Biology subjects

Green, N.

Publications and source records attributed to Green, N..

13 recordsLinked to original sources

bioRxiv2026

Decades of Parkinson's disease neuropathology yield a sparse and underpowered map of neuronal vulnerability: a systematic review and meta-analysis

Selective vulnerability is widely assumed in Parkinson's disease (PD), but whether dopaminergic neurons of the substantia nigra are uniquely vulnerable has not been established. Explanations of neuronal degeneration in Parkinson's disease often centre on the distinctive properties of substantia nigra dopaminergic neurons. Whether these properties are necessary for substantial neuronal loss remains unclear. We preregistered a systematic review of 166 post-mortem case-control studies published between 1963 and 2025 and synthesised neuronal counts and densities from 152 studies using a multilevel meta-analysis. After six decades, only 18% of countable brain atlas labels had been examined, and most populations were represented by a single study. Substantial loss beyond dopaminergic and classically pigmented populations shows that neither dopaminergic identity nor neuromelanin is necessary for marked degeneration, challenging key tenets of selective vulnerability in PD. Comparisons across other anatomical and physiological features remain limited by sparse sampling and uncertainty. We identify less-studied populations with substantial estimated loss and estimate the additional sampling needed to improve precision under specified assumptions. These findings direct replication and comparative counting towards uncertainties that limit explanations of neuronal loss across affected and potentially spared populations.

neuroscience↗

bioRxiv2025

Prediction of treatment response in infantile epileptic spasms syndrome using EEG phase-amplitude coupling

ObjectiveTreatment selection for infantile epileptic spasms syndrome (IESS) is complex and multifaceted, and currently no EEG biomarkers can guide this decision by predicting treatment response. We tested the predictive value of phase-amplitude coupling (PAC), as IESS patients are known to have elevated PAC. MethodsWe analyzed retrospective EEG recordings from 40 IESS patients, before and after treatment, and 20 healthy controls. Patients were classified as responders (n=25) or non-responders (n=15) based on short-term treatment outcomes. We measured PAC in each EEG using modulation index (MI) and mean vector length (MVL) and analyzed the relationship between pre- and post-treatment values and the ability of pre-treatment values to predict response. ResultsMI and MVL values decreased with treatment in almost all subjects. However, non-responders had significantly higher pre-treatment MI than responders (P<0.05), suggesting utility for predicting treatment response. Logistic regression modeling suggested that a 0.5 unit decrease in log(MI), which is approximately one IQR of the pre-treatment log(MI) values, results in a 6-fold increase in odds of positive treatment response. SignificanceMI reflects short-term treatment response and is a candidate predictive EEG biomarker for IESS. MI may offer individualized insights for treatment selection and management strategies for IESS. Key Points BoxO_LIInfantile epileptic spasms syndrome (IESS) is associated with high phase-amplitude coupling (PAC) that decreases with treatment C_LIO_LILow pre-treatment values of EEG PAC are predictive of positive short-term treatment response for IESS C_LIO_LIThe results were strongest when PAC was measured using the modulation index, as this method is known to be robust to noise C_LI

neuroscience↗

bioRxiv2025

The Analgesic and Dissociative Properties of Ketamine are Separate and Correspond to Distinct Neural Mechanisms

Ketamine, a psychoactive medication, exerts both analgesic and dissociative effects. However, whether its analgesic effect stems from its dissociative properties is a topic of debate. Our study aimed to determine whether ketamines analgesic and dissociative effects are supported by distinct neural mechanisms. In a within-subject, placebo-controlled study, 37 healthy volunteers were administered ketamine (0.4 mg/kg bolus followed by a continuous drip of 0.4 mg/kg/h) or saline during fMRI sessions where thermal pain was induced. Our results indicate that while ketamine significantly reduced thermal pain ratings and produced robust dissociative effects, these outcomes were not correlated. Neurally, ketamine reduced pain-related brain activations across a network of regions, including the insula and anterior cingulate cortex. Additionally, ketamine significantly diminished functional connectivity between default mode network regions, and this reduction was correlated with the intensity of dissociation. These findings suggest that ketamines analgesic and dissociative effects are independent and mediated by distinct neural pathways.

neuroscience↗

bioRxiv2025

A multi-institutional investigation of psilocybin's effects on mouse behavior

Studies reporting novel therapeutic effects of psychedelic drugs are rapidly emerging. However, the reproducibility and reliability of these findings could remain uncertain for years. Here, we implemented a multi-institutional collaborative approach to define the robust and replicable effects of the psychedelic drug psilocybin on mouse behavior. Five laboratories performed the same experiments to test the acute and persistent effects of psilocybin (2 mg/kg, IP) on various behaviors that psychedelics have been proposed to affect, including anxiety-related approach-avoidance, exploration, sociability, depression-related behaviors, fear extinction, and social reward learning. Through this coordinated approach, we found that psilocybin had several robust and replicable acute effects on mouse behavior, including increased anxiety- and avoidance-related behaviors and decreased fear expression. Surprisingly, however, we found that psilocybin did not have replicable effects 24 hours post psilocybin administration on reducing anxiety- and depression-like behaviors or facilitating fear extinction learning. Additionally, we were unable to observe psilocybin-induced alterations in social preference or social reward learning. Overall, our comprehensive characterization of psilocybins acute and persistent behavioral effects using [~]200 total male and female mice per experiment spread across five independent labs demonstrates with unique certainty several acute drug effects and suggests that psilocybins persistent effects in mice may be more modest and inconsistent than previously suggested. We believe this unusual multi-laboratory, highly coordinated research effort serves as a model for facilitating the generation of replicable results and consequently will reduce efforts based on unreliable and spurious results.

neuroscience↗

bioRxiv2024

Integrated Single-Cell Multiomic Profiling of Caudate Nucleus Suggests Key Mechanisms in Alcohol Use Disorder

Alcohol use disorder (AUD) induces complex transcriptional and regulatory changes across multiple brain regions including the caudate nucleus, which remains understudied. Using paired single-nucleus RNA-seq and ATAC-seq on caudate samples from 143 human postmortem brains, including 74 with AUD, we identified 17 distinct cell types. We found that a significant portion of the alcohol-induced changes in gene expression occurred through altered chromatin accessibility. Notably, we identified novel transcriptional and chromatin accessibility differences in medium spiny neurons, impacting pathways such as RNA metabolism and immune response. A small cluster of D1/D2 hybrid neurons showed distinct differences, suggesting a unique role in AUD. Microglia exhibited distinct activation states deviating from classical M1/M2 designations, and astrocytes entered a reactive state partially regulated by JUND, affecting glutamatergic synapse pathways. Oligodendrocyte dysregulation, driven in part by OLIG2, was linked to demyelination and increased TGF-{beta}1 signaling from microglia and astrocytes. We also observed increased microglia-astrocyte communication via the IL-1{beta} pathway. Leveraging our multiomic data, we performed cell type-specific expression quantitative trait loci analysis, integrating that with public genome-wide association studies to identify AUD risk genes such as ADAL and PPP2R3C, providing a direct link between genetic variants, chromatin accessibility, and gene expression in AUD. These findings not only provide new insights into the genetic and cellular mechanisms in the caudate related to AUD but also demonstrate the broader utility of large-scale multiomic studies in uncovering complex gene regulation across diverse cell types, which has implications beyond the substance use field.

neuroscience↗

bioRxiv2022

Preparing future STEM faculty nationwide through flexible teaching professional development

We report on a five-year initiative that has prepared thousands of future STEM faculty around the world to adopt evidence-based instructional practices by participating in two massive open online courses (MOOCs) and facilitated in-person learning communities. This novel combination of asynchronous online and coordinated, structured face-to-face learning community experiences provides flexible options for STEM graduate students and postdoctoral fellows to pursue teaching professional development, while leveraging the affordances of educational technologies and the geographically clustered nature of this target learner demographic. A total of 14,977 participants enrolled in seven offerings of the introductory course held 2014-2018, with 1,725 participants from approximately 60 countries completing at an average course completion rate of 13%. The preparation of future STEM faculty makes an important difference in establishing high-quality instruction that meets the diverse needs of all undergraduate students, and the initiative described here can serve as a model for increasing access to such preparation.

scientific communication and education↗

bioRxiv2021

Phylogenetic network analysis revealed the recombinant origin of the SARS-CoV-2 VOC202012/01 (B.1.1.7) variant first discovered in U.K.

The emergence of new variants of the SARS-CoV-2 virus poses serious problems to the control of the current COVID-19 pandemic. Understanding how the variants originate is critical for effective control of the spread of the virus and the global pandemic. The study of the virus evolution so far has been dominated by phylogenetic tree analysis, which however is inappropriate for a few important reasons. Here we used phylogenetic network approach to study the origin of the VOC202012/01 (Alpha) or so-called UK variant (PANGO Lineage B.1.1.7). The multiple network analyses using different methods consistently revealed that the VOC202012/01 variant was a result of recombination, in contrast to the common assumption that the variant evolved from step-wise mutations in a linear order. The study provides an example for the power and application of phylogenetic network analysis in studying virus evolution, which can be applied to study the evolutionary processes leading to the emergence of other variants of the SARS-CoV-2 virus as well as many other viruses. SignificanceThe emergence of new variants of the SARS-CoV-2 virus, including the Alpha variant first found in U.K., poses serious challenges to the control of the current COVID-19 pandemic. Understanding how new variant originated is paramount to end the pandemic as effectively and quickly as possible. The dominant phylogenetic tree approach to study virus evolution has been inadequate and even misleading. Here we used a phylogenetic network approach to study the origin of the VOC202012/01 (Alpha) variant which was first reported in U.K. last year but has soon spread into many other countries, leading to dramatic increase in infection and death. Multiple analyses consistently revealed that the variant originated through recombination of pre-existing virus strains, highlighting an important but largely ignored mechanism in the evolution of the SARS-CoV-2 virus so far.

microbiology↗

bioRxiv2020

Effective in-vitro inactivation of SARS-CoV-2 by commercially available mouthwashes

Infectious SARS-CoV-2 can be recovered from the oral cavities and saliva of COVID-19 patients with potential implications for disease transmission. Reducing viral load in patient saliva using antiviral mouthwashes may therefore have a role as a control measure in limiting virus spread, particularly in dental settings. Here, the efficacy of SARS-CoV-2 inactivation by seven commercially available mouthwashes with a range of active ingredients were evaluated in vitro. We demonstrate [≥]4.1 to [≥]5.5 log10 reduction in SARS-CoV-2 titre following a one minute treatment with commercially available mouthwashes containing 0.01-0.02% stabilised hypochlorous acid or 0.58% povidone iodine, and non-specialist mouthwashes with both alcohol-based and alcohol-free formulations designed for home use. In contrast, products containing 1.5% hydrogen peroxide or 0.2% chlorhexidine gluconate were ineffective against SARS-CoV-2 in these tests. This study contributes to the growing body of evidence surrounding virucidal efficacy of mouthwashes/oral rinses against SARS-CoV-2, and has important applications in reducing risk associated with aerosol generating procedures in dentistry and potentially for infection control more widely.

microbiology↗

bioRxiv2020

The complete genome sequence of the Staphylococcus bacteriophage Metroid

Phages infecting bacteria of the genus Staphylococcus play an important role in their hosts ecology and evolution. On one hand, horizontal gene transfer from phage can encourage the rapid adaptation of pathogenic Staphylococcus enabling them to escape host immunity or access novel environments. On the other hand, lytic phages are promising agents for the treatment of bacterial infections, especially those resistant to antibiotics. As part of an ongoing effort to gain novel insights into bacteriophage diversity, we characterized the complete genome of the Staphylococcus bacteriophage Metroid, a cluster C phage with a genome size of 151kb, encompassing 254 predicted protein-coding genes as well as 4 tRNAs. A comparative genomic analysis highlights strong similarities - including a conservation of the lysis cassette - with other Staphylococcus cluster C1 bacteriophages, several of which were previously characterized for therapeutic applications.

genomics↗

bioRxiv2019

Species-level microbiome composition of activated sludge - introducing the MiDAS 3 ecosystem-specific reference database and taxonomy

The function of microbial communities in wastewater treatment systems and anaerobic digesters is dictated by the physiological activity of its members and complex interactions between them. Since functional traits are often conserved at low taxonomic ranks (genus, species, strain), the development of high taxonomic resolution and reliable classification is the first crucial step towards understanding the role of microbes in any ecosystem. Here we present MiDAS 3, a comprehensive 16S rRNA gene reference database based on high-quality full-length sequences derived from activated sludge and anaerobic digester systems. The MiDAS 3 taxonomy proposes unique provisional names for all microorganisms down to species level. MiDAS 3 was applied for the detailed analysis of microbial communities in 20 Danish wastewater treatment plants with nutrient removal, sampled over 12 years, demonstrating community stability and many abundant core taxa. The top 50 most abundant species belonged to genera, of which >50% have no known function in the system, emphasizing the need for more efforts towards elucidating the role of important members of wastewater treatment ecosystems. The MiDAS 3 taxonomic database guided an update of the MiDAS Field Guide - an online resource linking the identity of microorganisms in wastewater treatment systems to available data related to their functional importance. The new field guide contains a complete list of genera (>1,800) and species (>4,200) found in activated sludge and anaerobic digesters. The identity of the microbes is linked to functional information, where available. The website also provides the possibility to BLAST the sequences against MiDAS 3 taxonomy directly online. The MiDAS Field Guide is a collaborative platform acting as an online knowledge repository and facilitating understanding of wastewater treatment ecosystem function.

microbiology↗

bioRxiv2018

A simian-adenovirus-vectored rabies vaccine suitable for thermostabilisation and clinical development for low-cost single-dose pre-exposure prophylaxis

BackgroundEstimates of current global rabies mortality range from 26,000 to 59,000 deaths per annum. Although pre-exposure prophylaxis using inactivated rabies virus vaccines (IRVs) is effective, it requires two to three doses and is regarded as being too expensive and impractical for inclusion in routine childhood immunization programmes.\n\nMethodology/ Principal FindingsHere we report the development of a simian-adenovirus-vectored rabies vaccine intended to enable cost-effective population-wide pre-exposure prophylaxis against rabies. ChAdOx2 RabG uses the chimpanzee adenovirus serotype 68 (AdC68) backbone previously shown to achieve pre-exposure protection against rabies in non-human primates. ChAdOx2 differs from AdC68 in that it contains the human adenovirus serotype 5 (AdHu5) E4 orf6/7 region in place of the AdC68 equivalents, enhancing ease of manufacturing in cell lines which provide AdHu5 E1 proteins in trans.\n\nWe show that immunogenicity of ChAdOx2 RabG in mice is comparable to that of AdC68 RabG and other adenovirus serotypes expressing rabies virus glycoprotein. High titers of rabies virus neutralizing antibody (VNA) are elicited after a single dose. The relationship between levels of VNA activity and rabies glycoprotein monomer-binding antibody differs after immunization with adenovirus-vectored vaccines and IRV vaccines, suggesting routes to further enhancement of the efficacy of the adenovirus-vectored candidates. We also demonstrate that ChAdOx2 RabG can be thermostabilised using a low-cost method suitable for clinical bio-manufacture and ambient-temperature distribution in tropical climates. Finally, we show that a dose-sparing effect can be achieved by formulating ChAdOx2 RabG with a simple chemical adjuvant. This approach could lower the cost of ChAdOx2 RabG and other adenovirus-vectored vaccines.\n\nConclusions/ SignificanceChAdOx2 RabG may prove to be a useful tool to reduce the human rabies death toll. We have secured funding for Good Manufacturing Practice-compliant bio-manufacture and Phase I clinical trial of this candidate.\n\nAuthor summaryRabies was, after smallpox, the second human disease for which an efficacious vaccine was developed, by Pasteur in 1885. Although it is eminently preventable, with highly efficacious vaccines available for both humans and animals, it still causes considerable mortality in low and middle-income countries. It is a particular problem in areas with the weakest healthcare and veterinary infrastructure, where achieving prompt post-exposure vaccination or high-coverage dog vaccination are challenging.\n\nHere, we report the development of a new candidate rabies vaccine, designed to enable low-cost single-dose pre-exposure human rabies prophylaxis in such settings. ChAdOx2 RabG is based upon a simian adenovirus-vectored candidate previously shown to achieve protection after a single dose in non-human primates, now modified to allow clinical-grade bio-manufacture. We show that it induces a potent immune response in mice, that this response can be further enhanced by clinically-relevant adjuvant, and that we can stabilise it such that it can withstand temperatures of up to 45 {degrees}C for a month. We will be performing a clinical trial of this candidate in the near future.

immunology↗

bioRxiv2018

An Ishihara-style test of animal colour vision

O_LIColour vision mediates ecologically relevant tasks for many animals, such as mate choice, foraging and predator avoidance. However, our understanding of animal colour perception is largely derived from human psychophysics, even though animal visual systems differ from our own. Behavioural tests of non-human animals are required to understand how colour signals are perceived by them.\nC_LIO_LIHere we introduce a novel test of colour vision in animals inspired by the Ishihara colour charts, which are widely used to identify human colour deficiencies. These charts consist of dots that vary in colour, brightness and size, and are designed so that a numeral or letter is distinguishable from distractor dots for humans with normal colour vision. In our method, distractor dots have a fixed chromaticity (hue and saturation) but vary in luminance. Animals can be trained to find single target dots that differ from distractor dots in chromaticity. We provide Matlab code for creating these stimuli, which can be modified for use with different animals.\nC_LIO_LIWe demonstrate the success of this method with triggerfish, Rhinecanthus aculeatus, and highlight behavioural parameters that can be measured, including success of finding the target dot, time to detect dot and error rate. Triggerfish quickly learnt to select target dots that differed from distractors dots regardless of the particular hue or saturation, and proved to use acute colour vision. We measured discrimination thresholds by testing the detection of target colours that were of increasing colour distances ({Delta}S) from distractor dots in different directions of colour space. At least for some colours, thresholds indicated better discrimination than expected from the Receptor Noise Limited (RNL) model assuming 5% Weber fraction for the long-wavelength cone.\nC_LIO_LIThis methodology seems to be highly effective because it resembles natural foraging behavior for the triggerfish and may well be adaptable to a range of other animals, including mammals, birds, bees and freshwater fish. Other questions may be addressed using this methodology, including luminance thresholds, sensory bias, effects of sensory noise in detection tasks, colour categorization and saliency.\nC_LI

animal behavior and cognition↗

bioRxiv2017

A National Estimate of the Health and Cost Burden of Escherichia coli Bacteraemia in the Hospital Setting: The Importance of Antibiotic Resistance.

BackgroundAntibiotic resistance poses a threat to public health and a burden to healthcare systems. Escherichia coli causes more bacteraemia cases in England than any other bacterial species, these infections, in part due to their high incidence, also pose a significant antibiotic resistance burden. The main aim of this study was to estimate the impact of E. coli bacteraemia on patient in-hospital mortality and length of stay. Secondarily, this study also aimed to estimate the effect of antibiotic resistance on these outcomes.\n\nMethods and FindingsCase patients were adult E. coli bacteraemia patients infected between July 2011 and June 2012, as reported in an English national mandatory surveillance database, with susceptibility data taken from a national laboratory surveillance database. Control patients were all non-case, adult patients with an English hospital admission record. Case and control patient characteristics and admission information were taken from NHS Digital Datasets. Resistance was defined as non-susceptible and intermediate isolates, whilst susceptible was defined as susceptible and non-tested isolates. Time to in-hospital mortality and discharge was investigated through Cox proportional hazards models. To acquire estimates of excess length of stay, multistate models were constructed, with a unit bed day cost applied to estimate cost burden. The total number of case and control hospital spells was 14,051 and 8,919,275 respectively. Acquisition of E. coli bacteraemia was associated with a statistically significant increased daily risk of in-hospital mortality, especially for the first eight days of someones hospital admission [Hazard Ratio = 2.77 (95% confidence interval; 2.61-2.94)]. Antibiotic resistance did not seem to significantly increase this risk further, though did significantly reduce risk of experiencing a discharge event (dead or alive). E.coli bacteraemia was estimated to cost {pound}14,340,900 over the study period (rounded to the nearest {pound}100), with resistance associated with excess costs per infection of {pound}220 - {pound}420 dependent on resistance type, for those where a significant impact was found (rounded to the nearest {pound}10).\n\nConclusionsE. coli bacteraemia places a significant burden on patient health and on the hospital sector in England. Resistance is an important factor on length of stay with regards to such infections.

epidemiology↗