapidly prototyped tooling without commensurate attention to engineering concerns, including performance and maintainability. These gaps are particularly visible in the life sciences, where the advent of high-throughput sequencing and molecular profiling has made the production and processing of datasets routine at scales that strain reliability and cost. Recently, LLM-based agents have become increasingly capable, with publicly available systems possessing both significant domain knowledge in many scientific fields and the ability to autonomously operate over complex and specialized codebases in pursuit of well-defined goals. Together, these developments create a practical opportunity for scientific computing. Many of the persistent weaknesses of the scientific computing ecosystem stem from technical debt and a shortage of sustained engineering labor and expertise. Here, we examine coding agents as a potential way to address these weaknesses: we present an exploratory field report of eight early case studies in the application of LLM agents to scientific computing across a range of project scopes, from lightweight maintenance tasks to full performance-oriented rewrites of scientific libraries, with a focus on the life sciences. Each of these case studies is accompanied by reflections from the individual or group responsible for the work, including lessons from the process. Overall, we find that the use of coding agents in scientific computing holds great promise for accelerating scientific research and increasing the reliability of critical systems, but that outstanding concerns remain, including responsibility and ownership for such projects, and we suggest collaboration and stewardship with existing maintainers when feasible.

bioinformatics↗

bioRxiv2026

Global topology of brain-wide co-fluctuations links task states, personality, and behavioral symptom dimensions

Functional connectivity in network neuroscience is traditionally characterized using time-averaged correlations between brain regions. While these summaries capture stable large-scale organization, they do not fully reflect the temporal structure of moment-to-moment interactions. Here, we investigate how the order of interaction used to represent brain dynamics shapes the organization recovered from neural data. We compare three interaction representations of fMRI dynamics: regional activation (node time series), pairwise co-fluctuations (edge time series), and higher-order triplet interactions (triangle time series); within a common topological framework using Mapper from topological data analysis (TDA). Across task and resting-state data, Mapper representations derived from pairwise co-fluctuations more distinctly segregate task conditions than activation-based or higher-order representations. This organization reflects structured coordination patterns beyond activation polarity and is driven by high-amplitude interaction events. Beyond task states, modularity quality computed across all Mapper representations is highest for edge time series and selectively associated with stable individual differences: higher modularity relates to higher conscientiousness and lower internalizing and externalizing symptom dimensions. Together, these findings suggest that behaviorally relevant information is reflected in the topology of moment-to-moment brain interactions. Topological analysis of interaction-level dynamics therefore provides a complementary and interpretable framework for linking large-scale neural coordination to cognition, personality, and mental health.

neuroscience↗

bioRxiv2025

Claudin 1-mediated positioning of DC1 to mTECs is essential for antigen transfer-coupled DC1 maturation and maintenance of central tolerance

The mechanisms of central tolerance, which rely on the presentation of self-antigens by medullary thymic epithelial cells (mTECs) and DCs, prevent autoimmunity by eliminating self-reactive T-cells. While mTECs produce self-antigens in an autonomous manner, DCs acquire them from mTECs via cooperative antigen transfer (CAT). Our recent data showed that preferential pairing occurs between distinct subsets of mTECs and DCs in CAT, providing a rationale for the existence of molecular determinants which control such pairing and the outcome of central tolerance. Here, we compared the transcriptomes of CAT-experienced and -inexperienced DCs and identified Claudin 1 as a molecule involved in CAT-coupled type 1 DC (DC1) maturation. By mapping thymic DC1 heterogeneity, we identified their early and late maturation states. DC1-specific ablation of Claudin 1 led to a reduction in CAT-experienced late mature DC1s and hampered DC1 maturation. These phenotypes correlated with the displacement of DC1s from the vicinity of mTECs. This translated into impaired Treg selection and clonal deletion of TRA-specific T-cells manifested via a break in tolerance and symptoms of multi-organ autoimmunity. Collectively, our results identify thymic DC1-derived Claudin 1 as a regulator of immune tolerance. One Sentence SummaryThe expression of Claudin 1 on type 1 dendritic cells regulates their proximity to mTECs, which is required for effective antigen transfer coupled with DC1 maturation and establishment of T-cell tolerance.

immunology↗

bioRxiv2024

Global genomics of Aedes aegypti unveils widespread and novel persistent infectious viruses capable of triggering a small RNA response

The mosquito Aedes aegypti is a prominent vector for arboviruses, but the breadth of mosquito viruses that infects this specie is not fully understood. In the broadest global survey to date of over 200 Ae. aegypti small RNA samples, we detected viral small interfering RNAs (siRNAs) and Piwi interacting RNAs (piRNAs) arising from mosquito viruses. We confirmed that most academic laboratory colonies of Ae. aegypti lack persisting viruses, yet two commercial strains were infected by a novel tombus-like virus. Ae. aegypti from North to South American locations were also teeming with multiple insect viruses, with Anphevirus and a bunyavirus displaying geographical boundaries from the viral small RNA patterns. Asian Ae. aegypti small RNA patterns indicate infections by similar mosquito viruses from the Americas and reveal the first wild example of dengue virus infection generating viral small RNAs. African Ae. aegypti also contained various viral small RNAs including novel viruses only found in these African substrains. Intriguingly, viral long RNA patterns can differ from small RNA patterns, indicative of viral transcripts evading the mosquitoes RNA interference (RNAi) machinery. To determine whether the viruses we discovered via small RNA sequencing were replicating and transmissible, we infected C6/36 and Aag2 cells with Ae. aegypti homogenates. Through blind passaging, we generated cell lines stably infected by these mosquito viruses which then generated abundant viral siRNAs and piRNAs that resemble the native mosquito viral small RNA patterns. This mosquito small RNA genomics approach augments surveillance approaches for emerging infectious diseases.

genomics↗

bioRxiv2024

TCA Cycle Dysfunction and Amino Acid Catabolism Drive Hepatic Steatosis in Mice with HFpEF

The prevalence of cardiometabolic heart failure with preserved ejection fraction (HFpEF) continues to grow worldwide, and now represents over half of current heart failure cases in the United States (1). Due to a lack of specific approved therapies, current treatment guidelines focus on the management of comorbidities related to metabolic syndrome (e.g. obesity, diabetes, hypertension) that promote HFpEF progression (1). The same comorbidities also drive cardiometabolic disease in non-cardiac tissues, and links between disease presentations in different organs are increasingly being recognized in the clinic. However, mechanistic studies examining the underlying pathophysiological connections have not kept pace, particularly in the cardio-hepatic disease axis (2). To address this, we used a recently developed and validated preclinical model of HFpEF (3) to examine how this disease impacts the liver. The development of HFpEF in mice leads to the simultaneous development of widespread hepatic steatosis that is consistent with human non-alcoholic fatty liver disease (NAFLD). Mechanistically, we show that the liver steatosis observed is driven by excess glucogenic amino acid entry into the TCA cycle, which promotes hepatic glucose production and de novo lipogenesis. Our findings suggest that HFpEF development is a multi-organ event, with implications for both preclinical and translational research.

physiology↗

bioRxiv2024

GCN5L1 regulates glucose and ketone body metabolism during cardiac ischemia-reperfusion injury

Myocardial infarction remains one of the leading causes of mortality. Reperfusion of the infarcted myocardium restores blood flow and reduces primary ischemic injury. However, despite its protective function, reperfusion is also associated with several deleterious outcomes that can result in ischemia-reperfusion (I/R) injury to cardiac tissue. While negative outcomes such as reactive oxygen species generation are strongly associated with I/R injury, cardiac energy metabolism is also greatly disrupted. Furthermore, previous studies have shown that the restoration of normal fuel oxidation in the myocardium regulates the extent of contractile recovery. A better understanding of the pathophysiological mechanisms underlying I/R injury may allow us to develop new treatments that limit the negative aspects of the process. In this study, we examined the role played by GCN5L1, a protein implicated in the regulation of energy metabolism, in I/R injury. We demonstrate that cardiac-specific loss of GCN5L1 promotes the inhibitory phosphorylation of pyruvate dehydrogenase in vitro and in vivo, a process likely to inhibit glucose oxidation, and that this corresponds to increased myocardial damage following ischemia-reperfusion (I/R) injury.

physiology↗

bioRxiv2023

Validation of GCN5L1/BLOC1S1/BLOS1 Antibodies Using Knockout Cells and Tissue

GCN5L1, also known as BLOC1S1 and BLOS1, is a small intracellular protein involved in a number of key biological processes. Over the last decade, GCN5L1 has been implicated in the regulation of protein lysine acetylation, energy metabolism, endo-lysosomal function, and cellular immune pathways. An increasing number of published papers have used commercially-available reagents to interrogate GCN5L1 function. However, in many cases these reagents have not been rigorously validated, leading to potentially misleading results. In this report we tested several commercially-available antibodies for GCN5L1, and found that two-thirds of those available did not unambiguously detect the protein by western blot in cultured mouse cells or ex vivo liver tissue. These data suggest that previously published studies which used these unverified antibodies to measure GCN5L1 protein abundance, in the absence of other independent methods of corroboration, should be interpreted with appropriate caution.

cell biology↗

bioRxiv2023

Therapeutic immunization with a whole cell vaccine reduces pneumococcal nasopharyngeal density, shedding, and middle ear infection in mice

Pneumococcal Conjugate Vaccines (PCVs) have substantially reduced the burden of disease caused by Streptococcus pneumoniae (the pneumococcus). However, protection is limited to vaccine serotypes, and when administered to children who are colonized with pneumococci at the time of vaccination, immune responses to the vaccine are blunted. Here, we investigate the potential of a killed whole cell pneumococcal vaccine (WCV) to reduce existing pneumococcal carriage and mucosal disease when given therapeutically to infant mice colonized with pneumococci. We show that a single dose of WCV reduced pneumococcal carriage density in an antibody-dependent manner. Therapeutic vaccination induced robust immune responses to pneumococcal surface antigens CbpA, PspA (family 1) and PiaA. In a co-infection model of otitis media, a single dose of WCV reduced pneumococcal middle ear infection. Lastly, in a two-dose model, therapeutic administration of WCV reduced nasal shedding of pneumococci. Taken together, our data demonstrate that WCV administered in colonized mice reduced pneumococcal density in the nasopharynx and the middle ear, and decreased shedding. A vaccine with similar properties in children would be beneficial in low and middle-income settings where pneumococcal carriage is high. ImportanceAlthough typically asymptomatic, pneumococcal carriage plays an essential role in transmission and the development of disease. Pneumococcal Conjugate Vaccines (PCVs) have reduced the burden of pneumococcal disease worldwide. However, their use has increased carriage and disease caused by non-vaccine serotypes, prompting investigations into serotype-independent pneumococcal vaccines. An additional limitation of PCVs is immune hypo-responsiveness to vaccines in children carrying pneumococci at the time of vaccination. Therefore, there is great interest in next generation vaccines such as whole cell vaccines. In this study we investigate a pneumococcal whole cell vaccine (WCV) for it effect on carriage in mice that are already colonized at the time of vaccination. We show that this therapeutic vaccination of mice can reduce pneumococcal carriage density, shedding and infection of the middle ear. Our study suggests that WCV could be beneficial in high burden settings where carriage at the time of vaccination is more common.

microbiology↗

bioRxiv2021

A model of preferential pairing between epithelial and dendritic cells in thymic antigen transfer

Medullary thymic epithelial cells (mTECs) which produce and present self-antigens are essential for the establishment of central tolerance. Since mTEC numbers are limited, their function is complemented by thymic dendritic cells (DCs), which transfer mTEC-produced self-antigens via cooperative antigen transfer (CAT). While CAT is required for effective T cell selection, many aspects remain enigmatic. Given the recently described heterogeneity of mTECs and DCs, it is unclear whether the antigen acquisition from a particular TEC subset is mediated by preferential pairing with specific subset of DCs. Using several relevant Cre-based mouse models controlling the expression of fluorescent proteins, we found that in regards to CAT, each subset of thymic DCs preferentially targets distinct mTEC subset(s) and importantly, XCR1+ activated DCs represented the most potent subset in CAT. Interestingly, one thymic DC can acquire antigen repetitively and of these, monocyte-derived DCs (moDC) were determined to be the most efficient in repetitive CAT. moDCs also represented the most potent DC subset in the acquisition of antigen from other DCs. These findings suggest a preferential pairing model for the distribution of mTEC-derived antigens among distinct populations of thymic DCs.

immunology↗

bioRxiv2020

Ungulate Responses to Unmanned Aerial Vehicles Flying at Different Altitudes in Africas Arid Savanna

This paper tests the hypothesis that ungulate-UAV interaction depends strongly on flight altitude, that there may be a lowest altitude range for which the ungulates are not exceedingly disturbed, dictating a practically achievable level of discernibility in flight observation. This question strongly influences the future viability of the UAV in the study and protection of the ungulates in Africas arid savanna. This paper examined the behavioral responses of a group of free ranging ungulate species (Oryx, Kudu, Springbok, Giraffe, Eland, Hartebeest, and Impala) found in an animal reserve in Namibia to the presence of different in-flight UAV models. The study included 99 flights (337 passes) at altitudes ranging from 15 to 55 meters. The ungulates were unhabituated to the UAVs and the study was conducted in the presence of stress-inducing events that occur naturally in the environment. The results suggest strong correlations between flight altitude and response across the different ungulates and anecdotal evidence suggests in some cases rapid habituation to the UAVs.

animal behavior and cognition↗

bioRxiv2018

The chemistry and pharmacology of putative synthetic cannabinoid receptor agonist (SCRA) new psychoactive substances (NPS) 5F-PY-PICA, 5F-PY-PINACA, and their analogues

The structural diversity of synthetic cannabinoid receptor agonist (SCRA) new psychoactive substances (NPS) has increased since the first examples were reported a decade ago. 5F-PY-PICA and 5F-PY-PINACA were identified in 2015 as putative SCRA NPS, although nothing is known of their pharmacology. 5F-PY-PICA, 5F-PY-PINACA, and analogues intended to explore structure-activity relationships within this class of SCRAs were synthesized and characterized by nuclear magnetic resonance spectroscopy and liquid chromatography-quadrupole time-of-flight-mass spectrometry. Using competitive binding experiments and fluorescence-based plate reader membrane potential assays, the affinities and activities of all analogues at cannabinoid type 1 and type 2 receptors (CB1 and CB2) were evaluated. All ligands showed minimal affinity for CB1 (pKi < 5), although several demonstrated moderate CB2 binding (pKi = 5.45-6.99). At 10 M none of the compounds produced an effect > 50% of CP55,950 at CB1, while several compounds showed a slightly higher relative efficacy at CB2. Unlike other SCRA NPS, 5F-PYPICA and 5F-PY-PINACA did not produce cannabimimetic effects in mice at doses up to 10 mg/kg.

pharmacology and toxicology↗

bioRxiv2018

On simulating cold stunned turtle strandings on Cape Cod

Kemps ridley turtles were on the verge of extinction in the 1960s. While they have slowly recovered, they are still endangered. In the last few years, the number of strandings on Cape Cod Massachusetts beaches has increased by nearly an order of magnitude relative to preceding decades. This study uses a combination of ocean observations and a well-respected ocean model to investigate the causes and transport of cold-stunned animals in Cape Cod Bay. After validating the model using satellite-tracked drifters and local temperature moorings, ocean currents were examined in the Cape Cod Bay in an attempt to explain stranding locations as observed by volunteers and, for some years, backtracking was conducted to examine the potential source regions. The general finding, as expected, is that sub 10.5{degrees}C water temperatures in combination with persistent strong wind stress (>0.4Pa) will result in increased strandings along particular sections of the coast dependent on the wind direction. However, it is still uncertain where in the water column the majority of cold stunned turtles reside and, if many of them are on the surface, considerable more work will need to be done to incorporate the direct effects of wind and waves on the advective processes.

ecology↗

bioRxiv2017

A probabilistic approach to discovering dynamic full-brain functional connectivity patterns

Recent research shows that the covariance structure of functional magnetic resonance imaging (fMRI) data - commonly described as functional connectivity - can change as a function of the participants cognitive state (for review see [35]). Here we present a Bayesian hierarchical matrix factorization model, termed hierarchical topographic factor analysis (HTFA), for efficiently discovering full-brain networks in large multi-subject neuroimaging datasets. HTFA approximates each subjects network by first re-representing each brain image in terms of the activities of a set of localized nodes, and then computing the covariance of the activity time series of these nodes. The number of nodes, along with their locations, sizes, and activities (over time) are learned from the data. Because the number of nodes is typically substantially smaller than the number of fMRI voxels, HTFA can be orders of magnitude more efficient than traditional voxel-based functional connectivity approaches. In one case study, we show that HTFA recovers the known connectivity patterns underlying a collection of synthetic datasets. In a second case study, we illustrate how HTFA may be used to discover dynamic full-brain activity and connectivity patterns in real fMRI data, collected as participants listened to a story. In a third case study, we carried out a similar series of analyses on fMRI data collected as participants viewed an episode of a television show. In these latter case studies, we found that the HTFA-derived activity and connectivity patterns can be used to reliably decode which moments in the story or show the participants were experiencing. Further, we found that these two classes of patterns contained partially non-overlapping information, such that decoders trained on combinations of activity-based and dynamic connectivity-based features performed better than decoders trained on activity or connectivity patterns alone. We replicated this latter result with two additional (previously developed) methods for efficiently characterizing full-brain activity and connectivity patterns.

neuroscience↗