1 4758 169 NOVEL TREATMENT STRATEGIES TARGETING MYELIN AND OLIGODENDROCYTE DYSFUNCTION IN SCHIZOPHRENIA. OLIGODENDROCYTES ARE THE GLIAL CELLS RESPONSIBLE FOR THE FORMATION OF THE MYELIN SHEATH AROUND AXONS. DURING NEURODEVELOPMENT, OLIGODENDROCYTES UNDERGO MATURATION AND DIFFERENTIATION, AND LATER REMYELINATION IN ADULTHOOD. ABNORMALITIES IN THESE PROCESSES HAVE BEEN ASSOCIATED WITH BEHAVIORAL AND COGNITIVE DYSFUNCTIONS AND THE DEVELOPMENT OF VARIOUS MENTAL ILLNESSES LIKE SCHIZOPHRENIA. SEVERAL STUDIES HAVE IMPLICATED OLIGODENDROCYTE DYSFUNCTION AND MYELIN ABNORMALITIES IN THE DISORDER, TOGETHER WITH ALTERED EXPRESSION OF MYELIN-RELATED GENES SUCH AS OLIG2, CNP, AND NRG1. HOWEVER, THE MOLECULAR MECHANISMS SUBJACENT OF THESE ALTERATIONS REMAIN ELUSIVE. SCHIZOPHRENIA IS A SEVERE, CHRONIC PSYCHIATRIC DISORDER AFFECTING MORE THAN 23 MILLION INDIVIDUALS WORLDWIDE AND ITS SYMPTOMS USUALLY APPEAR AT THE BEGINNING OF ADULTHOOD. CURRENTLY, THE MAJOR THERAPEUTIC STRATEGY FOR SCHIZOPHRENIA RELIES ON THE USE OF ANTIPSYCHOTICS. DESPITE THEIR WIDESPREAD USE, THE EFFECTS OF ANTIPSYCHOTICS ON GLIAL CELLS, ESPECIALLY OLIGODENDROCYTES, REMAIN UNCLEAR. THUS, IN THIS REVIEW WE HIGHLIGHT THE CURRENT KNOWLEDGE REGARDING OLIGODENDROCYTE DYSFUNCTION IN SCHIZOPHRENIA, COMPILING DATA FROM (EPI)GENETIC STUDIES AND UP-TO-DATE MODELS TO INVESTIGATE THE ROLE OF OLIGODENDROCYTES IN THE DISORDER. IN ADDITION, WE EXAMINED POTENTIAL TARGETS CURRENTLY INVESTIGATED FOR THE IMPROVEMENT OF SCHIZOPHRENIA SYMPTOMS. RESEARCH IN THIS AREA HAS BEEN INVESTIGATING POTENTIAL BENEFICIAL COMPOUNDS, INCLUDING THE D-AMINO ACIDS D-ASPARTATE AND D-SERINE, THAT ACT AS NMDA RECEPTOR AGONISTS, MODULATING THE GLUTAMATERGIC SIGNALING; THE ANTIOXIDANT N-ACETYLCYSTEINE, A PRECURSOR IN THE SYNTHESIS OF GLUTATHIONE, PROTECTING AGAINST THE REDOX IMBALANCE; AS WELL AS LITHIUM, AN INHIBITOR OF GLYCOGEN SYNTHASE KINASE 3BETA (GSK3BETA) SIGNALING, CONTRIBUTING TO OLIGODENDROCYTE SURVIVAL AND FUNCTIONING. IN CONCLUSION, THERE IS STRONG EVIDENCE LINKING OLIGODENDROCYTE DYSFUNCTION TO THE DEVELOPMENT OF SCHIZOPHRENIA. HENCE, A BETTER UNDERSTANDING OF OLIGODENDROCYTE DIFFERENTIATION, AS WELL AS THE EFFECTS OF ANTIPSYCHOTIC MEDICATION IN THESE CELLS, COULD HAVE POTENTIAL IMPLICATIONS FOR UNDERSTANDING THE DEVELOPMENT OF SCHIZOPHRENIA AND FINDING NEW TARGETS FOR DRUG DEVELOPMENT. 2020 2 129 32 A UNIQUE VIRULENCE GENE OCCUPIES A PRINCIPAL POSITION IN IMMUNE EVASION BY THE MALARIA PARASITE PLASMODIUM FALCIPARUM. MUTUALLY EXCLUSIVE GENE EXPRESSION, WHEREBY ONLY ONE MEMBER OF A MULTI-GENE FAMILY IS SELECTED FOR ACTIVATION, IS USED BY THE MALARIA PARASITE PLASMODIUM FALCIPARUM TO ESCAPE THE HUMAN IMMUNE SYSTEM AND PERPETUATE LONG-TERM, CHRONIC INFECTIONS. A FAMILY OF GENES CALLED VAR ENCODES THE CHIEF ANTIGENIC AND VIRULENCE DETERMINANT OF P. FALCIPARUM MALARIA. VAR GENES ARE TRANSCRIBED IN A MUTUALLY EXCLUSIVE MANNER, WITH SWITCHING BETWEEN ACTIVE GENES RESULTING IN ANTIGENIC VARIATION. WHILE RECENT WORK HAS SHED CONSIDERABLE LIGHT ON THE EPIGENETIC BASIS FOR VAR GENE ACTIVATION AND SILENCING, HOW SWITCHING IS CONTROLLED REMAINS A MYSTERY. IN PARTICULAR, SWITCHING SEEMS NOT TO BE RANDOM, BUT INSTEAD APPEARS TO BE COORDINATED TO RESULT IN TIMELY ACTIVATION OF INDIVIDUAL GENES LEADING TO SEQUENTIAL WAVES OF ANTIGENICALLY DISTINCT PARASITE POPULATIONS. THE MOLECULAR BASIS FOR THIS APPARENT COORDINATION IS UNKNOWN. HERE WE SHOW THAT VAR2CSA, AN UNUSUAL AND HIGHLY CONSERVED VAR GENE, OCCUPIES A UNIQUE POSITION WITHIN THE VAR GENE SWITCHING HIERARCHY. INDUCTION OF SWITCHING THROUGH THE DESTABILIZATION OF VAR SPECIFIC CHROMATIN USING BOTH GENETIC AND CHEMICAL METHODS REPEATEDLY LED TO THE RAPID AND EXCLUSIVE ACTIVATION OF VAR2CSA. ADDITIONAL EXPERIMENTS DEMONSTRATED THAT THESE REPRESENT "TRUE" SWITCHING EVENTS AND NOT SIMPLY DE-SILENCING OF THE VAR2CSA PROMOTER, AND THAT ACTIVATION IS LIMITED TO THE UNIQUE LOCUS ON CHROMOSOME 12. COMBINED WITH TRANSLATIONAL REPRESSION OF VAR2CSA TRANSCRIPTS, FREQUENT "DEFAULT" SWITCHING TO THIS LOCUS AND DETECTION OF VAR2CSA UNTRANSLATED TRANSCRIPTS IN NON-PREGNANT INDIVIDUALS, THESE DATA SUGGEST THAT VAR2CSA COULD PLAY A CENTRAL ROLE IN COORDINATING SWITCHING, FULFILLING A PREDICTION MADE BY MATHEMATICAL MODELS DERIVED FROM POPULATION SWITCHING PATTERNS. THESE STUDIES PROVIDE THE FIRST INSIGHTS INTO THE MECHANISMS BY WHICH VAR GENE SWITCHING IS COORDINATED AS WELL AS AN EXAMPLE OF HOW A PHARMACOLOGICAL AGENT CAN DISRUPT ANTIGENIC VARIATION IN PLASMODIUM FALCIPARUM. 2015 3 1681 27 DRUG-INDUCED LIVER INJURY: MECHANISMS, TYPES AND BIOMARKERS. DRUG-INDUCED LIVER INJURY IS A UBIQUITOUS ISSUE IN CLINICAL SETTINGS AND PHARMACEUTICAL INDUSTRY. HEPATOTOXICITY ELICITED BY DRUGS MAY BE INTRINSIC OR IDIOSYNCRATIC, BOTH WHICH ARE DRIVEN BY DIFFERENT MOLECULAR MECHANISMS. RECENTLY, A UNIFYING MECHANISTIC MODEL OF DRUG-INDUCED LIVER INJURY HAS BEEN INTRODUCED. ACCORDING TO THIS MODEL, DRUG-INDUCED HEPATOTOXICITY RELIES ON 3 CONSECUTIVE STEPS, NAMELY AN INITIAL CELLULAR INSULT THAT LEADS TO THE OCCURRENCE OF MITOCHONDRIAL PERMEABILITY TRANSITION, WHICH IN TURN ULTIMATELY BURGEONS INTO THE ONSET OF CELL DEATH. CLINICALLY, DRUG-INDUCED LIVER INJURY CAN BE MANIFESTED IN A NUMBER OF ACUTE AND CHRONIC CONDITIONS, INCLUDING HEPATITIS, CHOLESTASIS, STEATOSIS AND FIBROSIS. THESE PATHOLOGIES CAN BE DIAGNOSED AND MONITORED BY ADDRESSING WELL-ESTABLISHED PHYSICAL, CLINICAL CHEMISTRY AND HISTOPATHOLOGICAL BIOMARKERS. IN THE LAST FEW YEARS, SEVERAL NOVEL READ-OUTS OF DRUG-INDUCED LIVER INJURY HAVE BEEN PROPOSED, INVOLVING GENETIC, EPIGENETIC, TRANSCRIPTOMIC, PROTEOMIC AND METABOLOMIC PARAMETERS. THESE NEW CONCEPTS AND RECENT DEVELOPMENTS IN THE FIELD OF DRUG-INDUCED LIVER INJURY ARE REVISED IN THE CURRENT PAPER. 2013 4 5623 35 SECOND-HAND SMOKE AND HUMAN LUNG CANCER. SINCE THE EARLY 1980S, THERE HAS BEEN GROWING CONCERN ABOUT POTENTIAL HEALTH CONSEQUENCES OF EXPOSURE TO SECOND-HAND SMOKE (SHS). DESPITE SHS BEING ESTABLISHED AS A RISK FACTOR FOR LUNG CANCER DEVELOPMENT, THE ESTIMATED RISK HAS REMAINED SMALL YET SOMEHOW DEBATABLE. HUMAN EXPOSURE TO SHS IS COMPLICATED BECAUSE OF TEMPORAL VARIABILITIES IN SOURCE, COMPOSITION, AND CONCENTRATION OF SHS. THE TEMPORALITY OF EXPOSURE TO SHS IS IMPORTANT FOR HUMAN LUNG CARCINOGENESIS WITH A LATENCY OF MANY YEARS. TO EXPLORE THE CAUSAL EFFECT OF SHS IN LUNG CARCINOGENESIS, EXPOSURE ASSESSMENTS SHOULD ESTIMATE CHRONIC EXPOSURE TO SHS ON AN INDIVIDUAL BASIS. HOWEVER, CONVENTIONAL EXPOSURE ASSESSMENT FOR SHS RELIES ON ONE-OFF OR SHORT-TERM MEASUREMENTS OF SHS INDICES. A MORE RELIABLE APPROACH WOULD BE TO USE BIOLOGICAL MARKERS THAT ARE SPECIFIC FOR SHS EXPOSURE AND PERTINENT TO LUNG CANCER. THIS APPROACH REQUIRES AN UNDERSTANDING OF THE UNDERLYING MECHANISMS THROUGH WHICH SHS COULD CONTRIBUTE TO LUNG CARCINOGENESIS. THIS REVIEW IS A SYNOPSIS OF RESEARCH ON SHS AND LUNG CANCER, WITH SPECIAL FOCUS ON HYPOTHETICAL MODES OF ACTION OF SHS FOR CARCINOGENESIS, INCLUDING GENOTOXIC AND EPIGENETIC EFFECTS. 2008 5 1160 19 CONTINUING WAR ON PAIN: A PERSONALIZED APPROACH TO THE THERAPY WITH NONSTEROIDAL ANTI-INFLAMMATORY DRUGS AND OPIOIDS. SUCCESSFUL PAIN MANAGEMENT REQUIRES THE DELIVERY OF ANALGESIA WITH MINIMAL RISK OF ADVERSE DRUG REACTIONS. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS AND OPIOIDS REMAIN THE MAINSTAY OF TREATMENT FOR THE MAJORITY OF PATIENTS. UNFORTUNATELY, ALMOST 50% OF ALL PATIENTS EXPERIENCE INADEQUATE PAIN RELIEF AND SERIOUS SIDE EFFECTS. ALLELIC VARIANTS IN GENES CODING FOR TARGET PROTEINS, TRANSPORTERS AND ENZYMES, WHICH GOVERN ANALGESIC DRUGS ACTION AND THEIR FATE IN THE ORGANISM, MIGHT EXPLAIN INTER-INDIVIDUAL VARIABILITY IN PAIN SEVERITY AND IN DRUG-INDUCED PAIN RELIEF AND TOXICITIES. ADDITIONALLY, IT SEEMS THAT EPIGENETIC CHANGES CONTRIBUTE TO THE HIGHLY VARIABLE RESPONSE TO PAIN TREATMENT. THEREFORE, PHARMACOGENOMIC TESTING MIGHT BE A VALUABLE TOOL FOR PERSONALIZATION OF PAIN TREATMENT, WITH A MULTIDISCIPLINARY TEAM APPROACH INVOLVED. 2019 6 5725 37 SKIN MANIFESTATIONS OF INSULIN RESISTANCE: FROM A BIOCHEMICAL STANCE TO A CLINICAL DIAGNOSIS AND MANAGEMENT. WORLDWIDE, MORE THAN 1.9 BILLION ADULTS ARE OVERWEIGHT, AND AROUND 600 MILLION PEOPLE SUFFER FROM OBESITY. SIMILARLY, ~382 MILLION INDIVIDUALS LIVE WITH DIABETES, AND 40-50% OF THE GLOBAL POPULATION IS LABELED AT "HIGH RISK" (I.E., PREDIABETES). THE IMPACT OF THESE TWO CHRONIC CONDITIONS RELIES NOT ONLY ON THE BURDEN OF ILLNESSES PER SE (I.E., ASSOCIATED INCREASED MORBIDITY AND MORTALITY), BUT ALSO ON THEIR INCREASED COST, BURDEN OF TREATMENT, AND DECREASED HEALTH-RELATED QUALITY OF LIFE. FOR THIS REVIEW A COMPREHENSIVE SEARCH IN SEVERAL DATABASES INCLUDING PUBMED (MEDLINE), OVID EMBASE, WEB OF SCIENCE, AND SCOPUS WAS CONDUCTED. IN BOTH DIABETES AND OBESITY, GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS OVERLAP AND ARE INCLUSIVE RATHER THAN EXCLUSIVE. DE FACTO, 70-80% OF THE PATIENTS WITH OBESITY AND VIRTUALLY EVERY PATIENT WITH TYPE 2 DIABETES HAVE INSULIN RESISTANCE. INSULIN RESISTANCE IS A WELL-KNOWN PATHOPHYSIOLOGIC FACTOR IN THE DEVELOPMENT OF TYPE 2 DIABETES, CHARACTERISTICALLY APPEARING YEARS BEFORE ITS DIAGNOSIS. THE GOLD STANDARD FOR INSULIN RESISTANCE DIAGNOSIS (THE EUGLYCEMIC INSULIN CLAMP) IS A COMPLEX, INVASIVE, COSTLY, AND HENCE UNFEASIBLE TEST TO IMPLEMENT IN CLINICAL PRACTICE. LIKEWISE, LABORATORY MEASURES AND DERIVED INDEXES [E.G., HOMEOSTASIS MODEL ASSESSMENT OF INSULIN RESISTANCE (HOMA-IR-)] ARE INDIRECT, IMPRECISE, AND NOT HIGHLY ACCURATE AND REPRODUCIBLE TESTS. HOWEVER, SKIN MANIFESTATIONS OF INSULIN RESISTANCE (E.G., ACROCHORDONS, ACANTHOSIS NIGRICANS, ANDROGENETIC ALOPECIA, ACNE, HIRSUTISM) OFFER A RELIABLE, STRAIGHTFORWARD, AND REAL-TIME WAY TO DETECT INSULIN RESISTANCE. THE OBJECTIVE OF THIS REVIEW IS TO AID CLINICIANS IN RECOGNIZING SKIN MANIFESTATIONS OF INSULIN RESISTANCE. DIAGNOSING THESE SKIN MANIFESTATIONS ACCURATELY MAY CASCADE POSITIVELY IN THE PATIENT'S HEALTH BY TRIGGERING AN ADEQUATE METABOLIC EVALUATION, A TIMELY TREATMENT OR REFERRAL WITH THE ULTIMATE OBJECTIVE OF DECREASING DIABETES AND OBESITY BURDEN, AND IMPROVING THE HEALTH AND THE QUALITY OF CARE FOR THESE PATIENTS. 2017 7 6403 32 THE ROLES OF INDUCIBLE CHROMATIN AND TRANSCRIPTIONAL MEMORY IN CELLULAR DEFENSE SYSTEM RESPONSES TO REDOX-ACTIVE POLLUTANTS. PEOPLE ARE EXPOSED TO WIDE RANGE OF REDOX-ACTIVE ENVIRONMENTAL POLLUTANTS. AIR POLLUTION, HEAVY METALS, PESTICIDES, AND ENDOCRINE DISRUPTING CHEMICALS CAN DISRUPT CELLULAR REDOX STATUS. REDOX-ACTIVE POLLUTANTS IN OUR ENVIRONMENT ALL TRIGGER THEIR OWN SETS OF SPECIFIC CELLULAR RESPONSES, BUT THEY ALSO ACTIVATE A COMMON SET OF GENERAL STRESS RESPONSES THAT BUFFER THE CELL AGAINST HOMEOSTATIC INSULTS. THESE CELLULAR DEFENSE SYSTEM (CDS) PATHWAYS INCLUDE THE HEAT SHOCK RESPONSE, THE OXIDATIVE STRESS RESPONSE, THE HYPOXIA RESPONSE, THE UNFOLDED PROTEIN RESPONSE, THE DNA DAMAGE RESPONSE, AND THE GENERAL STRESS RESPONSE MEDIATED BY THE STRESS-ACTIVATED P38 MITOGEN-ACTIVATED PROTEIN KINASE. OVER THE PAST TWO DECADES, THE FIELD OF ENVIRONMENTAL EPIGENETICS HAS INVESTIGATED EPIGENETIC RESPONSES TO ENVIRONMENTAL POLLUTANTS, INCLUDING REDOX-ACTIVE POLLUTANTS. STUDIES OF THESE RESPONSES HIGHLIGHT THE ROLE OF CHROMATIN MODIFICATIONS IN CONTROLLING THE TRANSCRIPTIONAL RESPONSE TO POLLUTANTS AND THE ROLE OF TRANSCRIPTIONAL MEMORY, OFTEN REFERRED TO AS "EPIGENETIC REPROGRAMMING", IN PREDISPOSING PREVIOUSLY EXPOSED INDIVIDUALS TO MORE POTENT TRANSCRIPTIONAL RESPONSES ON SECONDARY CHALLENGE. MY CENTRAL THESIS IN THIS REVIEW IS THAT HIGH DOSE OR CHRONIC EXPOSURE TO REDOX-ACTIVE POLLUTANTS LEADS TO TRANSCRIPTIONAL MEMORIES AT CDS TARGET GENES THAT INFLUENCE THE CELL'S ABILITY TO MOUNT PROTECTIVE RESPONSES. TO SUPPORT THIS THESIS, I WILL: (1) SUMMARIZE THE KNOWN CHROMATIN FEATURES REQUIRED FOR INDUCIBLE GENE ACTIVATION; (2) REVIEW THE KNOWN FORMS OF TRANSCRIPTIONAL MEMORY; (3) DISCUSS THE ROLES OF INDUCIBLE CHROMATIN AND TRANSCRIPTIONAL MEMORY IN CDS RESPONSES THAT ARE ACTIVATED BY REDOX-ACTIVE ENVIRONMENTAL POLLUTANTS; AND (4) PROPOSE A CONCEPTUAL FRAMEWORK FOR CDS PATHWAY RESPONSIVENESS AS A READOUT OF TOTAL CELLULAR EXPOSURE TO REDOX-ACTIVE POLLUTANTS. 2021 8 2924 27 GENERAL ANESTHETIC NEUROTOXICITY IN THE YOUNG: MECHANISM AND PREVENTION. GENERAL ANESTHESIA (GA) IS USUALLY CONSIDERED TO SAFELY INDUCE A REVERSIBLE UNCONSCIOUS STATE ALLOWING SURGERY TO BE PERFORMED WITHOUT PAIN. A GROWING NUMBER OF STUDIES, IN PARTICULAR PRE-CLINICAL STUDIES, HOWEVER, DEMONSTRATE THAT GENERAL ANESTHETICS CAN CAUSE NEURONAL DEATH AND EVEN LONG-TERM NEUROLOGICAL DEFICITS. HEREIN, WE REPORT OUR LITERATURE REVIEW AND META-ANALYSIS DATA OF THE NEUROLOGICAL OUTCOMES AFTER ANESTHESIA IN THE YOUNG. WE ALSO REVIEW AVAILABLE MECHANISTIC AND EPIGENETIC DATA OF GA EXPOSURE RELATED TO COGNITIVE IMPAIRMENT PER SE AND THE POTENTIAL PREVENTIVE STRATEGIES INCLUDING NATURAL HERBAL COMPOUNDS TO ATTENUATE THOSE SIDE EFFECTS. IN SUMMARY, ANESTHETIC-INDUCED NEUROTOXICITY MAY BE TREATABLE AND NATURAL HERBAL COMPOUNDS AND OTHER MEDICATIONS MAY HAVE GREAT POTENTIAL FOR SUCH USE BUT WARRANTS FURTHER STUDY BEFORE CLINICAL APPLICATIONS CAN BE INITIATED. 2019 9 4856 35 OPTIMIZING RETROVIRAL GENE EXPRESSION FOR EFFECTIVE THERAPIES. WITH THEIR ABILITY TO INTEGRATE THEIR GENETIC MATERIAL INTO THE TARGET CELL GENOME, RETROVIRAL VECTORS (RV) OF BOTH THE GAMMA-RETROVIRAL (GAMMA-RV) AND LENTIVIRAL VECTOR (LV) CLASSES CURRENTLY REMAIN THE MOST EFFICIENT AND THUS THE SYSTEM OF CHOICE FOR ACHIEVING TRANSGENE RETENTION AND THEREFORE POTENTIALLY LONG-TERM EXPRESSION AND THERAPEUTIC BENEFIT. HOWEVER, GAMMA-RV AND LV INTEGRATION COMES AT A COST IN THAT TRANSCRIPTION UNITS WILL BE PRESENT WITHIN A NATIVE CHROMATIN ENVIRONMENT AND THUS BE SUBJECT TO EPIGENETIC EFFECTS (DNA METHYLATION, HISTONE MODIFICATIONS) THAT CAN NEGATIVELY IMPACT ON THEIR FUNCTION. INDEED, HIGHLY VARIABLE EXPRESSION AND SILENCING OF GAMMA-RV AND LV TRANSGENES ESPECIALLY RESULTING FROM PROMOTER DNA METHYLATION IS WELL DOCUMENTED AND WAS THE CAUSE OF THE FAILURE OF GENE THERAPY IN A CLINICAL TRIAL FOR X-LINKED CHRONIC GRANULOMATOUS DISEASE. THIS REVIEW WILL CRITICALLY EXPLORE THE USE OF DIFFERENT CLASSES OF GENETIC CONTROL ELEMENTS THAT CAN IN PRINCIPLE REDUCE VECTOR INSERTION SITE POSITION EFFECTS AND EPIGENETIC-MEDIATED SILENCING. THESE TRANSCRIPTIONAL REGULATORY ELEMENTS BROADLY DIVIDE THEMSELVES INTO EITHER THOSE WITH A CHROMATIN BOUNDARY OR BORDER FUNCTION (SCAFFOLD/MATRIX ATTACHMENT REGIONS, INSULATORS) OR THOSE WITH A DOMINANT CHROMATIN REMODELING AND TRANSCRIPTIONAL ACTIVATING CAPABILITY (LOCUS CONTROL REGIONS,, UBIQUITOUS CHROMATIN OPENING ELEMENTS). ALL THESE TYPES OF ELEMENTS HAVE THEIR STRENGTHS AND WEAKNESSES WITHIN THE CONSTRAINTS OF A GAMMA-RV AND LV BACKBONE, SHOWING VARYING DEGREES OF EFFICACY IN IMPROVING REPRODUCIBILITY AND STABILITY OF TRANSGENE FUNCTION. COMBINATIONS OF BOUNDARY AND CHROMATIN REMODELING; TRANSCRIPTIONAL ACTIVATING ELEMENTS, WHICH DO NOT IMPEDE VECTOR PRODUCTION; TRANSDUCTION EFFICIENCY; AND STABILITY ARE MOST LIKELY TO MEET THE REQUIREMENTS WITHIN A GENE THERAPY CONTEXT ESPECIALLY WHEN TARGETING A STEM CELL POPULATION. 2013 10 1697 37 DYNAMIC DNA METHYLATION CONTROLS GLUTAMATE RECEPTOR TRAFFICKING AND SYNAPTIC SCALING. HEBBIAN PLASTICITY, INCLUDING LONG-TERM POTENTIATION AND LONG-TERM DEPRESSION, HAS LONG BEEN REGARDED AS IMPORTANT FOR LOCAL CIRCUIT REFINEMENT IN THE CONTEXT OF MEMORY FORMATION AND STABILIZATION. HOWEVER, CIRCUIT DEVELOPMENT AND STABILIZATION ADDITIONALLY RELIES ON NON-HEBBIAN, HOMEOSTATIC, FORMS OF PLASTICITY SUCH AS SYNAPTIC SCALING. SYNAPTIC SCALING IS INDUCED BY CHRONIC INCREASES OR DECREASES IN NEURONAL ACTIVITY. SYNAPTIC SCALING IS ASSOCIATED WITH CELL-WIDE ADJUSTMENTS IN POSTSYNAPTIC RECEPTOR DENSITY, AND CAN OCCUR IN A MULTIPLICATIVE MANNER RESULTING IN PRESERVATION OF RELATIVE SYNAPTIC STRENGTHS ACROSS THE ENTIRE NEURON'S POPULATION OF SYNAPSES. BOTH ACTIVE DNA METHYLATION AND DEMETHYLATION HAVE BEEN VALIDATED AS CRUCIAL REGULATORS OF GENE TRANSCRIPTION DURING LEARNING, AND SYNAPTIC SCALING IS KNOWN TO BE TRANSCRIPTIONALLY DEPENDENT. HOWEVER, IT HAS BEEN UNCLEAR WHETHER HOMEOSTATIC FORMS OF PLASTICITY SUCH AS SYNAPTIC SCALING ARE REGULATED VIA EPIGENETIC MECHANISMS. THIS REVIEW DESCRIBES EXCITING RECENT WORK THAT HAS DEMONSTRATED A ROLE FOR ACTIVE CHANGES IN NEURONAL DNA METHYLATION AND DEMETHYLATION AS A CONTROLLER OF SYNAPTIC SCALING AND GLUTAMATE RECEPTOR TRAFFICKING. THESE FINDINGS BRING TOGETHER THREE MAJOR CATEGORIES OF MEMORY-ASSOCIATED MECHANISMS THAT WERE PREVIOUSLY LARGELY CONSIDERED SEPARATELY: DNA METHYLATION, HOMEOSTATIC PLASTICITY, AND GLUTAMATE RECEPTOR TRAFFICKING. THIS REVIEW DESCRIBES EXCITING RECENT WORK THAT HAS DEMONSTRATED A ROLE FOR ACTIVE CHANGES IN NEURONAL DNA METHYLATION AND DEMETHYLATION AS A CONTROLLER OF SYNAPTIC SCALING AND GLUTAMATE RECEPTOR TRAFFICKING. THESE FINDINGS BRING TOGETHER THREE MAJOR CATEGORIES OF MEMORY-ASSOCIATED MECHANISMS THAT WERE PREVIOUSLY CONSIDERED SEPARATELY: GLUTAMATE RECEPTOR TRAFFICKING, DNA METHYLATION, AND HOMEOSTATIC PLASTICITY. 2016 11 1893 42 ENDOMETRIOSIS: NEW PERSPECTIVE FOR THE DIAGNOSIS OF CERTAIN CYTOKINES IN WOMEN AND ADOLESCENT GIRLS, AS WELL AS THE PROGRESSION OF DISEASE OUTGROWTH: A SYSTEMATIC REVIEW. ENDOMETRIOSIS IS A COMMON CHRONIC GYNECOLOGICAL DISORDER THAT UNDOUBTEDLY IMPACTS ON QUALITY OF LIFE, AND IS ONE OF THE MORE COMPLEX AND MYSTERIOUS ILLNESSES OF OUR CENTURY, WHICH IS ASSOCIATED WITH THE IMPROPER GROWTH OF ENDOMETRIAL TISSUE OUTSIDE OF THE UTERINE CAVITY. THIS PATHOLOGICALLY IMPLANTED TISSUE CAN BE FOUND MOST FREQUENTLY IN THE MINOR PELVIS, BUT ALSO IN THE PERITONEAL CAVITY, AND CAN AFFECT MANY ORGANS, LEADING TO CHRONIC PELVIC PAIN SYNDROME, INFERTILITY, AND DYSMENORRHEA. ENDOMETRIAL TISSUE IS A PARTICULARLY DYNAMIC TISSUE THAT HAS A DIRECT IMPACT ON THE PROGRESSION OF THE DISEASE, WITH ALTERED IMMUNITY, AS WELL AS CYTOKINE STORMS WITHIN THE METAPLASTIC ENDOMETRIOTIC SITE, AS POSSIBLE KEY FACTORS. CURRENTLY, DIAGNOSIS OF THIS MYSTERIOUS CHRONIC ILLNESS RELIES ON PERFORMING A LAPAROSCOPIC PROCEDURE WITH TISSUE SAMPLING. ONE OF THE MOST TROUBLESOME OUTCOMES OF THIS UNINTENDED PROGRESSION IS THAT WE LACK ANY SPECIFIC, SENSITIVE, NON-INVASIVE DIAGNOSTIC TOOLS. CURRENTLY, THE VAST MAJORITY OF REGIME STEWARDSHIP OPTIONS RELY ON ANTI-CONTRACEPTIVE DRUGS, OR OTHER REMEDIES THAT SUPPRESS THE RELEASE OF ESTROGEN THROUGH THE GONADS-ALTHOUGH IN MOST CLINICAL TRIALS, ENDOMETRIOSIS IS A CHRONIC PROGRESSIVE DISORDER THAT DEPENDS MOSTLY ON THE HIGH CONCENTRATION OF ESTROGEN. MOREOVER, MANY SPECIFIC TRIALS HAVE DEMONSTRATED THAT THE EUTOPIC ENDOMETRIAL CELLS IN INDIVIDUALS WITH ENDOMETRIOSIS REMAIN MUCH MORE RESISTANT TO THE IMMUNOLOGICAL ANNIHILATION PROCESS CAUSED BY CERTAIN ELEMENTS OF THE IMMUNE SYSTEM. NEVERTHELESS, EUTOPIC ENDOMETRIAL CELLS HAVE THE POTENTIAL TO SIMILARLY ESCALATE THE EXPRESSION OF AROMATASE RECEPTORS ON THE SURFACE OF THE PATHOLOGICAL CELLS, WHICH IN THE FINAL CASCADE CAUSE AN INCREASE IN THE CONCENTRATION OF ESTROGEN, AS WELL AS OTHER INFLAMMATORY PROTEINS THAT CONTRIBUTE TO PATHOLOGICAL OUTGROWTH. DATA REVEAL OCCURRENCE AMONG FIRST-DEGREE RELATIVES, SUGGESTING THAT THE SPECIFIC CASCADE COULD BE RELATED TO INHERITED AS WELL AS EPIGENETIC (ACQUIRED) MECHANISMS. IN WOMEN WITH THE DISEASE, CONFIRMED BY LAPAROSCOPIC PROCEDURES, DIAGNOSIS OF ENDOMETRIOSIS CAN BE ESTABLISHED ALSO VIA DETECTION BY GENE POLYMORPHISM IN THE GENES WHICH ARE RESPONSIBLE FOR RESPONSIBLE FOR THE DETOXIFICATION PHASE OF ESTROGEN RECEPTORS AND OTHER IMMUNOMODULATOR COMPONENTS. A RECENT PUBLICATION AIMS TO REVEAL A NEW PROSPECT FOR THE NON-INVASIVE DIAGNOSIS, DETECTION, AND ESTIMATION OF CERTAIN BIOMARKERS FOR MUCH MORE SPECIFIC INVESTIGATION OF THE DISEASE'S PROGRESSION. 2021 12 4185 39 METABOLIC ADAPTIONS/REPROGRAMMING IN ISLET BETA-CELLS IN RESPONSE TO PHYSIOLOGICAL STIMULATORS-WHAT ARE THE CONSEQUENCES. IRREVERSIBLE PANCREATIC BETA-CELL DAMAGE MAY BE A RESULT OF CHRONIC EXPOSURE TO SUPRAPHYSIOLOGICAL GLUCOSE OR LIPID CONCENTRATIONS OR CHRONIC EXPOSURE TO THERAPEUTIC ANTI-DIABETIC DRUGS. THE BETA-CELLS ARE ABLE TO RESPOND TO BLOOD GLUCOSE IN A NARROW CONCENTRATION RANGE AND RELEASE INSULIN IN RESPONSE, FOLLOWING ACTIVATION OF METABOLIC PATHWAYS SUCH AS GLYCOLYSIS AND THE TCA CYCLE. THE BETA-CELL CANNOT PROTECT ITSELF FROM GLUCOSE TOXICITY BY BLOCKING GLUCOSE UPTAKE, BUT INDEED RELIES ON ALTERNATIVE METABOLIC PROTECTION MECHANISMS TO AVOID DYSFUNCTION AND DEATH. ALTERATION OF NORMAL METABOLIC PATHWAY FUNCTION OCCURS AS A COUNTER REGULATORY RESPONSE TO HIGH NUTRIENT, INFLAMMATORY FACTOR, HORMONE OR THERAPEUTIC DRUG CONCENTRATIONS. METABOLIC REPROGRAMMING IS A TERM WIDELY USED TO DESCRIBE A CHANGE IN REGULATION OF VARIOUS METABOLIC ENZYMES AND TRANSPORTERS, USUALLY ASSOCIATED WITH CELL GROWTH AND PROLIFERATION AND MAY INVOLVE RESHAPING EPIGENETIC RESPONSES, IN PARTICULAR THE ACETYLATION AND METHYLATION OF HISTONE PROTEINS AND DNA. OTHER METABOLIC MODIFICATIONS SUCH AS MALONYLATION, SUCCINYLATION, HYDROXYBUTYRYLATION, ADP-RIBOSYLATION, AND LACTYLATION, MAY IMPACT REGULATORY PROCESSES, MANY OF WHICH NEED TO BE INVESTIGATED IN DETAIL TO CONTRIBUTE TO CURRENT ADVANCES IN METABOLISM. BY DESCRIBING MULTIPLE MECHANISMS OF METABOLIC ADAPTION THAT ARE AVAILABLE TO THE BETA-CELL ACROSS ITS LIFESPAN, WE HOPE TO IDENTIFY SITES FOR METABOLIC REPROGRAMMING MECHANISMS, MOST OF WHICH ARE INCOMPLETELY DESCRIBED OR UNDERSTOOD. MANY OF THESE MECHANISMS ARE RELATED TO PROMINENT ANTIOXIDANT RESPONSES. HERE, WE HAVE ATTEMPTED TO DESCRIBE THE KEY BETA-CELL METABOLIC ADAPTIONS AND CHANGES WHICH ARE REQUIRED FOR SURVIVAL AND FUNCTION IN VARIOUS PHYSIOLOGICAL, PATHOLOGICAL AND PHARMACOLOGICAL CONDITIONS. 2022 13 1066 39 CLINICAL USE OF AMINO ACIDS AS DIETARY SUPPLEMENT: PROS AND CONS. NITROGEN SUPPLY IS PIVOTAL FOR THE MAINTENANCE OF LIFE. AMINO ACIDS CAN BE UTILIZED TO SYNTHESIZE BOTH GLUCOSE AND LIPIDS. THE OPPOSITE, I.E., PRODUCTION OF AMINO ACIDS FROM EITHER ONE OF THEM, IS NOT POSSIBLE IN THE ABSENCE OF OTHER AMINO ACIDS AS DONORS OF NITROGEN. THE QUALITY OF AMINO ACID CONTENT IN PROTEIN HAS BEEN RE-EVALUATED RECENTLY, AND THE RELEVANCE OF ESSENTIAL AMINO ACIDS HAS BEEN REPEATEDLY UNDERLINED. ESSENTIAL AMINO ACID REQUIREMENTS IN DIFFERENT MAMMALS ARE NOT IDENTICAL, AND RATIOS AMONG THEM SHOULD BE TAKEN INTO ACCOUNT WHEN PROJECTING AN EFFICIENT FORMULATION. RECENT RESEARCH HAS DEMONSTRATED THAT GENES RESPOND TO DIFFERENT QUALITIES AND QUANTITIES OF NUTRITIONAL SUPPLY, AND INCREASED PROVISION OF ESSENTIAL AMINO ACIDS INCREASES LIFESPAN IN ANIMAL EXPERIMENTS THROUGH MITOCHONDRIOGENESIS AND MAINTENANCE OF ELEVATED RATES OF SYNTHESIS OF ANTI-OXIDANT MOLECULES. MOREOVER, GENETIC EXPRESSION OF KEY CONTROLLERS OF SYNTHESIS, LIKE MTOR, MAY BE PARTICULARLY IMPORTANT FOR UNDERSTANDING SKELETAL MUSCLE MAINTENANCE. LOSSES OF MUSCLE MASS AND IMPAIRED IMMUNE FUNCTION ARE RELATED TO REDUCED PROTEIN SUPPLY, AND THERE IS INCREASING EVIDENCE THAT REGULAR ESSENTIAL AMINO ACID INTAKE AS PART OF AN ORAL DIET IS EFFECTIVE IN REVERSING MUSCLE CATABOLISM, PROMOTING MUSCLE ANABOLISM, AND RESTORING IMMUNOLOGICAL FUNCTION. THEREFORE, THE USE OF AMINO ACIDS AS SUPPLEMENTS TO DIET WOULD BE EXPANDING IN THE NEAR FUTURE. IS THIS SAFE? FEW DATA ARE AVAILABLE ON AMINO ACID TOXICITY, AND ONLY ONE ESSENTIAL AMINO ACID MAY BE CONSIDERED TO HAVE CLINICALLY RELEVANT TOXICITY: METHIONINE, BECAUSE IT IS TRANSFORMED INTO A TOXIC INTERMEDIATE, HOMOCYSTEINE, WHEN CYSTEINE SYNTHESIS IS REQUIRED BY METABOLIC NEEDS. MATCHING OF STOICHIOMETRIC RATIOS BETWEEN METHIONINE AND CYSTEINE MAY SOLVE THE PROBLEM OF SUPPLYING SUFFICIENT AMOUNTS OF SULFUR TO THE BODY. ARGININE AND GLUTAMINE ARE TWO NON-ESSENTIAL AMINO ACIDS THAN CAN BECOME "CONDITIONALLY ESSENTIAL" BECAUSE OF ELEVATED NEEDS DURING PATHOLOGICAL CONDITIONS, AND METABOLISM MAY NOT BE ABLE TO MAINTAIN THEIR CONCENTRATIONS AT SUFFICIENT LEVELS TO MATCH METABOLIC REQUIREMENTS. CHRONIC EXOGENOUS ARGININE SUPPLEMENTATION HAS NOT PROVEN TO EXERT POSITIVE CLINICAL EFFECTS IN DIFFERENT TRIALS, AND SEQUENTIAL ARTICULATION OF THE KNOWLEDGE OF INTRODUCTION OF ARGININE-DRIVEN TRANSCRIPTIONAL, TRANSLATIONAL, AND EPIGENETIC ADAPTATIONS MAY GIVE US A KEY FOR INTERPRETING THOSE PUZZLING RESULTS. 2011 14 5711 41 SIRT1 IS A HIGHLY NETWORKED PROTEIN THAT MEDIATES THE ADAPTATION TO CHRONIC PHYSIOLOGICAL STRESS. SIRT1 IS A NAD(+)-DEPENDENT PROTEIN DEACETYLASE THAT HAS A VERY LARGE NUMBER OF ESTABLISHED PROTEIN SUBSTRATES AND AN EQUALLY IMPRESSIVE LIST OF BIOLOGICAL FUNCTIONS THOUGHT TO BE REGULATED BY ITS ACTIVITY. PERHAPS AS NOTABLE IS THE REMARKABLE NUMBER OF POINTS OF CONFLICT CONCERNING THE ROLE OF SIRT1 IN BIOLOGICAL PROCESSES. FOR EXAMPLE, EVIDENCE EXISTS SUGGESTING THAT SIRT1 IS A TUMOR SUPPRESSOR, IS AN ONCOGENE, OR HAS NO EFFECT ON ONCOGENESIS. SIMILARLY, SIRT1 IS VARIABLY REPORTED TO INDUCE, INHIBIT, OR HAVE NO EFFECT ON AUTOPHAGY. WE BELIEVE THAT THE RESOLUTION OF MANY CONFLICTING RESULTS IS POSSIBLE BY CONSIDERING RECENT REPORTS INDICATING THAT SIRT1 IS AN IMPORTANT HUB INTERACTING WITH A COMPLEX NETWORK OF PROTEINS THAT COLLECTIVELY REGULATE A WIDE VARIETY OF BIOLOGICAL PROCESSES INCLUDING CANCER AND AUTOPHAGY. A NUMBER OF THE INTERACTING PROTEINS ARE THEMSELVES HUBS THAT, LIKE SIRT1, UTILIZE INTRINSICALLY DISORDERED REGIONS FOR THEIR PROMISCUOUS INTERACTIONS. MANY STUDIES INVESTIGATING SIRT1 FUNCTION HAVE BEEN CARRIED OUT ON CELL LINES CARRYING UNDETERMINED NUMBERS OF ALTERATIONS TO THE PROTEINS COMPRISING THE SIRT1 NETWORK OR ON INBRED MOUSE STRAINS CARRYING FIXED MUTATIONS AFFECTING SOME OF THESE PROTEINS. THUS, THE EFFECTS OF MODULATING SIRT1 AMOUNT AND/OR ACTIVITY ARE IMPORTANTLY DETERMINED BY THE GENETIC BACKGROUND OF THE CELL (OR THE INBRED STRAIN OF MICE), AND THE EFFECTS ATTRIBUTED TO SIRT1 ARE SYNTHETIC WITH THE BACKGROUND OF MUTATIONS AND EPIGENETIC DIFFERENCES BETWEEN CELLS AND ORGANISMS. WORK ON MICE CARRYING ALTERATIONS TO THE SIRT1 GENE SUGGESTS THAT THE NETWORK IN WHICH SIRT1 FUNCTIONS PLAYS AN IMPORTANT ROLE IN MEDIATING PHYSIOLOGICAL ADAPTATION TO VARIOUS SOURCES OF CHRONIC STRESS SUCH AS CALORIE RESTRICTION AND CALORIE OVERLOAD. WHETHER THE CATALYTIC ACTIVITY OF SIRT1 AND THE NUCLEAR CONCENTRATION OF THE CO-FACTOR, NAD(+), ARE RESPONSIBLE FOR MODULATING THIS ACTIVITY REMAINS TO BE DETERMINED. HOWEVER, THE EFFECT OF MODULATING SIRT1 ACTIVITY MUST BE INTERPRETED IN THE CONTEXT OF THE CELL OR TISSUE UNDER INVESTIGATION. INDEED, FOR SIRT1, WE ARGUE THAT CONTEXT IS EVERYTHING. 2013 15 6185 29 THE IMPACT OF GENERAL ANESTHESIA ON REDOX STABILITY AND EPIGENETIC INFLAMMATION PATHWAYS: CROSSTALK ON PERIOPERATIVE ANTIOXIDANT THERAPY. WORLDWIDE, THE PREVALENCE OF SURGERY UNDER GENERAL ANESTHESIA HAS SIGNIFICANTLY INCREASED, BOTH BECAUSE OF MODERN ANESTHETIC AND PAIN-CONTROL TECHNIQUES AND BECAUSE OF BETTER DIAGNOSIS AND THE INCREASED COMPLEXITY OF SURGICAL TECHNIQUES. APART FROM DEVELOPING NEW CONCEPTS IN THE SURGICAL FIELD, RESEARCHERS AND CLINICIANS ARE NOW WORKING ON MINIMIZING THE IMPACT OF SURGICAL TRAUMA AND OFFERING MINIMAL INVASIVE PROCEDURES DUE TO THE RECENT DISCOVERIES IN THE FIELD OF CELLULAR AND MOLECULAR MECHANISMS THAT HAVE REVEALED A SYSTEMIC INFLAMMATORY AND PRO-OXIDATIVE IMPACT NOT ONLY IN THE PERIOPERATIVE PERIOD BUT ALSO IN THE LONG TERM, CONTRIBUTING TO MORE DIFFICULT RECOVERY, INCREASED MORBIDITY AND MORTALITY, AND A NEGATIVE FINANCIAL IMPACT. DETAILED MOLECULAR AND CELLULAR ANALYSIS HAS SHOWN AN OVERPRODUCTION OF INFLAMMATORY AND PRO-OXIDATIVE SPECIES, RESPONSIBLE FOR AUGMENTING THE SYSTEMIC INFLAMMATORY STATUS AND MAKING POSTOPERATIVE RECOVERY MORE DIFFICULT. MOREOVER, THERE ARE A SERIES OF CHANGES IN CERTAIN EPIGENETIC STRUCTURES, THE MOST IMPORTANT BEING THE MICRORNAS. THIS REVIEW DESCRIBES THE MOST IMPORTANT MOLECULAR AND CELLULAR MECHANISMS THAT IMPACT THE SURGICAL PATIENT UNDERGOING GENERAL ANESTHESIA, AND IT PRESENTS A SERIES OF ANTIOXIDANT THERAPIES THAT CAN REDUCE SYSTEMIC INFLAMMATION. 2022 16 1932 41 ENVIRONMENTAL EXPOSURES: AN UNDERRECOGNIZED CONTRIBUTION TO NONCOMMUNICABLE DISEASES. PREVIOUS ATTEMPTS TO DETERMINE THE DEGREE TO WHICH EXPOSURE TO ENVIRONMENTAL FACTORS CONTRIBUTE TO NONCOMMUNICABLE DISEASES (NCDS) HAVE BEEN VERY CONSERVATIVE AND HAVE SIGNIFICANTLY UNDERESTIMATED THE ACTUAL CONTRIBUTION OF THE ENVIRONMENT FOR AT LEAST TWO REASONS. FIRSTLY, MOST PREVIOUS REPORTS HAVE EXCLUDED THE CONTRIBUTION OF LIFESTYLE BEHAVIORAL RISK FACTORS, BUT THESE USUALLY INVOLVE SIGNIFICANT EXPOSURE TO ENVIRONMENTAL CHEMICALS THAT INCREASE RISK OF DISEASE. SECONDLY, EARLY LIFE EXPOSURE TO CHEMICAL CONTAMINANTS IS NOW CLEARLY ASSOCIATED WITH AN ELEVATED RISK OF SEVERAL DISEASES LATER IN LIFE, BUT THESE CONNECTIONS ARE OFTEN DIFFICULT TO DISCERN. THIS IS ESPECIALLY TRUE FOR ASTHMA AND NEURODEVELOPMENTAL CONDITIONS, BUT THERE IS ALSO A MAJOR CONTRIBUTION TO THE DEVELOPMENT OF OBESITY AND CHRONIC DISEASES. MOST CANCERS ARE CAUSED BY ENVIRONMENTAL EXPOSURES IN GENETICALLY SUSCEPTIBLE INDIVIDUALS. IN ADDITION, NEW INFORMATION SHOWS SIGNIFICANT ASSOCIATIONS BETWEEN CARDIOVASCULAR DISEASES AND DIABETES AND EXPOSURE TO ENVIRONMENTAL CHEMICALS PRESENT IN AIR, FOOD, AND WATER. THESE RELATIONSHIPS LIKELY REFLECT THE COMBINATION OF EPIGENETIC EFFECTS AND GENE INDUCTION. ENVIRONMENTAL FACTORS CONTRIBUTE SIGNIFICANTLY MORE TO NCDS THAN PREVIOUS REPORTS HAVE SUGGESTED. PREVENTION NEEDS TO SHIFT FOCUS FROM INDIVIDUAL RESPONSIBILITY TO SOCIETAL RESPONSIBILITY AND AN UNDERSTANDING THAT EFFECTIVE PREVENTION OF NCDS ULTIMATELY RELIES ON IMPROVED ENVIRONMENTAL MANAGEMENT TO REDUCE EXPOSURE TO MODIFIABLE RISKS. 2013 17 3094 47 GENOMIC AND PERSONALIZED MEDICINE APPROACHES FOR SUBSTANCE USE DISORDERS (SUDS) LOOKING AT GENOME-WIDE ASSOCIATION STUDIES. DRUG ADDICTION, OR SUBSTANCE USE DISORDER (SUD), IS A CHRONIC, RELAPSING DISORDER IN WHICH COMPULSIVE DRUG-SEEKING AND DRUG-TAKING BEHAVIOUR PERSIST DESPITE SERIOUS NEGATIVE CONSEQUENCES. DRUG ABUSE REPRESENTS A PROBLEM THAT DESERVES GREAT ATTENTION FROM A SOCIAL POINT OF VIEW, AND FOCUSES ON THE IMPORTANCE OF GENETIC STUDIES TO HELP IN UNDERSTANDING THE GENETIC BASIS OF ADDICTION AND ITS MEDICAL TREATMENT. DESPITE THE COMPLEXITY OF DRUG ADDICTION DISORDERS, AND THE HIGH NUMBER OF ENVIRONMENTAL VARIABLES PLAYING A ROLE IN THE ONSET, RECURRENCE, AND DURATION OF THE SYMPTOMS, SEVERAL STUDIES HAVE HIGHLIGHTED THE NON-NEGLIGIBLE ROLE OF GENETICS, AS DEMONSTRATED BY HERITABILITY AND GENOME-WIDE ASSOCIATION STUDIES. A CORRELATION BETWEEN THE RELATIVE RISK OF ADDICTION TO SPECIFIC SUBSTANCES AND HERITABILITY HAS BEEN RECENTLY OBSERVED, SUGGESTING THAT NEUROBIOLOGICAL MECHANISMS MAY BE, AT LEAST IN PART, INHERITED. ALL THESE OBSERVATIONS POINT TOWARDS A SCENARIO WHERE THE CORE NEUROBIOLOGICAL FACTORS OF ADDICTION, INVOLVING THE REWARD SYSTEM, IMPULSIVITY, COMPULSIVITY, STRESS, AND ANXIETY RESPONSE, ARE TRANSMITTED, AND THEREFORE, GENES AND MUTATIONS UNDERLYING THEIR VARIATION MIGHT BE DETECTED. IN THE LAST FEW YEARS, THE DEVELOPMENT OF NEW AND MORE EFFICIENT SEQUENCING TECHNOLOGIES HAS PAVED THE WAY FOR LARGE-SCALE STUDIES IN SEARCHING FOR GENETIC AND EPIGENETIC FACTORS AFFECTING DRUG ADDICTION DISORDERS AND THEIR TREATMENTS. THESE STUDIES HAVE BEEN CRUCIAL TO PINPOINT SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) IN GENES THAT AFFECT THE REACTION TO MEDICAL TREATMENTS. THIS IS CRITICALLY IMPORTANT TO IDENTIFY PHARMACOGENOMIC APPROACHES FOR SUBSTANCE USE DISORDER, SUCH AS OPRM1 SNPS AND METHADONE REQUIRED DOSES FOR MAINTENANCE TREATMENT (MMT). NEVERTHELESS, DESPITE THE PROMISING RESULTS OBTAINED BY GENOME-WIDE ASSOCIATION AND PHARMACOGENOMIC STUDIES, SPECIFIC STUDIES RELATED TO POPULATION GENETICS DIVERSITY ARE LACKING, UNDERMINING THE OVERALL APPLICABILITY OF THE PRELIMINARY FINDINGS, AND THUS POTENTIALLY AFFECTING THE PORTABILITY AND THE ACCURACY OF THE GENETIC STUDIES. IN THIS REVIEW, FOCUSING ON CANNABIS, COCAINE AND HEROIN USE, WE REPORT THE STATE-OF-THE-ART GENOMICS AND PHARMACOGENOMICS OF SUDS, AND THE POSSIBLE FUTURE PERSPECTIVES RELATED TO MEDICAL TREATMENT RESPONSE IN PEOPLE THAT ASK FOR ASSISTANCE IN SOLVING DRUG-RELATED PROBLEMS. 2021 18 6406 29 THE SEARCH FOR RELIABLE BIOMARKERS OF DISEASE IN MULTIPLE CHEMICAL SENSITIVITY AND OTHER ENVIRONMENTAL INTOLERANCES. WHILST FACING A WORLDWIDE FAST INCREASE OF FOOD AND ENVIRONMENTAL ALLERGIES, THE MEDICAL COMMUNITY IS ALSO CONFRONTED WITH ANOTHER INHOMOGENEOUS GROUP OF ENVIRONMENT-ASSOCIATED DISABLING CONDITIONS, INCLUDING MULTIPLE CHEMICAL SENSITIVITY (MCS), FIBROMYALGIA, CHRONIC FATIGUE SYNDROME, ELECTRIC HYPERSENSITIVITY, AMALGAM DISEASE AND OTHERS. THESE SHARE THE FEATURES OF POLY-SYMPTOMATIC MULTI-ORGAN CUTANEOUS AND SYSTEMIC MANIFESTATIONS, WITH POSTULATED INHERITED/ACQUIRED IMPAIRED METABOLISM OF CHEMICAL/PHYSICAL/NUTRITIONAL XENOBIOTICS, TRIGGERING ADVERSE REACTIONS AT EXPOSURE LEVELS FAR BELOW TOXICOLOGICALLY-RELEVANT VALUES, OFTEN IN THE ABSENCE OF CLEAR-CUT ALLERGOLOGIC AND/OR IMMUNOLOGIC INVOLVEMENT. DUE TO THE LACK OF PROVEN PATHOGENIC MECHANISMS GENERATING MEASURABLE DISEASE BIOMARKERS, THESE ENVIRONMENTAL HYPERSENSITIVITIES ARE GENERALLY IGNORED BY SANITARY AND SOCIAL SYSTEMS, AS PSYCHOGENIC OR "MEDICALLY UNEXPLAINED SYMPTOMS". THE UNCONTROLLED APPLICATION OF DIAGNOSTIC AND TREATMENT PROTOCOLS NOT CORRESPONDING TO ACCEPTABLE LEVELS OF VALIDATION, SAFETY, AND CLINICAL EFFICACY, TO A STEADILY INCREASING NUMBER OF PATIENTS DEMANDING ASSISTANCE, OCCURS IN MANY COUNTRIES IN THE ABSENCE OF EVIDENCE-BASED GUIDELINES. HERE WE REVISE AVAILABLE INFORMATION SUPPORTING THE ORGANIC NATURE OF THESE CLINICAL CONDITIONS. FOLLOWING INTENSE RESEARCH ON GENE POLYMORPHISMS OF PHASE I/II DETOXIFICATION ENZYME GENES, SO FAR STATISTICALLY INCONCLUSIVE, EPIGENETIC AND METABOLIC FACTORS ARE UNDER INVESTIGATION, IN PARTICULAR FREE RADICAL/ANTIOXIDANT HOMEOSTASIS DISTURBANCES. THE FINDING OF RELEVANT ALTERATIONS OF CATALASE, GLUTATHIONE-TRANSFERASE AND PEROXIDASE DETOXIFYING ACTIVITIES SIGNIFICANTLY CORRELATING WITH CLINICAL MANIFESTATIONS OF MCS, HAS RECENTLY REGISTERED SOME PROGRESS TOWARDS THE IDENTIFICATION OF RELIABLE BIOMARKERS OF DISEASE ONSET, PROGRESSION, AND TREATMENT OUTCOMES. 2011 19 835 34 CHEMICAL CARCINOGEN MECHANISMS OF ACTION AND IMPLICATIONS FOR TESTING METHODOLOGY. CHEMICAL CARCINOGENS ARE OF TWO DISTINCT TYPES, DNA-REACTIVE AND EPIGENETIC. TESTING METHODOLOGY CAN BE DIRECTED TOWARD DETECTING EFFECTS OF BOTH TYPES OF CARCINOGEN. CARCINOGENS OF THE DNA-REACTIVE TYPE ARE DEFINED BY THE FORMATION OF COVALENTLY BOUND DNA ADDUCTS. THESE CHEMICALS HAVE STRUCTURES THAT YIELD ELECTROPHILIC REACTANTS EITHER DIRECTLY OR AFTER BIOACTIVATION. THESE AGENTS CAUSE GENOMIC ALTERATION IN THE STRUCTURE OR FUNCTION OF DNA IN THE TARGET CELL. IN ADDITION, THESE COMPOUNDS CAN EXERT OTHER CELLULAR AND TISSUE EPIGENETIC EFFECTS, SUCH AS CELL PROLIFERATION AND GROWTH PROMOTION. CARCINOGENS OF THE EPIGENETIC (PARAGENETIC) TYPE, IN CONTRAST, DO NOT REACT WITH DNA, BUT RATHER DISPLAY CELLULAR EFFECTS SUCH AS NEOPLASM GROWTH PROMOTION, CYTOTOXICITY, INHIBITION OF TISSUE GROWTH REGULATION, PEROXISOME PROLIFERATION, ENDOCRINE MODIFICATION, IMMUNOSUPPRESSION AND/OR SUSTAINED TISSUE ISCHEMIA THAT CAN BE THE BASIS FOR INCREASES IN NEOPLASIA. THEIR CHEMICAL STRUCTURE IS SUCH THAT THEY DO NOT GIVE RISE TO A REACTIVE ELECTROPHILE. THE TESTING METHODOLOGIES TO IDENTIFY EITHER TYPE FOLLOW A DECISION POINT APPROACH DESIGNED TO IDENTIFY POTENTIAL CARCINOGENICITY AND YIELD MECHANISTIC INFORMATION ON THE PRODUCTION OF EFFECTS THAT UNDERLIE CARCINOGENICITY. IT HAS 5 STAGES FOCUSING ON THE CHEMICAL STRUCTURE, DNA-REACTIVITY, EPIGENETIC EFFECTS, LIMITED BIOASSAYS AND FINALLY THE APPLICATION OF THE ACCELERATED BIOASSAY (ABA). ABA REQUIRES 40 WEEKS AND APPLIES THE USE OF SENSITIVE MARKERS FOR INDUCTION OF NEOPLASIA IN COMPARISON TO POSITIVE CONTROL COMPOUNDS FOR IMPORTANT ORGANS IN HUMAN CARCINOGENESIS. IT ENABLES DATA ACQUISITION OF THE ENTIRE CARCINOGENIC PROCESS DIRECTED TOWARD DEVELOPING MECHANISTIC INFORMATION. THE ABA HAS THE POTENTIAL TO REPLACE THE CHRONIC BIOASSAY IN RODENTS IN SOME CIRCUMSTANCES AND CAN SERVE AS AN ALTERNATIVE TO A CHRONIC BIOASSAY IN A SECOND SPECIES. 1996 20 1219 38 CRISPR/CAS9 GENOME EDITING REVEALS THAT THE INTRON IS NOT ESSENTIAL FOR VAR2CSA GENE ACTIVATION OR SILENCING IN PLASMODIUM FALCIPARUM. PLASMODIUM FALCIPARUM RELIES ON MONOALLELIC EXPRESSION OF 1 OF 60 VAR VIRULENCE GENES FOR ANTIGENIC VARIATION AND HOST IMMUNE EVASION. EACH VAR GENE CONTAINS A CONSERVED INTRON WHICH HAS BEEN IMPLICATED IN PREVIOUS STUDIES IN BOTH ACTIVATION AND REPRESSION OF TRANSCRIPTION VIA SEVERAL EPIGENETIC MECHANISMS, INCLUDING INTERACTION WITH THE VAR PROMOTER, PRODUCTION OF LONG NONCODING RNAS (LNCRNAS), AND LOCALIZATION TO REPRESSIVE PERINUCLEAR SITES. HOWEVER, FUNCTIONAL STUDIES HAVE RELIED PRIMARILY ON ARTIFICIAL EXPRESSION CONSTRUCTS. USING THE RECENTLY DEVELOPED P. FALCIPARUM CLUSTERED REGULARLY INTERSPACED SHORT PALINDROMIC REPEATS (CRISPR)/CAS9 SYSTEM, WE DIRECTLY DELETED THE VAR2CSA P. FALCIPARUM 3D7_1200600 (PF3D7_1200600) ENDOGENOUS INTRON, RESULTING IN AN INTRONLESS VAR GENE IN A NATURAL, MARKER-FREE CHROMOSOMAL CONTEXT. DELETION OF THE VAR2CSA INTRON RESULTED IN AN UPREGULATION OF TRANSCRIPTION OF THE VAR2CSA GENE IN RING-STAGE PARASITES AND SUBSEQUENT EXPRESSION OF THE PFEMP1 PROTEIN IN LATE-STAGE PARASITES. INTRON DELETION DID NOT AFFECT THE NORMAL TEMPORAL REGULATION AND SUBSEQUENT TRANSCRIPTIONAL SILENCING OF THE VAR GENE IN TROPHOZOITES BUT DID RESULT IN INCREASED RATES OF VAR GENE SWITCHING IN SOME MUTANT CLONES. TRANSCRIPTIONAL REPRESSION OF THE INTRONLESS VAR2CSA GENE COULD BE ACHIEVED VIA LONG-TERM CULTURE OR PANNING WITH THE CD36 RECEPTOR, AFTER WHICH REACTIVATION WAS POSSIBLE WITH CHONDROITIN SULFATE A (CSA) PANNING. THESE DATA SUGGEST THAT THE VAR2CSA INTRON IS NOT REQUIRED FOR SILENCING OR ACTIVATION IN RING-STAGE PARASITES BUT POINT TO A SUBTLE ROLE IN REGULATION OF SWITCHING WITHIN THE VAR GENE FAMILY.IMPORTANCEPLASMODIUM FALCIPARUM IS THE MOST VIRULENT SPECIES OF MALARIA PARASITE, CAUSING HIGH RATES OF MORBIDITY AND MORTALITY IN THOSE INFECTED. CHRONIC INFECTION DEPENDS ON AN IMMUNE EVASION MECHANISM TERMED ANTIGENIC VARIATION, WHICH IN TURN RELIES ON MONOALLELIC EXPRESSION OF 1 OF ~60 VAR GENES. UNDERSTANDING ANTIGENIC VARIATION AND THE TRANSCRIPTIONAL REGULATION OF MONOALLELIC EXPRESSION IS IMPORTANT FOR DEVELOPING DRUGS AND/OR VACCINES. THE VAR GENE FAMILY ENCODES THE ANTIGENIC SURFACE PROTEINS THAT DECORATE INFECTED ERYTHROCYTES. UNTIL RECENTLY, STUDYING THE UNDERLYING GENETIC ELEMENTS THAT REGULATE MONOALLELIC EXPRESSION IN P. FALCIPARUM WAS DIFFICULT, AND MOST STUDIES RELIED ON ARTIFICIAL SYSTEMS SUCH AS EPISOMAL REPORTER GENES. OUR STUDY WAS THE FIRST TO USE CRISPR/CAS9 GENOME EDITING FOR THE FUNCTIONAL STUDY OF AN IMPORTANT, CONSERVED GENETIC ELEMENT OF VAR GENES-THE INTRON-IN AN ENDOGENOUS, EPISOME-FREE MANNER. OUR FINDINGS SHED LIGHT ON THE ROLE OF THE VAR GENE INTRON IN TRANSCRIPTIONAL REGULATION OF MONOALLELIC EXPRESSION. 2017