Biology subjects

Jones, M.

Publications and source records attributed to Jones, M..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

Wild bird mass mortalities in eastern Canada associated with the Highly Pathogenic Avian Influenza A(H5N1) virus, 2022

In 2022, a severe outbreak of clade 2.3.4.4b Highly Pathogenic Avian Influenza (HPAI) H5N1 virus resulted in unprecedented mortality among wild birds in eastern Canada. Tens of thousands of birds were reported sick or dead, prompting a comprehensive assessment of mortality spanning the breeding season between April 1 and September 30, 2022. Mortality reports were collated from federal, Indigenous, provincial, and municipal agencies, the Canadian Wildlife Health Cooperative, non-governmental organizations, universities, and citizen science platforms. A scenario analysis was conducted to refine mortality estimates, accounting for potential double counts from multiple sources under a range of spatial and temporal overlap. Correcting for double counting, an estimated 40,966 wild birds were reported sick or dead in eastern Canada during the spring and summer of 2022. Seabirds and sea ducks, long-lived species that are slow to recover from perturbations, accounted for 98.7% of reported mortalities. Mortalities were greatest among Northern Gannets (Morus bassanus; 26,193), Common Murres (Uria aalge; 8,133), and American Common Eiders (Somateria mollissima dresseri; 1,945), however, these figures underestimate total mortality as they exclude unreported deaths on land and at sea. In addition to presenting mortality estimates, we compare mortalities with known population sizes and trends and make an initial assessment of whether population-level impacts are possible for the Northern Gannet, a species that has suffered significant global mortality, and two harvested species, Common Murre and American Common Eider, to support management decisions. We hypothesize that population-level impacts in eastern Canada are possible for Northern Gannets and American Common Eiders but are unlikely for Common Murres. This study underscores the urgent need for further research to understand the broader ecological ramifications of the HPAI outbreak on wild bird populations.

zoology↗

bioRxiv2023

Decoding mTOR signalling heterogeneity in the tumour microenvironment using multiplexed imaging and graph convolutional networks

Evaluating the contribution of the tumour microenvironment (TME) in tumour progression has proven a complex challenge due to the intricate interactions within the TME. Multiplexed imaging is an emerging technology that allows concurrent assessment of multiple of these components simultaneously. Here we utilise a highly multiplexed dataset of 61 markers across 746 colorectal tumours to investigate how complex mTOR signalling in different tissue compartments influences patient prognosis. We found that the signalling of mTOR pathway can have heterogeneous activation patterns in tumour and immune compartments which correlate with patient prognosis. Using graph neural networks, we determined the most predictive features of mTOR activity in immune cells and identified relevant cellular subpopulations. We validated our observations using spatial transcriptomics data analysis in an independent patient cohort. Our work provides a framework for studying complex cell signalling and reveals important insights for developing mTOR-based therapies.

cancer biology↗

bioRxiv2023

A high-density diffuse optical tomography dataset of naturalistic viewing

Traditional laboratory tasks offer tight experimental control but lack the richness of our everyday human experience. As a result, many cognitive neuroscientists have been motivated to adopt experimental paradigms that are more natural, such as stories and movies. Here we describe data collected from 58 healthy adult participants (aged 18-76 years) who viewed 10 minutes of a movie (The Good, the Bad, and the Ugly, 1966). Most (36) participants viewed the clip more than once, resulting in 106 sessions of data. Cortical responses were mapped using high-density diffuse optical tomography (first-through fourth nearest neighbor separations of 1.3, 3.0, 3.9, and 4.7 cm), covering large portions of superficial occipital, temporal, parietal, and frontal lobes. Consistency of measured activity across subjects was quantified using intersubject correlation analysis. Data are provided in both channel format (SNIRF) and projected to standard space (NIfTI) using an atlas-based light model. These data are suitable for methods exploration as well as investigating a wide variety of cognitive phenomena.

neuroscience↗

bioRxiv2023

Early Deficits in Dentate Circuit and Behavioral Pattern Separation after Concussive Brain Injury

Traumatic brain injury leads to cellular and circuit changes in the dentate gyrus, a gateway to hippocampal information processing. Intrinsic granule cell firing properties and strong feedback inhibition in the dentate are proposed as critical to its ability to generate unique representation of similar inputs by a process known as pattern separation. Here we evaluate the impact of brain injury on cellular decorrelation of temporally patterned inputs in slices and behavioral discrimination of spatial locations in vivo one week after concussive lateral fluid percussion injury (FPI) in mice. Despite posttraumatic increases in perforant path evoked excitatory drive to granule cells and enhanced {Delta}FosB labeling, indicating sustained increase in excitability, the reliability of granule cell spiking was not compromised after FPI. Although granule cells continued to effectively decorrelate output spike trains recorded in response to similar temporally patterned input sets after FPI, their ability to decorrelate highly similar input patterns was reduced. In parallel, encoding of similar spatial locations in a novel object location task that involves the dentate inhibitory circuits was impaired one week after FPI. Injury induced changes in pattern separation were accompanied by loss of somatostatin expressing inhibitory neurons in the hilus. Together, these data suggest that the early posttraumatic changes in the dentate circuit undermine dentate circuit decorrelation of temporal input patterns as well as behavioral discrimination of similar spatial locations, both of which could contribute to deficits in episodic memory.

neuroscience↗

bioRxiv2023

Medication-Invariant Resting Aperiodic and Periodic Neural Activity in Parkinson's Disease

Parkinsons Disease (PD) has been associated with greater total power in canonical frequency bands (i.e., alpha, beta) of the resting electroencephalogram (EEG). However, PD has also been associated with a reduction in the proportion of total power across all frequency bands. This discrepancy may be explained by aperiodic activity (exponent and offset) present across all frequency bands. Here, we examined differences in the eyes-open and eyes-closed resting EEG of PD participants (N = 26) on and off medication, and age-matched controls (CTL; N = 26). We extracted power from canonical frequency bands using traditional methods (total alpha and beta power) and extracted separate parameters for periodic (parameterized alpha and beta power) and aperiodic activity (exponent and offset). Cluster-based permutation tests over spatial and frequency dimensions indicated that total alpha and beta power, and aperiodic exponent and offset were greater in PD participants, independent of medication status. After removing the exponent and offset, greater alpha power in PD (vs. CTL) was only present in eyes-open recordings and no reliable differences in beta power were observed. Differences between PD and CTLs in the resting EEG are likely driven by aperiodic activity, suggestive of greater relative inhibitory neural activity and greater neuronal spiking. Our findings suggest that resting EEG activity in PD is characterized by medication-invariant differences in aperiodic activity which is independent of the increase in alpha power with EO. This highlights the importance of considering aperiodic activity contributions to the neural correlates of brain disorders.

neuroscience↗

bioRxiv2023

High pathogenicity avian influenza (H5N1) in Northern Gannets: Global spread, clinical signs, and demographic consequences

During 2021-22 High Pathogenicity Avian Influenza (HPAI) killed thousands of wild birds across Europe and North America, suggesting a change in infection dynamics and a shift to new hosts, including seabirds. Northern Gannets (Morus bassanus) appeared especially severely impacted, but limited understanding of how the virus spread across the metapopulation, or the demographic consequences of mass mortality limit our understanding of its severity. Accordingly, we collate information on HPAIV outbreaks across most North Atlantic gannet colonies and for the largest colony (Bass Rock, UK), provide impacts on population size, breeding success, adult survival, and preliminary results on serology. Unusually high numbers of dead gannets were first noted in Iceland during April 2022. Outbreaks in May occurred in many Scottish colonies, followed by colonies in Canada, Germany and Norway. By the end of June, outbreaks had occurred in five Canadian colonies and in the Channel Islands. Outbreaks in 12 UK and Ireland colonies appeared to follow a clockwise pattern with the last infected colonies recorded in late August/September. Unusually high mortality was recorded at 40 colonies (75% of global total colonies). Dead birds testing positive for HPAIV H5N1 were associated with 58% of these colonies. At Bass Rock, the number of occupied sites decreased by at least 71%, breeding success declined by [~]66% compared to the long-term UK mean and adult survival between 2021 and 2022 was 42% lower than the preceding 10-year average. Serological investigation detected antibodies specific to H5 in apparently healthy birds indicating that some gannets recover from HPAIV infection. Further, most of these recovered birds had black irises, suggestive of a phenotypic indicator of previous infection. Untangling the impacts of HPAIV infection from other key pressures faced by seabirds is key to establishing effective conservation strategies for threatened seabird populations, HPAIV being a novel and pandemic threat.

ecology↗

bioRxiv2023

Whole-genome sequencing confirms multiple species of Galapagos giant tortoises

Galapagos giant tortoises are endemic to the Galapagos Archipelago, where they are found in isolated populations. While these populations are widely considered distinguishable in morphology, behavior, and genetics, the recent divergence of these taxa has made their status as species controversial. Here, we apply multispecies coalescent methods for species delimitation to whole genome resequencing data from 38 tortoises across all 13 extant taxa to assess support for delimiting these taxa as species. In contrast to previous studies based solely on divergence time, we find strong evidence to reject the hypothesis that all Galapagos giant tortoises belong to a single species. Instead, a conservative interpretation of model-based and divergence-based results indicates that these taxa form a species complex consisting of a minimum of 9 species, with some analyses supporting as many as 13 species. There is mixed support for the species status of taxa living on the same island, with some methods delimiting them as separate species and others suggesting multiple populations of a single species per island. These results make clear that Galapagos giant tortoise taxa represent different stages in the process of speciation, with some taxa further along in that evolutionary process than others. A better understanding of the more complex parts of that process is urgently needed, given the threatened status of Galapagos giant tortoises. Lay SummarySpecies delimitation is a challenging problem in evolutionary biology, but one that is central to the field. Distinguishing species can affect conservation management practices, from conservation status assessments to strategies for breeding programs. More fundamentally, understanding species boundaries affects our ability to assess biodiversity and to study evolutionary processes. The Galapagos Archipelago presents several radiations of closely related taxa that inspired Charles Darwin to develop his theory of evolution by natural selection and later led to foundational case studies in speciation. The Galapagos giant tortoises were one such inspiration. Nearly two centuries later, there is still an ongoing debate about the taxonomic status of these tortoises, with opinions on their status ranging from barely differentiated populations to separate species. Here, we present the first genomic species delimitation of Galapagos giant tortoises and provide convincing evidence that this group is a complex consisting of between 9 and 13 species. These results provide valuable guidance to conservation stakeholders in the Galapagos, while also adding an important case study to the delimitation of island species.

evolutionary biology↗

bioRxiv2023

The Genome of the Soybean Gall Midge (Resseliella maxima)

The cecidomyiid fly, soybean gall midge, Resseliella maxima Gagne, is a recently discovered insect that feeds on soybean plants in the Midwest US. Resseliella maxima larvae feed on soybean stems which may induce plant death and can cause considerable yield losses, making it an important agricultural pest. From three pools of 50 adults each, we used long-read nanopore sequencing to assemble a R. maxima reference genome. The final genome assembly is 206 Mb with 64.88X coverage, consisting of 1009 contigs with an N50 size of 714 kb. The assembly is high quality with a BUSCO score of 87.8%. Genome-wide GC level is 31.60% and DNA methylation was measured at 1.07%. The R. maxima genome is comprised of 21.73% repetitive DNA, which is in line with other cecidomyiids. Protein prediction annotated 14,798 coding genes with 89.9% protein BUSCO score. Mitogenome analysis indicated that R. maxima assembly is a single circular contig of 15,301 bp and shares highest identity to the mitogenome of the Asian rice gall midge, Orseolia oryzae (Wood-Mason). The R. maxima genome has one of the highest completeness levels for a cecidomyiid and will provide a resource for research focused on the biology, genetics, and evolution of cecidomyiids, as well as plant-insect interactions in this important agricultural pest.

genomics↗

bioRxiv2023

Extensive hybridisation between multiple differently adapted species may aid persistence in a changing climate

Hybridisation and gene flow can have both deleterious and adaptive consequences for natural populations and species. To better understand the extent and consequences of hybridisation in nature, information on naturally hybridising non-model organisms is required, including characterising the structure and extent of natural hybrid zones. Here we study natural populations of five keystone mound-building wood ant (Formica rufa group) species across Finland. No genomic studies across the species group exist and the extent of hybridisation and genomic differentiation in sympatry is unknown. Combining genome-wide and morphological data, we show that Formica rufa, F. aquilonia, F. lugubris, and F. pratensis form distinct gene pools in Finland. We demonstrate more extensive hybridisation than previously thought between all five species and reveal a mosaic hybrid zone between F. aquilonia, F. rufa and F. polyctena. We show that hybrids between these climatically differently adapted species occupy warmer habitats than the cold-adapted parent F. aquilonia. This suggests hybrids occupy a different microclimatic niche compared to the locally abundant parent. We propose that wood ant hybridisation may increase with a warming climate, and warm winters, in particular, may provide a competitive advantage for the hybrids over F. aquilonia in the future. In summary, our results demonstrate how extensive hybridisation may help persistence in a changing climate. Additionally, they provide an example on how mosaic hybrid zones can have significant ecological and evolutionary consequences because of their large extent and independent hybrid populations that face both ecological and intrinsic selection pressures.

evolutionary biology↗

bioRxiv2022

An alpaca-derived nanobody neutralizes the SARS-CoV-2 omicron variant

The SARS-CoV2 Omicron variant sub-lineages spread rapidly through the world, mostly due to their immune-evasive properties. This has put a significant part of the population at risk for severe disease and underscores the need for anti-SARS-CoV-2 agents that are effective against emergent strains in vulnerable patients. Camelid nanobodies are attractive therapeutic candidates due to their high stability, ease of large-scale production and potential for delivery via inhalation. Here, we characterize the RBD-specific nanobody W25, which we previously isolated from an alpaca, and show superior neutralization activity towards Omicron lineage BA.1 in comparison to all other SARS-CoV2 variants. Structure analysis of W25 in complex with the SARS-CoV2 spike surface glycoprotein shows that W25 engages an RBD epitope not covered by any of the antibodies previously approved for emergency use. Furthermore, we show that W25 also binds the spike protein from the emerging, more infectious Omicron BA.2 lineage with picomolar affinity. In vivo evaluation of W25 prophylactic and therapeutic treatments across multiple SARS-CoV-2 variant infection models, together with W25 biodistribution analysis in mice, demonstrates favorable pre-clinical properties. Together, these data endorse prioritization of W25 for further clinical development.

microbiology↗

bioRxiv2022

FBXL4 suppresses mitophagy by restricting the accumulation of NIX and BNIP3 mitophagy receptors

Cells selectively remove damaged or excessive mitochondria through mitophagy, a specialized form of autophagy, to maintain mitochondrial quality and quantity. Mitophagy is induced in response to diverse conditions, including hypoxia, cellular differentiation, and mitochondrial damage. However, the mechanisms by which cells remove specific dysfunctional mitochondria under steady-state conditions to fine-tune mitochondrial content are not well understood. Here, we report that SCFFBXL4, an SKP1/CUL1/F-box protein ubiquitin ligase complex, localizes to the mitochondrial outer membrane in unstressed cells and mediates the constitutive ubiquitylation and degradation of the mitophagy receptors NIX and BNIP3 to suppress basal levels of mitophagy. We demonstrate that, unlike wild-type FBXL4, pathogenic variants of FBXL4 that cause encephalopathic mtDNA depletion syndrome (MTDPS13), do not efficiently interact with the core SCF ubiquitin ligase machinery or mediate the degradation of NIX and BNIP3. Thus, we reveal a molecular mechanism that actively suppresses mitophagy via preventing NIX and BNIP3 accumulation and propose that excessive basal mitophagy in the FBXL4-associated mtDNA depletion syndrome is caused by dysregulation of NIX and BNIP3 turnover. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=195 SRC="FIGDIR/small/511867v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@19c97f6org.highwire.dtl.DTLVardef@1bca5a3org.highwire.dtl.DTLVardef@1e9419org.highwire.dtl.DTLVardef@18d28a9_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2022

Patterning and growth are coordinated early in the cell cycle

Precise control of cell division is essential for proper patterning and growth during the development of multicellular organisms. Coordination of formative (asymmetric) divisions that generate new tissue patterns with proliferative (symmetric) divisions that promote growth is poorly understood. Here, we employed quantitative 4D light sheet and confocal microscopy to probe in vivo the dynamics of two transcription factors, SHORTROOT (SHR) and SCARECROW (SCR), which are required for asymmetric division in the stem cell niche of Arabidopsis roots [1,2]. Long-term (up to 48 hours), frequent (every 15 minutes) imaging of the two regulators in tandem in single cells, in conjunction with a SHR induction system, enabled us to challenge an existing bistable model[3] of the SHR/SCR gene regulatory network. By directly controlling SHR and SCR expression dynamics, we were able to identify key features that are essential for rescue of asymmetric division in shr mutants. We show that instead of high stable levels of nuclear SHR and SCR, only low transient levels of expression are required. Nuclear SHR kinetics do not follow predictions of the bistable model, and the regulatory relationship between SHR and SCR can be modeled by monostable alternatives. Furthermore, expression of these two regulators early in the cell cycle determines the orientation of the division plane, resulting in either formative or proliferative cell division. Our findings provide evidence for an uncharacterized mechanism by which developmental regulators directly coordinate patterning and growth.

developmental biology↗

bioRxiv2022

The Ecosystem Integrity Index: a novel measure of terrestrial ecosystem integrity with global coverage

While the importance of ecosystem integrity has long been recognised (Leopold, 1949), conservation science has tended to focus on measuring and monitoring species and habitats, avoiding the complexities of working at the ecosystem level. Ecosystems are highly dynamic, defined by both living and non-living components as well as their interactions (CBD, 1992), making it difficult to assess baseline levels of integrity. We present a novel index that represents the integrity of all terrestrial ecosystems globally at 1km2 resolution: the Ecosystem Integrity Index (EII). The index provides a simple, yet scientifically robust, way of measuring, monitoring and reporting on ecosystem integrity. It is formed of three components; structural, compositional and functional integrity, and measured against a natural (current potential) baseline on a scale of 0 to 1. We find that ecosystem integrity is severely impacted in terrestrial areas across the globe with approximately one fifth of all ecosystems and one quarter of all ecoregions having lost, on average, over half of their ecosystem integrity. At a national scale, we estimate similar challenges with 115 nations or territories having lost, on average, over half of their ecosystem integrity. This presents a significant threat for humanity as such levels of degradation are likely to be linked to substantial declines in the ecosystem services on which humanity is reliant. The EII has been developed principally to help national governments measure and report on Goal A of the Kunming-Montreal Global Biodiversity Framework (GBF) (CBD, 2022a), for which it has been listed as a Component Indicator. The EII will also be useful in helping non-state actors measure and report their contributions to the GBF and is listed as an indicator by both the Taskforce for Nature-Related Financial Disclosures (TNFD) (TNFD, 2023) and the Science Based Targets Network (SBTN) (SBTN, 2023). The EII aims to enable these actors to make informed decisions on the conservation, restoration and sustainable use of ecosystems for which they are wholly or partly responsible. We propose that with sufficient effort, ecosystem integrity can be restored and contribute towards the GBFs vision of living in harmony with nature, resulting in the safeguarding of the ecosystem services on which humanity depends.

ecology↗

bioRxiv2022

Post-vaccination Omicron infections induce broader immunity across antigenic space than prototype mRNA COVID-19 booster vaccination or primary infection

The rapid emergence of new SARS-CoV-2 variants challenges vaccination strategies. Here, we measured antigenic diversity among variants and interpreted neutralizing antibody responses following single and multiple exposures in longitudinal infection and vaccine cohorts. Antigenic cartography using primary infection antisera showed that BA.2, BA.4/BA.5, and BA.2.12.1 are distinct from BA.1 and closer to the Beta cluster. Three doses of an mRNA COVID-19 vaccine increased breadth to BA.1 more than to BA.4/BA.5 or BA.2.12.1. Omicron BA.1 post-vaccination infection elicited antibody landscapes characterized by broader immunity across antigenic space than three doses alone, although with less breadth than expected to BA.2.12.1 and BA.4/BA.5. Those with Omicron BA.1 infection after two or three vaccinations had similar neutralizing titer magnitude and antigenic breadth. Accounting for antigenic differences among variants of concern when interpreting neutralizing antibody titers aids understanding of complex patterns in humoral immunity and informs selection of future COVID-19 vaccine strains.

microbiology↗

bioRxiv2022

Genotyping, sequencing and analysis of 140,000 adults from the Mexico City Prospective Study

The Mexico City Prospective Study (MCPS) is a prospective cohort of over 150,000 adults recruited two decades ago from the urban districts of Coyoacan and Iztapalapa in Mexico City. We generated genotype and exome sequencing data for all individuals, and whole genome sequencing for 10,000 selected individuals. We uncovered high levels of relatedness and substantial heterogeneity in ancestry composition across individuals. Most sequenced individuals had admixed Native American, European and African ancestry, with extensive admixture from indigenous groups in Central, Southern and South Eastern Mexico. Native Mexican segments of the genome had lower levels of coding variation, but an excess of homozygous loss of function variants compared with segments of African and European origin. We estimated population specific allele frequencies at 142 million genomic variants, with an effective sample size of 91,856 for Native Mexico at exome variants, all available via a public browser. Using whole genome sequencing, we developed an imputation reference panel which outperforms existing panels at common variants in individuals with high proportions of Central, South and South Eastern Native Mexican ancestry. Our work illustrates the value of genetic studies in populations with diverse ancestry and provides foundational imputation and allele frequency resources for future genetic studies in Mexico and in the United States where the Hispanic/Latino population is predominantly of Mexican descent.

genetics↗

bioRxiv2022

CRISPR metabolic screen identifies ATM and KEAP1 as targetable genetic vulnerabilities in solid tumors.

Cancer treatments targeting DNA repair deficiencies often encounter drug resistance, possibly due to alternative metabolic pathways that counteract the most damaging effects. To identify such alternative pathways, we screened for metabolic pathways exhibiting synthetic lethality with inhibition of the DNA damage response kinase ATM using a metabolism-centered CRISPR/Cas9 library. Our data revealed Kelch-like ECH-associated protein 1 (KEAP1) as a key factor involved in desensitizing cancer cells to ATM inhibition both in vitro and in vivo. Cells depleted of KEAP1 exhibited an aberrant overexpression of the cystine transporter SLC7A11, robustly accumulated cystine inducing disulfide stress, and became hypersensitive to ATM inhibition. These hallmarks were reversed in a reducing cellular environment indicating that disulfide stress was a crucial factor. In the TCGA pan-cancer datasets, we found that ATM levels strongly correlated with KEAP1 levels across multiple solid malignancies. Together, our results unveil ATM and KEAP1 as new targetable vulnerabilities in solid tumors.

cancer biology↗

bioRxiv2022

Dual orexin antagonist DORA-22 suppressed posttraumatic seizures and enhances GABAergic inhibition in dentate granule cells

BackgroundTraumatic brain injury (TBI) can result in posttraumatic epilepsy (PTE) and sleep disturbances. We hypothesized that treatment with sleep aids after TBI can ameliorate PTE. MethodsCD-1 mice underwent controlled cortical impact (CCI), sham craniotomy or no craniotomy. Sham and CCI groups underwent a month-long treatment with sleep aids including a dual orexin antagonist (DORA-22) or THIP (gaboxadol). We performed week-long EEG recordings during week-1 of treatment and again at months 1, 2 and 3. Seizure analysis occurred at all-time points and sleep analysis occurred in week-1 and month-1 recordings in all groups. Subsets of animals in sleep aid-treated and untreated CCI, and sham groups were subjected to voltage clamp experiments. ResultsDORA-22 treated group had seizures at week-1 but none at months 1-3. TBI reduced amplitude and frequency of miniature inhibitory synaptic currents (mIPSCs) in dentate granule cells and these changes were rescued by DORA-22 treatment. Sleep analysis showed that DORA-22 increased non-rapid eye movement sleep (NREM) in the first 4hours of lights-off whereas THIP increased REM sleep in the first 4-hours of lights-on in week-1, At month-1 both treatments reduced time in NREM during lights-off. TBI increased NREM delta power (N{Delta}) along with loss of the homeostatic overnight decline of N{Delta} in week-1 regardless of treatment. DORA-22 and THIP treatment restored N{Delta} to levels similar to no craniotomy animals at month-1. ConclusionsDORA-22 treatment suppressed posttraumatic seizures possibly due to enhanced GABAergic inhibition in dentate granule cells. DORA-22 may have therapeutic potential in suppressing PTE. Summary for Social MediaTraumatic brain injury (TBI) can result is posttraumatic epilepsy and sleep disturbances. There are no treatments to prevent these complications. We tested whether treatment with sleep aids after TBI can mitigate seizures and sleep disturbances. We found that a sleep aid DORA-22 but not THIP suppressed post traumatic seizures possibly be enhancing GABAergic inhibition in the hippocampus. Sleep analysis showed that TBI disrupts the sleep homeostatic drive and DORA treatment restored it. Findings may lead to potential disease modifying therapy for posttraumatic epilepsy.

neuroscience↗

bioRxiv2022

Single Nucleus RNA Sequencing of Pre-Malignant Liver Reveals Disease-Associated Hepatocyte State with HCC Prognostic Potential

Current approaches to stage chronic liver diseases have limited utility to directly predict liver cancer risk. Here, we employed single nucleus RNA sequencing (snRNA-seq) to characterize the cellular microenvironment of healthy and chronically injured pre-malignant livers using two distinct mouse models. Analysis of 40,748 hepatic nuclei unraveled a previously uncharacterized disease-associated hepatocyte transcriptional state (daHep). These cells were absent in healthy livers, but were increasingly prevalent as chronic liver disease progressed towards hepatocarcinogenesis. Gene expression deconvolution of 1,439 human liver transcriptomes from publicly available datasets revealed that daHep frequencies highly correlate with current histopathological liver disease staging systems. Importantly, we show that high daHep levels precede carcinogenesis in mice and humans and predict a higher risk of hepatocellular carcinoma (HCC) development. This novel transcriptional signature with diagnostic and, more importantly, prognostic significance has the potential to change the way chronic liver disease patients are staged, surveilled and risk-stratified.

cancer biology↗