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Williams, S.

Publications and source records attributed to Williams, S..

At least 91 records · Page 5Linked to original sources

The Entwined African and Asian Genetic Roots of the Medieval Peoples of the Swahili Coast

The peoples of the Swahili coast of eastern Africa established a literate urban culture by the second millennium CE. They traded across eastern Africa and the Indian Ocean and were among the first sub-Saharan practitioners of Islam. An open question has been the extent to which these early interactions between Africans and non-Africans were accompanied by genetic admixture. We report genome-wide ancient DNA from 80 individuals in five medieval and early modern (1300-1800 CE) coastal towns, as well as people from an inland town postdating 1650 CE. Over half of the ancestry of most coastal individuals came from African ancestors; these African ancestors were primarily female. A slightly smaller proportion of ancestry was from Asia. This Asian component was approximately eighty to ninety percent from Near Eastern males and ten to twenty percent from Indian females. Peoples of African and Asian origins began to mix by around 1000 CE, a time when archaeological evidence documents changes on the coast that are often interpreted as marking the large-scale adoption of Islam. Before roughly 1500 CE, the Near Eastern ancestry detected in the individuals was mainly Persian-related, consistent with the narrative of the Kilwa Chronicle, the oldest history told by the Swahili themselves. After this time, the sources of Near Eastern ancestry became increasingly Arabian, consistent with the archaeological and historical evidence of growing interactions between the Swahili coast and parts of southern Arabia. Subsequent interactions of Swahili coast peoples with other Asian and African groups further changed the ancestry of present-day peoples relative to the ancient individuals we sequenced, highlighting how Swahili genetic legacies can be more clearly understood with ancient DNA.

genetics↗

Uncovering the spatial landscape of molecular interactions within the tumor microenvironment through latent spaces

Recent advances in spatial transcriptomics (ST) enable gene expression measurements from a tissue sample while retaining its spatial context. This technology enables unprecedented in situ resolution of the regulatory pathways that underlie the heterogeneity in the tumor and its microenvironment (TME). The direct characterization of cellular co-localization with spatial technologies facilities quantification of the molecular changes resulting from direct cell-cell interaction, as occurs in tumor-immune interactions. We present SpaceMarkers, a novel bioinformatics algorithm to infer molecular changes from cell-cell interaction from latent space analysis of ST data. We apply this approach to infer molecular changes from tumor-immune interactions in Visium spatial transcriptomics data of metastasis, invasive and precursor lesions, and immunotherapy treatment. Further transfer learning in matched scRNA-seq data enabled further quantification of the specific cell types in which SpaceMarkers are enriched. Altogether, SpaceMarkers can identify the location and context-specific molecular interactions within the TME from ST data.

bioinformatics↗

The Effects of Propofol Anaesthesia on Molecular-enriched Networks During Resting-state and Naturalistic Stimulation

Placing a patient in a state of anaesthesia is crucial for modern surgical practice. However, the mechanisms by which anaesthetic drugs, such as propofol, impart their effects on consciousness remain poorly understood. Propofol potentiates GABAergic transmission, which purportedly has direct actions on cortex as well as indirect actions via ascending neuromodulatory systems. Functional imaging studies to date have been limited in their ability to unravel how these effects on neurotransmission impact system-level dynamics of the brain. Here, we leveraged advances in multi-modal imaging, Receptor-Enriched Analysis of functional Connectivity by Targets (REACT), to investigate how different levels of propofol-induced sedation alters neurotransmission-related functional connectivity (FC), both at rest and when individuals are exposed to naturalistic auditory stimulation. Propofol increased GABA-A- and noradrenaline transporter-enriched FC within occipital and somatosensory regions respectively. Additionally, during auditory stimulation, the network related to the vesicular acetylcholine transporter showed reduced FC within the right superior temporal gyrus, regardless of level of anaesthesia, and a spatial configuration correlating with a broad range of meta-analytic measures of audition- and emotion-related cognition. In bringing together these micro- and macro-scale systems, we provide support for both direct GABAergic and indirect noradrenergic-related network changes under anaesthesia and describe a cognition-related reconfiguration of the cholinergic network, highlighting the utility of REACT to explore the molecular substrates consciousness and cognition.

neuroscience↗

Digital data repository and automatic analysis framework for FDOPA PET neuroimaging

IntroductionFDOPA PET has been used extensively to image the human brain in many clinical disorders and has the potential to be used for patient stratification and individualized treatment. However, to reach its full and effective clinical translation, FDOPA PET requires both a robust data infrastructure and analytical protocol that are capable of ensuring high quality data and metadata, accurate biological quantification, and replicable results. In this study we evaluate a digital data repository and automated analytical framework for FDOPA PET neuroimaging that can produce an individualised quantification of dopamine synthesis capacity in the living human brain. MethodsThe imaging platform XNAT was used to store the Kings College London institutional brain FDOPA PET imaging archive, alongside individual demographics and clinical information. A fully automated analysis pipeline for imaging processing and data quantification was developed in Python and integrated in XNAT using the Docker technology. Reproducibility was assessed in test-retest datasets both in controls and patients with psychosis. The agreement between the automated analysis estimates and the results derived by the manual analysis were compared. Finally, using a sample of healthy controls (N=115), a sensitivity analysis was performed to explore the impact of experimental and demographic variables on the FDOPA PET measures. ResultsThe final data repository includes 892 FDOPA PET scans organized from 23 different studies, collected at five different imaging sites. After removing commercials studies, the infrastructure consisted of 792 FDOPA PET scans from 666 individuals (female 33.9%, healthy controls 29.1%) collected from four different imaging sites between 2004-2021. The automated analysis pipeline provided results that were in agreement with the results from the manual analysis, with a Pearsons correlation that ranged from 0.64 to 0.99 for Kicer, and from 0.79 to 1.00 for SUVR. The mean absolute difference between the two pipelines ranges from 3.4% to 9.4% for Kicer, and from 2.5% to 12.4% for SUVR. Moreover, we found good reproducibility of the data analysis by the automated pipeline (in the whole striatum for the Kicer: ICC for the controls = 0.71, ICC for the psychotic patients = 0.88). From the demographic and experimental variables assessed, gender was found to most influence striatal dopamine synthesis capacity (F = 10.7, p <0.001), with women showing greater dopamine synthesis capacity than men, while the effects of weight, age, injected radioactivity, and scanner, varied by brain region and parameter of interest. ConclusionsCombining information from different neuroimaging studies has allowed us to test comprehensively the automated pipeline for quantification of dopamine synthesis capacity using FDOPA PET data and to validate its replicability and reproducibility performances on a large sample size. This validation process is a necessary methodological step for the development of the clinical application of FDOPA PET as precision medicine biomarker. The proposed infrastructure is generalisable behind the FDOPA radiotracer.

bioengineering↗

Medial septum glutamate neurons are essential for spatial goal-directed memory

The medial septum (MS), a brain region containing acetylcholine, GABA and glutamate neurons, is essential for learning and memory. However, whether MS glutamate neurons contribute to memory is unknown. Here, we use calcium imaging and optogenetic silencing to determine the function of MS glutamate neurons in mice performing a spatial allocentric memory navigation task. While MS glutamate neurons appeared randomly active during free exploration, two groups of glutamate neurons emerged during training in a five-arm star maze, distinguished by their peak activity. The largest group was predominantly activated before locomotion whereas the other was primarily active when mice reached the reward site. Both populations were preferentially activated for correct over incorrect trajectories. Interestingly, optogenetic silencing of MS glutamate neurons immediately before mice start navigating, induced significant spatial memory impairments. Together these results demonstrate that MS glutamate neurons heterogeneously encode navigationally relevant information and are essential for spatial learning.

neuroscience↗

Learning the Vector Coding of Egocentric Boundary Cells from Visual Data

The use of spatial maps to navigate through the world requires a complex ongoing transformation of egocentric views of the environment into position within the allocentric map. Recent research has discovered neurons in retrosplenial cortex and other structures that could mediate the transformation from egocentric views to allocentric views. These egocentric boundary cells respond to the egocentric direction and distance of barriers relative to an animals point of view. This egocentric coding based on the visual features of barriers would seem to require complex dynamics of cortical interactions. However, computational models presented here show that egocentric boundary cells can be generated with a remarkably simple synaptic learning rule that forms a sparse representation of visual input as an animal explores the environment. Simulation of this simple sparse synaptic modification generates a population of egocentric boundary cells with distributions of direction and distance coding that strikingly resemble those observed within the retrosplenial cortex. This provides a framework for understanding the properties of neuronal populations in the retrosplenial cortex that may be essential for interfacing egocentric sensory information with allocentric spatial maps of the world formed by neurons in downstream areas including the grid cells in entorhinal cortex and place cells in the hippocampus.

neuroscience↗

Optogenetic scrambling of hippocampal theta oscillations alters working memory retrieval but not hippocampal spatiotemporal codes

The precise temporal coordination of activity in the brain is thought to be fundamental for memory encoding and retrieval. Pacemaker GABAergic neurons in the medial septum (MS) provide the largest source of innervation to the hippocampus and play a major role in controlling hippocampal theta (~8 Hz) oscillations. While pharmacological inhibition of the MS is known to disrupt memory, the exact role of MS inhibitory neurons and theta frequency rhythms in hippocampal representations and memory is not fully understood. Here, we dissociate the role of theta rhythms in spatiotemporal coding and memory using an all-optical interrogation and recording approach in freely behaving mice. We propose a novel paradigm to dissociate encoding of space, time and distance in freely moving mice and apply complementary optogenetic stimulation paradigms of MS GABAergic neurons to either pace or abolish theta altogether while recording large hippocampal cell assemblies using calcium imaging conjointly. We first show that optogenetic frequency scrambling of MS GABAergic neuron activity abolished theta rhythms and modulated the activity of a subpopulation of CA1 neurons. Such stimulation led to decreased memory retrieval in both a delayed non-match to sample task, a novel place object recognition task, as well as spontaneous cue-guided linear alternation. Strikingly, scrambled stimulations were not associated with disrupted encoding of place, time, distance, or multiplexed information. Our study suggests that theta rhythms play a specific and essential role in supporting working memory retrieval and maintenance while not being necessary for hippocampal spatiotemporal codes.

neuroscience↗

Structural, functional and computational studies of membrane recognition by Plasmodium Perforin-Like Proteins 1 and 2.

Perforin-like proteins (PLPs) play key roles in the mechanisms associated with parasitic disease caused by apicomplexans such as Plasmodium (malaria) and Toxoplasma. The T. gondii PLP1 (TgPLP1) mediates tachyzoite egress from cells, while the five Plasmodium PLPs carry out various roles in the life cycle of the parasite and with respect to the molecular basis of disease. Here we focus on Plasmodium vivax PLP1 and PLP2 (PvPLP1 and PvPLP2) compared to TgPLP1; PvPLP1 is important for invasion of mammalian hosts by the parasite and establishment of a chronic infection, PvPLP2 is important during the symptomatic blood stage of the parasite life cycle. Determination of the crystal structure of the membrane-binding APC{beta} domain of PvPLP1 reveals notable differences with that of TgPLP1, which are reflected in its inability to bind lipid bilayers in the way that TgPLP1 and PvPLP2 can be shown to. Molecular dynamics simulations combined with site-directed mutagenesis and functional assays allow a dissection of the binding interactions of TgPLP1 and PvPLP2 on lipid bilayers, and reveal a similar tropism for lipids found enriched in the inner leaflet of the mammalian plasma membrane. In addition to this shared mode of membrane binding PvPLP2 displays a secondary synergistic interaction side-on from its principal bilayer interface. This study underlines the substantial differences between the biophysical properties of the APC{beta} domains of Apicomplexan PLPs, which reflect their significant sequence diversity. Such differences will be important factors in determining the cell targeting and membrane-binding activity of the different proteins, in their different developmental roles within parasite life cycles.

biophysics↗

De-novo generation of novel phenotypically active molecules for Chagas disease from biological signatures using AI-driven generative chemistry

Designing novel molecules with targeted biological activities and optimized physicochemical properties is a challenging endeavor in drug discovery. Recent developments in artificial intelligence have enhanced the early steps of de novo drug design and compound optimization. Herein, we present a generative adversarial network trained to design new chemical matter that satisfies a given biological signature. Our model, called pqsar2cpd, is based on the activity of compounds across multiple assays obtained via pQSAR (profile-quantitative structure-activity relationships). We applied pqsar2cpd to Chagas disease and designed a novel molecule that was experimentally confirmed to inhibit growth of parasites in vitro at low micromolar concentrations. Altogether, this approach bridges chemistry and biology into one single framework for the design of novel molecules with promising biological activity.

pharmacology and toxicology↗

Solvation dynamics-powered structure and function of multi-molecular cellular systems exemplified by non-equilibrium cereblon-degrader-CK1α ternary complex formation

Cellular functions are executed via a form of analog computing that is based on the switchable covalent and non-covalent states of multi-molecular fluxes (i.e., time-dependent species/state concentrations) operating in the non-linear dynamics regime. We and others have proposed that the non-covalent states and state transitions of aqueous fluxes are powered principally by the storage and release of potential energy to/from the anisotropic H-bond network of solvating water (which we refer to as the "solvation field"), which is a key tenet of a first principles theory on cellular structure and function (called Biodynamics) that we outlined previously. This energy is reflected in water occupancy as a function of solute surface position, which can be probed computationally using WATMD software. In our previous work, we used this approach to deduce the structural dynamics of the COVID main protease, including substrate binding-induced enzyme activation and dimerization, and product release-induced dimer dissociation. Here, we examine: 1) The general relationships between surface composition/topology and solvation field properties for both high and low molecular weight (HMW and LMW) solutes. 2) The general means by which structural dynamics are powered by solvation free energy, which we exemplify via binding between the E3 ligase CUL4A/RBX1/DDB1/CRBN, LMW degraders, and substrates. We propose that degraders organize the substrate binding surface of cereblon toward complementarity with native and neo substrates, thereby speeding the association rate constant and incrementally slowing the dissociation rate constant. 3) Structure-activity relationships (SAR) based on complementarity between the solvation fields of cognate protein-ligand partners exemplified via LMW degraders.

pharmacology and toxicology↗

General structure-free energy relationships of hERG blocker binding under native cellular conditions

We proposed previously that aqueous non-covalent barriers arise from solute-induced perturbation of the H-bond network of solvating water ("the solvation field") relative to bulk solvent, where the association barrier equates to enthalpic losses incurred from incomplete replacement of the H-bonds of expelled H-bond enriched solvation by inter-partner H-bonds, and the dissociation barrier equates to enthalpic + entropic losses incurred during dissociation-induced resolvation of H-bond depleted positions of the free partners (where dynamic occupancy is powered largely by the expulsion of such solvation to bulk solvent during association). We went on to analyze blockade of the human ether-a-go-go-related gene potassium channel (hERG) based on these principles, the results of which suggest that blockers: 1) project a single rod-shaped R-group (denoted as "BP") into the pore at a rate proportional to the desolvation cost of BP, with the largely solvated remainder (denoted as "BC") occupying the cytoplasmic "antechamber" of hERG; and 2) undergo second-order entry to the antechamber, followed by first-order association of BP to the pore. In this work, we used WATMD to qualitatively survey the solvation fields of the pore and a representative set of 16 blockers sampled from the Redfern dataset of marketed drugs spanning a range of pro-arrhythmicity. We show that the highly non-polar pore is solvated principally by H-bond depleted and bulk-like water (incurring zero desolvation cost), whereas blocker BP moieties are solvated by variable combinations of H-bond enriched and depleted water. With a few explainable exceptions, the blocker solvation fields (and implied desolvation/resolvation costs) are qualitatively well-correlated with both blocker potency and Redfern safety classification.

pharmacology and toxicology↗

An inactivated multivalent influenza A virus vaccine is broadly protective in mice and ferrets

Influenza A viruses (IAVs) present major public health threats from annual seasonal epidemics, from pandemics caused by novel virus subtypes, and from viruses adapted to a variety of animals including poultry, pigs and horses. Vaccines that broadly protect against all such IAVs, so-called "universal" influenza vaccines, do not currently exist, but are urgently needed. This study demonstrates that an inactivated, multivalent whole virus vaccine, delivered intramuscularly or intranasally, is broadly protective against challenges with multiple IAV HA/NA subtypes in both mice and ferrets, including challenges with IAV subtypes not contained in the vaccine. This vaccine approach indicates the feasibility of eliciting broad "universal" IAV protection, and identifies a promising candidate for influenza vaccine clinical development. One-Sentence SummaryAn inactivated, whole avian influenza virus vaccine delivered intramuscularly or intranasally provides extremely broad protection against antigenically divergent viral challenge and is a promising candidate for a "universal" influenza virus vaccine.

microbiology↗

A non-coding RNA network involved in KSHV tumorigenesis

Regulatory pathways involving non-coding RNAs (ncRNAs) such as microRNAs (miRNAs) and long non-coding RNAs (lncRNA) have gained great relevance due to their role in the control of gene expression modulation. Using RNA sequencing of KSHV Bac36 transfected mouse endothelial cells (mECK36) and tumors, we have analyzed the host and viral transcriptome to uncover the role lncRNA-miRNA-mRNA driven networks in KSHV tumorigenesis. The integration of the differentially expressed ncRNAs, with an exhaustive computational analysis of their experimentally supported targets, led us to dissect complex networks integrated by the cancer-related lncRNAs Malat, Neat1, H19, Meg3 and their associated miRNA-target pairs. These networks would modulate pathways related to KSHV pathogenesis, such as viral carcinogenesis, p53 signaling, RNA surveillance, and Cell cycle control. Finally, the ncRNA-mRNA analysis allowed us to develop signatures that can be used to an appropriate identification of druggable gene or networks defining relevant AIDS-KS therapeutic targets.

cancer biology↗

Recurrent Vulvovaginal Candidiasis; a dynamic interkingdom biofilm disease of Candida and Lactobacillus

Vulvovaginal Candidiasis (VVC) is the most prevalent Candida infection in humans affecting 75% of women at least once throughout their lifetime. In its debilitating recurrent form, RVVC is estimated to affect 140 million women annually. Despite this strikingly high prevalence, treatment options for RVVC remain limited with many women experiencing failed clinical treatment with frontline azoles. Further, the cause of onset and recurrence of disease is largely unknown with few studies identifying potential mechanisms of failed treatment. This study aimed to assess a panel of clinical samples from healthy women and those with RVVC to investigate the influence of Candida, vaginal microbiome and antagonism between Candida and Lactobacillus on disease pathology. 16S rRNA sequencing characterised disease by a reduction in specific health-associated Lactobacillus such as L. crispatus, coupled with an increase in L. iners. In vitro analysis showed Candida albicans clinical isolates are capable of heterogeneous biofilm formation and show the presence of hyphae and C. albicans aggregates in vaginal lavage. Additionally, the ability of Lactobacillus to inhibit C. albicans biofilm formation and biofilm-related gene expression was demonstrated. Using RNA sequencing technology, we were able to exploit a possible mechanism by which L. crispatus may aim to re-establish a healthy vaginal environment through amino-acid acquisition from C. albicans. This study suggests RVVC is not entirely due to an arbitrary switch in C. albicans from commensal to pathogen and understanding interactions between the yeast and vaginal Lactobacillus species may be more crucial to elucidating the cause of RVVC and developing appropriate therapies.

microbiology↗

Conjunctive spatial and idiothetic codes are topographically organized in the lateral septum

The hippocampal spatial codes relevance for downstream neuronal populations - particularly its major subcortical output the lateral septum (LS) - is still poorly understood. Here, using calcium imaging combined with unbiased analytical methods, we functionally characterized and compared the spatial tuning of LS GABAergic cells to those of dorsal CA3 and CA1 cells. We identified a significant number of LS cells that are modulated by place, speed, acceleration, and direction, as well as conjunctions of these properties, directly comparable to hippocampal CA1 and CA3 spatially modulated cells. Interestingly, Bayesian decoding of position based on LS spatial cells reflected the animals location as accurately as decoding using the activity of hippocampal pyramidal cells. A portion of LS cells showed stable spatial codes over the course of multiple days, potentially reflecting long-term episodic memory. The distributions of cells exhibiting these properties formed gradients along the anterior-posterior and dorsal-ventral axes of the LS, directly reflecting the topographical organization of hippocampal inputs to the LS. Finally, we show using trans-synaptic tracing that LS neurons receiving CA3 and CA1 excitatory input send projections to the hypothalamus and medial septum, regions that are not targeted directly by principal cells of the dorsal hippocampus. Together, our findings demonstrate that the LS accurately and robustly represents spatial, directional as well as self-motion information and is uniquely positioned to relay this information from the hippocampus to its downstream regions, thus occupying a key position within a distributed spatial memory network.

neuroscience↗

Sailing in rough waters: examining volatility of fMRI noise

BackgroundThe assumption that functional magnetic resonance imaging (fMRI) noise has constant volatility has recently been challenged by studies examining heteroscedasticity arising from head motion and physiological noise. The present study builds on this work using latest methods from the field of financial mathematics to model fMRI noise volatility. MethodsMulti-echo nd human fMRI scans were used and realised volatility was estimated. The Hurst parameter H [isin] (0, 1), which governs the roughness/irregularity of realised volatility time series, was estimated. Calibration of H was performed pathwise, using well-established neural network calibration tools. ResultsIn all experiments the volatility calibrated to values within the rough case, H < 0.5, and on average fMRI noise was very rough with 0.03 < H < 0.05. Some edge effects were also observed, whereby H was larger near the edges of the phantoms. DiscussionThe findings suggest that fMRI volatility is not only non-constant, but also substantially more irregular than a standard Brownian motion. Thus, further research is needed to examine the impact such pronounced oscillations in the volatility of fMRI noise have on data analyses.

neuroscience↗

A characterization of the electrophysiological, morphological and input domains of vasoactive intestinal peptide (VIP) interneurons in the medial entorhinal cortex (MEC)

Circuit interactions within the medial entorhinal cortex (MEC) translate movement into a coherent code for spatial location. Entorhinal principal cells are subject to strong lateral inhibition, suggesting that a disinhibitory mechanism may drive their activation. Cortical Vasoactive Intestinal Peptide (VIP) expressing inhibitory neurons predominantly contact interneurons, providing a local disinhibitory mechanism. Here, we investigate the electrophysiological and morphological properties of VIP cells using in vitro whole-cell patch clamp recordings and use rabies-mediated circuit tracing to discover long-range inputs that may modulate this population in mice. We report physiological and morphological properties of VIP cells that differ across lamina and along the dorsal-ventral MEC axis. Furthermore, we reveal long-range inputs to VIP neurons from regions known to encode proprioceptive and auditory information, including the mesencephalic trigeminal nucleus and superior para-olivary nuclei, respectively. These results characterize the properties of VIP cells and reveal sensory modalities that could drive disinhibition in the MEC.

neuroscience↗

Revealing heritability missed by single locus analyses by examining epistasis in mouse chromosome substitution strains

The genetic contribution of additive versus non-additive (epistatic) effects in the regulation of complex traits is unclear. While genome-wide association studies typically ignore gene-gene interactions, in part because of the lack of statistical power for detecting them, mouse chromosome substitution strains (CSSs) represent an alternate and powerful model for detecting epistasis given their limited allelic variation. Therefore, we utilized CSSs to identify and map both additive and epistatic loci that regulate a range of hematologic- and metabolism-related traits, as well as hepatic gene expression. Quantitative trait loci (QTLs) were identified using a CSS-based backcross strategy involving the segregation of variants on the A/J-derived substituted chromosomes 4 and 6 on an otherwise C57BL/6J genetic background. In the liver transcriptomes of offspring from this cross, we identified and mapped additive QTLs regulating the hepatic expression of 768 genes, and epistatic QTL pairs for 519 genes. Similarly, we identified additive QTLs for fat pad weight, platelets, and the percentage of granulocytes in blood, as well as epistatic QTL pairs controlling the percentage of lymphocytes in blood and red cell distribution width. The variance attributed to the epistatic QTL pairs was approximately equal to that of the additive QTLs; however, the SNPs in the epistatic QTL pairs that accounted for the largest variances were undetected in our single locus association analyses. These findings highlight the need to account for epistasis in association studies, and more broadly demonstrate the importance of identifying genetic interactions to understand the complete genetic architecture of complex traits.

genetics↗