1 5483 188 RETRACTION. RETRACTION: "AGING IS ASSOCIATED WITH ALTERED INFLAMMATORY, ARACHIDONIC ACID CASCADE, AND SYNAPTIC MARKERS, INFLUENCED BY EPIGENETIC MODIFICATIONS, IN THE HUMAN FRONTAL CORTEX" BY KELESHIAN VL, MODI HR, RAPOPORT SI, RAO JS. THE ABOVE ARTICLE FROM JOURNAL OF NEUROCHEMISTRY, PUBLISHED ONLINE ON 17 FEBRUARY 2013 IN WILEY ONLINE LIBRARY (WILEYONLINELIBRARY.COM) AND IN VOLUME 121, ISSUE 1, PP. 63-73, HAS BEEN RETRACTED BY AGREEMENT BETWEEN THE CORRESPONDING AUTHOR STANLEY RAPOPORT, THE JOURNAL'S EDITOR-IN-CHIEF, JORG SCHULZ, AND JOHN WILEY & SONS LTD. THE EDITORIAL OFFICE WAS CONTACTED BY THE AUTHOR STANLEY RAPOPORT WITH THE REQUEST TO RETRACT THIS AND A RELATED PUBLICATION (SEE BELOW), INFORMING THE EDITOR-IN-CHIEF THAT THE NATIONAL INSTITUTES OF HEALTH (NIH) HAD FOUND DR. JAGADEESH S. RAO GUILTY OF RESEARCH MISCONDUCT BY FALSIFYING DATA IN THE REFERENCED PAPER. THE EDITORIAL OFFICE WAS FORWARDED A LETTER, SIGNED BY INVESTIGATION COMMITTEE MEMBERS ON BEHALF OF NIH AND NIA, WHICH STATES: "[...] THE NATIONAL INSTITUTES OF HEALTH (NIH) INVESTIGATED ALLEGATIONS OF RESEARCH MISCONDUCT INVOLVING THE FALSIFICATION OF DATA IN "AGING IS ASSOCIATED WITH ALTERED INFLAMMATORY, ARACHIDONIC ACID CASCADE, AND SYNAPTIC MARKERS, INFLUENCED BY EPIGENETIC MODIFICATIONS, IN THE HUMAN FRONTAL CORTEX." KELESHIAN VL, MODI HR, RAPOPORT SI, RAO JS. JOURNAL OF NEUROCHEMISTRY 2013 APR; 125(1): 63-73. BASED ON THE UNANIMOUS DECISION OF A FIVE MEMBER COMMITTEE, COMPOSED OF NIH INVESTIGATORS, NIH FOUND THAT DR. JAGADEESH RAO, CORRESPONDING AUTHOR, KNOWINGLY AND INTENTIONALLY COMMITTED RESEARCH MISCONDUCT BY FALSIFYING DATA IN FIGURES 1A, 1G, 3G, AND 4D IN THE MANUSCRIPT(S) LISTED ABOVE. DR. RAO WAS SOLELY RESPONSIBLE FOR THE FALSIFICATION AND ALL OTHER AUTHORS WERE UNINVOLVED. THE REPORT WAS SUBMITTED TO THE HHS OFFICE OF RESEARCH INTEGRITY FOR ITS REVIEW. BECAUSE DR. RAO WAS THE CORRESPONDING AUTHOR, DR. STANLEY I. RAPOPORT, SENIOR ADVISOR FOR THE FORMER LABORATORY OF BRAIN PHYSIOLOGY AND METABOLISM SECTION, IS ACTING FOR DR. RAO, WHO WAS HIS REPRESENTATIVE, AND APPROVES THIS REQUEST TO RETRACT THIS PUBLICATION USING THE RECOMMENDED LANGUAGE, IN ITALICS ABOVE." A RELATED PAPER HAS ALSO BEEN RETRACTED: RAO JS, ERTLEY RN, RAPOPORT SI, BAZINET RP, LEE HJ. (2007) CHRONIC NMDA ADMINISTRATION TO RATS UP-REGULATES FRONTAL CORTEX CYTOSOLIC PHOSPHOLIPASE A(2) AND ITS TRANSCRIPTION FACTOR, ACTIVATOR PROTEIN-2. J. NEUROCHEM. 102: 1918-1927. REFERENCES KELESHIAN V. L., MODI H. R., RAPOPORT S. I. AND RAO J. S. (2013) AGING IS ASSOCIATED WITH ALTERED INFLAMMATORY, ARACHIDONIC ACID CASCADE, AND SYNAPTIC MARKERS, INFLUENCED BY EPIGENETIC MODIFICATIONS, IN THE HUMAN FRONTAL CORTEX. J. NEUROCHEM. 125, 63-73. RAO J. S., ERTLEY R. N., RAPOPORT S. I., BAZINET R. P. AND LEE H. J. (2007) CHRONIC NMDA ADMINISTRATION TO RATS UP-REGULATES FRONTAL CORTEX CYTOSOLIC PHOSPHOLIPASE A(2) AND ITS TRANSCRIPTION FACTOR, ACTIVATOR PROTEIN-2. J. NEUROCHEM. 102, 1918-1927. 2017 2 890 22 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 3 2649 16 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 4 1791 23 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 5 967 20 CHRONIC NICOTINE EXPOSURE AUGMENTS RENAL OXIDATIVE STRESS AND INJURY THROUGH TRANSCRIPTIONAL ACTIVATION OF P66SHC. BACKGROUND: CHRONIC NICOTINE (CH-NIC) EXPOSURE EXACERBATES ISCHEMIA/REPERFUSION (I/R)-INDUCED OXIDATIVE STRESS AND ACUTE KIDNEY INJURY (AKI), AND MITOCHONDRIAL PRODUCTION OF REACTIVE OXYGEN SPECIES (ROS) IN CULTURED RENAL PROXIMAL TUBULE CELLS (RPTCS). BECAUSE SER36-PHOSPHORYLATED P66SHC MODULATES MITOCHONDRIAL ROS PRODUCTION AND INJURY OF RPTCS, WE HYPOTHESIZED THAT CH-NIC EXACERBATES AKI BY INCREASING STRESS-INDUCED PHOSPHORYLATION OF P66SHC. METHODS: WE FIRST TESTED WHETHER CH-NIC AUGMENTS I/R-AKI-INDUCED EXPRESSION AND PHOSPHORYLATION OF P66SHC IN VIVO. WE THEN EXAMINED WHETHER KNOCKING DOWN P66SHC, OR IMPAIRING ITS SER36 PHOSPHORYLATION OR BINDING TO CYTOCHROME C, ALTERS THE EFFECTS OF CH-NIC ON OXIDATIVE STRESS (H(2)O(2))-INDUCED PRODUCTION OF ROS, MITOCHONDRIAL DEPOLARIZATION AND INJURY IN RPTCS IN VITRO. RESULTS: WE FOUND THAT CH-NIC INCREASED THE EXPRESSION OF P66SHC IN THE CONTROL AND ISCHEMIC KIDNEYS, BUT ONLY INCREASED ITS SER36 PHOSPHORYLATION AFTER RENAL I/R. KNOCKING DOWN P66SHC OR IMPAIRING PHOSPHORYLATION OF ITS SER36 RESIDUE, VIA THE S36A MUTATION (BUT NOT THE PHOSPHOMIMETIC S36D MUTATION), BLUNTED CH-NIC + H2O2-DEPENDENT ROS PRODUCTION, MITOCHONDRIAL DEPOLARIZATION AND INJURY IN RPTCS. ADDITIONALLY, CH-NIC + H2O2-DEPENDENT BINDING OF P66SHC TO MITOCHONDRIAL CYTOCHROME C WAS ATTENUATED BY S36A MUTATION OF P66SHC, AND IMPAIRING CYTOCHROME C BINDING (VIA W134F MUTATION) ABOLISHED ROS PRODUCTION, MITOCHONDRIAL DEPOLARIZATION AND INJURY, WHILE ECTOPIC OVEREXPRESSION OF P66SHC (WHICH MIMICS CH-NIC TREATMENT) AUGMENTED OXIDANT INJURY. WE DETERMINED THAT CH-NIC STIMULATES THE P66SHC PROMOTER THROUGH P53- AND EPIGENETIC MODIFICATION (PROMOTER HYPOMETHYLATION). CONCLUSIONS: CH-NIC WORSENS OXIDATIVE STRESS-DEPENDENT ACUTE RENAL INJURY BY INCREASING EXPRESSION AND CONSEQUENT OXIDATIVE STRESS-DEPENDENT SER36 PHOSPHORYLATION OF P66SHC. THUS, TARGETING THIS PATHWAY MAY HAVE THERAPEUTIC RELEVANCE IN PREVENTING/AMELIORATING TOBACCO-RELATED KIDNEY INJURY. 2013 6 1217 27 CREG PROTECTS FROM MYOCARDIAL ISCHEMIA/REPERFUSION INJURY BY REGULATING MYOCARDIAL AUTOPHAGY AND APOPTOSIS. AIMS: HUMAN CELLULAR REPRESSOR OF E1A-STIMULATED GENES (CREG) IS A SECRETED GLYCOPROTEIN THAT REGULATES TISSUE AND CELL HOMEOSTASIS AND HAS BEEN SHOWN TO ANTAGONIZE HEART FIBROSIS, WHICH INDICATES A POTENTIAL PROTECTIVE EFFECT OF CREG AGAINST CARDIOMYOCYTE CHRONIC DAMAGE. HOWEVER, LITTLE IS KNOWN ABOUT THE ROLE OF CREG IN MYOCARDIAL TISSUE ACUTE INJURY, IN THIS STUDY, WE AIMED TO INVESTIGATE THE ROLE OF CREG IN MYOCARDIAL ISCHEMIA/REPERFUSION (MI/R) INJURY AND CLARIFY THE MECHANISM OF ACTION. METHODS AND RESULTS: WILD-TYPE CREG (CREG(+/+)), HETEROZYGOUS CREG (CREG(+/-)) MICE AND MICE PRETREATED WITH INFUSION OF RECOMBINANT 0.3MG/KG.D CREG PROTEIN (RECREG(+/+)) WERE SUBJECTED TO 30MIN OF LEFT ASCENDING CORONARY ISCHEMIA AND 24H OF REPERFUSION. EVAN'S BLUE-TRIPHENYL- TETRAZOLIUM CHLORIDE (TTC) SOLUTION AND ECHOCARDIOGRAPHY ANALYSIS WERE USED TO EVALUATE THE EFFECTS OF CREG ON MI/R MICE. THE UNDERLYING MECHANISMS WERE FURTHER DETERMINED BY CULTURED MYOCARDIAL CELLS IN VITRO. OUR FINDINGS REVEALED THAT THE LEVEL OF CREG PROTEIN IN MOUSE HEARTS WAS SIGNIFICANTLY DECREASED AFTER MICE WERE SUBJECTED TO MI/R. MOREOVER, CREG(+/-) MICE HAD LARGER INFARCTION SIZE 2H AFTER REPERFUSION AND WORSE CARDIAC FUNCTION 28DAYS AFTER MI/R INJURY COMPARED TO THAT IN CREG(+/+) MICE. HOWEVER, RECREG(+/+) MICE COULD MAINTAIN CREG AT A HIGH LEVEL EVEN AFTER MI/R INJURY, AND MITIGATED INFARCTION SIZE AND IMPROVED CARDIAC FUNCTION SIGNIFICANTLY. IN CREG(+/-) MICE, MYOCARDIAL AUTOPHAGY WAS DYSFUNCTIONAL CHARACTERIZED BY ACCUMULATION OF LC3A AND P62, WHILE APOPTOTIC CELL NUMBER INCREASE WAS DETECTED BY CLEAVED CASPASE-3 BLOTTING AND TUNEL STAINING. CONVERSELY, DECREASED APOPTOSIS AND ACTIVATED AUTOPHAGY WERE DETECTED IN RECREG(+/+) MICE. FURTHERMORE, CHLOROQUINE, A KIND OF AUTOPHAGY BLOCKER, WAS USED TO DEMONSTRATE RECOMBINANT CREG PROTECTED CARDIOMYOCYTES AGAINST APOPTOSIS MEDIATED BY ACTIVATING AUTOPHAGY BOTH IN VIVO AND IN VITRO. FINALLY, WE FOUND CREG WAS INVOLVED INTO LYSOSOMAL PROTEIN TRANSFER AND IMPROVE CELLULAR AUTOPHAGY. CONCLUSION: CREG PROTECTS HEART AGAINST MI/R INJURY-INDUCED CARDIOMYOCYTES APOPTOSIS BY ACTIVATING LYSOSOMAL AUTOPHAGY. THIS ARTICLE IS PART OF A SPECIAL ISSUE ENTITLED: GENETIC AND EPIGENETIC CONTROL OF HEART FAILURE - EDITED BY JUN REN AND MEGAN YINGMEI ZHANG. 2017 7 16 27 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 8 2796 15 FBW7 MEDIATES SENESCENCE AND PULMONARY FIBROSIS THROUGH TELOMERE UNCAPPING. TISSUE STEM CELLS UNDERGO PREMATURE SENESCENCE UNDER STRESS, PROMOTING AGE-RELATED DISEASES; HOWEVER, THE ASSOCIATED MECHANISMS REMAIN UNCLEAR. HERE, WE REPORT THAT IN RESPONSE TO RADIATION, OXIDATIVE STRESS, OR BLEOMYCIN, THE E3 UBIQUITIN LIGASE FBW7 MEDIATES CELL SENESCENCE AND TISSUE FIBROSIS THROUGH TELOMERE UNCAPPING. FBW7 BINDING TO TELOMERE PROTECTION PROTEIN 1 (TPP1) FACILITATES TPP1 MULTISITE POLYUBIQUITINATION AND ACCELERATES DEGRADATION, TRIGGERING TELOMERE UNCAPPING AND DNA DAMAGE RESPONSE. OVEREXPRESSING TPP1 OR INHIBITING FBW7 BY GENETIC ABLATION, EPIGENETIC INTERFERENCE, OR PEPTIDOMIMETIC TELOMERE DYSFUNCTION INHIBITOR (TELODIN) REDUCES TELOMERE UNCAPPING AND SHORTENING, EXPANDING THE PULMONARY ALVEOLAR AEC2 STEM CELL POPULATION IN MICE. TELODIN, SYNTHESIZED FROM THE SEVENTH BETA STRAND BLADE OF FBW7 WD40 PROPELLER DOMAIN, INCREASES TPP1 STABILITY, LUNG RESPIRATORY FUNCTION, AND RESISTANCE TO SENESCENCE AND FIBROSIS IN ANIMALS CHRONICALLY EXPOSED TO ENVIRONMENTAL STRESS. OUR FINDINGS ELUCIDATE A PIVOTAL MECHANISM UNDERLYING STRESS-INDUCED PULMONARY EPITHELIAL STEM CELL SENESCENCE AND FIBROSIS, PROVIDING A FRAMEWORK FOR AGING-RELATED DISORDER INTERVENTIONS. 2020 9 608 25 BEYOND HOMEOSTASIS: UNDERSTANDING THE IMPACT OF PSYCHOSOCIAL FACTORS ON APPETITE USING NONHUMAN PRIMATE MODELS. ANIMAL MODELS HAVE PROVEN TO BE EXCEPTIONALLY INFORMATIVE IN DEFINING NEUROPEPTIDE REGULATION OF APPETITE AND ENERGY HOMEOSTASIS (GAO AND HORVATH 2007, BERTHOUD 2012, WILLIAMS AND ELMQUIST 2012). MORE RECENT STUDIES USING A RANGE OF ANIMAL MODELS AND MOLECULAR TOOLS ARE ELUCIDATING HOW EPIGENETIC CHANGES RESULTING FROM SPECIFIC PRENATAL AND POSTNATAL DIETARY ENVIRONMENTS OR EXPERIENCES AFFECT METABOLIC PROCESSES AND APPETITE REGULATION (LEVIN 2008, ZAMBRANO AND NATHANIELSZ 2013, BURDGE AND LILLYCROP 2014). TAKEN TOGETHER, THESE APPROACHES ARE HELPING TO DEFINE POSSIBLE TREATMENT INTERVENTIONS FOR EATING DISORDERS IN PEOPLE (CASPER, SULLIVAN, AND TECOTT 2008, FOLTIN 2012, VAN GESTEL ET AL. 2014, LUTTER, CROGHAN, AND CUI 2016). THE CHOICE OF ANIMAL USED IS BEST DICTATED BY THE QUESTION BEING ADDRESSED. BECAUSE OF SIMILARITIES IN PHYSIOLOGY AND NEUROBIOLOGY, STUDIES OF CAPTIVE NONHUMAN PRIMATES HAVE BEGUN TO CONTRIBUTE SIGNIFICANTLY TO OUR UNDERSTANDING OF APPETITE REGULATION (SEE WILSON ET AL. 2014 FOR A REVIEW). IMPORTANTLY, THE USE OF NONHUMAN PRIMATE MODELS PROVIDES THE UNIQUE OPPORTUNITY TO EXTEND ANALYSES BEYOND A FOCUS ON THE HOMEOSTATIC REGULATION OF APPETITE. THIS IS PARTICULARLY RELEVANT GIVEN THE WELL-ESTABLISHED NOTION THAT A NUMBER OF PSYCHOSOCIAL FACTORS INFLUENCE FOOD INTAKE IN PEOPLE (BRUCE AND RICCIARDELLI 2015), INCLUDING CHRONIC STRESSOR EXPOSURE (TSENKOVA, BOYLAN, AND RYFF 2013), EVEN IN CHILDREN (NGUYEN-RODRIGUEZ, UNGER, AND SPRUIJT-METZ 2009). WHILE THE IMPORTANCE OF PSYCHOSOCIAL FACTORS CAN BE MODELED IN NONPRIMATE ANIMALS (TAMASHIRO, HEGEMAN, AND SAKAI 2006), SOCIALLY HOUSED NONHUMAN PRIMATES SHARE MANY CHARACTERISTICS IN ADDITION TO PHYSIOLOGY AND NEUROBIOLOGY, WITH HUMANS INCREASING THE TRANSLATIONAL VALUE OF THESE PRE-CLINICAL STUDIES. 2017 10 5763 18 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 11 3279 24 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 12 3303 19 HIGH-FREQUENCY P16(INK) (4A) PROMOTER METHYLATION IS ASSOCIATED WITH HISTONE METHYLTRANSFERASE SETDB1 EXPRESSION IN SPORADIC CUTANEOUS MELANOMA. EPIGENETIC MECHANISMS PARTICIPATE IN MELANOMA DEVELOPMENT AND PROGRESSION. THE EFFECT OF HISTONE MODIFICATIONS AND THEIR CATALYSING ENZYMES OVER EUCHROMATIC PROMOTER DNA METHYLATION IN MELANOMA REMAINS UNCLEAR. THIS STUDY INVESTIGATED THE POTENTIAL ASSOCIATION OF P16(INK) (4A) PROMOTER METHYLATION WITH HISTONE METHYLTRANSFERASE SETDB1 EXPRESSION IN GREEK PATIENTS WITH SPORADIC MELANOMA AND THEIR CORRELATION WITH CLINICOPATHOLOGICAL CHARACTERISTICS. PROMOTER METHYLATION WAS DETECTED BY METHYLATION-SPECIFIC PCR IN 100 PERIPHERAL BLOOD SAMPLES AND 58 MELANOMA TISSUES FROM THE SAME PATIENTS. CELL PROLIFERATION (KI-67 INDEX), P16(INK) (4A) AND SETDB1 EXPRESSION WERE EVALUATED BY IMMUNOHISTOCHEMISTRY. HIGH-FREQUENCY PROMOTER METHYLATION (25.86%) WAS OBSERVED IN TISSUE SAMPLES AND CORRELATED WITH INCREASED CELL PROLIFERATION (P = 0.0514). P16(INK) (4A) PROMOTER METHYLATION WAS HIGHER IN VERTICAL GROWTH-PHASE (60%) MELANOMAS THAN IN RADIAL (40%, P = 0.063) AND THOSE DISPLAYING EPIDERMAL INVOLVEMENT (P = 0.046). IMPORTANTLY, P16(INK) (4A) METHYLATION CORRELATED WITH INCREASED MELANOMA THICKNESS ACCORDING TO BRESLOW INDEX (P = 0.0495) AND MARGINALLY WITH INCREASED CLARK LEVEL (I/II VS III/IV/V, P = 0.070). LOW (1-30%) P16(INK) (4A) EXPRESSION WAS DETECTED AT THE MAJORITY (19 OF 54) OF MELANOMA CASES (35.19%), BEING MARGINALLY CORRELATED WITH TUMOR LYMPHOCYTIC INFILTRATION (P = 0.078). SETDB1 NUCLEAR IMMUNOREACTIVITY WAS OBSERVED IN 47 OF 57 (82.46%) CASES, WHEREAS 27 OF 57 (47.37%) SHOWED CYTOPLASMIC IMMUNOEXPRESSION. CYTOPLASMIC SETDB1 EXPRESSION CORRELATED WITH HIGHER FREQUENCY OF P16(INK) (4A) METHYLATION AND P16(INK) (4A) EXPRESSION (P = 0.033, P = 0.011, RESPECTIVELY). INCREASED NUCLEAR SETDB1 LEVELS WERE ASSOCIATED WITH HIGHER MITOTIC COUNT (0-5/MM(2) VS >5/MM(2) , P = 0.0869), ADVANCED CLARK LEVEL (III-V, P = 0.0380), EPIDERMAL INVOLVEMENT (P = 0.0331) AND THE NON-CHRONIC SUN EXPOSURE-ASSOCIATED MELANOMA TYPE (P = 0.0664). OUR DATA DEMONSTRATE FOR THE FIRST TIME THE ASSOCIATION OF HISTONE METHYLTRANSFERASE SETDB1 WITH FREQUENT METHYLATION OF THE EUCHROMATIC P16(INK) (4A) PROMOTER AND SEVERAL PROGNOSTIC PARAMETERS IN MELANOMAS. 2014 13 4576 23 MYOGENIC POTENTIAL OF CANINE CRANIOFACIAL SATELLITE CELLS. THE SKELETAL FIBERS HAVE DIFFERENT EMBRYOLOGICAL ORIGIN; THE EXTRAOCULAR AND JAW-CLOSER MUSCLES DEVELOP FROM PRECHORDAL MESODERM WHILE THE LIMB AND TRUNK MUSCLES FROM SOMITES. THESE DIFFERENT ORIGINS CHARACTERIZE ALSO THE ADULT MUSCLE STEM CELLS, KNOWN AS SATELLITE CELLS (SCS) AND RESPONSIBLE FOR THE FIBER GROWTH AND REGENERATION. THE PHYSIOLOGICAL PROPERTIES OF PRESOMITIC SCS AND THEIR EPIGENETICS ARE POORLY STUDIED DESPITE THEIR PECULIAR CHARACTERISTICS TO PRESERVE MUSCLE INTEGRITY DURING CHRONIC MUSCLE DEGENERATION. HERE, WE ISOLATED SCS FROM CANINE SOMITIC [SOMITE-DERIVED MUSCLE (SDM): VASTUS LATERALIS, RECTUS ABDOMINIS, GLUTEUS SUPERFICIALIS, BICEPS FEMORIS, PSOAS] AND PRESOMITIC [PRE-SOMITE-DERIVED MUSCLE (PSDM): LATERAL RECTUS, TEMPORALIS, AND RETRACTOR BULBI] MUSCLES AS MYOGENIC PROGENITOR CELLS FROM YOUNG AND OLD ANIMALS. IN ADDITION, SDM AND PSDM-SCS WERE OBTAINED ALSO FROM GOLDEN RETRIEVERS AFFECTED BY MUSCULAR DYSTROPHY (GRMD). WE CHARACTERIZED THE LIFESPAN, THE MYOGENIC POTENTIAL AND FUNCTIONS, AND OXIDATIVE STRESS OF BOTH SOMITIC AND PRESOMITIC SCS WITH THE AIM TO REVEAL DIFFERENCES WITH AGING AND BETWEEN HEALTHY AND DYSTROPHIC ANIMALS. THE DIFFERENT PROLIFERATION RATE WAS CONSISTENT WITH HIGHER TELOMERASE ACTIVITY IN PSDM-SCS COMPARED TO SDM-SCS, ALTHOUGH RESTRICTED AT EARLY PASSAGES. SDM-SCS EXPRESS EARLY (PAX7, MYOD) AND LATE (MYOSIN HEAVY CHAIN, MYOGENIN) MYOGENIC MARKERS DIFFERENTLY FROM PSDM-SCS RESULTING IN A MORE EFFICIENT AND FASTER CELL DIFFERENTIATION. TAKEN TOGETHER, OUR RESULTS SHOWED THAT PSDM-SCS ELICIT A STRONGER STEM CELL PHENOTYPE COMPARED TO SDM ONES. FINALLY, MYOMIR EXPRESSION PROFILE REVEALS A UNIQUE EPIGENETIC SIGNATURE IN GRMD SCS AND MIR-206, HIGHLY EXPRESSED IN DYSTROPHIC SCS, SEEMS TO PLAY A CRITICAL ROLE IN MUSCLE DEGENERATION. THUS, MIR-206 COULD REPRESENT A POTENTIAL TARGET FOR NOVEL THERAPEUTIC APPROACHES. 2014 14 4527 21 MULTIGENERATIONAL EFFECTS OF 4-METHYLBENZYLIDENE CAMPHOR (4-MBC) ON THE SURVIVAL, DEVELOPMENT AND REPRODUCTION OF THE MARINE COPEPOD TIGRIOPUS JAPONICUS. ONE OF THE MOST WIDELY USED ORGANIC UV FILTERS, 4-METHYLBENZYLIDENE CAMPHOR (4-MBC), IS PRESENT AT HIGH CONCENTRATIONS IN OFFSHORE WATERS. THE MARINE COPEPOD TIGRIOPUS JAPONICUS WAS EXPOSED TO DIFFERENT CONCENTRATIONS OF 4-MBC (I.E., 0, 0.5, 1, 5 AND 10MUGL(-1)) FOR 4 CONSECUTIVE GENERATIONS (F0-F3) TO EVALUATE THE IMPACT OF 4-MBC ON MARINE ECOSYSTEMS. THE RESULTS SHOWED THAT IN THE F0 GENERATION, 4-MBC CAUSED SIGNIFICANT LETHAL TOXICITY IN T. JAPONICAS AT CONCENTRATIONS OF 5 AND 10MUGL(-1) AND THE NAUPLII WERE MORE SENSITIVE TO 4-MBC TOXICITY THAN THE ADULTS. HOWEVER IN THE F1-F3 GENERATIONS, 4-MBC EXPOSURE DID NOT AFFECT THE SURVIVAL RATE. THE HATCHING RATE AND THE DEVELOPMENTAL DURATION FROM THE NAUPLII TO THE COPEPODITE (N-C) AND FROM THE NAUPLII TO ADULT (N-A) DECREASED SIGNIFICANTLY IN THE F1-F2 GENERATIONS AND IN THE F2-F3 GENERATIONS, RESPECTIVELY, EVEN AT THE LOWEST EXPOSURE CONCENTRATION (0.5MUGL(-1)). IN THE SUBSEQUENT TWO GENERATIONS (I.E., THE F4-F5 GENERATIONS) OF RECOVERY EXPOSURE IN CLEAN SEAWATER, THE GROWTH RATES OF THE ORIGINAL 4-MBC EXPOSURE GROUPS WERE STILL FASTER THAN THE CONTROL IN BOTH THE N-C AND N-A STAGES, SUGGESTING POSSIBLE TRANSGENERATIONAL GENETIC AND/OR EPIGENETIC CHANGES UPON CHRONIC 4-MBC EXPOSURE. THE EXPRESSION OF THE ECDYSONE RECEPTOR GENE WAS UP-REGULATED BY 4-MBC, WHICH WAS CONSISTENT WITH THE DECREASE OF THE N-C/N-A DURATION. IN ADDITION, 4-MBC MAY INDUCE OXIDATIVE STRESS AND TRIGGER APOPTOSIS IN T. JAPONICAS, RESULTING IN DEVELOPMENTAL, REPRODUCTIVE AND EVEN LETHAL TOXICITY. A PRELIMINARY RISK ASSESSMENT SUGGESTED THAT UNDER ENVIRONMENTALLY REALISTIC CONCENTRATIONS, 4-MBC HAD SIGNIFICANT POTENTIAL TO POSE A THREAT TO MARINE CRUSTACEANS AND MARINE ECOSYSTEMS. 2018 15 56 25 A GENOME-WIDE ASSOCIATION META-ANALYSIS OF CIRCULATING SEX HORMONE-BINDING GLOBULIN REVEALS MULTIPLE LOCI IMPLICATED IN SEX STEROID HORMONE REGULATION. SEX HORMONE-BINDING GLOBULIN (SHBG) IS A GLYCOPROTEIN RESPONSIBLE FOR THE TRANSPORT AND BIOLOGIC AVAILABILITY OF SEX STEROID HORMONES, PRIMARILY TESTOSTERONE AND ESTRADIOL. SHBG HAS BEEN ASSOCIATED WITH CHRONIC DISEASES INCLUDING TYPE 2 DIABETES (T2D) AND WITH HORMONE-SENSITIVE CANCERS SUCH AS BREAST AND PROSTATE CANCER. WE PERFORMED A GENOME-WIDE ASSOCIATION STUDY (GWAS) META-ANALYSIS OF 21,791 INDIVIDUALS FROM 10 EPIDEMIOLOGIC STUDIES AND VALIDATED THESE FINDINGS IN 7,046 INDIVIDUALS IN AN ADDITIONAL SIX STUDIES. WE IDENTIFIED TWELVE GENOMIC REGIONS (SNPS) ASSOCIATED WITH CIRCULATING SHBG CONCENTRATIONS. LOCI NEAR THE IDENTIFIED SNPS INCLUDED SHBG (RS12150660, 17P13.1, P = 1.8 X 10(-106)), PRMT6 (RS17496332, 1P13.3, P = 1.4 X 10(-11)), GCKR (RS780093, 2P23.3, P = 2.2 X 10(-16)), ZBTB10 (RS440837, 8Q21.13, P = 3.4 X 10(-09)), JMJD1C (RS7910927, 10Q21.3, P = 6.1 X 10(-35)), SLCO1B1 (RS4149056, 12P12.1, P = 1.9 X 10(-08)), NR2F2 (RS8023580, 15Q26.2, P = 8.3 X 10(-12)), ZNF652 (RS2411984, 17Q21.32, P = 3.5 X 10(-14)), TDGF3 (RS1573036, XQ22.3, P = 4.1 X 10(-14)), LHCGR (RS10454142, 2P16.3, P = 1.3 X 10(-07)), BAIAP2L1 (RS3779195, 7Q21.3, P = 2.7 X 10(-08)), AND UGT2B15 (RS293428, 4Q13.2, P = 5.5 X 10(-06)). THESE GENES ENCOMPASS MULTIPLE BIOLOGIC PATHWAYS, INCLUDING HEPATIC FUNCTION, LIPID METABOLISM, CARBOHYDRATE METABOLISM AND T2D, ANDROGEN AND ESTROGEN RECEPTOR FUNCTION, EPIGENETIC EFFECTS, AND THE BIOLOGY OF SEX STEROID HORMONE-RESPONSIVE CANCERS INCLUDING BREAST AND PROSTATE CANCER. WE FOUND EVIDENCE OF SEX-DIFFERENTIATED GENETIC INFLUENCES ON SHBG. IN A SEX-SPECIFIC GWAS, THE LOCI 4Q13.2-UGT2B15 WAS SIGNIFICANT IN MEN ONLY (MEN P = 2.5 X 10(-08), WOMEN P = 0.66, HETEROGENEITY P = 0.003). ADDITIONALLY, THREE LOCI SHOWED STRONG SEX-DIFFERENTIATED EFFECTS: 17P13.1-SHBG AND XQ22.3-TDGF3 WERE STRONGER IN MEN, WHEREAS 8Q21.12-ZBTB10 WAS STRONGER IN WOMEN. CONDITIONAL ANALYSES IDENTIFIED ADDITIONAL SIGNALS AT THE SHBG GENE THAT TOGETHER ALMOST DOUBLE THE PROPORTION OF VARIANCE EXPLAINED AT THE LOCUS. USING AN INDEPENDENT STUDY OF 1,129 INDIVIDUALS, ALL SNPS IDENTIFIED IN THE OVERALL OR SEX-DIFFERENTIATED OR CONDITIONAL ANALYSES EXPLAINED ~15.6% AND ~8.4% OF THE GENETIC VARIATION OF SHBG CONCENTRATIONS IN MEN AND WOMEN, RESPECTIVELY. THE EVIDENCE FOR SEX-DIFFERENTIATED EFFECTS AND ALLELIC HETEROGENEITY HIGHLIGHT THE IMPORTANCE OF CONSIDERING THESE FEATURES WHEN ESTIMATING COMPLEX TRAIT VARIANCE. 2012 16 3903 20 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 17 1421 23 DIFFERENTIAL BRAIN ADRA2A AND ADRA2C GENE EXPRESSION AND EPIGENETIC REGULATION IN SCHIZOPHRENIA. EFFECT OF ANTIPSYCHOTIC DRUG TREATMENT. POSTSYNAPTIC ALPHA(2A)-ADRENOCEPTOR DENSITY IS ENHANCED IN THE DORSOLATERAL PREFRONTAL CORTEX (DLPFC) OF ANTIPSYCHOTIC-TREATED SCHIZOPHRENIA SUBJECTS. THIS ALTERATION MIGHT BE DUE TO TRANSCRIPTIONAL ACTIVATION, AND COULD BE REGULATED BY EPIGENETIC MECHANISMS SUCH AS HISTONE POSTTRANSLATIONAL MODIFICATIONS (PTMS). THE AIM OF THIS STUDY WAS TO EVALUATE ADRA2A AND ADRA2C GENE EXPRESSION (CODIFYING FOR ALPHA(2)-ADRENOCEPTOR SUBTYPES), AND PERMISSIVE AND REPRESSIVE HISTONE PTMS AT GENE PROMOTER REGIONS IN THE DLPFC OF SUBJECTS WITH SCHIZOPHRENIA AND MATCHED CONTROLS (N = 24 PAIRS). WE STUDIED THE EFFECT OF ANTIPSYCHOTIC (AP) TREATMENT IN AP-FREE (N = 12) AND AP-TREATED (N = 12) SUBGROUPS OF SCHIZOPHRENIA SUBJECTS AND IN RATS ACUTELY AND CHRONICALLY TREATED WITH TYPICAL AND ATYPICAL ANTIPSYCHOTICS. ADRA2A MRNA EXPRESSION WAS SELECTIVELY UPREGULATED IN AP-TREATED SCHIZOPHRENIA SUBJECTS (+93%) WHEREAS ADRA2C MRNA EXPRESSION WAS UPREGULATED IN ALL SCHIZOPHRENIA SUBJECTS (+53%) REGARDLESS OF ANTIPSYCHOTIC TREATMENT. ACUTE AND CHRONIC CLOZAPINE TREATMENT IN RATS DID NOT ALTER BRAIN CORTEX ADRA2A MRNA EXPRESSION BUT INCREASED ADRA2C MRNA EXPRESSION. BOTH ADRA2A AND ADRA2C PROMOTER REGIONS SHOWED EPIGENETIC MODIFICATION BY HISTONE METHYLATION AND ACETYLATION IN HUMAN DLPFC. THE UPREGULATION OF ADRA2A EXPRESSION IN AP-TREATED SCHIZOPHRENIA SUBJECTS MIGHT BE RELATED TO OBSERVED BIVALENT CHROMATIN AT ADRA2A PROMOTER REGION IN SCHIZOPHRENIA (DEPICTED BY INCREASED PERMISSIVE H3K4ME3 AND REPRESSIVE H3K27ME3) AND COULD BE TRIGGERED BY THE ENHANCED H4K16AC AT ADRA2A PROMOTER. IN CONCLUSION, EPIGENETIC PREDISPOSITION DIFFERENTIALLY MODULATED ADRA2A AND ADRA2C MRNA EXPRESSION IN DLPFC OF SCHIZOPHRENIA SUBJECTS. 2021 18 3239 24 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 19 4048 17 MAINTENANCE AND PHARMACOLOGIC TARGETING OF ROR1 PROTEIN LEVELS VIA UHRF1 IN T(1;19) PRE-B-ALL. EXPRESSION OF THE TRANSMEMBRANE PSEUDOKINASE ROR1 IS REQUIRED FOR SURVIVAL OF T(1;19)-PRE-B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (T(1;19) PRE-B-ALL), CHRONIC LYMPHOCYTIC LEUKEMIA, AND MANY SOLID TUMORS. HOWEVER, TARGETING ROR1 WITH SMALL-MOLECULES HAS BEEN CHALLENGING DUE TO THE ABSENCE OF ROR1 KINASE ACTIVITY. TO IDENTIFY GENES THAT REGULATE ROR1 EXPRESSION AND MAY, THEREFORE, SERVE AS SURROGATE DRUG TARGETS, WE EMPLOYED AN SIRNA SCREENING APPROACH AND DETERMINED THAT THE EPIGENETIC REGULATOR AND E3 UBIQUITIN LIGASE, UHRF1, IS REQUIRED FOR T(1;19) PRE-B-ALL CELL VIABILITY IN A ROR1-DEPENDENT MANNER. UPON UHRF1 SILENCING, ROR1 PROTEIN IS REDUCED WITHOUT ALTERING ROR1 MRNA, AND ECTOPICALLY EXPRESSED UHRF1 IS SUFFICIENT TO INCREASE ROR1 LEVELS. ADDITIONALLY, PROTEASOME INHIBITION RESCUES LOSS OF ROR1 PROTEIN AFTER UHRF1 SILENCING, SUGGESTING A ROLE FOR THE PROTEASOME IN THE UHRF1-ROR1 AXIS. FINALLY, WE SHOW THAT ROR1-POSITIVE CELLS ARE TWICE AS SENSITIVE TO THE UHRF1-TARGETING DRUG, NAPHTHAZARIN, AND UNDERGO INCREASED APOPTOSIS COMPARED TO ROR1-NEGATIVE CELLS. NAPHTHAZARIN ELICITS REDUCED EXPRESSION OF UHRF1 AND ROR1, AND COMBINATION OF NAPHTHAZARIN WITH INHIBITORS OF PRE-B CELL RECEPTOR SIGNALING RESULTS IN FURTHER REDUCTION OF CELL SURVIVAL COMPARED WITH EITHER INHIBITOR ALONE. THEREFORE, OUR WORK REVEALS A MECHANISM BY WHICH UHRF1 STABILIZES ROR1, SUGGESTING A POTENTIAL TARGETING STRATEGY TO INHIBIT ROR1 IN T(1;19) PRE-B-ALL AND OTHER MALIGNANCIES. 2018 20 6072 24 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