1 6644 174 UNRAVELLING THE MOLECULAR MECHANISMS OF NICKEL IN WOODLICE. DURING THE LAST FEW YEARS, THERE HAS BEEN AN ALARMING INCREASE IN THE AMOUNT OF NICKEL (NI) BEING RELEASED INTO THE ENVIRONMENT, PRIMARILY DUE TO ITS USE IN THE PRODUCTION OF STAINLESS STEEL BUT ALSO FROM OTHER SOURCES SUCH AS BATTERIES MANUFACTURING AND CONSEQUENT DISPOSAL. THE ESTABLISHED BIOTIC LIGAND MODELS PROVIDE PRECISE ESTIMATES FOR NI BIOAVAILABILITY, IN CONTRAST, STUDIES DESCRIBING THE MECHANISMS UNDERPINNING TOXICOLOGICAL EFFECT OF NI ARE SCARCE. THIS STUDY EXPLOITS RNA-SEQ TO DETERMINE THE TRANSCRIPTOMIC RESPONSES OF ISOPODS USING PORCELLIONIDES PRUINOSUS AS AN EXAMPLE OF A TERRESTRIAL METAL-RESISTANT WOODLOUSE. FURTHERMORE, THE RECENTLY PROPOSED MODEL FOR NI ADVERSE OUTCOME PATHWAYS (NI-AOP) PRESENTS AN UNPRECEDENTED OPPORTUNITY TO FIT ISOPOD RESPONSES TO NI TOXICITY AND DEFINE PORCELLIONIDES PRUINOSUS AS A METALOMIC MODEL. PRIOR TO THIS STUDY, P. PRUINOSUS REPRESENTED AN IMPORTANT ENVIRONMENTAL SENTINEL, THOUGH LACKING GENETIC/OMIC DATA. THE REFERENCE TRANSCRIPTOME GENERATED HERE THUS REPRESENTS A MAJOR ADVANCE AND A NOVEL RESOURCE. A DETAILED ANNOTATION OF THE TRANSCRIPTS OBTAINED IS PRESENTED TOGETHER WITH THE HOMOLOGY TO GENES/GENE PRODUCTS FROM METAZOAN AND ARTHROPODA PHYLUM, GENE ONTOLOGY (GO) CLASSIFICATION, CLUSTERS OF ORTHOLOGOUS GROUPS (COG) AND ASSIGNMENT TO KEGG METABOLIC PATHWAYS. THE DIFFERENTIAL GENE EXPRESSION COMPARISON WAS DETERMINED IN RESPONSE TO NICKEL (NI) EXPOSURE AND USED TO DERIVE THE ENRICHED PATHWAYS AND PROCESSES. IT REVEALED A SIGNIFICANT IMPACT ON ION TRAFFICKING AND STORAGE, OXIDATIVE STRESS, NEUROTOXICITY, REPRODUCTION IMPAIRMENT, GENETICS AND EPIGENETICS. MANY OF THE PROCESSES OBSERVED SUPPORT THE CURRENT NI-AOP ALTHOUGH THE DATA HIGHLIGHTS THAT THE CURRENT MODEL CAN BE IMPROVED BY INCLUDING EPIGENETIC ENDPOINTS, WHICH REPRESENTS KEY CHRONIC RISKS UNDER A SCENARIO OF NI TOXICITY.	2019	
                                                                                                                                                                                                                                                                                                                                                                                              
2 1162  36 CONTRASTING EFFECTS OF ACUTE AND CHRONIC STRESS ON THE TRANSCRIPTOME, EPIGENOME, AND IMMUNE RESPONSE OF ATLANTIC SALMON. STRESS EXPERIENCED DURING EARLY LIFE MAY HAVE LASTING EFFECTS ON THE IMMUNE SYSTEM, WITH IMPACTS ON HEALTH AND DISEASE DEPENDENT ON THE NATURE AND DURATION OF THE STRESSOR. THE EPIGENOME IS ESPECIALLY SENSITIVE TO ENVIRONMENTAL STIMULI DURING EARLY LIFE AND REPRESENTS A POTENTIAL MECHANISM THROUGH WHICH STRESS MAY CAUSE LONG-LASTING HEALTH EFFECTS. HOWEVER, THE EXTENT TO WHICH THE EPIGENOME RESPONDS DIFFERENTLY TO CHRONIC VS ACUTE STRESSORS IS UNCLEAR, ESPECIALLY FOR NON-MAMMALIAN SPECIES. WE EXAMINED THE EFFECTS OF ACUTE STRESS (COLD-SHOCK DURING EMBRYOGENESIS) AND CHRONIC STRESS (ABSENCE OF TANK ENRICHMENT DURING LARVAL-STAGE) ON GLOBAL GENE EXPRESSION (USING RNA-SEQ) AND DNA METHYLATION (USING RRBS) IN THE GILLS OF ATLANTIC SALMON (SALMO SALAR) FOUR MONTHS AFTER HATCHING. CHRONIC STRESS INDUCED PRONOUNCED TRANSCRIPTIONAL DIFFERENCES, WHILE ACUTE STRESS CAUSED FEW LASTING TRANSCRIPTIONAL EFFECTS. HOWEVER, BOTH ACUTE AND CHRONIC STRESS CAUSED LASTING AND CONTRASTING CHANGES IN THE METHYLOME. CRUCIALLY, WE FOUND THAT ACUTE STRESS ENHANCED TRANSCRIPTIONAL IMMUNE RESPONSE TO A PATHOGENIC CHALLENGE (BACTERIAL LIPOPOLYSACCHARIDE, LPS), WHILE CHRONIC STRESS SUPPRESSED IT. WE IDENTIFIED STRESS-INDUCED CHANGES IN PROMOTER AND GENE-BODY METHYLATION THAT WERE ASSOCIATED WITH ALTERED EXPRESSION FOR A SMALL PROPORTION OF IMMUNE-RELATED GENES, AND EVIDENCE OF WIDER EPIGENETIC REGULATION WITHIN SIGNALLING PATHWAYS INVOLVED IN IMMUNE RESPONSE. OUR RESULTS SUGGEST THAT STRESS CAN AFFECT IMMUNO-COMPETENCE THROUGH EPIGENETIC MECHANISMS, AND HIGHLIGHT THE MARKEDLY DIFFERENT EFFECTS OF CHRONIC LARVAL AND ACUTE EMBRYONIC STRESS. THIS KNOWLEDGE COULD BE USED TO HARNESS THE STIMULATORY EFFECTS OF ACUTE STRESS ON IMMUNITY, PAVING THE WAY FOR IMPROVED STRESS AND DISEASE MANAGEMENT THROUGH EPIGENETIC CONDITIONING.	2018	
                                                                                                                                                                                                                                                                                                                                                                     
3 3591  29 IMPAIRED ONE CARBON METABOLISM AND DNA METHYLATION IN ALCOHOL TOXICITY. EXCESSIVE ALCOHOL CONSUMPTION IS A PROMINENT PROBLEM AND ONE OF THE MAJOR CAUSES OF MORTALITY AND MORBIDITY AROUND THE WORLD. LONG-TERM, HEAVY ALCOHOL CONSUMPTION IS ASSOCIATED WITH A NUMBER OF DELETERIOUS HEALTH CONSEQUENCES, SUCH AS CANCER, HEART AND LIVER DISEASE, A VARIETY OF NEUROLOGICAL, COGNITIVE, AND BEHAVIORAL DEFICITS. ALCOHOL CONSUMPTION IS ALSO ASSOCIATED WITH DEVELOPMENTAL DEFECTS. THE CAUSES OF ALCOHOL-INDUCED TOXICITY ARE PRESENTLY UNCLEAR. ONE OF THE MECHANISMS UNDERLYING ALCOHOL TOXICITY HAS TO DO WITH ITS INTERACTION WITH FOLIC ACID/HOMOCYSTEINE OR ONE-CARBON METABOLISM (OCM). OCM IS A MAJOR DONOR OF METHYL GROUPS FOR METHYLATION, PARTICULARLY DNA METHYLATION CRITICAL FOR EPIGENETIC REGULATION OF GENE EXPRESSION, AND ITS DISTURBANCE MAY COMPROMISE DNA METHYLATION, THEREBY AFFECTING GENE EXPRESSION. OCM DISTURBANCE MEDIATED BY NUTRIENT DEFICITS IS A WELL-KNOWN RISK FACTOR FOR VARIOUS DISORDERS AND DEVELOPMENTAL DEFECTS (E.G., NEURAL TUBE DEFECTS). IN THIS REVIEW, WE SUMMARIZE THE ROLE OF OCM DISTURBANCE AND ASSOCIATED EPIGENETIC ABERRATIONS IN CHRONIC ALCOHOL-INDUCED TOXICITY. IN THIS REVIEW, WE SUMMARIZE THE ROLE OF ONE-CARBON METABOLISM (OCM) ABERRATIONS IN CHRONIC ALCOHOL-INDUCED TOXICITY. OCM IS A MAJOR DONOR OF METHYL GROUPS FOR METHYLATION REACTIONS, PARTICULARLY DNA METHYLATION CRITICAL FOR EPIGENETIC REGULATION OF GENE EXPRESSION. ALCOHOL INTERFERENCE WITH OCM AND CONSEQUENT REDUCED AVAILABILITY OF METHYL GROUPS, IMPROPER DNA METHYLATION, AND ABERRANT GENE EXPRESSION CAN PLAY A CAUSATIVE ROLE IN ALCOHOL TOXICITY.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
4 6137  36 THE EPIGENETICS OF PSYCHOSIS: A STRUCTURED REVIEW WITH REPRESENTATIVE LOCI. THE EVIDENCE FOR AN ENVIRONMENTAL COMPONENT IN CHRONIC PSYCHOTIC DISORDERS IS STRONG AND RESEARCH ON THE EPIGENETIC MANIFESTATIONS OF THESE ENVIRONMENTAL IMPACTS HAS COMMENCED IN EARNEST. IN REVIEWING THIS RESEARCH, THE FOCUS IS ON THREE GENES AS MODELS FOR DIFFERENTIAL METHYLATION, MCHR1, AKT1 AND TDO2, EACH OF WHICH HAVE BEEN INVESTIGATED FOR GENETIC ASSOCIATION WITH PSYCHOTIC DISORDERS. ENVIRONMENTAL FACTORS ASSOCIATED WITH PSYCHOTIC DISORDERS, AND WHICH INTERACT WITH THESE MODEL GENES, ARE EXPLORED IN DEPTH. THE LOCATION OF TRANSCRIPTION FACTOR MOTIFS RELATIVE TO KEY METHYLATION SITES IS EVALUATED FOR PREDICTED GENE EXPRESSION RESULTS, AND FOR OTHER SITES, EVIDENCE IS PRESENTED FOR METHYLATION DIRECTING ALTERNATIVE SPLICING. EXPERIMENTAL RESULTS FROM KEY STUDIES SHOW DIFFERENTIAL METHYLATION: FOR MCHR1, IN PSYCHOSIS CASES VERSUS CONTROLS; FOR AKT1, AS A PRE-EXISTING METHYLATION PATTERN INFLUENCING BRAIN ACTIVATION FOLLOWING ACUTE ADMINISTRATION OF A PSYCHOSIS-ELICITING ENVIRONMENTAL STIMULUS; AND FOR TDO2, IN A PATTERN ASSOCIATED WITH A DEVELOPMENTAL FACTOR OF RISK FOR PSYCHOSIS, IN ALL CASES THE PREDICTED EXPRESSION IMPACT BEING HIGHLY DEPENDENT ON LOCATION. METHYLATION INDUCED BY SMOKING, A CONFOUNDING VARIABLE, EXHIBITS AN INTRIGUING PATTERN FOR ALL THREE GENES. FINALLY, HOW DIFFERENTIAL METHYLATION MESHES WITH DARWINIAN PRINCIPLES IS EXAMINED, IN PARTICULAR AS IT RELATES TO THE "FLEXIBLE STEM" THEORY OF EVOLUTION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
5 4736  39 NOVEL EPIGENETIC BIOMARKERS MEDIATING BISPHENOL A EXPOSURE AND METABOLIC PHENOTYPES IN FEMALE MICE. THERE IS COMPELLING EVIDENCE THAT EPIGENETIC MODIFICATIONS LINK DEVELOPMENTAL ENVIRONMENTAL INSULTS TO ADULT DISEASE SUSCEPTIBILITY. ANIMAL STUDIES HAVE ASSOCIATED PERINATAL BISPHENOL A (BPA) EXPOSURE TO ALTERED DNA METHYLATION, BUT THESE STUDIES ARE OFTEN LIMITED TO CANDIDATE GENE AND GLOBAL NON-LOCI-SPECIFIC APPROACHES. BY USING AN EPIGENOME-WIDE DISCOVERY PLATFORM, WE ELUCIDATED EPIGENETIC ALTERATIONS IN LIVER TISSUE FROM ADULT MICE OFFSPRING (10 MONTHS) FOLLOWING PERINATAL BPA EXPOSURE AT HUMAN PHYSIOLOGICALLY RELEVANT DOSES (50-NG, 50-MUG, AND 50-MG BPA/KG DIET). BIOLOGICAL PATHWAY ANALYSIS IDENTIFIED AN ENRICHMENT OF SIGNIFICANT DIFFERENTIALLY METHYLATED REGIONS IN METABOLIC PATHWAYS AMONG FEMALES. FURTHERMORE, THROUGH THE USE OF TOP ENRICHED BIOLOGICAL PATHWAYS, 4 CANDIDATE GENES WERE CHOSEN TO ASSESS DNA METHYLATION AS A MEDIATING FACTOR LINKING THE ASSOCIATION OF PERINATAL BPA EXPOSURE TO METABOLIC PHENOTYPES PREVIOUSLY OBSERVED IN FEMALE OFFSPRING. DNA METHYLATION STATUS AT JANUS KINASE-2 (JAK-2), RETINOID X RECEPTOR (RXR), REGULATORY FACTOR X-ASSOCIATED PROTEIN (RFXAP), AND TRANSMEMBRANE PROTEIN 238 (TMEM238) WAS USED WITHIN A MEDIATIONAL REGRESSION ANALYSIS. DNA METHYLATION IN ALL FOUR OF THE CANDIDATE GENES WAS IDENTIFIED AS A MEDIATOR IN THE MECHANISTIC PATHWAY OF DEVELOPMENTAL BPA EXPOSURE AND FEMALE-SPECIFIC ENERGY EXPENDITURE, BODY WEIGHT, AND BODY FAT PHENOTYPES. DATA GENERATED FROM THIS STUDY ARE CRUCIAL FOR DECIPHERING THE MECHANISTIC ROLE OF EPIGENETICS IN THE PATHOGENESIS OF CHRONIC DISEASE AND THE DEVELOPMENT OF EPIGENETIC-BASED PREVENTION AND THERAPEUTIC STRATEGIES FOR COMPLEX HUMAN DISEASE.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
6 3418  31 HUMAN HEALTH CONSEQUENCES OF ENVIRONMENTALLY-MODULATED GENE EXPRESSION: POTENTIAL ROLES OF ELF-EMF INDUCED EPIGENETIC VERSUS MUTAGENIC MECHANISMS OF DISEASE. IN ORDER TO DETERMINE IF THERE MIGHT BE BIOLOGICAL AND HEALTH CONSEQUENCES AFTER EXPOSURES TO EXTREMELY-LOW FREQUENCY ELECTROMAGNETIC FIELDS (ELF-EMF), EITHER EXPERIMENTALLY OR EPIDEMIOLOGICALLY, MECHANISTIC UNDERSTANDING OF THE POTENTIAL MEANS BY WHICH ANY ENVIRONMENTAL AGENT CAN AFFECT CELLS IN A MULTICELLULAR ORGANISM HAS TO BE REVIEWED. THE GOAL OF THIS LIMITED REVIEW IS TO DEMONSTRATE THAT, WHILE THE PREVAILING PARADIGM OF THE ENVIRONMENTALLY-INDUCED ACUTE AND CHRONIC DISEASES INVOLVES EITHER CELL KILLING (CYTOTOXICITY) OR GENE/CHROMOSOME MUTATIONS (GENOTOXICITY), ALTERATION OF THE EXPRESSION OF GENETIC INFORMATION AT THE TRANSCRIPTIONAL (TURNING GENES "ON" OR "OFF"), TRANSLATIONAL (STABILIZING OR DE-STABILIZING THE GENETIC MESSAGE), OR POSTTRANSLATIONAL (ALTERING THE GENE PRODUCT OR PROTEIN) LEVELS HAS THE POTENTIAL TO CONTRIBUTE TO VARIOUS DISEASES. THIS LATTER MECHANISM, "EPIGENETIC" TOXICITY, UNLIKE THE FORMER TWO WHICH ARE IRREVERSIBLE, IS CHARACTERIZED BY THRESHOLD-LIKE ACTION, MULTIPLE BIOCHEMICAL PATHWAYS AND CHRONIC, REGULAR EXPOSURES TO BE EFFECTIVE. ULTIMATELY, EPIGENETIC TOXICANTS AFFECT ONE OF FOUR POTENTIAL CELL STATES, NAMELY ALTERATION OF CELL PROLIFERATION, CELL DIFFERENTIATION, PROGRAMMED CELL DEATH (APOPTOSIS) OR ADAPTIVE RESPONSES OF DIFFERENTIATED CELLS.	2000	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
7 5464  26 RESILIENCE IN LONG-TERM VIRAL INFECTION: GENETIC DETERMINANTS AND INTERACTIONS. VIRUS-INDUCED NEUROLOGICAL SEQUELAE RESULTING FROM INFECTION BY THEILER'S MURINE ENCEPHALOMYELITIS VIRUS (TMEV) ARE USED FOR STUDYING HUMAN CONDITIONS RANGING FROM EPILEPTIC SEIZURES TO DEMYELINATING DISEASE. MOUSE STRAINS ARE TYPICALLY CONSIDERED SUSCEPTIBLE OR RESISTANT TO TMEV INFECTION BASED ON VIRAL PERSISTENCE AND EXTREME PHENOTYPES, SUCH AS DEMYELINATION. WE HAVE IDENTIFIED A BROADER SPECTRUM OF PHENOTYPIC OUTCOMES BY INFECTING STRAINS OF THE GENETICALLY DIVERSE COLLABORATIVE CROSS (CC) MOUSE RESOURCE. WE EVALUATED THE CHRONIC-INFECTION GENE EXPRESSION PROFILES OF HIPPOCAMPI AND THORACIC SPINAL CORDS FOR 19 CC STRAINS IN RELATION TO PHENOTYPIC SEVERITY AND TMEV PERSISTENCE. STRAINS WERE CLUSTERED BASED ON SIMILAR PHENOTYPIC PROFILES AND TMEV LEVELS AT 90 DAYS POST-INFECTION, AND WE CATEGORIZED DISTINCT TMEV RESPONSE PROFILES. THE THREE MOST COMMON PROFILES INCLUDED "RESISTANT" AND "SUSCEPTIBLE," AS BEFORE, AS WELL AS A "RESILIENT" TMEV RESPONSE GROUP WHICH EXPERIENCED BOTH TMEV PERSISTENCE AND MILD NEUROLOGICAL PHENOTYPES EVEN AT 90 DAYS POST-INFECTION. EACH PROFILE HAD A DISTINCT GENE EXPRESSION SIGNATURE, ALLOWING THE IDENTIFICATION OF PATHWAYS AND NETWORKS SPECIFIC TO EACH TMEV RESPONSE GROUP. CC FOUNDER HAPLOTYPES FOR GENES INVOLVED IN THESE PATHWAYS/NETWORKS REVEALED CANDIDATE RESPONSE-SPECIFIC ALLELES. THESE ALLELES DEMONSTRATED PLEIOTROPY AND EPIGENETIC (MIRNA) REGULATION IN LONG-TERM TMEV INFECTION, WITH PARTICULAR RELEVANCE FOR RESILIENT MOUSE STRAINS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
8 6642  36 UNRAVELING THE PATHOGENESIS OF ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE OVERLAP: FOCUSING ON EPIGENETIC MECHANISMS. ASTHMA AND COPD OVERLAP (ACO) IS CHARACTERIZED BY PATIENTS PRESENTING WITH PERSISTENT AIRFLOW LIMITATION AND FEATURES OF BOTH ASTHMA AND COPD. IT IS ASSOCIATED WITH A HIGHER FREQUENCY AND SEVERITY OF EXACERBATIONS, A FASTER LUNG FUNCTION DECLINE, AND A HIGHER HEALTHCARE COST. SYSTEMIC INFLAMMATION IN COPD AND ASTHMA IS DRIVEN BY TYPE 1 T HELPER (TH1) AND TH2 IMMUNE RESPONSES, RESPECTIVELY, BOTH OF WHICH MAY CONTRIBUTE TO AIRWAY REMODELING IN ACO. ACO-RELATED BIOMARKERS CAN BE CLASSIFIED INTO FOUR CATEGORIES: NEUTROPHIL-MEDIATED INFLAMMATION, TH2 CELL RESPONSES, ARACHIDONIC ACID-EICOSANOIDS PATHWAY, AND METABOLITES. GENE-ENVIRONMENT INTERACTIONS ARE KEY CONTRIBUTORS TO THE COMPLEXITY OF ACO AND ARE REGULATED BY EPIGENETIC MECHANISMS, INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS, AND NON-CODING RNAS. THUS, THIS REVIEW FOCUSES ON THE LINK BETWEEN EPIGENETICS AND ACO, AND OUTLINES THE FOLLOWING: (I) INHERITING EPIGENOTYPES WITHOUT CHANGE WITH ENVIRONMENTAL STIMULI, OR EPIGENETIC CHANGES IN RESPONSE TO LONG-TERM EXPOSURE TO INHALED PARTICLES PLUS INTERMITTENT EXPOSURE TO SPECIFIC ALLERGENS; (II) EPIGENETIC MARKERS DISTINGUISHING ACO FROM COPD AND ASTHMA; (III) POTENTIAL EPIGENETIC DRUGS THAT CAN REVERSE OXIDATIVE STRESS, GLUCOCORTICOID INSENSITIVITY, AND CELL INJURY. IMPROVED UNDERSTANDING OF THE EPIGENETIC REGULATIONS HOLDS GREAT VALUE TO GIVE DEEPER INSIGHT INTO THE MECHANISMS, AND CLARIFY THEIR IMPLICATIONS FOR BIOMEDICAL RESEARCH IN ACO.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
9 4399  37 MODULATION OF GENOMIC AND POSTGENOMIC ALTERATIONS IN NONCANCER DISEASES AND CRITICAL PERIODS OF LIFE. GENOMIC AND POSTGENOMIC CHANGES ARE EXTENSIVELY INVESTIGATED IN CANCER RESEARCH. SIMILAR ALTERATIONS, AFFECTING GENOME, TRANSCRIPTOME, MIRNOME AND/OR PROTEOME END-POINTS, HAVE BEEN DETECTED IN A VARIETY OF OTHER CHRONIC DEGENERATIVE DISEASES, SUCH AS ATHEROSCLEROSIS, DEGENERATIVE HEART DISEASES, CHRONIC OBSTRUCTIVE PULMONARY DISEASES, NEUROLOGICAL DISORDERS, EYE DISEASES, DIABETES, METABOLIC SYNDROME, SKIN AGEING AND ALOPECIA. NO GENERALIZATION CAN BE MADE DUE TO THE MYRIAD OF DIVERSE CLINICAL ENTITIES CLASSIFIED AS CHRONIC DEGENERATIVE DISEASES. MOREOVER, THE DETECTION OF MOLECULAR CHANGES DOES NOT AUTOMATICALLY IMPLY THEIR CAUSAL ROLE. NEVERTHELESS, COMMON MECHANISMS, SUCH AS DNA DAMAGE, EPIGENETIC ALTERATIONS, OXIDATIVE STRESS, AND CHRONIC INFLAMMATION, IN ADDITION TO GENETIC PREDISPOSITION, ARE OFTEN INVOLVED IN NONCANCER DISEASES. WE DEBATE HERE IN MORE DETAIL THE SUBJECTS OF CARDIOVASCULAR DISEASES AND OF SKIN DISEASES. MOREOVER, WE DISCUSS OUR EXPERIMENTAL STUDIES SUGGESTING THAT GENOMIC AND POSTGENOMIC CHANGES DO ALSO OCCUR DURING CRITICAL PERIODS OF LIFE, INCLUDING THE PRENATAL LIFE, THE PERINATAL PERIOD, AND AGEING. IN ADDITION, WE COMMENT ON THE FINDING THAT STEM-DERIVED CELLS ARE MORE SUSCEPTIBLE TO MOLECULAR DAMAGE THAN MORE DIFFERENTIATED CELLS. ALL THESE DATA ARE VIEWED IN THE PERSPECTIVE OF PREVENTIVE MEDICINE. IN FACT, THERE IS EVIDENCE THAT THE GENOMIC AND POSTGENOMIC ALTERATIONS OCCURRING NOT ONLY IN SEVERAL PATHOLOGICAL CONDITIONS BUT ALSO IN PARAPHYSIOLOGICAL SITUATIONS THAT AFFECT CRITICAL PERIODS OF LIFE CAN BE MODULATED BY MEANS OF DIETARY AND PHARMACOLOGICAL AGENTS. THE DISCOVERY THAT CHEMOPREVENTIVE AGENTS ARE ALSO ABLE TO ATTENUATE NUCLEOTIDE DAMAGE IN STEM-DERIVED CELLS WARRANTS FURTHER STUDIES IN VIEW OF POSSIBLE CLINICAL APPLICATIONS.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                  
10 6334  21 THE ROLE OF DNA METHYLATION AND HYDROXYMETHYLATION IN IMMUNOSENESCENCE. A HEALTHY FUNCTIONING IMMUNE SYSTEM IS CRITICAL TO STAVE OFF INFECTIOUS DISEASES, BUT AS HUMANS AND OTHER ORGANISMS AGE, THEIR IMMUNE SYSTEMS DECLINE. AS A RESULT, DISEASES THAT WERE READILY THWARTED IN EARLY LIFE POSE NONTRIVIAL HARM AND CAN EVEN BE DEADLY IN LATE LIFE. IMMUNOSENESCENCE IS DEFINED AS THE GENERAL DETERIORATION OF THE IMMUNE SYSTEM WITH AGE, AND IT IS CHARACTERIZED BY FUNCTIONAL CHANGES IN HEMATOPOIETIC STEM CELLS (HSCS) AND SPECIFIC BLOOD CELL TYPES AS WELL AS CHANGES IN LEVELS OF NUMEROUS FACTORS, PARTICULARLY THOSE INVOLVED IN INFLAMMATION. POTENTIAL MECHANISMS UNDERLYING IMMUNOSENESCENCE INCLUDE EPIGENETIC CHANGES SUCH AS CHANGES IN DNA METHYLATION (DNAM) AND DNA HYDROXYMETHYLATION (DNAHM) THAT OCCUR WITH AGE. THE PURPOSE OF THIS REVIEW IS TO DESCRIBE WHAT IS CURRENTLY KNOWN ABOUT THE RELATIONSHIP BETWEEN IMMUNOSENESCENCE AND THE AGE-RELATED CHANGES TO DNAM AND DNAHM, AND TO DISCUSS EXPERIMENTAL APPROACHES BEST SUITED TO FILL GAPS IN OUR UNDERSTANDING.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
11 3777  22 INTERACTOME OF OBESITY: OBESIDOME : GENETIC OBESITY, STRESS INDUCED OBESITY, PATHOGENIC OBESITY INTERACTION. OBESITY IS A CHRONIC DISEASE OF INCREASING PREVALENCE REACHING EPIDEMIC PROPORTIONS. GENETIC DEFECTS AS WELL AS EPIGENETIC EFFECTS CONTRIBUTE TO THE OBESITY PHENOTYPE. INVESTIGATING GENE (E.G. MC4R DEFECTS)-ENVIRONMENT (BEHAVIOR, INFECTIOUS AGENTS, STRESS) INTERACTIONS IS A RELATIVE NEW FIELD OF GREAT RESEARCH INTEREST. IN THIS STUDY, WE HAVE MADE AN EFFORT TO CREATE AN INTERACTOME (HENCEFORTH REFERRED TO AS "OBESIDOME"), WHERE EXTRINSIC STRESSORS RESPONSE, INTRINSIC PREDISPOSITION, IMMUNITY RESPONSE TO INFLAMMATION AND AUTONOMOUS NERVOUS SYSTEM IMPLICATIONS ARE INTEGRATED. THESE PATHWAYS ARE PRESENTED IN ONE INTERACTOME NETWORK FOR THE FIRST TIME. IN OUR STUDY, OBESITY-RELATED GENES/GENE PRODUCTS WERE FOUND TO FORM A COMPLEX INTERACTIONS NETWORK.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
12 4019  32 LOW-DOSE OR LOW-DOSE-RATE IONIZING RADIATION-INDUCED BIOEFFECTS IN ANIMAL MODELS. ANIMAL EXPERIMENTAL STUDIES INDICATE THAT ACUTE OR CHRONIC LOW-DOSE IONIZING RADIATION (LDIR) (</=100 MSV) OR LOW-DOSE-RATE IONIZING RADIATION (LDRIR) (<6 MSV/H) EXPOSURES MAY BE HARMFUL. IT INDUCES GENETIC AND EPIGENETIC CHANGES AND IS ASSOCIATED WITH A RANGE OF PHYSIOLOGICAL DISTURBANCES THAT INCLUDES ALTERED IMMUNE SYSTEM, ABNORMAL BRAIN DEVELOPMENT WITH RESULTANT COGNITIVE IMPAIRMENT, CATARACTOGENESIS, ABNORMAL EMBRYONIC DEVELOPMENT, CIRCULATORY DISEASES, WEIGHT GAIN, PREMATURE MENOPAUSE IN FEMALE ANIMALS, TUMORIGENESIS AND SHORTENED LIFESPAN. PATERNAL OR PRENATAL LDIR/LDRIR EXPOSURE IS ASSOCIATED WITH REDUCED FERTILITY AND NUMBER OF LIVE FETUSES, AND TRANSGENERATIONAL GENOMIC ABERRATIONS. ON THE OTHER HAND, IN SOME EXPERIMENTAL STUDIES, LDIR/LDRIR EXPOSURE HAS ALSO BEEN REPORTED TO BRING ABOUT BENEFICIAL EFFECTS SUCH AS REDUCTION IN TUMORIGENESIS, PROLONGED LIFESPAN AND ENHANCED FERTILITY. THE DIFFERENCES IN REPORTED EFFECTS OF LDIR/LDRIR EXPOSURE ARE DEPENDENT ON ANIMAL GENETIC BACKGROUND (SUSCEPTIBILITY), AGE (PRENATAL OR POSTNATAL DAYS), SEX, NATURE OF RADIATION EXPOSURE (I.E. ACUTE, FRACTIONATED OR CHRONIC RADIATION EXPOSURE), TYPE OF RADIATION, COMBINATION OF RADIATION WITH OTHER TOXIC AGENTS (SUCH AS SMOKING, PESTICIDES OR OTHER CHEMICAL TOXINS) OR ANIMAL EXPERIMENTAL DESIGNS. IN THIS REVIEW PAPER, WE AIMED TO UPDATE RADIATION RESEARCHERS AND RADIOLOGISTS ON THE CURRENT PROGRESS ACHIEVED IN UNDERSTANDING THE LDIR/LDRIR-INDUCED BIONEGATIVE AND BIOPOSITIVE EFFECTS REPORTED IN THE VARIOUS ANIMAL MODELS. THE ROLES PLAYED BY A VARIETY OF MOLECULES THAT ARE IMPLICATED IN LDIR/LDRIR-INDUCED HEALTH EFFECTS WILL BE ELABORATED. THE REVIEW WILL HELP IN FUTURE INVESTIGATIONS OF LDIR/LDRIR-INDUCED HEALTH EFFECTS BY PROVIDING CLUES FOR DESIGNING IMPROVED ANIMAL RESEARCH MODELS IN ORDER TO CLARIFY THE CURRENT CONTROVERSIAL/CONTRADICTORY FINDINGS FROM EXISTING STUDIES.	2017	
                                                                                                                                                                                                                                                                                                                               
13 4209  36 METALLOTHIONEIN 2A GENE POLYMORPHISMS IN RELATION TO DISEASES AND TRACE ELEMENT LEVELS IN HUMANS. HUMAN METALLOTHIONEINS ARE A SUPERFAMILY OF LOW MOLECULAR WEIGHT INTRACELLULAR PROTEINS, WHOSE SYNTHESIS CAN BE INDUCED BY ESSENTIAL ELEMENTS (PRIMARILY ZN AND CU), TOXIC ELEMENTS AND CHEMICAL AGENTS, AND STRESS-PRODUCING CONDITIONS. OF THE FOUR KNOWN ISOFORMS IN THE HUMAN BODY MT2 IS THE MOST COMMON. THE EXPRESSION OF METALLOTHIONEINS IS ENCODED BY A MULTIGENE FAMILY OF LINKED GENES AND CAN BE INFLUENCED BY SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) IN THESE GENES. TO DATE, 24 SNPS IN THE MT2A GENE HAVE BEEN IDENTIFIED WITH THE INCIDENCE OF ABOUT 1 % IN VARIOUS POPULATION GROUPS, AND THREE OF THEM WERE SHOWN TO AFFECT PHYSIOLOGICAL AND PATHOPHYSIOLOGICAL PROCESSES. THIS REVIEW SUMMARISES CURRENT KNOWLEDGE ABOUT THESE THREE SNPS IN THE MT2A GENE AND THEIR ASSOCIATIONS WITH ELEMENT CONCENTRATIONS IN THE BODY OF HEALTHY AND DISEASED PERSONS. THE MOST INVESTIGATED SNP IS RS28366003 (MT2A -5 A/G). REPORTS ASSOCIATE IT WITH LONGEVITY, CANCER (BREAST, PROSTATE, LARYNGEAL, AND IN PARANASAL SINUSES), AND CHRONIC RENAL DISEASE. THE SECOND MOST INVESTIGATED SNP, RS10636 (MT2A +838G/C), IS ASSOCIATED WITH BREAST CANCER, CARDIOVASCULAR DISEASE, AND TYPE 2 DIABETES. BOTH ARE ALSO ASSOCIATED WITH SEVERAL METAL/METALLOID CONCENTRATIONS IN THE ORGANISM. THE THIRD SNP, RS1610216 (MT2A -209A/G), HAS BEEN STUDIED FOR ASSOCIATION WITH TYPE 2 DIABETES, CARDIOMYOPATHY, HYPERGLYCAEMIA, AND ZN CONCENTRATIONS. METALLOTHIONEIN CONCENTRATIONS AND MT2A POLYMORPHISMS HAVE A POTENTIAL TO BE USED AS BIOMARKERS OF METAL EXPOSURE AND CLINICAL MARKERS OF A NUMBER OF CHRONIC DISEASES. THIS POTENTIAL NEEDS TO BE STUDIED AND VERIFIED IN A LARGE NUMBER OF WELL-DEFINED GROUPS OF PARTICIPANTS (SEVERAL HUNDREDS AND THOUSANDS) WITH A FOCUS ON PARTICULAR PHYSIOLOGICAL OR PATHOLOGICAL CONDITION AND TAKING INTO CONSIDERATION OTHER CONTRIBUTING FACTORS, SUCH AS ENVIRONMENTAL EXPOSURE AND INDIVIDUAL GENETIC AND EPIGENETIC MAKEUP.	2020	
                                                                                                                                                                                                                                                                                               
14 3899  28 LATE NEUROLOGICAL CONSEQUENCES OF ZIKA VIRUS INFECTION: RISK FACTORS AND PHARMACEUTICAL APPROACHES. ZIKA VIRUS (ZIKV) INFECTION WAS HISTORICALLY CONSIDERED A DISEASE WITH MILD SYMPTOMS AND NO MAJOR CONSEQUENCES TO HUMAN HEALTH. HOWEVER, SEVERAL LONG-TERM, LATE ONSET, AND CHRONIC NEUROLOGICAL COMPLICATIONS, BOTH IN CONGENITALLY-EXPOSED BABIES AND IN ADULT PATIENTS, HAVE BEEN REPORTED AFTER ZIKV INFECTION, ESPECIALLY AFTER THE 2015 EPIDEMICS IN THE AMERICAN CONTINENT. THE DEVELOPMENT OR SEVERITY OF THESE CONDITIONS CANNOT BE FULLY PREDICTED, BUT IT IS POSSIBLE THAT GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS MAY CONTRIBUTE TO DETERMINE ZIKV INFECTION OUTCOMES. THIS REINFORCES THE IMPORTANCE THAT INDIVIDUALS EXPOSED TO ZIKV ARE SUBMITTED TO LONG-TERM CLINICAL SURVEILLANCE AND HIGHLIGHTS THE URGENT NEED FOR THE DEVELOPMENT OF THERAPEUTIC APPROACHES TO REDUCE OR ELIMINATE THE NEUROLOGICAL BURDEN OF INFECTION. HERE, WE REVIEW THE EPIDEMIOLOGY OF ZIKV-ASSOCIATED NEUROLOGICAL COMPLICATIONS AND THE ROLE OF FACTORS THAT MAY INFLUENCE DISEASE OUTCOME. MOREOVER, WE DISCUSS EXPERIMENTAL AND CLINICAL EVIDENCE OF DRUGS THAT HAVE SHOWN PROMISING RESULTS IN VITRO OR IN VITRO AGAINST VIRAL REPLICATION AND AND/OR ZIKV-INDUCED NEUROTOXICITY.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
15 5890  39 SYSTEMS BIOLOGY ELUCIDATES COMMON PATHOGENIC MECHANISMS BETWEEN NONALCOHOLIC AND ALCOHOLIC-FATTY LIVER DISEASE. THE ABNORMAL ACCUMULATION OF FAT IN THE LIVER IS OFTEN RELATED EITHER TO METABOLIC RISK FACTORS ASSOCIATED WITH METABOLIC SYNDROME IN THE ABSENCE OF ALCOHOL CONSUMPTION (NONALCOHOLIC FATTY LIVER DISEASE, NAFLD) OR TO CHRONIC ALCOHOL CONSUMPTION (ALCOHOLIC FATTY LIVER DISEASE, AFLD). CLINICAL AND HISTOLOGICAL STUDIES SUGGEST THAT NAFLD AND AFLD SHARE PATHOGENIC MECHANISMS. NEVERTHELESS, CURRENT DATA ARE STILL INCONCLUSIVE AS TO WHETHER THE UNDERLYING BIOLOGICAL PROCESS AND DISEASE PATHWAYS OF NAFLD AND AFLD ARE ALIKE. OUR PRIMARY AIM WAS TO INTEGRATE OMICS AND PHYSIOLOGICAL DATA TO ANSWER THE QUESTION OF WHETHER NAFLD AND AFLD SHARE MOLECULAR PROCESSES THAT LEAD TO DISEASE DEVELOPMENT. WE ALSO EXPLORED THE EXTENT TO WHICH INSULIN RESISTANCE (IR) IS A DISTINCTIVE FEATURE OF NAFLD. TO ANSWER THESE QUESTIONS, WE USED SYSTEMS BIOLOGY APPROACHES, SUCH AS GENE ENRICHMENT ANALYSIS, PROTEIN-PROTEIN INTERACTION NETWORKS, AND GENE PRIORITIZATION, BASED ON MULTI-LEVEL DATA EXTRACTED BY COMPUTATIONAL DATA MINING. WE OBSERVED THAT THE LEADING DISEASE PATHWAYS ASSOCIATED WITH NAFLD DID NOT SIGNIFICANTLY DIFFER FROM THOSE OF AFLD. HOWEVER, SYSTEMS BIOLOGY REVEALED THE IMPORTANCE OF EACH MOLECULAR PROCESS BEHIND EACH OF THE TWO DISEASES, AND DISSECTED DISTINCTIVE MOLECULAR NAFLD AND AFLD-SIGNATURES. COMPARATIVE CO-ANALYSIS OF NAFLD AND AFLD CLARIFIED THE PARTICIPATION OF NAFLD, BUT NOT AFLD, IN CARDIOVASCULAR DISEASE, AND SHOWED THAT INSULIN SIGNALING IS IMPAIRED IN FATTY LIVER REGARDLESS OF THE NOXA, BUT THE PUTATIVE REGULATORY MECHANISMS ASSOCIATED WITH NAFLD SEEM TO ENCOMPASS A COMPLEX NETWORK OF GENES AND PROTEINS, PLAUSIBLE OF EPIGENETIC MODIFICATIONS. GENE PRIORITIZATION SHOWED A CANCER-RELATED FUNCTIONAL MAP THAT SUGGESTS THAT THE FATTY TRANSFORMATION OF THE LIVER TISSUE IS REGARDLESS OF THE CAUSE, AN EMERGING MECHANISM OF UBIQUITOUS ONCOGENIC ACTIVATION. IN CONCLUSION, SIMILAR UNDERLYING DISEASE MECHANISMS LEAD TO NAFLD AND AFLD, BUT SPECIFIC ONES DEPICT A PARTICULAR DISEASE SIGNATURE THAT HAS A DIFFERENT IMPACT ON THE SYSTEMIC CONTEXT.	2013	
                                                                                                                          
16 2616  28 EPIGENOME MODULATION INDUCED BY KETOGENIC DIETS. KETOGENIC DIETS (KD) ARE DIETARY STRATEGIES LOW IN CARBOHYDRATES, NORMAL IN PROTEIN, AND HIGH, NORMAL, OR REDUCED IN FAT WITH OR WITHOUT (VERY LOW-CALORIES KETOGENIC DIET, VLCKD) A REDUCED CALORIC INTAKE. KDS HAVE BEEN SHOWN TO BE USEFUL IN THE TREATMENT OF OBESITY, METABOLIC DISEASES AND RELATED DISORDERS, NEUROLOGICAL DISEASES, AND VARIOUS PATHOLOGICAL CONDITIONS SUCH AS CANCER, NONALCOHOLIC LIVER DISEASE, AND CHRONIC PAIN. SEVERAL STUDIES HAVE INVESTIGATED THE INTRACELLULAR METABOLIC PATHWAYS THAT CONTRIBUTE TO THE BENEFICIAL EFFECTS OF THESE DIETS. ALTHOUGH EPIGENETIC CHANGES ARE AMONG THE MOST IMPORTANT DETERMINANTS OF AN ORGANISM'S ABILITY TO ADAPT TO ENVIRONMENTAL CHANGES, DATA ON THE EPIGENETIC CHANGES ASSOCIATED WITH THESE DIETARY PATHWAYS ARE STILL LIMITED. THIS REVIEW PROVIDES AN OVERVIEW OF THE MAJOR EPIGENETIC CHANGES ASSOCIATED WITH KDS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
17 2597  39 EPIGENETICS OF SUBCELLULAR STRUCTURE FUNCTIONING IN THE ORIGIN OF RISK OR RESILIENCE TO COMORBIDITY OF NEUROPSYCHIATRIC AND CARDIOMETABOLIC DISORDERS. MECHANISMS CONTROLLING MITOCHONDRIAL FUNCTION, PROTEIN FOLDING IN THE ENDOPLASMIC RETICULUM (ER) AND NUCLEAR PROCESSES SUCH AS TELOMERE LENGTH AND DNA REPAIR MAY BE SUBJECT TO EPIGENETIC CUES THAT RELATE THE GENOMIC EXPRESSION AND ENVIRONMENTAL EXPOSURES IN EARLY STAGES OF LIFE. THEY MAY ALSO BE INVOLVED IN THE COMORBID APPEARANCE OF CARDIOMETABOLIC (CMD) AND NEUROPSYCHIATRIC DISORDERS (NPD) DURING ADULTHOOD. MITOCHONDRIAL FUNCTION AND PROTEIN FOLDING IN THE ENDOPLASMIC RETICULUM ARE ASSOCIATED WITH OXIDATIVE STRESS AND ELEVATED INTRACELLULAR CALCIUM LEVELS AND MAY ALSO UNDERLIE THE VULNERABILITY FOR COMORBID CMD AND NPD. MITOCHONDRIA PROVIDE KEY METABOLITES SUCH AS NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD+), ATP, ALPHA-KETOGLUTARATE AND ACETYL COENZYME A THAT ARE REQUIRED FOR MANY TRANSCRIPTIONAL AND EPIGENETIC PROCESSES. THEY ARE ALSO A SOURCE OF FREE RADICALS. ON THE OTHER HAND, EPIGENETIC MARKERS IN NUCLEAR DNA DETERMINE MITOCHONDRIAL BIOGENESIS. THE ER IS THE SUBCELLULAR ORGANELLE IN WHICH SECRETORY PROTEINS ARE FOLDED. MANY ENVIRONMENTAL FACTORS STOP THE ABILITY OF CELLS TO PROPERLY FOLD PROTEINS AND MODIFY POST-TRANSLATIONALLY SECRETORY AND TRANSMEMBRANE PROTEINS LEADING TO ENDOPLASMIC RETICULUM STRESS AND OXIDATIVE STRESS. ER FUNCTIONING MAY BE EPIGENETICALLY DETERMINED. CHRONIC ER STRESS IS EMERGING AS A KEY CONTRIBUTOR TO A GROWING LIST OF HUMAN DISEASES, INCLUDING CMD AND NPD. TELOMERE LOSS CAUSES CHROMOSOMAL FUSION, ACTIVATION OF THE CONTROL OF DNA DAMAGE-RESPONSES, UNSTABLE GENOME AND ALTERED STEM CELL FUNCTION, WHICH MAY UNDERLIE THE COMORBIDITY OF CMD AND NPD. THE LENGTH OF TELOMERES IS RELATED TO OXIDATIVE STRESS AND MAY BE EPIGENETICALLY PROGRAMMED. PATHWAYS INVOLVED IN DNA REPAIR MAY BE EPIGENETICALLY PROGRAMMED AND MAY CONTRIBUTE TO DISEASES. IN THIS PAPER, WE DESCRIBE SUBCELLULAR MECHANISMS THAT ARE DETERMINED BY EPIGENETIC MARKERS AND THEIR POSSIBLE RELATION TO THE DEVELOPMENT OF INCREASED SUSCEPTIBILITY TO DEVELOP CMD AND NPD.	2018	
                                                                                                                                                                      
18 6141  43 THE ETIOLOGY OF PEYRONIE'S DISEASE: PATHOGENESIS AND GENETIC CONTRIBUTIONS. INTRODUCTION: PEYRONIE'S DISEASE (PD) IS A CHRONIC FIBROSING CONDITION THAT CONTRIBUTES TO PENILE DEFORMITY, CURVATURE, AND PAIN. INITIAL FAMILIAL STUDIES DEMONSTRATED POTENTIAL GENETIC LINKS TO PD. SINCE THAT TIME, VERY FEW INVESTIGATIONS HAVE SIGNIFICANTLY ADVANCED THE SCIENCE IN THIS AREA. HENCE, THERE IS A LARGE OPPORTUNITY AND SIGNIFICANT NEED TO BETTER STUDY THE UNDERLYING GENOMICS AND PATHOGENESIS OF PD. AIM: TO SUMMARIZE THE CURRENT GENOMIC LITERATURE RELEVANT TO PD. METHODS: A REVIEW WAS PERFORMED OF ALL PUBMED-INDEXED LITERATURE FROM 1970-2018 RELATING TO THE PATHOPHYSIOLOGY AND GENETICS OF PD. KEY FINDINGS WERE CATEGORICALLY SUMMARIZED TO INCLUDE EPIDEMIOLOGY, RISK FACTORS, INHERITANCE PATTERNS, CHROMOSOMAL INSTABILITY, GENETIC ASSOCIATIONS, EPIGENETICS, DIFFERENTIAL GENE EXPRESSION, AND PRECLINICAL MODELS OF PD. MAIN OUTCOME MEASURES: SUMMARY OF THE CURRENT LITERATURE ON THE GENETICS OF PD. RESULTS: PD IS A COMMON CONDITION AND HAS SEVERAL KNOWN RISK FACTORS AND COMORBID DISEASE ASSOCIATIONS. ALTHOUGH MEN WITH PD ARE BELIEVED TO BE GENETICALLY PREDISPOSED, THERE ARE LIKELY SEVERAL SUBTYPES OF THE CONDITION, EACH WITH VARIED PATHOPHYSIOLOGICAL DISORDERS AND CONTRIBUTING FACTORS. AVAILABLE DATA SUGGEST THAT PD IS ASSOCIATED WITH UNDERLYING GENETIC INSTABILITY, INCLUDING DYSREGULATION OF GENES RELATING TO FIBROSIS AND CELLULAR DEGRADATION, THUS, RESULTING IN ABNORMAL PLAQUE DEVELOPMENT AND PENILE DEFORMITY. PRECLINICAL MODELS, INCLUDING CELL CULTURES AND RAT MODELS, DEMONSTRATE SEVERAL CONSISTENCIES WITH PD CLINICAL AND HISTOPATHOLOGIC CHARACTERISTICS; HOWEVER, AN IDEAL MODEL WITH SPONTANEOUS DEVELOPMENT OF PD IS LACKING. CONCLUSION: BASED ON LIMITED DATA, PD LIKELY REPRESENTS A HETEROGENEOUS CONDITION, WITH BOTH HERITABLE AND ENVIRONMENTALLY-DRIVEN EPIGENETIC FACTORS CONTRIBUTING TO ITS DEVELOPMENT AND PROGRESSION. HOWEVER, THERE REMAINS A SIGNIFICANT GAP IN THE LITERATURE ON THE UNDERLYING CAUSE AND PATHOPHYSIOLOGY OF THE CONDITION, SUGGESTING A SUBSTANTIAL NEED FOR FURTHER INVESTIGATION AND STUDY. SHARMA KL, ALOM M, TROST L. THE ETIOLOGY OF PEYRONIE'S DISEASE: PATHOGENESIS AND GENETIC CONTRIBUTIONS. SEX MED REV 2020;8:314-323.	2020	
                                             
19 2533  30 EPIGENETICS IN AUTOIMMUNE CONNECTIVE TISSUE DISEASES. BACKGROUND. AUTOIMMUNE CONNECTIVE TISSUE DISEASES (ACTDS) ENCOMPASS A HETEROGENEOUS GROUP OF CHRONIC IMMUNE-MEDIATED INFLAMMATORY DISORDERS, PRIMARILY AFFECTING CONNECTIVE TISSUES AND CLINICALLY CHARACTERIZED BY VARIABLE MULTISYSTEM MANIFESTATIONS, FREQUENTLY OVERLAPPING. ENVIRONMENTAL FACTORS ARE THOUGHT TO PROMOTE ACTD DEVELOPMENT IN GENETIC PREDISPOSING/ENDOCRINE PERMISSIVE BACKGROUND THROUGH THE INDUCTION OF EPIGENETIC MODIFICATIONS, CONSISTING OF STABLE, HERITABLE, BUT POTENTIALLY REVERSIBLE CHANGES IN GENE EXPRESSION, OCCURRING WITHOUT ALTERATIONS OF THE DNA SEQUENCE. ACTUALLY, EPIGENETIC MECHANISMS (SUCH AS HISTONE MODIFICATIONS, DNA METHYLATION, NUCLEOSOME POSITIONING, AND RNA INTERFERENCE) LINK GENOTYPE UPSTREAM AND PHENOTYPE DOWNSTREAM, AND, IF PERSISTENTLY ABERRANT, MAY CAUSE A VARIETY OF HUMAN DISEASES, INCLUDING ACTDS. WE AIMED TO REVIEW THE RECENT ADVANCES IN THE KNOWLEDGE OF THE ACTD EPIGENETIC ALTERATIONS. METHODS: A DETAILED SEARCH OF THE AVAILABLE LITERATURE WAS PERFORMED IN THE PUBMED (U.S. NATIONAL LIBRARY OF MEDICINE) DATABASE. RESULTS: GROWING EVIDENCE UNDERLINES THE RELEVANT ROLE OF EPIGENETIC DEFECTS IN THE ACTD PATHOGENESIS, AND SPECIFIC EPIGENETIC PATTERNS CAN REPRESENT DISEASE BIOMARKERS. IN PATIENTS WITH RHEUMATOID ARTHRITIS (RA), EPIGENETIC VARIATIONS INTERACT DETERMINING THE TYPICAL "AGGRESSIVE" PHENOTYPE DISPLAYED BY RA SYNOVIAL FIBROBLASTS. EPIGENETIC MODIFICATIONS ARE INVOLVED IN THE PROFIBROTIC PROCESS THAT CHARACTERIZES SYSTEMIC SCLEROSIS. IN SYSTEMIC LUPUS ERYTHEMATOSUS AND SJOGREN'S SYNDROME, COMPLEX EPIGENETIC CHANGES ALTERING GENE EXPRESSION HAVE BEEN DEMONSTRATED. CONCLUSIONS: COMPREHENSIVE STUDIES WILL CONTRIBUTE TO FURTHER DEFINE THE ABERRANT EPIGENETIC MECHANISMS INVOLVED IN THE ACTDS ETIOPATHOGENESIS. MOREOVER, BEING EPIGENETIC CHANGES POTENTIALLY REVERSIBLE, THE IDENTIFICATION OF ACTDS EPIGENETIC BIOMARKERS WILL ALLOW THE DEVELOPMENT OF THERAPEUTIC STRATEGIES ADDRESSED TO TARGET DYSREGULATED GENES AND CORRECT ABERRANT EPIGENOMIC ALTERATIONS.	2014	
                                                                                                                                                                                                                               
20 4875  43 OVEREXPRESSION OF AKT1 ENHANCES ADIPOGENESIS AND LEADS TO LIPOMA FORMATION IN ZEBRAFISH. BACKGROUND: OBESITY IS A COMPLEX, MULTIFACTORIAL DISORDER INFLUENCED BY THE INTERACTION OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. OBESITY INCREASES THE RISK OF CONTRACTING MANY CHRONIC DISEASES OR METABOLIC SYNDROME. RESEARCHERS HAVE ESTABLISHED SEVERAL MAMMALIAN MODELS OF OBESITY TO STUDY ITS UNDERLYING MECHANISM. HOWEVER, A LOWER VERTEBRATE MODEL FOR CONVENIENTLY PERFORMING DRUG SCREENING AGAINST OBESITY REMAINS ELUSIVE. THE SPECIFIC AIM OF THIS STUDY WAS TO CREATE A ZEBRAFISH OBESITY MODEL BY OVER EXPRESSING THE INSULIN SIGNALING HUB OF THE AKT1 GENE. METHODOLOGY/PRINCIPAL FINDINGS: SKIN ONCOGENIC TRANSFORMATION SCREENING SHOWS THAT A STABLE ZEBRAFISH TRANSGENIC OF TG(KRT4HSA.MYRAKT1)(CY18) DISPLAYS SEVERELY OBESE PHENOTYPES AT THE ADULT STAGE. IN TG(KRT4:HSA.MYRAKT1)(CY18), THE EXPRESSION OF EXOGENOUS HUMAN CONSTITUTIVELY ACTIVE AKT1 (MYRAKT1) CAN ACTIVATE ENDOGENOUS DOWNSTREAM TARGETS OF MTOR, GSK-3ALPHA/BETA, AND 70S6K. DURING THE EMBRYONIC TO LARVAL TRANSITORY PHASE, THE SPECIFIC OVER EXPRESSION OF MYRAKT1 IN SKIN CAN PROMOTE HYPERTROPHIC AND HYPERPLASTIC GROWTH. FROM 21 HOUR POST-FERTILIZATION (HPF) ONWARDS, MYRAKT1 TRANSGENE WAS ECTOPICALLY EXPRESSED IN SEVERAL MESENCHYMAL DERIVED TISSUES. THIS MAY BE THE RESULT OF THE INTEGRATION POSITION EFFECT. TG(KRT4:HSA.MYRAKT1)(CY18) CAUSED A RAPID INCREASE OF BODY WEIGHT, HYPERPLASTIC GROWTH OF ADIPOCYTES, ABNORMAL ACCUMULATION OF FAT TISSUES, AND BLOOD GLUCOSE INTOLERANCE AT THE ADULT STAGE. REAL-TIME RT-PCR ANALYSIS SHOWED THE MAJORITY OF KEY GENES ON REGULATING ADIPOGENESIS, ADIPOCYTOKINE, AND INFLAMMATION ARE HIGHLY UPREGULATED IN TG(KRT4:HSA.MYRAKT1)(CY18). IN CONTRAST, THE MYOGENESIS- AND SKELETOGENESIS-RELATED GENE TRANSCRIPTS ARE SIGNIFICANTLY DOWNREGULATED IN TG(KRT4:HSA.MYRAKT1)(CY18), SUGGESTING THAT EXCESS ADIPOCYTE DIFFERENTIATION OCCURS AT THE EXPENSE OF OTHER MESENCHYMAL DERIVED TISSUES. CONCLUSION/SIGNIFICANCE: COLLECTIVELY, THE FINDINGS OF THIS STUDY PROVIDE DIRECT EVIDENCE THAT AKT1 SIGNALING PLAYS AN IMPORTANT ROLE IN BALANCING NORMAL LEVELS OF FAT TISSUE IN VIVO. THE OBESE ZEBRAFISH EXAMINED IN THIS STUDY COULD BE A NEW POWERFUL MODEL TO SCREEN NOVEL DRUGS FOR THE TREATMENT OF HUMAN OBESITY.	2012