Biology subjects

Abraham, M.

Publications and source records attributed to Abraham, M..

5 recordsLinked to original sources

bioRxiv2026

NO VEIN is an ancestral immunity protein involved in plant-virus interaction

The conservation of immune systems from prokaryotes to eukaryotes can guide discovery of immunity genes across the tree of life. Most studies to date have focused on metazoan systems, while the extent of ancestral immunity conservation in plants remains underexplored. Here we show that NO VEIN (NOV), a plant protein previously characterized for its essential developmental roles in Arabidopsis thaliana, shares domain composition and structural similarity with Tiamat, a bacterial antiphage protein. In light of the antiviral function of the bacterial protein, we asked whether NOV is involved in plant-virus interactions. We found that NOV knockdown in the model plant Nicotiana benthamiana resulted in an impaired transcriptional response to tobacco rattle virus, including reduced induction of defense genes, and observed increased potato virus x accumulation in a secondary infection. We also reveal that NOV, previously considered plant-specific, has homologs in animals - pointing to a shared origin. Together, these findings uncover a deeply conserved protein involved in plant-virus interaction, and demonstrate the power of prokaryote-eukaryote homology to reveal new aspects of plant biology.

plant biology↗

bioRxiv2021

Defining the Yeast Resistome through in vitro Evolution and Whole Genome Sequencing

In vitro evolution and whole genome analysis were used to comprehensively identify the genetic determinants of chemical resistance in the model microbe, Saccharomyces cerevisiae. Analysis of 355 curated, laboratory-evolved clones, resistant to 80 different compounds, demonstrates differences in the types of mutations that are identified in selected versus neutral evolution and reveals numerous new, compound-target interactions. Through enrichment analysis we further identify a set of 137 genes strongly associated with or conferring drug resistance as indicated by CRISPR-Cas9 engineering. The set of 25 most frequently mutated genes was enriched for transcription factors and for almost 25 percent of the compounds, resistance was mediated by one of 100 independently derived, gain-of-function, single nucleotide variants found in 170-amino-acid domains in two Zn2C6 transcription factors, YRR1 and YRM1 (p < 1x 10 -100). This remarkable enrichment for transcription factors as drug resistance genes may explain why it is challenging to develop effective antifungal killing agents and highlights their important role in evolution.

genetics↗

bioRxiv2020

Utility of cell-free DNA concentrations and illness severity scores to predict survival in critically ill neonatal foals

Plasma cell-free DNA (cfDNA) levels have been associated with disease and survival status in septic humans and dogs. To date, studies investigating cfDNA levels in association with critical illness in foals are lacking. We hypothesized that cfDNA would be detectable in the plasma of foals, that septic and sick-nonseptic foals would have significantly higher cfDNA levels compared to healthy foals, and that increased cfDNA levels would be associated with non-survival. Animals used include 80 foals of 10 days of age or less admitted to a tertiary referral center between January and July, 2020 were stratified into three categories: healthy (n=34), sick non-septic (n=11) and septic (n=35) based on specific criteria. This was a prospective clinical study. Blood was collected from critically ill foals at admission or born in hospital for cfDNA quantification and blood culture. Previously published sepsis score (SS) and neonatal SIRS score (NSIRS) were also calculated. SS, NSIRS, blood culture status and cfDNA concentrations were evaluated to predict survival. Continuous variables between groups were compared using Kruskal-Wallis ANOVA with Dunns post hoc test. Comparisons between two groups were assessed using the Mann-Whitney U-test or Spearman rank for correlations. The performance of cfDNA, sepsis score and NSIRS score to predict survival was assessed by receiver operator characteristic (ROC) curve analysis including area under the curve, sensitivity and specificity using cutoffs. Plasma cfDNA was detectable in all foals. No significant differences in cfDNA concentration were detected between healthy foals and septic foals (P=0.65) or healthy foals and sick non-septic foals (P=0.88). There was no significant association between cfDNA and culture status, SS, NSIRS or foal survival. SS (AUC 0.85) and NSIRS (AUC 0.83) were superior to cfDNA (AUC 0.64) in predicting survival. cfDNA was detectable in foal plasma however offers negligible utility to diagnose sepsis or predict survival in critical illness in neonates.

microbiology↗

bioRxiv2020

Kcns3 Deficiency Disrupts Parvalbumin Neuron Physiology in Mouse Prefrontal Cortex: Implications for the pathophysiology of schizophrenia

The unique fast spiking (FS) phenotype of cortical parvalbumin-positive (PV) neurons depends on multiple subtypes of voltage-gated potassium channels (Kv). PV neurons selectively express Kcns3, the gene encoding Kv9.3 subunits, suggesting that Kcns3 expression is critical for the FS phenotype. KCNS3 expression is lower in PV neurons in schizophrenia, but the effects of this alteration are unclear, because Kv9.3 subunit function is poorly understood. We therefore assessed the role of Kv9.3 subunits in PV neuron function by combining gene expression analyses, computational modeling, and electrophysiology in acute slices from the cortex of Kcns3-deficient mice Kcns3 mRNA levels were ~50% lower in cortical PV neurons from Kcns3-deficient relative to wildtype mice. While silent per se, Kv9.3 subunits are believed to amplify the Kv2.1 current in Kv2.1-Kv9.3 channel complexes. Hence, to assess the consequences of reducing Kv9.3 levels, we simulated the effects of decreasing the Kv2.1-mediated current in a computational model. The FS cell model with reduced Kv2.1 produced spike trains with irregular inter-spike intervals, or stuttering, and greater Na+ channel inactivation, possibly due to a smaller afterhyperpolarization. As in the computational model, PV basket cells (PVBCs) from Kcns3-deficient mice displayed spike trains with strong stuttering, which depressed PVBC firing, and smaller afterhyperpolarization. Moreover, Kcns3 deficiency impaired the recruitment of PVBCs by stimuli mimicking synaptic input during cortical UP states, which elicited bursts of spikes at gamma frequency. Our data suggest that Kv9.3 subunits are critical for PVBC physiology, and that KCNS3 deficiency in schizophrenia may impair the substrate of gamma oscillations. Significance statementIn the neocortex, Kcns3, the gene encoding voltage-dependent potassium (Kv) channel subunits Kv9.3, is selectively expressed by parvalbumin-positive (PV) neurons. Moreover, KCNS3 expression is decreased in PV neurons in schizophrenia. Kv 9.3 subunits are believed to amplify the current mediated by Kv2.1 subunits, however Kv9.3 function has not been investigated in PV cells. Here, simulations in a computational model and electrophysiological experiments with Kcns3-deficient mice revealed that Kcns3 deficiency disrupts repetitive firing in cortical PV neurons, possibly enhancing Na+ channel inactivation, and particularly with stimuli eliciting firing at gamma frequency band (30-80Hz). Our results suggest that Kv9.3 subunits are essential for PV neuron electrophysiology and that KCNS3 deficiency likely contributes to PV neuron dysfunction and gamma oscillation impairments in schizophrenia.

neuroscience↗

bioRxiv2017

Mapping The Malaria Parasite Drug-Able Genome Using In Vitro Evolution And Chemogenomics

Chemogenetic characterization through in vitro evolution combined with whole genome analysis is a powerful tool to discover novel antimalarial drug targets and identify drug resistance genes. Our comprehensive genome analysis of 262 Plasmodium falciparum parasites treated with 37 diverse compounds reveals how the parasite evolves to evade the action of small molecule growth inhibitors. This detailed data set revealed 159 gene amplifications and 148 nonsynonymous changes in 83 genes which developed during resistance acquisition. Using a new algorithm, we show that gene amplifications contribute to 1/3 of drug resistance acquisition events. In addition to confirming known multidrug resistance mechanisms, we discovered novel multidrug resistance genes. Furthermore, we identified promising new drug target-inhibitor pairs to advance the malaria elimination campaign, including: thymidylate synthase and a benzoquinazolinone, farnesyltransferase and a pyrimidinedione, and a dipeptidylpeptidase and an arylurea. This deep exploration of the P. falciparum resistome and drug-able genome will guide future drug discovery and structural biology efforts, while also advancing our understanding of resistance mechanisms of the deadliest malaria parasite.\n\nOne Sentence SummaryWhole genome sequencing reveals how Plasmodium falciparum evolves resistance to diverse compounds and identifies new antimalarial drug targets.

genomics↗