Biology subjects
Publications and source records attributed to Williams, M..
High-frequency stimulation of the subthalamic nucleus (STN) has shown therapeutic potential in preclinical models of addiction. However, its rewarding properties remain unclear. Here, we show that cocaine withdrawal enhances STN intracranial self-stimulation, revealing a reward-based mechanism that may contribute to the beneficial effects of STN deep brain stimulation in addiction and related neuropsychiatric disorders.
Biological O2 sensing is crucial for diverse physiological functions across all forms of life. Heme-containing proteins achieve this by binding O2 to their iron center and have been found to display O2 affinities spanning several orders of magnitude. Despite decades of investigation into the structure and function of heme-based O2 sensors, the molecular mechanisms that enable the tuning of O2 affinity to match specific physiological roles remain unclear. Here, we utilize the O2 sensing mycobacterial DosS protein as a model system to explore the role of heme irons tertiary coordination sphere in controlling its O2 affinity. By rationally and systematically modifying the tertiary coordination sphere to promote the formation of a Trp-Tyr-Asn H-bond triad within the hemes distal pocket, we have enhanced the O2 affinity of WT DosS by over 150-fold. The rationally designed DosS exhibited a Kd value of 3 {+/-} 1 nM, compared to 460 {+/-} 80 nM for WT DosS. Employing a combination of structural, biochemical, spectroscopic, and computational studies, our analysis of WT and designed DosS variants highlights how the interplay between distal H-bond networks and heme-pocket electrostatics drives large differences in their O2 sensing capabilities. Ultimately, our work shows how metalloenzymes can dramatically alter their sensitivity to diatomic signaling molecules by tuning the tertiary coordination sphere, broadly impacting how we understand related biological sensing and signaling.
Successful hematopoietic stem cell transplantation (HSCT) critically depends on efficient T cell recovery, which is limited by compromised bone marrow niches following irradiation. While various factors influence the regeneration of bone and bone marrow niches, the dynamics of this process remain elusive. Here, we explore the kinetics of de novo bone and bone marrow development under varying BMP-2 doses, host immune status, and biological sex, using a cryogel of covalently crosslinked alginate and gelatin releasing BMP-2. Bone formation was monitored by ultrasonography and microcomputed tomography (microCT) analysis, while histological analysis provided insights into the relation between mineralized tissue and bone marrow formation. Bone developed within 2-4 weeks, resulting in cortical bone around the cryogels, and a trabecular bone network with hematopoietic tissue within the cryogels. Higher BMP-2 doses significantly accelerated mineralization kinetics and doubled the resident hematopoietic stem cell population. Notably, immunocompromised status delayed niche development by two weeks and reduced hematopoietic stem cells fourfold. We also found that female mice exhibited enhanced niche formation compared to males under the identical conditions. These findings provide insights into the factors that govern the spatiotemporal regulation of bone and bone marrow niche development and establish this hybrid click cryogel system as a promising platform for improving T cell reconstitution in HSCT patients.
PsiConnect is a large-scale neuroimaging study designed to investigate the neural and subjective effects of psilocybin using multimodal neuroimaging. It combines functional, structural, and diffusion-weighted MRI with EEG to examine brain activity in 62 participants before and after a 19 mg dose of psilocybin. The design includes resting-state scans and three naturalistic conditions: guided meditation, music listening, and movie watching. Half of the cohort underwent an 8-week meditation training program, enabling the exploration of interactions among meditation, psilocybin, and brain function. The fMRI data was obtained through multi-echo fMRI, which enhances the signal-to-noise ratio and reduces susceptibility artifacts, thereby improving the reliability of the analyses. A comprehensive battery of behavioural and self-report measures captured both acute and longitudinal cognitive and subjective effects, with follow-ups extending to one year post-administration. The large sample size, multimodal neuroimaging, diversity of contexts, and longitudinal behavioural follow-ups enable the study of psilocybin-induced changes in brain and behaviour with an unprecedented level of detail and reliability. Furthermore, the data is curated according to open science principles to ensure accessibility and interoperability with established neuroimaging processing pipelines. These factors make PsiConnect a valuable and highly reusable resource for researchers in cognitive and computational neuroscience.
Chromatin architecture governs transcriptional output and cell identity; however, how its disruption promotes leukemic transformation remains incompletely understood. Here, we show that loss of the cohesin subunit STAG2 creates a hyper-accessible chromatin landscape that amplifies FLI1 activity and extends its binding to ectopic loci. Using multi-omic analyses in human AML samples, cell lines, and mouse models, we identify chromatin-dependent co-occupancy of FLI1 and Menin, accompanied by amplification of Menin occupancy at non-canonical loci beyond its HOXA/MEIS1 targets. Therapeutically, the aberrant expansion of Menin binding drives an altered response towards Revumenib and activates interferon response pathways, creating a therapeutic vulnerability to Menin inhibition. Functionally, STAG2/NPM1c co-mutation drives a stem cell-like immunophenotype and a fully penetrant leukemia in vivo. Collectively, these findings define a model in which cohesin loss rewires transcription factor occupancy to amplify oncogenic chromatin programs and expose context-specific therapeutic dependencies.
Psychedelics can profoundly alter consciousness by reorganising brain connectivity; however, their effects are context-sensitive. To understand how this reorganisation depends on context, we collected and comprehensively analysed the largest psychedelic neuroimaging dataset to date. Sixty-two adults were scanned with functional MRI and EEG during rest and naturalistic stimuli (meditation, music, and movie), before and after ingesting 19 mg of psilocybin (functional MRI {approx}80 min post-dose; EEG {approx}150 min post-dose). Half the participants ranked the experience among the most meaningful of their lives. Under psilocybin, functional MRI and EEG signals recorded during eyes-closed conditions became similar to those recorded during an eyes-open condition. Global functional connectivity increased in associative regions and decreased in sensory areas. Using machine learning to represent neural activity as low-dimensional trajectories, we found that psilocybin reorganised these into structured, context-sensitive patterns of brain activity that reflected both experimental condition and the quality of subjective experience, revealing an organisation that was missed by time-averaged connectivity measures. Under psilocybin, brain networks that ordinarily segregate internal and external processing coherently integrated and aligned neural dynamics with context. This context-alignment manifested as distinct and cohesive neural trajectories in participants reporting positively felt self- and boundary-dissolving effects, corresponding to the felt experience of being part of the environment, which we refer to as embeddedness--the subjective experience of being continuous with, rather than separate from, the surrounding environment. The strength of this context-alignment was associated with next-day mindset change, bridging the neural, experiential, and therapeutic dimensions of the psychedelic state. These findings show that the organisation of brain activity covaries with the experiential coherence of the psychedelic state, and provide a systems-level framework for how context-sensitive brain dynamics link neurobiology to subjective experience and behavioural change.
Polyethylene (PE) is the most commonly used plastic on Earth due to its favorable material properties such as high ductility, mechanical strength, and bond homogeneity that make the material resistant to deconstruction. However, the lack of robust recycling infrastructure for PE end-of-life management is leading to an estimated 4 million tons of environmental accumulation annually, with implications for human and environmental health. Biological deconstruction and upcycling could potentially aid in PE waste management by allowing for high-yield conversion of waste plastics to high value products, although such processes are not yet possible. In this work, we mined the gut of low-density PE (LDPE) fed mealworms that can reduce LDPE molecular weight by >40% and discovered dye decolorizing peroxidases (DyPs) that oxidized LDPE, initiating biological deconstruction. A plastic-active DyP is characterized by a hydrophobic loop near its active site that helps mediate binding and tunes activity. LDPE oxidation is driven by surface exposed residues proximal to the active site enabling activity on polymeric substrates. Our work provides robust evidence for enzymatic LDPE deconstruction and identifies molecular targets for further development to realize scalable biological LDPE upcycling. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=41 SRC="FIGDIR/small/640435v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@146b8fborg.highwire.dtl.DTLVardef@1a72adorg.highwire.dtl.DTLVardef@5ece5forg.highwire.dtl.DTLVardef@3ee20a_HPS_FORMAT_FIGEXP M_FIG C_FIG
When does compulsive-like drug seeking emerge? Despite decades of research, and critical advances in our understanding of brain processes leading to addiction, this question remains widely unanswered. So far, behavioral models assessing compulsive-like cocaine seeking following an extended access to cocaine failed to capture the development of its compulsive seeking. In fact, compulsive-like animals immediately displayed pathological seeking when facing its negative consequences of drug seeking, usually materialized by an unescapable mild electric shock on the paws. Here, we designed a new task, Punished Seeking during Extended access (PSE), by inserting punished seeking trials within the sessions of extended access to cocaine. We show that compulsive-like cocaine seeking progressively emerges after several PSE sessions, once cocaine intake has been escalated. We thus provide the addiction community a pertinent model to explore brain mechanisms sustaining the emergence of compulsive-like cocaine seeking.
Over a century after two introduced pathogens decimated American chestnut populations, breeding programs continue to incorporate resistance from Chinese chestnut to recover self-sustaining populations. Due to complex genetics of chestnut blight resistance, it is challenging to obtain trees with sufficient resistance and competitive growth. We developed high quality reference genomes for Chinese and American chestnut and leveraged large disease phenotype and genotype datasets to develop accurate genomic selection. Inoculation and simulation results indicate that resistance may be substantially increased in trees that inherited 70% to 100% of their genome from American chestnut. To facilitate gene editing, we integrated multiple lines of evidence to discover candidate alleles for blight resistance and susceptibility. These genomic resources provide a strong foundation to accelerate restoration of this iconic tree.
AbstractProgrammed cell death (PCD) is a crucial, genetically-encoded, and evolutionarily-conserved process required for development and homeostasis. We previously identified a genetically non-apoptotic, highly ordered, and stereotyped killing program called Compartmentalized Cell Elimination (CCE) in the C. elegans tail-spike epithelial cell (TSC). Here we identify the transcription factor EOR-1/PLZF as an important coordinator of CCE. Loss of EOR-1 results in a large, persisting, un-engulfed soma with enlarged nuclei. We find that EOR-1 and its partners positively regulate the transcription of the Apoptosis Inducing Factor AIF homolog, WAH-1/AIF. We report stereotyped and sequential spatiotemporal dynamics of WAH-1/AIF1 during phagocytosis, with defined roles acting early and late, within the dying cells. Mitochondria to plasma membrane translocation within the TSC soma is required its internalization by its phagocyte, and plasma membrane to nuclear translocation is required for DNA degradation and ultimately, corpse resolution. Our study suggests that EOR-1 serves as a master regulator for the transcriptional control of DNA degradation is essential for changes in nuclear morphology required for cellular dismantling and infers that tight spatiotemporal regulation of WAH-1/AIF is required for this function. Summary StatementThis work describes the genetic control and cellular dynamics of a factor linked to cancer, metabolic and degenerative disease acting in developmentally dying cells to instruct their own removal.
The grass family (Poaceae, Poales) holds immense economic and ecological significance, exhibiting unique metabolic traits, including dual starch and lignin biosynthetic pathways. To investigate when and how the metabolic innovations known in grasses evolved, we sequenced the genomes of four Poales species, including Joinvillea ascendens and Ecdeiocolea monostachya representing the sister clade to Poaceae. The rho whole genome duplication ({rho}WGD) in the ancestral lineage for all grasses contributed to the gene family expansions underlying cytosolic starch biosynthesis, whereas an earlier tandem duplication of phenylalanine ammonia lyase (PAL) gave rise to phenylalanine/tyrosine ammonia lyase (PTAL) responsible for the dual lignin biosynthesis. Integrated functional genomic and biochemical analyses of grass relatives further revealed the molecular basis of key metabolic innovations predating the evolution of grasses. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=149 SRC="FIGDIR/small/622220v2_ufig1.gif" ALT="Figure 1"> View larger version (108K): org.highwire.dtl.DTLVardef@117dd71org.highwire.dtl.DTLVardef@1cb5daborg.highwire.dtl.DTLVardef@72a331org.highwire.dtl.DTLVardef@38124e_HPS_FORMAT_FIGEXP M_FIG C_FIG
O_LIThe legume family originated ca. 70 million years ago and soon diversified into at least six lineages (now extant subfamilies). The signal of whole genome duplications (WGD) is apparent in species sampled from all six subfamilies. The early diversification has posed difficulties for resolving the legume backbone structure and the timing of WGDs. C_LIO_LIIn this study, we report the genome sequences and annotations for Cercis canadensis (Cercidoideae) and Chamaecrista fasciculata (Caesalpinoideae) to help resolve the relative taxonomic placements along the legume backbone, the timings of WGDs relative to subfamily origins, and the ancestral legume karyotype. C_LIO_LIAnalyses of genome assemblies from four subfamilies within Fabaceae show that the last common ancestor of all legumes likely had seven chromosomes, with a genome structure similar to the extant Cercis genome. Our analysis supports an allopolyploid origin of the subfamily Caesalpinoideae, with progenitors involving lineages along the backbone of the legume phylogeny. C_LIO_LIA probable allopolyploid origin of Caesalpinoideae subfamily provides a partial explanation for the difficulty in resolving the structure of the legume backbone. The retained karyotype structure and lack of a WGD in the last 100+ Mya, underscore the utility of the Cercis genome as an ancestral reference for the legume family. C_LI
The global reliance on Bacillus thuringiensis (Bt) proteins for controlling lepidopteran pests in cotton, corn, and soybean crops underscores the critical need to understand resistance mechanisms. Vip3Aa, one of the most widely deployed and currently effective Bt proteins in genetically modified crops, plays a pivotal role in pest management. This study identifies the molecular basis of Vip3Aa resistance in Australian Helicoverpa armigera through genetic crosses, and integrated genomic and transcriptomic analyses. We identified a previously uncharacterized gene, LOC110373801 (designated HaVipR1), as a crucial determinant of Vip3Aa resistance in two field-derived resistant lines. Functional validation using CRISPR-Cas9 knockout in susceptible lines confirmed the genes role in conferring resistance. Despite extensive laboratory selection of Vip3Aa-resistant colonies in Lepidoptera, the biochemical mechanisms underlying resistance have remained elusive. Our research demonstrates that HaVipR1-mediated resistance operates independently of known resistance genes, including midgut-specific chitin synthase and the transcription factor SfMyb. The identification of HaVipR1 offers further insights into the Vip3Aa mechanism of action. This discovery is vital for devising strategies to counteract resistance and sustain the efficacy of Bt crops. Future research should focus on elucidating the biochemical pathways involving HaVipR1 and investigating its interactions with other resistance mechanisms. Our findings underscore the utility of analysing field-derived resistant lines in providing biologically relevant insights and stress the necessity for comprehensive management strategies to maintain agricultural productivity. Significance StatementThis is the first identification of a specific gene in Helicoverpa armigera which mediates resistance to the Bacillus thuringiensis (Bt) protein Vip3Aa. We identify that this gene is disrupted in two different ways in separate field-derived resistant lines, one being a large transposable element insertion in the first intron of the HaVipR1 gene, confirmed using long-read sequencing. Disruption of this gene using CRISPR-Cas9 knockout in a susceptible H. armigera line confers Vip3A resistance. The identification of a specific gene is important for molecular monitoring and management of H. armigera as well as other global pests of concern like Spodoptera frugiperda. These findings also offer insights for researchers aiming to understand how Vip3Aa functions, as the action pathway remains unclear.
Several disease-causing bacteria have transitioned from tick-borne to louse-borne transmission, a process associated with increased virulence and genome reduction. However, the historical time frame and speed of such evolutionary transitions have not been documented with ancient genomes. Here, we discover four ancient cases of Borrelia recurrentis, the causative agent of louse-borne relapsing fever, in Britain between [~]600 and 2,300 years ago, and sequence whole genomes up to 29-fold coverage. We estimate a recent divergence from the closest tick-borne ancestor, likely within the last [~]8,000 years. We reconstruct a chronology of gene losses and acquisitions using the pan-genome of related species, and show that almost all of the reductive evolution observed in B. recurrentis had occurred by [~]2,000 years ago, and was thus a rapid process after divergence. Our observations provide a new understanding of the origins of B. recurrentis and document complex reductive evolution in a specialist vector-borne pathogen.
Epithelial-to-mesenchymal transition (EMT) plays a key role in the progression of cancer tumours and can make treatment significantly less successful for patients. EMT occurs when a cell gains a different phenotype and possesses different behaviours to those previously exhibited. This may result in enhanced drug resistance, higher cell plasticity, and increased metastatic abilities. It has therefore has become essential to encapsulate this change and study tumour progression and its response to treatments. Here, we use a 3D agent-based multiscale modelling framework based on Physicell to investigate the role of EMT over time in two cell lines, OVCAR-3 and SKOV-3. The impact of conditions in the microenvironment are incorporated into the model by modifying cellular behaviours dependant on variables such as substrate concentrations and proximity to neighbouring cells. OVCAR-3 and SKOV-3 cell lines possess highly contrasting tumour layouts, allowing a vast array of different tumour dynamics and morphologies to be tested and studied. The model encapsulates the biological observations and trends seen in tumour growth and development, thus can help to obtain further insights into OVCAR-3 and SKOV-3 cell line dynamics. Sensitivity analysis was performed to investigate the impact of parameter sensitivity on model outcome. Sensitivity analysis showed that parameters used in generating the rate of EMT and cycle rates within the cells are relatively more sensitive than other parameters used.
The North Pontic region, which encompasses present-day Ukraine, was a crossroads of migration as it connected the vast Eurasian Steppe with Central Europe. We generated shotgun-sequenced genomic data for 91 individuals dating from around 7,000 BCE to 1,800 CE to study migration and mobility history in the region, with a particular focus on historically attested migrating groups during the Iron Age and the medieval period, such as Scythian, Chernyakhiv, Saltiv and Nogai associated peoples. We infer a high degree of temporal heterogeneity in ancestry, with fluctuating genetic affinities to present-day Western European, Eastern European, Western Steppe and East Asian groups. We also infer high heterogeneity in ancestry within geographically, culturally and socially defined groups. Despite this, we find that ancestry components which are widespread in Eastern and Central Europe have been present in the Ukraine region since the Bronze Age.
Advances in cell therapy offer promise for some of the most devastating neural injuries, including spinal cord injury (SCI). Endogenous VSX2-expressing spinal V2a interneurons have been implicated as a key component in plasticity and therapeutically driven recovery post-SCI. While transplantation of generic V2a neurons may have therapeutic value, generation of human spinal V2a neurons with rostro-caudal specificity and assessment of their functional synaptic integration with the injured spinal cord has been elusive. Here, we efficiently differentiated optogenetically engineered cervical V2a spinal interneurons (SpINs) from human induced pluripotent stem cells and tested their capacity to form functional synapses with injured diaphragm motor networks in a clinically-relevant sub-acute model of cervical contusion injury. Neuroanatomical tracing and immunohistochemistry demonstrated transplant integration and synaptic connectivity with injured host tissue. Optogenetic activation of transplanted human V2a SpINs revealed functional synaptic connectivity to injured host circuits, culminating in improved diaphragm activity assessed by electromyography. Furthermore, optogenetic activation of host supraspinal pathways revealed functional innervation of transplanted cells by host neurons, which also led to enhanced diaphragm contraction indicative of a functional neuronal relay. Single cell analyses pre- and post-transplantation suggested the in vivo environment resulted in maturation of cervical SpINs that mediate the formation of neuronal relays, as well as differentiation of glial progenitors involved in repair of the damaged spinal cord. This study rigorously demonstrates feasibility of generating human cervical spinal V2a interneurons that develop functional host-transplant and transplant-host connectivity resulting in improved muscle activity post-SCI.
RationalThe immediate social context significantly influences alcohol consumption in humans. Recent studies have revealed that peer presence could modulate drugs use in rats. The most efficient condition to reduce cocaine intake is the presence of a stranger peer, naive to drugs. Deep brain stimulation (DBS) of the Subthalamic Nucleus (STN), which was shown to have beneficial effects on addiction to cocaine or alcohol, also modulate the protective influence of peers presence on cocaine use. ObjectivesThis study aimed to: 1) explore how the presence of an alcohol-naive stranger peer affects recreational and escalated alcohol intake, and 2) assess the involvement of STN on alcohol use and in the modulation induced by the presence of an alcohol-naive stranger peer. MethodsRats with STN DBS and control animals self-administered 10% (v/v) ethanol in presence, or absence, of an alcohol-naive stranger peer, before and after escalation of ethanol intake (observed after intermittent alcohol (20% (v/v) ethanol) access). ResultsNeither STN DBS nor the presence of an alcohol-naive stranger peer modulated significantly recreational alcohol intake. After the escalation procedure, STN DBS gradually reduced ethanol consumption. The presence of an alcohol-naive stranger peer increased consumption only in low drinkers, which effect was suppressed by STN DBS. ConclusionsThese results highlight the influence of a peers presence on escalated alcohol intake, and confirm the role of STN in addiction-like alcohol intake and in the social influence on drug consumption.