Biology subjects

Mickael, M. E.

Publications and source records attributed to Mickael, M. E..

8 recordsLinked to original sources

bioRxiv2022

Investigation of mutated in colorectal cancer evolution history indicate a putative role in Th17/Treg differentiation.

The MCC family of genes plays a role in colorectal cancer development through various immunological pathways, including the Th17/Treg axis. We have previously shown that MCC1 and not MCC2 play a role in Treg differentiation. Our understanding of the genetic divergence patterns and evolutionary history of the MCC family in relation to its function, in general, and the Th17/Treg axis, in particular, remains incomplete. In this investigation, we explored 12 species genomes to study the phylogenetic origin, structure, and functional specificity of this family. In vertebrates, both MCC1 and MCC2 homologs have been discovered, while invertebrates have a single MCC homolog. We found MCC homologs as early as Cnidarians and Trichoplax, suggesting that the MCC family first appeared 741 million years ago (Ma), whereas MCC divergence into MCC1 and MCC2 families occurred at 540 Ma. In general, we did not detect significant positive selection regulating MCC evolution. Our investigation, based on MCC1 structural similarity, suggests that they may play a role in the evolutionary changes in Tregs emergence towards complexity, including the ability to utilize calcium for differentiation through the use of the EFH calcium-binding domain. We also found that the motif NPSTGE was highly conserved in MCC1 but not in MCC2. The NPSTGE motif binds KEAP1 with high affinity, suggesting an Nrf2-mediated function for Nrf2. In the case of MCC2, we found that the "Modifier of rudimentary" motif is highly conserved. This motif contributes to the regulation of alternative splicing. Overall, our study sheds light on how the evolution of the MCC family is connected to its function in regulating the Th17/Treg axis.

evolutionary biology↗

bioRxiv2022

Adera: A drug repurposing workflow for neuro-immunological investigations using neural networks.

Drug repurposing in the context of neuro-immunological (NI) investigations is still in its primary stages. Drug repurposing is an important method that bypasses lengthy drug discovery procedures and rather focuses on discovering new usage for known medications. Neuro-immunological diseases such as Alzheimers, Parkinson, multiple sclerosis and depression include various pathologies that resulted from the interaction between the central nervous system and the immune system. However, repurposing of medications is hindered by the vast amount of information that needs mining. To challenge the need for repurposing known medications for neuro-immunological diseases, we built a deep neural network named Adera to perform drug repurposing. The model uses two deep learning networks. The first network is an encoder and its main task is to embed text into matrices. The second network we explored the usage of two different loss function, binary cross entropy and means square error (MSE). Furthermore, we investigated the effect of ten different network architecture with each loss function. Our results show that for the binary cross entropy loss function, the best architecture consists of a two layers of convolution neural network and it achieves a loss of less than 0.001. In the case of MSE loss function a shallow network using aRelu activation achieved an accuracy of over 98 % and loss of 0.001. Additionally, Adera was able to predict various drug repurposing targets in agreement with DRUG Repurposing Hub. These results establish the ability of Adera to repurpose with high accuracy drug candidates that can shorten the development of the drug cycle. The software could be downloaded from https://github.com/michel-phylo/ADERA1.

bioinformatics↗

bioRxiv2022

Fezf2 and Aire1 evolutionary trade-off in negative selection of T cells in the thymus

In vertebrates, thymus expression of various body proteins to eliminate autoreactive T cells during the negative selection process is orchestrated by AIRE and FEZF2. T cells first appeared in vertebrates. However, the evolutionary history of these two genes in relation to T cells emergence is still not clear. Specifically, it is still not known, whether these two genes emerged concurrently to support the negative selection process. Furthermore, whether there is an evolutionary trade-off between these two genes is not known. Whether these two genes play a similar role in controlling auto-reactivity elimination in lampreys and invertebrates is also unknown. We used a plethora of phylogenetic analysis tools including; multiple sequence alignment, phylogenetic tree building, ancestral sequence reconstruction, functional specificity investigation, and positive selection analysis to address these questions. We found that these two genes represent two distinct pathways of negative selection with two unique origins. While AIRE emerged during the divergence of T cells in vertebrates, FEZF2 is far ancient with homologs in invertebrates including Cnidaria, Trichoplax. We found that FEZF2 structure is highly conserved between invertebrates and vertebrates. Moreover, the genes controlled by both families included a mixture of ancient and recently diverged genes. However, we found that AIRE contains an LXXLL motif for binding nuclear receptors. Conversely, FEZF2 possesses several motifs known to play a role in autophagy, such as DKFPHP, SYSELWKSSL, and SYSEL. However, both genes contain similar motifs such as MAPK regulating motifs. Interestingly, AIRE seems to be lacking in lampreys, in contrast to FEZF2. Taken together, our investigation hints that FEZF2 was initially employed to control a rudimentary auto-reactivity elimination process in invertebrates, then evolved to play a part in controlling a negative selection process in early vertebrates and higher vertebrates. The emergence of AIRE seems to be correlated with controlling the negative selection process in higher vertebrates. The results demonstrate a strong evolutionary trading-off process, where FEZF2 kept controlling certain biological processes whereas AIRE gained control of others. Several critical genes are controlled by both genes, to ensure an adequate negative selection process.

evolutionary biology↗

bioRxiv2021

RORγt-Expressing Pathogenic CD4+T Cells Cause Brain Inflammation During Chronic Colitis

Neurobehavioral disorders and brain abnormalities have been extensively reported in both Crohns Disease (CD) and Ulcerative Colitis (UC) patients. However, the mechanism causing neuropathological disorders in inflammatory bowel disease (IBD) patients remains unknown. Studies have linked the Th17 subset of CD4+T cells to brain diseases associated with neuroinflammation and cognitive impairment, including multiple sclerosis (MS), ischemic brain injury and Alzheimers disease. To better understand how CD4+T lymphocytes, contribute to brain pathology in chronic intestinal inflammation, we investigated the development of brain inflammation in the T cell transfer model of chronic colitis. Our findings demonstrate that CD4+T cells infiltrate the brain of colitic Rag1-/- mice in proportional levels to colitis severity. Colitic mice developed hypothalamic astrogliosis that correlated with neurobehavioral disorders. Moreover, the brain-infiltrating CD4+T cells expressed Th17 cell transcription factor ROR{gamma}t and displayed a pathogenic Th17 cellular phenotype similar to colonic Th17 cells. Adoptive transfer of ROR{gamma}t-deficient naive CD4+T cells failed to cause brain inflammation and neurobehavioral disorders in Rag1-/- recipients, with significantly less brain infiltration of CD4+T cells. These findings suggest that pathogenic ROR{gamma}t+CD4+T cells that aggravate colitis migrate preferentially into the brain, contributing to brain inflammation and neurobehavioral disorders, thereby linking colitis severity to neuroinflammation.

immunology↗

bioRxiv2021

Predicting epitopes Based on TCR sequence using an embedding deep neural network artificial intelligence approach

T cells receptors are fundamental in recognizing antigens and mediating an appropriate specific immune response against them. Today TCR sequencing has contributed to forming a large repertoire for different immune-associated pathologies. However, predicting epitopes based on TCR sequences has not been satisfactory achieved. We formed a deep neural network using a combination of an embedding autoencoder and selu and relu layers to predict epitopes based on TCR TCR {beta}-chain CDR3. We trained our model using the VDJ database (VDJdb) and validated it using the manually curated catalog of pathology-associated T cell receptor sequences (McPAS-TCR). We used various metrics to measure the accuracy of our tool. We found that our tool can achieve an accuracy of 98 %. Overall our approach presents a step toward identifying microbes crosslinking epitopes that could be playing an important role in various immune diseases.

bioinformatics↗

bioRxiv2021

Evolution of molecular pathways of Tregs mediated Suppression

Treg-mediated suppression of conventional T cells is a fundamental step in regulating the adaptive immune response. It is known that Treg first appeared in vertebrates. However, little is known about the of major suppression pathways mediated by Tregs. We employed artificial intelligence text mining system to highlight the suppression pathways currently known to be utilized by Tregs. Our system identified various pathways mediated by CTLA4, calcium signaling, NfkB and NFAT. We simultaneously employed detailed phylogenetic analysis including multiple sequence alignment, phylogenetic tree building, ancestral sequence reconstruction, neutrality tests and positive selection test to investigate the evolution of Treg mediated pathways. We found that CTLA4 first appeared in vertebrates possibly arising from an IGV containing protein in cartilaginous fish. Conversely, we found that Tregs repurposed ancient pathways such as Calcineurin and CAMP Response Element Modulator. Interestingly, these two pathways were highly conserved between vertebrates and lower invertebrates indicating conservation of function. Taken together, our research indicate that Tregs developed its regulatory systems through evolution in vertebrates as well as reusing conserved ancient regulatory systems that are related to the innate immune system.

evolutionary biology↗

bioRxiv2021

Evolutionary history and origin of Tre1 superfamily shed light on its role in regulating blood brain barrier.

Understanding how the evolutionary relationship between immune cells and the blood-brain is important to devise therapeutic strategies that can regulate their critical function. In vertebrates, immune cells follow either a paracellular or transcellular pathway to infiltrate the BBB. In drosophila glial cells form the BBB that regulates the access of immune-like cells to the drosophila brain. However, it is still not known which route immune-like cells follow to infiltrate the drosophila brain. In vertebrates, paracellular migration is dependent on PECAM1, while transcellular migration is dependent on the expression of CAV1. Interestingly drosophila genome lacks both genes. Tre1 superfamily (Tre1, Moody, and Dmel_CG4313) play a diverse role in regulating transepithelial migration in drosophila. However, its evolutionary history and origin are not yet known. We performed phylogenetic analysis, together with HH search, positive selection, and ancestral reconstruction to investigate the Tre1 family Interestingly we found that Tre1 exists in mollusks, insects, ambulacria, and sclaidphora. Moody is shown to be a more ancient protein and it existed since cnidaria emergence and has a homolog (GPCR84) in mammals. The third family member (Dmel_CG4313) only exists in insects. The origin of the family seems to be related to the rhodopsin-like family and in particular family . We found that opsin is the nearest receptor to have a common ancestor with the Tre1 superfamily that seems to have diverged in sponges. We investigated the positive selection of the Tre1 family using PAML. Tre1 seems to have evolved under negative selection, whereas Moody has evolved during positive selection. The sites that we found under positive selection are Likely to play a role in the speciation of function in the case of Moody. We have identified an SH3, in Tre1 and, moody and Dmel_CG4313. Sh3 is known to play a fundamental role in regulating actin movement in a Rho-dependent manner. We suggest that Tre1 could be playing an important role in paracellular diapedesis in drosophila.

immunology↗

bioRxiv2020

Asip (Agouti-signaling protein) aggression gene regulate auditory processing genes in mice

Covid-19 strategy of lockdown has affected the lives of millions. The strict actions to enclose the epidemic have exposed many households to inner tensions. Domestic violence has been reported to increase during the lockdown. However, the reasons for this phenomenon have not been thoroughly investigated. Melanocortin GPCRs family contribution to aggression is well documented. ASIP (nonagouti) gene plays a vital role in regulating the melanocortin GPCRs family function, and it is responsible for regulating aggression in mice. We conducted a selection analysis of ASIP. We found that it negatively purified from Shark to humans. In order to better asses the effect of this gene in mammals, we performed RNA-seq analysis of a knockout of an ASIP crisper-cas mouse model. We found that ASIP KO in mice upregulates several genes controlling auditory function, including Phox2b, Mpk13, Fat2, Neurod2, Slc18a3, Gon4l Gbx2, Slc6a3(Dat1) Aldh1a7 Tyrp1 and Lbx1. Interestingly, we found that Slc6a5, and Lamp5 as well as IL33, which are associated with startle disease, are also upregulated in response to knocking out ASIP. These findings are indicative of a direct autoimmune effect between aggression-associated genes and startle disease. Furthermore, in order to validate the link between aggression and auditory inputs processing. We conducted psychological tests of persons who experienced lockdown. We found that aggression has risen by 16 % during the lockdown. Furthermore, 3% of the subjects interviewed reported a change in their hearing abilities. Our data shed light on the importance of the auditory input in aggression and open perceptions to interpret how hearing and aggression interact at the molecular neural circuit level.

neuroscience↗