The role of inflammation in takotsubo syndrome: A new therapeutic target?

Takotsubo syndrome (TTS) is a particular form of acute heart failure that can be challenging to distinguish from acute coronary syndrome at presentation. TTS was previously considered a benign self-limiting condition, but it is now known to be associated with substantial short- and long-term morbidity and mortality. Because of the poor understanding of its underlying pathophysiology, there are few evidence-based interventions to treat TTS. The hypotheses formulated so far can be grouped into endogenous adrenergic surge, psychological stress or preexisting psychiatric illness, coronary vasospasm with microvascular dysfunction, metabolic and energetic alterations, and inflammatory mechanisms. Current evidence demonstrates that the infiltration of immune cells such as macrophages and neutrophils play a pivotal role in TTS. At baseline, resident macrophages were the dominant subset in cardiac macrophages, however, it underwent a shift from resident macrophages to monocyte-derived infiltrating macrophages in TTS. Depletion of macrophages and monocytes in mice strongly protected them from isoprenaline-induced cardiac dysfunction. It is probable that immune cells, especially macrophages, may be new targets for the treatment of TTS.

Targeted next-generation sequencing and long-read HiFi sequencing provide novel insights into clinically significant KLF1 variants.

BACKGROUND: Krüppel-like factor 1 (KLF1), a crucial erythroid transcription factor, plays a significant role in various erythroid changes and haemolytic diseases. The rare erythrocyte Lutheran inhibitor (In(Lu)) blood group phenotype serves as an effective model for identifying KLF1 hypomorphic and loss-of-function variants. In this study, we aimed to analyse the genetic background of the In(Lu) phenotype in a population-based sample group by high-throughput technologies to find potentially clinically significant KLF1 variants. RESULTS: We included 62 samples with In(Lu) phenotype, screened from over 300,000 Chinese blood donors. Among them, 36 samples were sequenced using targeted Next Generation Sequencing (NGS), whereas 19 samples were sequenced using High Fidelity (HiFi) technology. In addition, seven samples were simply sequenced using Sanger sequencing. A total of 29 hypomorphic or loss-of-function variants of KLF1 were identified, 21 of which were newly discovered. All new variants discovered by targeted NGS or HiFi sequencing were validated through Sanger sequencing, and the obtained results were found to be consistent. The KLF1 haplotypes of all new variants were further confirmed using clone sequencing or HiFi sequencing. The lack of functional KLF1 variants detected in the four samples indicates the presence of additional regulatory mechanisms. In addition, some samples exhibited BCAM polymorphisms, which encodes antigens of the Lutheran (LU) blood group system. However, no BCAM mutations which leads to the absence of LU proteins were detected. CONCLUSIONS: High-throughput sequencing methods, particularly HiFi sequencing, were introduced for the first time into genetic analysis of the In(Lu) phenotype. Targeted NGS and HiFi sequencing demonstrated the accuracy of the results, providing additional advantages such as simultaneous analysis of other blood group genes and clarification of haplotypes. Using the In(Lu) phenotype, a powerful model for identifying hypomorphic or loss-of-function KLF1 variants, numerous novel variants have been detected, which have contributed to the comprehensive understanding of KLF1. These clinically significant KLF1 mutations can serve as a valuable reference for the diagnosis of related blood cell diseases.

Detection of cryptic balanced chromosomal rearrangements using high-resolution optical genome mapping.

BACKGROUND: Chromosomal rearrangements have profound consequences in diverse human genetic diseases. Currently, the detection of balanced chromosomal rearrangements (BCRs) mainly relies on routine cytogenetic G-banded karyotyping. However, cryptic BCRs are hard to detect by karyotyping, and the risk of miscarriage or delivering abnormal offspring with congenital malformations in carrier couples is significantly increased. In the present study, we aimed to investigate the potential of single-molecule optical genome mapping (OGM) in unravelling cryptic chromosomal rearrangements. METHODS: Eleven couples with normal karyotypes that had abortions/affected offspring with unbalanced rearrangements were enrolled. Ultra-high-molecular-weight DNA was isolated from peripheral blood cells and processed via OGM. The genome assembly was performed followed by variant calling and annotation. Meanwhile, multiple detection strategies, including FISH, long-range-PCR amplicon-based next-generation sequencing and Sanger sequencing were implemented to confirm the results obtained from OGM. RESULTS: High-resolution OGM successfully detected cryptic reciprocal translocation in all recruited couples, which was consistent with the results of FISH and sequencing. All high-confidence cryptic chromosomal translocations detected by OGM were confirmed by sequencing analysis of rearrangement breakpoints. Moreover, OGM revealed additional complex rearrangement events such as inverted aberrations, further refining potential genetic interpretation. CONCLUSION: To the best of our knowledge, this is the first study wherein OGM facilitate the rapid and robust detection of cryptic chromosomal reciprocal translocations in clinical practice. With the excellent performance, our findings suggest that OGM is well qualified as an accurate, comprehensive and first-line method for detecting cryptic BCRs in routine clinical testing.

Preimplantation genetic testing in the current era, a review.

BACKGROUND: Preimplantation genetic testing (PGT), also referred to as preimplantation genetic diagnosis (PGD), is an advanced reproductive technology used during in vitro fertilization (IVF) cycles to identify genetic abnormalities in embryos prior to their implantation. PGT is used to screen embryos for chromosomal abnormalities, monogenic disorders, and structural rearrangements. DEVELOPMENT OF PGT: Over the past few decades, PGT has undergone tremendous development, resulting in three primary forms: PGT-A, PGT-M, and PGT-SR. PGT-A is utilized for screening embryos for aneuploidies, PGT-M is used to detect disorders caused by a single gene, and PGT-SR is used to detect chromosomal abnormalities caused by structural rearrangements in the genome. PURPOSE OF REVIEW: In this review, we thoroughly summarized and reviewed PGT and discussed its pros and cons down to the minutest aspects. Additionally, recent studies that highlight the advancements of PGT in the current era, including their future perspectives, were reviewed. CONCLUSIONS: This comprehensive review aims to provide new insights into the understanding of techniques used in PGT, thereby contributing to the field of reproductive genetics.

Complex Interplay Between Metabolism and CD4+ T-Cell Activation, Differentiation, and Function: a Novel Perspective for Atherosclerosis Immunotherapy.

Atherosclerosis is a complex pathological process that results from the chronic inflammatory reaction of the blood vessel wall and involves various immune cells and cytokines. An imbalance in the proportion and function of the effector CD4+ T-cell (Teff) and regulatory T-cell (Treg) subsets is an important cause of the occurrence and development of atherosclerotic plaques. Teff cells depend on glycolytic metabolism and glutamine catabolic metabolism for energy, while Treg cells mainly rely on fatty acid oxidation (FAO), which is crucial for determining the fate of CD4+ T cells during differentiation and maintaining their respective immune functions. Here, we review recent research achievements in the field of immunometabolism related to CD4+ T cells, focusing on the cellular metabolic pathways and metabolic reprogramming involved in the activation, proliferation, and differentiation of CD4+ T cells. Subsequently, we discuss the important roles of mTOR and AMPK signaling in regulating CD4+ T-cell differentiation. Finally, we evaluated the links between CD4+ T-cell metabolism and atherosclerosis, highlighting the potential of targeted modulation of CD4+ T-cell metabolism in the prevention and treatment of atherosclerosis in the future.

Study on the mechanism of nitrapyrin microcapsule suspension effectively improving nitrification inhibition rate in black soil.

Nitrification inhibitors (NIs) have been widely applied to inhibit nitrification and reduce N2O emissions in agriculture. However, there are still some shortcomings, e.g. short effective periods, large applying amounts, low effectiveness, easy deactivation and different effect. Thus, a nitrapyrin microcapsule suspension (CPCS) was used as a new experimental material to elaborate its effects on nitrogen transformation and microbial response mechanisms in black soil by cultivation experiments with six treatments of no fertilization (CK), urea, urea+ 0.2 % CPES, urea+ 0.1 % CPCS, urea+ 0.2 % CPCS, and urea+ 0.3 % CPCS. The content of ammonium, nitrate nitrogen, functional microbial activity, degradation rate and adsorption characteristics of CPCS in the soil at different incubating times were determine. Compared with the nitrapyrin emulsifiable concentrate (CPEC) treatment, the degradation rate of CPCS decreased by 21.54 %, the half-life increased by 10.2 days, and the adsorption rate of nitrapyrin on black soil decreased more than 6-fold. CPCS effectively inhibited the transformation of ammonium nitrogen to nitrate nitrogen within more than 42 days. CPCS had a negative effect on amoA gene abundance and a positive effect on nrfA gene abundance. The research results provide a basic theoretical support for the application of CPCS on black soil.

The Loss-Function of KNL1 Causes Oligospermia and Asthenospermia in Mice by Affecting the Assembly and Separation of the Spindle through Flow Cytometry and Immunofluorescence.

KNL1 (kinetochore scaffold 1) has attracted much attention as one of the assembly elements of the outer kinetochore, and the functions of its different domains have been gradually revealed, most of which are associated with cancers, but few links have been made between KNL1 and male fertility. Here, we first linked KNL1 to male reproductive health and the loss-function of KNL1 resulted in oligospermia and asthenospermia in mice (an 86.5% decrease in total sperm number and an 82.4% increase in static sperm number, respectively) through CASA (computer-aided sperm analysis). Moreover, we introduced an ingenious method to pinpoint the abnormal stage in the spermatogenic cycle using flow cytometry combined with immunofluorescence. Results showed that 49.5% haploid sperm was reduced and 53.2% diploid sperm was increased after the function of KNL1 was lost. Spermatocytes arrest was identified at the meiotic prophase I of spermatogenesis, which was induced by the abnormal assembly and separation of the spindle. In conclusion, we established an association between KNL1 and male fertility, providing a guide for future genetic counseling regarding oligospermia and asthenospermia, and a powerful method for further exploring spermatogenic dysfunction by utilizing flow cytometry and immunofluorescence.

Modelling maize yield, soil nitrogen balance and organic carbon changes under long-term fertilization in Northeast China.

Optimized fertilization is an effective strategy for improving nitrogen (N) use efficiency and maintaining high crop yield, but its long-term impacts on soil organic carbon (C) and inorganic N dynamics remain unclear. The objectives of this study were to 1) explore the economic optimum N rate and evaluate the DSSAT CERES-Maize model using the measurements from three 3-year maize (Zea mays L.) field experiments, in Gongzhuling and Yushu County, Northeast China, and 2) assess the long-term impacts of farmers' N rate (N250), optimum N rate (N180) and organic-inorganic combined N rate (MN180) on maize yields, soil N and C changes from 1985 to 2020. Results showed that similar maize yields of 8000-11,000 kg ha-1 were achieved under the average economic optimum N rate of 170 kg N ha-1 relative to N250 in both counties. Good agreements were observed between the simulated and measured maize yield, above-ground biomass, N uptake and soil nitrate (NO3--N). Long-term simulation confirmed that N180 and MN180 can achieve the same yield as N250 in both counties. The lowest annual soil inorganic N balance, NO3--N leaching, and nitrous oxide (N2O) and ammonia (NH3) emissions were achieved under MN180, followed by N180 in both sites. Higher NO3--N leaching was found in sandy clay loam soil than silt clay loam and clay loam soils. Average soil organic C (SOC, 0-0.2 m) increased from 1.3 to 2.4% in Gongzhuling and from 2.2 to 2.4% in Yushu under MN180 during the 35-year period, but it showed declining trends under N180 and N250. We concluded that the economic optimum N rate could be an option to replace current farmers' N rate for the continuous maize. Substitution of inorganic fertilizer by 20-30% manure under the optimum N rate showed advantage on maintaining high yield, reducing soil inorganic N losses as well as increasing SOC stock for sustainable agriculture.

Responses of antioxidant enzymes and key resistant substances in perennial ryegrass (Lolium perenne L.) to cadmium and arsenic stresses.

Cadmium (Cd) and arsenic (As) exist simultaneously in soil environment, which poses a serious threat to the safety of agricultural products and forage production. Four Perennial Ryegrass (Lolium perenne L.) cultivars with different accumulation characteristics ('Nicaragua', 'Venus', 'Excellent' and 'Monro') were selected as the material for pot experiment. The coupled responses of key components and related enzyme activities under combined stresses of Cd and As were investigated. key components contents include Non protein sulfhydryl (NPT), glutathione (GSH) and phytochelatins (PCs). The related enzyme includes (superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), γ-glutamylcysteine synthetase (γ-ECS), glutathione synthetase (GSS), phytochelatin synthetases (PCSase) and arsenate reductase (AR). The results showed that Cd contents of perennial ryegrass were higher than those of As contents with TFCd/As < 1. Cd and As contents in roots were in the higher proportion than those in shoots. Compared to control, POD activities increased by 2.72 folds under 120 mg kg-1 As treatment. The contents of PCs increased by 5.68 folds under 120 mg kg-1 As treatment. Under combined Cd and As stress, the MDA contents and antioxidant enzyme activities of 'Venus' were higher than those of 'Nicaragua'. 'Nicaragua', a high accumulation cultivar. Under the combined stresses of Cd and As, the enzyme activities and the key components were significantly correlated (P < 0.05) with the contents of Cd and As. The tolerance to Cd and As was improved with increase in GSH and PCs contents and γ-ECS, GSS, PCSase and AR activities. In conclusion, the antioxidant enzyme system and key resistant substances of perennial ryegrass have important and antagonistic effects on Cd and As stresses.

New insights into the roles of glucocorticoid signaling dysregulation in pathological cardiac hypertrophy.

Pathological cardiac hypertrophy is a process of abnormal remodeling of the myocardium in response to stress overload or ischemia that results in myocardial injury, which is an independent risk factor for the increased morbidity and mortality of heart failure. Elevated circulating glucocorticoids (GCs) levels are associated with an increased risk of pathological cardiac hypertrophy, but the exact role remains unclear. In the heart, GCs exerts physiological and pharmacological effects by binding the glucocorticoid receptor (GR, NR3C1). However, under the state of tissue damage or oxidative stress, GCs can also bind the closely related mineralocorticoid receptor (MR, NR3C2) to exert a detrimental effect on cardiac function. In addition, the bioavailability of GCs at the cellular level is mainly regulated by tissue-specific metabolic enzymes 11ß-hydroxysteroid dehydrogenases (11ß-HSDs), including 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) and type 2 (11ß-HSD2), which catalyze the interconversion of active GCs. In this paper, we provide an overview of GC signaling and its physiological roles in the heart and highlight the dynamic and diverse roles of GC signaling dysregulation, mediated by excessive ligand GCs levels, GR/MR deficiency or overexpression, and local GCs metabolic disorder by 11ß-HSDs, in the pathology of cardiac hypertrophy. Our findings will provide new ideas and insights for the search for appropriate intervention targets for pathological cardiac hypertrophy.

A reliable tool for detecting 7-dehydrocholesterol and cholesterol in human plasma and its use in diagnosis of Smith-Lemli-Opitz syndrome.

BACKGROUND: Smith-Lemli-Opitz syndrome is a birth defect caused by the deficiency of 7-dehydrocholesterol reductase in cholesterol biosynthesis pathway, which leads to accumulation of 7-dehydrocholesterol and reduction of cholesterol in body fluids. To effectively diagnose Smith-Lemli-Opitz syndrome and monitor therapy, a reliable method for simultaneous detection of 7-dehydrocholesterol and cholesterol is needed. METHODS: In the presence of antioxidants (2,6-ditert-butyl-4-methylphenol and triphenylphosphine), 50 µL of human plasma were hydrolyzed at 70℃ for 40 min with 1 M potassium hydroxide in 90% ethanol, and then 7-dehydrocholesterol and cholesterol were extracted by 600 µL of n-hexane for three times. After microwave-assisted derivatization with 70 µL of N,O-bis(trimethylsilyl)trifluoroacetamide at 460 W for 3 min, the analytes were measured by gas chromatography-mass spectrometry. RESULTS: The limits of detection were 100 ng/mL for 7-dehydrocholesterol and 300 ng/mL for cholesterol. Good linearity was obtained in the range of 1-600 µg/mL for 7-dehydrocholesterol and 10-600 µg/mL for cholesterol, which completely covered the biochemical levels of Smith-Lemli-Opitz syndrome patients that have been reported. CONCLUSION: A time-saving and accurate gas chromatography with mass spectrometry based method was developed for the determination of 7-dehydrocholesterol and cholesterol in human plasma, which also serves as a useful tool for Smith-Lemli-Opitz syndrome diagnosis, treatment, and research.

An Adaptive Calibration Algorithm Based on RSSI and LDPLM for Indoor Ranging and Positioning.

The positioning algorithm based on received signal strength indication (RSSI) and the logarithmic distance path loss model (LDPLM) is widely used in indoor positioning scenarios due to its convenient detection and low costs. However, the classic LDPLM with fixed coefficients and fixed error estimation usually reduces the ranging accuracy, but it is rarely studied in previous literature. This study proposes an adaptive calibration ranging algorithm based on LDPLM, which consists of two parts: coefficient adaptive algorithm and error correction algorithm. The coefficient adaptive algorithm is derived by utilizing the error theory and the least squares method. The error correction algorithm is defined as the linear regression equation, in which coefficients are determined by the least squares method. In addition, to reduce the influence of RSSI's fluctuation on ranging accuracy, we propose a simple but effective filtering algorithm based on Gaussian. The experimental results show that compared with the classic LDPLM and polynomial fitting model, the ranging accuracy of the proposed algorithm is improved by 58% and 51%, respectively, and the positioning cumulative prediction error of the proposed model is reduced by 69% and 80%, respectively.

Calibration-Free 3D Indoor Positioning Algorithms Based on DNN and DIFF.

The heterogeneity of wireless receiving devices, co-channel interference, and multi-path effect make the received signal strength indication (RSSI) of Wi-Fi fluctuate greatly, which seriously degrades the RSSI-based positioning accuracy. Signal strength difference (DIFF), a calibration-free solution for handling the received signal strength variance between diverse devices, can effectively reduce the negative impact of signal fluctuation. However, DIFF also leads to the explosion of the RSSI data dimension, expanding the number of dimensions from m to Cm2, which reduces the positioning efficiency. To this end, we design a data hierarchical processing strategy based on a building-floor-specific location, which effectively improves the efficiency of high-dimensional data processing. Moreover, based on a deep neural network (DNN), we design three different positioning algorithms for multi-building, multi-floor, and specific-location respectively, extending the indoor positioning from the single plane to three dimensions. Specifically, in the stage of data preprocessing, we first create the original RSSI database. Next, we create the optimized RSSI database by identifying and deleting the unavailable data in the RSSI database. Finally, we perform DIFF processing on the optimized RSSI database to create the DIFF database. In the stage of positioning, firstly, we design an improved multi-building positioning algorithm based on a denoising autoencoder (DAE). Secondly, we design an enhanced DNN for multi-floor positioning. Finally, the newly deep denoising autoencoder (DDAE) used for specific location positioning is proposed. The experimental results show that the proposed algorithms have better positioning efficiency and accuracy compared with the traditional machine learning algorithms and the current advanced deep learning algorithms.

A Design and Application of Municipal Service Platform Based on Cloud-Edge Collaboration for Smart Cities.

Information and Communication Technology (ICT) makes cities "smart", capable of providing advanced municipal services to citizens more efficiently. In the literature, many applications of municipal service platform based on cloud computing and edge computing have been proposed, but the reference model and application instance based on cloud-edge collaboration specially for municipal service platform is rarely studied. In this context, this paper first develops a reference model, including resource collaboration, application collaboration, service collaboration, and security collaboration, and discusses the main contents and challenges of each part. Then, aiming at the problem of computing and communication resources allocation in the cloud-edge collaboration, a game-theory-based dynamic resource allocation model is introduced. Finally, an e-government self-service system based on the cloud-edge collaboration is designed and implemented. The cloud side is a cloud computing server, and the edge side are the self-service terminals integrating various edge computing devices with Artificial Intelligence (AI) embedded. The experimental results show that the designed system combines the advantages of cloud computing and edge computing, and provides a better user experience with lower processing latency, larger bandwidth, and more concurrent tasks. Meanwhile, the findings show that the evolutionary equilibrium and the Nash equilibrium are the optimal solutions, respectively.

Adsorption Characteristics of Modified Eucalyptus Sawdust for Cadmium and Arsenic and Its Potential for Soil Remediation.

In order to explore the utilization of Eucalyptus sawdust (C) and develop its remediation potential in cadmium and arsenic contaminated soil, Eucalyptus sawdust were modified by FeCl3 and NaOH coprecipitation (MC). Characterization technology and pot experiment were used to explore the adsorption mechanism of cadmium and arsenic by MC and the effect of soil remediation. The results showed that iron oxide was loaded on the surface of Eucalyptus sawdust and destroyed the semi fiber structure. The adsorption mechanisms of cadmium and arsenic included electrostatic attraction, precipitation, complexation, redox. The soil pH value reduced by 0.12-0.18 units with 0.25%-1% ratio of application rates of MC to soil weight treatment; The contents of available cadmium and arsenic were reduced by 18%-25% and 12%-18%; MC could promote the transformation of Cd and As from highly active formation to low active formation and had a good application prospect for Cd and As compound pollution remediation.

Long noncoding RNA HBBP1 enhances γ-globin expression through the ETS transcription factor ELK1.

ß-Thalassemia is an autosomal recessive genetic disease caused by defects in the production of adult hemoglobin (HbA, α2ß2), which leads to an imbalance between α- and non-α-globin chains. Reactivation of γ-globin expression is an effective strategy to treat ß-thalassemia patients. Previously, it was demonstrated that hemoglobin subunit beta pseudogene 1 (HBBP1) is associated with elevated fetal hemoglobin (HbF, α2γ2) in ß-thalassemia patients. However, the mechanism underlying HBBP1-mediated HbF production is unknown. In this study, using bioinformatics analysis, we found that HBBP1 is involved in γ-globin production, and then preliminarily confirmed this finding in K562 cells. When HBBP1 was overexpressed, γ-globin expression was increased at the transcript and protein levels in HUDEP-2 cells. Next, we found that ETS transcription factor ELK1 (ELK1) binds to the HBBP1 proximal promoter and significantly promotes its activity. Moreover, the synthesis of γ-globin was enhanced when ELK1 was overexpressed in HUDEP-2 cells. Surprisingly, ELK1 also directly bound to and activated the γ-globin proximal promoter. Furthermore, we found that HBBP1 and ELK1 can interact with each other in HUDEP-2 cells. Collectively, these findings suggest that HBBP1 can induce γ-globin by enhancing ELK1 expression, providing some clues for γ-globin reactivation in ß-thalassemia.

Research Progress on the Involvement of ANGPTL4 and Loss-of-Function Variants in Lipid Metabolism and Coronary Heart Disease: Is the "Prime Time" of ANGPTL4-Targeted Therapy for Coronary Heart Disease Approaching?

BACKGROUND: Multiple genetic studies have confirmed the definitive link among the loss-of-function variants of angiogenin-like protein 4 (ANGPTL4), significantly decreased plasma triglyceride (TG) levels, and reduced risk of coronary heart disease (CHD). The potential therapeutic effect of ANGPTL4 on dyslipidemia and CHD has been widely studied. OBJECTIVE: This review provides a detailed introduction to the research progress on the involvement of ANGPTL4 in lipid metabolism and atherosclerosis and evaluates the efficacy and safety of ANGPTL4 as a therapeutic target for CHD. RELEVANT FINDINGS: By inhibiting lipoprotein lipase (LPL) activity, ANGPTL4 plays a vital role in the regulation of lipid metabolism and energy balance. However, the role of ANGPTL4 in regulating lipid metabolism is tissue-specific. ANGPTL4 acts as a locally released LPL inhibitor in the heart, skeletal muscle and small intestine, while ANGPTL4 derived from liver and adipose tissue mainly acts as an endocrine factor that regulates systemic lipid metabolism. As a multifunctional protein, ANGPTL4 also inhibits the formation of foam cells in macrophages, exerting an anti-atherogenic role. The function of ANGPTL4 in endothelial cells is still uncertain. The safety of ANGPTL4 monoclonal antibodies requires further evaluation due to their potential adverse effects. CONCLUSION: The biological characteristics of ANGPTL4 are much more complex than those demonstrated by genetic studies. Future studies must elucidate how to effectively reduce the risk of CHD while avoiding potential atherogenic effects and other complications before the "prime time" of ANGPTL4-targeted therapy arrives.

Soluble epoxide hydrolase inhibitors improve angiogenic function of endothelial progenitor cells via ERK/p38-mediated miR-126 upregulation in myocardial infarction mice after exercise.

It is well established that exercise could protect against myocardial infarction (MI). Previously, we found that epoxyeicosatrienoic acids (EETs) could be induced by exercise and has been found to protect against MI via promoting angiogenic function of endothelial progenitor cells (EPCs). However, the underling mechanism of EETs in promoting EPC functions is unclear. C57BL/6 mice were fed with a novel soluble epoxide hydrolase inhibitor (sEHi), TPPU, to increase EET levels, for 1 week before undergoing MI surgery. Mice were then subjected to exercise training for 4 weeks. Bone marrow-derived EPCs were isolated and cultured in vitro. Exercise upregulated miR-126 expression but downregulated the protein levels of its target gene, Spred1, in EPCs from MI mice. TPPU further enhanced the effects of exercise on EPCs. Spred1 overexpression abolished the protective effects of TPPU on EPC functions. Downregulation of miR-126 by antagomiR-126 impaired the inhibitor effects of TPPU on Spred1 mRNA and protein expression. Additionally, TPPU upregulated miR-126 is partially mediated through ERK/p38 MAPK pathway. This study showed that sEHi promoted miR-126 expression, which might be related to the beneficial effect of sEHi on EPC functions in MI mice under exercise conditions, by increasing ERK and p38 MAPK phosphorylation and inhibiting Spred1.

Trans-acting non-synonymous variant of FOXA1 predisposes to hepatocellular carcinoma through modulating FOXA1-ERα transcriptional program and may have undergone natural selection.

Interplay of pioneer transcription factor forkhead box A1 (FOXA1) and estrogen receptor has been implicated in sexual dimorphism in hepatocellular carcinoma (HCC), but etiological relevance of its polymorphism was unknown. In the case control study (1152 patients versus1242 controls), we observed significant increase in HCC susceptibility in hepatitis B virus carriers associated with a non-synonymous Thr83Ala variant of FOXA1 (odds ratio [OR], 1.28; 95% confidence interval [CI], 1.11-1.48, for Ala83-containing genotype, after validation in an independent population with 933 patients versus 1030 controls), a tightly linked (CGC)5/6or7 repeat polymorphism at its promoter (OR 1.32; 95% CI 1.10-1.60, for (CGC)6or7-repeat-containing genotype), and their combined haplotype (OR 1.50; 95% CI 1.24-1.81, for (CGC)6or7-Ala83 haplotype). The susceptible FOXA1-Ala83 impairs its interaction with ERα, attenuates transactivation toward some of their dual target genes, such as type 1 iodothyronine deiodinase, UDP glucuronosyltransferase 2 family, polypeptide B17 and sodium/taurocholate cotransporting polypeptide, but correlates with strengthened cellular expression of α-fetoprotein (AFP) and elevated AFP serum concentration in HCC patients (n = 1096). The susceptible FOXA1 cis-variant with (CGC)6or7 repeat strengthens the binding to transcription factor early growth response 1 and enhances promoter activity and gene expression. Evolutionary population genetics analyses with public datasets reveal significant population differentiation and unique haplotype structure of the derived protective FOXA1-Thr83 and suggest that it may have undergone positive natural selection in Chinese population. These findings epidemiologically highlight the functional significance of FOXA1-ERα transcriptional program and regulatory network in liver cancer development.

Whole-exome sequencing identifies a novel mutation in spermine synthase gene (SMS) associated with Snyder-Robinson Syndrome.

BACKGROUND: Loss of function mutations in the spermine synthase gene (SMS) have been reported to cause a rare X-linked intellectual disability known as Snyder-Robinson Syndrome (SRS). Besides intellectual disability, SRS is also characterized by reduced bone density, osteoporosis and facial dysmorphism. SRS phenotypes evolve with age from childhood to adulthood. METHODS: Whole exome sequencing was performed to know the causative gene/pathogenic variant. Later we confirmed the pathogenic variant through Sanger sequencing. Furthermore, we also performed the mutational analysis through HOPE SERVER and SWISS-MODEL. Also, radiographs were also obtained for affected individual to confirm the disease features. RESULTS: In this article, we report the first Pakistani family consisting of three patients with SRS and a novel missense pathogenic variant in the SMS gene (c.905 C > T p.(Ser302Leu)). In addition to the typical phenotypes, one patient presented with early-onset seizures. Clinical features, genetic and in-silico analysis linked the affected patients of the family with Snyder-Robinson and suggest that this novel mutation affects the spermine synthase activity. CONCLUSION: A novel missense variant in the SMS, c.905C > T p. (Ser302Leu), causing Snyder- Robinson Syndrome (SRS) is reported in three members of Pakistani Family.