Biology subjects

MA, L.

Publications and source records attributed to MA, L..

3 recordsLinked to original sources

bioRxiv2020

Circulating Mitochondrial DNA is an Early Indicator of Severe Illness and Mortality from COVID-19

Mitochondrial DNA (MT-DNA) are intrinsically inflammatory nucleic acids released by damaged solid organs. Whether the appearance of cell-free MT-DNA is linked to poor COVID-19 outcomes remains undetermined. Here, we quantified circulating MT-DNA in prospectively collected, cell-free plasma samples from 97 subjects with COVID-19 at the time of hospital presentation. Circulating MT-DNA were sharply elevated in patients who eventually died, required ICU admission or intubation. Multivariate regression analysis revealed that high circulating MT-DNA levels is an independent risk factor for all of these outcomes after adjusting for age, sex and comorbidities. Additionally, we found that circulating MT-DNA has a similar or superior area-under-the curve when compared to clinically established measures of systemic inflammation, as well as emerging markers currently of interest as investigational targets for COVID-19 therapy. These results show that high circulating MT-DNA levels is a potential indicator for poor COVID-19 outcomes.

immunology↗

bioRxiv2019

The NALCN regulator UNC-80 functions in a subset of interneurons to affect C. elegans avoidance response to the plant hormone methyl salicylate.

NALCN (Na+ leak channel, non-selective), UNC80 and UNC79 form a non-selective, voltage-independent cation channel complex that affects a broad array of neuronal activities. The molecular and neuronal mechanisms underlying the functions of the NALCN complex remain unclear. In a screen for Caenorhabditis elegans mutants with defective avoidance response to the plant hormone methyl salicylate (MeSa), we isolated novel loss-of-function (lf) mutations in unc-80 and unc-79. unc-80 and unc-79 lf mutants exhibited defective MeSa avoidance but wild type-like responses to other odorants. Lf mutants of C. elegans nca/NALCN exhibited similar MeSa-specific avoidance defect, while lf mutants of the NALCN regulatory gene nlf-1 avoided MeSa like wild type. Using fluorescent transgenic animals, we identified a subset of unc-80-expressing neurons. Neuron-specific transgene rescue and knockdown experiments suggest that a subset of interneurons, primarily including AVA, AVE and AVG, might play a necessary and sufficient role in mediating unc-80 regulation of the MeSa avoidance. We found that unc-79 was expressed in neurons largely overlapping those expressing unc-80, which is supported by the rescue of unc-80(lf) defects using an unc-80 transgene driven by an unc-79 promoter. We also suggest that C. elegans locomotion responds more sensitively to the changes of expression levels of NALCN-related genes than the MeSa avoidance does. Together, our results identified NALCN-related genes as key regulators of the MeSa avoidance behavior and provided novel genetic and neuronal insights into the function of the NALCN channel complex.\n\nAuthor summaryNALCN (Na+ leak channel, non-selective) is a non-selective, voltage-independent cation channel that affects multiple neuronal activities and behaviors. Mutations in NALCN and its regulator UNC80 can cause serious neurological diseases. The regulation and function of the NALCN channel complex remain to be understood. From a genetic screen, we surprisingly found that the nematode Caenorhabditis elegans requires NALCN and its two regulators UNC-80 and UNC-79 to escape from the plant stress hormone methyl salicylate (MeSa). Using methods including transgenic neuronal labeling, rescues and knockdowns, we found that unc-80-expression in a subset of head interneurons, including AVA, AVE and AVG, might be necessary and sufficient to elicit the MeSa avoidance response. We also found that unc-79 functions in overlapping neurons as unc-80 to regulate C. elegans behaviors. Our findings provide novel molecular and neuronal mechanisms for understanding the regulation and function of the NALCN channel complex.

genetics↗

bioRxiv2018

RBM-5 modulates U2AF large subunit-dependent alternative splicing in C. elegans

A key step in pre-mRNA splicing is the recognition of 3 splicing sites by the U2AF large and small subunits, a process regulated by numerous trans-acting splicing factors. How these trans-acting factors interact with U2AF in vivo is unclear. From a screen for suppressors of the temperature-sensitive (ts) lethality of the C. elegans U2AF large subunit gene uaf-1(n4588) mutants, we identified mutations in the RNA binding motif gene rbm-5, a homolog of the tumor suppressor RBM5. rbm-5 mutations can suppress uaf-1(n4588) ts-lethality by loss of function and neuronal expression of rbm-5 was sufficient to rescue the suppression. Transcriptome analyses indicate that uaf-1(n4588) affected the expression of numerous genes and rbm-5 mutations can partially reverse the abnormal gene expression to levels similar to that of wild type. Though rbm-5 mutations did not obviously affect alternative splicing per se, they can suppress or enhance, in a gene-specific manner, the altered splicing of genes in uaf-1(n4588) mutants. Specifically, the recognition of a weak 3 splice site was more susceptible to the effect of rbm-5. Our findings provide novel in vivo evidence that RBM-5 can modulate UAF-1-dependent RNA splicing and suggest that RBM5 might interact with U2AF large subunit to affect tumor formation.\n\nAuthor summaryRNA splicing is a critical regulatory step for eukaryotic gene expression and has been involved in the pathogenesis of multiple diseases. How RNA splicing factors interact in vivo to affect the splicing and expression of genes is unclear. In studying the temperature-sensitive lethal phenotypes of a mutation affecting the splicing factor U2AF large subunit gene uaf-1 in the nematode Caenorhabditis elegans, we isolated suppressive mutations in the rbm-5 gene, a homolog of the human tumor suppressor gene RBM5. rbm-5 is broadly expressed in neurons to enhance the lethality of the uaf-1 mutants. We found that the uaf-1 mutation causes aberrant expression of genes in numerous biological pathways, a large portion of which can be corrected by rbm-5 mutations. The abnormal splicing of multiple genes caused by the uaf-1 mutation is either corrected or enhanced by rbm-5 mutations in a gene-specific manner. We propose that RBM-5 interacts with UAF-1 to affect RNA splicing and the tumor suppressor function of RBM5 might involve U2AF-dependent RNA splicing.

genetics↗