Biology subjects

Barker, H.

Publications and source records attributed to Barker, H..

5 recordsLinked to original sources

bioRxiv2020

Ovarian carcinosarcoma genomics and pre-clinical models highlight the N-MYC pathway as a key driver and susceptibility to EMT-targeting therapy

Ovarian carcinosarcoma (OCS) is an aggressive and rare tumour type with limited treatment options. OCS is hypothesised to develop via the combination theory from a single progenitor, resulting in carcinomatous and sarcomatous components, or alternatively via the conversion theory, with the sarcomatous component developing from the carcinomatous component through epithelial-to-mesenchymal transition (EMT). We show OCS from 18 women to be monoclonal through analysis of DNA variants from isolated carcinoma and sarcoma components. RNA sequencing indicated the carcinoma components were more mesenchymal when compared with pure ovarian carcinomas, supporting the conversion theory. We used pre-clinical OCS models to test the efficacy of microtubule-targeting drugs, including eribulin, which has been shown to reverse EMT characteristics. We demonstrated that microtubule inhibitors, vinorelbine and eribulin, were more effective than standard-of-care platinum-based chemotherapy. Eribulin reduced mesenchymal characteristics, N-MYC expression and cholesterol biosynthesis. Finally, eribulin induced a strong immune response, supporting immunotherapy combinations in the clinic.

cancer biology↗

bioRxiv2020

Daily and Intermittent Smoking Decrease Gray Matter Volume and Concentrations of Glutamate, Creatine, Myo-Inositol and N-acetylaspartate in the Prefrontal Cortex

Cigarette smoking is still the largest contributor to disease and death worldwide. Successful cessation is hindered by decreases in prefrontal glutamate concentrations and gray matter volume due to daily smoking. Because non-daily, intermittent smoking also contributes greatly to disease and death, understanding whether infrequent tobacco use is associated with reductions in prefrontal glutamate concentrations and gray matter volume may aid public health. Eighty-five young participants (41 non-smokers, 24 intermittent smokers, 20 daily smokers, mean age ~23 years old), underwent 1H-magnetic resonance spectroscopy of the medial prefrontal cortex, as well as structural MRI to determine whole-brain gray matter volume. Compared to non-smokers, both daily and intermittent smokers exhibited lower concentrations of glutamate, creatine, N-acetylaspartate and myo-inositol in the medial prefrontal cortex, and lower gray matter volume in the right inferior frontal gyrus; these measures of prefrontal metabolites and structure did not differ between daily and intermittent smokers. Finally, medial prefrontal metabolite concentrations and right inferior frontal gray matter volume were positively correlated, but these relationships were not influenced by smoking status. This study provides the first evidence that both daily and intermittent smoking are associated with low concentrations of glutamate, creatine, N-acetylaspartate and myo-inositol, and low gray matter volume in the prefrontal cortex. Future tobacco cessation efforts should not ignore potential deleterious effects of intermittent smoking by considering only daily smokers. Finally, because low glutamate concentrations hinder cessation, treatments that can normalize tonic levels of prefrontal glutamate, such as N-acetylcysteine, may help intermittent and daily smokers to quit.

neuroscience↗

bioRxiv2020

Evolution is in the details: Regulatory differences in modern human and Neandertal

Transcription factor proteins play a critical role in the regulation of eukaryote gene expression via sequence- specific binding to genomic locations known as transcription factor binding sites. We studied sites of genomic variation between modern human and Neanderthal promoters. We detected significant differences in the binding affinities of 110 transcription factors to the promoters of 74 target genes. The transcription factors were enriched for terms related to vision, motor neurons, homeobox, and brain, whereas the target genes and their direct interactors were enriched in terms related to autism, brain, connective tissue, trachea, prostate, skull morphology, and vision. Secondary analysis of single-cell data revealed that a subset of the identified transcription factors (CUX1, CUX2, ESRRG, FOXP1, FOXP2, MEF2C, POU6F2, PRRX1 and RORA) co-occur as marker genes in L4 glutamatergic neurons. The majority of these genes have known roles in autism and/or schizophrenia and are associated with human accelerated regions (elevated divergence in humans vs. other primates). These results support the value of gene regulation studies for the evolution of human cognitive abilities and the neuropsychiatric disorders that accompany it.

genomics↗

bioRxiv2020

Did I imagine that? The functional role of paracingulate cortex in reality monitoring

Reality monitoring describes our ability to distinguish between internally and externally generated experiences. Individuals show significant variation in this ability and impaired reality monitoring has been linked to the experience of hallucinations. We undertook two studies to investigate the association between reality monitoring and morphology of the paracingulate region of medial prefrontal cortex. In Study 1 we compared reality monitoring accuracy and functional connectivity within paracingulate cortex in groups of healthy controls (N=20) and patients with schizophrenia and hallucinations (N=19). Controls showed greater reality monitoring accuracy that was associated with resting-state functional connectivity between paracingulate, precuneus and occipital cortices, while reality monitoring in patients was associated with more lateral functional connectivity. In Study 2 we used real-time fMRI neurofeedback to obtain causal evidence for the role of the paracingulate cortex in reality monitoring. Healthy individuals received Active feedback from paracingulate cortex (N=21) or Sham feedback based on randomised signal (N=18). Active-group participants showed a specific behavioural effect of improved reality monitoring for Imagined items, as well as increases in both activity within the paracingulate region, and its posterior functional connectivity with precuneus and lateral parietal cortices, and occipital cortex. Our findings suggest reality monitoring in healthy individuals is causally supported by a paracingulate mediated flexible network including the precuneus. Network connectivity can be enhanced using neurofeedback and tracks with improved reality monitoring ability. In contrast, patients with schizophrenia may utilise a distinct and more lateral network which may explain observed sub-optimal reality monitoring accuracy, contributing to the experience of hallucinations. Significance StatementReality monitoring refers to our ability to distinguish imagination from our experiences in the outside world, and is linked both to hallucinations in schizophrenia as well as to the morphology of paracingulate cortex area of the brain. Here, we revealed less paracingulate involvement in the functional reality monitoring networks in patients with schizophrenia compared to healthy individuals. Thereafter, we used real-time fMRI neurofeedback to show that healthy individuals can learn to upregulate brain activity within the paracingulate cortex, with this resulting in both improved reality monitoring ability and changes in paracingulate functional connectivity. This suggests that paracingulate cortex activity and connectivity play a causal role in reality monitoring, with implications for both the understanding and treatment of hallucinations.

neuroscience↗

bioRxiv2020

Bioinformatic characterization of angiotensin-converting enzyme 2, the entry receptor for SARS-CoV-2

The World Health Organization declared the COVID-19 epidemic a public health emergency of international concern on March 11th, 2020, and the pandemic is rapidly spreading worldwide. COVID-19 is caused by a novel coronavirus SARS-CoV-2, which enters human target cells via angiotensin converting enzyme 2 (ACE2). We used a number of bioinformatics tools to computationally characterize ACE2 by determining its cell-specific expression in trachea, lung, and small intestine, derive its putative functions, and predict transcriptional regulation. The small intestine expressed higher levels of ACE2 than any other organ. The large intestine, kidney and testis showed moderate signals, whereas the signal was weak in the lung. Single cell RNA-Seq data from trachea indicated positive signals along the respiratory tract in key protective cell types including club, goblet, proliferating, and ciliary epithelial cells; while in lung the ratio of ACE2-expressing cells was low in all cell types (<2.6%), but was highest in vascular endothelial and goblet cells. Gene ontology analysis suggested that, besides its classical role in renin-angiotensin system, ACE2 may be functionally associated with angiogenesis/blood vessel morphogenesis. Using a novel tool for the prediction of transcription factor binding sites we identified several putative binding sites within two tissue-specific promoters of the ACE2 gene. Our results also confirmed that age and gender play no significant role in the regulation of ACE2 mRNA expression in the lung. IMPORTANCEVaccines and new medicines are urgently needed to prevent spread of COVID-19 pandemic, reduce the symptoms, shorten the duration of disease, prevent virus spread in the body, and most importantly to save lives. One of the key drug targets could be angiotensin-converting enzyme 2 (ACE2), which is a crucial receptor for the corona virus (SARS-CoV-2). It is known that SARS coronavirus infections lead to worse outcome in the elderly and in males. Therefore, one aim of the present study was to investigate whether age or sex could contribute to the regulation of ACE2 expression. We also decided to explore the transcriptional regulation of ACE2 gene expression. Since data on ACE2 distribution is still conflicting, we aimed to get a more comprehensive view of the cell types expressing the receptor of SARS-CoV-2. Finally, we studied the coexpression of ACE2 with other genes and explored its putative functions using gene ontology enrichment analysis.

bioinformatics↗