Genetic Model Research Articles

Genetic polymorphism of IL-40 in male patients with ankylosing spondylitis

Background: Ankylosing spondylitis (AS) is a kind of arthritis marked by persistent inflammation in the spine's joints, usually at the point where the spine and pelvis meet. Such a disease has different causes, including immunological causes. Therefore, it is necessary to investigate the role of the immune system in this disease to improve a potential treatment strategy. In this context, the present study examined the single nucleotide polymorphisms (SNPs) of the IL-40 gene of IL-40 in a group of Iraqi males with AS to determine their associations in AS pathogenesis. Method: The study included a total of 200 Iraqi male participants (100 with AS and 100 healthy subjects). The detection of SNPs of IL-40 was performed using polymerase chain reaction (PCR) techniques followed by the Sanger sequencing method. Multinomial logistic regression analysis was used to analyze the SNPs under five genetic models (allele, recessive, dominant, and co-dominant). Results: Detected that the heterozygous genotype (GA and AA) and alleles (G and A) of rs72896265, the heterozygous genotype (AG and GG) and alleles (A and G) of rs60316778 and both heterozygous genotype (CC) and alleles (C and T) of rs9915090 were significantly associated with AS risk (p < 0.001).

Research on cargo volume prediction and personnel scheduling optimization of sorting center based on BP neural network and improved genetic algorithm

With the development of Internet technology, e-commerce has become the primary choice for consumers to shop, and the huge order transaction volume has generated logistics problems. As an important part of the logistics network, the sorting platform is essential to improve its management efficiency. To enhance the efficiency of the sorting center, the topological relationship diagram is used to show the logistics network, and the cargo volume of the sorting center in the next 30 days and every hour is predicted based on the BP neural network model. Based on the mixed integer linear programming model and the improved genetic algorithm SCAGA model, the total man-days are minimized to ensure that the cargo volume is processed. At the same time, to ensure that the actual hourly efficiency is as balanced as possible, the optimization problem of personnel scheduling is studied. To maintain the efficient operation of the logistics industry, the accurate prediction of the number of goods and the reasonable scheduling of personnel, to provide a set of efficient and economical personnel scheduling programs for the logistics company, thus improving the overall operational efficiency and service quality.

Glycerol Kinase Drives Hepatic de novo Lipogenesis and Triglyceride Synthesis in Nonalcoholic Fatty Liver by Activating SREBP-1c Transcription, Upregulating DGAT1/2 Expression, and Promoting Glycerol Metabolism.

Glycerol kinase (GK) participates in triglyceride (TG) synthesis by catalyzing glycerol metabolism. Whether GK contributes to nonalcoholic fatty liver (NAFL) is unclear. The expression of hepatic Gk is found to be increased in diet-induced and genetic mouse models of NAFL and is positively associated with hepatic SREBP-1c expression and TG levels. Cholesterol and fatty acids stimulate GK expression in hepatocytes. In HFD-induced NAFL mice, knockdown of hepatic Gk decreases expression of SREBP-1c and its target lipogenic genes as well as DGAT1/2, increases serum glycerol levels, decreases serum TG levels, and attenuates hepatic TG accumulation. Overexpression of GK in hepatocytes in mice or in culture produces opposite results. Mechanistic studies reveal that GK stimulates SREBP-1c transcription directly by binding to its gene promoter and indirectly by binding to SREBP-1c protein, thereby increasing lipogenic gene expression and de novo lipogenesis. Studies with truncated GK and mutant GKs indicate that GK induces SREBP-1c transcription independently of its enzyme activity. GK contributes to lipid homeostasis under physiological conditions by catalyzing glycerol metabolism rather than by regulating SREBP-1c transcription. Collectively, these results demonstrate that increased hepatic GK promotes de novo lipogenesis and TG synthesis in NAFL by stimulating SREBP-1c transcription and DGAT1/2 expression and catalyzing glycerol metabolism.

Urban Street Landscape Design System Driven by Optimized Genetic Algorithm

With the acceleration of urbanization in China, urban and rural construction land continues to expand. In order to avoid “urban street view disease” in the process of urbanization, dynamic simulation of urban street view land is of great significance. The dynamic model of urban street view land can simulate the dynamic expansion process of street view concretely and effectively, and predict the distribution and form of urban street view land in the future more accurately. How to improve the accuracy of urban street view dynamic model based on geographic cellular automata has always been the direction of unremitting exploration in academic circles. In view of the limitations of the traditional genetic algorithm model, this study constructs a genetic algorithm-logistic regression model, and takes Chengdu-Chongqing Economic Zone as a case, and optimizes the best regression coefficient of the logistic regression model through genetic algorithm fitting, so as to realize the accurate simulation of the dynamic change of urban street view land.

Akkermansia muciniphila: biology, microbial ecology, host interactions and therapeutic potential.

Akkermansia muciniphila is a gut bacterium that colonizes the gut mucosa, has a role in maintaining gut health and shows promise for potential therapeutic applications. The discovery of A. muciniphila as an important member of our gut microbiome, occupying an extraordinary niche in the human gut, has led to new hypotheses on gut health, beneficial microorganisms and host-microbiota interactions. This microorganism has established a unique position in human microbiome research, similar to its role in the gut ecosystem. Its unique traits in using mucin sugars and mechanisms of action that can modify host health have made A. muciniphila a subject of enormous attention from multiple research fields. A. muciniphila is becoming a model organism studied for its ability to modulate human health and gut microbiome structure, leading to commercial products, a genetic model and possible probiotic formulations. This Review provides an overview of A. muciniphila and Akkermansia genus phylogeny, ecophysiology and diversity. Furthermore, the Review discusses perspectives on ecology, strategies for harnessing beneficial effects of A. muciniphila for human mucosal metabolic and gut health, and its potential as a biomarker for diagnostics and prognostics.

Integrating Multi-Omics Data to Uncover Prostate Tissue DNA Methylation Biomarkers and Target Genes for Prostate Cancer Risk.

Previous studies have indicated that specific CpG sites may be linked to the risk of prostate cancer (PCa) by regulating the expression of PCa target genes. However, most existing studies aim to identify DNA methylation (DNAm) biomarkers through blood tissue genetic instruments, which impedes the identification of relevant biomarkers in prostate tissue. To identify PCa risk-associated CpG sites in prostate tissue, we established genetic prediction models of DNAm levels using data from normal prostate samples in the GTEx (N = 108) and assessed associations between genetically predicted DNAm in prostate and PCa risk by studying 122,188 cases and 604,640 controls. We observed significant associations for 3879 CpG sites, including 926 at novel genomic loci. Among them, DNAm levels of 80 CpG sites located at novel loci are significantly associated with expression levels of 45 neighboring genes in normal prostate tissue. Of these genes, 11 further exhibit significant associations with PCa risk for their predicted expression levels in prostate tissue. Intriguingly, a total of 31 CpG sites demonstrate consistent association patterns across the methylation-gene expression-PCa risk pathway. Our findings suggest that specific CpG sites may be related to PCa risk by modulating the expression of nearby target genes.

Polymorphism Of Orosomucoid-Like 3 ORMDL3 Rs4795405 C>T In Iraqi Patients with Asthma

The aim of this study was to investigate the association of polymorphism of Orosomucoid-like 3 ORMDL3 rs4795405 C/T gene to the susceptibility of asthma among Iraqi asthmatic patients. Forty-five asthmatic patients (23 males and 22 females), their age 19-70 years and 35 healthy controls( 18 males and 17 females) ,their age 18-71years were selected from Wasit Province using a convenient sampling method. Genetic polymorphism of Orosomucoid-like 3 ORMDL3 rs4795405 C>T was carried out using TaqMan -PCR. both patients and control groups, the distribution frequencies of genotypes and alleles of the rs4795405 C/T gene were in Hardy-Weinberg equilibrium (P<0.05) .The most common genotype in both control and asthma patients was the heterozygous genotype CT with a percentage of 67% and 66% respectively. The genotype CC was higher in the asthmatic group (20%) compared to the control group (14%). In contrast, genotype TT, the less predominant genotype, was less in the asthmatic group were less in asthmatic group (13%) compared control group (20%).The C allele was more frequent in asthma patients than in healthy controls (53.33%vs47.14%), whereas the T allele was frequent in healthy controls than in asthma patients (52.86% vs 46.67%) with no significant differences. The association analysis displayed that the individuals carrying the homozygous CC genotype were more likely to have a increased risk of asthma with OR=1.5(CI95% 0.4537to4.9593) ,P=0.5063.The heterozygous genotypes CT was not associated with asthma with OR=1.0 (CI95%0.4103 to2.6538 ),P=0.9288 . The TT genotype decreases the association with asthma OR=0.6 (CI950.1865 to2.0302), P =0.4253. These results suggested that the T allele might play a protective role against asthma whereas the C allele might consider a risk factor in asthma. The subgroup analysis revealed that the asthma risk of females with ORMDL3 CC genotype was 2.4 fold increases the risk of asthma OR=2.4889 (CI95% 0.5478to11.3081), P= 0.2377 The TC and TT genotype decreases the association with the disease with with OR = 0.8485 (CI 95% 0.2312to3.1142), P = 0.8044 and OR= 0.2121(CI95% 0.02 to2.2473)P =0.1979 respectively. Among males, ORMDL3 CT genotype ncreased asthmatic risk among patients’ males 1.3 fold, OR= 1.3333 (CI95%0.3433 to 5.1781), P=0.6777. The genotype CC decreases the association with the disease OR=0.3810 (CI95%0.0317to 4.5813), P=0.4469. While, the homozygous TT genotype was not associated with the disease OR=1.0294 (CI95% 0,2313 to4.5814), P=0.9696. The analysis of genetic model for Orosomucoid-lik 3 ORMDL3 rs4795405 showed the recessive model (CC+CT/ TT ) increased the association with the asthma OR=1.6250 P=0.4253.The Over-dominant model(CT+TT/ CC) and the dominant model(CT+TT/ CC) decreased the association with asthma OR=0.9583,P=0.9288and OR= 0.6667 ,P=0.5063 respectively.

A novel genetic mouse model of osteoporosis with double heterozygosity of Irx3 and Irx5 characterizes sex-dependent phenotypes in bone homeostasis

Iroquois homeobox gene 3 (Irx3) and Irx5 encode transcription factors that play crucial roles in limb development and bone formation. Previous studies using knockout mice have revealed a role of Irx3 and Irx5 in osteogenesis in young adult mice. However, whether these genes are also essential for bone homeostasis in adulthood and contribute to bone diseases remain poorly understood. Osteoporosis is a disease characterized by lower bone mineral density and disrupted bone microarchitecture, typically occurs in postmenopausal women. Here, we demonstrate that Irx3/5dHet mice with a half-reduction of Irx3 and Irx5 dosage serve as a novel model of osteoporosis. By micro-computed tomography, we found that Irx3/5dHet mice exhibited sex-dependent bone loss patterns. While male Irx3/5dHet mice progressively lost trabecular microstructures with aging, female mutants exhibited lower bone mineral density (BMD) and bone volume fraction (BV/TV) at early adulthood (9–15 weeks old) but without further loss later at 1 year of age. Bone marrow adipocytes are known to be elevated at the expenses of lower osteogenesis in osteoporotic bone marrow. Surprisingly, we found sex-dependent changes in adipogenesis at the age of skeletal maturity that bone marrow adipocytes were reduced in female Irx3/5dHet mice along with deteriorated osteogenesis, while male mice exhibited elevated adipogenesis. In summary, we reported a novel genetic model for osteoporosis-like phenotypes, highlighting sex-dependent bone mineral density and bone marrow adipocyte characteristics.

Genetic parameters for Mycoplasma ovipneumoniae nasal DNA copy number provide progress to promote domestic and bighorn sheep coexistence on public lands

Discord between domestic sheep producers and bighorn sheep conservationists primarily involves concerns over the transmission of Mycoplasma ovipneumoniae between domestic and wild sheep. To discern if selective breeding within the Rambouillet could serve to reduce transmission, a genetic approach utilizing an existing phenotype was evaluated for additive genetic variance. The phenotype employs the measure of nasally shed bacterial DNA, or M. ovipneumoniae nasal DNA copy number (MONCN). Following estimation of the additive genetic variation associated with MONCN, the heritability and repeatability for this trait was calculated. The level of MONCN was measured at least three times per year at the U.S. Sheep Experiment Station (USSES) from ewes ranging from 1 to 7 years of age. Repeated measures animal models were evaluated from 320 ewes with a total of 1223 samples (mean = 3.8 per ewe). The MONCN values ranged from 0 (non-detected) to 71,654 copies per 2 μl of extracted nasal swab DNA. Four genetic models were evaluated with the categorical model having the highest heritability (0.12 ± 0.09) and repeatability (0.60 ± 0.05). Fixed effects included season/year (n = 9) and ewe age (n = 7). Outcomes from this research resulted in heritability estimates from which breeding values can be estimated to select USSES ewes and rams for reduced MONCN. This research provides a practical approach that can be immediately implemented to manage domestic sheep to be more compatible with bighorn sheep on public lands, providing positive welfare benefits for both species.

Apollo: A comprehensive GPU-powered within-host simulator for viral evolution and infection dynamics across population, tissue, and cell.

Modern sequencing instruments bring unprecedented opportunity to study within-host viral evolution in conjunction with viral transmissions between hosts. However, no computational simulators are available to assist the characterization of within-host dynamics. This limits our ability to interpret epidemiological predictions incorporating within-host evolution and to validate computational inference tools. To fill this need we developed Apollo, a GPU-accelerated, out-of-core tool for within-host simulation of viral evolution and infection dynamics across population, tissue, and cellular levels. Apollo is scalable to hundreds of millions of viral genomes and can handle complex demographic and population genetic models. Apollo can replicate real within-host viral evolution; accurately recapturing observed viral sequences from an HIV cohort derived from initial population-genetic configurations. For practical applications, using Apollo-simulated viral genomes and transmission networks, we validated and uncovered the limitations of a widely used viral transmission inference tool.

Ferroptosis related CPT1A and GDF15 gene polymorphisms are risk factors for lung adenocarcinoma: A case-control study

BackgroundFerroptosis is not only a consequence of inflammation, but also a dynamic process. Recent bioinformatics analysis suggests that ferroptosis related genes might be associated with lung adenocarcinoma (LUAD). CPT1A and GDF15 are critical for the process of ferroptosis and development of inflammation; however, little study focused on the mutation level of these genes in patients with LUAD. MethodsThe candidate SNPs in CPT1A and GDF15 were genotyped in 320 pairs of LUAD patients and controls using Mass ARRAY platform. Moreover, the different expression of CPT1A and GDF15 in LUAD cases and healthy controls were validated by qRT-PCR and ELISA. ResultsThe rs80356779 G > A, rs3019594 C > T, rs888663 T > G and rs4808793 G > C all exhibited an increased risk of the disease (p < 0.05). Moreover, the rs80356779-GA, rs3019594-TT, rs888663-TG and rs4808793-CC genotypes were all related to different levels of increase in LUAD risk (p < 0.05). Genetic model results showed that rs80356779 G > A, rs888663 T > G and rs4808793 G > C were associated with LUAD susceptibility under dominant and additive models (p < 0.05), while rs3019594 C > T was correlated with an elevated risk of the disease in all three models (p < 0.05). Additionally, patients with rs80356779 G > A and rs3019594 C > T exhibited lower expression and serum concentration of CPT1A compared with wile types, and patients with rs888663 T > G and rs4808793 G > C exhibited higher serum and expression level of GDF15. ConclusionThe results provided new clues for the role of ferroptosis in LUAD and new potential targets for screening of susceptible population.

Association of vitamin D receptor gene polymorphisms with caries risk in children: a systematic review and meta-analysis

BackgroundTo investigate the association of vitamin D receptor (VDR) gene polymorphism with caries risk in children(< 18 years).MethodsThe electronic databases PubMed, Cochrane, EMBASE, Web of Science, CNKI, Cqvip, and Wanfang were searched for observational studies on the relationship between VDR single nucleotide polymorphism(SNP) and caries, including cohort, case–control, and cross-sectional studies. Quality assessment of selected studies was conducted using the Newcastle Ottawa scale. Odds ratios (OR) with 95% confidence intervals (CI) values for associations of individual VDR SNP with dental caries were calculated based on four genetic models: allelic, recessive, dominant, and over-dominant.ResultsOf 79 studies considered, 10 (nine case–control and one cross-sectional) were selected for analysis; the studies involved seven VDR SNPs: ApaI(rs7975232),BsmI(rs1544410),FokI(rs2228570),TaqI(rs731236), TaqI/BglI(rs739837), FokI(rs10735810) and Cdx-2(rs11568820). Alleles C and T of FokI(rs10735810) were significantly differently distributed in the caries and caries-free groups (OR = 1.33, 95% CI: 1.30–2.30, P = 0.03), with CC + CT genotypes at this locus associated with greater risk of developing caries than the TT genotype (OR = 1.87, 95%CI: 1.15–3.04, P = 0.01). Further, TT + CC genotype at TaqI(rs731236) was associated with a 1.33-fold higher risk of caries development than the TC genotype (OR = 1.33, 95%CI: 1.06–1.67, P = 0.02). On subgroup analysis, the association between TaqI(rs731236) and caries risk was affected by dentition type, and ethnicity (permanent dentition: OR = 1.48, 95%CI: 1.07–2.03, P = 0.02; Asian: OR = 1.38, 95%CI: 1.02–1.87, P = 0.03;). Genotype distributions at BsmI(rs1544410), TaqI/BglI(rs739837), FokI(rs2228570), and ApaI(rs7975232) did not differ significantly between the caries and caries-free groups.ConclusionsCaries risk could be associated with TaqI(rs731236) and FokI(rs10735810) genotypes, and TaqI(rs731236) may be a risk factor for permanent teeth caries among Asian people.

Prognostic risk model of LIHC T-cells based on scRNA-seq and RNA-seq and the regulation of the tumor immune microenvironment

BackgroundT-cell-related genes play a crucial role in LIHC development. However, a reliable prognostic profile based on risk models of these genes has yet to be identified.MethodsSingle-cell datasets from both tumor and normal tissue samples were obtained from the GEO database. We identified T-cell marker genes and developed a genetic risk model using the TCGA-LIHC dataset, which was subsequently validated with an independent GEO dataset. We also explored the relationship between risk model predictions and immune responses.ResultsWe constructed a prognostic risk model using eight gene features identified through screening 860 T-cell marker genes via scRNA-seq and RNA-seq, which was subsequently integrated with the TCGA dataset. Its validity was independently confirmed using GEO and ICGC datasets. The TCGA dataset was stratified into high-risk and low-risk groups based on the risk model. Multivariate Cox regression analysis confirmed the risk score as an independent prognostic factor. GSEA indicated ribosomal transporter metabolism enrichment in the high-risk group and significant transcriptional activation in the low-risk group. ESTIMATE analysis showed higher ESTIMATE, immune, and stromal scores in the low-risk group, which also exhibited lower tumor purity than the high-risk group. Immunophenotyping revealed distinct patterns of immune cell infiltration and an immunosuppressive environment in the high-risk group.ConclusionsThis study introduces a T-cell marker-based prognostic risk model for LIHC patients. This model effectively predicted survival outcomes and immunotherapy effectiveness in LIHC patients, aligning with diverse immune responses and the distinct immunological profiles observed in the high-risk group.

Lack of Cannabinoid Type 2 Promoter Activity in Normal or Injured Kidneys Using a Cnr2-GFP Reporter Mouse.

Introduction: Although cannabinoid type 2 (CB2) receptor activity is known to promote diverse biological functions in the kidney, published data regarding CB2 receptor protein levels and cellular distribution within the kidney is inconsistent. The goal of the present study was to investigate the changes of CB2 in the kidney obtained from mice exposed to various forms of kidney injury using a genetic mouse model expressing green fluorescent protein (GFP) driven by the endogenous cannabinoid receptor 2 (Cnr2) promoter. Materials and Methods: Kidney injury was established in a genetic mouse model expressing green fluorescent protein (GFP) driven by the endogenous Cnr2 promoter. Kidney injury was initiated by either treatment with different chemicals [cisplatin or lipopolysaccharide (LPS)] or by unilateral ureteral obstruction (UUO). Changes in the detection of GFP were used as a proxy for CB2 levels and localization. Histological changes due to the injury stimuli were observed by time-related, morphological changes in kidney cytoarchitecture and blood parameters, such as serum creatinine levels. Cnr2 mRNA levels were detected by reverse transcription coupled to polymerase chain reaction (RT-PCR) while protein changes in the tissue lysates were measured by Western blot analysis. Cellular localization of GFP was detected by fluorescent microscopy. Results: Our data demonstrated that there was no band or a minimally detectable band for GFP using kidney lysates from vehicle- or cisplatin-treated mice. A similar lack of GFP was detected in the UUO kidney versus the contralateral control kidney. This is consistent with the low, albeit detectable levels of Cnr2 mRNA in the kidney samples from control or cisplatin treatment. In frozen kidney sections from vehicle and cisplatin-treated mice, GFP fluorescence was not detectable in tubular epithelia, glomeruli or blood vessels in the cortex. Instead, GFP was detected in rare cells within the interstitial space. A second chemical injury model using LPS found a similar lack of GFP protein levels and an absence of legitimate GFP fluorescence in the main cell types within the kidney. Conclusion: These findings suggest that Cnr2 promoter activity is minimally active in normal or injured kidneys, and that pharmacological manipulation of CB2 receptors may be associated with receptors being expressed in cells recruited to the kidney.

The Benkar Fault Zone: An Orogen-Scale Cross Fault in the Eastern Nepal Himalaya

Abstract The Benkar Fault Zone (BFZ) is a recently recognized, NNE-striking, brittle to ductile, cross fault that cuts across the dominant metamorphic fabric of the Greater Himalayan Sequence (GHS) and the Lesser Himalayan Sequence (LHS) in eastern Nepal. 40Ar/39Ar-muscovite cooling ages along a transect across the BFZ in the GHS indicate movement younger than 12 Ma. To understand the mode of genesis, and seismo-tectonic implications of the BFZ, we mapped this fault from the Everest region in the upper Khumbu valley toward the south, across the Main Central Thrust, into the LHS and the Greater Himalayan Nappe. We recognize a series of cross faults segments, which we interpret the BFZ system. The currently mapped section of the BFZ is &amp;gt;100 km long, and its width is up to 4 km in the LHS. The BFZ is semi-ductile in the GHS region but is brittle in the south, where it is expressed as gouge zones, tectonically brecciated zones, sharp fault planes, and segments of nonpenetrative brittle deformation zones. From petrographic and kinematic analysis, we interpret largely a right-lateral, extensional sense of shear. Our work did not continue into the Sub-Himalaya, but the BFZ may continue through this zone into the foreland as documented in other Himalayan cross faults. While several genetic models have been proposed for cross faults in the Himalaya and other convergent orogens, we suggest that the BFZ may be related to extensional structures in Tibet. Understanding cross faults is not only important for the tectonic history of the Himalaya but due to the co-location of cross faults and seismogenic boundaries, there may be a causal relationship. Cross faults also follow many of the north-south river segments of the Himalaya and weakened fault rocks on the valley walls may enhance the landslide hazard in these areas.

Sharp habitat shifts, evolutionary tipping points and rescue: Quantifying the perilous path of a specialist species towards a refugium in a changing environment

Specialist species thriving under specific environmental conditions in narrow geographic ranges are widely recognized as heavily threatened by climate deregulation. Many might rely on both their potential to adapt and to disperse towards a refugium to avoid extinction. It is thus crucial to understand the influence of environmental conditions on the unfolding process of adaptation. Here, I study the eco-evolutionary dynamics of a sexually reproducing specialist species in a two-patch quantitative genetic model with moving optima. Thanks to a separation of ecological and evolutionary time scales and the phase-line study of the selection gradient, I derive the critical environmental speed for persistence, which reflects how the existence of a refugium impacts extinction patterns and how it relates to the cost of dispersal. Moreover, the analysis provides key insights about the dynamics that arise on the path towards this refugium. I show that after an initial increase of population size, there exists a critical environmental speed above which the species crosses a tipping point, resulting into an abrupt habitat switch. In addition, when selection for local adaptation is strong, this habitat switch passes through an evolutionary “death valley”, leading to a phenomenon related to evolutionary rescue, which can promote extinction for lower environmental speeds than the critical one.

A spike is a spike: On the universality of spike features in four epilepsy models.

Frequency properties of the EEG characteristics of different seizure types including absence seizures have been described for various rodent models of epilepsy. However, little attention has been paid to the frequency properties of individual spike-wave complexes (SWCs), the constituting elements characterizing the different generalized seizure types. Knowledge of their properties is not only important for understanding the mechanisms underlying seizure generation but also for the identification of epileptiform activity in various seizure types. Here, we compared the frequency properties of SWCs in different epilepsy models. A software package was designed and used for the extraction and frequency analysis of SWCs from long-term EEG of four spontaneously seizing, chronic epilepsy models: a post-status epilepticus model of temporal lobe epilepsy, a lateral fluid percussion injury model of post-traumatic epilepsy, and two genetic models of absence epilepsy-GAERS and rats of the WAG/Rij strain. The SWCs within the generalized seizures were separated into fast (three-phasic spike) and slow (mostly containing the wave) components. Eight animals from each model were used (32 recordings, 104 510 SWCs in total). A limitation of our study is that the recordings were hardware-filtered (high-pass), which could affect the frequency composition of the EEG. We found that the three-phasic spike component was similar in all animal models both in time and frequency domains, their amplitude spectra showed a single expressed peak at 18-20 Hz. The slow component showed a much larger variability across the rat models. Despite differences in the morphology of the epileptiform activity in different models, the frequency composition of the spike component of single SWCs is identical and does not depend on the particular epilepsy model. This fact may be used for the development of universal algorithms for seizure detection applicable to different rat models of epilepsy. There is a large variety between people with epilepsy regarding the clinical manifestations and the electroencephalographic (EEG) phenomena accompanying the epileptic seizures. Here, we show that one of the EEG signs of epilepsy, an epileptic spike, is universal, since it has the same shape and frequency characteristics in different animal models of generalized epilepsies, despite differences in recording sites and location.

The small inhibitor WM-1119 effectively targets KAT6A-rearranged AML, but not KMT2A-rearranged AML, despite shared KAT6 genetic dependency

BackgroundThe epigenetic factors KAT6A (MOZ/MYST3) and KMT2A (MLL/MLL1) interact in normal hematopoiesis to regulate progenitors’ self-renewal. Both proteins are recurrently translocated in AML, leading to impairment of critical differentiation pathways in these malignant cells. We evaluated the potential of different KAT6A therapeutic targeting strategies to alter the growth of KAT6A and KMT2A rearranged AMLs.MethodsWe investigated the action and potential mechanisms of the first-in-class KAT6A inhibitor, WM-1119 in KAT6A and KMT2A rearranged (KAT6Ar and KMT2Ar) AML using cellular (flow cytometry, colony assays, cell growth) and molecular (shRNA knock-down, CRISPR knock-out, bulk and single-cell RNA-seq, ChIP-seq) assays. We also used two novel genetic murine KAT6A models combined with the most common KMT2Ar AML, KMT2A::MLLT3 AML. In these murine models, the catalytic activity of KAT6A, or the whole protein, can be conditionally abrogated or deleted. These models allowed us to compare the effects of specific KAT6A KAT activity inhibition with the complete deletion of the whole protein. Finally, we also tested these therapeutic approaches on human AML cell lines and primary patient AMLs.ResultsWe found that WM-1119 completely abrogated the proliferative and clonogenic potential of KAT6Ar cells in vitro. WM-1119 treatment was associated with a dramatic increase in myeloid differentiation program. The treatment also decreased stemness and leukemia pathways at the transcriptome level and led to loss of binding of the fusion protein at critical regulators of these pathways. In contrast, our pharmacologic and genetic results indicate that the catalytic activity of KAT6A plays a more limited role in KMT2Ar leukemogenicity, while targeting the whole KAT6A protein dramatically affects leukemic potential in murine KMT2A::MLLT3 AML.ConclusionOur study indicates that inhibiting KAT6A KAT activity holds compelling promise for KAT6Ar AML patients. In contrast, targeted degradation of KAT6A, and not just its catalytic activity, may represent a more appropriate therapeutic approach for KMT2Ar AMLs.

Interplay of Nav1.8 and Nav1.7 channels drives neuronal hyperexcitability in neuropathic pain.

While voltage-gated sodium channels Nav1.7 and Nav1.8 both contribute to electrogenesis in dorsal root ganglion (DRG) neurons, details of their interactions have remained unexplored. Here, we studied the functional contribution of Nav1.8 in DRG neurons using a dynamic clamp to express Nav1.7L848H, a gain-of-function Nav1.7 mutation that causes inherited erythromelalgia (IEM), a human genetic model of neuropathic pain, and demonstrate a profound functional interaction of Nav1.8 with Nav1.7 close to the threshold for AP generation. At the voltage threshold of -21.9 mV, we observed that Nav1.8 channel open-probability exceeded Nav1.7WT channel open-probability ninefold. Using a kinetic model of Nav1.8, we showed that a reduction of Nav1.8 current by even 25-50% increases rheobase and reduces firing probability in small DRG neurons expressing Nav1.7L848H. Nav1.8 subtraction also reduces the amplitudes of subthreshold membrane potential oscillations in these cells. Our results show that within DRG neurons that express peripheral sodium channel Nav1.7, the Nav1.8 channel amplifies excitability at a broad range of membrane voltages with a predominant effect close to the AP voltage threshold, while Nav1.7 plays a major role at voltages closer to resting membrane potential. Our data show that dynamic-clamp reduction of Nav1.8 conductance by 25-50% can reverse hyperexcitability of DRG neurons expressing a gain-of-function Nav1.7 mutation that causes pain in humans and suggests, more generally, that full inhibition of Nav1.8 may not be required for relief of pain due to DRG neuron hyperexcitability.

A novel GWAS locus influences microvascular response to mental stress and predicts adverse cardiovascular events.

Excessive peripheral microvascular constriction during acute psychologicalstress reflects similar changes in coronary blood flow and is a predictor of adverse cardiovascular outcomes. Among individuals with coronary artery disease (CAD), we sought to determine if genetic factors contribute to the degree of microvascular constriction during mental stress. A total of 580 stable CAD individuals from two prospective cohort studies underwent mental stress testing. Digital pulse wave amplitude was continuously measured and the stress/rest (sPAT) ratio of pulse wave amplitude was calculated. Race stratified genome-wide association studies (GWAS) of sPAT-ratio were conducted using linear regression of additive genetic models. A trans-ethnic meta-analysis integrated the four sets of GWAS results. Participants were followed for the outcome of recurrent cardiovascular events (myocardial infarction, heart failure, revascularization, and CV death) for a median of 5years. We used Wei-Lin-Weissfeld (WLW) model to assess the association between sPAT-ratio with recurrent events. Mean age was 63 ± 9. We identified three SNPs in linkage disequilibrium, closely related to chr7:111,666,943T > C (rs6466396) that were associated with sPAT-ratio (p = 6.68E-09). Participants homozygous for the T allele had 80% higher risk of incident adverse events (HR 1.8, 95% CI, 1.4-2.2). Also, participants with a lower sPAT-ratio (< median) had a higher adverse event rate, hazard ratio (HR) = 1.3, [95%confidence interval (CI), 1.1-1.6]. However, adjustment for the genotypes did not substantially alter the impact of sPAT ratio on adverse outcome rate.In conclusion,we have identified a genetic basis for stress-induced vasomotion. The 3 linked variants modulate vasoconstriction during mental stress may have a prognostic importance.