Genes In Different Types Research Articles

Genetic polymorphisms and bruxism: A scoping review

BackgroundRecent studies have highlighted the multifactorial nature of bruxism, with behavioral, psychosocial, and physiological factors, including genetic predisposition, contributing to its development. However, the role of genetic markers in determining susceptibility to bruxism remains poorly understood, with limited studies offering significant findings. ObjectivesTo identify the current knowledge to investigate the susceptibility of genetic markers for sleep (SB) and/or awake bruxism (AB). Materials and methodsSeven electronic databases and two grey literature platforms were searched up to January 2024. We included studies that related different types of genes and/or genetic polymorphisms with different types of bruxism, regardless of age or sex of the participants. To be included the study must have described the form of detection of bruxism. ResultsA total of 21 reports were included. Of these, 16 were primary research reports. The remaining five articles consisted of four systematic reviews and a literature review incorporating a systematic mapping process, and network visualization. Within the pool of 16 primary study reports, seven focused on the association of genetic polymorphisms with both SB and AB, while seven concentrated solely on the association with SB. One primary study reported results related to probable AB and one article did not specify the bruxism type. Regarding all the studied genes and polymorphisms, significant association results were obtained for 15 polymorphisms from 11 different genes. Self-reported SB was associated with genes from the serotonergic (5HTR2A) and dopaminergic pathways (DRD2, DRD3, and ANKK1), as well as genes encoding enzymes (COMT and MMP9) and proteins (ACTN3 and ANKK1). Instrumentally reported SB was linked only to the reverse telomerase gene (TERT). Self-reported AB was associated with the ACTN3 and ANKK1 genes. ConclusionThis review identified 30 genes and 56 polymorphisms variations potentially associated with either SB or AB. However, few presented significant results regarding positive associations, mostly acting at neurotransmitter pathways. The authors recommend further studies to determine the susceptibility of genetic markers as a risk factor for bruxism.

Revisiting Dominance in Population Genetics.

Dominance refers to the effect of a heterozygous genotype relative to that of the two homozygous genotypes. The degree of dominance of mutations for fitness can have a profound impact on how deleterious and beneficial mutations change in frequency over time as well as on the patterns of linked neutral genetic variation surrounding such selected alleles. Since dominance is such a fundamental concept, it has received immense attention throughout the history of population genetics. Early work from Fisher, Wright, and Haldane focused on understanding the conceptual basis for why dominance exists. More recent work has attempted to test these theories and conceptual models by estimating dominance effects of mutations. However, estimating dominance coefficients has been notoriously challenging and has only been done in a few species in a limited number of studies. In this review, we first describe some of the early theoretical and conceptual models for understanding the mechanisms for the existence of dominance. Second, we discuss several approaches used to estimate dominance coefficients and summarize estimates of dominance coefficients. We note trends that have been observed across species, types of mutations, and functional categories of genes. By comparing estimates of dominance coefficients for different types of genes, we test several hypotheses for the existence of dominance. Lastly, we discuss how dominance influences the dynamics of beneficial and deleterious mutations in populations and how the degree of dominance of deleterious mutations influences the impact of inbreeding on fitness.

Aerosol Inhalation of Gene Delivery Therapy for Pulmonary Diseases.

Gene delivery therapy has emerged as a popular approach for the treatment of various diseases. However, it still poses the challenges of accumulation in target sites and reducing off-target effects. Aerosol gene delivery for the treatment of pulmonary diseases has the advantages of high lung accumulation, specific targeting and fewer systemic side effects. However, the key challenge is selecting the appropriate formulation for aerosol gene delivery that can overcome physiological barriers. There are numerous existing gene carriers under study, including viral vectors and non-viral vectors. With the development of biomaterials, more biocompatible substances have applied gene delivery via inhalation. Furthermore, many types of genes can be delivered through aerosol inhalation, such as DNA, mRNA, siRNA and CRISPR/Cas9. Aerosol delivery of different types of genes has proven to be efficient in the treatment of many diseases such as SARS-CoV-2, cystic fibrosis and lung cancer. In this paper, we provide a comprehensive review of the ongoing research on aerosol gene delivery therapy, including the basic respiratory system, different types of gene carriers, different types of carried genes and clinical applications.

Identification and functionalization of thyrotropin receptor antibodies with different antigenic epitopes.

One of the sensitive markers for autoimmune thyroid disease (AITD) clinical identification is thyroid-stimulating hormone receptor antibodies (TRAbs). To quickly distinguish TRAb with distinct antigenic epitopes, a straightforward and uncomplicated technique has not yet been created. The objective of this study is to search for molecular diagnostic targets for different types of AITD {Graves' disease (GD), Graves' orbitopathy (GO), GD with third-degree goiter [GD(3)], hypothyroidism combined with positive TRAb [HT(TRAb+)]} as molecular diagnostic targets. Following action on thyroid cells, differential genes (DEGs) generated by TRAb with distinct antigenic epitopes were detected and identified by RNA sequencing (RNA-Seq), bioinformatics analysis, and quantitative reverse transcription-polymerase chain reaction (RT-qPCR) in the serum of patients with AITD. Using the 5-ethynyl-2'-deoxyuridine (EdU) assay, the effect of coculturing thyroid cells with different antigenic TRAb epitopes on the cells' capacity to proliferate was investigated. Bioinformatics analysis and RT-qPCR validation identified one GD key gene alpha 2-HS glycoprotein (AHSG), two GO key genes [adrenoceptor alpha 1D (ADRA1D) and H2B clustered histone 18 (H2BC18)], two GD(3) key genes [suppressor of cytokine signaling 1 (SOCS1) and cytochrome b-245 beta (CYBB)], and one HT(TRAb+) key gene (MASP2). Correlation analysis and ROC curves showed that the abovementioned genes could be used as molecular diagnostic targets for different types of AITD. Finally, EdU results showed that TRAb inhibited thyroid cell proliferation in the HT(TRAb+) group compared with the normal control group, whereas the remaining three groups promoted thyroid cell proliferation, with a statistically significant difference (P < 0.05). We identified six key genes for different types of AITD, which have diagnostic value for different types of AITD. Meanwhile, we found that TRAbs with different antigenic epitopes in AITD have different biological functions.NEW & NOTEWORTHY We identified six molecular targets of different types of AITD [GD, GO, GD(3), and HT(TRAb+)], which have diagnostic value for different types of AITD. Meanwhile, we found that TRAb with different antigenic epitopes extracted from the sera of patients with AITD had different biological functions, which also provided a new idea for further research on the mechanism of action of TRAb with different antigenic epitopes in AITD.

Dynamic intrauterine crosstalk promotes porcine embryo implantation during early pregnancy.

Dynamic crosstalk between the embryo and mother is crucial during implantation. Here, we comprehensively profile the single-cell transcriptome of pig peri-implantation embryos and corresponding maternal endometrium, identifying 4 different lineages in embryos and 13 cell types in the endometrium. Cell-specific gene expression characterizes 4 distinct trophectoderm subpopulations, showing development from undifferentiated trophectoderm to polar and mural trophectoderm. Dynamic expression of genes in different types of endometrial cells illustrates their molecular response to embryos during implantation. Then, we developed a novel tool, ExtraCellTalk, generating an overall dynamic map of maternal-foetal crosstalk using uterine luminal proteins as bridges. Through cross-species comparisons, we identified a conserved RBP4/STRA6 pathway in which embryonic-derived RBP4 could target the STRA6 receptor on stromal cells to regulate the interaction with other endometrial cells. These results provide insight into the maternal-foetal crosstalk during embryo implantation and represent a valuable resource for further studies to improve embryo implantation.

MiR827 positively regulates the resistance to chilli veinal mottle virus by affecting the expression of FBPase in Nicotiana benthamiana.

MicroRNA(miRNA) is a class of non-coding small RNA that plays an important role in plant growth, development, and response to environmental stresses. Unlike most miRNAs, which usually target homologous genes across a variety of species, miR827 targets different types of genes in different species. Research on miR827 mainly focuses on its role in regulating phosphate (Pi) homeostasis of plants, however, little is known about its function in plant response to virus infection. In the present study, miR827 was significantly upregulated in the recovery tissue of virus-infected Nicotiana tabacum. Overexpression of miR827 could improve plants resistance to the infection of chilli veinal mottle virus (ChiVMV) in Nicotiana benthamiana, whereas interference of miR827 increased the susceptibility of the virus-infected plants. Further experiments indicated that the antiviral defence regulated by miR827 was associated with the reactive oxygen species and salicylic acid signalling pathways. Then, fructose-1,6-bisphosphatase (FBPase) was identified to be a target of miR827, and virus infection could affect the expression of FBPase. Finally, transient expression of FBPase increased the susceptibility to ChiVMV-GFP infection in N. benthamiana. By contrast, silencing of FBPase increased plant resistance. Taken together, our results demonstrate that miR827 plays a positive role in tobacco response to virus infection, thus providing new insights into understanding the role of miR827 in plant-virus interaction.

Population genetics reveals new introgression in the nucleus herd of min pigs.

Min pigs are a unique genetic resource among local pig breeds in China. They have more excellent characteristics in cold and stress resistance, good meat quality, and a high reproductive rate. However, the genetic structure and driving factors remain unclear in the nucleus herd. In this study, the genetic diversity of Min pigs was studied to reveal the formation mechanism of its unique genetic structure. We hope to protect and develop the genetic resources of Min pigs. We analyzed different types of genes to identify the genetic structure and gene introgression pattern of Min pigs. The nuclear DNA dataset includes information on 21 microsatellite loci and 6 Y-chromosome genes, and the mitochondrial D-loop gene is selected to represent maternal lineages. The above genes are all from the nucleus herd of Min pigs. The results of genetic structure identification and analysis of potential exogenous gene introgression patterns indicate that the nucleus herd of Min pigs maintains a high level of genetic diversity (polymorphism information content = 0.713, expected heterozygosity = 0.662, observed heterozygosity = 0.612). Compared with other Asian pig breeds, the formation of Min pig breeds is more special. Gene introgression from European pig breeds to Min pigs has occurred, which is characterized by complete introgression of paternal genes and incomplete introgression of maternal genes. Gene introgression caused by cross-breeding is not the main factor leading to the formation of the current genetic structure of Min pigs, but this process has increased the level of genetic diversity in the nucleus herd. Compared with the influence of gene introgression, our research suggest that artificial selection and environmental adaptive evolution make Min pigs form unique genetic characteristics.

Retinitis Pigmentosa: From Pathomolecular Mechanisms to Therapeutic Strategies.

Retinitis pigmentosa is an inherited disease, in which mutations in different types of genes lead to the death of photoreceptors and the loss of visual function. Although retinitis pigmentosa is the most common type of inherited retinal dystrophy, a clear line of therapy has not yet been defined. In this review, we will focus on the therapeutic aspect and attempt to define the advantages and disadvantages of the protocols of different therapies. The role of some therapies, such as antioxidant agents or gene therapy, has been established for years now. Many clinical trials on different genes and mutations causing RP have been conducted, and the approval of voretigene nepavorec by the FDA has been an important step forward. Nonetheless, even if gene therapy is the most promising type of treatment for these patients, other innovative strategies, such as stem cell transplantation or hyperbaric oxygen therapy, have been shown to be safe and improve visual quality during clinical trials. The treatment of this disease remains a challenge, to which we hope to find a solution as soon as possible.

Characterization of the effects of Chinese peony (Radix paeoniae Alba) and its active ingredients on the hematopoietic function of the Chinese mitten crab (Eriocheir sinensis)

Hematopoietic tissue (HPT) is crucial for the proliferation and release of newly produced hemocytes during infection in crustaceans. Very few studies have reported how herbs affected the hematopoietic function of crustaceans. Radix paeoniae Alba is a candidate immunopotentiator herb with the potential to be a blood-tonifying drug. In this study, the effects of Radix paeoniae Alba and its monomers (paeoniflorin, albiflorin, and paeonol) on HPT and hemocytes of Eriocheir sinensis were evaluated. After feeding them commercial diets containing different ingredients for three weeks, the HPT development was determined via morphological observation and hematopoietic tissue body index (HTBI) calculation. The count and classification of hemocytes were evaluated using the hemocytometer and flow cytometer. The expression of hematopoietic factor astakine, transglutaminase (TGase), and marker genes for different types of hemocytes (KPI and SOD) and undifferentiated HPT cells (PCNA) were detected using real-time quantitative PCR (qRT-PCR) assay. The results indicated that the HTBI in the Radix Paeoniae Alba, paeoniflorin, and albiflorin groups increased by 114.96%, 111.42%, and 112.50%, which were higher than the control group. The Radix Paeoniae Alba, paeoniflorin, albiflorin, and paeonol groups had higher proportions of ovoid lobules than the control group, especially in the Radix Paeoniae Alba group. The total hemocyte count (THC) of the crab in the Radix Paeoniae Alba, paeoniflorin, and paeonol groups were 8.12, 9.69, and 8.57×106 ind/mL, respectively, which were higher than the control group. Furthermore, all experimental groups showed a higher proportion of granulocytes than the control group, with increased astakine protein being simultaneously detected in the HPT. The qRT-PCR results showed a relatively higher KPI expression in all the experimental groups, and also higher SOD mRNA expression in the Radix Paeoniae Alba, paeoniflorin, and paeonol groups, as compared with the control group. Therefore, these results implied the potential effect of Radix Paeoniae Alba and its monomers on the hematopoietic function of E. sinensis. However, due to the complex ingredient composition in Radix Paeoniae Alba and their different activities in the hematopoietic process, further research needs to be conducted in the future.

Identification and bioinformatics analysis of MADS-box family genes containing K-box domain in maize

The MADS-box family genes are involved in the development of plant roots, leaves, flowers, and fruits, and play a crucial role in plant growth and development. Studying MADS-box genes with K-box domain is crucial to distinguish different types of MADS-box genes. This study systematically analysed the genomic structural information of maize MADS-box family members containing the K-box Domain at the genome-wide level using the maize (Zea mays) B73 genome as the reference sequence, and provided insight into the biological functions of the maize MADS-box family containing the K-box domain. According to the findings, 52 MADS-box family genes with K-box domain were identified and divided into 4 subgroups. The distribution of motif in the same subgroup was found to be relatively conservative, and all of them had MADS-box conserved domain and K-box domain. Gene structure analysis showed that the introns and exons of the same subgroup genes have similar gene structure, and different types of genes containing the K-box domain showed different exon/intron structure characteristics. Chromosome mapping showed that 52 genes containing the K-box domain were unevenly distributed on the 10 chromosomes of maize, most of which were distributed at both ends of the chromosome and a small number of genes were distributed near the centromere. Based on the analysis of cis-acting elements of it up-stream promoter, it was found that MADS-box family genes may be involved in light response, IAA, GA, ABA, and LTR signal pathways, indicating that they play a certain role in stress response and hormone signal transduction. The expression analysis of genes with the K-box domain in maize leaves treated with auxin and gibberellin revealed that MADS-box genes may have a regulatory effect on certain plant hormones. Through the identification and bioinformatics analysis of MADS-box family genes containing the K-box domain, it is helpful to further study the function and pathway of MADS-box family genes, and provide a theoretical basis for further re-search for the molecular mechanism of maize growth and development.

Role of NF-κB pathway in kidney renal clear cell carcinoma and its potential therapeutic implications.

Kidney renal clear cell carcinoma (KIRC), a common malignant tumor of the urinary system, is the most aggressive renal tumor subtype. Since the discovery of nuclear factor kappa B (NF-κB) in 1986, many studies have demonstrated abnormal NF-κB signaling is associated with the development of various cancers, including kidney renal clear cell carcinoma. In this study, the relationship between NF-κB and kidney renal clear cell carcinoma was confirmed using bioinformatics analysis. First, we explored the differential expression of copy number variation (CNV), single nucleotide variant (SNV), and messenger RNA (mRNA) in NF-κB-related genes in different types of cancer, as well as the impact on cancer prognosis and sensitivity to common chemotherapy drugs. Then, we divided the mRNA expression levels of NF-κB-related genes in KIRC patients into three groups through GSVA cluster analysis and explored the correlation between the NF-κB pathway and clinical data of KIRC patients, classical cancer-related genes, common anticancer drug responsiveness, and immune cell infiltration. Finally, 11 tumor-related genes were screened using least absolute shrinkage and selection operator (LASSO) regression to construct a prognostic model. In addition, we used the UALCAN and HPA databases to verify the protein levels of three key NF-κB-related genes (CHUK, IKGGB, and IKBKG) in KIRC. In conclusion, our study established a prognostic survival model based on NF-κB-related genes, which can be used to predict the prognosis of patients with KIRC.

Deciphering the dynamic characteristics of non-neuronal cells in dorsal root ganglion of rat at different developmental stage based on single cell transcriptome data

Dorsal root ganglia (DRG) is an essential part of the peripheral nervous system and the hub of the peripheral sensory afferent. The dynamic changes of neuronal cells and their gene expression during the development of dorsal root ganglion have been studied through single-cell RNAseq analysis, while the dynamic changes of non-neuronal cells have not been systematically studied. Using single cell RNA sequencing technology, we conducted a research on the non-neuronal cells in the dorsal root ganglia of rats at different developmental stage. In this study, primary cell suspension was obtained from using the dorsal root ganglions (DRGs, L4-L5) of ten 7-day-old rats and three 3-month-old rats. The 10×Genomics platform was used for single cell dissociation and RNA sequencing. Twenty cell subsets were acquired through cluster dimension reduction analysis, and the marker genes of different types of cells in DRG were identified according to previous researches about DRG single cell transcriptome sequencing. In order to find out the non-neuronal cell subsets with significant differences at different development stage, the cells were classified into different cell types according to markers collected from previous researches. We performed pseudotime analysis of 4 types Schwann cells. It was found that subtype Ⅱ Schwann cells emerged firstly, and then were subtype Ⅲ Schwann cells and subtype Ⅳ Schwann cells, while subtype Ⅰ Schwann cells existed during the whole development procedure. Pseudotime analysis indicated the essential genes influencing cell fate of different subtypes of Schwann cell in DRG, such as Ntrk2 and Pmp2, which affected cell fate of Schwann cells during the development period. GO analysis of differential expressed genes showed that the up-regulated genes, such as Cst3 and Spp1, were closely related to biological process of tissue homeostasis and multi-multicellular organism process. The down regulated key genes, such as Col3a1 and Col4a1, had close relationship with the progress of extracellular structure organization and negative regulation of cell adhesion. This suggested that the expression of genes enhancing cell homestasis increased, while the expression of related genes regulating ECM-receptor interaction pathway decreased during the development. The discovery provided valuable information and brand-new perspectives for the study on the physical and developmental mechanism of Schwann cell as well as the non-neuronal cell changes in DRG at different developmental stage. The differential gene expression results provided crucial references for the mechanism of somatosensory maturation during development.

CBX8 promotes lung adenocarcinoma growth and metastasis through transcriptional repression of CDKN2C and SCEL.

Dysregulation of polycomb group (PcG) proteins that mediate epigenetic gene silencing contributes to tumorigenesis. As core components of the polycomb repressive complex 1 (PRC1), chromobox (CBX) proteins recognize H3K27me3 to recruit PRC1 to maintain a repressive transcriptional state. However, the individual biological functions of these CBX proteins in tumorigenesis warrant in-depth investigation. In this study, we analyzed the mRNA expression of CBX family genes across multiple cancers using The Cancer Genome Atlas data and found different expression patterns of the five CBX genes in different types of cancer. This analyses together with the result of immunohistochemistry indicated that CBX8 expression was significantly higher in lung adenocarcinoma (LUAD) tissues compared to adjacent nontumor tissues. Overexpression approaches demonstrated that CBX8 facilitated LUAD cell proliferation and migration in vitro. Consistently, CBX8 knockdown reduced LUAD cell proliferation and migration in both cell culture and mouse models. RNA sequencing combined with real-time RT-PCR assays revealed CDKN2C and SCEL as target genes of CBX8. Furthermore, chromatin immunoprecipitation assays indicated that CBX8 directly bound to the promoters of CDKN2C and SCEL to establish H2AK119ub. CBX8 depletion reduced the enrichment of H2AK119ub on CDKN2C and SCEL promoters. Moreover, depletion of CDKN2C and SCEL restored the repressed growth and invasion ability of LUAD cells caused by CBX8 knockdown. These findings demonstrate that CBX8 promotes LUAD growth and metastasis through the transcriptional repression of CDKN2C and SCEL. Our study uncovers the oncogenic role of CBX8 in LUAD progression and provides a new target for the diagnosis and therapy of LUAD.

Effect of different metabolic pathways on itaconic acid production in engineered Corynebacterium glutamicum

Itaconic acid (IA), a C5-dicarboxylic acid, is a potential bio-based building block for the polymer industry. There are three pathways for IA production from natural IA producers; however, most of the engineered strains were used for IA production by heterologous expression of cis-aconitate decarboxylase gene (cadA) from Aspergillus terreus. In this study, IA was produced by an engineered Corynebacterium glutamicum ATCC 13032 expressing two different types of genes from two distinct pathways. The first involves the mammalian immunoresponsive gene1 (Irg1) derived from Mus musculus. The second (termed here the trans-pathway) involves two genes from the natural IA producer Ustilago maydis which are aconitate-delta-isomerase (Adi1) and trans-aconitate decarboxylase (Tad1) genes. The constructed strains developing the two distinct IA production pathways: C.glutamicum ATCC 13032 pCH-Irg1opt and C.glutamicum ATCC 13032 pCH-Tad1optadi1opt were used for production of IA from different carbon sources. The results reflect the possibility for IA production from C.glutamicum expressing the trans-pathway (Adi1/Tad1 genes) and cis-pathway (Irg1 gene) other than the well-known cis-pathway that depends mainly on cadA gene from A.terreus. The developed strain expressing trans-pathway from U.maydis; however, proved to be better at IA production with high titers of 12.25, 11.34, and 11.02g/L, and a molar yield of 0.22, 0.42, and 0.43mol/mol from glucose, maltose, and sucrose, respectively, via fed-batch fermentation. The present study suggests that trans-pathway is better than cis-pathway for IA production in engineered C.glutamicum.

A dynamic multi-objective evolutionary algorithm based on gene sequencing and gene editing

Evolutionary Algorithm is a mature global optimization method with high robustness and wide applicability. It can effectively address complex problems that are difficult to be solved by traditional optimization algorithms. In evolution, it is still uncertain which gene parent can produce offspring through competition and eventually become an excellent individual of the last generation population. Inspired by the fact that gene sequencing can discover biological gene defects, this paper proposes a dynamic multi-objective evolutionary algorithm based on gene sequencing and gene editing (GSGE). The gene sequencing algorithm is designed using support vector machine (SVM), and correlation coefficient, as the result of sequencing, has also been verified. Combining stratified sampling and multi-population strategy, a prediction strategy that can use all chromosome information is designed. The new gene editing strategy edits individual genes to optimize the Pareto optimal front (PF) distribution, for the first time different types of genes can match different optimization strategies, which greatly improves the distribution of the population without affecting the convergence. The comparison experiment between GSGE and the state of the art algorithms is performed on 25 test functions and the Pareto optimal set (PS) curves obtained by dimension reduction fully demonstrate the significant advantages of GSGE.

CDH4 inhibits ferroptosis in oral squamous cell carcinoma cells

BackgroundThe cadherin-4 gene (CDH4), a member of the cadherin family genes, encodes R-cadherin (R-cad); however, the function of this gene in different types of cancer remains controversial. The function of CDH4 in OSCC (oral squamous cell carcinoma) is unknown.Materials and methodsWe use the Cancer Genome Atlas (TCGA) database to find the expression of CDH4 in OSCC is more than normal tissue. Our tissue samples also confirmed that CDH4 gene was highly expressed in OSCC. The related cell function assay detected that CDH4 promotes the ability of cell proliferation, migration, self-renewal and invasion. Cell staining experiment confirmed that the change of CDH4 expression would change the cell mortality. The western blot of GPX4 (glutathione-dependent peroxidase-4), GSH (reduced glutathione) test assay and MDA(Malondialdehyde) test assay show that the expression of CDH4 may resist the sensitivity of ferropotosis in OSCC.ResultsCDH4 was upregulated in OSCC samples and was correlation with poor survival of patients. High expression of CDH4 effectively promotes the proliferation, mobility of OSCC cells and reduce the sensitivity of OSCC cells to ferroptosis. CDH4 is positively correlated with EMT pathway genes, negatively correlated with fatty acid metabolism pathway genes and peroxisome pathway genes, and positively correlated with ferroptosis suppressor genes in OSCC.ConclusionsThese results indicate that CDH4 may play a positive role in tumor progression and resistance ferroptosis and may be a potential therapeutic target for OSCC.

Identification of Proteins Involved in Cell Membrane Permeabilization by Nanosecond Electric Pulses (nsEP).

The study was aimed at identifying endogenous proteins which assist or impede the permeabilized state in the cell membrane disrupted by nsEP (20 or 40 pulses, 300 ns width, 7 kV/cm). We employed a LentiArray CRISPR library to generate knockouts (KOs) of 316 genes encoding for membrane proteins in U937 human monocytes stably expressing Cas9 nuclease. The extent of membrane permeabilization by nsEP was measured by the uptake of Yo-Pro-1 (YP) dye and compared to sham-exposed KOs and control cells transduced with a non-targeting (scrambled) gRNA. Only two KOs, for SCNN1A and CLCA1 genes, showed a statistically significant reduction in YP uptake. The respective proteins could be part of electropermeabilization lesions or increase their lifespan. In contrast, as many as 39 genes were identified as likely hits for the increased YP uptake, meaning that the respective proteins contributed to membrane stability or repair after nsEP. The expression level of eight genes in different types of human cells showed strong correlation (R > 0.9, p < 0.02) with their LD50 for lethal nsEP treatments, and could potentially be used as a criterion for the selectivity and efficiency of hyperplasia ablations with nsEP.

Abstract 2053: Structural variants detected by optical genome mapping in acute lymphoblastic leukemia patient-derived xenografts models

Abstract Background: The established classification of acute lymphoblastic leukemia (ALL) does not cover all high-risk patients because of the difficulty in detecting novel or rare structural variants (SVs). Furthermore, many SVs and formed gene fusions have adverse prognostic effects on hematological malignancies. This study aims to investigate SVs in 22 patient-derived xenografts (PDX) of ALL and to assess rare SVs and chromosomal aberrations, particularly hematological malignancy genes and gene fusions in different individuals detected by optical genome mapping (OGM). Methods: Leukemia cells from 16 patients with B-cell precursor acute lymphoblastic leukemia (B-ALL) and 6 patients with T-cell acute lymphoblastic leukemia (T-ALL) were inoculated into immuno-deficient mice, growth curves were monitored, and leukemia cells were collected after human CD45 was more than 80%. OGM (Bionano Genomics), RNA sequencing (RNA-seq) and whole genome sequencing (WGS) techniques were used to detect SVs and gene fusions. In validation, polymerase chain reaction (PCR) and fluorescence in situ hybridization (FISH) tests were performed to identify specific SVs. Results: On average, each model detected 42 rare SVs with known overlapping genes in different types by OGM: 12 insertions, 25 deletions, 1 inversion, 3 duplications, 2 inter-chromosomal translocations and 1 intra-chromosomal translocation. 5 rare SVs were found in multiple models (&amp;gt;=5), and two of them were never reported in B-ALL and T-ALL. Gene fusions were detected in all ALL models by OGM, and 17% were novel fusions. At the mRNA level, gene fusions were detected only in 19 models, and 24% of the predicted gene fusions by OGM were identical to the results of RNA-seq (high confidence results including pseudogenes). These two technologies could detect different fusion partners. For example, MLLT1 was seen at the mRNA level, and ACER1 was detected at the DNA level in the same KMT2A rearrangement model. Of the 16 B-ALL models, 6 were p190 BCR-ABL1 (a fusion of BCR exon 1 and ABL1 exon 2), 1 was p210 BCR-ABL1 (a fusion of BCR exon 13 and ABL1 exon 2) and 5 of 7 had IKZF1 gene deletions. 2 p190 BCR-ABL1 models were insensitive to imatinib and 2 p190 BCR-ABL1 models as well as the model with IKZF1 exons 4-7 deletion were sensitive to imatinib when treatment was initiated early in the disease. A novel ARL15-IKZF1 fusion was identified in one of the sensitive models. Deletion of the PRKAR2B gene was another rare SV in both models sensitive to imatinib besides the IKZF1 deletion. Conclusion: OGM assays were more comprehensive, and novel rare SVs were identified in ALL. Combining the results of gene fusions between different technologies will provide more accurate predictions for ALL classifications. The combination of aberrant SVs may synergize to influence the efficacy of imatinib, which warrants further investigations. Citation Format: Yueying Wang, Mengting Qin, JinPing Liu, Xiaobo Chen, Jia Xue, Sheng Guo. Structural variants detected by optical genome mapping in acute lymphoblastic leukemia patient-derived xenografts models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2053.

Thioredoxin A of Streptococcus suis Serotype 2 Contributes to Virulence by Inhibiting the Expression of Pentraxin 3 to Promote Survival Within Macrophages.

Streptococcus suis serotype 2 (SS2) is an important zoonotic pathogen that can infect humans in contact with infected pigs or their byproducts. It can employ different types of genes to defend against oxidative stress and ensure its survival. The thioredoxin (Trx) system is a key antioxidant system that contributes adversity adaptation and pathogenicity. SS2 has been shown to encode putative thioredoxin genes, but the biological roles, coding sequence, and underlying mechanisms remains uncharacterized. Here, we demonstrated that SSU05_0237-ORF, from a clinical SS2 strain, ZJ081101, encodes a protein of 104 amino acids with a canonical CGPC active motif and an identity 70-85% similar to the thioredoxin A (TrxA) in other microorganisms. Recombinant TrxA efficiently catalyzed the thiol-disulfide oxidoreduction of insulin. The deletion of TrxA led to a significantly slow growth and markedly compromised tolerance of the pathogen to temperature stress, as well as impaired adhesion ability to pig intestinal epithelial cells (IPEC-J2). However, it was not involved in H2O2 and paraquat-induced oxidative stress. Compared with the wild-type strain, the ΔTrxA strain was more susceptible to killing by macrophages through increasing NO production. Treatment with TrxA mutant strain also significantly attenuated cytotoxic effects on RAW 264.7 cells by inhibiting inflammatory response and apoptosis. Knockdown of pentraxin 3 in RAW 264.7 cells was more vulnerable to phagocytic activity, and TrxA promoted SS2 survival in phagocytic cells depending on pentraxin 3 activity compared with the wild-type strain. Moreover, a co-inoculation experiment in mice revealed that TrxA mutant strain is far more easily cleared from the body than the wild type strain in the period from 8-24h, and exhibits significantly attenuated oxidative stress and liver injury. In summary, we reveal the important role of TrxA in the pathogenesis of SS2.

Developmental diversity: Putting the development back into research about developmental conditions.

The dominant discourse surrounding neurodevelopmental conditions such as autism and ADHD emphasizes biological explanations. Neurodevelopmental conditions are conceived as different types of brains, the result of different types of genes. This way of thinking is present both in medical research and in clinical practice. Indeed, it is widely acknowledged that the idea of having a biological diagnosis helps people see beyond blame and guilt. It aids acceptance. However, simplistic approaches to biology risks neglecting the experiences and stories of autistic people in favor of finding etiological causes. At the same time, there is growing awareness that risks, functioning, and resilience are not solely defined by genes and brains but have a cultural and experiential component as well. Furthermore, atypical cognitive trajectories are not straightforwardly associated with poor outcomes. In this paper we describe the concept of developmental diversity as an alternative to more categorical approaches to neurodevelopmental conditions. We explore how dynamic models of life offer possibilities to look at neurodevelopmental conditions differently: rather than seeing autistic people as people with fundamental flaws in their genes or software faults in their brains that have to be explained, autism appears as a phenomenon that exists in interaction with the context, as a meaningful reaction to the environment. We explore what it would mean for research to go from a diagnosis-based approach to a developmental diversity approach that will define wellbeing and functioning in a more granular way across developmental trajectories. We argue that this would mean incorporating lived experiences into biological research and going beyond genes-environment dichotomies. Next to yielding a more complete picture on the phenomenon of autism, we describe how an approach that takes developmental diversity as a starting point offers a new way to look at existing challenges of autism research, such as how to deal with the significant overlap between diagnosis. Our hypothesis is that thinking with developmental diversity rather than categorical difference both represents an opportunity for a more inclusive society, and fundamentally can alter the way we perform research. As such, it is in line with requests of neurodiversity and disability movements.