1 3903 159 LEP, LDLR AND APOA4 GENE POLYMORPHISMS AND THEIR RELATIONSHIP WITH THE RISK OF OVERWEIGHT, OBESITY AND CHRONIC DISEASES IN ADULTS OF THE STATE OF SUCRE, VENEZUELA. INTRODUCTION: OVERWEIGHT, OBESITY AND SOME CHRONIC DISEASES HAVE BECOME MORE PREVALENT RECENTLY. IT IS WELL KNOWN THAT THEIR CAUSES MAY BE GENETIC, EPIGENETIC, ENVIRONMENTAL, OR A MIXTURE OF THESE. OBJECTIVE: TO ANALYZE THE RELATIONSHIP BETWEEN NINE SINGLE NUCLEOTIDE POLYMORPHISMS OF GENES LEP (RS2167270), LDLR (RS885765, RS688, RS5925, RS55903358, RS5742911) AND APOA4 (RS5095, RS675, RS5110) WITH OBESITY-RELATED PHENOTYPES AND OTHER COMORBIDITIES. MATERIAL AND METHODS: WE RECRUITED 144 ADULTS (76 MALES AND 68 FEMALES, WITH AVERAGE AGES OF 29.93+/-8.29 AND 32.49+/-11.15 YEARS, RESPECTIVELY) IN THE STATE OF SUCRE, VENEZUELA. CLINICAL AND ANTHROPOMETRIC PARAMETERS WERE OBTAINED. GENOTYPE-RISK ASSOCIATIONS WERE STUDIED. WE THEN COMPARED THE AVERAGES REGISTERED FOR ANTHROPOMETRIC AND BIOCHEMICAL VARIABLES PREVIOUSLY ADJUSTED FOR BIOLOGICAL AND ENVIRONMENTAL FACTORS. RESULTS: ACCORDING TO THE BODY MASS INDEX, 38.9% OF THE INDIVIDUALS IN THE SAMPLE WERE OVERWEIGHT (25/=30 KG/M2). GENOTYPE AND ALLELE FREQUENCIES DID NOT DIFFER STATISTICALLY FOR GROUPS WITH NORMAL AND HIGH BODY MASS INDEX (OVERWEIGHT PLUS OBESITY). THE ASSOCIATION BETWEEN LDLR RS5742911 ANCESTRAL GENOTYPE A/A AND HIGH RISK CONDITION RELATED TO HDL-CHOLESTEROL WAS THE ONLY ONE FOUND TO BE SIGNIFICANT (OR=2.944, 95% CI: 1.446-5.996; P=0.003). THE DIFFERENCE IN ADJUSTED MEAN HDL-CHOLESTEROL FOR LDLR RS5742911 GENOTYPES WAS STATISTICALLY SIGNIFICANT (P=0.005) (A/A: 41.50+/-14.81 MG/DL; A/G: 45.00+/-12.07 MG/DL; G/G: 47.17+/-9.43 MG/DL). CONCLUSIONS: FOR MOST OF THE GENETIC VARIANTS STUDIED, THERE WAS AN ASSOCIATION WITH THE PRESENCE OF OVERWEIGHT AND OBESITY AMONG ANCESTRAL GENOTYPE CARRIERS, ALTHOUGH THIS WAS NOT STATISTICALLY SIGNIFICANT. THE RS5742911 POLYMORPHISM MAY BE USEFUL AS AN INDICATOR OF A RISK OF CHRONIC DISEASES. 2016 2 1791 30 EFFECT OF CHRONIC RADIATION ON THE FLAX (LINUM USITATISSIMUM L.) GENOME GROWN FOR SIX CONSECUTIVE GENERATIONS IN THE RADIOACTIVE CHERNOBYL AREA. THE GROWTH OF PLANTS UNDER CHRONIC RADIATION STRESS IN THE CHERNOBYL AREA MAY CAUSE CHANGES IN THE GENOME OF PLANTS. TO ASSESS THE EXTENT OF GENETIC AND EPIGENETIC CHANGES IN NUCLEAR DNA, SEEDS OF THE ANNUAL CROP FLAX (LINUM USITATISSIMUM L.) OF THE KYIVSKYI VARIETY, SOWN 21 YEARS AFTER THE ACCIDENT AND GROWN FOR SIX GENERATIONS IN RADIOACTIVE (RAD) AND REMEDIATED (REM) FIELDS WERE ANALYSED. FLAXSEED USED FOR SOWING FIRST GENERATION, WHICH SERVED AS A REFERENCE (REF), WAS ALSO ANALYSED. THE AFLP (AMPLIFIED FRAGMENT LENGTH POLYMORPHISM) REVEALED A HIGHER NUMBER OF SPECIFIC ECORI-MSEI LOCI (3.4-FOLD) IN POOLED FLAXSEED SAMPLES HARVESTED FROM THE RAD FIELD COMPARED WITH THE REM FIELD, INDICATING A LINK BETWEEN THE MUTATION PROCESS IN THE FLAX GENOME AND THE ONGOING ADAPTATION PROCESS. MSAP (METHYLATION-SENSITIVE AMPLIFIED POLYMORPHISM) DETECTING ECORI-MSPI AND ECORI-HPAII LOCI IN FLAX NUCLEAR DNA GENOME SHOWED NO SIGNIFICANT DIFFERENCES IN METHYLATION LEVEL, REACHING ABOUT 33% IN EACH OF THE GROUPS STUDIED. ON THE OTHER HAND, SIGNIFICANT CHANGES IN THE DNA METHYLATION PATTERN OF FLAXSEED SAMPLES HARVESTED FROM THE RAD FIELD COMPARED WITH CONTROLS WERE DETECTED. PAIRWISE F(ST) COMPARISON REVEALED WITHIN BOTH, ECORI-MSPI AND TRANSFORMED METHYLATION-SENSITIVE DATA SETS MORE THAN A 3-FOLD INCREASE OF GENETIC DIVERGENCE IN THE RAD FIELD COMPARED WITH BOTH CONTROLS. THESE RESULTS INDICATE THAT THE NUCLEAR GENOME OF FLAX EXPOSED TO CHRONIC RADIATION FOR SIX GENERATIONS HAS MORE MUTATIONS AND USES DNA METHYLATION AS ONE OF THE ADAPTATION MECHANISMS FOR SUSTAINABILITY UNDER ADVERSE CONDITIONS. 2022 3 515 36 ASSOCIATION OF SOCS1 (- 820) (RS33977706) GENE POLYMORPHISM WITH CHRONIC PERIODONTITIS: A CASE-CONTROL STUDY IN BRAZILIANS. IT IS EVIDENT THAT THE ACCUMULATION OF PERIODONTAL PATHOGENS OVER THE TEETH SURFACE TRIGGERS PERIODONTITIS; HOWEVER, ITS AGGRAVATION AND SEVERITY DEPEND ON OTHER ELEMENTS SUCH AS ENVIRONMENTAL FACTORS, SYSTEMIC HEALTH AND THE HOST GENETIC AND/OR EPIGENETIC BACKGROUND. TO ADDRESS THIS ISSUE, WE INVESTIGATED THE ASSOCIATION OF TWO GENETIC POLYMORPHISMS PLACED ON PROMOTER REGION OF SOCS1 GENE WITH CHRONIC PERIODONTAL DISEASE. SOCS1 REGULATES JAK/KINASE SIGNALING PATHWAY AND CHANGES IN ITS MRNA EXPRESSION HAVE BEEN RELATED TO DIFFERENT TYPES OF CANCER AND CHRONIC INFLAMMATION, INCLUDING CHRONIC PERIODONTITIS. THE FREQUENCY OF ALLELES AND GENOTYPES OF TWO POLYMORPHISMS IN SOCS1 GENE PROMOTER (POSITION - 820 (RS33977706) AND POSITION - 1478 (RS33989964)) WERE ANALYZED BY PERFORMING RFLP AND TAQMAN SYSTEM IN A TOTAL OF 257 NON-SMOKING SUBJECTS. WE FOUND A LOW FREQUENCY OF A ALLELE AND A/A GENOTYPE OF SOCS1(- 820) POLYMORPHISM IN THE CHRONIC PERIODONTITIS GROUP, ESPECIALLY WHEN SEVERE PERIODONTITIS SAMPLES WERE SEPARATELY ANALYZED (OR = 0.3933; P = 0.0084 (IC95% 0.2112 < MU < 0.7324)), SUGGESTING THAT A ALLELE PLAYS PROTECTIVE EFFECT AGAINST CHRONIC PERIODONTITIS. WE DID NOT FIND ASSOCIATION BETWEEN SOCS1-1478 POLYMORPHISM AND PERIODONTITIS. IN ADDITION, ANALYSIS OF SOCS1 (- 820/- 1478) HAPLOTYPE REVEALED THAT THE FREQUENCY OF A(- 820)/CA(- 1478) HAPLOTYPE DECREASES IN CHRP (P = 0.0089). IN CONCLUSION, OUR STUDY FOUND THAT SOCS1(- 820) POLYMORPHISM IS ASSOCIATED WITH CHRONIC PERIODONTITIS. 2015 4 1496 25 DNA IS HYPOMETHYLATED IN CIRCADIAN MANIFESTATIONS OF BRUXISM. OBJECTIVE: THE AIM OF THIS STUDY WAS TO COMPARE THE GLOBAL DNA METHYLATION LEVELS IN PATIENTS UNDER BRUXISM TREATMENT AND A CONTROL GROUP. METHODS: SUBJECTS UNDERGOING BRUXISM TREATMENT WERE CLASSIFIED IN AWAKE BRUXISM (42 PATIENTS), SLEEP BRUXISM (32 PATIENTS) AND BOTH CONDITIONS (42 PATIENTS). THE CONTROL GROUP INCLUDED 42 INDIVIDUALS. A COLORIMETRIC ASSAY (METHYLFLASH METHYLATED DNA 5-MC QUANTIFICATION KIT, EPIGENETIC GROUP INC., NY, USA) WAS USED TO DETERMINE THE GLOBAL DNA METHYLATION LEVELS. RESULTS: STATISTICALLY SIGNIFICANT DIFFERENCES WERE FOUND IN AMOUNTS OF METHYLATED DNA IN ALL CIRCADIAN MANIFESTATIONS OF BRUXISM COMPARED WITH A CONTROL GROUP (SLEEP BRUXISM = 0.95% +/- 2.02%; AWAKE BRUXISM = 0.87% +/- 2.1%; SLEEP AND AWAKE BRUXISM = 0.17% +/- 0.25%; CONTROL = 1.69% +/- 1.6%; KRUSKAL-WALLIS TEST [P = .0001] FOLLOWED BY DUNN'S TEST [P < .05]). CONCLUSION: PATIENTS UNDERGOING BRUXISM TREATMENT EXHIBITED HYPOMETHYLATED DNA LEVELS WHEN COMPARED TO CONTROL GROUP. OUR RESULTS SUGGEST THAT DNA HYPOMETHYLATION MIGHT BE A NOVEL AETIOLOGIC FACTOR IN BRUXISM AETIOLOGY. FURTHER RESEARCHES MUST BE PERFORMED EXPLORING THE ROLE OF EPIGENETICS MODIFICATIONS IN CIRCADIAN MANIFESTATIONS OF BRUXISM. 2018 5 6632 28 UNDERSTANDING THE ROLE OF THE CHROMOSOME 15Q25.1 IN COPD THROUGH EPIGENETICS AND TRANSCRIPTOMICS. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A MAJOR HEALTH BURDEN IN ADULTS AND CIGARETTE SMOKING IS CONSIDERED THE MOST IMPORTANT ENVIRONMENTAL RISK FACTOR OF COPD. CHROMOSOME 15Q25.1 LOCUS IS ASSOCIATED WITH BOTH COPD AND SMOKING. OUR STUDY AIMS AT UNDERSTANDING THE MECHANISM UNDERLYING THE ASSOCIATION OF CHROMOSOME 15Q25.1 WITH COPD THROUGH EPIGENETIC AND TRANSCRIPTIONAL VARIATION IN A POPULATION-BASED SETTING. TO ASSESS IF COPD-ASSOCIATED VARIANTS IN 15Q25.1 ARE METHYLATION QUANTITATIVE TRAIT LOCI, EPIGENOME-WIDE ASSOCIATION ANALYSIS OF FOUR GENETIC VARIANTS, PREVIOUSLY ASSOCIATED WITH COPD (P < 5 X 10(-8)) IN THE 15Q25.1 LOCUS (RS12914385:C>T-CHRNA3, RS8034191:T>C-HYKK, RS13180:C>T-IREB2 AND RS8042238:C>T-IREB2), WAS PERFORMED IN THE ROTTERDAM STUDY (N = 1489). ALL FOUR VARIANTS WERE SIGNIFICANTLY ASSOCIATED (P < 1.4 X 10(-6)) WITH BLOOD DNA METHYLATION OF IREB2, CHRNA3 AND PSMA4, OF WHICH TWO, INCLUDING IREB2 AND PSMA4, WERE ALSO DIFFERENTIALLY METHYLATED IN COPD CASES AND CONTROLS (P < 0.04). FURTHER ADDITIVE AND MULTIPLICATIVE EFFECTS OF SMOKING WERE EVALUATED AND NO SIGNIFICANT EFFECT WAS OBSERVED. TO EVALUATE IF THESE FOUR GENETIC VARIANTS ARE EXPRESSION QUANTITATIVE TRAIT LOCI, TRANSCRIPTOME-WIDE ASSOCIATION ANALYSIS WAS PERFORMED IN 1087 LUNG SAMPLES. ALL FOUR VARIANTS WERE ALSO SIGNIFICANTLY ASSOCIATED WITH DIFFERENTIAL EXPRESSION OF THE IREB2 3'UTR IN LUNG TISSUES (P < 5.4 X 10(-95)). WE CONCLUDE THAT REGULATORY MECHANISMS AFFECTING THE EXPRESSION OF IREB2 GENE, SUCH AS DNA METHYLATION, MAY EXPLAIN THE ASSOCIATION BETWEEN GENETIC VARIANTS IN CHROMOSOME 15Q25.1 AND COPD, LARGELY INDEPENDENT OF SMOKING. 2018 6 5001 41 PERINATAL RISK FACTORS IN TOURETTE'S AND CHRONIC TIC DISORDERS: A TOTAL POPULATION SIBLING COMPARISON STUDY. ADVERSE PERINATAL EVENTS MAY INCREASE THE RISK OF TOURETTE'S AND CHRONIC TIC DISORDERS (TD/CTD), BUT PREVIOUS STUDIES HAVE BEEN UNABLE TO CONTROL FOR UNMEASURED ENVIRONMENTAL AND GENETIC CONFOUNDING. WE AIMED TO PROSPECTIVELY INVESTIGATE POTENTIAL PERINATAL RISK FACTORS FOR TD/CTD, TAKING UNMEASURED FACTORS SHARED BETWEEN FULL SIBLINGS INTO ACCOUNT. A POPULATION-BASED BIRTH COHORT, CONSISTING OF ALL SINGLETONS BORN IN SWEDEN IN 1973-2003, WAS FOLLOWED UNTIL DECEMBER 2013. A TOTAL OF 3 026 861 INDIVIDUALS WERE IDENTIFIED, 5597 OF WHICH HAD A REGISTERED TD/CTD DIAGNOSIS. WE THEN STUDIED DIFFERENTIALLY EXPOSED FULL SIBLINGS FROM 947 942 FAMILIES; OF THESE, 3563 FAMILIES INCLUDED SIBLINGS THAT WERE DISCORDANT FOR TD/CTD. PERINATAL DATA WERE COLLECTED FROM THE MEDICAL BIRTH REGISTER AND TD/CTD DIAGNOSES WERE COLLECTED FROM THE NATIONAL PATIENT REGISTER, USING A PREVIOUSLY VALIDATED ALGORITHM. IN THE FULLY ADJUSTED MODELS, IMPAIRED FETAL GROWTH, PRETERM BIRTH, BREECH PRESENTATION AND CESAREAN SECTION WERE ASSOCIATED WITH A HIGHER RISK OF TD/CTD, LARGELY INDEPENDENT FROM SHARED FAMILY CONFOUNDERS AND MEASURED COVARIATES. MATERNAL SMOKING DURING PREGNANCY WAS ASSOCIATED WITH RISK OF TD/CTD IN A DOSE-RESPONSE MANNER BUT THE ASSOCIATION WAS NO LONGER STATISTICALLY SIGNIFICANT IN THE SIBLING COMPARISON MODELS OR AFTER THE EXCLUSION OF COMORBID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER. A DOSE-RESPONSE RELATIONSHIP BETWEEN THE NUMBER OF ADVERSE PERINATAL EVENTS AND INCREASED RISK FOR TD/CTD WAS ALSO OBSERVED, WITH HAZARD RATIOS RANGING FROM 1.41 (95% CONFIDENCE INTERVAL (CI): 1.33-1.50) FOR ONE EVENT TO 2.42 (95% CI: 1.65-3.53) FOR FIVE OR MORE EVENTS. THESE RESULTS PAVE THE WAY FOR FUTURE GENE BY ENVIRONMENT INTERACTION AND EPIGENETIC STUDIES IN TD/CTD. 2018 7 6636 44 UNRAVELING A NEW PLAYER IN MULTIPLE SCLEROSIS PATHOGENESIS: THE RNA-BINDING PROTEIN HUR. BACKGROUND: ELAV-LIKE PROTEINS ARE A SMALL FAMILY OF RNA-BINDING PROTEINS THAT ARE FUNDAMENTAL PLAYERS IN POST-TRANSCRIPTIONAL MECHANISMS AND ARE INVOLVED IN THE PATHOGENESIS OF NEUROLOGIC AND PSYCHIATRIC DISORDERS. HUR, THE UBIQUITOUSLY EXPRESSED MEMBER OF THE FAMILY, IS ALSO IMPLICATED IN SUSTAINING INFLAMMATION AND INFLAMMATORY DISEASES, SUPPORTING THE PRODUCTION OF PRO-INFLAMMATORY CYTOKINES. INFLAMMATION PLAYS A CENTRAL ROLE IN MULTIPLE SCLEROSIS (MS), WHICH REPRESENTS THE MOST COMMON CAUSE OF PERMANENT PHYSICAL DISABILITY IN YOUNG ADULTS. MS IS A CHRONIC AUTOIMMUNE DISEASE AFFECTING THE CENTRAL NERVOUS SYSTEM, WITH A COMPLEX AETIOLOGY INVOLVING GENETIC, ENVIRONMENTAL AND EPIGENETIC FACTORS. NO DATA ARE AVAILABLE ON THE POTENTIAL ENTANGLEMENT OF HUR IN MS PATHOGENESIS IN PATIENTS. IN THE PRESENT WORK, WE AIMED AT EXPLORING HUR PROTEIN LEVELS IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM MS PATIENTS, COMPARED TO HEALTHY CONTROLS. TO FURTHER ELUCIDATE THE POSSIBLE INVOLVEMENT OF HUR IN MS, WE ALSO INVESTIGATED THE RELATIONSHIP BETWEEN THIS SPECIFIC RNA-BINDING PROTEIN AND HSP70-2 PROTEIN, ALSO CONSIDERING THE HSP70-2 RS1061581 POLYMORPHISM, GIVEN THAT HSP70-2 MRNA HAS BEEN REPORTED AS A HUR TARGET AND THIS SPECIFIC POLYMORPHISM TO BE ASSOCIATED WITH MS RISK. METHODS: ALLELES AND GENOTYPES FOR HSP70-2 RS1061581 POLYMORPHISM WERE ASSESSED, BY USING A POLYMERASE CHAIN REACTION-RESTRICTION FRAGMENT LENGTH POLYMORPHISM, FOLLOWED BY DIGESTION WITH RESTRICTION ENZYME, IN MS PATIENTS AND HEALTHY CONTROLS. PBMCS FROM A SUBGROUP OF PATIENTS AND CONTROLS WERE USED TO EVALUATE HUR AND HSP70-2 PROTEIN CONTENT BY WESTERN BLOT. RESULTS: PBMCS FROM 52 MS PATIENTS HAD A LOWER HUR AND HIGHER HSP70-2 PROTEIN CONTENT COMPARED TO 43 HEALTHY CONTROLS. AN INCREASE OF 100 UNITS OF HUR SIGNIFICANTLY DECREASED THE RISK OF DEVELOPING MS BY 9.8% (OR: 0.902, 95% CI: 0.83-0.98), CONTROLLING FOR HSP70-2 PROTEIN EXPRESSION, HSP70-2 RS1061581 GENOTYPE, AGE AND SEX. MOREOVER, HOLDING HUR LEVELS, AN INCREASE OF 100 UNITS OF HSP70-2 PROTEIN SIGNIFICANTLY INCREASED THE MS RISK BY 18.1% (OR: 1.181, 95% CI: 1.03-1.36) AND THE GENETIC SUSCEPTIBILITY OF DEVELOPING MS FOR HSP70-2 RS1061581 GG CARRIERS IS CONFIRMED. OF INTEREST, MS PATIENTS WITH A MODERATE TO SEVERE FORM OF MS (MSSS >/= 3) SHOWED A TREND TOWARDS A REDUCTION OF HUR PROTEIN LEVELS COMPARED TO PATIENTS WITH MILD DISEASE SEVERITY (MSSS < 3). CONCLUSIONS: HUR PROTEIN LEVELS ARE REDUCED IN MS PATIENTS COMPARED TO HEALTHY SUBJECTS, AND THE PROTEIN AMOUNT MAY CONTINUE TO DECLINE WITH DISEASE PROGRESSION, SUGGESTING A PUTATIVE ROLE OF THIS RNA-BINDING PROTEIN. MOREOVER, OUR RESULTS SUGGEST THAT MS PATHOLOGY MAY HAVE DISRUPTED THE LINK BETWEEN HUR AND ITS TARGET TRANSCRIPT HSP70-2. IT WILL BE IMPORTANT TO FURTHER EXPLORE THE EXACT ROLE OF HUR IN MS, CONSIDERING THE COMPLEX INTERPLAY WITH OTHER RNA-BINDING FACTORS AND TARGET MRNAS. 2020 8 3907 37 LEUCOCYTIC DNA METHYLATION OF INTERLEUKIN-6 PROMOTER REDUCTION IN PRE-HYPERTENSIVE YOUNG ADULTS. BACKGROUND: PRE-HYPERTENSION IS ASSOCIATED WITH INCREASED RISK OF CARDIOVASCULAR DISEASE. CHRONIC INFLAMMATION PLAYS AN IMPORTANT ROLE IN THE PATHOPHYSIOLOGY OF ESSENTIAL HYPERTENSION, WITH EPIGENETIC DYSREGULATION INVOLVEMENT. NEVERTHELESS, THE ROLE OF DNA METHYLATION IN PREHYPERTENSIVE STATE IS UNKNOWN. THE AIM OF THIS STUDY WAS TO INVESTIGATE THE ASSOCIATION BETWEEN DNA METHYLATION LEVEL OF INTERLEUKIN-6 (IL-6) PROMOTER IN PRE-HYPERTENSIVE (PREHT) AND NORMOTENSIVE (NT) YOUNG ADULTS. METHODS: A TOTAL OF 80 NT AND 80 PREHT HEALTHY SUBJECTS AGED BETWEEN 18-45 YEARS WERE RECRUITED IN KUANTAN, PAHANG, MALAYSIA USING AN OBSERVATIONAL CROSS-SECTIONAL STUDY APPROACH. DNA METHYLATION LEVEL OF IL-6 PROMOTER IN PERIPHERAL LEUKOCYTES WERE MEASURED USING BISULPHITE CONVERSION AND METHYLIGHT ASSAY. RESULTS: THERE WAS NO SIGNIFICANT DIFFERENCE IN AGE BETWEEN NT AND PREHT (P = 0.655). THE MEAN BLOOD PRESSURE WAS 110(8)/73(5) MMHG IN NT AND 125(7)/82(5) MMHG IN PREHT SUBJECTS. THE IL-6 PROMOTER METHYLATION LEVEL WAS SIGNIFICANTLY LOWER IN PREHT COMPARED TO NT SUBJECTS (P < 0.001). CONCLUSION: THE CURRENT STUDY DEMONSTRATES THAT HYPOMETHYLATION OF IL-6 PROMOTER WAS ASSOCIATED WITH PRE-HYPERTENSION IN YOUNG ADULTS. THUS, IL-6 METHYLATION COULD BE USED AS AN EARLY INDICATOR FOR PREDICTING HYPERTENSION AND RELATED RISK OF CARDIOVASCULAR DISEASES IN PREHYPERTENSIVE SUBJECTS. GENE EXPRESSION AND LONGITUDINAL STUDIES ARE WARRANTED TO EXAMINE THE METHYLATION EFFECT ON IL-6 EXPRESSION OVER TIME. 2019 9 6072 27 THE DNA METHYLOME OF HUMAN VASCULAR ENDOTHELIUM AND ITS USE IN LIQUID BIOPSIES. BACKGROUND: VASCULAR ENDOTHELIAL CELLS (VECS) ARE AN ESSENTIAL COMPONENT OF EACH TISSUE, CONTRIBUTE TO MULTIPLE PATHOLOGIES, AND ARE TARGETED BY IMPORTANT DRUGS. YET, THERE IS A SHORTAGE OF BIOMARKERS TO ASSESS VEC TURNOVER. METHODS: TO DEVELOP DNA METHYLATION-BASED LIQUID BIOPSIES FOR VECS, WE DETERMINED THE METHYLOME OF VECS ISOLATED FROM FRESHLY DISSOCIATED HUMAN TISSUES. FINDINGS: A COMPARISON WITH A HUMAN CELL-TYPE METHYLOME ATLAS YIELDED THOUSANDS OF LOCI THAT ARE UNIQUELY UNMETHYLATED IN VECS. THESE SITES ARE TYPICALLY GENE ENHANCERS, OFTEN RESIDING ADJACENT TO VEC-SPECIFIC GENES. WE ALSO IDENTIFIED HUNDREDS OF GENOMIC LOCI THAT ARE DIFFERENTIALLY METHYLATED IN ORGANOTYPIC VECS, INDICATING THAT VECS FEEDING SPECIFIC ORGANS ARE DISTINCT CELL TYPES WITH A STABLE EPIGENETIC IDENTITY. WE ESTABLISHED UNIVERSAL AND LUNG-SPECIFIC VEC MARKERS AND EVALUATED THEIR PRESENCE IN CIRCULATING CELL-FREE DNA (CFDNA). NEARLY 2.5% OF CFDNA IN THE PLASMA OF HEALTHY INDIVIDUALS ORIGINATES FROM VECS. SEPSIS, GRAFT VERSUS HOST DISEASE, AND CARDIAC CATHETERIZATION ARE ASSOCIATED WITH ELEVATED LEVELS OF VEC-DERIVED CFDNA, INDICATIVE OF VASCULAR DAMAGE. LUNG-SPECIFIC VEC CFDNA IS SELECTIVELY ELEVATED IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) OR LUNG CANCER, REVEALING TISSUE-SPECIFIC VASCULAR TURNOVER. CONCLUSIONS: VEC CFDNA BIOMARKERS INFORM VASCULAR DYNAMICS IN HEALTH AND DISEASE, POTENTIALLY CONTRIBUTING TO EARLY DIAGNOSIS AND MONITORING OF PATHOLOGIES, AND ASSESSMENT OF DRUG ACTIVITY. FUNDING: THIS WORK WAS SUPPORTED BY THE BEUTLER RESEARCH PROGRAM, HELMSLEY CHARITABLE TRUST, JDRF, GRAIL AND THE DON FOUNDATION (TO Y.D.). Y.D HOLDS THE WALTER & GRETA STIEL CHAIR IN HEART STUDIES. B.G., R.S., J.M., D.N., T.K., AND Y.D. FILED PATENTS ON CFDNA ANALYSIS. 2023 10 6036 35 THE CHARACTERISTICS OF EXTRACHROMOSOMAL CIRCULAR DNA IN PATIENTS WITH END-STAGE RENAL DISEASE. BACKGROUND: END-STAGE RENAL DISEASE (ESRD) IS THE FINAL STAGE OF CHRONIC KIDNEY DISEASE (CKD). IN ADDITION TO THE STRUCTURALLY INTACT CHROMOSOME GENOMIC DNA, THERE IS A DOUBLE-STRANDED CIRCULAR DNA CALLED EXTRACHROMOSOMAL CIRCULAR DNA (ECCDNA), WHICH IS THOUGHT TO BE INVOLVED IN THE EPIGENETIC REGULATION OF HUMAN DISEASE. HOWEVER, THE FEATURES OF ECCDNA IN ESRD PATIENTS ARE BARELY KNOWN. IN THIS STUDY, WE IDENTIFIED ECCDNA FROM ESRD PATIENTS AND HEALTHY PEOPLE, AS WELL AS REVEALED THE CHARACTERISTICS OF ECCDNA IN PATIENTS WITH ESRD. METHODS: USING THE HIGH-THROUGHPUT CIRCLE-SEQUENCING TECHNIQUE, WE EXAMINED THE ECCDNA IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM HEALTHY PEOPLE (NC) (N = 12) AND ESRD PATIENTS (N = 16). WE ANALYZED THE LENGTH DISTRIBUTION, GENOME ELEMENTS, AND MOTIFS FEATURE OF ECCDNA IN ESRD PATIENTS. THEN, AFTER IDENTIFYING THE SPECIFIC ECCDNA IN ESRD PATIENTS, WE EXPLORED THE POTENTIAL FUNCTIONS OF THE TARGET GENES OF THE SPECIFIC ECCDNA. FINALLY, WE INVESTIGATED THE PROBABLE HUB ECCDNA USING ALGORITHMS. RESULTS: IN TOTAL, 14,431 AND 11,324 ECCDNAS WERE FOUND IN THE ESRD AND NC GROUPS, RESPECTIVELY, WITH SIZES RANGING FROM 0.01 KB TO 60 KB AT MOST. ADDITIONALLY, THE ESRD GROUP HAD A GREATER DISTRIBUTION OF ECCDNA ON CHROMOSOMES 4, 11, 13, AND 20. IN TWO GROUPS, WE ALSO DISCOVERED SEVERAL MOTIFS OF SPECIFIC ECCDNAS. FURTHERMORE, WE IDENTIFIED 13,715 SPECIFIC ECCDNAS IN THE ESRD GROUP AND 10,585 SPECIFIC ECCDNAS IN THE NC GROUP, BOTH OF WHICH WERE LARGELY ANNOTATED AS MRNA CATALOG. PATHWAY STUDIES USING GENE ONTOLOGY (GO) AND THE KYOTO ENCYCLOPEDIA OF GENES AND GENOMES (KEGG) SHOWED THAT THE SPECIFIC ECCDNA IN ESRD WAS MARKEDLY ENRICHED IN CELL JUNCTION AND COMMUNICATION PATHWAYS. FURTHERMORE, WE IDENTIFIED POTENTIALLY 20 HUB ECCDNA-TARGETING GENES FROM ALL ESRD-SPECIFIC ECCDNA-TARGETING GENES. ALSO, WE FOUND THAT 39 ECCDNA-TARGETING GENES WERE ASSOCIATED WITH ESRD, AND SOME OF THESE ECCDNAS MAY BE RELATED TO THE PATHOGENESIS OF ESRD. CONCLUSIONS: OUR FINDINGS REVEALED THE CHARACTERISTICS OF ECCDNA IN ESRD PATIENTS AND DISCOVERED POTENTIALLY HUB AND ESRD-RELEVANT ECCDNA-TARGETING GENES, SUGGESTING A NOVEL PROBABLE MECHANISM OF ESRD. 2023 11 4492 25 MONOZYGOTIC TWINS DISCORDANT FOR ROHHAD PHENOTYPE. RAPID-ONSET OBESITY WITH HYPOTHALAMIC DYSFUNCTION, HYPOVENTILATION, AND AUTONOMIC DYSREGULATION (ROHHAD) FALLS WITHIN A GROUP OF PEDIATRIC DISORDERS WITH BOTH RESPIRATORY CONTROL AND AUTONOMIC NERVOUS SYSTEM DYSREGULATION. CHILDREN WITH ROHHAD TYPICALLY PRESENT AFTER 1.5 YEARS OF AGE WITH RAPID WEIGHT GAIN AS THE INITIAL SIGN. SUBSEQUENTLY, THEY DEVELOP ALVEOLAR HYPOVENTILATION, AUTONOMIC NERVOUS SYSTEM DYSREGULATION, AND, IF UNTREATED, CARDIORESPIRATORY ARREST. TO OUR KNOWLEDGE, THIS IS THE FIRST REPORT OF DISCORDANT PRESENTATION OF ROHHAD IN MONOZYGOTIC TWINS. TWIN GIRLS, BORN AT TERM, HAD CONCORDANT GROWTH AND DEVELOPMENT UNTIL 8 YEARS OF AGE. FROM 8 TO 12 YEARS OF AGE, THE AFFECTED TWIN DEVELOPED FEATURES CHARACTERISTIC OF ROHHAD INCLUDING OBESITY, ALVEOLAR HYPOVENTILATION, SCOLIOSIS, HYPOTHALAMIC DYSFUNCTION (CENTRAL DIABETES INSIPIDUS, HYPOTHYROIDISM, PREMATURE PUBARCHE, AND GROWTH HORMONE DEFICIENCY), RIGHT PARASPINAL/THORACIC GANGLIONEUROBLASTOMA, SEIZURES, AND AUTONOMIC DYSREGULATION INCLUDING ALTERED PAIN PERCEPTION, LARGE AND SLUGGISHLY REACTIVE PUPILS, HYPOTHERMIA, AND PROFOUND BRADYCARDIA THAT REQUIRED A CARDIAC PACEMAKER. RESULTS OF GENETIC TESTING FOR PHOX2B (CONGENITAL CENTRAL HYPOVENTILATION SYNDROME DISEASE-DEFINING GENE) MUTATIONS WERE NEGATIVE. WITH EARLY RECOGNITION AND CONSERVATIVE MANAGEMENT, THE AFFECTED TWIN HAD EXCELLENT NEUROCOGNITIVE OUTCOME THAT MATCHED THAT OF THE UNAFFECTED TWIN. THE UNAFFECTED TWIN DEMONSTRATED RAPID WEIGHT GAIN LATER IN AGE BUT NOT DEVELOPMENT OF SIGNS/SYMPTOMS CONSISTENT WITH ROHHAD. THIS DISCORDANT TWIN PAIR DEMONSTRATES KEY FEATURES OF ROHHAD INCLUDING THE IMPORTANCE OF EARLY RECOGNITION (ESPECIALLY HYPOVENTILATION), COMPLEXITY OF SIGNS/SYMPTOMS AND CLINICAL COURSE, AND IMPORTANCE OF INITIATING COMPREHENSIVE, MULTISPECIALTY CARE. THESE CASES CONFOUND THE HYPOTHESIS OF A MONOGENIC ETIOLOGY FOR ROHHAD AND INDICATE ALTERNATIVE ETIOLOGIES INCLUDING AUTOIMMUNE OR EPIGENETIC PHENOMENON OR A COMBINATION OF GENETIC PREDISPOSITION AND ACQUIRED PRECIPITANT. 2011 12 4740 37 NOVEL GENETIC VARIANTS ASSOCIATED WITH CHRONIC KIDNEY DISEASE PROGRESSION. SIGNIFICANCE STATEMENT: EGFR SLOPE HAS BEEN USED AS A SURROGATE OUTCOME FOR PROGRESSION OF CKD. HOWEVER, GENETIC MARKERS ASSOCIATED WITH EGFR SLOPE AMONG PATIENTS WITH CKD WERE UNKNOWN. WE AIMED TO IDENTIFY GENETIC SUSCEPTIBILITY LOCI ASSOCIATED WITH EGFR SLOPE. A TWO-PHASE GENOME-WIDE ASSOCIATION STUDY IDENTIFIED SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) IN TPPP AND FAT1-LINC02374 , AND 22 OF THEM WERE USED TO DERIVE POLYGENIC RISK SCORES THAT MARK THE DECLINE OF EGFR BY DISRUPTING BINDING OF NEARBY TRANSCRIPTION FACTORS. THIS WORK IS THE FIRST TO IDENTIFY THE IMPACT OF TPPP AND FAT1-LINC02374 ON CKD PROGRESSION, PROVIDING PREDICTIVE MARKERS FOR THE DECLINE OF EGFR IN PATIENTS WITH CKD. BACKGROUND: THE INCIDENCE OF CKD IS ASSOCIATED WITH GENETIC FACTORS. HOWEVER, GENETIC MARKERS ASSOCIATED WITH THE PROGRESSION OF CKD HAVE NOT BEEN FULLY ELUCIDATED. METHODS: WE CONDUCTED A GENOME-WIDE ASSOCIATION STUDY AMONG 1738 PATIENTS WITH CKD, MAINLY FROM THE KOREAN COHORT STUDY FOR OUTCOMES IN PATIENTS WITH CKD. THE OUTCOME WAS EGFR SLOPE. WE PERFORMED A REPLICATION STUDY FOR DISCOVERED SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) WITH P <10 -6 IN 2498 PATIENTS WITH CKD FROM THE CHRONIC RENAL INSUFFICIENCY COHORT STUDY. SEVERAL EXPRESSION QUANTITATIVE TRAIT LOCI (EQTL) STUDIES, PATHWAY ENRICHMENT ANALYSES, EXPLORATION OF EPIGENETIC ARCHITECTURE, AND PREDICTING DISRUPTION OF TRANSCRIPTION FACTOR (TF) BINDING SITES EXPLORED POTENTIAL BIOLOGICAL IMPLICATIONS OF THE LOCI. WE DEVELOPED AND EVALUATED THE EFFECT OF POLYGENIC RISK SCORES (PRS) ON INCIDENT CKD OUTCOMES. RESULTS: SNPS IN TWO NOVEL LOCI, TPPP AND FAT1-LINC02374 , WERE REPLICATED (RS59402340 IN TPPP , PDISCOVERY =7.11X10 -7 , PCRIC =8.13X10 -4 , PMETA =7.23X10 -8 ; RS28629773 IN FAT1-LINC02374 , PDISCOVERY =6.08X10 -7 , PCRIC =4.33X10 -2 , PMETA =1.87X10 -7 ). THE EQTL STUDIES REVEALED THAT THE REPLICATED SNPS REGULATED THE EXPRESSION LEVEL OF NEARBY GENES ASSOCIATED WITH KIDNEY FUNCTION. FURTHERMORE, THESE SNPS WERE NEAR GENE ENHANCER REGIONS AND PREDICTED TO DISRUPT THE BINDING OF TFS. PRS BASED ON THE INDEPENDENTLY SIGNIFICANT TOP 22 SNPS WERE SIGNIFICANTLY ASSOCIATED WITH CKD OUTCOMES. CONCLUSIONS: THIS STUDY DEMONSTRATES THAT SNP MARKERS IN THE TPPP AND FAT1-LINC02374 LOCI COULD BE PREDICTIVE MARKERS FOR THE DECLINE OF EGFR IN PATIENTS WITH CKD. 2023 13 3279 23 HERITABLE ALTERATION IN DNA METHYLATION INDUCED BY NITROGEN-DEFICIENCY STRESS ACCOMPANIES ENHANCED TOLERANCE BY PROGENIES TO THE STRESS IN RICE (ORYZA SATIVA L.). CYTOSINE METHYLATION IS RESPONSIVE TO VARIOUS BIOTIC- AND ABIOTIC-STRESSES, WHICH MAY PRODUCE HERITABLE EPIALLELES. NITROGEN (N)-DEFICIENCY IS AN ABIOTIC STRESS BEING REPEATEDLY EXPERIENCED BY PLANTS. TO ADDRESS POSSIBLE EPIGENETIC CONSEQUENCES OF N-DEFICIENCY-STRESS, WE INVESTIGATED THE STABILITY OF CYTOSINE METHYLATION IN RICE (ORYZA SATIVA L.) SUBSEQUENT TO A CHRONIC (A WHOLE-GENERATION) N-DEFICIENCY AT TWO LEVELS, MODERATE (20MG/L) AND SEVERE (10MG/L), UNDER HYDROPONIC CULTURE. MSAP ANALYSIS REVEALED THAT LOCUS-SPECIFIC METHYLATION ALTERATION OCCURRED IN LEAF-TISSUE OF THE STRESSED PLANTS (S(0)) EXPERIENCING EITHER LEVEL OF N-DEFICIENCY, WHICH WAS VALIDATED BY GEL-BLOTTING. ANALYSIS ON THREE NON-STRESSED SELF-FED PROGENIES (S(1), S(2) AND S(3)) BY GEL-BLOTTING INDICATED THAT CA. 50% OF THE ALTERED METHYLATION PATTERNS IN SOMATIC CELLS (LEAF) OF THE STRESSED S(0) PLANTS WERE RECAPTURED IN S(1), WHICH WERE THEN STABLY INHERITED TO S(2) AND S(3). BISULFITE SEQUENCING OF TWO VARIANT MSAP LOCI WITH HOMOLOGY TO LOW-COPY RETROTRANSPOSONS ON ONE STRESSED PLANT (S(0)) AND ITS NON-STRESSED PROGENIES (S(1) AND S(2)) SHOWED THAT WHEREAS ONE LOCUS EXHIBITED LIMITED AND NON-HERITABLE CHH METHYLATION ALTERATION, THE OTHER LOCUS MANIFESTED DRAMATIC HERITABLE HYPERMETHYLATION AT NEARLY ALL CYTOSINE SITES WITHIN THE ASSAYED REGION. INTRIGUINGLY, WHEN TWO GROUPS OF S(2) PLANTS DESCENDED FROM THE SAME N-DEFICIENCY-STRESSED S(0) PLANT WERE RE-SUBJECTED TO THE STRESS, THE GROUP INHERITING THE MODIFIED METHYLATION PATTERNS SHOWED ENHANCED TOLERANCE TO THE N-DEFICIENCY-STRESS COMPARED WITH THE GROUP BEARING THE ORIGINAL PATTERNS. OUR RESULTS THUS DEMONSTRATE HERITABILITY OF AN ACQUIRED ADAPTIVE TRAIT IN RICE, WHICH WAS ACCOMPANIED BY EPIGENETIC INHERITANCE OF MODIFIED CYTOSINE METHYLATION PATTERNS, IMPLICATING AN EPIGENETIC BASIS UNDERLYING THE INHERITANCE OF AN ACQUIRED TRAIT IN PLANTS. 2011 14 2649 23 EPIGENOMIC, GENOMIC, AND TRANSCRIPTOMIC LANDSCAPE OF SCHWANNOMATOSIS. SCHWANNOMATOSIS (SWNTS) IS A GENETIC CANCER PREDISPOSITION SYNDROME THAT MANIFESTS AS MULTIPLE AND OFTEN PAINFUL NEURONAL TUMORS CALLED SCHWANNOMAS (SWNS). WHILE GERMLINE MUTATIONS IN SMARCB1 OR LZTR1, PLUS SOMATIC MUTATIONS IN NF2 AND LOSS OF HETEROZYGOSITY IN CHROMOSOME 22Q HAVE BEEN IDENTIFIED IN A SUBSET OF PATIENTS, LITTLE IS KNOWN ABOUT THE EPIGENOMIC AND GENOMIC ALTERATIONS THAT DRIVE SWNTS-RELATED SWNS (SWNTS-SWNS) IN A MAJORITY OF THE CASES. WE PERFORMED MULTIPLATFORM GENOMIC ANALYSIS AND ESTABLISHED THE MOLECULAR SIGNATURE OF SWNTS-SWNS. WE SHOW THAT SWNTS-SWNS HARBOR DISTINCT GENOMIC FEATURES RELATIVE TO THE HISTOLOGICALLY IDENTICAL NON-SYNDROMIC SPORADIC SWNS (NS-SWNS). WE DEMONSTRATE THE EXISTENCE OF FOUR DISTINCT DNA METHYLATION SUBGROUPS OF SWNTS-SWNS THAT ARE ASSOCIATED WITH SPECIFIC TRANSCRIPTIONAL PROGRAMS AND TUMOR LOCATION. WE SHOW SEVERAL NOVEL RECURRENT NON-22Q DELETIONS AND STRUCTURAL REARRANGEMENTS. WE DETECTED THE SH3PXD2A-HTRA1 GENE FUSION IN SWNTS-SWNS, WITH PREDOMINANCE IN LZTR1-MUTANT TUMORS. IN ADDITION, WE IDENTIFIED SPECIFIC GENETIC, EPIGENETIC, AND ACTIONABLE TRANSCRIPTIONAL PROGRAMS ASSOCIATED WITH PAINFUL SWNTS-SWNS INCLUDING PIGF, VEGF, MEK, AND MTOR PATHWAYS, WHICH MAY BE HARNESSED FOR MANAGEMENT OF THIS SYNDROME. 2021 15 5340 34 QUORUM SENSING AND VIRULENCE OF PSEUDOMONAS AERUGINOSA DURING LUNG INFECTION OF CYSTIC FIBROSIS PATIENTS. PSEUDOMONAS AERUGINOSA IS THE PREDOMINANT MICROORGANISM IN CHRONIC LUNG INFECTION OF CYSTIC FIBROSIS PATIENTS. THE CHRONIC LUNG INFECTION IS PRECEDED BY INTERMITTENT COLONIZATION. WHEN THE CHRONIC INFECTION BECOMES ESTABLISHED, IT IS WELL ACCEPTED THAT THE ISOLATED STRAINS DIFFER PHENOTYPICALLY FROM THE INTERMITTENT STRAINS. DOMINATING CHANGES ARE THE SWITCH TO MUCOIDITY (ALGINATE OVERPRODUCTION) AND LOSS OF EPIGENETIC REGULATION OF VIRULENCE SUCH AS THE QUORUM SENSING (QS). TO ELUCIDATE THE DYNAMICS OF P. AERUGINOSA QS SYSTEMS DURING LONG TERM INFECTION OF THE CF LUNG, WE HAVE INVESTIGATED 238 ISOLATES OBTAINED FROM 152 CF PATIENTS AT DIFFERENT STAGES OF INFECTION RANGING FROM INTERMITTENT TO LATE CHRONIC. ISOLATES WERE CHARACTERIZED WITH REGARD TO QS SIGNAL MOLECULES, ALGINATE, RHAMNOLIPID AND ELASTASE PRODUCTION AND MUTANT FREQUENCY. THE GENETIC BASIS FOR CHANGE IN QS REGULATION WERE INVESTIGATED AND IDENTIFIED BY SEQUENCE ANALYSIS OF LASR, RHLR, LASI AND RHLI. THE FIRST QS SYSTEM TO BE LOST WAS THE ONE ENCODED BY LAS SYSTEM 12 YEARS (MEDIAN VALUE) AFTER THE ONSET OF THE LUNG INFECTION WITH SUBSEQUENT LOSS OF THE RHL ENCODED SYSTEM AFTER 17 YEARS (MEDIAN VALUE) SHOWN AS DEFICIENCIES IN PRODUCTION OF THE 3-OXO-C12-HSL AND C4-HSL QS SIGNAL MOLECULES RESPECTIVELY. THE CONCOMITANT DEVELOPMENT OF QS MALFUNCTION SIGNIFICANTLY CORRELATED WITH THE REDUCED PRODUCTION OF RHAMNOLIPIDS AND ELASTASE AND WITH THE OCCURRENCE OF MUTATIONS IN THE REGULATORY GENES LASR AND RHLR. ACCUMULATION OF MUTATIONS IN BOTH LASR AND RHLR CORRELATED WITH DEVELOPMENT OF HYPERMUTABILITY. INTERESTINGLY, A HIGHER NUMBER OF MUCOID ISOLATES WERE FOUND TO PRODUCE C4-HSL SIGNAL MOLECULES AND RHAMNOLIPIDS COMPARED TO THE NON-MUCOID ISOLATES. AS SEEN FROM THE PRESENT DATA, WE CAN CONCLUDE THAT P. AERUGINOSA AND PARTICULARLY THE MUCOID STRAINS DO NOT LOSE THE QS REGULATION OR THE ABILITY TO PRODUCE RHAMNOLIPIDS UNTIL THE LATE STAGE OF THE CHRONIC INFECTION. 2010 16 3239 31 HEPATIC INACTIVATION OF THE TYPE 2 DEIODINASE CONFERS RESISTANCE TO ALCOHOLIC LIVER STEATOSIS. BACKGROUND: A MOUSE WITH HEPATOCYTE-SPECIFIC DEIODINASE TYPE II INACTIVATION (ALB-D2KO) IS RESISTANT TO DIET-INDUCED OBESITY, HEPATIC STEATOSIS, AND HYPERTRIGLYCERIDEMIA DUE TO PERINATAL EPIGENETIC MODIFICATIONS IN THE LIVER. THIS PHENOTYPE IS LINKED TO LOW LEVELS OF ZFP125, A HEPATIC TRANSCRIPTIONAL REPRESSOR THAT PROMOTES LIVER STEATOSIS BY INHIBITING GENES INVOLVED IN PACKAGING AND SECRETION OF VERY-LOW-DENSITY LIPOPROTEIN. METHODS: HERE, WE USED CHRONIC AND BINGE ETHANOL (ETOH) IN MICE TO CAUSE LIVER STEATOSIS. RESULTS: THE ETOH TREATMENT CAUSES A 2.3-FOLD INCREASE IN HEPATIC TRIGLYCERIDE CONTENT; ZFP125 LEVELS WERE APPROXIMATELY 50% HIGHER IN THESE ANIMALS. IN CONTRAST, ALB-D2KO MICE DID NOT DEVELOP ETOH-INDUCED LIVER STEATOSIS. THEY ALSO FAILED TO ELEVATE ZFP125 TO THE SAME LEVELS, DESPITE BEING ON THE ETOH-CONTAINING DIET FOR THE SAME PERIOD OF TIME. THEIR PHENOTYPE WAS ASSOCIATED WITH 1.3- TO 2.9-FOLD UP-REGULATION OF HEPATIC GENES INVOLVED IN LIPID TRANSPORT AND EXPORT THAT ARE NORMALLY REPRESSED BY ZFP125, THAT IS, MTTP, ABCA1, LDLR, APOC1, APOC3, APOE, APOH, AND AZGP1. FURTHERMORE, GENES INVOLVED IN THE ETOH METABOLIC PATHWAY, THAT IS, ALDH2 AND ACSS2, WERE ALSO 1.6- TO 3.1-FOLD UP-REGULATED IN ALB-D2KO ETOH MICE COMPARED WITH CONTROL ANIMALS KEPT ON ETOH. CONCLUSIONS: ETOH CONSUMPTION ELEVATES EXPRESSION OF ZFP125. ALB-D2KO ANIMALS, WHICH HAVE LOWER LEVELS OF ZFP125, ARE MUCH LESS SUSCEPTIBLE TO ETOH-INDUCED LIVER STEATOSIS. 2019 17 5763 16 SOME COMMENTS ON MASOCHISM AND THE DELUSION OF OMNIPOTENCE FROM A DEVELOPMENTAL PERSPECTIVE. THIS PAPER EXPLORES THE RELATION OF THE DELUSION OF OMNIPOTENCE TO MASOCHISM AND SUGGESTS THAT THIS FANTASY CONSTITUTES A MAJOR COMPONENT OF THE RESISTANCE SO PROMINENT IN WORK WITH MASOCHISTIC PATIENTS. THE CONNECTIONS AMONG MASOCHISM, OMNIPOTENCE, NEGATIVE THERAPEUTIC REACTION, AND CLINGING TO PAIN ARE DISCUSSED. THE CLASSICAL VIEW HAS BEEN THAT THE FAILURE OF INFANTILE OMNIPOTENCE FORCES THE CHILD TO TURN TO REALITY. OUR EXPERIENCE WITH MASOCHISTIC PATIENTS SUGGESTS THAT IT IS THE REAL FAILURE TO ACHIEVE COMPETENT INTERACTIONS WITH OTHERS THAT FORCES THE CHILD TO TURN TO OMNIPOTENT SOLUTIONS. THE DISTINCTION IS MADE BETWEEN FANTASIES THAT ENHANCE THE REAL CAPACITIES OF THE SELF AND THOSE AIMED AT DENYING AND TRANSFORMING THE PAIN AND INADEQUACY OF THE MOTHER-CHILD RELATIONSHIP. THE EPIGENETIC TRANSFORMATIONS OF OMNIPOTENT FANTASIES THROUGH ALL LEVELS OF DEVELOPMENT ARE DESCRIBED. THE PATIENT'S NEED TO PROTECT THE OMNIPOTENT FANTASY IS DISCUSSED IN RELATION TO RESISTANCE AT EACH PHASE OF ANALYSIS. 1991 18 890 25 CHRONIC DIETARY EXPOSURE OF ROOSTERS TO A GLYPHOSATE-BASED HERBICIDE INCREASES SEMINAL PLASMA GLYPHOSATE AND AMPA CONCENTRATIONS, ALTERS SPERM PARAMETERS, AND INDUCES METABOLIC DISORDERS IN THE PROGENY. THE EFFECTS OF CHRONIC DIETARY ROUNDUP (RU) EXPOSURE ON ROOSTER SPERM PARAMETERS, FERTILITY, AND OFFSPRING ARE UNKNOWN. WE INVESTIGATED THE EFFECTS OF CHRONIC RU DIETARY EXPOSURE (46.8 MG KG(-1) DAY(-1) GLYPHOSATE) FOR 5 WEEKS IN 32-WEEK-OLD ROOSTERS (N = 5 RU-EXPOSED AND N = 5 CONTROL (CT)). ALTHOUGH THE CONCENTRATIONS OF GLYPHOSATE AND ITS MAIN METABOLITE AMPA (AMINOMETHYLPHOSPHONIC ACID) INCREASED IN BLOOD PLASMA AND SEMINAL FLUID DURING EXPOSURE, NO SIGNIFICANT DIFFERENCES IN TESTIS WEIGHT AND SPERM CONCENTRATIONS WERE OBSERVED BETWEEN RU AND CT ROOSTERS. HOWEVER, SPERM MOTILITY WAS SIGNIFICANTLY REDUCED, ASSOCIATED WITH DECREASED CALCIUM AND ATP CONCENTRATIONS IN RU SPERMATOZOA. PLASMA TESTOSTERONE AND OESTRADIOL CONCENTRATIONS INCREASED IN RU ROOSTERS. THESE NEGATIVE EFFECTS CEASED 14 DAYS AFTER RU REMOVAL FROM THE DIET. EPIGENETIC ANALYSIS SHOWED A GLOBAL DNA HYPOMETHYLATION IN RU ROOSTERS. AFTER ARTIFICIAL INSEMINATION OF HENS (N = 40) WITH SPERM FROM CT OR RU ROOSTERS, EGGS WERE COLLECTED AND ARTIFICIALLY INCUBATED. EMBRYO VIABILITY DID NOT DIFFER, BUT CHICKS FROM RU ROOSTERS (N = 118) HAD A HIGHER FOOD CONSUMPTION, BODY WEIGHT AND SUBCUTANEOUS ADIPOSE TISSUE CONTENT. CHRONIC DIETARY RU EXPOSURE IN ROOSTERS REDUCES SPERM MOTILITY AND INCREASES PLASMA TESTOSTERONE LEVELS, GROWTH PERFORMANCE, AND FATTENING IN OFFSPRING. 2021 19 16 29 4CRNA NEAT1 SPONGE ADSORPTION OF MIR-378 MODULATES ACTIVITY OF LIPOPOLYSACCHARIDE-TREATED ARTICULAR CHONDROCYTES AND INFLUENCES THE PATHOLOGICAL DEVELOPMENT OF OSTEOARTHRITIS. CONTEXT: OSTEOARTHRITIS (OA) IS A CHRONIC JOINT DISEASE THAT CAN EVENTUALLY LEAD TO DEGENERATION, FIBROSIS, FRACTURES, AND DEFECTS OF THE ARTICULAR CARTILAGE. LONG NON-CODING RNA (LNCRNA) IS A KEY SUBSTANCE IN MANY PROCESSES, SUCH AS EPIGENETIC REGULATION AND CELL-CYCLE AND CELL-DIFFERENTIATION MODULATION, AND ITS RELATIONSHIP WITH OA HAS BEEN REPEATEDLY VERIFIED. OBJECTIVE: THE STUDY INTENDED TO CLARIFY THE INFLUENCE OF LNCRNA NUCLEAR ENRICHED ABUNDANT TRANSCRIPT 1 (NEAT1), LNCRNA NEAT1, ON LIPOPOLYSACCHARIDE (LPS)-INDUCED OA CHONDROCYTES THROUGH SPONGE ADSORPTION OF MICRORNA-378 (MIR-378) AND TO PROVIDE NOVEL INSIGHTS INTO FUTURE DIAGNOSIS AND TREATMENT OF OA. DESIGN: THE RESEARCH TEAM PERFORMED AN ANIMAL STUDY. SETTING: THE STUDY TOOK PLACE IN THE DEPARTMENT OF REHABILITATION MEDICINE AT LINYI PEOPLE'S HOSPITAL IN LINYI, SHANGDONG, CHINA. ANIMALS: THE STUDY'S ANIMALS WERE 10 SPRAGUE DAWLEY (SD) RATS, 3-5 DAYS OLD AND 10-15 G IN WEIGHT, OF THE SPECIFIC-PATHOGEN-FREE (SPF) GRADE. INTERVENTION: THE RAT CHONDROCYTES FOR THE POSITIVE CONTROL GROUP (THE MODEL GROUP) WERE TREATED WITH 500 NG/ML OF LPS TO INDUCE OA. CHONDROCYTES TREATED WITH THE SAME AMOUNT OF NORMAL SALINE WERE USED AS THE NEGATIVE CONTROL GROUP. THE CHONDROCYTES OF THE LPS-INDUCED RATS WERE INTO SIX GROUPS: (1) A POSITIVE CONTROL GROUP TRANSFECTED WITH NEAT1-INTERFERING RNA, THE SH-NEAT1 GROUP; (2) A NEGATIVE CONTROL GROUP NOT TRANSFECTED WITH NEAT1-INTERFERING RNA, THE NEAT1 EMPTY VECTOR (NC-NEAT1) GROUP; (3) AN INTERVENTION GROUP CO-TRANSFECTED WITH NEAT1 INTERFERING RNA AND THE MIR-378 INHIBITOR SEQUENCE (INH-MIR-378 THE SH-NEAT1+ INH-MIR-378 GROUP; (4) A NEGATIVE CONTROL GROUP TRANSFECTED WITH NEAT1 INTERFERING RNA BUT NOT TRANSFECTED WITH THE MIR-378 INHIBITOR SEQUENCE, THE SH-NEAT1+ MIR-378 NEGATIVE CONTROL (NC-MIR-378) GROUP; (5) A NEGATIVE CONTROL GROUP TRANSFECTED WITH THE MIR-378 INHIBITOR SEQUENCE BUT NOT TRANSFECTED WITH NEAT1 INTERFERING RNA, THE NEAT1 EMPTY VECTOR (NC-NEAT1) + INH-MIR-378 GROUP; (6) A NEGATIVE CONTROL GROUP NOT TRANSFECTED WITH EITHER NEAT1 INTERFERING RNA OR THE MIR-378 INHIBITOR SEQUENCE, THE NC-NEAT1 + NC-MIR-378 GROUP. OUTCOME MEASURES: AN OA-CHONDROCYTE MODEL WAS INDUCED BY LPS AND MEASUREMENTS OF NEAT1 AND MIR-378 EXPRESSION WERE MADE BY REAL-TIME QUANTITATIVE REVERSE TRANSCRIPTION (QRT)- POLYMERASE CHAIN REACTION (PCR). THEN, SMALL NEAT1-INTERFERING RNA (SH-NEAT1), EMPTY VECTOR NEAT1 (NC-NEAT1), INHIBITOR-SEQUENCE-MIR-378 (INH-MIR-378), AND NEGATIVE-CONTROL-MIR-378 (NC-MIR-378) WERE TRANSFECTED INTO CELLS, AND CELL VIABILITY AND APOPTOSIS RATE WERE MEASURED. FINALLY, THE STUDY VERIFIED THE RELATIONSHIP BETWEEN NEAT1 AND MIR-378. RESULTS: COMPARED TO THE CONTROL GROUP, NEAT1 WAS SIGNIFICANTLY ELEVATED IN THE MODEL GROUP, AND ITS MIR-378 WAS SIGNIFICANTLY DECREASED. SILENCING NEAT1 CAN ENHANCE OA-CHONDROCYTE ACTIVITY AND DECREASE APOPTOSIS. WHEN NEAT1 AND MIR-378 WERE INHIBITED TOGETHER, AS SHOWN FORT THE NC-NEAT1 + NC-MIR-378 GROUP, NEAT1 EXPRESSION, AS WELL AS THE MULTIPLICATION AND APOPTOSIS ABILITY OF THE OA-MODEL CELLS, WERE THE SAME AS THOSE OF CELLS TRANSFECTED WITH AN EMPTY VECTOR, THE NC-NEAT1 GROUP. ALSO, THE NEAT1 + NC-MIR-378 GROUP'S CELL ACTIVITY WAS LOWER THAN THAT OF THE SH-NEAT1+NC-MIR-378 GROUP BUT HIGHER THAN THAT OF THE NC-NEAT1 + INH-MIR-378 GROUP. FINALLY, HIGHER FLUORESCENCE ACTIVITY OCCURRED FOR NEAT1-MUTANT TYPE (MUT) TRANSFECTED WITH INH-MIR-378. CONCLUSIONS: NEAT1, WHICH IS HIGHLY EXPRESSED IN OA, MEDIATES LPS-INDUCED OA-CHONDROCYTE ACTIVITY THROUGH SPONGE ADSORPTION OF MIR-378. 2022 20 511 36 ASSOCIATION OF RASSF1A HYPERMETHYLATION WITH RISK OF HBV/HCV-INDUCED HEPATOCELLULAR CARCINOMA: A META-ANALYSIS. BACKGROUND: RESEARCHERS HAVE DISCOVERED A LARGE NUMBER OF DNA METHYLATION PATTERNS IN HUMAN CANCER. THESE CANCER-SPECIFIC METHYLATION PATTERNS CAN PROVIDE INFORMATION FOR THE DIAGNOSIS, TREATMENT, AND PROGNOSIS OF CANCER. METHYLATION STUDIES CAN FIND NEW BIOMARKERS BASED ON EPIGENETIC ANALYSIS AND APPLY THESE BIOMARKERS TO CLINICAL ONCOLOGY. MANY STUDIES ON THE ASSOCIATION BETWEEN RAASF1A METHYLATION STATUS AND SUSCEPTIBILITY TO HEPATITIS B VIRUS (HBV)/HEPATITIS C VIRUS (HCV)-INDUCED HEPATOCELLULAR CARCINOMA (HCC) HAVE REACHED CONTROVERSIAL CONCLUSIONS. HENCE, THE CURRENT REVIEW COMPREHENSIVELY ASSESSED THE CORRELATION BETWEEN RAS ASSOCIATION DOMAIN FAMILY 1A (RASSF1A) METHYLATION AND THE RISK OF THE HCV/HBV-INDUCED HCC. METHODS: THE APPROPRIATED PUBLICATIONS WERE EXTRACTED IN EMBASE, PUBMED, WEB OF SCIENCE, COCHRANE LIBRARY, AND CHINA NATIONAL KNOWLEDGE INFRASTRUCTURE DATABASES USING STATA 5.0 SOFTWARE. THE ODDS RATIOS (ORS) WITH 95 % CONFIDENCE INTERVAL (95 % CI) OF RASSF1A METHYLATION WERE COMPUTED. RESULTS: A TOTAL OF 1015 HBV/HCV-RELATED HCC SAMPLES, 124 NON-HBV/HCV-RELATED HCC (NBNC-HCC) SAMPLES, AND 1225 NONTUMOROUS CONTROLS WERE EXTRACTED AND EXAMINED IN THIS RESEARCH. THE FREQUENCY OF THE METHYLATED RASSF1A IN THE HBV/HCV-RELATED TUMOR CASES DISPLAYED A SIGNIFICANTLY INCREASED OR COMPARED WITH THE OVERALL NONTUMOR SAMPLES (OR = 19.372, 95 % CI = 11.060-33.931, P = 0.000). THE FREQUENCY OF THE METHYLATED RASSF1A IN HBV/HCV-RELATED NEOPLASM CASES DISPLAYED A SIGNIFICANTLY INCREASED OR COMPARED WITH THE NON-HBV/HCV-RELATED NEOPLASM (NBNC-NEOPLASM) SAMPLES (OR = 2.150, 95 % CI = 1.398-3.308, P = 0.000). COMPARED WITH NORMAL, CHRONIC HEPATITIS B OR C, CIRRHOSIS, AND PARACANCEROUS SAMPLES, THE POOLED OR OF THE RASSF1A PROMOTER METHYLATION IN THE HBV/HCV-INDUCED HCC SAMPLES WAS 62.785(95 % CI = 35.224-111.909), 25.07 (95 % CI = 13.85-45.36), 6.89 (95 % CI = 3.33-14.264) AND 9.02 (95 % CI = 0.91-89.80), RESPECTIVELY. THE RATE OF RASSF1A HYPERMETHYLATION WAS ROBUSTLY CORRELATED WITH TUMOR SIZE AND VASCULAR INVASION, AND THE POOLED OR WAS 0.346 (95 % CI = 0.210 - 0.569) AND 0.081 (95 % CI = 0.022 - 0.303), RESPECTIVELY. CONCLUSION: RESULTS SHOWED ROBUST ASSOCIATIONS BETWEEN RASSF1A GENE METHYLATION IN PROMOTER REGION AND ENHANCED HBV/HCV-RELATED HCC SUSCEPTIBILITY, THEREBY REVEALING THAT RASSF1A METHYLATION STATUS MAY SERVE AS AN IMPORTANT INDICATOR FOR HCC ONCOGENESIS. 2020