Biology subjects

Press, C.

Publications and source records attributed to Press, C..

At least 19 recordsLinked to original sources

bioRxiv2026

Autistic and non-autistic adults similarly experience statistical regularities

Bayesian accounts of autism propose that perception is less influenced by prior expectations and more strongly driven by incoming sensory information in autistic than non-autistic individuals, with this altered balance cascading through the cognitive hierarchy to also influence higher cognitive functions. However, empirical support for these accounts remains mixed. Previous work has mostly tested these ideas in the context of objective environmental statistics, but recent work suggests that it may be subjective experience of structure, rather than structure itself, that shapes perceptual processing. Characterising these subjective experiences in autistic individuals is therefore crucial for understanding predictive processing in autism. In the present study, we thus examined subjective experience of statistical structure in autistic and non-autistic adults and tested how this experience relates to perceptual decisions. Participants were exposed to statistical regularities between action cues and visual stimuli (shapes), and we measured their speed and accuracy in reporting which shape they had seen. At the end of the study, participants were asked to estimate the probability and rate their surprise for each action-shape combination. Autistic and non-autistic participants showed similar subjective probability and surprise ratings and a comparable relationship between these ratings and perceptual decisions. Across participants, subjective ratings explained perceptual decisions better than objective structure. Together, these findings show that autistic and non-autistic adults experience statistical structure similarly, with these experiences exerting a similar influence on perceptual decisions - therefore suggesting that subjective experience plays a comparable role in predictive processing in autistic and non-autistic adults. Lay summaryOur brains constantly learn patterns from past experience - for example, that dark clouds are often followed by rain - and use this knowledge to predict and interpret what we see. We studied how autistic and non-autistic adults experience these learned patterns by asking them how likely and surprising they found different events. We found that both groups gave similar ratings, and that these experiences shaped perception in similar ways.

neuroscience↗

bioRxiv2026

Recent history attracts and repels perceptual decisions depending on surprise

Past sensory experience shapes our perceptual decision-making in the now. Popular models frame perceptual decisions as either attracted towards or repelled away from recent sensory information, but it is unclear when and why these distinct effects emerge. We here ask whether effects turn from attractive to repulsive depending on the level of surprise elicited by the precision-weighted discrepancy between past and present sensory states. This model is based upon the idea that attraction is adaptive for optimising efficiency and accuracy when discrepancies are small, because they likely reflect sensory noise rather than real change in the environment. In contrast, repulsion may reflect the upweighting of counterfactual evidence when discrepancies are large because they more likely signal the need for model updating. We test this model on a large amount of recently-collated trial-by-trial serial dependence data and consistently find support for it across the dataset, participant, and trial-by-trial level. Specifically, serial dependence effects are attractive at low discrepancies between past and current sensory states but turn repulsive when discrepancies are larger. Higher sensory precision is found to accelerate this flip by reducing the modal discrepancy threshold required to trigger repulsion effects. We discuss how these findings necessitate extending existing theories of serial dependence, and how they may resolve conflicts in the broader predictive processing, learning and perception literatures.

neuroscience↗

bioRxiv2026

Gravitational expectations simultaneously attract and repel perception

Perception is typically biased towards prior expectations. In some cases, however, it seems repelled away from expectations, such that percepts appear less like what is expected. Even more intriguingly, separate studies have recently reported that predictions derived from gravity may shape perception in opposing ways. Specifically, gravity causes unsupported objects to accelerate downwards, leading to two predictions; that objects will move downwards (location prior) and at an increasing speed (acceleration prior). There is evidence that perceptual judgements are attracted towards location priors yet repelled from acceleration ones. Here we examine these effects in the same paradigm to determine whether they result from different types of stimuli and judgement, or more interestingly, might result from opposite influences of common predictive mechanisms influencing perception. We first replicate previous reports of a systematic bias to report upward moving objects as more accelerating than downward moving objects: effectively a repulsion from acceleration priors. We then show that the effect applies both at the level of retinal space and due to contextual cues concerning gravitational direction. Finally, we find that participants errors in a location reproduction task are similarly consistent with a repulsion from acceleration priors and, simultaneously, with an attraction towards location priors. We conclude by considering the ways in which these concurrent attractive and repulsive biases may reflect mechanisms optimising fast, accurate, and informative experiences in our ever-changing sensory world, therefore optimising the interface between perception and learning. Public Significance StatementIn a series of behavioural experiments, we show that expectations about how objects move due to gravity concurrently attract perception towards the prediction that objects move downwards, and repel perception away from the prediction that they do so at an increasing rate. These opposing influences inform current theories of perceptual processing, which explain how expectations may generate percepts that are fast, veridical, and informative.

neuroscience↗

bioRxiv2026

The dynamic relationship between pupil dilation and neural surprise in natural language comprehension

Predictive processing accounts hold that the brain continuously generates predictions and updates internal models from error signals, but it remains unclear whether prediction representation and model-updating reflect a single graded computation or computationally distinct operations implemented in dissociable systems. We recorded magnetoencephalography (MEG) and pupillometry while participants listened to continuous natural speech, quantifying word-by-word lexical surprise and semantic prediction error with a GPT-2 model. Broadly speaking, lexical surprise was tracked in a predominantly graded fashion, whereas the response to semantic error was better captured by a rectified linear (ReLU) gating function - i.e., that responds only when the error exceeds a recent contextual baseline. There were also some interesting dissociations in the strength of these relative effects. The auditory cortex tracked lexical surprise in a graded, continuous manner, with later cortical stages reflecting semantic error. By contrast, tonic pupil diameter and source-localised brainstem responses were predominantly captured by a gated response to semantic error. A pupil-coupling analysis confirmed that this gating signature was statistically shared between pupil-linked arousal and brainstem-localised, but not cortical, responses. Together, these findings reveal a division of labour in which the cortex maintains a continuous, high-fidelity map of predictive information while a pupil-linked model-update system acts as a selective gate, engaged specifically by meaning-disrupting events that have crossed a threshold level of error. This asymmetry suggests that signals serving continuous parsing of prediction error and signals serving model revision may be computationally dissociated, with a range of implications for our understanding of the intrinsic interactions between mechanisms serving perception and learning.

neuroscience↗

bioRxiv2026

Paradoxical influences of prediction are resolved across time

It is widely thought that our brains use expectations to optimise perception, yet theoretical accounts disagree about the form of this optimisation. Bayesian accounts propose that perception is biased towards expected events, rapidly generating more veridical experiences, whereas cancellation accounts argue that unexpected inputs are perceptually prioritised as they are more informative. A recent opposing process theory reconciles these views by proposing a temporal reversal in prioritisation: perceptual processing is pre-emptively biased towards what is expected, followed by later enhancement of only particularly surprising inputs that are informative for learning and model updating. Here, we tested this account using time-resolved decoding of EEG data, while participants observed avatar action outcomes that were either expected or unexpected based on their own movements. Expectation effects on the neural representations of these action outcomes indeed unfolded over time in such a manner, with higher decoding for task-relevant expected outcomes starting before stimulus onset, followed by a later post-stimulus advantage for unexpected outcomes. These findings support the opposing process theory, demonstrating a reversal in prioritisation that is not predicted by current Bayesian or cancellation accounts. By exerting distinct influences across time, expectations can thus render perception veridical, while still allowing for the accurate perception of particularly unexpected events that are important for updating our beliefs or ongoing courses of action. Significance statementHow we perceive the world is shaped by our expectations. Yet it remains unclear how the brain can use these expectations to make perception both more accurate and more informative, given these demands require opposite influences of expectation on processing - upweighting versus downweighting the expected, respectively. Here, we show that this apparent conflict is resolved across time. The expected is enhanced before a stimulus appears by pre-activating what we expect, whereas unexpected inputs are enhanced later. This temporal reversal allows expectations to support both demands, rapidly generating generally more accurate perceptual experiences, while also remaining sensitive to unexpected information that is critical for learning and adaptive behaviour.

neuroscience↗

bioRxiv2025

Perceptual predictions track subjective, over objective, statistical structure

Over the past two decades, converging evidence from neuroscience and psychology has shown that predictions based on learnt statistical regularities exert a widespread influence on perception, action and cognition. Predictive processes in cognition and the brain are usually modelled as tracking objective event probabilities, deriving predictions and prediction errors from the statistical structure of the environment. However, our subjective models of our environments do not always align with these objective statistics. Currently we know little about how these subjective representations may determine the predictive functions. To separate subjective and objective contributions to prediction, we conducted three studies where cues (actions or tones) predicted visual outcomes (shapes or Gabors) with varying contingencies, and adult participants discriminated these outcomes. Uniquely to our paradigm, participants also reported their experiences of the statistical structure embedded in the task - the subjective probability (Experiment 1; N = 68), expectedness (Experiment 2; N = 35), or surprise (Experiment 3; N = 35) associated with the outcomes. When modelling subjective ratings alongside objective structure, the speed of perceptual decisions was best explained by independent, additive contributions of both. The decision itself was usually only explained by the subjective ratings, with little additional variance explained by objective statistical structure. These findings suggest that subjective experience may play a key, overlooked role in predictive processes, and open a host of interesting questions about the relative objective and subjective contributions to prediction, perception, and learning.

animal behavior and cognition↗

bioRxiv2025

Tracking visual rhythms: a concert of sensory and motor simulation

When will I see something and what will it be? Temporal predictions are crucial for adaptive interaction with the environment and are typically accompanied by predictions about sensory content, yet these two types of what and when predictions are usually studied separately. Specifically, oscillatory phase-coupling (or entrainment) has been proposed to align our neural sensitivity with likely moments of stimulus appearance, however these accounts ignore that predictions about when something will appear are usually accompanied by predictions about what it will be. Thus, temporal predictions may not enhance all sensory processing but rather modulate particular channels encoding predicted content. We here demonstrate oscillatory phase-coupling in vision and show how it relates to content-specific encoding. In a magnetoencephalography (MEG) study, participants observed rhythmic Gabors at 1.33 or 2 Hz with predictable orientations. They judged the timing or orientation of a delayed probe which manipulated the requirement to covertly maintain the sequence rhythm. We found sustained oscillatory phase-coupling to the entrained rhythm in motor areas specifically when participants judged stimulus timing, where its extent was associated with perceptual performance. Meanwhile, neural decoding revealed content predictions in early visual areas ( what) that fluctuated in line with temporal predictions ( when). These temporally-specific content predictions appeared regardless of task instruction but were correlated and phase-aligned with the motor phase-coupling during timing judgements. These findings suggest that temporal predictions may be derived from motor readouts of temporally-specific sensory predictions, with broad implications for our understanding of entrainment and prediction, and how we represent time more generally.

neuroscience↗

bioRxiv2025

A Spray Dried Replicon Vaccine Platform for Pandemic Response

The recent COVID-19 pandemic, as well as the threat of a global pandemic caused by H5N1 avian influenza virus, has highlighted the need for the development of thermostable vaccines that can be manufactured and distributed rapidly to combat the next global pandemic. To address this need, we previously developed a replicon vaccine platform that utilizes a nanostructured lipid carrier (NLC) to protect and efficiently deliver antigen-expressing replicon molecules in vivo. The replicon-NLC vaccine platform uses readily sourced components and can be rapidly manufactured at scale with the potential for stockpiling, thus enhancing pandemic preparedness. Spray drying is a promising method of vaccine desiccation with reduced costs and increased scale-up capabilities compared to lyophilization. As proof of concept, we demonstrate for the first time the successful spray drying of a replicon-NLC vaccine complex designed to protect against H5N1 avian influenza A virus to enhance its long-term thermostability while maintaining vaccine immunogenicity in an in vivo mouse model. Several glass-forming disaccharide excipients were screened for formulation and process compatibility under low-temperature spray drying conditions, and it was determined that a suitable shell-forming excipient, L-leucine, was necessary to prevent excessive accumulation of replicon-NLC vaccine complexes on the dry powder surface and a subsequent loss in process yield. The spray dried replicon-NLC vaccine powders were chemically stable for 1 month of storage at 40{degrees}C. Immunogenicity of the spray dried drug product was also well maintained for at least 3 months of storage at 4{degrees}C when administered intramuscularly into C57BL/6 mice as a reconstituted liquid. Finally, we demonstrate the ability to precisely control the aerodynamic particle size of the spray dried vaccine product to generate dry powders that are theoretically suitable for nasal or pulmonary delivery without reconstitution. This work establishes the feasibility of spray drying a thermostable replicon-NLC vaccine for rapid pandemic response.

immunology↗

bioRxiv2025

Development of an Intranasally- and Intramuscularly-Administrable Replicon Vaccine Efficacious Against H5N1 Influenza Virus

The risk of a respiratory viral pandemic is significant, including from the now widespread panzootic H5N1 influenza virus, highlighting the need for effective, stable, and inexpensive vaccine technologies that elicit strongly protective immunity. Intranasal vaccines can stimulate local immune responses at the site of natural respiratory viral infection, a key characteristic that can not only reduce morbidity and mortality caused by respiratory viruses but also potentially reduce viral transmissibility to limit outbreaks. Nucleic acid vaccines are now a valuable tool in pandemic responses, with high potency and rapid adaptability to target circulating or emerging viral strains; however, data are limited on which vaccine attributes are needed for efficient transmucosal delivery and immune stimulation following intranasal delivery. To demonstrate proof of concept, here we have developed a replicon vaccine expressing an H5 influenza antigen that uses a nanostructured lipid carrier (NLC) delivery system. A relationship was established between the molar ratio of positive charges on the NLC to the negative charges on the nucleic acid (N:P ratio) and the immunogenicity of the vaccine formulations, with higher N:P ratios resulting in an increase in vaccine immunogenicity. We demonstrated the ability of this replicon vaccine to be administered via intramuscular and intranasal routes with a singular vaccine formulation. The vaccine induced systemic immunity when dosed intramuscularly or intranasally in an immunocompetent mouse model, whereas intranasal dosing uniquely stimulated a strong mucosal immune response. Moreover, a mixed intramuscular/intranasal dosing strategy using this unified formulation stimulated a balanced systemic and mucosal immune response. Finally, we demonstrated the protective efficacy of this intranasally and intramuscularly/intranasally delivered H5 replicon-NLC vaccine against morbidity and mortality in a lethal H5N1 influenza challenge ferret model. This work establishes the replicon-NLC vaccine platform as a potential novel intranasal technology for rapid pandemic response.

immunology↗

bioRxiv2025

An intranasal, NLC-delivered self-amplifying RNA vaccine establishes protective immunity against pre-pandemic H5N1 and H7N9 influenza

Seasonal and pandemic influenzas are continuous threats to human health, requiring rapid development of vaccines to multiple evolving viral strains. New RNA vaccine technologies have the adaptability and manufacturability to facilitate pandemic preparedness but have limited flexibility in their route of administration, reducing the ability to establish local protective immune responses such as respiratory mucosal immunity. Here, we describe monovalent and bivalent self-amplifying RNA (saRNA) vaccines against A/Vietnam/1203/2004 H5N1 and A/Anhui/2013 H7N9. These saRNA vaccines express either H5 or H7 hemagglutinin and are formulated with a nanostructured lipid carrier (NLC) that permits both intramuscular (IM) and intranasal (IN) dosing. In mice, IM vaccination established systemic humoral and cellular responses but no detectable mucosal response, while IN administration induced robust systemic and mucosal immunity. The saRNA-NLC vaccines provided complete protection against morbidity and mortality in ferret challenge models, establishing this intranasally-administered saRNA-NLC vaccine platform as a potential pandemic response tool. ONE SENTENCE SUMMARYA self-amplifying RNA-NLC vaccine, delivered intranasally, induces robust mucosal immunity in mice and protects against H5N1 and H7N9 in ferrets

immunology↗

bioRxiv2024

The "Ocular Response Function" for encoding and decoding oculomotor related neural activity

Oculomotor activity provides critical insights into cognition and health, with growing evidence demonstrating its involvement in various cognitive functions such as attention, memory, and sensory processing, and that it is a significant indicator of psychopathologies and neurological disorders. Despite its crucial importance across domains, the neural mechanisms supporting oculomotion have been underexplored, largely because eye movements are typically treated as artefacts to be removed from the neural signal. While useful for data cleaning, this approach risks discarding valuable information about oculomotor control, and there has been recent interest in modelling these signals instead to understand them. Using time-resolved regression methods with magnetoencephalography (MEG) and eye tracking during the resting state, we thus here sought to model Ocular Response Functions (ORFs), that characterise the neural signatures of distinct oculomotor events, specifically saccades, blinks, and pupil dilation. We demonstrate the relationships between ocular action and neural activity (encoding), revealing a range of sensory cortical, cerebellar and frontal signatures preceding and following such ocular events. We conversely show how we can reconstruct ocular events from brain activity, and further apply resting-state derived ORFs to a passive listening task - demonstrating how some neural markers interpreted as directly related to sensation may in principle indirectly result from oculomotor contributions to task-related neural processing. By providing an accessible framework for examining the interplay between eye movements and neural processes, we offer a range of insights with potential applications across cognitive and clinical neuroscience.

neuroscience↗

bioRxiv2023

Dopamine challenge reduces mental state attribution accuracy

Difficulties in reasoning about others mental states (i.e., mentalising / Theory of Mind) are highly prevalent among disorders featuring dopamine dysfunctions (e.g., Parkinsons disease) and significantly affect individuals quality of life. However, due to multiple confounding factors inherent to existing patient studies, currently little is known about whether these socio-cognitive symptoms originate from aberrant dopamine signalling or from psychosocial changes unrelated to dopamine. The present study therefore investigated the role of dopamine in modulating mentalising in a sample of healthy volunteers. We used a double-blind, placebo-controlled procedure to test the effect of the D2 antagonist haloperidol on mental state attribution, using an adaptation of the Heider & Simmel (1944) animations task. On two separate days, once after receiving 2.5mg haloperidol and once after receiving placebo, 33 healthy adult participants viewed and labelled short videos of two triangles depicting mental state (e.g., surprising) and non-mental state (e.g., following) interactions. Using Bayesian mixed effects models we observed that haloperidol decreased accuracy in labelling both mental- and non-mental state animations. Our secondary analyses suggest that dopamine modulates inference from mental- and non-mental state animations via independent mechanisms, pointing towards two putative pathways underlying the dopaminergic modulation of mental state attribution: Action representation and a shared mechanism supporting mentalising and emotion recognition. We conclude that dopamine is causally implicated in Theory of Mind. Our results have implications for the neurochemical basis of socio-cognitive difficulties in patients with dopamine dysfunctions and generate new hypotheses about the specific dopamine-mediated mechanisms underlying social cognition.

neuroscience↗

bioRxiv2023

Predictions and errors are distinctly represented across V1 layers

Predictive processing frameworks of cortical functioning propose that neural populations in different cortical layers serve distinct roles in representing the world. There are distinct testable theories within this framework that we examined with a 7T fMRI study, where we contrasted responses in primary visual cortex (V1) to expected (75% likely) and unexpected (25%) Gabor orientations. Multivariate decoding analyses revealed an interaction between expectation and layer, such that expected events could be decoded with comparable accuracy across layers, while unexpected events could only be decoded in superficial laminae. These results are in line with predictive processing accounts where expected virtual input is injected into deep layers, while superficial layers process the error with respect to expected signals. While this account of cortical processing has been popular for decades, such distinctions have not previously been demonstrated in the human sensory brain. We discuss how both prediction and error processes may operate together to shape our unitary perceptual experiences.

neuroscience↗

bioRxiv2022

A self-amplifying RNA vaccine against COVID-19 with long-term room-temperature stability

mRNA vaccines were the first to be authorized for use against SARS-CoV-2 and have since demonstrated high efficacy against serious illness and death. However, limitations in these vaccines have been recognized due to their requirement for cold storage, short durability of protection, and lack of access in low-resource regions. We have developed an easily-manufactured, potent self-amplifying RNA (saRNA) vaccine against SARS-CoV-2 that is stable at room temperature. This saRNA vaccine is formulated with a nanostructured lipid carrier (NLC), providing enhanced stability, improved manufacturability, and protection against degradation. In preclinical studies, this saRNA/NLC vaccine induced strong humoral immunity, as demonstrated by high pseudovirus neutralization titers to the Alpha, Beta, and Delta variants of concern and induction of long-lived bone marrow-resident antibody secreting cells. Robust Th1-biased T-cell responses were also observed after prime or homologous prime-boost in mice. Notably, the saRNA/NLC platform demonstrated thermostability at room temperature for at least 6 months when lyophilized. Taken together, this saRNA delivered by NLC represents a potential improvement in RNA technology that could allow wider access to RNA vaccines for the current COVID-19 and future pandemics.

immunology↗

bioRxiv2022

Dopaminergic modulation of dynamic emotion perception

Emotion recognition abilities are fundamental to our everyday social interaction. A large number of clinical populations show impairments in this domain, with emotion recognition atypicalities being particularly prevalent among disorders exhibiting a dopamine system disruption (e.g., Parkinsons disease). Although this suggests a role for dopamine in emotion recognition, studies employing dopamine manipulation in healthy volunteers have exhibited mixed neural findings and no behavioural modulation. Interestingly, whilst a dependence of dopaminergic drug effects on individual baseline dopamine function has been well established in other cognitive domains, the emotion recognition literature so far has failed to account for these possible interindividual differences. The present within-subjects study therefore tested the effects of the dopamine D2 antagonist haloperidol on emotion recognition from dynamic, whole-body stimuli while accounting for interindividual differences in baseline dopamine. 33 healthy male and female adults rated emotional point-light walkers (PLWs) once after ingestion of 2.5 mg haloperidol and once after placebo. To evaluate potential mechanistic pathways of the dopaminergic modulation of emotion recognition, participants also performed motoric and counting-based indices of temporal processing. Confirming our hypotheses, effects of haloperidol on emotion recognition depended on baseline dopamine function, where individuals with low baseline dopamine showed enhanced, and those with high baseline dopamine decreased emotion recognition. Drug effects on emotion recognition were related to drug effects on movement-based and explicit timing mechanisms, indicating possible mediating effects of temporal processing. Results highlight the need for future studies to account for baseline dopamine and suggest putative mechanisms underlying the dopaminergic modulation of emotion recognition. Significance statementA high prevalence of emotion recognition difficulties amongst clinical conditions where the dopamine system is affected suggests an involvement of dopamine in emotion recognition processes. However, previous psychopharmacological studies seeking to confirm this role in healthy volunteers thus far have failed to establish whether dopamine affects emotion recognition and lack mechanistic insights. The present study uncovered effects of dopamine on emotion recognition in healthy individuals by controlling for interindividual differences in baseline dopamine function and investigated potential mechanistic pathways via which dopamine may modulate emotion recognition. Our findings suggest that dopamine may influence emotion recognition via its effects on temporal processing, providing new directions for future research on typical and atypical emotion recognition.

neuroscience↗

bioRxiv2021

Bacterial competition systems share a domain required for inner membrane transport of the nuclease bacteriocin pyocin G

Bacteria exploit a variety of attack strategies to gain dominance within ecological niches. Prominent amongst these are contact-dependent inhibition (CDI), type VI secretion (T6SS) and bacteriocins. The cytotoxic endpoint of these systems is often the delivery of a nuclease to the cytosol. How such nucleases translocate across the cytoplasmic membrane of Gram-negative bacteria is unknown. Here, we identify a small, conserved, 15-kDa domain, which we refer to as the inner membrane translocation (IMT) domain that is common to T6SS and bacteriocins and linked to nuclease effector domains. Through fluorescence microscopy assays using intact and spheroplasted cells, we demonstrate that the IMT domain of the Pseudomonas aeruginosa specific bacteriocin pyocin G (PyoG) is required for import of the toxin nuclease domain to the cytoplasm. We also show that translocation of PyoG into the cytosol is dependent on inner membrane proteins FtsH, a AAA+ATPase/protease, and TonB1, the latter more typically associated with transport of bacteriocins across the outer membrane. Our study reveals that the IMT domain directs the cytotoxic nuclease of PyoG to cross the cytoplasmic membrane and, more broadly, has been adapted for the transport of other toxic nucleases delivered into Gram-negative bacteria by both contact dependent- and contact-independent means. ImportanceNuclease bacteriocins are potential antimicrobials for the treatment of antibiotic resistant bacterial infections. While the mechanism of outer membrane translocation is beginning to be understood, the mechanism of inner membrane transport is not known. This study uses PyoG as a model nuclease bacteriocin and defines a conserved domain which is essential for inner membrane translocation and which is widespread in other bacterial competition systems. Additionally, the presented data links two membrane proteins, FtsH and TonB1, with inner membrane translocation of PyoG. These findings point to the general importance of this domain to the cellular uptake mechanisms of nucleases delivered by otherwise diverse and distinct bacterial competition systems. The work is also of importance for the design of new protein antibiotics.

microbiology↗

bioRxiv2020

Azetidines kill Mycobacterium tuberculosis without detectable resistance by blocking mycolate assembly.

Tuberculosis (TB) is the leading cause of global morbidity and mortality resulting from infectious disease, with over 10 million new cases and 1.5 million deaths in 2019. This global emergency is exacerbated by the emergence of multi-drug-resistant MDR-TB and extensively-drug-resistant XDR-TB, therefore new drugs and new drug targets are urgently required. From a whole-cell phenotypic screen a series of azetidines derivatives termed BGAz, that elicit potent bactericidal activity with MIC99 values <10 M against drug-sensitive Mycobacterium tuberculosis and MDR-TB were identified. These compounds demonstrate no detectable drug resistance. Mode of action and target deconvolution studies suggest that these compounds inhibit mycobacterial growth by interfering with cell envelope biogenesis, specifically late-stage mycolic acid biosynthesis. Transcriptomic analysis demonstrates that the BGAz compounds tested display a mode of action distinct from existing mycobacterial cell-wall inhibitors. In addition, the compounds tested exhibit toxicological and PK/PD profiles that pave the way for their development as anti-tubercular chemotherapies.

microbiology↗

bioRxiv2020

High-Accuracy Multiplexed SARS-CoV-2 Antibody Assay with Avidity and Saliva Capability on a Nano-Plasmonic Platform

The outbreak and rapid spread of SARS-CoV-2 virus has led to a dire global pandemic with millions of people infected and ~ 400,000 deaths thus far. Highly accurate detection of antibodies for COVID-19 is an indispensable part of the effort to combat the pandemic1,2. Here we developed two-plex antibody detection against SARS-CoV-2 spike proteins3 (the S1 subunit and receptor binding domain RBD) in human serum and saliva on a near-infrared nano-plasmonic gold (pGOLD) platform4-8. By testing nearly 600 serum samples, pGOLD COVID-19 assay achieved ~ 99.78 % specificity for detecting both IgG and IgM with 100 % sensitivity in sera collected > 14 days post disease symptom onset, with zero cross-reactivity to other diseases. Two-plex correlation analysis revealed higher binding of serum IgM to RBD than to S1. IgG antibody avidity toward multiple antigens were measured, shedding light on antibody maturation in COVID-19 patients and affording a powerful tool for differentiating recent from remote infections and identifying re-infection by SARS-CoV-2. Just as important, due to high analytical sensitivity, the pGOLD COVID-19 assay detected minute amounts of antibodies in human saliva, offering the first non-invasive detection of SARS-CoV-2 antibodies.

biochemistry↗