Biology subjects

Thomas, K.

Publications and source records attributed to Thomas, K..

31 records · Page 2Linked to original sources

bioRxiv2023

Neuronal and Astrocyte Insulin-like Growth Factor-1 Signaling Differentially Modulates Ischemic Stroke Damage

Ischemic stroke is a leading cause of death and disability, as therapeutic options for mitigating the long-term deficits precipitated by the event remain limited. Acute administration of the neuroendocrine modulator insulin-like growth factor-1 (IGF-1) attenuates ischemic stroke damage in preclinical models, and clinical studies suggest IGF-1 can reduce the risk of stroke and improve overall outcomes. The cellular mechanism by which IGF-1 exerts this protection is poorly defined, as all cells within the neurovascular unit express the IGF-1 receptor. We hypothesize that the functional regulation of both neurons and astrocytes by IGF-1 is critical in minimizing damage in ischemic stroke. To test this, we utilized inducible astrocyte-specific or neuron-specific transgenic mouse models to selectively reduce IGF-1R in the adult mouse brain prior to photothrombotic stroke. Acute changes in blood brain barrier permeability, microglial activation, systemic inflammation, and biochemical composition of the brain were assessed 3 hours following photothrombosis, and significant protection was observed in mice deficient in neuronal and astrocytic IGF-1R. When the extent of tissue damage and sensorimotor dysfunction was assessed for 3 days following stroke, only the neurological deficit score continued to show improvements, and the extent of improvement was enhanced with additional IGF-1 supplementation. Overall, results indicate that neuronal and astrocytic IGF-1 signaling influences stroke damage but IGF-1 signaling within these individual cell types is not required for minimizing tissue damage or behavioral outcome.

neuroscience↗

bioRxiv2023

Myomatrix arrays for high-definition muscle recording

Neurons coordinate their activity to produce an astonishing variety of motor behaviors. Our present understanding of motor control has grown rapidly thanks to new methods for recording and analyzing populations of many individual neurons over time. In contrast, current methods for recording the nervous systems actual motor output - the activation of muscle fibers by motor neurons - typically cannot detect the individual electrical events produced by muscle fibers during natural behaviors and scale poorly across species and muscle groups. Here we present a novel class of electrode devices ("Myomatrix arrays") that record muscle activity at unprecedented resolution across muscles and behaviors. High-density, flexible electrode arrays allow for stable recordings from the muscle fibers activated by a single motor neuron, called a "motor unit", during natural behaviors in many species, including mice, rats, primates, songbirds, frogs, and insects. This technology therefore allows the nervous systems motor output to be monitored in unprecedented detail during complex behaviors across species and muscle morphologies. We anticipate that this technology will allow rapid advances in understanding the neural control of behavior and in identifying pathologies of the motor system.

neuroscience↗

bioRxiv2023

First record of highly invasive Chinese sleeper Perccottus glenii Dybowski, 1877 (Perciformes: Odontobutidae) in the Elbe River Basin, Czechia

The Chinese sleeper (Perccottus glenii) has invaded European freshwaters and we present evidence of its first documented occurrence in the Elbe River basin in Czechia. The individual fish was caught by a fisherman and posted on social media. After immediately contacting the person in question, we obtained a live fish from him. The Chinese sleeper appears to have been present in interconnected ponds and streams for ten years and may have spread over a larger area. We recommend that eradication measures be implemented to prevent further spread. Statement of SignificanceThe Chinese sleeper has invaded many European countries in the last 50 years, and it is expected to invade western Europe because of the favourable conditions for its establishment. This finding indicates that it could spread in the Elbe River Basin, which could have serious impacts on floodplain and wetland ecosystems. To prevent this scenario, eradication measures should be implemented.

ecology↗

bioRxiv2022

The fidelity of transcription in human cells

Accurate transcription is required for the faithful expression of genetic information. To provide insight into the molecular mechanisms that control the fidelity of transcription, we analyzed the landscape of transcription errors in human embryonic stem cells. These measurements provide the first reasonable estimate of the fidelity of transcription in human cells and identify multiple genetic and epigenetic factors that control its accuracy. In addition, we developed a new reporter mouse to identify cell types and tissues that commit these errors the most. These experiments revealed that CA1 and dentate gyrus neurons are highly sensitive to transcriptional mutagenesis, lending new support to the hypothesis that transcription errors play a role in the progression of Alzheimers disease. Taken together, these experiments provide unprecedented insight into the fidelity of gene expression in human cells and the molecular mechanisms that govern the central dogma of life.

genetics↗

bioRxiv2022

Cross-kingdom metagenomic profiling of Lake Hillier reveals pigment-rich polyextremophiles and wide-ranging metabolic adaptations

Background Lake Hillier is a hypersaline lake known for its distinctive bright pink color. The cause of this phenomenon in other hypersaline sites has been attributed to halophiles, Dunaliella, and Salinibacter, however, a systematic analysis of the microbial communities, their functional features, and the prevalence of pigment-producing-metabolisms has not been previously studied. Our results are evidence that Lake Hillier is composed of a diverse set of microorganisms including archaea, bacteria, algae, and viruses. Our data indicate a core microbiome in Lake Hillier composed of multiple pigment-producer microbes, many of which are cataloged as polyextremophiles. Additionally, we estimated the diversity of metabolic pathways in the lake and determined that many of these are related to pigment production. We reconstructed complete or partial genomes for 21 discrete bacteria (N = 14) and archaea (N = 7), only 2 of which could be taxonomically annotated to previously observed species. Our findings provide the first metagenomic study to decipher the source of the pink color of Australias Lake Hillier. The study of this pink hypersaline environment is evidence of a microbial consortium of pigment producers, a repertoire of polyextremophiles, a core microbiome and potentially novel species.

microbiology↗

bioRxiv2021

Leukocyte adhesion is governed by endolysosomal two pore channel 2 (TPC2)

In response to pro-inflammatory challenges including pathogenic attack and tissue damage, the endothelial cell surface is rearranged to present leukocyte-engaging cell surface receptors. The initial contact needed for leukocyte tethering and rolling is mediated via adhesion demand-driven exocytosis of Weibel-Palade bodies (WPB) that contain the leukocyte receptor P-selectin together with the stabilizing co-factor CD63. We found that diminished expression of the endolysosomal non-selective cation channel TPC2 or inhibition of TPC2-mediated Ca2+-release via trans-Ned 19 led to reduced endolysosomal Ca2+ efflux, and blocked transfer of CD63 from late endosomes/lysosomes (LEL) to WPB, and a concomitant loss of P-selectin on the endothelial cell surface. Accordingly, P-selectin-mediated leukocyte recruitment to trans-Ned 19-treated HUVEC under flow was significantly reduced without disturbing VWF exocytosis. Our findings establish the endolysosome-related TPC2 Ca2+ channel as a key element in the maintenance of proper endothelial functions and a potential pharmacological target in the control of inflammatory leukocyte recruitment.

immunology↗

bioRxiv2021

Pharmacokinetic Effects of Combined Exposure to Nicotine and THC via E-Cigarettes in Pregnant Rats

Nicotine and cannabis are two of the most commonly consumed licit and illicit drugs during pregnancy, often consumed together via e-cigarettes. Vaping is assumed to be a safer alternative than traditional routes of consumption, yet the potential consequences of prenatal e-cigarette exposure are largely unknown, particularly when these two drugs are co-consumed. In a novel co-exposure model, pregnant Sprague-Dawley rats received nicotine (36 mg/mL), THC (100 mg/mL), the combination, or the vehicle via e-cigarettes daily from gestational days 5-20, mimicking the first and second human trimesters. Maternal blood samples were collected throughout pregnancy to measure drug and metabolite levels, and core body temperatures before and after exposure were also measured. Pregnant dams exposed to combined nicotine and THC had lower plasma nicotine and cotinine levels than those exposed to nicotine alone; similarly, the combined exposure group also had lower plasma THC and THC metabolite (THC-OH and THC-COOH) levels than those exposed to THC alone. Prenatal nicotine exposure gradually decreased basal core body temperatures each day, with chronic exposure, whereas exposure to THC alone decreased temperatures during the individual sessions. Despite these physiological effects, no changes were observed in food or water intake, weight gain, or basic litter outcomes. These data suggest that combined exposure to nicotine and THC elicits both separate and interactive physiological effects of nicotine and THC on pregnant dams. These data and use of this model can help improve education for pregnant mothers about prenatal e-cigarette use and has important implications for public policy. HIGHLIGHTSO_LIRepeated prenatal nicotine exposure via e-cigarettes gradually decreased temperatures C_LIO_LIPrenatal THC exposure via e-cigarettes decreased temperatures during intoxication C_LIO_LICombined prenatal exposure via e-cigarettes altered plasma drug and metabolite levels C_LIO_LIThis co-exposure model elicits separate and interactive effects of nicotine and THC C_LI

pharmacology and toxicology↗

bioRxiv2021

Distinct Patterns of Emergence of SARS-CoV-2 Spike Variants including N501Y in Clinical Samples in Columbus Ohio

Following the worldwide emergence of the p.Asp614Gly shift in the Spike (S) gene of SARS-CoV-2, there have been few recurring pathogenic shifts occurring during 2020, as assessed by genomic sequencing. This situation has evolved in the last several months with the emergence of several distinct variants (first identified in the United Kingdom and South Africa) that manifest multiple changes in the S gene, particularly p.Asn501Tyr (N501Y), that likely have clinical impact. We report here the emergence in Columbus, Ohio in December 2020 of two novel SARS-CoV-2 clade 20G variants. One variant, that has become the predominant virus found in nasopharyngeal swabs in the December 2020-January 2021 period, harbors S p.Gln677His (Q677H), affecting a consensus QTQTN domain near the S1/S2 furin cleavage site, nucleocapsid (N) p.Asp377Tyr (D377Y) and membrane glycoprotein (M) p.Ala85Ser (A85S) mutations, with additional S mutations in subsets. The other variant present in two samples, contains S N501Y, which is a marker of the UK-B.1.1.7 (clade 20I/501Y.V1) strain, but lacks all other mutations from that virus. The Ohio variant is from a different clade and shares multiple mutations with the clade 20G viruses circulating in the area prior to December 2020. These two SARS-CoV-2 viruses, which we show are also present and evolving currently in several other parts of North America, add to the diversity of S gene shifts occurring worldwide. These and other shifts in this period of the pandemic support multiple independent acquisition of functionally significant and potentially complementing mutations affecting the S QTQTN site (Q675H or Q677H) and certain receptor binding domain mutations (e.g., E484K and N501Y).

genomics↗

bioRxiv2019

Beyond Conventional Models: Recreating the Initiation, Evolution, and Genome of GBM

BackgroundImagining ways to prevent or treat glioblastoma (GBM) have been hindered by a lack of understanding of its pathogenesis. Although PDGF-AA overexpression may be an early event, critical details of the core biology are lacking. Existing PDGF-driven models replicate its microscopic appearance but not the genomic architecture characteristic of the human disease. Here we report a new model of GBM that overcomes this barrier to authenticity. MethodsUsing a method developed to study neural stem cells, we investigated the effects of PDGF-AA on subventricular zone (SVZ) cells, the putative cell of origin of GBM. We micro-dissected SVZ tissue from p53-null and wild-type adult mice, established primary cultures in media supplemented with PDGF-AA, and assessed cell viability, proliferation, genome stability, and tumour forming potential. ResultsCounterintuitive to its canonical role as a growth factor, we observed immediate and massive death of SVZ cells in PDGF-AA. Wild-type cells did not survive in PDGF-AA. However, a small fraction of null cells evaded apoptosis, displayed attenuated proliferation, gradually accumulated whole chromosome gains and losses, and, signalled by sudden rapid proliferation and growth factor independence, became tumorigenic in immune-competent syngeneic mice. Transformed cells had an OPC-like profile, were resistant to PDGFR- inhibition, and harboured highly abnormal karyotypes similar to those seen in human GBMs. ConclusionThis model associates genome instability in SVZ cells with chronic exposure to PDGF-AA; it is the first model to replicate the genomic landscape of GBM and first in which the earliest phases of GBM can be directly observed. IMPORTANCE OF STUDYWe have developed a mouse model in which the initiation, evolution and genomic landscape of GBM can be thoroughly studied thus paving the way for ideas about how this deadly brain cancer might be prevented, interrupted at an occult stage, or treated with very different therapies.

cancer biology↗

bioRxiv2019

Early life stress impairs social function through AVP-dependent mechanisms

Impaired social function is a core feature of many psychiatric illnesses. Adverse experiences during childhood increase risk for mental illness, however it is currently unclear whether stress early in life plays a direct role in the development of social difficulties. Using an animal model of pre-pubertal stress (PPS), we investigated effects on social behaviour, oxytocin and arginine vasopressin (AVP). We also explored social performance and AVP expression in participants with borderline personality disorder (BPD) who experienced a high incidence of childhood stress. Social behaviour was impaired and AVP expression increased in animals experiencing PPS and participants with BPD. Behavioural deficits in animals were rescued through administration of the AVP receptor 1a antagonist Relcovaptan (SR49059). AVP levels and recognition of negative emotions were significantly correlated in BPD participants only. In conclusion, early life stress plays a profound role in the precipitation of social dysfunction, and AVP mediates at least part of this effect.

neuroscience↗

bioRxiv2019

Altered hypothalamic microstructure in human obesity

Obesity is a multifactorial disorder driven by sustained energy imbalance. The hypothalamus is an important regulator of energy homeostasis and therefore likely involved in obesity pathophysiology. Animal studies suggest that obesity-related diets induce structural changes in the hypothalamus through inflammation-like processes. Whether this translates to humans is however largely unknown. Therefore, we aimed to assess obesity-related differences in hypothalamic macro- and microstructure based on a multimodal approach using T1-weighted and diffusion-weighted magnetic resonance imaging (MRI) acquired at 3 Tesla in a large well-characterized sample of the Leipzig Research Center for Civilization Diseases (LIFE) cohort (n1 = 338, 48% females, age 21-78 years, BMI 18-43 kg/m2). We found that higher body mass index (BMI) selectively predicted higher mean proton diffusivity (MD) within the hypothalamus, indicative of compromised microstructure in the underlying tissue. Results were independent from confounders and confirmed in another independent sample (n2 = 236). In addition, while hypothalamic volume was not associated with obesity, we identified a sexual dimorphism and larger hypothalamic volumes in the left compared to the right hemisphere. Using two large samples of the general population, we showed that a higher BMI specifically relates to altered microstructure in the hypothalamus, independent from confounders such as age, sex and obesity-associated co-morbidities. This points to persisting microstructural changes in a key regulatory area of energy homeostasis occurring with excessive weight. These findings may help to better understand the pathomechanisms of obesity and other eating-related disorders.

neuroscience↗

bioRxiv2018

Modulation of ERK1/MAPK3 potentiates ERK nuclear signalling, facilitates neuronal cell survival and improves memory in mouse models of neurodegenerative disorders

Cell signalling mechanisms are central to neuronal activity and their dysregulation may lead to neurodegenerative processes and associated cognitive decline. So far, a major effort has been directed toward the dissection of disease specific pathways with the still unmet promise to develop precision medicine strategies. With a different approach, here we show that a selective genetic potentiation of neuronal ERK signalling prevents cell death in vitro and in vivo in the mouse brain while ERK attenuation does the opposite. This neuroprotective effect can also be induced pharmacologically by a cell permeable peptide mimicking the loss of ERK1 MAP kinase, leading to a selective enhancement of ERK2 mediated nuclear cell signalling. The drug treatment prevents neurodegeneration in mouse models of Huntingtons (HD), Alzheimers (AD), and Parkinsons disease (PD). Importantly, the selective potentiation of ERK2 signalling facilitates both structural and synaptic plasticity, enhances cognition in healthy mice and rescues mild cognitive impairments in both models of AD and HD. Altogether, our observation truly represents a remarkable example of a shared molecular mechanism across multiple neurodegenerative disorders and a potentially valuable therapeutic target for neuro-enhancement.

neuroscience↗

bioRxiv2018

Divergent selection and drift shape the genomes of two avian sister species spanning a saline-freshwater ecotone

The role of species divergence due to ecologically-based divergent selection - or ecological speciation - in generating and maintaining biodiversity is a central question in evolutionary biology. Comparison of the genomes of phylogenetically related taxa spanning a selective habitat gradient enables discovery of divergent signatures of selection and thereby provides valuable insight into the role of divergent ecological selection in speciation. Tidal marsh ecosystems provide tractable opportunities for studying organisms adaptations to selective pressures that underlie ecological divergence. Sharp environmental gradients across the saline-freshwater ecotone within tidal marshes present extreme adaptive challenges to terrestrial vertebrates. Here we sequence 20 whole genomes of two avian sister species endemic to tidal marshes - the Saltmarsh Sparrow (Ammodramus caudacutus) and Nelsons Sparrow (A. nelsoni) - to evaluate the influence of selective and demographic processes in shaping genome-wide patterns of divergence. Genome-wide divergence between these two recently diverged sister species was notably high (genome-wide FST = 0.32). Against a background of high genome-wide divergence, regions of elevated divergence were widespread throughout the genome, as opposed to focused within islands of differentiation. These patterns may be the result of genetic drift acting during past tidal march colonization events in addition to divergent selection to different environments. We identified several candidate genes that exhibited elevated divergence between Saltmarsh and Nelsons sparrows, including genes linked to osmotic regulation, circadian rhythm, and plumage melanism - all putative candidates linked to adaptation to tidal marsh environments. These findings provide new insights into the roles of divergent selection and genetic drift in generating and maintaining biodiversity.

evolutionary biology↗