1 5822 78 STRESS IN THE ONSET AND AGGRAVATION OF LEARNING DISABILITIES. DESPITE SUBSTANTIAL GROUNDS FOR SUCH RESEARCH, THE ROLE OF CHRONIC EXPOSURE TO STRESSORS IN THE ONSET AND AGGRAVATION OF LEARNING DISABILITIES (LDS) IS LARGELY UNEXPLORED. IN THIS REVIEW, WE FIRST CONSIDER THE HORMONAL, (EPI)GENETIC, AND NEUROBIOLOGICAL MECHANISMS THAT MIGHT UNDERLIE THE IMPACT OF ADVERSE CHILDHOOD EXPERIENCES, A FORM OF CHRONIC STRESSORS, ON THE ONSET OF LDS. WE THEN FOUND THAT STRESS FACTORS COMBINED WITH FEELINGS OF INFERIORITY, LOW SELF-ESTEEM, AND PEER VICTIMIZATION COULD POTENTIALLY FURTHER AGGRAVATE ACADEMIC FAILURES IN CHILDREN WITH LDS. SINCE EFFECTIVE EVIDENCE-BASED INTERVENTIONS FOR REDUCING CHRONIC STRESS IN CHILDREN WITH LDS COULD IMPROVE THEIR ACADEMIC PERFORMANCE, CONSIDERATION OF THE ROLE OF EXPOSURE TO STRESSORS IN CHILDREN WITH LDS HAS BOTH THEORETICAL AND PRACTICAL IMPORTANCE, ESPECIALLY WHEN DELIVERED IN COMBINATION WITH ACADEMIC INTERVENTIONS. 2021 2 5763 13 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 3 890 13 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 4 608 23 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 5 3407 28 HOW WELL DO WE UNDERSTAND THE LONG-TERM HEALTH IMPLICATIONS OF CHILDHOOD BULLYING? ONCE DISMISSED AS AN INNOCUOUS EXPERIENCE OF CHILDHOOD, BULLYING IS NOW RECOGNIZED AS HAVING SIGNIFICANT PSYCHOLOGICAL EFFECTS, PARTICULARLY WITH CHRONIC EXPOSURE. VICTIMS OF BULLYING ARE AT RISK FOR A NUMBER OF PSYCHIATRIC DISTURBANCES, AND GROWING EVIDENCE SUGGESTS THAT THE PATHOPHYSIOLOGICAL EFFECTS OF BULLYING, AS WITH OTHER FORMS OF TRAUMA AND CHRONIC STRESS, CREATE ADDITIONAL HEALTH RISKS. WE REVIEW THE LITERATURE ON THE KNOWN SEQUELAE OF BULLYING, INCLUDING PSYCHIATRIC AND PHYSIOLOGICAL HEALTH EFFECTS, WITH A FOCUS ON IMPLICATIONS FOR THE VICTIM. IN ADDITION, SINCE IT IS NOW WELL ESTABLISHED THAT EARLY AND CHRONIC EXPOSURE TO STRESS HAS A SIGNIFICANT NEGATIVE IMPACT ON HEALTH OUTCOMES, WE EXPLORE THE IMPLICATIONS OF THIS RESEARCH IN RELATION TO BULLYING AND VICTIMIZATION IN CHILDHOOD. IN PARTICULAR, WE EXAMINE HOW ASPECTS OF THE STRESS RESPONSE, VIA EPIGENETIC, INFLAMMATORY, AND METABOLIC MEDIATORS, HAVE THE CAPACITY TO COMPROMISE MENTAL AND PHYSICAL HEALTH, AND TO INCREASE THE RISK OF DISEASE. RESEARCH ON THE RELEVANT MECHANISMS ASSOCIATED WITH BULLYING AND ON POTENTIAL INTERVENTIONS TO DECREASE MORBIDITY IS URGENTLY NEEDED. 2017 6 967 15 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 7 2796 12 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 8 2649 12 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 9 4527 17 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 10 3416 17 HTR1A, HTR1B, HTR2A, HTR2C AND HTR6 GENE POLYMORPHISMS AND EXTRAPYRAMIDAL SIDE EFFECTS IN HALOPERIDOL-TREATED PATIENTS WITH SCHIZOPHRENIA. SCHIZOPHRENIA IS A SERIOUS, CHRONIC PSYCHIATRIC DISORDER REQUIRING LIFELONG TREATMENT. EXTRAPYRAMIDAL SIDE EFFECTS (EPS) ARE COMMON ADVERSE REACTIONS TO ANTIPSYCHOTIC MEDICATIONS. IN ADDITION TO THE DOPAMINERGIC SYSTEM, SEROTONERGIC MECHANISMS, INCLUDING SEROTONIN (5-HT) RECEPTORS, MIGHT BE INVOLVED IN EPS DEVELOPMENT. THIS STUDY AIMED TO EXAMINE MOLECULAR ASSOCIATIONS OF HTR1A, HTR1B, HTR2A, HTR2C AND HTR6 GENE POLYMORPHISMS WITH ACUTE EPS IN 229 MALE SCHIZOPHRENIA PATIENTS, FOLLOWING TWO WEEKS OF HALOPERIDOL MONOTHERAPY. THE SIMPSON-ANGUS RATING SCALE FOR EXTRAPYRAMIDAL SIDE EFFECTS (SAS), BARNES AKATHISIA RATING SCALE (BARS) AND EXTRAPYRAMIDAL SYMPTOM RATING SCALE (ESRS) WERE USED TO EVALUATE EPS SEVERITY. GENOTYPING WAS PERFORMED USING REAL-TIME PCR, FOLLOWING EXTRACTION OF BLOOD DNA. SIGNIFICANT ACUTE EPS APPEARED IN 48.03% OF SCHIZOPHRENIA PATIENTS. FOR THE RS13212041 HTR1B GENE POLYMORPHISM, AFFECTING MICRORNA REGULATION OF HTR1B GENE EXPRESSION, A HIGHER FREQUENCY OF TT CARRIERS WAS FOUND AMONG HALOPERIDOL-TREATED PATIENTS WITH AKATHISIA WHEN COMPARED TO THE GROUP WITHOUT AKATHISIA SYMPTOMS. IN COMPARISON TO C-ALLELE CARRIERS, PATIENTS CARRYING THE TT GENOTYPE HAD HIGHER AKATHISIA SEVERITY, AS DETERMINED BY THE SAS, BARS AND ESRS SCALES. THESE MOLECULAR FINDINGS SUGGEST POTENTIAL INVOLVEMENT OF 5-HT(1B) RECEPTORS IN AKATHISIA DEVELOPMENT FOLLOWING HALOPERIDOL TREATMENT, AS WELL AS POSSIBLE EPIGENETIC MECHANISMS OF SEROTONERGIC MODULATION ASSOCIATED WITH ANTIPSYCHOTIC-INDUCED EPS. 2020 11 760 19 CASZ1: CURRENT IMPLICATIONS IN CARDIOVASCULAR DISEASES AND CANCERS. CASTOR ZINC FINGER 1 (CASZ1) IS A C2H2 ZINC FINGER FAMILY PROTEIN THAT HAS TWO SPLICING VARIANTS, CASZ1A AND CASZ1B. IT IS INVOLVED IN MULTIPLE PHYSIOLOGICAL PROCESSES, SUCH AS TISSUE DIFFERENTIATION AND ALDOSTERONE ANTAGONISM. GENETIC AND EPIGENETIC ALTERNATIONS OF CASZ1 HAVE BEEN CHARACTERIZED IN MULTIPLE CARDIOVASCULAR DISORDERS, SUCH AS CONGENITAL HEART DISEASES, CHRONIC VENOUS DISEASES, AND HYPERTENSION. HOWEVER, LITTLE IS KNOWN ABOUT HOW CASZ1 MECHANICALLY PARTICIPATES IN THE PATHOGENESIS OF THESE DISEASES. OVER THE PAST DECADES, AT FIRST GLANCE, PARADOXICAL INFLUENCES ON CELL BEHAVIORS AND PROGRESSIONS OF DIFFERENT CANCER TYPES HAVE BEEN DISCOVERED FOR CASZ1, WHICH MAY BE EXPLAINED BY A "DOUBLE-AGENT" ROLE FOR CASZ1. IN THIS REVIEW, WE DISCUSS THE PHYSIOLOGICAL FUNCTION OF CASZ1, AND FOCUS ON THE ASSOCIATION OF CASZ1 ABERRATIONS WITH THE PATHOGENESIS OF CARDIOVASCULAR DISEASES AND CANCERS. 2023 12 6463 13 TISSUE METHYLATION AND DEMETHYLATION INFLUENCE TRANSLESION SYNTHESIS DNA POLYMERASES (TLS) CONTRIBUTING TO THE GENESIS OF CHROMOSOMAL ABNORMALITIES IN MYELODYSPLASTIC SYNDROME. AIMS: DNA METHYLATION HAS ITS DISTRIBUTION INFLUENCED BY DNA DEMETHYLATION PROCESSES WITH THE CATALYTIC CONVERSION OF 5-METHYLCYTOSINE (5MC) INTO 5-HYDROXYMETHYLCYTOSINE (5HMC). MYELODYSPLASTIC SYNDROME (MDS) HAS BEEN ASSOCIATED WITH EPIGENETIC DYSREGULATION OF GENES RELATED TO DNA REPAIR SYSTEM, CHRONIC IMMUNE RESPONSE AND CELL CYCLE. METHODS: WE EVALUATED THE TISSUE DNA METHYLATION/HYDROXYMETHYLATION IN BONE MARROW TREPHINE BIOPSIES OF 73 PATIENTS WITH MDS, TRYING TO CORRELATE WITH THE MRNA EXPRESSION OF 21 GENES (POLH, POLL, REV3L, POLN, POLQ, POLI, POLK, IRF-1, IRF-2, IRF-3, IRF-4, IRF-5, IRF6, IRF-7, IRF-8,IRF-9, MAD2, CDC20, AURKA, AURKB AND TPX2). RESULTS: THE M-SCORE (5MC) WAS SIGNIFICANTLY HIGHER IN PATIENTS WITH CHROMOSOMAL ABNORMALITIES THAN PATIENTS WITH NORMAL KARYOTYPE (95% CI -27.127779 TO -2.368020; P=0.022). WE OBSERVED A HIGHER 5MC/5HMC RATIO IN PATIENTS CLASSIFIED AS HIGH-RISK SUBTYPES COMPARED WITH LOW-RISK SUBTYPES (95% CI -72.922115 TO -1.855662; P=0.040) AS WELL AS PATIENTS WITH HYPERCELLULAR BONE MARROW COMPARED WITH PATIENTS WITH NORMOCELLULAR/HYPOCELLULAR BONE MARROW (95% CI -69.189259 TO -0.511828; P=0.047) AND WITH THE PRESENCE OF DYSERYTHROPOIESIS (95% CI 17.077703 TO 51.331388; P=0.001). DNA POLS WITH TRANSLESION ACTIVITY ARE SIGNIFICANTLY INFLUENCED BY METHYLATION. AS 5MC IMMUNOEXPRESSION INCREASES, THE EXPRESSIONS OF POLH (R=-0.816; R(2) =0.665; P=0.000), POLQ (R=-0.790; R(2)=0.624; P=0.001), PCNA (R=-0.635; R(2)=0.403; P=0.020), POLK (R=-0.633; R(2)=0.400; P=0.036 AND REV1 (R=-0.578; R(2)=0.334; P=0.049) DECREASE. CONCLUSIONS: OUR RESULTS CONFIRM THAT THERE IS AN IMBALANCE IN THE DNA METHYLATION IN MDS, INFLUENCING THE DEVELOPMENT OF CHROMOSOMAL ABNORMALITIES WHICH MAY BE ASSOCIATED WITH THE LOW EXPRESSION OF DNA POLYMERASES WITH TRANSLESION SYNTHESIS POLYMERASES ACTIVITY. 2022 13 3570 19 IMPACT OF JUVENILE HORMONE ANALOGUE INSECTICIDES ON THE WATER FLEA MOINA MACROCOPA: GROWTH, REPRODUCTION AND TRANSGENERATIONAL EFFECT. THE INCREASING QUANTITIES OF INSECTICIDES THAT LEACH INTO WATER BODIES SEVERELY AFFECT THE HEALTH OF THE AQUATIC ENVIRONMENT. JUVENILE HORMONE ANALOGUE (JHA) INSECTICIDES ARE ENDOCRINE DISRUPTERS THAT INTERFERE WITH HORMONAL ACTIVITY IN INSECTS BY MIMICKING JUVENILE HORMONES (JHS). BECAUSE THE STRUCTURE AND FUNCTIONS OF METHYL FARNESOATE IN CRUSTACEANS ARE SIMILAR TO THE INSECT JHS, EXOGENOUS JHA INSECTICIDES MAY CAUSE ADVERSE EFFECTS ON THE GROWTH AND REPRODUCTION IN CRUSTACEANS SIMILAR TO THOSE OBSERVED IN INSECTS. THIS STUDY EXAMINED THE TOXIC EFFECTS OF TWO JHA INSECTICIDES, METHOPRENE AND FENOXYCARB, ON THE WATER FLEA MOINA MACROCOPA. THE 24-H AND 48-H LC(50) VALUES FOR FENOXYCARB AND METHOPRENE WERE 0.53 AND 0.32 MG/L AND 0.70 AND 0.54 MG/L, RESPECTIVELY. CHRONIC EXPOSURE TO THE TWO JHAS CAUSED A SERIES OF TOXIC EFFECTS IN M. MACROCOPA, INCLUDING SHORTENING OF LIFE EXPECTANCY, REPRESSION OF BODY GROWTH, REDUCTION IN FECUNDITY, AND DISTURBED THE EXPRESSION OF GENES INVOLVED IN THE JH SIGNALING PATHWAY, IN CUTICLE DEVELOPMENT, AND IN THE CARBOHYDRATE, AMINO ACID, AND ATP METABOLIC PROCESSES. MOREOVER, JHA EXPOSURE IMPAIRED THE GROWTH AND REPRODUCTION OF THE OFFSPRING OF M. MACROCOPA EXPOSED TO JHAS, EVEN WHEN THE NEONATES WERE NOT EXPOSED TO THE CHEMICALS. IN ADDITION, CHANGES IN THE EXPRESSION OF GENES RELATED TO HISTONE METHYLATION INDICATE THAT EPIGENETIC CHANGES MAY PROMOTE TRANSGENERATIONAL IMPAIRMENT IN M. MACROCOPA. THESE RESULTS DEMONSTRATE THE TOXIC EFFECTS OF FENOXYCARB AND METHOPRENE ON NON-TARGET AQUATIC ORGANISMS. THE DAMAGES DONE BY THESE JHA INSECTICIDES TO THE AQUATIC ENVIRONMENT IS WORTHY OF OUR ATTENTION AND FURTHER STUDIES. 2020 14 5483 17 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 15 5022 10 PERSISTENT SUBCLINICAL INFLAMMATION AMONG A-BOMB SURVIVORS. PURPOSE: TO INVESTIGATE THE ASSOCIATIONS BETWEEN INFLAMMATION TESTS AND RADIATION DOSE IN A-BOMB SURVIVORS. SUBJECTS AND METHODS: SUBJECTS WERE A-BOMB SURVIVORS WHO UNDERWENT INFLAMMATION TESTS OF LEUKOCYTE COUNTS, NEUTROPHIL COUNTS, ERYTHROCYTE SEDIMENTATION RATE, CORRECTED ERYTHROCYTE SEDIMENTATION RATE, ALPHA-1 GLOBULIN, ALPHA-2 GLOBULIN AND SIALIC ACID BETWEEN 1988 AND 1992. ASSOCIATIONS WITH RADIATION DOSE (DS86) WERE ANALYZED BY REGRESSION ANALYSIS AND HETEROGENEITY AMONG INFLAMMATORY DISEASES, ANAEMIA AT EXAMINATION, OR HISTORY OF CANCER WAS ALSO TESTED. RESULTS: THE ASSOCIATIONS WITH RADIATION DOSE WERE STATISTICALLY SIGNIFICANT FOR LEUKOCYTE COUNTS (71.0MM(-3) GY(-1), P=0.015), ERYTHROCYTE SEDIMENTATION RATE (1.58 MM H(-1) GY(-1) , P = 0.0001), CORRECTED ERYTHROCYTE SEDIMENTATION RATE (1.14MM H(-1) GY(-1), P=0.0001), ALPHA-1 GLOBULIN (0.0057 G DL(-1) GY(-1), P=0.0001), ALPHA-2 GLOBULIN (0.0128 G DL(-1) GY(-1), P=0.0001), AND SIALIC ACID (1.2711 MG DL(-1) GY(-1), P=0.0001) BUT NOT FOR NEUTROPHIL COUNTS (29.9 MM(-3) GY(-1), P=0.17). HETEROGENEITY WAS NOT STATISTICALLY SIGNIFICANT. AMONG INFLAMMATORY DISEASES, ASSOCIATIONS WERE THE STRONGEST FOR CHRONIC THYROIDITIS AND CHRONIC LIVER DISEASES. CONCLUSIONS: THIS STUDY SUGGESTS STATISTICALLY SIGNIFICANT ASSOCIATION BETWEEN INFLAMMATION IN A-BOMB SURVIVORS AND RADIATION DOSE OF DURING 1988-1992. THE ASSOCIATION MIGHT CONTRIBUTE, AS AN EPIGENETIC AND/OR BYSTANDER EFFECT, TO DEVELOPMENT OF SEVERAL RADIATION-INDUCED DISORDERS. 2001 16 2998 16 GENETIC VARIANTS IN TELOMERASE REVERSE TRANSCRIPTASE CONTRIBUTE TO SOLAR LENTIGINES. SOLAR LENTIGINES (SLS) ARE A HALLMARK OF HUMAN SKIN AGING. THEY RESULT FROM CHRONIC EXPOSURE TO SUNLIGHT AND OTHER ENVIRONMENTAL STRESSORS. RECENT STUDIES ALSO IMPLY GENETIC FACTORS, BUT FINDINGS ARE PARTIALLY CONFLICTING AND LACK OF REPLICATION. THROUGH A MULTI-TRAIT BASED ANALYSIS STRATEGY, WE DISCOVERED THAT GENETIC VARIANTS IN TELOMERASE REVERSE TRANSCRIPTASE WERE SIGNIFICANTLY ASSOCIATED WITH NON-FACIAL SL IN TWO EAST ASIAN (TAIZHOU LONGITUDINAL COHORT, N = 2,964 AND NATIONAL SURVEY OF PHYSICAL TRAITS, N = 2,954) AND ONE CAUCASIAN POPULATION (SALIA, N = 462), TOP SNP RS2853672 (P-VALUE FOR TAIZHOU LONGITUDINAL COHORT = 1.32 X 10(?28) AND P-VALUE FOR NATIONAL SURVEY OF PHYSICAL TRAITS = 3.66 X 10(?17) AND P-VALUE FOR SALIA = 0.0007 AND P(META) = 4.93 X 10(?44)). THE SAME VARIANTS WERE NOMINALLY ASSOCIATED WITH FACIAL SL BUT NOT WITH OTHER SKIN AGING OR SKIN PIGMENTATION TRAITS. THE SL-ENHANCED ALLELE/HAPLOTYPE UPREGULATED THE TRANSCRIPTION OF THE TELOMERASE REVERSE TRANSCRIPTASE GENE. OF NOTE, WELL-KNOWN TELOMERASE REVERSE TRANSCRIPTASE?RELATED AGING MARKERS SUCH AS LEUKOCYTE TELOMERE LENGTH AND INTRINSIC EPIGENETIC AGE ACCELERATION WERE NOT ASSOCIATED WITH SL. OUR RESULTS INDICATE A PREVIOUSLY UNRECOGNIZED ROLE OF TELOMERASE REVERSE TRANSCRIPTASE IN SKIN AGING?RELATED LENTIGINES FORMATION. 2023 17 5814 15 STRESS AND FELINE HEALTH. IN THE HEALTH SCIENCES, STRESS OFTEN IS DEFINED IN TERMS OF STRESSORS; EVENTS THAT ARE PERCEIVED AS THREATS TO ONE'S PERCEPTION OF CONTROL. FROM THIS PERSPECTIVE, A STRESSOR IS ANYTHING THAT ACTIVATES THE CENTRAL THREAT RESPONSE SYSTEM (CTRS). RECENT RESEARCH SHOWS THAT THE CTRS CAN BE SENSITIZED TO ENVIRONMENTAL EVENTS THROUGH EPIGENETIC MODULATION OF GENE EXPRESSION. WHEN CTRS ACTIVATION IS CHRONIC, HEALTH AND WELFARE MAY BE HARMED. ENVIRONMENTAL MODIFICATION CAN MITIGATE THE HARMFUL EFFECTS OF CHRONIC CTRS ACTIVATION BY REDUCING THE INDIVIDUAL'S PERCEPTION OF THREAT AND INCREASING ITS PERCEPTION OF CONTROL, WHICH IMPROVES HEALTH AND WELFARE. 2020 18 3903 17 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 19 56 19 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 20 1791 17 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