1 1156 173 CONSIDERING THE USE OF THE TERMS STRAIN AND ADAPTATION IN PRION RESEARCH. EVOLUTIONARY BIOLOGISTS AND DISEASE BIOLOGISTS USE THE TERMS STRAIN AND ADAPTATION IN CHRONIC WASTING DISEASE (CWD) RESEARCH IN DIFFERENT WAYS. IN EVOLUTIONARY BIOLOGY, A STRAIN IS A NASCENT GENETIC LINEAGE THAT CAN BE DESCRIBED BY A GENEALOGY, AND A PHYLOGENETIC NOMENCLATURE CONSTRUCTED TO REFLECT THAT GENEALOGY. PRION STRAINS ARE DESCRIBED AS SHOWING DISTINCT HOST RANGE, CLINICAL PRESENTATION, DISEASE PROGRESSION, AND NEUROPATHOLOGICAL AND PRP BIOCHEMICAL PROFILES, AND LACK INFORMATION THAT WOULD PERMIT PHYLOGENETIC RECONSTRUCTION OF THEIR HISTORY. PRION STRAINS ARE ALTERNATIVE PROTEIN CONFORMATIONS, SOMETIMES DERIVED FROM THE SAME GENOTYPE. I SUGGEST REFERRING TO PRION STRAINS AS ECOTYPES, BECAUSE THE VARIANT PHENOTYPIC CONFORMATIONS ("STRAINS") ARE A FUNCTION OF THE INTERACTION BETWEEN PRNP AMINO ACID GENOTYPE AND THE HOST ENVIRONMENT. IN THE CASE OF CWD, A PRION ECOTYPE IN WHITE-TAILED DEER WOULD BE DESCRIBED BY ITS GENOTYPE AND THE HOST IN WHICH IT OCCURS, SUCH AS THE H95 + ECOTYPE. HOWEVER, AN EVOLUTIONARY NOMENCLATURE IS DIFFICULT BECAUSE NOT ALL INDIVIDUALS WITH THE SAME PRNP GENOTYPE SHOW SIGNS OF CWD, THEREFORE CREATING A NOMENCLATURE REFLECTING AND ONE-TO-ONE RELATIONSHIP BETWEEN PRNP GENEALOGY AND CWD PRESENCE IS DIFFICULT. FURTHERMORE, VERY LITTLE INFORMATION EXISTS ON THE PHYLOGENETIC DISTRIBUTION OF CWD ECOTYPES IN WILD DEER POPULATIONS. ADAPTATION HAS A CLEAR MEANING IN EVOLUTIONARY BIOLOGY, THE DIFFERENTIAL SURVIVAL AND REPRODUCTION OF INDIVIDUAL GENOTYPES. IF A NEW PRION ECOTYPE ARISES IN A PARTICULAR HOST AND KILLS MORE HOSTS OR KILLS AT AN EARLIER AGE, IT IS THE ANTITHESIS OF THE EVOLUTIONARY DEFINITION OF ADAPTATION. HOWEVER, PRION STRAINS MIGHT BE TRANSMITTED ACROSS GENERATIONS EPIGENETICALLY, BUT WHETHER THIS REPRESENTS ADAPTATION DEPENDS ON THE FITNESS CONSEQUENCES OF THE STRAIN. PROTEIN PHENOTYPES OF PRNP THAT CAUSE TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES (TSES), AND CWD, ARE MALADAPTIVE AND WOULD NOT BE PROPAGATED GENETICALLY OR EPIGENETICALLY VIA A PROCESS CONSISTENT WITH AN EVOLUTIONARY VIEW OF ADAPTATION. I SUGGEST TERMING THE PROCESS OF PRION STRAIN ORIGINATION "PHENOTYPIC TRANSFORMATION", AND ONLY ADAPTATION IF EVIDENCE SHOWS THEY ARE NOT MALADAPTIVE AND PERSIST OVER EVOLUTIONARY TIME PERIODS (E.G., THOUSANDS OF GENERATIONS) AND ACROSS DISTINCT SPECIES BOUNDARIES (VIA INHERITANCE). THUS, PRION BIOLOGISTS USE STRAIN AND ADAPTATION, HISTORICALLY EVOLUTIONARY TERMS, IN QUITE DIFFERENT WAYS. 2021 2 3393 50 HOST DETERMINANTS OF PRION STRAIN DIVERSITY INDEPENDENT OF PRION PROTEIN GENOTYPE. PHENOTYPIC DIVERSITY IN PRION DISEASES CAN BE SPECIFIED BY PRION STRAINS IN WHICH BIOLOGICAL TRAITS ARE PROPAGATED THROUGH AN EPIGENETIC MECHANISM MEDIATED BY DISTINCT PRP(SC) CONFORMATIONS. WE INVESTIGATED THE ROLE OF HOST-DEPENDENT FACTORS ON PHENOTYPIC DIVERSITY OF CHRONIC WASTING DISEASE (CWD) IN DIFFERENT HOST SPECIES THAT EXPRESS THE SAME PRION PROTEIN GENE (PRNP). TWO CWD STRAINS THAT HAVE DISTINCT BIOLOGICAL, BIOCHEMICAL, AND PATHOLOGICAL FEATURES WERE IDENTIFIED IN TRANSGENIC MICE THAT EXPRESS THE SYRIAN GOLDEN HAMSTER (SGH) PRNP. THE CKY STRAIN OF CWD HAD A SHORTER INCUBATION PERIOD THAN THE WST STRAIN OF CWD, BUT AFTER TRANSMISSION TO SGH, THE INCUBATION PERIOD OF CKY CWD WAS APPROXIMATELY 150 DAYS LONGER THAN WST CWD. LIMITED PROTEINASE K DIGESTION REVEALED STRAIN-SPECIFIC PRP(SC) POLYPEPTIDE PATTERNS THAT WERE MAINTAINED IN BOTH HOSTS, BUT THE SOLUBILITY AND CONFORMATIONAL STABILITY OF PRP(SC) DIFFERED FOR THE CWD STRAINS IN A HOST-DEPENDENT MANNER. WST CWD PRODUCED PRP(SC) AMYLOID PLAQUES IN THE BRAIN OF THE SGH THAT WERE PARTIALLY INSOLUBLE AND STABLE AT A HIGH CONCENTRATION OF PROTEIN DENATURANT. HOWEVER, IN TRANSGENIC MICE, PRP(SC) FROM WST CWD DID NOT ASSEMBLE INTO PLAQUES, WAS HIGHLY SOLUBLE, AND HAD LOW CONFORMATIONAL STABILITY. SIMILAR STUDIES USING THE HY AND DY STRAINS OF TRANSMISSIBLE MINK ENCEPHALOPATHY RESULTED IN MINOR DIFFERENCES IN PRION BIOLOGICAL AND PRP(SC) PROPERTIES BETWEEN TRANSGENIC MICE AND SGH. THESE FINDINGS INDICATE THAT HOST-SPECIFIC PATHWAYS THAT ARE INDEPENDENT OF PRNP CAN ALTER THE PRP(SC) CONFORMATION OF CERTAIN PRION STRAINS, LEADING TO CHANGES IN THE BIOPHYSICAL PROPERTIES OF PRP(SC), NEUROPATHOLOGY, AND CLINICAL PRION DISEASE. IMPORTANCE: PRIONS ARE MISFOLDED PATHOGENIC PROTEINS THAT CAUSE NEURODEGENERATION IN HUMANS AND ANIMALS. TRANSMISSIBLE PRION DISEASES EXHIBIT A SPECTRUM OF DISEASE PHENOTYPES AND THE BASIS OF THIS DIVERSITY IS ENCODED IN THE STRUCTURE OF THE PATHOGENIC PRION PROTEIN AND PROPAGATED BY AN EPIGENETIC MECHANISM. IN THE PRESENT STUDY, WE INVESTIGATED PRION DIVERSITY IN TWO HOSTS SPECIES THAT EXPRESS THE SAME PRION PROTEIN GENE. WHILE PRIOR REPORTS HAVE DEMONSTRATED THAT PRION STRAIN PROPERTIES ARE STABLE UPON INFECTION OF THE SAME HOST SPECIES AND PRION PROTEIN GENOTYPE, OUR FINDINGS INDICATE THAT CERTAIN PRION STRAINS CAN UNDERGO DRAMATIC CHANGES IN BIOLOGICAL PROPERTIES THAT ARE NOT DEPENDENT ON THE PRION PROTEIN. THEREFORE, HOST FACTORS INDEPENDENT OF THE PRION PROTEIN CAN AFFECT PRION DIVERSITY. UNDERSTANDING HOW HOST PATHWAYS CAN MODIFY PRION DISEASE PHENOTYPES MAY PROVIDE CLUES ON HOW TO ALTER PRION FORMATION AND LEAD TO TREATMENTS FOR PRION, AND OTHER, HUMAN NEURODEGENERATIVE DISEASES OF PROTEIN MISFOLDING. 2015 3 3418 31 HUMAN HEALTH CONSEQUENCES OF ENVIRONMENTALLY-MODULATED GENE EXPRESSION: POTENTIAL ROLES OF ELF-EMF INDUCED EPIGENETIC VERSUS MUTAGENIC MECHANISMS OF DISEASE. IN ORDER TO DETERMINE IF THERE MIGHT BE BIOLOGICAL AND HEALTH CONSEQUENCES AFTER EXPOSURES TO EXTREMELY-LOW FREQUENCY ELECTROMAGNETIC FIELDS (ELF-EMF), EITHER EXPERIMENTALLY OR EPIDEMIOLOGICALLY, MECHANISTIC UNDERSTANDING OF THE POTENTIAL MEANS BY WHICH ANY ENVIRONMENTAL AGENT CAN AFFECT CELLS IN A MULTICELLULAR ORGANISM HAS TO BE REVIEWED. THE GOAL OF THIS LIMITED REVIEW IS TO DEMONSTRATE THAT, WHILE THE PREVAILING PARADIGM OF THE ENVIRONMENTALLY-INDUCED ACUTE AND CHRONIC DISEASES INVOLVES EITHER CELL KILLING (CYTOTOXICITY) OR GENE/CHROMOSOME MUTATIONS (GENOTOXICITY), ALTERATION OF THE EXPRESSION OF GENETIC INFORMATION AT THE TRANSCRIPTIONAL (TURNING GENES "ON" OR "OFF"), TRANSLATIONAL (STABILIZING OR DE-STABILIZING THE GENETIC MESSAGE), OR POSTTRANSLATIONAL (ALTERING THE GENE PRODUCT OR PROTEIN) LEVELS HAS THE POTENTIAL TO CONTRIBUTE TO VARIOUS DISEASES. THIS LATTER MECHANISM, "EPIGENETIC" TOXICITY, UNLIKE THE FORMER TWO WHICH ARE IRREVERSIBLE, IS CHARACTERIZED BY THRESHOLD-LIKE ACTION, MULTIPLE BIOCHEMICAL PATHWAYS AND CHRONIC, REGULAR EXPOSURES TO BE EFFECTIVE. ULTIMATELY, EPIGENETIC TOXICANTS AFFECT ONE OF FOUR POTENTIAL CELL STATES, NAMELY ALTERATION OF CELL PROLIFERATION, CELL DIFFERENTIATION, PROGRAMMED CELL DEATH (APOPTOSIS) OR ADAPTIVE RESPONSES OF DIFFERENTIATED CELLS. 2000 4 1639 37 DOES EPIGENETIC 'MEMORY' OF EARLY-LIFE STRESS PREDISPOSE TO CHRONIC PAIN IN LATER LIFE? A POTENTIAL ROLE FOR THE STRESS REGULATOR FKBP5. ANIMAL BEHAVIOURS ARE AFFECTED NOT ONLY BY INHERITED GENES BUT ALSO BY ENVIRONMENTAL EXPERIENCES. FOR EXAMPLE, IN BOTH RATS AND HUMANS, STRESSFUL EARLY-LIFE EVENTS SUCH AS BEING REARED BY AN INATTENTIVE MOTHER CAN LEAVE A LASTING TRACE AND AFFECT LATER STRESS RESPONSE IN ADULT LIFE. THIS IS OWING TO A CHEMICAL TRACE LEFT ON THE CHROMATIN ATTRIBUTED TO SO-CALLED EPIGENETIC MECHANISMS. SUCH AN EPIGENETIC TRACE OFTEN HAS CONSEQUENCES, SOMETIMES LONG-LASTING, ON THE FUNCTIONING OF OUR GENES, THEREBY ALLOWING INDIVIDUALS TO RAPIDLY ADAPT TO A NEW ENVIRONMENT. ONE GENE UNDER SUCH EPIGENETIC CONTROL IS FKBP5, THE GENE THAT ENCODES THE PROTEIN FKPB51, A CRUCIAL REGULATOR OF THE STRESS AXIS AND A SIGNIFICANT DRIVER OF CHRONIC PAIN STATES. IN THIS ARTICLE, WE WILL DISCUSS THE POSSIBILITY THAT EXPOSURE TO STRESS COULD DRIVE THE SUSCEPTIBLY TO CHRONIC PAIN VIA EPIGENETIC MODIFICATIONS OF GENES WITHIN THE STRESS AXIS SUCH AS FKBP5. THE POSSIBILITY THAT SUCH MODIFICATIONS, AND THEREFORE, THE SUSCEPTIBILITY TO CHRONIC PAIN, COULD BE TRANSMITTED ACROSS GENERATIONS IN MAMMALS AND WHETHER SUCH MECHANISMS MAY BE EVOLUTIONARILY CONSERVED ACROSS PHYLA WILL ALSO BE DEBATED. THIS ARTICLE IS PART OF THE THEO MURPHY MEETING ISSUE 'EVOLUTION OF MECHANISMS AND BEHAVIOUR IMPORTANT FOR PAIN'. 2019 5 761 35 CATEGORIZING THE CHARACTERISTICS OF HUMAN CARCINOGENS: A NEED FOR SPECIFICITY. THE INTERNATIONAL AGENCY FOR RESEARCH ON CANCER (IARC) HAS RECENTLY PROPOSED EMPLOYING "TEN KEY CHARACTERISTICS OF HUMAN CARCINOGENS" (TKCS) TO DETERMINE THE POTENTIAL OF AGENTS FOR HARMFUL EFFECTS. THE TKCS SEEM LIKELY TO CONFUSE THE UNSATISFACTORY CORRELATION FROM TESTING REGIMES THAT HAVE IGNORED THE DIFFERENCES EVIDENT WHEN CELLULAR CHANGES ARE COMPARED IN SHORT AND LONG-LIVED SPECIES, WITH THEIR VERY DIFFERENT STEM CELL AND SOMATIC CELL PHYLOGENIES. THE PROPOSED CHARACTERISTICS ARE SO BROAD THAT THEIR USE WILL LEAD TO AN INCREASE IN THE CURRENT UNACCEPTABLY HIGH RATE OF FALSE POSITIVES. IT COULD BE AN INFORMATIVE EXPERIMENT TO TAKE WELL-ESTABLISHED APPROVED THERAPEUTICS WITH WELL-KNOWN HUMAN SAFETY PROFILES AND TEST THEM AGAINST THIS NEW TKC PARADIGM. CANCERS ARE INITIATED AND DRIVEN BY HERITABLE AND TRANSIENT CHANGES IN GENE EXPRESSION, EXPAND CLONALLY, AND PROGRESS VIA ADDITIONAL ASSOCIATED ACQUIRED MUTATIONS AND EPIGENETIC ALTERATIONS THAT PROVIDE CELLS WITH AN EVOLUTIONARY ADVANTAGE. THE GENOTOXICITY TESTING PROTOCOLS CURRENTLY EMPLOYED AND REQUIRED BY REGULATION, EMPHASIZE TESTING FOR THE MUTATIONAL POTENTIAL OF THE TEST AGENT. TWO-YEAR, CHRONIC RODENT CANCER BIOASSAYS ARE INTENDED TO TEST FOR THE ENTIRE SPECTRUM OF CARCINOGENIC TRANSFORMATION. THE USE OF CYTOTOXIC DOSES CAUSING INCREASED, SUSTAINED CELL PROLIFERATION THAT FACILITATES ACCUMULATED GENETIC DAMAGE LEADS TO A HIGH FALSE-POSITIVE RATE OF TUMOR INDUCTION. CURRENT CANCER HAZARD ASSESSMENT PROTOCOLS AND WEIGHT-OF-THE-EVIDENCE ANALYSIS OF AGENT-SPECIFIC CANCER RISK ALIGN POORLY WITH THE PATHOGENESIS OF HUMAN CARCINOMA AND SO NEED MODERNIZATION AND IMPROVEMENT IN WAYS SUGGESTED HERE. 2021 6 2471 28 EPIGENETIC TRANSGENERATIONAL INHERITANCE OF ALTERED STRESS RESPONSES. ANCESTRAL ENVIRONMENTAL EXPOSURES HAVE PREVIOUSLY BEEN SHOWN TO PROMOTE EPIGENETIC TRANSGENERATIONAL INHERITANCE AND INFLUENCE ALL ASPECTS OF AN INDIVIDUAL'S LIFE HISTORY. IN ADDITION, PROXIMATE LIFE EVENTS SUCH AS CHRONIC STRESS HAVE DOCUMENTED EFFECTS ON THE DEVELOPMENT OF PHYSIOLOGICAL, NEURAL, AND BEHAVIORAL PHENOTYPES IN ADULTHOOD. WE USED A SYSTEMS BIOLOGY APPROACH TO INVESTIGATE IN MALE RATS THE INTERACTION OF THE ANCESTRAL MODIFICATIONS CARRIED TRANSGENERATIONALLY IN THE GERM LINE AND THE PROXIMATE MODIFICATIONS INVOLVING CHRONIC RESTRAINT STRESS DURING ADOLESCENCE. WE FIND THAT A SINGLE EXPOSURE TO A COMMON-USE FUNGICIDE (VINCLOZOLIN) THREE GENERATIONS REMOVED ALTERS THE PHYSIOLOGY, BEHAVIOR, METABOLIC ACTIVITY, AND TRANSCRIPTOME IN DISCRETE BRAIN NUCLEI IN DESCENDANT MALES, CAUSING THEM TO RESPOND DIFFERENTLY TO CHRONIC RESTRAINT STRESS. THIS ALTERATION OF BASELINE BRAIN DEVELOPMENT PROMOTES A CHANGE IN NEURAL GENOMIC ACTIVITY THAT CORRELATES WITH CHANGES IN PHYSIOLOGY AND BEHAVIOR, REVEALING THE INTERACTION OF GENETICS, ENVIRONMENT, AND EPIGENETIC TRANSGENERATIONAL INHERITANCE IN THE SHAPING OF THE ADULT PHENOTYPE. THIS IS AN IMPORTANT DEMONSTRATION IN AN ANIMAL THAT ANCESTRAL EXPOSURE TO AN ENVIRONMENTAL COMPOUND MODIFIES HOW DESCENDANTS OF THESE PROGENITOR INDIVIDUALS PERCEIVE AND RESPOND TO A STRESS CHALLENGE EXPERIENCED DURING THEIR OWN LIFE HISTORY. 2012 7 5810 32 STRESS & SLEEP: A RELATIONSHIP LASTING A LIFETIME. STRESS IS AN ADAPTATIVE RESPONSE AIMED AT RESTORING BODY HOMEOSTASIS. THE CLASSICAL NEUROENDOCRINE STRESS RESPONSE INVOLVING THE ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS MODULATES MANY PHYSIOLOGICAL ASPECTS, SUCH AS THE WAKE-SLEEP CYCLE. IN THE PRESENT REVIEW, WE WILL FIRST REPORT A SERIES OF HUMAN AND RODENT STUDIES SHOWING THAT EACH ACTOR OF THE HPA AXIS HAS THE POTENTIAL TO INTERFERE WITH SLEEP HOMEOSTASIS AND, THEN, WE WILL HIGHLIGHT HOW ACUTE OR CHRONIC STRESS DIFFERENTLY MODULATES THE WAKE-SLEEP CYCLE. MOREOVER, WE WILL PRESENT NEW AND INTERESTING STUDIES DEALING WITH THE RELATIONSHIP BETWEEN SLEEP AND STRESS ON A DIFFERENT (LONGER) TIME SCALE. PARTICULARLY, WE WILL DISCUSS HOW THE EXPOSURE TO PERINATAL STRESS, PROBABLY THROUGH EPIGENETIC MODULATIONS, IS SUFFICIENT TO CAUSE PERSISTENT SLEEP DERANGEMENTS DURING ADULT LIFE. IN LIGHT OF THIS EVIDENCE, THE MAIN MESSAGE OF THE PRESENT REVIEW IS THAT THE COMPLEX RELATIONSHIP BETWEEN SLEEP AND STRESS CHANGES DRAMATICALLY ON THE BASIS OF THE TIME SCALE CONSIDERED AND, CONSEQUENTLY, "TIME" SHOULD BE CONSIDERED AS A CRITICAL FACTOR WHEN FACING THIS TOPIC. 2020 8 1647 37 DOES THE STRESS OF LABORATORY LIFE AND EXPERIMENTATION ON ANIMALS ADVERSELY AFFECT RESEARCH DATA? A CRITICAL REVIEW. RECURRENT ACUTE AND/OR CHRONIC STRESS CAN AFFECT ALL VERTEBRATE SPECIES, AND CAN HAVE SERIOUS CONSEQUENCES. IT IS INCREASINGLY AND WIDELY APPRECIATED THAT LABORATORY ANIMALS EXPERIENCE SIGNIFICANT AND REPEATED STRESS, WHICH IS UNAVOIDABLE AND IS CAUSED BY MANY ASPECTS OF LABORATORY LIFE, SUCH AS CAPTIVITY, TRANSPORT, NOISE, HANDLING, RESTRAINT AND OTHER PROCEDURES, AS WELL AS THE EXPERIMENTAL PROCEDURES APPLIED TO THEM. SUCH STRESS IS DIFFICULT TO MITIGATE, AND LACK OF SIGNIFICANT DESENSITISATION/HABITUATION CAN RESULT IN CONSIDERABLE PSYCHOLOGICAL AND PHYSIOLOGICAL WELFARE PROBLEMS, WHICH ARE MEDIATED BY THE ACTIVATION OF VARIOUS NEUROENDOCRINE NETWORKS THAT HAVE NUMEROUS AND PERVASIVE EFFECTS. PSYCHOLOGICAL DAMAGE CAN BE REFLECTED IN STEREOTYPICAL BEHAVIOURS, INCLUDING REPETITIVE PACING AND CIRCLING, AND EVEN SELF-HARM. PHYSICAL CONSEQUENCES INCLUDE ADVERSE EFFECTS ON IMMUNE FUNCTION, INFLAMMATORY RESPONSES, METABOLISM, AND DISEASE SUSCEPTIBILITY AND PROGRESSION. FURTHER, SOME OF THESE EFFECTS ARE EPIGENETIC, AND ARE THEREFORE POTENTIALLY TRANSGENERATIONAL: THE BIOLOGY OF ANIMALS WHOSE PARENTS/GRANDPARENTS WERE WILD-CAUGHT AND/OR HAVE EXPERIENCED CHRONIC STRESS IN LABORATORIES COULD BE ALTERED, AS COMPARED TO FREE-LIVING INDIVIDUALS. IT IS ARGUED THAT THESE EFFECTS MUST HAVE CONSEQUENCES FOR THE RELIABILITY OF EXPERIMENTAL DATA AND THEIR EXTRAPOLATION TO HUMANS, AND THIS MAY NOT BE RECOGNISED SUFFICIENTLY AMONG THOSE WHO USE ANIMALS IN EXPERIMENTS. 2018 9 5966 31 TERMINAL ADDITION IN A CELLULAR WORLD. RECENT ADVANCES IN OUR UNDERSTANDING OF EVOLUTIONARY DEVELOPMENT PERMIT A REFRAMED APPRAISAL OF TERMINAL ADDITION AS A CONTINUOUS HISTORICAL PROCESS OF CELLULAR-ENVIRONMENTAL COMPLEMENTARITY. WITHIN THIS FRAME OF REFERENCE, EVOLUTIONARY TERMINAL ADDITIONS CAN BE IDENTIFIED AS ENVIRONMENTAL INDUCTION OF EPISODIC ADJUSTMENTS TO CELL-CELL SIGNALING PATTERNS THAT YIELD THE CELLULAR-MOLECULAR PATHWAYS THAT LEAD TO DIFFERING DEVELOPMENTAL FORMS. PHENOTYPES DERIVE, THEREBY, THROUGH CELLULAR MUTUALISTIC/COMPETITIVE NICHE CONSTRUCTIONS IN RECIPROCATING RESPONSIVENESS TO ENVIRONMENTAL STRESSES AND EPIGENETIC IMPACTS. IN SUCH TERMS, TERMINAL ADDITION FLOWS ACCORDING TO A LOGIC OF CELLULAR NEEDS CONFRONTING ENVIRONMENTAL CHALLENGES OVER SPACE-TIME. A RECONCILIATION OF EVOLUTIONARY DEVELOPMENT AND TERMINAL ADDITION CAN BE ACHIEVED THROUGH A COMBINED FOCUS ON CELL-CELL SIGNALING, MOLECULAR PHYLOGENIES AND A BROADER UNDERSTANDING OF EPIGENETIC PHENOMENA AMONG EUKARYOTIC ORGANISMS. WHEN UNDERSTOOD IN THIS MANNER, TERMINAL ADDITION HAS AN IMPORTANT ROLE IN EVOLUTIONARY DEVELOPMENT, AND CHRONIC DISEASE MIGHT BE CONSIDERED AS A FORM OF 'REVERSE EVOLUTION' OF THE SELF-SAME PROCESSES. 2018 10 2137 30 EPIGENETIC INHERITANCE AND EVOLUTION: A PATERNAL PERSPECTIVE ON DIETARY INFLUENCES. THE EARLIEST INDICATIONS FOR PATERNALLY INDUCED TRANSGENERATIONAL EFFECTS FROM THE ENVIRONMENT TO FUTURE GENERATIONS WERE BASED ON A SMALL NUMBER OF LONG-TERM EPIDEMIOLOGICAL STUDIES AND SOME EMPIRICAL OBSERVATIONS. ONLY RECENTLY HAVE EXPERIMENTAL ANIMAL MODELS AND A FEW ANALYSES ON HUMAN DATA EXPLORED THE TRANSGENERATIONAL NATURE OF PHENOTYPIC CHANGES OBSERVED IN OFFSPRING. CHANGES INCLUDE MULTIPLE METABOLIC DISORDERS, CANCER AND OTHER CHRONIC DISEASES. THESE PHENOTYPES CANNOT ALWAYS BE EXPLAINED BY MENDELIAN INHERITANCE, DNA MUTATIONS OR GENETIC DAMAGE. HENCE, A NEW COMPELLING THEORY ON EPIGENETIC INHERITANCE IS GAINING INTEREST, PROVIDING NEW CONCEPTS THAT EXTEND DARWIN'S EVOLUTIONARY THEORY. EPIGENETIC ALTERATIONS OR "EPIMUTATIONS" ARE BEING CONSIDERED TO EXPLAIN TRANSGENERATIONAL INHERITANCE OF PARENTALLY ACQUIRED TRAITS. THE RESPONSIBLE MECHANISMS FOR THESE EPIMUTATIONS INCLUDE DNA METHYLATION, HISTONE MODIFICATION, AND RNA-MEDIATED EFFECTS. THIS REVIEW EXPLORES THE LITERATURE ON A NUMBER OF TIME-DEPENDENT ENVIRONMENTALLY INDUCED EPIGENETIC ALTERATIONS, SPECIFICALLY THOSE FROM DIETARY EXPOSURES. WE SUGGEST A ROLE FOR THE MALE GERM LINE AS ONE OF NATURE'S TOOLS TO CAPTURE MESSAGES FROM OUR CONTINUOUSLY CHANGING ENVIRONMENT AND TO TRANSFER THIS INFORMATION TO SUBSEQUENT GENERATIONS. FURTHER, WE OPEN THE DISCUSSION THAT THE PATERNALLY INHERITED EPIGENETIC INFORMATION MAY CONTRIBUTE TO EVOLUTIONARY ADAPTATION. 2015 11 4399 31 MODULATION OF GENOMIC AND POSTGENOMIC ALTERATIONS IN NONCANCER DISEASES AND CRITICAL PERIODS OF LIFE. GENOMIC AND POSTGENOMIC CHANGES ARE EXTENSIVELY INVESTIGATED IN CANCER RESEARCH. SIMILAR ALTERATIONS, AFFECTING GENOME, TRANSCRIPTOME, MIRNOME AND/OR PROTEOME END-POINTS, HAVE BEEN DETECTED IN A VARIETY OF OTHER CHRONIC DEGENERATIVE DISEASES, SUCH AS ATHEROSCLEROSIS, DEGENERATIVE HEART DISEASES, CHRONIC OBSTRUCTIVE PULMONARY DISEASES, NEUROLOGICAL DISORDERS, EYE DISEASES, DIABETES, METABOLIC SYNDROME, SKIN AGEING AND ALOPECIA. NO GENERALIZATION CAN BE MADE DUE TO THE MYRIAD OF DIVERSE CLINICAL ENTITIES CLASSIFIED AS CHRONIC DEGENERATIVE DISEASES. MOREOVER, THE DETECTION OF MOLECULAR CHANGES DOES NOT AUTOMATICALLY IMPLY THEIR CAUSAL ROLE. NEVERTHELESS, COMMON MECHANISMS, SUCH AS DNA DAMAGE, EPIGENETIC ALTERATIONS, OXIDATIVE STRESS, AND CHRONIC INFLAMMATION, IN ADDITION TO GENETIC PREDISPOSITION, ARE OFTEN INVOLVED IN NONCANCER DISEASES. WE DEBATE HERE IN MORE DETAIL THE SUBJECTS OF CARDIOVASCULAR DISEASES AND OF SKIN DISEASES. MOREOVER, WE DISCUSS OUR EXPERIMENTAL STUDIES SUGGESTING THAT GENOMIC AND POSTGENOMIC CHANGES DO ALSO OCCUR DURING CRITICAL PERIODS OF LIFE, INCLUDING THE PRENATAL LIFE, THE PERINATAL PERIOD, AND AGEING. IN ADDITION, WE COMMENT ON THE FINDING THAT STEM-DERIVED CELLS ARE MORE SUSCEPTIBLE TO MOLECULAR DAMAGE THAN MORE DIFFERENTIATED CELLS. ALL THESE DATA ARE VIEWED IN THE PERSPECTIVE OF PREVENTIVE MEDICINE. IN FACT, THERE IS EVIDENCE THAT THE GENOMIC AND POSTGENOMIC ALTERATIONS OCCURRING NOT ONLY IN SEVERAL PATHOLOGICAL CONDITIONS BUT ALSO IN PARAPHYSIOLOGICAL SITUATIONS THAT AFFECT CRITICAL PERIODS OF LIFE CAN BE MODULATED BY MEANS OF DIETARY AND PHARMACOLOGICAL AGENTS. THE DISCOVERY THAT CHEMOPREVENTIVE AGENTS ARE ALSO ABLE TO ATTENUATE NUCLEOTIDE DAMAGE IN STEM-DERIVED CELLS WARRANTS FURTHER STUDIES IN VIEW OF POSSIBLE CLINICAL APPLICATIONS. 2009 12 3385 40 HOMEOSTATIC IMBALANCE AND COLON CANCER: THE DYNAMIC EPIGENETIC INTERPLAY OF INFLAMMATION, ENVIRONMENTAL TOXINS, AND CHEMOPREVENTIVE PLANT COMPOUNDS. THE ADVENT OF MODERN MEDICINE HAS ALLOWED FOR SIGNIFICANT ADVANCES WITHIN THE FIELDS OF EMERGENCY CARE, SURGERY, AND INFECTIOUS DISEASE CONTROL. HEALTH THREATS THAT WERE HISTORICALLY RESPONSIBLE FOR IMMEASURABLE TOLLS ON HUMAN LIFE ARE NOW ALL BUT ERADICATED WITHIN CERTAIN POPULATIONS, SPECIFICALLY THOSE THAT ENJOY HIGHER DEGREES OF SOCIO-ECONOMIC STATUS AND ACCESS TO HEALTHCARE. HOWEVER, MODERNIZATION AND ITS RESULTING LIFESTYLE TRENDS HAVE USHERED IN A NEW ERA OF CHRONIC ILLNESS; ONE IN WHICH AN UNPRECEDENTED NUMBER OF PEOPLE ARE ESTIMATED TO CONTRACT CANCER AND OTHER INFLAMMATORY DISEASES. HERE, WE EXPLORE THE IDEA THAT HOMEOSTASIS HAS BEEN REDEFINED WITHIN JUST A FEW GENERATIONS, AND THAT DISEASES SUCH AS COLORECTAL CANCER ARE THE RESULT OF FLUCTUATING PHYSIOLOGICAL AND MOLECULAR IMBALANCES. PHYTOCHEMICAL-DEPRIVED, PRO-INFLAMMATORY DIETS COMBINED WITH LOW-DOSE EXPOSURES TO ENVIRONMENTAL TOXINS, INCLUDING BISPHENOL-A (BPA) AND OTHER ENDOCRINE DISRUPTORS, ARE NOW LINKED TO INCREASING INCIDENCES OF CANCER IN WESTERNIZED SOCIETIES AND DEVELOPING COUNTRIES. THERE IS RECENT EVIDENCE THAT DISEASE DETERMINANTS ARE LIKELY SET IN UTERO AND FURTHER PERPETUATED INTO ADULTHOOD DEPENDENT UPON THE INNATE AND ENVIRONMENTALLY ACQUIRED PHENOTYPE UNIQUE TO EACH INDIVIDUAL. IN ORDER TO ADDRESS A DISEASE AS MULTI-FACTORIAL, CASE-SPECIFIC, AND REMARKABLY ADAPTIVE AS CANCER, RESEARCH MUST FOCUS ON ITS ROOT CAUSES IN ORDER TO ELUCIDATE THE MOLECULAR MECHANISMS BY WHICH THEY CAN BE PREVENTED OR COUNTERACTED VIA PLANT-DERIVED COMPOUNDS SUCH AS EPIGALLOCATECHIN-3-GALLATE (EGCG) AND RESVERATROL. THE SIGNIFICANT ROLE OF EPIGENETICS IN THE REGULATION OF THESE COMPLEX PROCESSES IS EMPHASIZED HERE TO FORM A COMPREHENSIVE VIEW OF THE DYNAMIC INTERACTIONS THAT INFLUENCE MODERN-DAY CARCINOGENESIS, AND HOW SENSIBLY RESTORING HOMEOSTATIC BALANCE MAY BE THE KEY TO THE CANCER RIDDLE. 2012 13 6853 36 [NEUROBIOLOGY OF EARLY LIFE TRAUMATIC STRESS AND TRAUMA: PROLONGED NEUROENDOCRINE DYSREGULATION AS A NEURODEVELOPMENTAL RISK FACTOR]. EARLY LIFE STRESSORS DISPLAY A HIGH UNIVERSAL PREVALENCE AND CONSTITUTE A MAJOR PUBLIC HEALTH PROBLEM WITH TWO THIRDS OF YOUTH BEING EXPOSED TO POTENTIALLY TRAUMATIC EXPERIENCES BY THE AGE OF 17. TRAUMATIC STRESS EXPOSURE DURING CRITICAL PERIODS OF DEVELOPMENT MAY HAVE ESSENTIAL AND LONG-LASTING EFFECTS ON THE PHYSICAL AND MENTAL HEALTH OF INDIVIDUALS AND REPRESENTS A DEVELOPMENTAL RISK FACTOR MEDIATING RISK FOR DISEASE. EARLY-LIFE STRESS (ELS) AND CHILDHOOD TRAUMA (CT) CAN BOTH HAVE AN IMPACT ON SENSITIVE NEURONAL BRAIN NETWORKS INVOLVED IN STRESS REACTIONS, AND COULD EXERT A PROGRAMMING EFFECT ON GLUCOCORTICOID SIGNALING LEADING TO CHRONIC HYPER- OR HYPO-ACTIVATION OF THE STRESS SYSTEM. IN ADDITION, ALTERATIONS IN EMOTIONAL AND AUTONOMIC REACTIVITY, CIRCADIAN RHYTHM DISRUPTION, FUNCTIONAL AND STRUCTURAL CHANGES IN THE BRAIN, AS WELL AS IMMUNE AND METABOLIC DYSREGULATION HAVE BEEN LATELY IDENTIFIED AS IMPORTANT RISK FACTORS FOR A CHRONICALLY IMPAIRED HOMEOSTATIC BALANCE AFTER ELS/CT. FURTHERMORE, HUMAN GENETIC BACKGROUND AND EPIGENETIC MODIFICATIONS THROUGH STRESS-RELATED GENE EXPRESSION COULD INTERACT WITH THESE ALTERATIONS AND EXPLAIN INTER-INDIVIDUAL VARIATION IN VULNERABILITY OR RESILIENCE TO STRESS. THIS NARRATIVE REVIEW PRESENTS RELEVANT EVIDENCE FROM MAINLY HUMAN RESEARCH ON THE MOST ACKNOWLEDGED NEUROBIOLOGICAL ALLOSTATIC PATHWAYS EXERTING ENDURING ADVERSE EFFECTS OF ELS/CT EVEN DECADES LATER. FUTURE STUDIES SHOULD PROSPECTIVELY INVESTIGATE POTENTIAL CONFOUNDERS, THEIR TEMPORAL SEQUENCE AND COMBINED EFFECTS AT THE BIOLOGICAL LEVEL, WHILE CONSIDERING THE POTENTIALLY DELAYED TIME-FRAME FOR THE EXPRESSION OF THEIR EFFECTS. FINALLY, SCREENING STRATEGIES FOR ELS/CT AND TRAUMA NEED TO BE IMPROVED. INFORMATION ABOUT ELS/CT HISTORY AND THE NUMBER OF ADVERSE EXPERIENCES COULD HELP TO BETTER IDENTIFY THE INDIVIDUAL RISK FOR DISEASE DEVELOPMENT, PREDICT INDIVIDUAL TREATMENT RESPONSE AND DESIGN PREVENTION STRATEGIES TO REDUCE THE NEGATIVE EFFECTS OF ELS/CT. 2023 14 2000 28 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 15 1749 28 EARLY LIFE INTERVENTIONS CAN SHAPE AGING. IT IS WELL DOCUMENTED THAT THE ENVIRONMENT OF THE DEVELOPING FETUS, INCLUDING AVAILABILITY OF NUTRIENTS AND PRESENCE OF TOXINS, CAN HAVE MAJOR IMPACT ON ADULT PHENOTYPE, AGE-RELATED TRAITS AND RISK OF CHRONIC DISEASE. THERE IS ALSO ACCUMULATING EVIDENCE THAT POSTNATAL ENVIRONMENT CAN IMPACT ADULT CHARACTERISTICS RELATED TO EVOLUTIONARY FITNESS, HEALTH, AND AGING. TO DETERMINE WHETHER EARLY LIFE HORMONAL INTERVENTIONS CAN ALTER TRAJECTORY OF AGING, WE HAVE EXAMINED THE EFFECTS OF EARLY LIFE GROWTH HORMONE (GH) REPLACEMENT THERAPY IN PROP1(DF) (AMES DWARF) MICE WHICH ARE GH DEFICIENT AND REMARKABLY LONG LIVED. TWICE-DAILY GH INJECTIONS BETWEEN THE AGES OF TWO AND EIGHT WEEKS COMPLETELY NORMALIZED ("RESCUED") A NUMBER OF ADULT METABOLIC CHARACTERISTICS BELIEVED TO CONTRIBUTE TO EXTENDED LONGEVITY OF THESE MUTANTS. IMPORTANTLY, LONGEVITY OF AMES DWARF MICE WAS REDUCED BY EARLY LIFE GH TREATMENT. THIS WAS ASSOCIATED WITH HISTONE H3 MODIFICATIONS. WE CONCLUDE THAT THE TRAJECTORY OF MAMMALIAN AGING CAN BE MODIFIED BY EARLY LIFE INTERVENTIONS. MECHANISTIC LINKS AMONG INTERVENTIONS DURING POSTNATAL DEVELOPMENT, ADULT METABOLIC CHARACTERISTICS, AGING, AND LONGEVITY, APPARENTLY INVOLVE EPIGENETIC PHENOMENA. 2022 16 2901 29 GENDER DIFFERENCES IN GERM-CELL MUTAGENESIS AND GENETIC RISK. CURRENT INTERNATIONAL CLASSIFICATION SYSTEMS FOR CHEMICAL MUTAGENS ARE HAZARD-BASED RATHER THAN AIMED AT ASSESSING RISKS QUANTITATIVELY. IN THE PAST, GERM-CELL TESTS HAVE BEEN MAINLY PERFORMED WITH A LIMITED NUMBER OF SOMATIC CELL MUTAGENS, AND RARELY UNDER CONDITIONS AIMED AT COMPARING GENDER-SPECIFIC DIFFERENCES IN SUSCEPTIBILITY TO MUTAGEN EXPOSURES. THERE ARE PROFOUND DIFFERENCES IN THE GENETIC CONSTITUTION, AND IN HORMONAL, STRUCTURAL, AND FUNCTIONAL ASPECTS OF DIFFERENTIATION AND CONTROL OF GAMETOGENESIS BETWEEN THE SEXES. A CRITICAL REVIEW OF THE LITERATURE SUGGESTS THAT THESE DIFFERENCES MAY HAVE A PROFOUND IMPACT ON THE RELATIVE SUSCEPTIBILITY, STAGE OF HIGHEST SENSITIVITY AND THE RELATIVE RISK FOR THE GENESIS OF GENE MUTATION, AS WELL AS STRUCTURAL AND NUMERICAL CHROMOSOMAL ABERRATIONS IN MALE AND FEMALE GERM CELLS. TRANSMISSION OF GERM-CELL MUTATIONS TO THE OFFSPRING MAY ALSO ENCOUNTER GENDER-SPECIFIC INFLUENCES. GENDER DIFFERENCES IN SUSCEPTIBILITY TO CHEMICALLY DERIVED ALTERATIONS IN IMPRINTING PATTERNS MAY POSE A THREAT FOR THE HEALTH OF THE OFFSPRING AND MAY ALSO BE TRANSMITTED TO FUTURE GENERATIONS. RECENT REPORTS ON DIFFERENT GENETIC EFFECTS FROM HIGH ACUTE AND FROM CHRONIC LOW-DOSE EXPOSURES CHALLENGE THE VALIDITY OF CONCLUSIONS DRAWN FROM STANDARD METHODS OF MUTAGENICITY TESTING. IN CONCLUSION, RESEARCH IS URGENTLY NEEDED TO IDENTIFY GENETIC HAZARDS FOR A LARGER RANGE OF CHEMICAL COMPOUNDS, INCLUDING THOSE SUSPECTED TO DISTURB PROPER CHROMOSOME SEGREGATION. ALTERATIONS IN EPIGENETIC PROGRAMMING AND THEIR HEALTH CONSEQUENCES WILL HAVE TO BE INVESTIGATED. MORE ATTENTION SHOULD BE PAID TO GENDER-SPECIFIC GENETIC EFFECTS. FINALLY, THE DATABASE FOR GERM-CELL MUTAGENS SHOULD BE ENLARGED USING MOLECULAR METHODOLOGIES, AND GENETIC EPIDEMIOLOGY STUDIES SHOULD BE PERFORMED WITH THESE TECHNIQUES TO VERIFY HUMAN GENETIC RISK. 2007 17 49 31 A CURRENT GENETIC AND EPIGENETIC VIEW ON HUMAN AGING MECHANISMS. THE PROCESS OF AGING IS ONE OF THE MOST COMPLEX AND INTRIGUING BIOLOGICAL PHENOMENONS. AGING IS A GENETICALLY REGULATED PROCESS IN WHICH THE ORGANISM'S MAXIMUM LIFESPAN POTENTIAL IS PRE-DETERMINED, WHILE THE RATE OF AGING IS INFLUENCED BY ENVIRONMENTAL FACTORS AND LIFESTYLE. CONSIDERING THE COMPLEXITY OF MECHANISMS INVOLVED IN THE REGULATION OF AGING PROCESS, UP TO THIS DATE THERE ISN'T A MAJOR, UNIFYING THEORY WHICH COULD EXPLAIN THEM. AS GENETIC/EPIGENETIC AND ENVIRONMENTAL FACTORS BOTH INEVITABLY INFLUENCE THE AGING PROCESS, HERE WE PRESENT A REVIEW ON THE GENETIC AND EPIGENETIC REGULATION OF THE MOST IMPORTANT MOLECULAR AND CELLULAR MECHANISMS INVOLVED IN THE PROCESS OF AGING. BASED ON THE STUDIES ON OXIDATIVE STRESS, METABOLISM, GENOME STABILITY, EPIGENETIC MODIFICATIONS AND CELLULAR SENESCENCE IN ANIMAL MODELS AND HUMANS, WE GIVE AN OVERVIEW OF KEY GENETIC AND MOLECULAR PATHWAYS RELATED TO AGING. AS MOST OF GENETIC MANIPULATIONS WHICH INFLUENCE THE AGING PROCESS ALSO AFFECT REPRODUCTION, WE DISCUSS AGING IN HUMANS AS A POST-REPRODUCTIVE GENETICALLY DETERMINED PROCESS. AFTER THE AGE OF REPRODUCTIVE SUCCESS, AGING CONTINOUSLY PROGRESSES WHICH CLINICALLY COINCIDES WITH THE ONSET OF MOST CHRONIC DISEASES, CANCERS AND DEMENTIONS. AS EVOLUTION SHAPES THE GENOMES FOR REPRODUCTIVE SUCCESS AND NOT FOR POST-REPRODUCTIVE SURVIVAL, AGING COULD BE DEFINED AS A PROTECTIVE MECHANISM WHICH ENSURES THE PRESERVATION AND PROGRESS OF SPECIES THROUGH THE MODIFICATION, TRASMISSION AND IMPROVEMENT OF GENETIC MATERIAL. 2009 18 4 33 "MIX OF MICS"- PHENOTYPIC AND BIOLOGICAL HETEROGENEITY OF "MULTIPOTENT" MUSCLE INTERSTITIAL CELLS (MICS). THE CAPACITY OF ADULT SKELETAL MUSCLE FOR REGENERATION APPEARS TO BE LIMITED, WITH PROGRESSIVE IMPAIRMENT IN REPAIR EFFICIENCY OF INJURED MUSCLES OBSERVED IN CHRONIC MUSCULAR DISORDERS AND DURING AGING. WHILE SATELLITE CELLS, THE COMMITTED ADULT MUSCLE STEM CELLS, ARE THE MAIN DIRECT CELL SOURCE SUPPORTING THE REGENERATIVE POTENTIAL OF ADULT SKELETAL MUSCLES, THE CHARACTERIZATION OF THE CELL TYPES AND SIGNALS THAT CONSTITUTE THE FUNCTIONAL "NICHE" OF SATELLITE CELLS IS CURRENTLY THE OBJECT OF INTENSE INVESTIGATION. RECENT STUDIES HAVE IDENTIFIED A FUNCTIONAL RELATIONSHIP BETWEEN SATELLITE CELLS AND VARIOUS CELL TYPES LOCATED IN KEY ANATOMICAL POSITION, SUCH AS THE INTERSTITIUM OF SKELETAL MUSCLES. THIS HETEROGENEOUS POPULATION OF MUSCLE INTERSTITIAL CELLS (MICS) APPEARS TO RETAIN AN INTRINSIC MULTIPOTENCY WITHIN THE MESODERMAL LINEAGE, AND THEIR DIRECT OR INDIRECT CONTRIBUTION TO MYOFIBER TURNOVER, REPAIR AND DEGENERATION HAS BEEN SUGGESTED BY MANY STUDIES THAT WILL BE REVIEWED HERE. GIVEN THE EXISTING GAP OF KNOWLEDGE ON LINEAGE IDENTITY AND FUNCTIONAL PROPERTIES OF MICS, THEIR DETAILED CHARACTERIZATION AT THE SINGLE CELL LEVEL HOLDS THE PROMISE TO PROVIDE KEY INSIGHT INTO THE COMPOSITION OF THIS HETEROGENEOUS POPULATION AND THE DYNAMIC TRANSITION THROUGH DISTINCT SUB-POPULATIONS IN HEALTHY, DISEASED AND AGING MUSCLES. THIS REVIEW PROVIDES AN OVERVIEW OF THE RESULTS OF VARIOUS STUDIES DESCRIBING THE PHENOTYPE AND THE FUNCTION OF CELLS ISOLATED FROM SKELETAL MUSCLE INTERSTITIUM, AND DISCUSSES THE IMPORTANCE OF SINGLE CELL TRANSCRIPTION PROFILING IN ORDER TO DECIPHER THE FUNCTIONAL AND PHENOTYPICAL HETEROGENEITY OF MUSCLE INTERSTITIAL CELLS (MICS). 2012 19 4996 37 PERINATAL EPIGENETIC DETERMINANTS OF COGNITIVE AND METABOLIC DISORDERS. MULTIPLE CUES FROM THE ENVIRONMENT OF OUR INDIRECT AND IMMEDIATE ANCESTORS, WHICH OFTEN PERSIST THROUGHOUT THE PRENATAL PERIOD AND ADULTHOOD, ARE SHAPING OUR PHENOTYPES THROUGH EITHER DIRECT, PARENT-TO-CHILD INFLUENCES, OR TRANSGENERATIONAL INHERITANCE. THESE EFFECTS ARE DUE TO GENE-ENVIRONMENT INTERACTIONS, WHICH ARE INTENDED TO BE A PREDICTIVE TOOL AND A MECHANISM OF QUICK ADAPTATION TO THE ENVIRONMENT, AS COMPARED WITH GENETIC VARIATIONS THAT ARE INHERITED OVER MANY GENERATIONS. IN CERTAIN CIRCUMSTANCES THE INFLUENCES INDUCED BY THE GENE-ENVIRONMENT INTERACTIONS CAN HAVE DELETERIOUS EFFECTS UPON THE HEALTH STATUS, IN THE CONTEXT OF A RADICAL CHANGE IN THE ENVIRONMENT THAT DOES NOT FIT WITH THE PREDICTED CONDITIONS, VIA EPIGENETIC ALTERATIONS. CONVERSELY THE BEST FIT TO THE EXPECTED ENVIRONMENT MIGHT HAVE A DELAYED AGING PROCESS AND A LONGER LIFE SPAN. THIS REVIEW WILL TOUCH UPON THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE (DOHAD) CONCEPT, WHILE DISCUSSING RECENT ADVANCES IN THE UNDERSTANDING OF METABOLIC AND COGNITIVE DISRUPTIONS, WITH A FOCUS ON EPIGENETIC FACTORS, THEIR TRANSGENERATIONAL EFFECTS, AND THE CONSEQUENCES THEY MIGHT HAVE UPON THE ONSET OF CHRONIC DISEASE AND PREMATURE EXITUS. 2012 20 3736 34 INNATE IMMUNE TOLERANCE IN MICROGLIA DOES NOT IMPACT ON CENTRAL NERVOUS SYSTEM PRION DISEASE. PRION DISEASES SUCH AS CREUTZFELDT-JAKOB DISEASE IN HUMANS, BOVINE SPONGIFORM ENCEPHALOPATHY IN CATTLE, AND SCRAPIE IN SHEEP, ARE INFECTIOUS AND CHRONIC NEURODEGENERATIVE DISEASES TO WHICH THERE ARE NO CURES. INFECTION WITH PRIONS IN THE CENTRAL NERVOUS SYSTEM (CNS) ULTIMATELY CAUSES EXTENSIVE NEURODEGENERATION, AND THIS IS ACCOMPANIED BY PROMINENT MICROGLIAL AND ASTROCYTIC ACTIVATION IN AFFECTED REGIONS. THE MICROGLIA ARE THE CNS MACROPHAGES AND HELP MAINTAIN NEURONAL HOMEOSTASIS, CLEAR DEAD OR DYING CELLS AND PROVIDE DEFENSE AGAINST PATHOGENS. THE MICROGLIA ALSO PROVIDE NEUROPROTECTION DURING CNS PRION DISEASE, BUT THEIR PRO-INFLAMMATORY ACTIVATION MAY EXACERBATE THE DEVELOPMENT OF THE NEUROPATHOLOGY. INNATE IMMUNE TOLERANCE INDUCED BY CONSECUTIVE SYSTEMIC BACTERIAL LIPOPOLYSACCHARIDE (LPS) TREATMENT CAN INDUCE LONG-TERM EPIGENETIC CHANGES IN THE MICROGLIA IN THE BRAIN THAT SEVERAL MONTHS LATER CAN DAMPEN THEIR RESPONSIVENESS TO SUBSEQUENT LPS TREATMENT AND IMPEDE THE DEVELOPMENT OF NEURITIC DAMAGE IN A TRANSGENIC MOUSE MODEL OF ALZHEIMER'S DISEASE-LIKE PATHOLOGY. WE THEREFORE REASONED THAT INNATE IMMUNE TOLERANCE IN MICROGLIA MIGHT SIMILARLY IMPEDE THE SUBSEQUENT DEVELOPMENT OF CNS PRION DISEASE. TO TEST THIS HYPOTHESIS GROUPS OF MICE WERE FIRST INFECTED WITH PRIONS BY INTRACEREBRAL INJECTION, AND 35 DAYS LATER GIVEN FOUR CONSECUTIVE SYSTEMIC INJECTIONS WITH LPS TO INDUCE INNATE IMMUNE TOLERANCE. OUR DATA SHOW THAT CONSECUTIVE SYSTEMIC LPS TREATMENT DID NOT AFFECT THE SUBSEQUENT DEVELOPMENT OF CNS PRION DISEASE. OUR DATA SUGGESTS INNATE IMMUNE TOLERANCE IN MICROGLIA DOES NOT INFLUENCE THE SUBSEQUENT ONSET OF PRION DISEASE-INDUCED NEUROPATHOLOGY IN MICE, DESPITE PREVIOUSLY PUBLISHED EVIDENCE OF THIS EFFECT IN AN ALZHEIMER'S DISEASE MOUSE MODEL. 2022