1 6433 108 THE VINDICATION OF LAMARCK? EPIGENETICS AT THE INTERSECTION OF LAW AND MENTAL HEALTH. RESEARCH ON EPIGENETIC MECHANISMS IS GAINING TRACTION, YET IS POORLY UNDERSTOOD BY CRIMINOLOGISTS AND BEHAVIORAL SCIENTISTS. THE CURRENT OBJECTIVE IS TO REVIEW RELEVANT STUDIES OF INTEREST TO BEHAVIORAL SCIENTISTS WHO STUDY CRIME, AND TO TRANSLATE ADMITTEDLY CHALLENGING SCIENTIFIC INFORMATION INTO TEXT THAT IS DIGESTIBLE TO THE AVERAGE CRIMINOLOGIST. USING SYSTEMATIC SEARCH PROCEDURES THE AUTHORS IDENTIFIED AND REVIEWED 41 STUDIES OF EPIGENETIC MECHANISMS IN PSYCHIATRIC AND BEHAVIORAL PHENOTYPES AMONG HUMANS. FINDINGS REVEALED SIGNIFICANT EPIGENETIC EFFECTS IN AN ASSORTMENT OF GENES THAT ARE IMPLICATED IN THE ETIOLOGY OF DEPRESSION, SUICIDALITY, CALLOUS-UNEMOTIONAL TRAITS, AND CHRONIC AND INTERGENERATIONAL AGGRESSIVE BEHAVIOR. SEVERAL POLYMORPHISMS THAT MEDIATE THE HPA AXIS, NEUROTRANSMISSION, IMMUNE RESPONSE, BRAIN DEVELOPMENT, SEROTONIN SYNTHESIS, AND OTHER PROCESSES WERE FOUND. ALTHOUGH PRESCRIPTIVE KNOWLEDGE BASED ON EPIGENETIC FINDINGS TO DATE IS PREMATURE, EPIGENETICS IS A NEW AND EXCITING SCIENTIFIC FRONTIER NOT TOO DIFFERENT IN SPIRIT FROM LAMARCK'S OBSERVATIONS CENTURIES AGO.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
2 4834  26 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	

3 3899  15 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
4 6911  20 [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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
5 2568  18 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
6 4019  28 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
7 5213  17 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
8 4665  22 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 6351  33 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
10 2603  29 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	
                                                                                                                                                                                                                                                                                                                                                                                                           
11 6815  20 [EVOLUTIONARY ONTOGENETIC ASPECTS OF PATHOGENETICS OF CHRONIC HUMAN DISEASES]. THIS ARTICLE IS A REVIEW OF SCIENTIFIC PUBLICATIONS, IN WHICH ISSUES OF PATHOGENETICS OF MULTIFACTORIAL DISEASES (MFDS) ARE CONSIDERED FROM THE VIEWPOINT OF EVOLUTION AND ONTOGENY. CONCEPTS EXPLAINING SIGNIFICANCE OF EVOLUTIONARY PROCESSES IN THE FORMATION OF GENETIC ARCHITECTURE OF HUMAN CHRONIC DISEASES ("THRIFTY" GENOMES AND PHENOTYPES, "DRIFTING GENES," DECANALIZATION) ARE ANALYZED. THE ROLES OF NATURAL SELECTION AND GENETIC DRIFT IN THE FORMATION OF HEREDITARY DIVERSITY OF GENES FOR SUSCEPTIBILITY TO MFDS ARE CONSIDERED. THE MODERN CONCEPT OF DISEASE ONTOGENY (SOMATIC MOSAICISM, LOSS OFHETEROZYGOSITY, PARADOMINANT INHERITANCE, EPIGENETIC VARIABILITY) IS DISCUSSED. IT IS DEMONSTRATED THAT THE EVOLUTIONARY AND ONTOGENETIC APPROACHES TO ANALYSIS OF GENIMUC AND OTHER "-OMIC" DATA ARE ESSENTIAL FOR UNDERSTANDING THE BIOLOGY OF DISEASES.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
12 5374  27 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
13 3002  23 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
14 6484  22 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
15 5500  23 REVISITING MIGRAINE: THE EVOLVING PATHOPHYSIOLOGY AND THE EXPANDING MANAGEMENT ARMAMENTARIUM. MIGRAINE AFFECTS ABOUT ONE BILLION PEOPLE WORLDWIDE YEARLY AND IS ONE OF THE MOST COMMON NEUROLOGIC ILLNESSES, WITH A HIGH PREVALENCE AND MORBIDITY, PARTICULARLY AMONG YOUNG ADULTS AND FEMALES. MIGRAINE IS ASSOCIATED WITH MANY COMORBIDITIES, INCLUDING STRESS, SLEEP DIFFICULTIES, AND SUICIDAL IDEATION. MIGRAINE, DESPITE ITS WIDESPREAD OCCURRENCE, IS UNDERDIAGNOSED AND UNDERTREATED. BECAUSE OF THE COMPLICATED AND PRIMARILY UNKNOWN MECHANISMS OF MIGRAINE FORMATION, SEVERAL SOCIAL AND BIOLOGICAL RISK FACTORS, SUCH AS HORMONE IMBALANCES, GENETIC AND EPIGENETIC IMPACTS, AND CARDIOVASCULAR, NEUROLOGICAL, AND AUTOIMMUNE ILLNESSES, HAVE BEEN PROPOSED. THROUGH THE MID-20TH CENTURY DIVERSION OF THE NOW-DEFUNCT VASCULAR THEORY, THE PATHOPHYSIOLOGY OF MIGRAINE HAS DEVELOPED FROM A HISTORICAL STUDY OF THE "HUMOURS" TO A DISTINCT ENTITY AS A NEUROLOGICAL DISORDER. THE RANGE OF THERAPEUTIC TARGETS HAS BROADENED SIGNIFICANTLY, INCREASING THE NUMBER OF SPECIALIZED CLINICAL TRIALS. UNDERSTANDING THE BIOLOGY OF MIGRAINE THROUGH CAREFUL RESEARCH HAS RESULTED IN THE IDENTIFICATION OF MAJOR THERAPEUTIC CLASSES: (I) TRIPTANS, SEROTONIN 5-HT1B/1D RECEPTOR AGONISTS, (II) GEPANTS, CALCITONIN GENE-RELATED PEPTIDE (CGRP) RECEPTOR ANTAGONISTS, (III) DITANS, 5-HT1F RECEPTOR AGONISTS, (IV) CGRP MONOCLONAL ANTIBODIES, AND (V) GLURANTS, MGLU5 MODULATORS, WITH FURTHER TARGETS BEING EXPLORED. THIS REVIEW PROVIDES A COMPREHENSIVE OVERVIEW OF THE MOST RECENT LITERATURE ON EPIDEMIOLOGY AND RISK FACTORS AND EXPOSES KNOWLEDGE GAPS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
16 1732  17 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
17 5809  22 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
18 4968  24 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
19 3465  29 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	
                                                                                                                                                                                                                                                                                      
20 5814  17 STRESS AND FELINE HEALTH. IN THE HEALTH SCIENCES, STRESS OFTEN IS DEFINED IN TERMS OF STRESSORS; EVENTS THAT ARE PERCEIVED AS THREATS TO ONE'S PERCEPTION OF CONTROL. FROM THIS PERSPECTIVE, A STRESSOR IS ANYTHING THAT ACTIVATES THE CENTRAL THREAT RESPONSE SYSTEM (CTRS). RECENT RESEARCH SHOWS THAT THE CTRS CAN BE SENSITIZED TO ENVIRONMENTAL EVENTS THROUGH EPIGENETIC MODULATION OF GENE EXPRESSION. WHEN CTRS ACTIVATION IS CHRONIC, HEALTH AND WELFARE MAY BE HARMED. ENVIRONMENTAL MODIFICATION CAN MITIGATE THE HARMFUL EFFECTS OF CHRONIC CTRS ACTIVATION BY REDUCING THE INDIVIDUAL'S PERCEPTION OF THREAT AND INCREASING ITS PERCEPTION OF CONTROL, WHICH IMPROVES HEALTH AND WELFARE.	2020