1 5374 160 RECENT ADVANCES IN UNDERSTANDING/MANAGEMENT OF PREMENSTRUAL DYSPHORIC DISORDER/PREMENSTRUAL SYNDROME. PREMENSTRUAL SYNDROME (PMS) AND PREMENSTRUAL DYSPHORIC DISORDER (PMDD) ARE COMMON DISORDERS OF THE LUTEAL PHASE OF THE MENSTRUAL CYCLE AND ARE CHARACTERIZED BY MODERATE TO SEVERE PHYSICAL, AFFECTIVE, OR BEHAVIORAL SYMPTOMS THAT IMPAIR DAILY ACTIVITIES AND QUALITY OF LIFE. PMS AND PMDD HAVE RECENTLY RAISED GREAT INTEREST IN THE RESEARCH COMMUNITY FOR THEIR CONSIDERABLE GLOBAL PREVALENCE. THE ETIOLOGY OF PMS/PMDD IS COMPLEX. OVARIAN REPRODUCTIVE STEROIDS (ESTRADIOL AND PROGESTERONE) ARE CONSIDERED PATHOGENETIC EFFECTORS, BUT THE KEY FEATURE SEEMS TO BE AN ALTERED SENSITIVITY OF THE GABAERGIC CENTRAL INHIBITORY SYSTEM TO ALLOPREGNANOLONE, A NEUROSTEROID DERIVED FROM PROGESTERONE PRODUCED AFTER OVULATION. ALSO, A REDUCED AVAILABILITY OF SEROTONIN SEEMS TO BE INVOLVED. NEW INSIGHTS POINT TO A ROLE FOR GENETIC AND EPIGENETIC MODIFICATIONS OF HORMONAL AND NEUROTRANSMITTER PATHWAYS, AND INFLAMMATION IS THE POTENTIAL LINK BETWEEN PERIPHERAL AND NEUROLOGICAL INTEGRATED RESPONSES TO STRESSORS. THUS, NEW THERAPEUTIC APPROACHES TO PMS/PMDD INCLUDE INHIBITION OF PROGESTERONE RECEPTORS IN THE BRAIN (I.E., WITH ULIPRISTAL ACETATE), REDUCED CONVERSION OF PROGESTERONE TO ITS METABOLITE ALLOPREGNANOLONE WITH DUTASTERIDE, AND POSSIBLE MODULATION OF THE ACTION OF ALLOPREGNANOLONE ON THE BRAIN GABAERGIC SYSTEM WITH SEPRANOLONE. FURTHER RESEARCH IS NEEDED TO BETTER UNDERSTAND THE INTERACTION BETWEEN PERIPHERAL INFLAMMATORY MOLECULES (CYTOKINES, INTERLEUKINS, C-REACTIVE PROTEIN, AND REACTIVE OXYGEN SPECIES) AND THE BRAIN NEUROTRANSMITTER SYSTEMS IN WOMEN WITH PMS/PMDD. IF CONFIRMED, NEUROINFLAMMATION COULD LEAD BOTH TO DEVELOP TARGETED ANTI-INFLAMMATORY THERAPIES AND TO DEFINE PREVENTION STRATEGIES FOR THE ASSOCIATED CHRONIC INFLAMMATORY RISK IN PMS/PMDD. FINALLY, THE OBSERVED ASSOCIATION BETWEEN PREMENSTRUAL DISORDERS AND PSYCHOLOGICAL DISEASES MAY GUIDE PROMPT AND ADEQUATE INTERVENTIONS TO ACHIEVE A BETTER QUALITY OF LIFE. 2022 2 3899 29 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 4834 39 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 4 4968 36 PATHOLOGICAL MECHANISMS AND THERAPEUTIC OUTLOOKS FOR ARTHROFIBROSIS. ARTHROFIBROSIS IS A FIBROTIC JOINT DISORDER THAT BEGINS WITH AN INFLAMMATORY REACTION TO INSULTS SUCH AS INJURY, SURGERY AND INFECTION. EXCESSIVE EXTRACELLULAR MATRIX AND ADHESIONS CONTRACT POUCHES, BURSAE AND TENDONS, CAUSE PAIN AND PREVENT A NORMAL RANGE OF JOINT MOTION, WITH DEVASTATING CONSEQUENCES FOR PATIENT QUALITY OF LIFE. ARTHROFIBROSIS AFFECTS PEOPLE OF ALL AGES, WITH PUBLISHED RATES VARYING. THE RISK FACTORS AND BEST MANAGEMENT STRATEGIES ARE LARGELY UNKNOWN DUE TO A POOR UNDERSTANDING OF THE PATHOLOGY AND LACK OF DIAGNOSTIC BIOMARKERS. HOWEVER, CURRENT RESEARCH INTO THE PATHOGENESIS OF FIBROSIS IN ORGANS NOW INFORMS THE UNDERSTANDING OF ARTHROFIBROSIS. THE PROCESS BEGINS WHEN STRESS SIGNALS STIMULATE IMMUNE CELLS. THE RESULTING CASCADE OF CYTOKINES AND MEDIATORS DRIVES FIBROBLASTS TO DIFFERENTIATE INTO MYOFIBROBLASTS, WHICH SECRETE FIBRILLAR COLLAGENS AND TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA). POSITIVE FEEDBACK NETWORKS THEN DYSREGULATE PROCESSES THAT NORMALLY TERMINATE HEALING PROCESSES. WE PROPOSE TWO SUBTYPES OF ARTHROFIBROSIS OCCUR: ACTIVE ARTHROFIBROSIS AND RESIDUAL ARTHROFIBROSIS. IN THE LATTER THE FIBROGENIC PROCESSES HAVE RESOLVED BUT THE JOINT REMAINS STIFF. THE BEST THERAPEUTIC APPROACH FOR EACH SUBTYPE MAY DIFFER SIGNIFICANTLY. TREATMENT TYPICALLY INVOLVES SURGERY, HOWEVER, A PHARMACOLOGICAL APPROACH TO CORRECT DYSREGULATED CELL SIGNALLING COULD BE MORE EFFECTIVE. RECENT RESEARCH SHOWS THAT MYOFIBROBLASTS ARE CAPABLE OF REVERSING DIFFERENTIATION, AND UNDERSTANDING THE MECHANISMS OF PATHOGENESIS AND RESOLUTION WILL BE ESSENTIAL FOR THE DEVELOPMENT OF CELL-BASED TREATMENTS. THERAPIES WITH SIGNIFICANT PROMISE ARE CURRENTLY AVAILABLE, WITH MORE IN DEVELOPMENT, INCLUDING THOSE THAT INHIBIT TGF-BETA SIGNALLING AND EPIGENETIC MODIFICATIONS. THIS REVIEW FOCUSES ON PATHOGENESIS OF STERILE ARTHROFIBROSIS AND THERAPEUTIC TREATMENTS. 2019 5 2597 33 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 6 4665 31 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 7 2568 25 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 8 4999 36 PERINATAL PROGRAMMING OF CIRCADIAN CLOCK-STRESS CROSSTALK. AN INTACT COMMUNICATION BETWEEN CIRCADIAN CLOCKS AND THE STRESS SYSTEM IS IMPORTANT FOR MAINTAINING PHYSIOLOGICAL HOMEOSTASIS UNDER RESTING CONDITIONS AND IN RESPONSE TO EXTERNAL STIMULI. THERE IS ACCUMULATING EVIDENCE FOR A RECIPROCAL INTERACTION BETWEEN BOTH-FROM THE SYSTEMIC TO THE MOLECULAR LEVEL. DISRUPTION OF THIS INTERACTION BY EXTERNAL FACTORS SUCH AS SHIFTWORK, JETLAG, OR CHRONIC STRESS INCREASES THE RISK OF DEVELOPING METABOLIC, IMMUNE, OR MOOD DISORDERS. FROM EXPERIMENTS IN RODENTS, WE KNOW THAT BOTH SYSTEMS MATURATE DURING THE PERINATAL PERIOD. DURING THAT TIME, EXOGENOUS FACTORS SUCH AS STRESS OR ALTERATIONS IN THE EXTERNAL PHOTOPERIOD MAY CRITICALLY AFFECT-OR PROGRAM-PHYSIOLOGICAL FUNCTIONS LATER IN LIFE. THIS DEVELOPMENTAL PROGRAMMING PROCESS HAS BEEN ATTRIBUTED TO MATERNAL STRESS SIGNALS REACHING THE EMBRYO, WHICH LASTINGLY CHANGE GENE EXPRESSION THROUGH THE INDUCTION OF EPIGENETIC MECHANISMS. DESPITE THE WELL-KNOWN FUNCTION OF THE ADULT CIRCADIAN SYSTEM IN TEMPORAL COORDINATION OF PHYSIOLOGY AND BEHAVIOR, THE ROLE OF MATERNAL AND EMBRYONIC CIRCADIAN CLOCKS DURING PREGNANCY AND POSTNATAL DEVELOPMENT IS STILL POORLY DEFINED. A BETTER UNDERSTANDING OF THE CIRCADIAN-STRESS CROSSTALK AT DIFFERENT PERIODS OF DEVELOPMENT MAY HELP TO IMPROVE STRESS RESISTANCE AND DEVISE PREVENTIVE AND THERAPEUTIC STRATEGIES AGAINST CHRONIC STRESS-ASSOCIATED DISORDERS. 2018 9 1643 30 DOES RHEUMATOID ARTHRITIS REPRESENT AN ADAPTIVE, THRIFTY CONDITION? THE PRESENT ARTICLE PRESENTS EPIDEMIOLOGICAL, AND COMPARATIVE EVIDENCE SUPPORTING THE HYPOTHESIS THAT RHEUMATOID ARTHRITIS (RA) MAY REPRESENT A THRIFTY ADAPTATION SELECTED TO COMPEL ANIMALS TO MINIMIZE VOLUNTARY ENERGY EXPENDITURE. THE AUTOIMMUNE, PATHOPHYSIOLOGICAL MANIFESTATIONS UNDERLYING RA ARE FRAMED HERE AS CONSTITUTING AN EVOLVED, PROTECTIVE MECHANISM THAT WOULD HAVE INFLUENCED ANIMALS TO AVOID EXERTION AND MAINTAIN A SEDENTARY LIFESTYLE IN ORDER TO MINIMIZE METABOLIC OUTPUT AND ULTIMATELY ESCAPE STARVATION. ARTHRITIC PAIN IS CHARACTERIZED HERE AS A DEFENSIVE, INNATE SIGNAL MUCH LIKE FATIGUE, FEVER, NAUSEA AND REFLEXIVE PAIN, AND LIKE THESE, IS SEEN ON A CONTINUUM VARYING BETWEEN IMPERCEPTIBLE ENCUMBRANCE AND DEBILITATING DISABILITY. THE EPIGENETIC RELATIONSHIP BETWEEN ACUTE PSYCHOLOGICAL STRESS AND FLARE-UP OF ARTHRITIC SYMPTOMS IS EXAMINED AND TAKEN TO SUGGEST THAT ARTHRITIS MAY BE A PREDICTIVE, ADAPTIVE RESPONSE TO SEVERE STRESS ALLOWING REDUCTIONS IN METABOLISM TO FOLLOW ADVERSE CONDITIONS OR NUTRITIONAL SCARCITY. THE CLOSE ASSOCIATIONS BETWEEN RHEUMATOID ARTHRITIS AND THE METABOLIC SYNDROME ARE ALSO EXPLORED ALONG WITH POTENTIAL TIES TO THE "THRIFTY GENOTYPE" AND "THRIFTY PHENOTYPE" PHENOMENA. THIS HYPOTHESIS IS EXAMINED IN THE CONTEXTS OF EVOLUTIONARY MEDICINE, PHENOTYPIC PLASTICITY, THE STRESS RESPONSE AND THE BIOENERGETICS OF THRIFT. A BRIEF AND EXPLORATORY REVIEW OF PERTINENT EVIDENCE SUGGESTS THAT RA, ITS SUBCLINICAL MANIFESTATIONS, AND EVEN OTHER FORMS OF ARTHROPATHY MAY POSSIBLY REPRESENT ADAPTATIONS THAT PROMOTED METABOLIC THRIFT DURING OUR EVOLUTIONARY PAST. 2010 10 3002 31 GENETIC, EPIGENETIC AND POSTTRANSCRIPTIONAL MECHANISMS FOR TREATMENT OF MAJOR DEPRESSION: THE 5-HT1A RECEPTOR GENE AS A PARADIGM. MAJOR DEPRESSION AND ANXIETY ARE HIGHLY PREVALENT AND INVOLVE CHRONIC DYSREGULATION OF SEROTONIN, BUT THEY REMAIN POORLY UNDERSTOOD. HERE, WE REVIEW NOVEL TRANSCRIPTIONAL (GENETIC, EPIGENETIC) AND POSTTRANSCRIPTIONAL (MICRORNA, ALTERNATIVE SPLICING) MECHANISMS IMPLICATED IN MENTAL ILLNESS, FOCUSING ON A KEY SEROTONIN-RELATED REGULATOR, THE SEROTONIN 1A (5-HT1A) RECEPTOR. FUNCTIONAL SINGLE-NUCLEOTIDE POLYMORPHISMS AND STRESS-INDUCED DNA METHYLATION OF THE 5-HT1A PROMOTER CONVERGE TO DIFFERENTIALLY ALTER PRE- AND POSTSYNAPTIC 5-HT1A RECEPTOR EXPRESSION ASSOCIATED WITH MAJOR DEPRESSION AND REDUCED THERAPEUTIC RESPONSE TO SEROTONERGIC ANTIDEPRESSANTS. MAJOR DEPRESSION IS ALSO ASSOCIATED WITH ALTERED LEVELS OF SPLICE FACTORS AND MICRORNA, POSTTRANSCRIPTIONAL MECHANISMS THAT REGULATE RNA STABILITY. THE HUMAN 5-HT1A 3'-UNTRANSLATED REGION IS ALTERNATIVELY SPLICED, REMOVING MICRORNA SITES AND INCREASING 5-HT1A EXPRESSION, WHICH IS REDUCED IN MAJOR DEPRESSION AND MAY BE GENOTYPE-DEPENDENT. THUS, THE 5-HT1A RECEPTOR GENE ILLUSTRATES THE CONVERGENCE OF GENETIC, EPIGENETIC AND POSTTRANSCRIPTIONAL MECHANISMS IN GENE EXPRESSION, NEURODEVELOPMENT AND NEUROPLASTICITY, AND MAJOR DEPRESSION. UNDERSTANDING GENE REGULATORY MECHANISMS COULD ENHANCE THE DETECTION, CATEGORIZATION AND PERSONALIZED TREATMENT OF MAJOR DEPRESSION. 2019 11 1732 31 DYSTONIA AND LEVODOPA-INDUCED DYSKINESIAS IN PARKINSON'S DISEASE: IS THERE A CONNECTION? DYSTONIA AND LEVODOPA-INDUCED DYSKINESIA (LID) ARE BOTH HYPERKINETIC MOVEMENT DISORDERS. DYSTONIA ARISES MOST OFTEN SPONTANEOUSLY, ALTHOUGH IT MAY BE SEEN AFTER STROKE, INJURY, OR AS A RESULT OF GENETIC CAUSES. LID IS ASSOCIATED WITH PARKINSON'S DISEASE (PD), EMERGING AS A CONSEQUENCE OF CHRONIC THERAPY WITH LEVODOPA, AND MAY BE EITHER DYSTONIC OR CHOREIFORM. LID AND DYSTONIA SHARE IMPORTANT PHENOMENOLOGICAL PROPERTIES AND MECHANISMS. BOTH LID AND DYSTONIA ARE GENERATED BY AN INTEGRATED CIRCUIT INVOLVING THE CORTEX, BASAL GANGLIA, THALAMUS AND CEREBELLUM. THEY ALSO SHARE DYSREGULATION OF STRIATAL CHOLINERGIC SIGNALING AND ABNORMALITIES OF STRIATAL SYNAPTIC PLASTICITY. THE LONG DURATION NATURE OF BOTH LID AND DYSTONIA SUGGESTS THAT THERE MAY BE UNDERLYING EPIGENETIC DYSREGULATION AS A PROXIMATE CAUSE. WHILE BOTH MAY IMPROVE AFTER INTERVENTIONS SUCH AS DEEP BRAIN STIMULATION (DBS), NEITHER CURRENTLY HAS A SATISFACTORY MEDICAL THERAPY, AND MANY PEOPLE ARE DISABLED BY THE SYMPTOMS OF DYSTONIA AND LID. FURTHER STUDY OF THE FUNDAMENTAL MECHANISMS CONNECTING THESE TWO DISORDERS MAY LEAD TO NOVEL APPROACHES TO TREATMENT OR PREVENTION. 2019 12 2616 27 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 13 2000 30 EPIGENETIC AND NON-CODING REGULATION OF ALCOHOL ABUSE AND ADDICTION. ALCOHOL USE DISORDER IS A CHRONIC DEBILITATED CONDITION ADVERSELY AFFECTING THE LIVES OF MILLIONS OF INDIVIDUALS THROUGHOUT THE MODERN WORLD. INDIVIDUALS SUFFERING FROM AN ALCOHOL USE DISORDER DIAGNOSIS FREQUENTLY HAVE SERIOUS COOCCURRING CONDITIONS, WHICH OFTEN FURTHER EXACERBATES PROBLEMATIC DRINKING BEHAVIOR. COMPREHENDING THE BIOCHEMICAL PROCESSES UNDERLYING THE PROGRESSION AND PERPETUATION OF DISEASE IS ESSENTIAL FOR MITIGATING MALADAPTIVE BEHAVIOR IN ORDER TO RESTORE BOTH PHYSIOLOGICAL AND PSYCHOLOGICAL HEALTH. THE RANGE OF CELLULAR AND BIOLOGICAL SYSTEMS CONTRIBUTING TO, AND AFFECTED BY, ALCOHOL USE DISORDER AND OTHER COMORBID DISORDERS NECESSITATES A FUNDAMENTAL GRASP OF INTRICATE FUNCTIONAL RELATIONSHIPS THAT GOVERN MOLECULAR BIOLOGY. EPIGENETIC FACTORS ARE RECOGNIZED AS ESSENTIAL MEDIATORS OF CELLULAR BEHAVIOR, ORCHESTRATING A SYMPHONY OF GENE EXPRESSION CHANGES WITHIN MULTICELLULAR ENVIRONMENTS THAT ARE ULTIMATELY RESPONSIBLE FOR DIRECTING HUMAN BEHAVIOR. UNDERSTANDING THE EPIGENETIC AND TRANSCRIPTIONAL REGULATORY MECHANISMS INVOLVED IN THE PATHOGENESIS OF DISEASE IS IMPORTANT FOR IMPROVING AVAILABLE PHARMACOTHERAPIES AND REDUCING THE INCIDENCE OF ALCOHOL ABUSE AND COOCCURRING CONDITIONS. 2021 14 5809 26 STRAWBERRY AND HUMAN HEALTH: EFFECTS BEYOND ANTIOXIDANT ACTIVITY. THE USEFULNESS OF A DIET RICH IN VEGETABLES AND FRUITS ON HUMAN HEALTH HAS BEEN WIDELY RECOGNIZED: A HIGH INTAKE OF ANTIOXIDANT AND BIOACTIVE COMPOUNDS MAY IN FACT PLAY A CRUCIAL ROLE IN THE PREVENTION OF SEVERAL DISEASES, SUCH AS CANCER, CARDIOVASCULAR, NEURODEGENERATIVE, AND OTHER CHRONIC PATHOLOGIES. THE STRAWBERRY (FRAGARIA X ANANASSA DUCH.) POSSESSES A REMARKABLE NUTRITIONAL COMPOSITION IN TERMS OF MICRONUTRIENTS, SUCH AS MINERALS, VITAMIN C, AND FOLATES, AND NON-NUTRIENT ELEMENTS, SUCH AS PHENOLIC COMPOUNDS, THAT ARE ESSENTIAL FOR HUMAN HEALTH. ALTHOUGH STRAWBERRY PHENOLICS ARE KNOWN MAINLY FOR THEIR ANTI-INFLAMMATORY AND ANTIOXIDANT ACTIONS, RECENT STUDIES HAVE DEMONSTRATED THAT THEIR BIOLOGICAL ACTIVITIES ALSO SPREAD TO OTHER PATHWAYS INVOLVED IN CELLULAR METABOLISM AND CELLULAR SURVIVAL. THIS PAPER HAS THE MAIN OBJECTIVE OF REVIEWING CURRENT INFORMATION ABOUT THE POTENTIAL MECHANISMS INVOLVED IN THE EFFECTS ELICITED BY STRAWBERRY POLYPHENOLS ON HUMAN HEALTH, DEVOTING SPECIAL ATTENTION TO THE LATEST FINDINGS. 2014 15 6642 37 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 16 6398 33 THE ROLE OF VITAMIN D AND VDR IN CARCINOGENESIS: THROUGH EPIDEMIOLOGY AND BASIC SCIENCES. IN THE LAST TWO DECADES VITAMIN D (VD) RESEARCH HAS DEMONSTRATED NEW EXTRASKELETAL ACTIONS OF THIS PRE-HORMONE, SUGGESTING A PROTECTIVE ROLE OF THIS SECOSTEROID IN THE ONSET, PROGRESSION AND PROGNOSIS OF SEVERAL CHRONIC NONCOMMUNICABLE DISEASES, SUCH AS CARDIOVASCULAR DISEASE, DIABETES MELLITUS OR CANCER. REGARDING CARCINOGENESIS, BOTH PRECLINICAL AND EPIDEMIOLOGICAL EVIDENCE AVAILABLE SHOW ONCOPROTECTIVE ACTIONS OF VD AND ITS RECEPTOR, THE VDR. HOWEVER, IN LATE NEOPLASTIC STAGES THE VD SYSTEM (VDS) SEEMS TO BE LESS FUNCTIONAL, WHICH APPEARS TO BE DUE TO AN EPIGENETIC SILENCING OF THE SYSTEM. IN PRECLINICAL EXPERIMENTAL STUDIES, VD PRESENTS ONCOPROTECTIVE ACTIONS THROUGH MODULATION OF INFLAMMATION, CELL PROLIFERATION, CELL DIFFERENTIATION, ANGIOGENESIS, INVASIVE AND METASTATIC POTENTIAL, APOPTOSIS, MIRNA EXPRESSION REGULATION AND MODULATION OF THE HEDGEHOG SIGNALLING PATHWAY. MOREOVER, EPIDEMIOLOGICAL EVIDENCE POINTS TOWARDS AN ONCOPROTECTIVE ROLE OF VITAMIN D AND VDR IN COLORECTAL CANCER. THIS ASSOCIATION IS MORE CONTROVERSIAL WITH BREAST, OVARIAN AND PROSTATE CANCERS, ALTHOUGH WITH A FEW ADVERSE EFFECTS. NONETHELESS, WE SHOULD CONSIDER OTHER FACTORS TO DETERMINE THE BENEFIT OF INCREASED SERUM CONCENTRATION OF VD. MUCH OF THE EPIDEMIOLOGICAL EVIDENCE IS STILL INCONCLUSIVE, AND WE WILL HAVE TO WAIT FOR NEW, BETTER-DESIGNED ONGOING RCTS AND THEIR RESULTS TO DISCERN THE REAL EFFECT OF VITAMIN D IN CANCER RISK REDUCTION AND THERAPY. THE OBJECTIVE OF THIS LITERATURE REVIEW IS TO OFFER AN UP-TO-DATE ANALYSIS OF THE ROLE OF THE VD AND VDR, IN THE ONSET, PROGRESSION AND PROGNOSIS OF ALL TYPES OF CANCER. WE FURTHER DISCUSS THE AVAILABLE LITERATURE AND SUGGEST NEW HYPOTHESES AND FUTURE CHALLENGES IN THE FIELD OF VD RESEARCH. 2017 17 68 39 A MECHANISTIC MODEL FOR YOGA AS A PREVENTIVE AND THERAPEUTIC MODALITY. YOGA IS AN ANCIENT INDIAN TECHNIQUE OF HEALTHY LIVING. NUMEROUS STUDIES HAVE CORROBORATED YOGA'S BENEFICIAL EFFECTS, INCLUDING A FAVORABLE INFLUENCE ON AUTONOMIC FUNCTION AND NEGATIVE EMOTIONS. EXTENSIVE RESEARCH IN THE LAST FEW DECADES HAS REVEALED THE CRITICAL ROLE THAT YOGA CAN PLAY IN ERADICATING STRESS. THIS HAS LAID TO THE FOUNDATION FOR A SCIENTIFIC UNDERSTANDING OF PATHOPHYSIOLOGICAL CHANGES ATTRIBUTED TO STRESS, PARTICULARLY AT THE MOLECULAR AND GENETIC LEVELS. THIS PRIMARILY HAS HELPED UNDERSTAND THE EPIGENETIC AND GENETIC MECHANISM AT PLAY TO INDUCE AND ALLEVIATE STRESS, PARTICULARLY THOSE RELATED TO EMOTIONAL ABERRATIONS. AS RESEARCH HAS INDICATED, NEGATIVE EMOTIONS ARE TRANSLATED INTO VASCULAR INFLAMMATION APPROPRIATELY ACCENTUATED BY A SYMPATHETIC PREDOMINANT AUTONOMIC FUNCTION. THIS CASCADE IS BOLSTERED BY MULTIPLE FACTORS, INCLUDING ACTIVATION OF "STRESSOR" GENES AND ELABORATING HORMONES, INCLUDING STEROIDS WITH SOMETIMES NOCUOUS CONSEQUENCES, PARTICULARLY WHEN CHRONIC. YOGA HAS BEEN CATEGORICALLY FOUND TO HAVE INHIBITED EACH AND EVERY ONE OF THESE BANEFUL EFFECTS OF STRESS. IN FACT, IT ALSO CHANGES THE NEURONAL CIRCUITS THAT POTENTIATE SUCH A PLETHORA OF PATHOLOGICAL CHANGES. THIS, IN TURN, HAS ACCENTUATED YOGA'S RELEVANCE AS A POWERFUL PREVENTIVE INTERVENTION IN NONCOMMUNICABLE DISEASES (NCD). NCDS, INCLUDING HEART DISEASE, STROKE, AND RHEUMATOLOGICAL DISORDERS, ARE ESSENTIALLY INFLAMMATORY DISEASES THAT PERPETUATE INFLAMMATION IN DIFFERENT BEDS LIKE VASCULAR OR JOINT SPACES. THE PRECISE MECHANISM BY WHICH YOGA INDUCES SUCH BENEFICIAL CHANGES IS YET TO BE DELINEATED. HOWEVER, A CORNUCOPIA OF POINTERS INDICATES THAT NEURAL, ENDOCRINE, IMMUNOLOGICAL, CELLULAR, GENETIC, AND EPIGENETIC MECHANISMS ARE AT PLAY. THIS ARTICLE ATTEMPTS TO COBBLE TOGETHER NEWFANGLED RESEARCH TO DELINEATE A MEDICAL MODEL FOR THIS 5000-YEAR-OLD PRACTICE FROM INDIA. THIS IS IMPERATIVE, AS A MECHANISTIC MODEL OF THIS ANCIENT-BUT-COMPLEX SYSTEM WOULD ENABLE A MORE COMPREHENSIVE UNDERSTANDING OF ITS MECHANISM AND REVEAL ITS YET-UNDISCOVERED POSITIVE HEALTH EFFECTS. 2021 18 3515 40 IDO AND KYNURENINE METABOLITES IN PERIPHERAL AND CNS DISORDERS. THE IMPORTANCE OF THE KYNURENINE PATHWAY IN NORMAL IMMUNE SYSTEM FUNCTION HAS LED TO AN APPRECIATION OF ITS POSSIBLE CONTRIBUTION TO AUTOIMMUNE DISORDERS SUCH AS RHEUMATOID ARTHRITIS. INDOLEAMINE-2,3-DIOXYGENASE (IDO) ACTIVITY EXERTS A PROTECTIVE FUNCTION, LIMITING THE SEVERITY OF EXPERIMENTAL ARTHRITIS, WHEREAS DELETION OR INHIBITION EXACERBATES THE SYMPTOMS. OTHER CHRONIC DISORDER WITH AN INFLAMMATORY COMPONENT, SUCH AS ATHEROSCLEROSIS, ARE ALSO SUPPRESSED BY IDO ACTIVITY. IT IS SUGGESTED THAT THIS OVERALL ANTI-INFLAMMATORY ACTIVITY IS MEDIATED BY A CHANGE IN THE RELATIVE PRODUCTION OR ACTIVITY OF TH17 AND REGULATORY T CELL POPULATIONS. KYNURENINES MAY PLAY AN ANTI-INFLAMMATORY ROLE ALSO IN CNS DISORDERS SUCH AS HUNTINGTON'S DISEASE, ALZHEIMER'S DISEASE AND MULTIPLE SCLEROSIS, IN WHICH SIGNS OF INFLAMMATION AND NEURODEGENERATION ARE INVOLVED. THE POSSIBILITY IS DISCUSSED THAT IN HUNTINGTON'S DISEASE KYNURENINES INTERACT WITH OTHER ANTI-INFLAMMATORY MOLECULES SUCH AS HUMAN LYMPHOCYTE ANTIGEN-G WHICH MAY BE RELEVANT IN OTHER DISORDERS. KYNURENINE INVOLVEMENT MAY ACCOUNT FOR THE PROTECTION AFFORDED TO ANIMALS WITH CEREBRAL MALARIA AND TRYPANOSOMIASIS WHEN THEY ARE TREATED WITH AN INHIBITOR OF KYNURENINE-3-MONOXYGENASE (KMO). THERE IS SOME EVIDENCE THAT CHANGES IN IL-10 MAY CONTRIBUTE TO THIS PROTECTION AND THE RELATIONSHIP BETWEEN KYNURENINES AND IL-10 IN ARTHRITIS AND OTHER INFLAMMATORY CONDITIONS SHOULD BE EXPLORED. IN ADDITION, METABOLITES OF KYNURENINE DOWNSTREAM OF KMO, SUCH AS ANTHRANILIC ACID AND 3-HYDROXY-ANTHRANILIC ACID CAN INFLUENCE INFLAMMATION, AND THE RATIO OF THESE COMPOUNDS IS A VALUABLE BIOMARKER OF INFLAMMATORY STATUS ALTHOUGH THE UNDERLYING MOLECULAR MECHANISMS OF THE CHANGES REQUIRE CLARIFICATION. HENCE IT IS ESSENTIAL THAT MORE EFFORT BE EXPENDED TO IDENTIFY THEIR SITES OF ACTION AS POTENTIAL TARGETS FOR DRUG DEVELOPMENT. FINALLY, WE DISCUSS INCREASING AWARENESS OF THE EPIGENETIC REGULATION OF IDO, FOR EXAMPLE BY DNA METHYLATION, A PHENOMENON WHICH MAY EXPLAIN DIFFERENCES BETWEEN INDIVIDUALS IN THEIR SUSCEPTIBILITY TO ARTHRITIS AND OTHER INFLAMMATORY DISORDERS. 2020 19 4019 31 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) (