1 5642 81 SETMELANOTIDE: FIRST APPROVAL. SETMELANOTIDE (IMCIVREE, RHYTHM PHARMACEUTICALS) IS A MELANOCORTIN-4 (MC4) RECEPTOR AGONIST DEVELOPED FOR THE TREATMENT OF OBESITY ARISING FROM PROOPIOMELANOCORTIN (POMC), PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 1 (PCSK1), OR LEPTIN RECEPTOR (LEPR) DEFICIENCY. THE DRUG HAS RECEIVED ITS FIRST APPROVAL IN THE USA FOR CHRONIC WEIGHT MANAGEMENT IN PATIENTS 6 YEARS AND OLDER WITH OBESITY CAUSED BY POMC, PCSK1 AND LEPR DEFICIENCY AND HAS BEEN GRANTED PRIORITY MEDICINES (PRIME) DESIGNATION BY THE EUROPEAN MEDICINES AGENCY FOR THE TREATMENT OF OBESITY AND THE CONTROL OF HUNGER ASSOCIATED WITH DEFICIENCY DISORDERS OF THE MC4 RECEPTOR PATHWAY. SETMELANOTIDE IS ALSO BEING DEVELOPED IN OTHER RARE GENETIC DISORDERS ASSOCIATED WITH OBESITY INCLUDING BARDET-BIEDL SYNDROME, ALSTROM SYNDROME, POMC AND OTHER MC4R PATHWAY HETEROZYGOUS DEFICIENCY OBESITIES, AND POMC EPIGENETIC DISORDERS. THIS ARTICLE SUMMARIZES THE MILESTONES IN THE DEVELOPMENT OF SETMELANOTIDE LEADING TO THIS FIRST APPROVAL FOR OBESITY CAUSED BY POMC, PCSK1 AND LEPR DEFICIENCY. 2021 2 3899 18 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 3 6911 15 [TWO GERMAN BIRTH COHORTS: GINIPLUS AND LISAPLUS]. NUMEROUS CHRONIC DISEASES IN CHILDHOOD AND ADULTHOOD HAVE THEIR ORIGINS IN PERINATAL LIFE AND ARE POTENTIALLY INFLUENCED BY TRANS-GENERATIONAL EPIGENETIC PROCESSES. THEREFORE, PROSPECTIVE BIRTH COHORTS CAN SUBSTANTIALLY CONTRIBUTE TO OUR KNOWLEDGE ABOUT THE ETIOLOGY OF DISEASES INCLUDING MODIFIABLE RISK FACTORS. THE TWO POPULATION-BASED GERMAN BIRTH COHORTS GINIPLUS AND LISAPLUS AIM TO DESCRIBE THE NATURAL COURSE OF CHRONIC DISEASES AND INTERMEDIATE PHENOTYPES IN CHILDHOOD AND ITS DETERMINANTS, AND TO IDENTIFY POTENTIAL GENETIC EFFECT MODIFICATIONS. IN THE MID-1990S, 5,991 (GINIPLUS) AND 3,097 (LISAPLUS) HEALTHY, TERM NEWBORNS WERE RECRUITED FOR LONG-TERM FOLLOW-UP IN FOUR REGIONS OF GERMANY. THE FOLLOW-UP RATE FOR THE FIRST 10 YEARS WAS ABOUT 55%. WE ANALYZED THE GROWTH AND DEVELOPMENT OF OVERWEIGHT, INFECTIONS AND ALLERGIC DISEASES, MENTAL AND ORAL HEALTH, METABOLIC AND INFLAMMATORY PARAMETERS AND THE ROLE OF POTENTIAL RISK FACTORS INCLUDING GENETICS. THE RESULTS OF THESE TWO BIRTH COHORTS SUBSTANTIALLY CONTRIBUTE TO THE CURRENT KNOWLEDGE ABOUT THE NATURAL COURSE OF THESE HEALTH PARAMETERS. THESE DATA WERE INCLUDED IN MANY INTERNATIONAL PROJECTS AND CONSORTIA FOR PURPOSES OF INTERNATIONAL COMPARISONS OF PREVALENCE AND CONSISTENCY OF FINDINGS, AND TO INCREASE THE POWER OF THE ANALYSES. 2012 4 6351 26 THE ROLE OF EPIGENOMICS IN MAPPING POTENTIAL PRECURSORS FOR FOOT AND ANKLE TENDINOPATHY: A SYSTEMATIC REVIEW. TENDINOPATHY OF THE FOOT AND ANKLE IS A COMMON CLINICAL PROBLEM FOR WHICH THE EXACT ETIOLOGY IS POORLY UNDERSTOOD. THE FIELD OF EPIGENETICS HAS BEEN A RECENT FOCUS OF THIS INVESTIGATION. THE PURPOSE OF THIS ARTICLE WAS TO REVIEW THE GENOMIC ADVANCES IN FOOT AND ANKLE TENDINOPATHY THAT COULD POTENTIALLY BE USED TO STRATIFY DISEASE RISK AND CREATE PREVENTATIVE OR THERAPEUTIC AGENTS. A MULTI-DATABASE SEARCH OF PUBMED, COCHRANE, GOOGLE SCHOLAR, AND CLINICALTRIALS.GOV FROM JANUARY 1, 2000 TO JULY 1, 2022 WAS PERFORMED. A TOTAL OF 18 ARTICLES MET INCLUSION AND EXCLUSION CRITERIA FOR THIS REVIEW. THE MAJORITY OF SUCH RESEARCH UTILIZED CASE-CONTROL CANDIDATE GENE ASSOCIATION TO IDENTIFY DIFFERENT GENETIC RISK FACTORS ASSOCIATED WITH CHRONIC TENDINOPATHY. POLYMORPHISMS IN COLLAGEN GENES COL5A1, COL27A1, AND COL1A1 WERE NOTED AT A SIGNIFICANTLY HIGHER FREQUENCY IN ACHILLES TENDINOPATHY VERSUS CONTROL GROUPS. OTHER ALLELIC VARIATIONS THAT WERE OBSERVED AT AN INCREASED INCIDENCE IN ACHILLES TENDINOPATHY WERE TNC AND CASP8. THE EXTRACELLULAR MATRIX (ECM) DEMONSTRATED MACROSCOPIC CHANGES IN ACHILLES TENDINOPATHY, INCLUDING AN INCREASE IN AGGRECAN AND BIGLYCAN MRNA EXPRESSION, AND INCREASED EXPRESSION OF MULTIPLE MATRIX METALLOPROTEINASES. CYTOKINE EXPRESSION WAS ALSO INFLUENCED IN PATHOLOGY AND ABERRANTLY DEMONSTRATED DYNAMIC RESPONSE TO MECHANICAL LOAD. THE PATHOLOGIC ACCUMULATION OF ECM PROTEINS AND CYTOKINE EXPRESSION ALTERS THE ADAPTIVE RESPONSE NORMAL TENDON HAS TO PHYSIOLOGIC STRESS, FURTHER PROPAGATING THE RISK FOR TENDINOPATHY. BY IDENTIFYING AND UNDERSTANDING THE EPIGENETIC MEDIATORS THAT LEAD TO TENDINOPATHY, THERAPEUTIC AGENTS CAN BE DEVELOPED TO TARGET THE EXACT UNDERLYING ETIOLOGY AND MINIMIZE SIDE EFFECTS.LEVEL OF EVIDENCE: LEVEL IV: SYSTEMATIC REVIEW OF LEVEL II-IV STUDIES. 2023 5 4834 18 ON THE INTERPLAY BETWEEN THE MEDICINE OF HILDEGARD OF BINGEN AND MODERN MEDICINE: THE ROLE OF ESTROGEN RECEPTOR AS AN EXAMPLE OF BIODYNAMIC INTERFACE FOR STUDYING THE CHRONIC DISEASE'S COMPLEXITY. INTRODUCTION: HILDEGARD OF BINGEN (1098-1179) INTERPRETED THE ORIGINS OF CHRONIC DISEASE HIGHLIGHTING AND ANTICIPATING, ALTHOUGH ONLY IN A LIMITED FASHION, THE IMPORTANCE THAT COMPLEX INTERACTIONS AMONG NUMEROUS GENETIC, INTERNAL MILIEU AND EXTERNAL ENVIRONMENTAL FACTORS HAVE IN DETERMINING THE DISEASE PHENOTYPE. TODAY, WE RECOGNIZE THOSE FACTORS, CAPABLE OF MEDIATING THE TRANSMISSION OF MESSAGES BETWEEN HUMAN BODY AND ENVIRONMENT AND VICE VERSA, AS BIODYNAMIC INTERFACES. AIM: WE ANALYZED, IN THE LIGHT OF MODERN SCIENTIFIC EVIDENCE, HILDEGARD OF BINGEN'S MEDICAL APPROACH AND HER ORIGINAL HUMORAL THEORY IN ORDER TO IDENTIFY POSSIBLE INSIGHTS INCLUDED IN HER MEDICINE THAT COULD BE REFERRED TO IN THE CONTEXT OF MODERN EVIDENCE-BASED MEDICINE. IN PARTICULAR, THE ABBESS'S HUMORAL THEORY SUGGESTS THE IDENTIFICATION OF BIODYNAMIC INTERFACES WITH SEX HORMONES AND THEIR RECEPTORS. FINDINGS: WE FOUND THAT THE HILDEGARDIAN HOLISTIC VISION OF THE ORGANISM-ENVIRONMENT RELATIONSHIP CAN ACTUALLY REPRESENT A VISIONARY APPROACH TO MODERN ENDOCRINOLOGY AND THAT SEX HORMONES, IN PARTICULAR ESTROGENS, COULD REPRESENT AN EXAMPLE OF A BIODYNAMIC INTERFACE. ESTROGEN RECEPTORS ARE FOUND IN REGIONS OF THE BRAIN INVOLVED IN EMOTIONAL AND COGNITIVE REGULATION, CONTROLLING THE MOLECULAR MECHANISM OF BRAIN FUNCTION. ESTROGEN RECEPTORS ARE INVOLVED IN THE REGULATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS AND IN THE EPIGENETIC REGULATION OF RESPONSES TO PHYSIOLOGICAL, SOCIAL, AND HORMONAL STIMULI. FURTHERMORE, ESTROGEN AFFECTS GENE METHYLATION ON ITS OWN AND RELATED RECEPTOR PROMOTERS IN DISCRETE REGIONS OF THE DEVELOPING BRAIN. THIS SCENARIO WAS STRIKINGLY PERCEIVED BY THE ABBESS IN THE XIITH CENTURY, AND DEPICTED AS A COMPLEX INTERPLAY AMONG DIFFERENT HUMORS AND FLEGMATA THAT SHE RECOGNIZED TO BE SEX SPECIFIC AND ENVIRONMENTALLY REGULATED. VIEWPOINT: CONSIDERING THE FUNCTION PLAYED BY HORMONES, ANALYZED THROUGH THE LAST SCIENTIFIC EVIDENCE, AND SCIENTIFIC LITERATURE ON BIODYNAMIC INTERFACES, WE COULD SUGGEST HILDEGARDIAN INSIGHTS AND THEORIES AS THE FIRST ATTEMPT TO DESCRIBE THE MODERN HOLISTIC, SEX-BASED MEDICINE. CONCLUSION: HILDEGARD ANTICIPATED A CONCEPT OF PATHOGENESIS THAT SEES A CENTRAL ROLE FOR ENDOCRINOLOGY IN SEX-SPECIFIC DISEASE. FURTHERMORE, ESTROGENS AND ESTROGEN RECEPTORS COULD REPRESENT A GOOD EXAMPLE OF MOLECULAR INTERFACES CAPABLE OF MODULATING THE INTERACTION BETWEEN THE ORGANISM INTERNAL MILIEU AND THE ENVIRONMENTAL FACTORS. 2022 6 6484 18 TOXICOLOGIC PROFILE OF ACRYLONITRILE. ACRYLONITRILE IS A MONOMER USED EXTENSIVELY AS A RAW MATERIAL IN THE MANUFACTURING OF ACRYLIC FIBERS, PLASTICS, SYNTHETIC RUBBERS, AND ACRYLAMIDE. IT HAS BEEN CLASSIFIED AS A PROBABLE HUMAN CARCINOGEN ACCORDING TO THE RESULTS OF NUMEROUS CHRONIC RAT BIOASSAYS. THE PRESENT REPORT SUMMARIZES THE TOXICITY DATA ON ACRYLONITRILE AND REVIEWS AVAILABLE DATA CONCERNING THE MECHANISM (GENETIC VERSUS EPIGENETIC) BY WHICH ACRYLONITRILE IS CARCINOGENIC IN RATS. FROM THE EVALUATION OF THE RELEVANT TOXICITY DATA, IT CAN BE CONCLUDED THAT ACRYLONITRILE IS INDEED CARCINOGENIC TO RATS AFTER EITHER ORAL OR INHALATIONAL EXPOSURE. HOWEVER, INFORMATION ON OTHER MAMMALIAN SPECIES IS LACKING, AND, MOREOVER, THE EXACT MECHANISM OF THE CARCINOGENIC PROCESS IS UNCLEAR. THEREFORE, IT IS RECOMMENDED TO CONDUCT AN ADDITIONAL LONG-TERM INHALATION CARCINOGENICITY STUDY WITH ACRYLONITRILE IN MICE, AS WELL AS STUDIES INTO THE MECHANISM BY WHICH ACRYLONITRILE INDUCES (BRAIN) TUMORS IN RATS (GENETIC VERSUS EPIGENETIC). 1998 7 2603 24 EPIGENETICS, ENVIRONMENT AND EPIDEMIOLOGY: AN INTERVIEW WITH KARL KELSEY. IN THIS INTERVIEW, PROFESSOR KARL KELSEY SPEAKS WITH STORM JOHNSON, COMMISSIONING EDITOR FOR EPIGENOMICS, ON HIS WORK TO DATE IN THE FIELD OF ENVIRONMENTAL EPIGENOMICS AND EPIDEMIOLOGY. DR KARL KELSEY, MD, MOH IS A PROFESSOR OF EPIDEMIOLOGY AND PATHOLOGY AND LABORATORY MEDICINE AT BROWN UNIVERSITY. HE IS THE FOUNDING DIRECTOR OF THE CENTER FOR ENVIRONMENTAL HEALTH AND TECHNOLOGY AND HEAD OF THE ENVIRONMENTAL HEALTH SECTION AT THE DEPARTMENT OF EPIDEMIOLOGY. DR KELSEY IS INTERESTED IN THE APPLICATION OF LABORATORY-BASED BIOMARKERS IN ENVIRONMENTAL DISEASE, WITH EXPERIENCE IN CHRONIC DISEASE EPIDEMIOLOGY AND TUMOR BIOLOGY. THE GOALS OF HIS WORK INCLUDE A MECHANISTIC UNDERSTANDING OF INDIVIDUAL SUSCEPTIBILITY TO EXPOSURE-RELATED CANCERS. IN ADDITION, HIS LABORATORY IS INTERESTED IN TUMOR BIOLOGY, INVESTIGATING SOMATIC ALTERATIONS IN TUMOR TISSUE FROM THE PATIENTS WHO HAVE DEVELOPED EXPOSURE-RELATED CANCERS. THIS WORK INVOLVES THE USE OF AN EPIDEMIOLOGIC APPROACH TO CHARACTERIZE EPIGENETIC AND GENETIC ALTERATION OF GENES IN THE CAUSAL PATHWAY FOR MALIGNANCY. ACTIVE WORK INCLUDES SEVERAL STUDIES OF INDIVIDUAL SUSCEPTIBILITY TO CANCER. DR KELSEY'S LABORATORY MAINLY INVESTIGATES SUSCEPTIBILITY TO SMOKING-RELATED LUNG CANCER AND STUDIES MULTI-RACIAL AND ETHNIC POPULATIONS. IN ADDITION, THE LABORATORY IS ALSO INVOLVED WITH THE STUDY OF INHERITED SUSCEPTIBILITY TO BRAIN TUMORS AND PANCREATIC CANCER. MAJOR CASE CONTROL STUDIES THAT ARE ONGOING IN THE LABORATORY INCLUDE STUDIES DESIGNED TO UNDERSTAND INHERITED AND ACQUIRED SUSCEPTIBILITY IN HEAD AND NECK CANCERS. THE LABORATORY IS ALSO INVOLVED IN A CASE CONTROL STUDY OF ASBESTOS-ASSOCIATED MESOTHELIOMA, ARSENIC EXPOSURE, CIGARETTE SMOKING AND BLADDER CANCER. CONSIDERABLE WORK IS BEING DEVOTED TO UNDERSTANDING THE MECHANISMS OF ACTION OF BOTH ASBESTOS AND ARSENIC INCLUDING THEIR ABILITY TO AFFECT PROMOTER METHYLATION AND GENE SILENCING IN CARCINOGENESIS. RECENT LABORATORY STUDIES INCLUDES AN INTEREST IN USING NEWLY DEVELOPED DNA METHYLATION BIOMARKERS TO PROBE IMMUNE PROFILES FROM ARCHIVED BLOOD. DR KELSEY RECEIVED HIS MD FROM THE UNIVERSITY OF MINNESOTA AND MASTERS OF OCCUPATIONAL HEALTH FROM HARVARD UNIVERSITY. 2022 8 4665 16 NEW INSIGHTS AND ADVANCES IN PATHOGENESIS AND TREATMENT OF VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE. VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE (VEO-IBD) IS CHARACTERIZED BY MULTIFACTORIAL CHRONIC RECURRENT INTESTINAL INFLAMMATION. COMPARED WITH ELDERLY PATIENTS, THOSE WITH VEO-IBD HAVE A MORE SERIOUS CONDITION, NOT RESPONSIVE TO CONVENTIONAL TREATMENTS, WITH A POOR PROGNOSIS. RECENT STUDIES FOUND THAT GENETIC AND IMMUNOLOGIC ABNORMALITIES ARE CLOSELY RELATED TO VEO-IBD. INTESTINAL IMMUNE HOMEOSTASIS MONOGENIC DEFECTS (IIHMDS) ARE CHANGED THROUGH VARIOUS MECHANISMS. RECENT STUDIES HAVE ALSO REVEALED THAT ABNORMALITIES IN GENES AND IMMUNE MOLECULAR MECHANISMS ARE CLOSELY RELATED TO VEO-IBD. IIHMDS CHANGE THROUGH VARIOUS MECHANISMS. EPIGENETIC FACTORS CAN MEDIATE THE INTERACTION BETWEEN THE ENVIRONMENT AND GENOME, AND GENETIC FACTORS AND IMMUNE MOLECULES MAY BE INVOLVED IN THE PATHOGENESIS OF THE ENVIRONMENT AND GUT MICROBIOTA. THESE DISCOVERIES WILL PROVIDE NEW DIRECTIONS AND IDEAS FOR THE TREATMENT OF VEO-IBD. 2022 9 3537 25 IMMUNE DYSREGULATION IN KABUKI SYNDROME: A CASE REPORT OF EVANS SYNDROME AND HYPOGAMMAGLOBULINEMIA. KABUKI SYNDROME (KS) IS A RARE MULTISYSTEMIC DISEASE DUE TO MUTATIONS IN THE KMT2D OR KDM6A GENES, WHICH ACT AS EPIGENETIC MODULATORS OF DIFFERENT PROCESSES, INCLUDING IMMUNE RESPONSE. THE SYNDROME IS CHARACTERIZED BY ANOMALIES IN MULTIPLE ORGAN SYSTEMS, AND IT IS ASSOCIATED WITH AUTOIMMUNE AND INFLAMMATORY DISORDERS, AND AN UNDERLYING IMMUNOLOGICAL PHENOTYPE CHARACTERIZED BY IMMUNODEFICIENCY AND IMMUNE DYSREGULATION. UP TO 17% OF KS PATIENTS PRESENT WITH IMMUNE THROMBOCYTOPENIA CHARACTERIZED BY A SEVERE, CHRONIC OR RELAPSING COURSE, AND OFTEN ASSOCIATED TO OTHER HEMATOLOGICAL AUTOIMMUNE DISEASES INCLUDING AUTOIMMUNE HEMOLYTIC ANEMIA, EVENTUALLY RESULTING IN EVANS SYNDROME (ES). A 23-YEAR-OLD WOMAN, CLINICALLY DIAGNOSED WITH KS AND PRESENTING FROM THE AGE OF 3 YEARS WITH ES WAS REFERRED TO THE RARE DISEASES CENTRE OF OUR PEDIATRIC DEPARTMENT FOR CORTICOSTEROID-INDUCED HYPERGLYCEMIA. SEVERAL ES RELAPSES AND RECURRENT RESPIRATORY INFECTIONS IN THE PREVIOUS YEARS WERE REPORTED. SEVERE HYPOGAMMAGLOBULINEMIA, SPLENOMEGALY AND SIGNS OF CHRONIC LUNG INFLAMMATION WERE DIAGNOSED ONLY AT THE TIME OF OUR OBSERVATION. SUPPORTIVE TREATMENT WITH AMOXICILLIN-CLAVULANATE PROPHYLAXIS AND RECOMBINANT HUMAN HYALURONIDASE-FACILITATED SUBCUTANEOUS IMMUNOGLOBULIN REPLACEMENT WERE IMMEDIATELY STARTED. IN KS PATIENTS, THE FAILURE OF B-CELL DEVELOPMENT AND THE LACK OF AUTOREACTIVE IMMUNE CELLS SUPPRESSION CAN LEAD TO IMMUNODEFICIENCY AND AUTOIMMUNITY THAT MAY BE UNDIAGNOSED FOR A LONG TIME. OUR PATIENT'S CASE IS PARADIGMATIC SINCE SHE PRESENTED WITH PREVENTABLE MORBIDITY AND SEVERE LUNG DISEASE YEARS AFTER DISEASE ONSET. THIS CASE EMPHASIZES THE IMPORTANCE OF SUSPECTING IMMUNE DYSREGULATION IN KS. PATHOGENESIS AND IMMUNOLOGICAL COMPLICATIONS OF KS ARE DISCUSSED. MOREOVER, THE NEED TO PERFORM IMMUNOLOGIC EVALUATIONS IS HIGHLIGHTED BOTH AT THE TIME OF KS DIAGNOSIS AND DURING DISEASE FOLLOW-UP, IN ORDER TO ALLOW PROPER TREATMENT WHILE INTERCEPTING AVOIDABLE MORBIDITY IN THESE PATIENTS. 2023 10 5213 16 PRESYMPTOMATIC RISK ASSESSMENT FOR CHRONIC NON-COMMUNICABLE DISEASES. THE PREVALENCE OF COMMON CHRONIC NON-COMMUNICABLE DISEASES (CNCDS) FAR OVERSHADOWS THE PREVALENCE OF BOTH MONOGENIC AND INFECTIOUS DISEASES COMBINED. ALL CNCDS, ALSO CALLED COMPLEX GENETIC DISEASES, HAVE A HERITABLE GENETIC COMPONENT THAT CAN BE USED FOR PRE-SYMPTOMATIC RISK ASSESSMENT. COMMON SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) THAT TAG RISK HAPLOTYPES ACROSS THE GENOME CURRENTLY ACCOUNT FOR A NON-TRIVIAL PORTION OF THE GERM-LINE GENETIC RISK AND WE WILL LIKELY CONTINUE TO IDENTIFY THE REMAINING MISSING HERITABILITY IN THE FORM OF RARE VARIANTS, COPY NUMBER VARIANTS AND EPIGENETIC MODIFICATIONS. HERE, WE DESCRIBE A NOVEL MEASURE FOR CALCULATING THE LIFETIME RISK OF A DISEASE, CALLED THE GENETIC COMPOSITE INDEX (GCI), AND DEMONSTRATE ITS PREDICTIVE VALUE AS A CLINICAL CLASSIFIER. THE GCI ONLY CONSIDERS SUMMARY STATISTICS OF THE EFFECTS OF GENETIC VARIATION AND HENCE DOES NOT REQUIRE THE RESULTS OF LARGE-SCALE STUDIES SIMULTANEOUSLY ASSESSING MULTIPLE RISK FACTORS. COMBINING GCI SCORES WITH ENVIRONMENTAL RISK INFORMATION PROVIDES AN ADDITIONAL TOOL FOR CLINICAL DECISION-MAKING. THE GCI CAN BE POPULATED WITH HERITABLE RISK INFORMATION OF ANY TYPE, AND THUS REPRESENTS A FRAMEWORK FOR CNCD PRE-SYMPTOMATIC RISK ASSESSMENT THAT CAN BE POPULATED AS ADDITIONAL RISK INFORMATION IS IDENTIFIED THROUGH NEXT-GENERATION TECHNOLOGIES. 2010 11 5356 18 REAC-INDUCED ENDOGENOUS BIOELECTRIC CURRENTS IN THE TREATMENT OF VENOUS ULCERS: A THREE-ARM RANDOMIZED CONTROLLED PROSPECTIVE STUDY. INTRODUCTION: ENDOGENOUS BIOELECTRIC FIELDS (EBFS) PLAY A FUNDAMENTAL ROLE IN PROMOTING REPAIR AND REGENERATION PROCESSES, INCLUDING IN LEG VENOUS ULCERS (LVUS). UNFORTUNATELY, THE MECHANISM UNDERLYING THE PRODUCTION OF EBFS IS EASILY ALTERED BY INFECTIOUS, TRAUMATIC, AND EPIGENETIC FACTORS. THIS ALTERATION IS ONE OF THE DETERMINING FACTORS FOR THE CHRONICITY OF LVUS. THIS STUDY INVESTIGATES HOW RADIOELECTRIC ASYMMETRIC CONVEYER (REAC) TECHNOLOGY TREATMENTS, SPECIFICALLY DESIGNED TO OPTIMIZE EBFS, AND IN PARTICULAR TISSUE OPTIMIZATION-REPARATIVE (TO-RPR) TREATMENT, CAN IMPROVE THE RESULTS OF STANDARD DRESSING WITH AND WITHOUT ELASTIC COMPRESSION IN LVU PATIENTS. METHODS: A TOTAL OF 30 PATIENTS WERE ENROLLED (12 MALES AND 18 FEMALES) AND RANDOMIZED INTO THREE GROUPS. ALL PATIENTS COMPLETED THE STUDY. GROUP A WAS TREATED WITH STANDARD DRESSING, ELASTIC COMPRESSION, AND REAC TO-RPR TREATMENT; GROUP B WAS TREATED WITH STANDARD DRESSING AND REAC TO-RPR TREATMENT; AND GROUP C WAS TREATED WITH STANDARD DRESSING AND ELASTIC COMPRESSION. RESULTS: THE RESULTS SHOW THAT THE COMBINATION OF REAC TREATMENT AND STANDARD DRESSING ASSOCIATED WITH ELASTIC COMPRESSION HAS THE GREATEST THERAPEUTIC EFFICACY IN PROMOTING THE HEALING PROCESS FOR ULCERS, REDUCING PERCEIVED PAIN, AND IMPROVING THE QUALITY OF LIFE OF THE PATIENTS TREATED. CONCLUSIONS: FURTHER STUDIES WILL BE USEFUL TO INVESTIGATE THESE PROSPECTIVE RESULTS. 2020 12 5464 13 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 13 6914 16 [VITAMIN D DEFICIENCY IN PREGNANCY AND ITS IMPACT ON THE FETUS, THE NEWBORN AND IN CHILDHOOD]. OBJECTIVE: VITAMIN D DEFICIENCY (VDD) IN PREGNANT WOMEN AND THEIR CHILDREN IS AN IMPORTANT HEALTH PROBLEM WITH SEVERE CONSEQUENCES FOR THE HEALTH OF BOTH. THUS, THE OBJECTIVES OF THIS REVIEW WERE TO REASSESS THE MAGNITUDE AND CONSEQUENCES OF VDD DURING PREGNANCY, LACTATION AND INFANCY, ASSOCIATED RISK FACTORS, PREVENTION METHODS, AND TO EXPLORE EPIGENETIC MECHANISMS IN EARLY FETAL LIFE CAPABLE OF EXPLAINING MANY OF THE NON-SKELETAL BENEFITS OF VITAMIN D (VID). DATA SOURCE: ORIGINAL AND REVIEW ARTICLES, AND CONSENSUS DOCUMENTS WITH ELEVATED LEVEL OF EVIDENCE FOR VDD-RELATED CLINICAL DECISIONS ON THE HEALTH OF PREGNANT WOMEN AND THEIR CHILDREN, AS WELL AS ARTICLES ON THE INFLUENCE OF VID ON EPIGENETIC MECHANISMS OF FETAL PROGRAMMING OF CHRONIC DISEASES IN ADULTHOOD WERE SELECTED AMONG ARTICLES PUBLISHED ON PUBMED OVER THE LAST 20 YEARS, USING THE SEARCH TERM VITD STATUS, IN COMBINATION WITH PREGNANCY, OFFSPRING HEALTH, CHILD OUTCOMES, AND PROGRAMMING. DATA SYNTHESIS: THE FOLLOWING ITEMS WERE ANALYZED: VID PHYSIOLOGY AND METABOLISM, RISK FACTORS FOR VDD AND IMPLICATIONS IN PREGNANCY, LACTATION AND INFANCY, CONCENTRATION CUTOFF TO DEFINE VDD, THE VARIABILITY OF METHODS FOR VDD DETECTION, RECOMMENDATIONS ON VID REPLACEMENT IN PREGNANT WOMEN, THE NEWBORN AND THE CHILD, AND THE EPIGENETIC INFLUENCE OF VID. CONCLUSIONS: VDD IS A COMMON CONDITION AMONG HIGH-RISK PREGNANT WOMEN AND THEIR CHILDREN. THE ROUTINE MONITORING OF SERUM 25(OH)D3 LEVELS IN ANTENATAL PERIOD IS MANDATORY. EARLY PREVENTIVE MEASURES SHOULD BE TAKEN AT THE SLIGHTEST SUSPICION OF VDD IN PREGNANT WOMEN, TO REDUCE MORBIDITY DURING PREGNANCY AND LACTATION, AS WELL AS ITS SUBSEQUENT IMPACT ON THE FETUS, THE NEWBORN AND THE CHILD. 2015 14 6464 16 TISSUE MISREPAIR HYPOTHESIS FOR RADIATION CARCINOGENESIS. DOSE-RESPONSE CURVES FOR CHRONIC LEUKEMIA IN A-BOMB SURVIVORS AND LIVER TUMORS IN PATIENTS GIVEN THOROTRAST (COLLOIDAL THORIUM DIOXIDE) SHOW LARGE THRESHOLD EFFECTS. THE EXISTENCE OF THESE THRESHOLD EFFECTS CAN BE EXPLAINED BY THE FOLLOWING HYPOTHESIS. A HIGH DOSE OF RADIATION CAUSES A PERSISTENT WOUND IN A CELL-RENEWABLE TISSUE. DISORDER OF THE INJURED CELL SOCIETY PARTLY FREES THE COMPONENT CELLS FROM TERRITORIAL RESTRAINTS ON THEIR PROLIFERATION, ENABLING THEM TO CONTINUE DEVELOPMENT OF THEIR CELLULAR FUNCTIONS TOWARD ADVANCED AUTONOMY. THIS PROGRESSION MIGHT BE ACHIEVED BY CONTINUED EPIGENETIC AND GENETIC CHANGES AS A RESULT OF OCCASIONAL ERRORS IN THE OTHERWISE CONCERTED HEALING ACTION OF VARIOUS ENDOGENOUS FACTORS RECRUITED FOR TISSUE REPAIR. CARCINOGENESIS IS NOT SIMPLY A SINGLE-CELL PROBLEM BUT A CELL-SOCIETY PROBLEM. THEREFORE, IT IS NOT WARRANTED TO ESTIMATE RISK AT LOW DOSES BY LINEAR EXTRAPOLATION FROM CANCER DATA AT HIGH DOSES WITHOUT KNOWLEDGE OF THE MECHANISM OF RADIATION CARCINOGENESIS. 1991 15 2568 21 EPIGENETICS OF ALCOHOL-RELATED LIVER DISEASES. ALCOHOL-RELATED LIVER DISEASE (ARLD) IS A PRIMARY CAUSE OF CHRONIC LIVER DISEASE IN THE UNITED STATES. DESPITE ADVANCES IN THE DIAGNOSIS AND MANAGEMENT OF ARLD, IT REMAINS A MAJOR PUBLIC HEALTH PROBLEM ASSOCIATED WITH SIGNIFICANT MORBIDITY AND MORTALITY, EMPHASISING THE NEED TO ADOPT NOVEL APPROACHES TO THE STUDY OF ARLD AND ITS COMPLICATIONS. EPIGENETIC CHANGES ARE INCREASINGLY BEING RECOGNISED AS CONTRIBUTING TO THE PATHOGENESIS OF MULTIPLE DISEASE STATES. HARNESSING THE POWER OF INNOVATIVE TECHNOLOGIES FOR THE STUDY OF EPIGENETICS (E.G., NEXT-GENERATION SEQUENCING, DNA METHYLATION ASSAYS, HISTONE MODIFICATION PROFILING AND COMPUTATIONAL TECHNIQUES LIKE MACHINE LEARNING) HAS RESULTED IN A SEISMIC SHIFT IN OUR UNDERSTANDING OF THE PATHOPHYSIOLOGY OF ARLD. KNOWLEDGE OF THESE TECHNIQUES AND ADVANCES IS OF PARAMOUNT IMPORTANCE FOR THE PRACTICING HEPATOLOGIST AND RESEARCHERS ALIKE. ACCORDINGLY, IN THIS REVIEW ARTICLE WE WILL SUMMARISE THE CURRENT KNOWLEDGE ABOUT ALCOHOL-INDUCED EPIGENETIC ALTERATIONS IN THE CONTEXT OF ARLD, INCLUDING BUT NOT LIMITED TO, DNA HYPER/HYPO METHYLATION, HISTONE MODIFICATIONS, CHANGES IN NON-CODING RNA, 3D CHROMATIN ARCHITECTURE AND ENHANCER-PROMOTER INTERACTIONS. ADDITIONALLY, WE WILL DISCUSS THE STATE-OF-THE-ART TECHNIQUES USED IN THE STUDY OF ARLD (E.G. SINGLE-CELL SEQUENCING). WE WILL ALSO HIGHLIGHT THE EPIGENETIC REGULATION OF CHEMOKINES AND THEIR PROINFLAMMATORY ROLE IN THE CONTEXT OF ARLD. LASTLY, WE WILL EXAMINE THE CLINICAL APPLICATIONS OF EPIGENETICS IN THE DIAGNOSIS AND MANAGEMENT OF ARLD. 2022 16 3465 18 HYPOTHESIS: REGULATION OF NEUROPLASTICITY MAY INVOLVE I-MOTIF AND G-QUADRUPLEX DNA FORMATION MODULATED BY EPIGENETIC MECHANISMS. RECENT STUDIES DEMONSTRATED THE EXISTENCE IN VIVO OF VARIOUS FUNCTIONAL DNA STRUCTURES THAT DIFFER FROM THE DOUBLE HELIX. THE G-QUADRUPLEX (G4) AND INTERCALATED MOTIF (I-MOTIF OR IM) DNA STRUCTURES ARE FORMED AS KNOTS WHERE, CORRESPONDINGLY, GUANINES OR CYTOSINES ON THE SAME STRAND OF DNA BIND TO EACH OTHER. THERE ARE GROUNDS TO BELIEVE THAT G4 AND IM SEQUENCES PLAY A SIGNIFICANT ROLE IN REGULATING GENE EXPRESSION CONSIDERING THEIR TENDENCY TO BE FOUND IN OR NEAR REGULATORY SITES (SUCH AS PROMOTERS, ENHANCERS, AND TELOMERES) AS WELL AS THE CORRELATION BETWEEN THE PREVALENCE OF G4 OR IM CONFORMATIONS AND SPECIFIC PHASES OF CELL CYCLE. NOTABLY, G4 AND IM CAPABLE SEQUENCES TEND TO BE FOUND ON THE OPPOSITE STRANDS OF THE SAME DNA SITE WITH AT MOST ONE OF THE TWO STRUCTURES FORMED AT ANY GIVEN TIME. THE RECENT EVIDENCE THAT K(+), MG(2+) CONCENTRATIONS DIRECTLY AFFECT IM FORMATION (AND LIKELY G4 FORMATION INDIRECTLY) LEAD US TO BELIEVE THAT THESE STRUCTURES MAY PLAY A MAJOR ROLE IN SYNAPTIC PLASTICITY OF NEURONS, AND, THEREFORE, IN A VARIETY OF CENTRAL NERVOUS SYSTEM (CNS) FUNCTIONS INCLUDING MEMORY, LEARNING, HABITUAL BEHAVIORS, PAIN PERCEPTION AND OTHERS. FURTHERMORE, EPIGENETIC MECHANISMS, WHICH HAVE AN IMPORTANT ROLE IN SYNAPTIC PLASTICITY AND MEMORY FORMATION, WERE ALSO SHOWN TO INFLUENCE FORMATION AND STABILITY OF G4S AND IMS. OUR HYPOTHESIS IS THAT NON-CANONICAL DNA AND RNA STRUCTURES COULD BE AN INTEGRAL PART OF NEUROPLASTICITY CONTROL VIA GENE EXPRESSION REGULATION AT THE LEVEL OF TRANSCRIPTION, TRANSLATION AND SPLICING. WE PROPOSE THAT THE REGULATORY ACTIVITY OF DNA IM AND G4 STRUCTURES IS MODULATED BY DNA METHYLATION/DEMETHYLATION OF THE IM AND/OR G4 SEQUENCES, WHICH FACILITATES THE SWITCH BETWEEN CANONICAL AND NON-CANONICAL CONFORMATION. OTHER NEURONAL MECHANISMS INTERACTING WITH THE FORMATION AND REGULATORY ACTIVITY OF NON-CANONICAL DNA AND RNA STRUCTURES, PARTICULARLY G4, IM AND TRIPLEXES, MAY INVOLVE MICRORNAS AS WELL AS ION AND PROTON FLUXES. WE ARE PROPOSING EXPERIMENTS IN ACUTE BRAIN SLICES AND IN VIVO TO TEST OUR HYPOTHESIS. THE PROPOSED STUDIES WOULD PROVIDE NEW INSIGHTS INTO FUNDAMENTAL NEURONAL MECHANISMS IN HEALTH AND DISEASE AND POTENTIALLY OPEN NEW AVENUES FOR TREATING MENTAL HEALTH DISORDERS. 2019 17 2967 20 GENETIC AND EPIGENETIC REGULATION OF CATECHOL-O-METHYLTRANSFERASE IN RELATION TO INFLAMMATION IN CHRONIC FATIGUE SYNDROME AND FIBROMYALGIA. BACKGROUND: CATECHOL-O-METHYLTRANSFERASE (COMT) HAS BEEN SHOWN TO INFLUENCE CLINICAL PAIN, DESCENDING MODULATION, AND EXERCISE-INDUCED SYMPTOM WORSENING. COMT REGULATES NOCICEPTIVE PROCESSING AND INFLAMMATION, KEY PATHOPHYSIOLOGICAL FEATURES OF CHRONIC FATIGUE SYNDROME AND FIBROMYALGIA (CFS/FM). WE AIMED TO DETERMINE THE INTERACTIONS BETWEEN GENETIC AND EPIGENETIC MECHANISMS REGULATING COMT AND ITS INFLUENCE ON INFLAMMATORY MARKERS AND SYMPTOMS IN PATIENTS WITH CFS/FM. METHODS: A CASE-CONTROL STUDY WITH REPEATED-MEASURES DESIGN WAS USED TO REDUCE THE CHANCE OF FALSE POSITIVE AND INCREASE THE POWER OF OUR FINDINGS. FIFTY-FOUR PARTICIPANTS (28 PATIENTS WITH CFS/FM AND 26 CONTROLS) WERE ASSESSED TWICE WITHIN 4 DAYS. THE ASSESSMENT INCLUDED CLINICAL QUESTIONNAIRES, NEUROPHYSIOLOGICAL ASSESSMENT (PAIN THRESHOLDS, TEMPORAL SUMMATION, AND CONDITIONED PAIN MODULATION), AND BLOOD WITHDRAWAL IN ORDER TO ASSESS RS4818, RS4633, AND RS4680 COMT POLYMORPHISMS AND PERFORM HAPLOTYPE ESTIMATION, DNA METHYLATION IN THE COMT GENE (BOTH MB-COMT AND S-COMT PROMOTERS), AND CYTOKINE EXPRESSION (TNF-ALPHA, IFN-GAMMA, IL-6, AND TGF-BETA). RESULTS: COMT HAPLOTYPES WERE ASSOCIATED WITH DNA METHYLATION IN THE S-COMT PROMOTER, TGF-BETA EXPRESSION, AND SYMPTOMS. HOWEVER, THIS WAS NOT SPECIFIC FOR ONE CONDITION. SIGNIFICANT BETWEEN-GROUP DIFFERENCES WERE FOUND FOR INCREASED DNA METHYLATION IN THE MB-COMT PROMOTER AND DECREASED IFN-GAMMA EXPRESSION IN PATIENTS. DISCUSSION: OUR RESULTS ARE CONSISTENT WITH BASIC AND CLINICAL RESEARCH, PROVIDING INTERESTING INSIGHTS INTO GENETIC-EPIGENETIC REGULATORY MECHANISMS. MB-COMT DNA METHYLATION MIGHT BE AN INDEPENDENT FACTOR CONTRIBUTING TO THE PATHOPHYSIOLOGY OF CFS/FM. FURTHER RESEARCH ON DNA METHYLATION IN COMPLEX CONDITIONS SUCH AS CFS/FM IS WARRANTED. WE RECOMMEND FUTURE RESEARCH TO EMPLOY A REPEATED-MEASURE DESIGN TO CONTROL FOR BIOMARKERS VARIABILITY AND WITHIN-SUBJECT CHANGES. 2022 18 6490 20 TRACING SLOW PHENOPTOSIS TO THE PRENATAL STAGE IN SOCIAL VERTEBRATES. VLADIMIR SKULACHEV'S COINING OF THE TERM "PHENOPTOSIS" 25 YEARS AGO (SKULACHEV, V. P., BIOCHEMISTRY (MOSCOW), 62, 1997) HIGHLIGHTED THE THEORETICAL POSSIBILITY THAT AGING IS A PROGRAMMED PROCESS TO SPEED THE EXIT OF INDIVIDUALS POSING SOME DANGER TO THEIR SOCIAL GROUP. WHILE RAPID "ACUTE PHENOPTOSIS" MIGHT OCCUR AT ANY AGE (E.G., TO PREVENT SPREAD OF DEADLY INFECTIONS), "SLOW PHENOPTOSIS" IS GENERALLY CONSIDERED TO OCCUR LATER IN LIFE IN THE FORM OF CHRONIC AGE-RELATED DISORDERS. HOWEVER, RECENT RESEARCH INDICATES THAT RISKS FOR SUCH CHRONIC DISORDERS CAN BE GREATLY RAISED BY EARLY LIFE ADVERSITY, ESPECIALLY DURING THE PRENATAL STAGE. MUCH OF THIS RESEARCH USES INDICATORS OF BIOLOGICAL AGING, THE SPEEDING OR SLOWING OF NATURAL PHYSIOLOGICAL DETERIORATION IN RESPONSE TO ENVIRONMENTAL INPUTS, LEADING TO DIVERGENCE FROM CHRONOLOGICAL AGE. STUDIES USING BIOLOGICAL AGING INDICATORS COMMONLY FIND IT IS ACCELERATED NOT ONLY IN OLDER INDIVIDUALS WITH CHRONIC DISORDERS, BUT ALSO IN VERY YOUNG INDIVIDUALS WITH HEALTH PROBLEMS. THIS REVIEW WILL EXPLAIN HOW ACCELERATED BIOLOGICAL AGING EQUATES TO SLOW PHENOPTOSIS. ITS OCCURRENCE EVEN IN THE PRENATAL STAGE IS THEORETICALLY SUPPORTED BY W. D. HAMILTON'S PROPOSAL THAT OFFSPRINGS DETECTING THEY HAVE DANGEROUS MUTATIONS SHOULD THEN AUTOMATICALLY SPEED THEIR DEMISE, IN ORDER TO IMPROVE THEIR INCLUSIVE FITNESS BY GIVING THEIR PARENTS THE CHANCE TO PRODUCE OTHER FITTER SIBLINGS. 2022 19 227 14 ADAPTATION OF AN OUTBREAKING INSECT DEFOLIATOR TO CHRONIC NUTRITIONAL STRESS. DURING INSECT OUTBREAKS, THE HIGH NUMBER OF INDIVIDUALS FEEDING ON ITS HOST PLANT CAUSES A DEPLETION OF THE FOOD SOURCE. REDUCED AVAILABILITY AND DECREASED QUALITY OF NUTRIENTS NEGATIVELY INFLUENCE LIFE-HISTORY TRAITS OF INSECTS DRIVING THEM TO DEVELOP ADAPTIVE STRATEGIES TO PERSIST IN THE ENVIRONMENT. IN A LABORATORY EXPERIMENT WITH THREE REPETITIONS, WE TESTED THE EFFECT OF CHRONIC NUTRITIONAL STRESS ON SPRUCE BUDWORM PERFORMANCE DURING THREE GENERATIONS TO DETERMINE THE ADAPTIVE STRATEGIES EMPLOYED BY THE INSECT TO DEAL WITH A SELECTION PRESSURE PRODUCED BY LOW-QUALITY DIET. OUR RESULTS SHOW THAT ALL TESTED LIFE-HISTORY TRAITS (MORTALITY, DEVELOPMENTAL TIME, PUPAL MASS, GROWTH RATE AND FEMALE FECUNDITY) BUT FEMALE FERTILITY WERE NEGATIVELY INFLUENCED BY THE LOW-QUALITY DIET SIMULATING FOOD DEPLETION DURING OUTBREAK CONDITIONS. HOWEVER, ESPECIALLY FEMALES IN THE THIRD GENERATION UNDER CHRONIC NUTRITIONAL STRESS SHOW AN ADAPTIVE RESPONSE IN LIFE-HISTORY TRAITS WHEN COMPARED TO THOSE REARED ONLY ONE GENERATION ON LOW-QUALITY DIET. LARVAL DEVELOPMENTAL TIME SIGNIFICANTLY DECREASED AND PUPAL MASS, GROWTH RATE AND FECUNDITY SIGNIFICANTLY INCREASED. THE STUDY DEMONSTRATES THE CAPACITY OF SPRUCE BUDWORM TO REACT TO CHRONIC NUTRITIONAL STRESS WITH ADAPTATIONS THAT MAY BE CAUSED BY EPIGENETIC PARENTAL EFFECTS. THIS INFORMATION CAN HELP TO UNDERSTAND THE COURSE OF AN OUTBREAK ESPECIALLY AT PEAK DENSITIES AND DURING THE COLLAPSE. 2015 20 3074 13 GENOME-WIDE DNA METHYLOME AND TRANSCRIPTOME CHANGES INDUCED BY INORGANIC NANOPARTICLES IN HUMAN KIDNEY CELLS AFTER CHRONIC EXPOSURE. THE UNIQUE PHYSICOCHEMICAL PROPERTIES MAKE INORGANIC NANOPARTICLES (INPS) AN EXCITING TOOL IN DIAGNOSIS AND DISEASE MANAGEMENT. HOWEVER, AS INPS ARE RELATIVELY DIFFICULT TO FULLY DEGRADE AND EXCRETE, THEIR UNINTENDED ACCUMULATION IN THE TISSUE MIGHT RESULT IN ADVERSE HEALTH EFFECTS. HEREIN, WE PROVIDE A METHYLOME-TRANSCRIPTOME FRAMEWORK FOR CHRONIC EFFECTS OF INPS, COMMONLY USED IN BIOMEDICAL APPLICATIONS, IN HUMAN KIDNEY TH-1 CELLS. RENAL CLEARANCE IS ONE OF THE MOST IMPORTANT ROUTES OF NANOPARTICLE EXCRETION; THEREFORE, A DETAILED EVALUATION OF NANOPARTICLE-MEDIATED NEPHROTOXICITY IS AN IMPORTANT TASK. INTEGRATED ANALYSIS OF METHYLOME AND TRANSCRIPTOME CHANGES INDUCED BY INPS (PEG-AUNPS, FE(3)O(4)NPS, SIO(2)NPS, AND TIO(2)NPS) REVEALED SIGNIFICANTLY DEREGULATED GENES WITH FUNCTIONAL CLASSIFICATION IN IMMUNE RESPONSE, DNA DAMAGE, AND CANCER-RELATED PATHWAYS. ALTHOUGH MOST DEREGULATED GENES WERE UNIQUE TO INDIVIDUAL INPS, A RELATIVELY HIGH PROPORTION OF THEM ENCODED THE TRANSCRIPTION FACTORS. INTERESTINGLY, FOS HYPERMETHYLATION INVERSELY CORRELATING WITH GENE EXPRESSION WAS ASSOCIATED WITH ALL INPS EXPOSURES. OUR STUDY EMPHASIZES THE NEED FOR A MORE COMPREHENSIVE INVESTIGATION OF INPS' BIOLOGICAL SAFETY, ESPECIALLY AFTER CHRONIC EXPOSURE. 2022