Biology subjects

Rice, A.

Publications and source records attributed to Rice, A..

18 recordsLinked to original sources

bioRxiv2026

Disrupted RGS coupling underlies a clinically distinct subset of GNAO1-related disorder

Heterotrimeric G proteins are transducers for a wide variety of neurotransmitter receptors. Mutations in the G protein o subunit are implicated in an early-onset neurological condition, GNAO1-related disorder, that manifests as movement disorders, developmental delays, and/or epileptic seizures. In a screen of disease-linked mutations in Go, we identified a subset that had no obvious biochemical defects, warranting further investigation. By structural modeling, protein-protein binding experiments in vitro and in cells, as well as measures of downstream ion channel electrophysiology, we identified a subset that impairs interactions with regulator of G protein signaling (RGS) proteins. RGS proteins accelerate G protein GTPase activity and are therefore critical for proper neurotransmitter signaling. Further, synthesis of current clinical data revealed that patients harboring these variants have comparatively mild symptoms. Our study demonstrates the importance of RGS regulation in G protein function, cell signaling, and human neurobiology.

biochemistry↗

bioRxiv2026

Systematic evidence map of research on life-history traits in native and introduced earthworms

Invasive species constitute one of the most significant threats to biodiversity worldwide, and are responsible for more than $400 billion in losses each year. An organism's life-history strategy, defined by how it allocates resources among growth, survival, and reproduction, plays a central role in determining whether it becomes invasive. While the life-history profiles of aboveground invaders are increasingly well characterised, those of invasive species below ground remain poorly understood. Earthworms are a diverse group of soil invertebrates that can help fill this knowledge gap. Of the ~5,800 earthworm species described to date, nearly 2% are cosmopolitan, meaning they have achieved wide geographic distributions despite limited ability for active dispersal. While life-history traits are likely to contribute to their worldwide distribution, the existing research on earthworm trait variation has not been systematically reviewed. To address this gap, we assessed the taxonomic scope, geographic coverage, and methodologies of studies on earthworm life history traits for species occurring in the US and Brazil, spanning a broad latitudinal range. Our literature search yielded over 8,000 articles across 180 species and revealed that introduced species have received considerably more research attention than native species. Research was concentrated on a few model species, most studies were experimental, and variation in life history traits was most commonly assessed in response to chemical compounds, vermicompost feed type, and environmental factors such as temperature, moisture and soil composition. Variation in adult survival was reported most frequently, followed by adult growth and cocoon production, with the bulk of life history research conducted in India (20%) and China (9%). To better understand the effect invasive earthworm species might have on native fauna, future research on life histories should address taxonomic biases and prioritise detailed study of the life cycles of native species in their natural habitat.

ecology↗

bioRxiv2026

Sparse Stimulus Generation Improves Reverse Correlation Efficiency and Interpretability

Reverse correlation is a widely-used and well-established method for probing latent perceptual representations in which subjects render subjective preference responses to ambiguous stimuli. Stimuli are purposefully designed to have no direct relationship with the target representation (e.g., they are randomly-generated), a property which makes each individual stimulus minimally informative toward reconstructing the target, and often difficult to interpret for subjects. As a result, a large number of stimulus-response pairs must be gathered from a given subject in order for reconstructions to be of sufficient quality, making the task fatiguing. Recent work has demonstrated that the number of trials needed can be substantially reduced using a compressive sensing framework that incorporates the assumption that the target representation can be sparsely represented in some basis into the reconstruction process. Here, we introduce an alternative method that incorporates the sparsity assumption directly into stimulus generation, which holds promise not only for improving efficiency, but also for improving the interpretability of stimuli from subjects perspective. We develop this new method as a mathematical variation of the compressive sensing approach, before conducting one simulation study and two human subjects experiments to assess the benefits of this method to reconstruction quality, sample size efficiency, and subjective interpretability. Results show that sparse stimulus generation improves all three of these areas relative to conventional reverse correlation approaches, and also relative to compressive sensing in most conditions.

neuroscience↗

bioRxiv2026

Context-dependent determinants of CRISPR-Cas9 editing efficiency revealed through cross-species endogenous editing analysis

Accurate prediction of CRISPR-Cas9 guide RNA (gRNA) editing efficiency remains limited, particularly outside human systems, where models trained on exogenous human datasets show poor generalization. We analyzed Cas9 efficiency and repair outcomes using novel endogenous editing data from four human cell types, two tomato cell types, and cells from giant river prawn and black soldier fly. While integrating publicly available predictors via ensemble frameworks improved performance, our analysis revealed hundreds of novel features affecting activity. Crucially, dominant features related to sites competition for gRNA, and local geometric properties varied across systems, highlighting the strong context dependence of Cas9 efficiency and arguing against a universal model. Interestingly, codon usage bias-based features also emerged as informative predictors, as they are proxies for chromatin accessibility. In contrast, trends in repair outcomes remained conserved. This work provides essential resources for more generalizable CRISPR guide design.

synthetic biology↗

bioRxiv2026

Lunar gravity predicts sleep timing

Biological rhythms are fundamental to survival, synchronizing physiological and behavioural processes like the sleep-wake cycle with predictable environmental cycles like the solar day1. However, the extent to which human sleep responds to the lunar cycle remains a subject of controversy, particularly given the ubiquity of artificial light and conflicting reports regarding the influence of moonlight2-5. While lunar illuminance has been the primary candidate for such modulation, it fails to account for semilunar rhythms2,6 or effects observed during the dark new moon phase2,7. Here, we show that human and non-human primate sleep timing is synchronized with the gravimetric cycles exerted by the Moon and Sun. By analysing longitudinal actigraphic recordings from urban cohorts in Seattle, indigenous Toba/Qom communities in Argentina, and captive titi monkeys with attenuated access to natural light, we found that sleep onset is consistently delayed around periods of maximal gravitational variations. Crucially, this synchronization aligns with gravimetric peaks regardless of whether they occur at the full or new moon. Furthermore, while human sleep timing is heavily influenced by social constraints and self-selected light exposure, this synchronization persists in titi monkeys, in which these confounds are absent. These findings identify lunar gravity as a distinct environmental cue that may regulate sleep-wake behaviour. Although this regulation may be mediated by other geophysical factors oscillating with lunisolar gravitational tides, the results suggest that the mechanism is an evolutionarily conserved trait that shapes biological timing beyond the influence of light.

animal behavior and cognition↗

bioRxiv2025

Sleep in People Experiencing Homelessness Under Different Conditions and Seasons

Poor sleep represents a central health disparity for people experiencing homelessness, and any intervention to alleviate the impacts of homelessness should aim to improve sleep. We measured actimetry-based sleep in homeless adults spending their nights in four types of shelters in Seattle, WA, during the summer and winter. Homeless participants experienced more sleepless nights than housed participants in both seasons. During the summer sleeping nights, homeless participants experienced sleep patterns similar to housed subjects, but during the winter, their sleep duration was up to 1.5 hours shorter. Similarly, sleep quality, determined through sleep variability index, activity during the night, and intraindividual variability of sleep parameters, was poorer during the winter in homeless than in housed participants. Our study demonstrates the feasibility of using objectively measured sleep as a proxy for assessing the value of specific interventions to improve living conditions in people experiencing homelessness. Given the bidirectional relationship between sleep and both physical and mental health, our study reveals the health inequities of chronic sleep disparity for those living outdoors. Significance statementSleep disparities are central to the poor physical and mental health experienced by houseless people. Here we show that measured sleep through wrist actigraphy captures different aspects of this sleep disparity and represents a useful, objective metric of the impact of interventions to improve living conditions among people experiencing homelessness.

physiology↗

bioRxiv2025

Peptidic tryptophan halogenation by a promiscuous flavin-dependent enzyme

Amino acids undergo numerous enzymatic modifications. However, the broad applicability of amino acid-modifying enzymes for synthetic purposes is limited by narrow substrate scope and often unknown regulatory or accessory factor requirements. Here, we characterize ChlH, a flavin-dependent halogenase (FDH) from the chlorolassin biosynthetic gene cluster. Unlike characterized peptide-modifying FDHs, which are limited to either specifically modified peptides or the termini of linear peptides, ChlH halogenates internal Trp residues of linear peptides, as well as N- and C-terminal Trp. Scanning mutagenesis of the substrate peptide ChlA revealed Trp was tolerated by ChlH at nearly every position. Molecular dynamics simulations corroborated the importance of a C-terminal motif in ChlA and provided insight into the lack of Trp14 chlorination in native chlorolassin. Furthermore, halogenation of disparate ribosomally synthesized and post-translationally modified peptide (RiPP) precursor peptides, pharmacologically relevant peptides, and an internal Trp of a protein was achieved using wild-type ChlH. A rapid cell-free biosynthetic assay provided insight into ChlHs preferences. In contrast to characterized FDHs, ChlH halogenates diverse peptide sequences, and we predict this promiscuity may find utility in the modification of additional peptide and protein substrates of biotechnological value. Entry for the Table of ContentsChlH, a flavin-dependent tryptophan halogenase, is reconstituted in vitro and found to be capable of modifying a wide array of diverse peptidic substrates despite showing selectivity on its native substrate peptide ChlA. This highlights its potential use in the biocatalytic production of chlorinated peptides. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=93 SRC="FIGDIR/small/632611v2_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@897b21org.highwire.dtl.DTLVardef@1f2bafborg.highwire.dtl.DTLVardef@d1e800org.highwire.dtl.DTLVardef@d68381_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2024

Nutribloods: novel synthetic lepidopteran haemolymphs for understanding insect-microbe interactions in vitro

Understanding the role of nutrients in microbial population dynamics relies on a sound appreciation of their nutritional environment and how this may vary in different habitats. For microbial pathogens and commensals, this can be especially challenging because the microbe may share nutritional resources with its host. Here we design a series of 20 synthetic haemolymphs (nutribloods) that mimic haemolymph nutrient profiles of caterpillars fed on one of 20 chemically-defined diets, that vary in their protein:carbohydrate (P:C) ratio and caloric density. Using these, we are able to simulate the range of nutritional conditions that insect blood pathogens might face, providing a model system for understanding the role of nutrition in microbial growth. We tested this using the entomopathogen, Xenorhabdus nematophila, a gram-positive extracellular bacterium of insect hosts. This revealed that whilst bacterial fitness peaked in nutriblood nutrient space that was high in carbohydrates and low in proteins, levels of amino acids in the nutribloods also appear to be an important driving force for bacterial growth. Using synthetic haemolymphs that had average levels of all nutrients other than carbohydrate, protein or amino acids, we also established that bacterial growth is generally enhanced by carbohydrate and amino acids but reduced by proteins. Here, we have established a tractable model system for examining the role that nutrition plays in the growth of an entomopathogenic bacterium. In future work, this model host-pathogen system can be used to test a range of nutritionally-driven processes, including competition during co-infection and interactions with the host microbiome, as well as comparative studies of other entomopathogens.

physiology↗

bioRxiv2022

Lung extracellular matrix modulates KRT5+ basal cell activity in pulmonary fibrosis

Aberrant expansion of KRT5+ basal cells in the distal lung accompanies progressive alveolar epithelial cell loss and tissue remodelling during fibrogenesis in idiopathic pulmonary fibrosis (IPF). The mechanisms determining activity of KRT5+ cells in IPF have not been delineated. Here, we reveal a potential mechanism by which KRT5+ cells migrate within the fibrotic lung, navigating regional differences in collagen topography. In vitro, KRT5+ cell migratory characteristics and expression of remodelling genes are modulated by extracellular matrix (ECM) composition and organisation. Mass spectrometry-based proteomics revealed compositional differences in ECM components secreted by primary human lung fibroblasts (HLF) from IPF patients compared to controls. Over-expression of ECM glycoprotein, Secreted Protein Acidic and Cysteine Rich (SPARC) in the IPF HLF matrix restricts KRT5+ cell migration in vitro. Together, our findings demonstrate how changes to the ECM in IPF directly influence KRT5+ cell behaviour and function contributing to remodelling events in the fibrotic niche.

cell biology↗

bioRxiv2022

Towards generalizable prediction of antibody thermostability using machine learning on sequence and structure features

Over the last three decades, the appeal for monoclonal antibodies (mAbs) as therapeutics has been steadily increasing as evident with FDAs recent landmark approval of the 100th mAb. Unlike mAbs that bind to single targets, multispecific biologics (bsAbs) with their single-chain variable fragment (scFv) modules have garnered particular interest owing to the advantage of engaging distinct targets. Despite their exquisite specificity and affinity, the relatively poor thermostability of these scFv modules often hampers their development as a potential therapeutic drug. In recent years, engineering antibody sequences to enhance their stability by mutations has gained considerable momentum. As experimental methods for antibody engineering are time-intensive, laborious, and expensive, computational methods serve as a fast and inexpensive alternative to conventional routes. In this work, we show two machine learning methods - one with pre-trained language models (PTLM) capturing functional effects of sequence variation, and second, a supervised convolutional neural network (CNN) trained with Rosetta energetic features - to better classify thermostable scFv variants from sequence. Both these models are trained over temperature-specific data (TS50 measurements) derived from multiple libraries of scFv sequences. In this work, we show that a sufficiently simple CNN model trained with energetic features generalizes better than a pre-trained language model on out-of-distribution (blind) sequences (average Spearman correlation coefficient of 0.4 as opposed to 0.15). Further, we demonstrate that for an independent mAb with available thermal melting temperatures for 20 experimentally characterized thermostable mutations, these models trained on TS50 data could identify 18 residue positions and 5 identical amino-acid mutations showing remarkable generalizability. Our results suggest that such models can be broadly applicable for improving the biological characteristics of antibodies. Further, transferring such models for alternative physico-chemical properties of scFvs can have potential applications in optimizing large-scale production and delivery of mAbs or bsAbs.

bioinformatics↗

bioRxiv2021

Heterologous Vaccination with SARS-CoV-2 Spike saRNA Prime followed by DNA Dual-Antigen Boost Induces Robust Antibody and T-Cell Immunogenicity against both Wild Type and Delta Spike as well as Nucleocapsid Antigens

We assessed if immune responses are enhanced in CD-1 mice by heterologous vaccination with two different nucleic acid-based COVID-19 vaccines: a next-generation human adenovirus serotype 5 (hAd5)-vectored dual-antigen spike (S) and nucleocapsid (N) vaccine (AdS+N) and a self-amplifying and -adjuvanted S RNA vaccine (SASA S) delivered by a nano-lipid carrier. The AdS+N vaccine encodes S modified with a fusion motif to increase cell-surface expression. The N antigen is modified with an Enhanced T-cell Stimulation Domain (N-ETSD) to direct N to the endosomal/lysosomal compartment and increase MHC class I and II stimulation potential. The S sequence in the SASA S vaccine comprises the D614G mutation, two prolines to stabilize S in the prefusion conformation, and 3 glutamines in the furin cleavage region to increase cross-reactivity across variants. CD-1 mice received vaccination by homologous and heterologous prime > boost combinations. Humoral responses to S were the highest with any regimen including the SASA S vaccine, and IgG bound to wild type and Delta (B.1.617.2) variant S1 at similar levels. An AdS+N boost of an SASA S prime particularly enhanced both CD4+ and CD8+ T-cell responses to both wild type and Delta S peptides relative to all other vaccine regimens. Sera from mice receiving SASA S homologous or heterologous vaccination were found to be highly neutralizing of all pseudovirus strains tested: Wuhan, Beta, Delta, and Omicron strain. The findings here support the clinical testing of heterologous vaccination by an SASA S > AdS+N regimen to provide increased protection against emerging SARS-CoV-2 variants.

immunology↗

bioRxiv2021

Condensation of the influenza viral fusion peptide alters membrane structure and water permeability

To infect, enveloped viruses employ spike protein, spearheaded by its amphipathic fusion peptide (FP), that upon activation extends out from the viral surface to embed into the target cellular membrane. Here we report that synthesized influenza virus FP are membrane active, generating pores in giant unilamellar vesicles (GUV), and thus potentially explain both influenza virus hemolytic activity and the liposome poration seen in cryo-electron tomography. Experimentally, FP were heterogeneously distributed on the GUV at the time of poration. Consistent with this heterogeneous distribution, molecular dynamics (MD) simulations of asymmetric bilayers with different numbers of FP in one leaflet show FP aggregation. At the center of FP aggregates, a profound change in the membrane structure results in thinning, higher water permeability, and curvature. Ultimately, a hybrid bilayer nanodomain can form with one lipidic leaflet and one peptidic leaflet. Membrane elastic theory predicts a reduced barrier to water pore formation when even a dimer of FP thins the membrane as above, and the FP of that dimer tilts, to continue the leaflet bending initiated by the hydrophobic mismatch between the FP dimer and the surrounding lipid.

biophysics↗

bioRxiv2021

The Dual-Antigen Ad5 COVID-19 Vaccine Delivered as an Intranasal Plus Subcutaneous Prime Elicits Th1 Dominant T-Cell and Humoral Responses in CD-1 Mice

In response to the need for an efficacious, thermally-stable COVID-19 vaccine that can elicit both humoral and cell-mediated T-cell responses, we have developed a dual-antigen human adenovirus serotype 5 (hAd5) COVID-19 vaccine in formulations suitable for subcutaneous (SC), intranasal (IN), or oral delivery. The vaccine expresses both the SARS-CoV-2 spike (S) and nucleocapsid (N) proteins using an hAd5 platform with E1, E2b, and E3 sequences deleted (hAd5[E1-, E2b-, E3-]) that is effective even in the presence of hAd5 immunity. In the vaccine, S is modified (S-Fusion) for enhanced cell-surface display to elicit humoral responses and N is modified with an Enhanced T-cell Stimulation Domain (N-ETSD) to direct N to the endosomal/lysosomal pathway to increase MHC I and II presentation. Initial studies using subcutaneous (SC) prime and SC boost vaccination of CD-1 mice demonstrated that the hAd5 S-Fusion + N-ETSD vaccine elicits T-helper cell 1 (Th1) dominant T-cell and humoral responses to both S and N. We then compared SC to IN prime vaccination with either an SC or IN boost post-SC prime and an IN boost after IN prime. These studies reveal that IN prime/IN boost is as effective at generating Th1 dominant humoral responses to both S and N as the other combinations, but that the SC prime with either an IN or SC boost elicits greater T cell responses. In a third study to assess the power of the two routes of delivery when used together, we used a combined SC plus IN prime with or without a boost and found the combined prime alone to be as effective as the combined prime with either an SC or IN boost in generating both humoral and T-cell responses. The findings here in CD-1 mice demonstrate that combined SC and IN prime-only delivery has the potential to provide broad immunity - including mucosal immunity - against SARS-CoV-2 and supports further testing of this delivery approach in additional animal models and clinical trials.

immunology↗

bioRxiv2020

Complete Protection of Nasal and Lung Airways Against SARS-CoV-2 Challenge by Antibody Plus Th1 Dominant N- and S-Specific T-Cell Responses to Subcutaneous Prime and Thermally-Stable Oral Boost Bivalent hAd5 Vaccination in an NHP Study

We have developed a dual-antigen COVID-19 vaccine incorporating genes for a modified SARS-CoV-2 spike (S-Fusion) protein and the viral nucleocapsid (N) protein with an Enhanced T-cell Stimulation Domain (N-ETSD) with the potential to increase MHC class I/II responses. The adenovirus serotype 5 platform used, hAd5 [E1-, E2b-, E3-], previously demonstrated to be effective in the presence of Ad immunity, can be delivered in an oral formulation that overcomes cold-chain limitations. The hAd5 S-Fusion + N-ETSD vaccine was evaluated in rhesus macaques showing that a subcutaneous prime followed by oral boosts elicited both humoral and Th1 dominant T-cell responses to both S and N that protected the upper and lower respiratory tracts from high titer (1 x 106 TCID50) SARS-CoV-2 challenge. Notably, viral replication was inhibited within 24 hours of challenge in both lung and nasal passages, becoming undetectable within 7 days post-challenge. ONE SENTENCE SUMMARYhAd5 spike + nucleocapsid SC prime/oral boost vaccine elicits humoral and T-cell responses and protects rhesus macaques from SARS-CoV-2 challenge.

immunology↗

bioRxiv2020

Model Adequacy Tests for Likelihood Models of Chromosome-Number Evolution

O_LIChromosome number is a central feature of eukaryote genomes. Deciphering patterns of chromosome-number change along a phylogeny is central to the inference of whole genome duplications and ancestral chromosome numbers. ChromEvol is a probabilistic inference tool that allows the evaluation of several models of chromosome-number evolution and their fit to the data. However, fitting a model does not necessarily mean that the model describes the empirical data adequately. This vulnerability may lead to incorrect conclusions when model assumptions are not met by real data. C_LIO_LIHere, we present a model adequacy test for likelihood models of chromosome-number evolution. The procedure allows to determine whether the model can generate data with similar characteristics as those found in the observed ones. C_LIO_LIWe demonstrate that using inadequate models can lead to inflated errors in several inference tasks. Applying the developed method to 200 angiosperm genera, we find that in many of these, the best-fitted model provides poor fit to the data. The inadequacy rate increases in large clades or in those in which hybridizations are present. C_LIO_LIThe developed model adequacy test can help researchers to identify phylogenies whose underlying evolutionary patterns deviate substantially from current modelling assumptions and should guide future methods developments. C_LI

evolutionary biology↗

bioRxiv2020

A Next Generation Bivalent Human Ad5 COVID-19 Vaccine Delivering Both Spike and Nucleocapsid Antigens Elicits Th1 Dominant CD4+, CD8+ T-cell and Neutralizing Antibody Responses

In response to the health crisis presented by the COVID-19 pandemic, rapid development of safe and effective vaccines that elicit durable immune responses is imperative. Recent reports have raised the concern that antibodies in COVID-19 convalescent patients may not be long lasting and thus even these individuals may require vaccination. Vaccine candidates currently in clinical testing have focused on the SARS-CoV-2 wild type spike (S) protein (S-WT) as the major antigen of choice and while pre-clinical and early clinical testing have shown that S elicits an antibody response, we believe the optimal vaccine candidate should be capable of inducing robust, durable T-cell responses as well as humoral responses. We report here on a next generation bivalent human adenovirus serotype 5 (hAd5) vaccine capable of inducing immunity in patients with pre-existing adenovirus immunity, comprising both an S sequence optimized for cell surface expression (S-Fusion) and a conserved nucleocapsid (N) antigen designed to be transported to the endosomal subcellular compartment, with the potential to generate durable immune protection. Our studies suggest that this bivalent vaccine is optimized for immunogenicity as evidenced by the following findings: (i) The optimized S-Fusion displayed improved S receptor binding domain (RBD) cell surface expression compared to S-WT where little surface expression was detected; (ii) the expressed RBD from S-Fusion retained conformational integrity and recognition by ACE2-Fc; (iii) the viral N protein modified with an enhanced T-cell stimulation domain (ETSD) localized to endosomal/lysosomal subcellular compartments for MHC I/II presentation; and (iv) these optimizations to S and N (S-Fusion and N-ETSD) generated enhanced de novo antigen-specific B cell and CD4+ and CD8+ T-cell responses in antigen-naive pre-clinical models. Both the T-cell and antibody immune responses to S and N demonstrated a T-helper 1 (Th1) bias. The antibody responses were neutralizing as demonstrated by two independent SARS-CoV-2 neutralization assays. Based on these findings, we are advancing this next generation bivalent hAd5 S-Fusion + N-ETSD vaccine as our lead clinical candidate to test for its ability to provide robust, durable cell-mediated and humoral immunity against SARS-CoV-2 infection. Further studies are ongoing to explore utilizing this vaccine construct in oral, intranasal, and sublingual formulations to induce mucosal immunity in addition to cell-mediated and humoral immunity. The ultimate goal of an ideal COVID-19 vaccine is to generate long-term T and B cell memory.

immunology↗

bioRxiv2019

Lipopolysaccharide Simulations are Sensitive to Phosphate Charge and Ion Parameterization

The high proportion of lipopolysaccharide (LPS) molecules in the outer membrane of Gram-negative bacteria make it a highly effective barrier to small molecules, antibiotic drugs, and other antimicrobial agents. Given this vital role in protecting bacteria from potentially hostile environments, simulations of LPS bilayers and outer membrane systems represent a critical tool for understanding the mechanisms of bacterial resistance and the development of new antibiotic compounds that circumvent these defenses. The basis of these simulations are parameterizations of LPS, which have been developed for all major molecular dynamics force fields. However, these parameterizations differ in both the protonation state of LPS as well as how LPS membranes behave in the presence of various ion species. To address these discrepancies and understand the effects of phosphate charge on bilayer properties, simulations were performed for multiple distinct LPS chemotypes with different ion parameterizations in both protonated or deprotonated lipid A states. These simulations show that bilayer properties, such as the area per lipid and inter-lipid hydrogen bonding, are highly influenced by the choice of phosphate group charges, cation type, and ion parameterization, with protonated LPS and monovalent cations with modified nonbonded parameters providing the best match to experiments. Additionally, alchemical free energy simulations were performed to determine theoretical pKa values for LPS, and subsequently validated by 31P solid-state NMR experiments. Results from these complementary computational and experimental studies demonstrate that the protonated state dominates at physiological pH, contrary to the deprotonated form modeled by many LPS force fields. In all, these results highlight the sensitivity of LPS simulations to phosphate charge and ion parameters, while offering recommendations for how existing models should be updated for consistency between force fields as well as to best match experiments.

biophysics↗

bioRxiv2018

Automation of citation screening in pre-clinical systematic reviews

BackgroundThe amount of published in vivo studies and the speed researchers are publishing them make it virtually impossible to follow the recent development in the field. Systematic review emerged as a method to summarise and analyse the studies quantitatively and critically but it is often out-of-date due to its lengthy process. MethodWe invited five machine learning and text-mining groups to build classifiers for identifying publications relevant to neuropathic pain (33814 training publications). We kept 1188 publications for the assessment of the performance of different classifiers. Two groups participated in the next stage: testing their algorithm on datasets labeled for psychosis (11777/2944) and datasets labeled for Vitamin D in multiple sclerosis (train/text: 2038/510). ResultThe performances (sensitive/specificity) of the most promising classifier built for neuropathic pain are: 95%/84%. The performance for psychosis and Vitamin D in multiple sclerosis datasets are 95%/73% and 100%/45%. ConclusionsMachine learning can significantly reduce the irrelevant publications in a systematic review, and save the scientists time and money. Classifier algorithms built for one dataset can be reapplied on another dataset in different field. We are building a machine learning service at the back of Systematic Review & Meta-analysis Facility (SyRF).

scientific communication and education↗