1   745 300 CANNABIS ALTERS EPIGENETIC INTEGRITY AND ENDOCANNABINOID SIGNALLING IN THE HUMAN FOLLICULAR NICHE. STUDY QUESTION: DO PHYTOCANNABINOIDS (PCS) AFFECT FOLLICULAR ENDOCANNABINOID SIGNALLING AND THE EPIGENOME IN THE SURROUNDING GRANULOSA CELLS (GCS)? SUMMARY ANSWER: EXPOSURE TO PCS INCREASES THE EXPRESSION OF ENDOCANNABINOID RECEPTORS AND REDUCES DNA METHYLATION ENZYME EXPRESSION AND GLOBAL DNA METHYLATION IN NAIVE GCS. WHAT IS KNOWN ALREADY: CANNABIS PLANT DERIVATIVES, KNOWN AS PCS, ARE USED FOR MEDICINAL AND RECREATIONAL PURPOSES. THE MAIN PC, TETRAHYDROCANNABINOL (THC), IS THE THIRD MOST COMMONLY USED SUBSTANCE BY WOMEN OF CHILDBEARING AGE, HENCE KNOWLEDGE OF THE EFFECT IT HAS ON REPRODUCTION IS OF UTMOST IMPORTANCE. THC EXERTS ITS EFFECTS VIA RECEPTORS OF THE ENDOCANNABINOID SYSTEM (ECS) AND CAN INTERFERE WITH FOLLICULOGENESIS, OOCYTE DEVELOPMENT AND OVULATION. ENDOCANNABINOIDS HAVE BEEN MEASURED IN FOLLICULAR FLUID (FF) OBTAINED DURING OOCYTE RETRIEVAL AND ARE IMPLICATED IN CONTROLLING FOLLICULOGENESIS. IT HAS BEEN ESTABLISHED THAT IN THE PLACENTA, PCS DISRUPT ENDOCANNABINOID HOMEOSTASIS VIA IMPAIRMENT OF THE SYNTHETIC AND DEGRADING ENZYMES, LEADING TO A NET INCREASE OF ENDOCANNABINOID LEVELS. FINALLY, PREVIOUS STUDIES HAVE SHOWN THAT THC ALTERS METHYLATION AND HISTONE MODIFICATIONS IN SPERM, BRAIN AND BLOOD CELLS. STUDY DESIGN, SIZE, DURATION: THIS STUDY INCLUDED AN IN VIVO COHORT ASSESSMENT OF CANNABIS EXPOSURE AND ITS EFFECTS ON THE FOLLICLE AND IN VITRO ASSAYS CONDUCTED TO VALIDATE THE IN VIVO FINDINGS AND TO EXPLORE POSSIBLE MECHANISMS OF ACTION. PARTICIPANTS/MATERIALS, SETTING, METHODS: A TOTAL OF 318 FF SAMPLES, FROM 261 PATIENTS UNDERGOING IVF TREATMENT AT A PRIVATE FERTILITY CLINIC WHO CONSENTED FOR BIOBANKING BIOLOGICAL WASTE MATERIAL BETWEEN JANUARY 2018 AND JULY 2019, WERE INCLUDED IN THIS STUDY. CONCENTRATIONS OF PCS AND ENDOCANNABINOIDS WERE ASSESSED IN FF BY LIQUID CHROMATOGRAPHY-MASS SPECTROMETRY (LC-MS/MS). EXPOSURE TO PCS WAS DETERMINED BASED ON THESE MEASURED LEVELS. LEVELS OF BOTH ENDOCANNABINOID RECEPTORS (CB1R, CB2R) AND THE DE NOVO DNA METHYLATING ENZYME, DNMT3B, IN GCS WERE ASSESSED BY FLOW CYTOMETRY BOTH IN VITRO AND IN VIVO AND GLOBAL DNA METHYLATION WAS ASSESSED IN VITRO BY ELISA. IN VIVO EFFECTS WERE ASSESSED BY COMPARING SAMPLES POSITIVE FOR AT LEAST ONE PC, WITH SAMPLES NEGATIVE FOR ALL MEASURED PCS. IN VITRO EFFECTS WERE DETERMINED IN NAIVE GCS, OBTAINED CONCURRENTLY WITH FF SAMPLES THAT HAD TESTED NEGATIVE FOR ALL PCS. THESE GCS WERE TREATED WITH DIFFERENT COMBINATIONS OF THE MAIN THREE PCS. MAIN RESULTS AND THE ROLE OF CHANCE: OVERALL, 17 PATIENTS (6.4%) WERE POSITIVE FOR CANNABIS CONSUMPTION. FURTHERMORE, THE PREVALENCE OF CANNABIS POSITIVITY IN THE FF INCREASED FROM 4% OF THE TESTED SAMPLES THAT WERE COLLECTED PRIOR TO NATIONAL LEGALISATION IN OCTOBER 2018 TO 12% OF THOSE COLLECTED FOLLOWING LEGALISATION. OF NOTE, 59% OF PATIENTS WHO TESTED POSITIVE FOR PCS (10 OF 17) REPORTED PREVIOUS OR ONGOING EXPOSURE TO CANNABIS UPON THEIR INITIAL INTAKE. ENDOCANNABINOID LEVELS WERE NOT AFFECTED BY THE PRESENCE OF PCS. CB2R WAS MORE PREVALENT THAN CB1R IN GCS AND ITS EXPRESSION INCREASED FOLLOWING ACUTE AND CHRONIC IN VITRO EXPOSURE TO PCS. THE EXPRESSION OF DNMT3B AND GLOBAL METHYLATION DECREASED FOLLOWING EXPOSURE, SUGGESTING THAT CANNABIS MAY AFFECT THE EPIGENOME IN THE FOLLICULAR NICHE. THE ACUTE CHANGES WERE SUSTAINED THROUGHOUT CHRONIC TREATMENT. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: OUR STUDY IS LIMITED BY LACK OF DETAILS REGARDING MODE, FREQUENCY AND TIMING OF PC CONSUMPTION. MOREOVER, WE WERE NOT ABLE TO ADEQUATELY ASSESS THE EFFECT OF PCS ON IMMEDIATE OR LONG-TERM CLINICAL OUTCOMES, DUE TO THE SMALL SAMPLE SIZE AND THE LACK OF FOLLOW UP. FUTURE, LARGE-SCALE STUDIES SHOULD FOCUS ON ASSESS THE CLINICAL IMPLICATIONS OF CANNABIS EXPOSURE, VALIDATE OUR FINDINGS, AND DETERMINE TO WHAT EXTENT CANNABIS AFFECTS THE EPIGENOME OVARIAN FOLLICLE AND THE DEVELOPING OOCYTE. WIDER IMPLICATIONS OF THE FINDINGS: TO OUR KNOWLEDGE, THIS IS THE FIRST STUDY MEASURING PCS IN FF BY LC-MS/MS. WE SHOW THAT CONSUMING CANNABIS ALTERS THE ECS IN THE DEVELOPING FOLLICLE, AND DIRECTLY AFFECTS DNMT EXPRESSION AND GLOBAL DNA METHYLATION LEVELS. CANNABIS LEGALISATION AND USE IS INCREASING WORLDWIDE, THEREFORE FURTHER UNDERSTANDING ITS ROLE IN FEMALE FERTILITY AND FOLLICULOGENESIS IS CRITICAL. STUDY FUNDING/COMPETING INTEREST(S): ALL FUNDING WAS PROVIDED BY CREATE FERTILITY CENTRE THROUGH THE REINVESTMENT OF CLINICAL EARNINGS. THE AUTHORS DECLARE NO COMPETING INTERESTS.	2021	

2   840  38 CHEMOENZYMATIC LABELING OF DNA METHYLATION PATTERNS FOR SINGLE-MOLECULE EPIGENETIC MAPPING. DNA METHYLATION, SPECIFICALLY, METHYLATION OF CYTOSINE (C) NUCLEOTIDES AT THE 5-CARBON POSITION (5-MC), IS THE MOST STUDIED AND SIGNIFICANT EPIGENETIC MODIFICATION. HERE WE DEVELOPED A CHEMOENZYMATIC PROCEDURE TO FLUORESCENTLY LABEL NON-METHYLATED CYTOSINES IN CPG CONTEXT, ALLOWING EPIGENETIC PROFILING OF SINGLE DNA MOLECULES SPANNING HUNDREDS OF THOUSANDS OF BASE PAIRS. WE USED A CPG METHYLTRANSFERASE WITH A SYNTHETIC S-ADENOSYL-L-METHIONINE COFACTOR ANALOG TO TRANSFER AN AZIDE TO CYTOSINES INSTEAD OF THE NATURAL METHYL GROUP. A FLUOROPHORE WAS THEN CLICKED ONTO THE DNA, REPORTING ON THE AMOUNT AND POSITION OF NON-METHYLATED CPGS. WE FOUND THAT LABELING EFFICIENCY WAS INCREASED UP TO 2-FOLD BY THE ADDITION OF A NUCLEOSIDASE, PRESUMABLY BY DEGRADING THE INACTIVE BY-PRODUCT OF THE COFACTOR AFTER LABELING, PREVENTING ITS INHIBITORY EFFECT. WE USED THE METHOD TO DETERMINE THE DECLINE IN GLOBAL DNA METHYLATION IN A CHRONIC LYMPHOCYTIC LEUKEMIA PATIENT AND THEN PERFORMED WHOLE-GENOME METHYLATION MAPPING OF THE MODEL PLANT ARABIDOPSIS THALIANA. OUR GENOME MAPS SHOW HIGH CONCORDANCE WITH PUBLISHED BISULFITE SEQUENCING METHYLATION MAPS. ALTHOUGH MAPPING RESOLUTION IS LIMITED BY OPTICAL DETECTION TO 500-1000 BP, THE LABELED DNA MOLECULES PRODUCED BY THIS APPROACH ARE HUNDREDS OF THOUSANDS OF BASE PAIRS LONG, ALLOWING ACCESS TO LONG REPETITIVE AND STRUCTURALLY VARIABLE GENOMIC REGIONS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
3  3782  42 INTERFERON THERAPY OF CHRONIC HEPATITIS B. CHRONIC HEPATITIS B (CHB) RESULTS FROM THE INABILITY OF THE HOST'S IMMUNE SYSTEM TO CONTROL VIRAL REPLICATION. INTERFERON-ALPHA (IFN-ALPHA) THERAPY CAN CONVERT CHB INTO INACTIVE HEPATITIS B VIRUS (HBV) INFECTION IN 20-30% OF THE TREATED PATIENTS. IN SPITE OF THE LOW RESPONSE RATE, IFN-ALPHA THERAPY HAS THE ADVANTAGE OF HAVING A LIMITED DURATION AND BEING EFFECTIVE EVEN AFTER THERAPY, AS DEMONSTRATED BY A MUCH HIGHER INCIDENCE OF HBSAG CLEARANCE IN RESPONDERS TO IFN-ALPHA THAN IN NATURALLY OCCURRING INACTIVE HBSAG CARRIERS. IFN-ALPHA HAS MULTIPLE ANTIVIRAL, ANTIPROLIFERATIVE, AND IMMUNOMODULATORY ACTIVITIES AND TARGETS: CELLULAR GENES (IFN-STIMULATED GENES) ACTIVATING DIFFERENT PATHWAYS OF ANTIVIRAL DEFENSE IN INFECTED AND NONINFECTED CELLS, HBV REPLICATION BLOCKING THE RNA-CONTAINING CORE PARTICLE FORMATION AND ACCELERATING THEIR DECAY, DEGRADING PREGENOMIC RNA, AND MODULATING THE NUCLEAR VIRAL MINICHROMOSOME (COVALENTLY CLOSED CIRCULAR DNA) ACTIVITY BY TARGETING ITS EPIGENETIC REGULATION AND BOTH INNATE AND ADAPTIVE IMMUNE RESPONSE. THE INTERFERENCE OF VIRAL HETEROGENEITY AND GENETIC POLYMORPHISMS OF THE HOST ON IFN-ALPHA SUSCEPTIBILITY IS UNDER INVESTIGATION. ONLY A BETTER UNDERSTANDING OF THE COMPLEX INTERPLAY BETWEEN THE DIFFERENT ACTIVITIES OF IFN-ALPHA WOULD WARRANT THE AMELIORATION OF CURRENT THERAPEUTIC STRATEGIES AND THE DESIGN OF NEW THERAPEUTIC APPROACHES. THE STUDY OF ON-TREATMENT DYNAMICS OF HBV INFECTION BY MEANS OF COMBINED QUANTITATIVE MONITORING OF SERUM HBV DNA AND HBSAG WARRANT TAILORING TREATMENT AT THE SINGLE-PATIENT LEVEL AND CAN HELP TO MAKE TREATMENT MORE COST-EFFECTIVE BY USING THE DIFFERENT COMBINATIONS OF CURRENTLY AVAILABLE ANTIVIRALS, INCLUDING IFN, MORE APPROPRIATELY. INTEGRATED MOLECULAR AND CLINICAL KNOWLEDGE IN A SYSTEMS MEDICINE FASHION IS MANDATORY TO FURTHER IMPROVE ANTIVIRAL THERAPY IN CHB.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
4  4935  38 PATERNAL COCAINE TAKING ELICITS EPIGENETIC REMODELING AND MEMORY DEFICITS IN MALE PROGENY. PATERNAL ENVIRONMENTAL PERTURBATIONS INCLUDING EXPOSURE TO DRUGS OF ABUSE CAN PRODUCE PROFOUND EFFECTS ON THE PHYSIOLOGY AND BEHAVIOR OF OFFSPRING VIA EPIGENETIC MODIFICATIONS. HERE WE SHOW THAT ADULT DRUG-NAIVE MALE OFFSPRING OF COCAINE-EXPOSED SIRES HAVE MEMORY FORMATION DEFICITS AND ASSOCIATED REDUCTIONS IN NMDA RECEPTOR-MEDIATED HIPPOCAMPAL SYNAPTIC PLASTICITY. REDUCED LEVELS OF THE ENDOGENOUS NMDA RECEPTOR CO-AGONIST D-SERINE WERE ACCOMPANIED BY INCREASED EXPRESSION OF THE D-SERINE DEGRADING ENZYME D-AMINO ACID OXIDASE (DAO1) IN THE HIPPOCAMPUS OF COCAINE-SIRED MALE PROGENY. INCREASED DAO1 TRANSCRIPTION WAS ASSOCIATED WITH ENRICHMENT OF PERMISSIVE EPIGENETIC MARKS ON HISTONE PROTEINS IN THE HIPPOCAMPUS OF MALE COCAINE-SIRED PROGENY, SOME OF WHICH WERE ENHANCED NEAR THE DAO1 LOCUS. FINALLY, HIPPOCAMPAL ADMINISTRATION OF D-SERINE REVERSED BOTH THE MEMORY FORMATION AND SYNAPTIC PLASTICITY DEFICITS. COLLECTIVELY, THESE RESULTS DEMONSTRATE THAT PATERNAL COCAINE EXPOSURE PRODUCES EPIGENETIC REMODELING IN THE HIPPOCAMPUS LEADING TO NMDA RECEPTOR-DEPENDENT MEMORY FORMATION AND SYNAPTIC PLASTICITY IMPAIRMENTS ONLY IN MALE PROGENY, WHICH HAS SIGNIFICANT IMPLICATIONS FOR THE MALE DESCENDANTS OF CHRONIC COCAINE USERS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
5  3699  29 INFLAMMATORY MEMORIES: IS EPIGENETICS THE MISSING LINK TO PERSISTENT STROMAL CELL ACTIVATION IN RHEUMATOID ARTHRITIS? RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY DISEASE LEADING TO JOINT DESTRUCTION. SYNOVIAL FIBROBLASTS ARE RECOGNIZED AS KEY CELLS IN THE PATHOGENESIS OF RA SINCE THEY ATTRACT AND ACTIVATE IMMUNE CELLS AND PRODUCE MATRIX DEGRADING ENZYMES. MOST NOTABLY SYNOVIAL FIBROBLASTS FROM PATIENTS WITH RA ARE STABLY ACTIVATED AND PRODUCE HIGH LEVELS OF DISEASE-PROMOTING MOLECULES WITHOUT FURTHER STIMULATION BY IMMUNE CELLS. ACCUMULATING DATA SUGGEST THAT EPIGENETIC CHANGES IN STROMAL CELL POPULATIONS MIGHT BE CRUCIALLY INVOLVED IN THE PATHOLOGY OF RA AND OTHER CHRONIC INFLAMMATORY DISEASES. IN THE CURRENT REVIEW, WE DISCUSS THE MECHANISMS BY WHICH EPIGENETIC CHANGES MIGHT CAUSE THE STABLE ACTIVATION OF SYNOVIAL FIBROBLASTS IN RA AND HOW CHANGES IN THE EPIGENOME MIGHT ALTER IMMUNE FUNCTION AND INFLAMMATORY RESPONSE AND THEREBY PROMOTE THE DEVELOPMENT OF CHRONIC DISEASES.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
6  1980  51 EPIGENETIC ALTERATIONS IN CYTOCHROME P450 OXIDOREDUCTASE (POR) IN SPERM OF RATS EXPOSED TO TETRAHYDROCANNABINOL (THC). AS MARIJUANA LEGALIZATION IS INCREASING, RESEARCH REGARDING POSSIBLE LONG-TERM RISKS FOR USERS AND THEIR OFFSPRING IS NEEDED. LITTLE DATA EXISTS ON EFFECTS OF PATERNAL TETRAHYDROCANNABINOL (THC) EXPOSURE PRIOR TO REPRODUCTION. THIS STUDY DETERMINED IF CHRONIC THC EXPOSURE ALTERS SPERM DNA METHYLATION (DNAM) AND IF SUCH EFFECTS ARE INTERGENERATIONALLY TRANSMITTED. ADULT MALE RATS UNDERWENT ORAL GAVAGE WITH THC OR VEHICLE CONTROL. DIFFERENTIALLY METHYLATED (DM) LOCI IN MOTILE SPERM WERE IDENTIFIED USING REDUCED REPRESENTATION BISULFITE SEQUENCING (RRBS). ANOTHER COHORT WAS INJECTED WITH VEHICLE OR THC, AND SPERM DNAM WAS ANALYZED. FINALLY, THC-EXPOSED AND CONTROL ADULT MALE RATS WERE MATED WITH THC-NAIVE FEMALES. DNAM LEVELS OF TARGET GENES IN BRAIN TISSUES OF THE OFFSPRING WERE DETERMINED BY PYROSEQUENCING. RRBS IDENTIFIED 2,940 DM CPGS MAPPING TO 627 GENES. SIGNIFICANT HYPERMETHYLATION WAS CONFIRMED (P < 0.05) FOLLOWING ORAL THC ADMINISTRATION FOR CYTOCHROME P450 OXIDOREDUCTASE (POR), INVOLVED IN TOXIN PROCESSING AND DISORDERS OF SEXUAL DEVELOPMENT. POR HYPERMETHYLATION WAS NOT OBSERVED AFTER THC INJECTION OR IN THE SUBSEQUENT GENERATION. THESE RESULTS SUPPORT THAT THC ALTERS DNAM IN SPERM AND THAT ROUTE OF EXPOSURE CAN HAVE DIFFERENTIAL EFFECTS. ALTHOUGH WE DID NOT OBSERVE EVIDENCE OF INTERGENERATIONAL TRANSMISSION OF THE DNAM CHANGE, LARGER STUDIES ARE REQUIRED TO DEFINITIVELY EXCLUDE THIS POSSIBILITY.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
7  4239  48 METHYLATION PROFILE OF HEPATITIS B VIRUS IS NOT INFLUENCED BY INTERFERON ALPHA IN HUMAN LIVER CANCER CELLS. INTERFERON (IFN) ALPHA IS USED FOR THE TREATMENT OF CHRONIC HEPATITIS B VIRUS (HBV) INFECTION, BUT THE MOLECULAR MECHANISMS UNDERLYING ITS ANTIVIRAL EFFECT HAVE NOT BEEN FULLY ELUCIDATED. EPIGENETIC MODIFICATIONS REGULATE THE TRANSCRIPTIONAL ACTIVITY OF COVALENTLY CLOSED CIRCULAR DNA (CCCDNA) IN CELLS WITH CHRONIC HBV INFECTION. IFN?ALPHA HAS BEEN SHOWN TO MODIFY CCCDNA?BOUND HISTONES, BUT IT IS NOT KNOWN WHETHER THE ANTI?HBV EFFECT OF IFN?ALPHA INVOLVES METHYLATION OF CCCDNA. THE PRESENT STUDY AIMED TO DETERMINE WHETHER IFN?ALPHA INDUCED METHYLATION OF HBV CCCDNA IN A CELL?BASED MODEL IN WHICH HEPG2 CELLS WERE DIRECTLY INFECTED WITH WILD?TYPE HBV VIRIONS. METHYLATION STATUS OF HBV CCCDNA WAS ASSESSED USING GLOBAL DNA METHYLATION ELISA ASSAY, METHYLATION?SPECIFIC PCR AND BISULFITE SEQUENCING. IFN?ALPHA SUPPRESSED HBV DNA AND RNA TRANSCRIPTS, BUT METHYLATION PROFILES WERE SIMILAR BETWEEN THE CONTROL AND IFN?ALPHA TREATED GROUPS. CHROMATIN IMMUNOPRECIPITATION RESULTS REVEALED BINDING OF DNA METHYLTRANSFERASES (DNMT) 3A AND DNMT3B TO HBV CCCDNA AND TREATMENT WITH IFN?ALPHA SUPPRESSED THE RECRUITMENT OF DNMT3B TO CCCDNA. TAKEN TOGETHER, THESE RESULTS SUGGEST THAT IFN?ALPHA DOES NOT INDUCE METHYLATION OF HBV CCCDNA. THEREFORE, IT WAS CONCLUDED THAT METHYLATION IS UNLIKELY TO CONTRIBUTE TO THE ANTI?HBV EFFECT OF IFN?ALPHA IN HEPG2 CELLS, AND THAT ALTERNATIVE MECHANISMS NEED TO BE SOUGHT TO ENHANCE CCCDNA METHYLATION AS A NOVEL THERAPY AGAINST HBV.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
8  1087  56 COCAINE ALTERS THE MOUSE TESTICULAR EPIGENOME WITH DIRECT IMPACT ON HISTONE ACETYLATION AND DNA METHYLATION MARKS. RESEARCH QUESTION: RECENT EVIDENCE SUGGESTS THAT COCAINE ADMINISTRATION IN ANIMAL MODELS CAN TRIGGER NON-GENETIC INHERITANCE OF ADDICTION TRAITS FROM FATHER TO OFFSPRING, AFFECTING DEVELOPMENT AND BEHAVIOUR. IS CHRONIC COCAINE INTAKE INVOLVED IN ALTERATIONS OF EPIGENETIC HOMEOSTASIS IN THE TESTIS? DESIGN: EPIGENETIC MARKS AND MEDIATORS IN TESTIS AND ISOLATED GERM CELLS OF ADULT MICE TREATED WITH COCAINE (10 MG/KG) OR VEHICLE (STERILE SALINE SOLUTION) WERE EVALUATED IN AN INTERMITTENT BINGE PROTOCOL: THREE INTRAPERITONEAL INJECTIONS, 1 H APART, ONE DAY ON/OFF FOR 13 DAYS, COLLECTING TISSUE 24 H AFTER THE LAST BINGE ADMINISTRATION (DAY 14). RESULTS: IT WAS SHOWN THAT CHRONIC COCAINE INTAKE IN MICE DISRUPTS TESTICULAR EPIGENETIC HOMEOSTASIS, INCREASING GLOBAL METHYLATED CYTOSINE LEVELS IN DNA FROM GERM CELLS AND SPERM. COCAINE ALSO INCREASED TESTICULAR AND GERM CELL ACETYLATED HISTONE 3 AND 4 AND DECREASED EXPRESSION OF HISTONE DEACETYLASES HDAC1/2. IMMUNOLOCALIZATION STUDIES SHOWED THAT HDAC1/2 AND ACETYLATED HISTONE 3 AND 4 PROTEINS LOCALIZE TO MEIOTIC GERM CELLS. ANALYSIS OF MRNA EXPRESSION IN ISOLATED GERM CELLS SHOWS DECREASED LEVELS OF HDAC1/2/8, DNMT3B AND TET1 AND INCREASED LEVELS OF DNMT3A GENE EXPRESSION AFTER COCAINE TREATMENT. CONCLUSIONS: COCAINE INTAKE IS ASSOCIATED WITH TESTICULAR TOXICITY AND SIGNIFICANT REPRODUCTIVE FUNCTION IMPAIRMENT. THE RESULTS PRESENTED HERE BROADEN THE BASIC KNOWLEDGE OF THE IMPACT OF ADDICTIVE STIMULANTS ON TESTICULAR PATHOPHYSIOLOGY, FERTILITY AND MALE REPRODUCTIVE HEALTH AND IMPLY THAT ALTERED EPIGENETIC HOMEOSTASIS BY COCAINE MAY HAVE POTENTIAL CONSEQUENCES ON FUTURE GENERATIONS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
9  3304  92 HIGH-GLUCOSE CONCENTRATIONS CHANGE DNA METHYLATION LEVELS IN HUMAN IVM OOCYTES. STUDY QUESTION: WHAT ARE THE EFFECTS OF HIGH-GLUCOSE CONCENTRATIONS ON DNA METHYLATION OF HUMAN OOCYTES? SUMMARY ANSWER: HIGH-GLUCOSE CONCENTRATIONS ALTERED DNA METHYLATION LEVELS OF PEG3 AND ADIPONECTIN IN HUMAN IN VITRO MATURATION OOCYTES. WHAT IS KNOWN ALREADY: MATERNAL DIABETES HAS A DETRIMENTAL INFLUENCE ON OOCYTE QUALITY INCLUDING EPIGENETIC MODIFICATIONS, AS SHOWN IN NON-HUMAN MAMMALIAN SPECIES. STUDY DESIGN, SIZE, DURATION: IMMATURE METAPHASE I (MI) STAGE OOCYTES OF GOOD QUALITY WERE RETRIEVED FROM PATIENTS WHO HAD NORMAL OVARIAN POTENTIAL AND WHO UNDERWENT ICSI IN THE REPRODUCTIVE MEDICINE CENTER OF PEOPLE'S HOSPITAL OF ZHENGZHOU UNIVERSITY. MI OOCYTES WERE CULTURED IN MEDIUM WITH DIFFERENT GLUCOSE CONCENTRATIONS (CONTROL, 10 MM AND 15 MM) IN VITRO AND 48 H LATER, OOCYTES WITH FIRST POLAR BODY EXTRUSION WERE COLLECTED TO CHECK THE DNA METHYLATION LEVELS. PARTICIPANTS/MATERIALS, SETTING, METHODS: MI OOCYTES UNDERWENT IN VITRO MATURATION (IVM) AT 37 DEGREES C WITH 5% MIXED GAS FOR 48 H. THEN THE MATURE OOCYTES WERE TREATED WITH BISULFITE BUFFER. TARGET SEQUENCES WERE AMPLIFIED USING NESTED OR HALF-NESTED PCR AND THE DNA METHYLATION STATUS WAS TESTED USING COMBINED BISULFITE RESTRICTION ANALYSIS (COBRA) AND BISULFITE SEQUENCING (BS). MAIN RESULTS AND THE ROLE OF CHANCE: HIGH-GLUCOSE CONCENTRATIONS SIGNIFICANTLY DECREASED THE FIRST POLAR BODY EXTRUSION RATE. COMPARED TO CONTROLS, THE DNA METHYLATION LEVELS OF PEG3 IN HUMAN IVM OOCYTES WERE SIGNIFICANTLY HIGHER IN 10 MM (P < 0.001) AND 15 MM (P < 0.001) CONCENTRATIONS OF GLUCOSE. BUT THE DNA METHYLATION LEVEL OF H19 WAS NOT AFFECTED BY HIGH-GLUCOSE CONCENTRATIONS IN HUMAN IVM OOCYTES. WE ALSO FOUND THAT THERE WAS A DECREASE IN DNA METHYLATION LEVELS IN THE PROMOTER OF ADIPONECTIN IN HUMAN IVM OOCYTES BETWEEN CONTROLS AND OOCYTES EXPOSED TO 10 MM GLUCOSE (P = 0.028). LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: IT IS NOT CLEAR WHETHER THE ALTERATIONS ARE BENEFICIAL OR NOT FOR THE EMBRYO DEVELOPMENT AND OFFSPRING HEALTH. THE EFFECTS OF HIGH-GLUCOSE CONCENTRATIONS ON THE WHOLE PROCESS OF OOCYTE MATURATION ARE STILL NOT ELUCIDATED. ANOTHER ISSUE IS THAT THE NUMBER OF OOCYTES USED IN THIS STUDY WAS LIMITED. WIDER IMPLICATIONS OF THE FINDINGS: THIS IS THE FIRST TIME THAT THE EFFECTS OF HIGH-GLUCOSE CONCENTRATION ON DNA METHYLATION OF HUMAN OOCYTES HAVE BEEN ELUCIDATED. OUR RESULT INDICATES THAT IN HUMANS, THE HIGH RISK OF CHRONIC DISEASES IN OFFSPRING FROM DIABETIC MOTHERS MAY ORIGINATE FROM ABNORMAL DNA MODIFICATIONS IN OOCYTES. STUDY FUNDING/COMPETING INTEREST(S): THIS WORK WAS SUPPORTED BY THE FUND OF NATIONAL NATURAL SCIENCE FOUNDATION OF CHINA (81401198) AND DOCTOR FOUNDATION OF QINGDAO AGRICULTURAL UNIVERSITY (1116008).THE AUTHORS DECLARE THAT THERE ARE NO POTENTIAL CONFLICTS OF INTEREST RELEVANT TO THIS ARTICLE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
10  3186  41 HBV COVALENTLY CLOSED CIRCULAR DNA MINICHROMOSOMES IN DISTINCT EPIGENETIC TRANSCRIPTIONAL STATES DIFFER IN THEIR VULNERABILITY TO DAMAGE. BACKGROUND AND AIMS: HBV COVALENTLY CLOSED CIRCULAR DNA (CCCDNA) IS A MAJOR OBSTACLE FOR A CURE OF CHRONIC HEPATITIS B. ACCUMULATING EVIDENCE SUGGESTS THAT EPIGENETIC MODIFICATIONS REGULATE THE TRANSCRIPTIONAL ACTIVITY OF CCCDNA MINICHROMOSOMES. HOWEVER, IT REMAINS UNCLEAR HOW THE EPIGENETIC STATE OF CCCDNA AFFECTS ITS STABILITY. APPROACHES AND RESULTS: BY USING HBV INFECTION CELL MODELS AND IN VITRO AND IN VIVO RECOMBINANT CCCDNA (RCCCDNA) AND HBVCIRCLE MODELS, THE REDUCTION RATE OF HBV CCCDNA AND THE EFFICACY OF APOLIPOPROTEIN B MRNA EDITING ENZYME CATALYTIC SUBUNIT 3A (APOBEC3A)-MEDIATED AND CRISPR/CRISPR-ASSOCIATED 9 (CAS9)-MEDIATED CCCDNA TARGETING WERE COMPARED BETWEEN CCCDNAS WITH DISTINCT TRANSCRIPTIONAL ACTIVITIES. INTERFERON-ALPHA TREATMENT AND HEPATITIS B X PROTEIN (HBX) DELETION WERE APPLIED AS TWO STRATEGIES FOR CCCDNA REPRESSION. CHROMATIN IMMUNOPRECIPITATION AND MICROCOCCAL NUCLEASE ASSAYS WERE PERFORMED TO DETERMINE THE EPIGENETIC PATTERN OF CCCDNA. HBV CCCDNA LEVELS REMAINED STABLE IN NONDIVIDING HEPATOCYTES; HOWEVER, THEY WERE SIGNIFICANTLY REDUCED DURING CELL DIVISION, AND THE REDUCTION RATE WAS SIMILAR BETWEEN CCCDNAS IN TRANSCRIPTIONALLY ACTIVE AND TRANSCRIPTIONALLY REPRESSED STATES. STRIKINGLY, HBV RCCCDNA WITHOUT HBX EXPRESSION EXHIBITED A SIGNIFICANTLY LONGER PERSISTENCE IN MICE. THE CCCDNA WITH LOW TRANSCRIPTIONAL ACTIVITY EXHIBITED AN EPIGENETICALLY INACTIVE PATTERN AND WAS MORE DIFFICULT TO ACCESS BY APOBEC3A AND ENGINEERED CRISPR-CAS9. THE EPIGENETIC REGULATOR ACTIVATING CCCDNA INCREASED ITS VULNERABILITY TO APOBEC3A. CONCLUSIONS: HBV CCCDNA MINICHROMOSOMES IN DISTINCT EPIGENETIC TRANSCRIPTIONAL STATES SHOWED A SIMILAR REDUCTION RATE DURING CELL DIVISION BUT SIGNIFICANTLY DIFFERED IN THEIR ACCESSIBILITY AND VULNERABILITY TO TARGETED NUCLEASES AND ANTIVIRAL AGENTS. EPIGENETIC SENSITIZATION OF CCCDNA MAKES IT MORE SUSCEPTIBLE TO DAMAGE AND MAY POTENTIALLY CONTRIBUTE TO AN HBV CURE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
11  2489  44 EPIGENETICALLY MODIFIED NUCLEOTIDES IN CHRONIC HEROIN AND COCAINE TREATED MICE. EPIGENETIC CHANGES INCLUDE THE ADDITION OF A METHYL GROUP TO THE 5' CARBON OF THE CYTOSINE RING, KNOWN AS DNA METHYLATION, WHICH RESULTS IN THE GENERATION OF THE FIFTH DNA BASE, NAMELY 5-METHYLCYTOSINE. DURING ACTIVE OR PASSIVE DEMETHYLATION, AN INTERMEDIATE MODIFIED BASE IS FORMED, 5-HYDROXYMETHYLCYTOSINE. WE HAVE CURRENTLY QUANTIFIED 5-METHYLCYTOSINE AND 5-HYDROXYMETHYLCYTOSINE IN THE LIVER AND BRAIN OF MICE TREATED WITH COCAINE OR HEROIN, USING LIQUID CHROMATOGRAPHY/TANDEM MASS SPECTROMETRY (LC-MS/MS). OUR RESULTS SHOW THAT GLOBAL 5-METHYLCYTOSINE LEVELS ARE NOT AFFECTED BY HEROIN OR COCAINE ADMINISTRATION, NEITHER IN THE LIVER NOR IN THE BRAIN. HOWEVER, 5-HYDROXYMETHYLCYTOSINE LEVELS ARE REDUCED IN THE LIVER FOLLOWING COCAINE ADMINISTRATION, WHILE THEY ARE NOT AFFECTED BY COCAINE IN THE BRAIN OR BY HEROIN ADMINISTRATION IN THE LIVER AND THE BRAIN. ELUCIDATION OF THE EPIGENETIC PHENOMENA THAT TAKES PLACE WITH RESPECT TO DRUG ABUSE AND ADDICTION, VIA QUANTITATIVE ANALYSIS OF DIFFERENT MODIFIED BASES, MAY ENABLE A BETTER UNDERSTANDING OF THE UNDERLYING MECHANISMS AND MAY LEAD TO MORE PERSONALIZED AND EFFECTIVE TREATMENT OPTIONS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
12   387  37 AN INDIVIDUALITY OF RESPONSE TO CANNABINOIDS: CHALLENGES IN SAFETY AND EFFICACY OF CANNABIS PRODUCTS. SINCE LEGALIZATION, CANNABIS/MARIJUANA HAS BEEN GAINING CONSIDERABLE ATTENTION AS A FUNCTIONAL INGREDIENT IN FOOD. ?-9 TETRAHYDROCANNABINOL (THC), CANNABIDIOL (CBD), AND OTHER CANNABINOIDS ARE KEY BIOACTIVE COMPOUNDS WITH HEALTH BENEFITS. THE ORAL CONSUMPTION OF CANNABIS TRANSPORTS MUCH LESS HAZARDOUS CHEMICALS THAN SMOKING. NEVERTHELESS, THE RESPONSE TO CANNABIS IS BIPHASICALLY DOSE-DEPENDENT (HORMESIS; A LOW-DOSE STIMULATION AND A HIGH-DOSE INHIBITION) WITH WIDE INDIVIDUALITY IN RESPONSES. THUS, THE EXACT SAME DOSE AND PREPARATION OF CANNABIS MAY BE BENEFICIAL FOR SOME BUT TOXIC TO OTHERS. THE PURPOSE OF THIS REVIEW IS TO HIGHLIGHT THE CONCEPT OF INDIVIDUAL VARIATIONS IN RESPONSE TO CANNABINOIDS, WHICH LEADS TO THE CHALLENGE OF ESTABLISHING STANDARD SAFE DOSES OF CANNABIS PRODUCTS FOR THE GENERAL POPULATION. THE MECHANISMS OF ACTIONS, ACUTE AND CHRONIC TOXICITIES, AND FACTORS AFFECTING RESPONSES TO CANNABIS PRODUCTS ARE UPDATED. BASED ON THE LITERATURE REVIEW, WE FOUND THAT THE RESPONSE TO CANNABIS PRODUCTS DEPENDS ON EXPOSURE FACTORS (DELIVERY ROUTE, DURATION, FREQUENCY, AND INTERACTIONS WITH FOOD AND DRUGS), INDIVIDUAL FACTORS (AGE, SEX), AND SUSCEPTIBILITY FACTORS (GENETIC POLYMORPHISMS OF CANNABINOID RECEPTOR GENE, N-ACYLETHANOLAMINE-HYDROLYZING ENZYMES, THC-METABOLIZING ENZYMES, AND EPIGENETIC REGULATIONS). OWING TO THE INDIVIDUALITY OF RESPONSES, THE SAFEST WAY TO USE CANNABIS-CONTAINING FOOD PRODUCTS IS TO START LOW, GO SLOW, AND STAY LOW.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
13  1052  37 CLINICAL IMPLICATIONS OF HEPATITIS B VIRUS RNA AND COVALENTLY CLOSED CIRCULAR DNA IN MONITORING PATIENTS WITH CHRONIC HEPATITIS B TODAY WITH A GAZE INTO THE FUTURE: THE FIELD IS UNPREPARED FOR A STERILIZING CURE. . CHRONIC HEPATITIS B VIRUS (HBV) INFECTION HAS LONG REMAINED A CRITICAL GLOBAL HEALTH ISSUE. COVALENTLY CLOSED CIRCULAR DNA (CCCDNA) IS A PERSISTENT FORM OF THE HBV GENOME THAT MAINTAINS HBV CHRONICITY. DECADES OF EXTENSIVE RESEARCH RESULTED IN THE TWO THERAPEUTIC OPTIONS CURRENTLY AVAILABLE: NUCLEOT(S)IDE ANALOGS AND INTERFERON (IFN) THERAPY. A PLETHORA OF RELIABLE MARKERS TO MONITOR HBV PATIENTS HAS BEEN ESTABLISHED, INCLUDING THE RECENTLY DISCOVERED ENCAPSIDATED PREGENOMIC RNA IN SERUM, WHICH CAN BE USED TO DETERMINE TREATMENT END-POINTS AND TO PREDICT THE SUSCEPTIBILITY OF PATIENTS TO IFN. ADDITIONALLY, HBV RNA SPLICE VARIANTS AND CCCDNA AND ITS EPIGENETIC MODIFICATIONS ARE ASSOCIATED WITH THE CLINICAL COURSE AND RISKS OF HEPATOCELLULAR CARCINOMA (HCC) AND LIVER FIBROSIS. HOWEVER, NEW ANTIVIRALS, INCLUDING CRISPR/CAS9, APOBEC-MEDIATED DEGRADATION OF CCCDNA, AND T-CELL THERAPIES AIM AT COMPLETELY ELIMINATING HBV, AND IT IS CLEAR THAT THE DIAGNOSTIC ARSENAL FOR DEFINING THE LONG-AWAITED STERILIZING CURE IS MISSING. IN THIS REVIEW, WE DISCUSS THE CURRENTLY AVAILABLE TOOLS FOR DETECTING AND MEASURING HBV RNAS AND CCCDNA, AS WELL AS THE STATE-OF-THE-ART IN CLINICAL IMPLICATIONS OF THESE MARKERS, AND DEBATE NEEDS AND GOALS WITHIN THE CONTEXT OF THE STERILIZING CURE THAT IS SOON TO COME.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
14  5057  34 PHENOBARBITAL MECHANISTIC DATA AND RISK ASSESSMENT: ENZYME INDUCTION, ENHANCED CELL PROLIFERATION, AND TUMOR PROMOTION. CHRONIC EXPOSURE TO HIGH DOSES OF PHENOBARBITAL (PB) CAUSES HEPATOCELLULAR ADENOMAS IN BOTH MICE AND RATS AND HEPATOCELLULAR CARCINOMAS IN SOME STRAINS OF MICE. LONG-TERM PB THERAPY HAS NOT BEEN FOUND TO CAUSE HUMAN TUMORS. PB IS NOT DNA REACTIVE, AND MOST GENOTOXICITY TESTS HAVE YIELDED NEGATIVE RESULTS. PB HAS BEEN EXTENSIVELY STUDIED AS AN EPIGENETIC, RODENT LIVER TUMOR PROMOTER. AT EXPOSURES CAUSING RODENT LIVER TUMORS, PB HAS MEASURABLE EFFECTS ON HEPATOCYTES: PB INHIBITS CELL-TO-CELL COMMUNICATION; PB INDUCES ENZYMES, INCLUDING P450 CYTOCHROMES; PB STIMULATES PROLIFERATION AND INHIBITS APOPTOSIS OF HEPATOCYTES IN NEOPLASTIC FOCI. THRESHOLD EXPOSURES FOR SOME OF THESE ENDPOINTS COINCIDE WITH THE THRESHOLD EXPOSURE FOR TUMORIGENESIS.	1996	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
15  4816  32 OCCULT HEPATITIS B VIRUS INFECTION: A COMPLEX ENTITY WITH RELEVANT CLINICAL IMPLICATIONS. OCCULT HEPATITIS B VIRUS (HBV) INFECTION IS A WORLD-WIDE ENTITY, FOLLOWING THE GEOGRAPHICAL DISTRIBUTION OF DETECTABLE HEPATITIS B. THIS ENTITY IS DEFINED AS THE PERSISTENCE OF VIRAL GENOMES IN THE LIVER TISSUE AND IN SOME INSTANCES ALSO IN THE SERUM, ASSOCIATED TO NEGATIVE HBV SURFACE ANTIGEN SEROLOGY. THE MOLECULAR BASIS OF THE OCCULT INFECTION IS RELATED TO THE LIFE CYCLE OF HBV, WHICH PRODUCES A COVALENTLY CLOSED CIRCULAR DNA THAT PERSISTS IN THE CELL NUCLEI AS AN EPISOME, AND SERVES AS A TEMPLATE FOR GENE TRANSCRIPTION. THE MECHANISM RESPONSIBLE FOR THE HBSAG NEGATIVE STATUS IN OCCULT HBV CARRIERS IS A STRONG SUPPRESSION OF VIRAL REPLICATION, PROBABLY DUE TO THE HOST'S IMMUNE RESPONSE, CO-INFECTION WITH OTHER INFECTIOUS AGENTS AND EPIGENETIC FACTORS. THERE IS EMERGING EVIDENCE OF THE POTENTIAL CLINICAL RELEVANCE OF OCCULT HBV INFECTION, SINCE THIS COULD BE INVOLVED IN OCCULT HBV TRANSMISSION THROUGH ORTHOTOPIC LIVER TRANSPLANT AND BLOOD TRANSFUSION, REACTIVATION OF HBV INFECTION DURING IMMUNOSUPPRESSION, IMPAIRING CHRONIC LIVER DISEASE OUTCOME AND ACTING AS A RISK FACTOR FOR HEPATOCELLULAR CARCINOMA. THEREFORE IT IS IMPORTANT TO BEAR IN MIND THIS ENTITY IN CRYPTOGENETIC LIVER DISEASES, HEPATITIS C VIRUS/HIV INFECTED PATIENTS AND IMMUNOSUPRESSED INDIVIDUALS. IT IS ALSO NECESSARY TO INCREASE OUR KNOWLEDGE IN THIS FASCINATING FIELD TO DEFINE BETTER STRATEGIES TO DIAGNOSE AND TREAT THIS INFECTION.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
16  2985  38 GENETIC DIVERSITY FOR NITROGEN USE EFFICIENCY IN ARABIDOPSIS THALIANA. THE PLASTICITY OF PLANT GROWTH RESPONSE TO DIFFERING NITRATE AVAILABILITY RENDERS THE IDENTIFICATION OF BIOMARKERS DIFFICULT, BUT ALLOWS ACCESS TO GENETIC FACTORS AS TOOLS TO MODULATE ROOT SYSTEMS TO A WIDE RANGE OF SOIL CONDITIONS. NITROGEN AVAILABILITY IS A MAJOR DETERMINANT OF CROP YIELD. WHILE THE APPLICATION OF FERTILISER SUBSTANTIALLY INCREASES THE YIELD ON POOR SOILS, IT ALSO CAUSES NITRATE POLLUTION OF WATER RESOURCES AND HIGH COSTS FOR FARMERS. INCREASING NITROGEN USE EFFICIENCY IN CROP PLANTS IS A NECESSARY STEP TO IMPLEMENT LOW-INPUT AGRICULTURAL SYSTEMS. WE EXPLOITED THE GENETIC DIVERSITY PRESENT IN THE WORLDWIDE ARABIDOPSIS THALIANA POPULATION TO STUDY ADAPTIVE GROWTH PATTERNS AND CHANGES IN GENE EXPRESSION ASSOCIATED WITH CHRONIC LOW NITRATE STRESS, TO IDENTIFY BIOMARKERS ASSOCIATED WITH GOOD PLANT PERFORMANCE UNDER LOW NITRATE AVAILABILITY. ARABIDOPSIS ACCESSIONS WERE GROWN ON AGAR PLATES WITH LIMITED AND SUFFICIENT SUPPLY OF NITRATE TO MEASURE ROOT SYSTEM ARCHITECTURE AS WELL AS SHOOT AND ROOT FRESH WEIGHT. DIFFERENTIAL GENE EXPRESSION WAS DETERMINED USING AFFYMETRIX ATH1 ARRAYS. WE SHOW THAT THE RESPONSE TO DIFFERING NITRATE AVAILABILITY IS HIGHLY VARIABLE IN ARABIDOPSIS ACCESSIONS. ANALYSES OF VEGETATIVE SHOOT GROWTH AND ROOT SYSTEM ARCHITECTURE IDENTIFIED ACCESSION-SPECIFIC REACTION MODES TO COPE WITH LIMITED NITRATE AVAILABILITY. TRANSCRIPTION AND EPIGENETIC FACTORS WERE IDENTIFIED AS IMPORTANT PLAYERS IN THE ADAPTION TO LIMITED NITROGEN IN A GLOBAL GENE EXPRESSION ANALYSIS. FIVE NITRATE-RESPONSIVE GENES EMERGED AS POSSIBLE BIOMARKERS FOR NUE IN ARABIDOPSIS. THE PLASTICITY OF PLANT GROWTH IN RESPONSE TO DIFFERING NITRATE AVAILABILITY IN THE SUBSTRATE RENDERS THE IDENTIFICATION OF MORPHOLOGICAL AND MOLECULAR FEATURES AS BIOMARKERS DIFFICULT, BUT AT THE SAME TIME ALLOWS ACCESS TO A MULTITUDE OF GENETIC FACTORS WHICH CAN BE USED AS TOOLS TO MODULATE AND ADJUST ROOT SYSTEMS TO A WIDE RANGE OF SOIL CONDITIONS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
17   747  37 CANNABIS-INDUCED HYPODOPAMINERGIC ANHEDONIA AND COGNITIVE DECLINE IN HUMANS: EMBRACING PUTATIVE INDUCTION OF DOPAMINE HOMEOSTASIS. OVER YEARS, THE REGULAR USE OF CANNABIS HAS SUBSTANTIALLY INCREASED AMONG YOUNG ADULTS, AS INDICATED BY THE RISE IN CANNABIS USE DISORDER (CUD), WITH AN ESTIMATED PREVALENCE OF 8. 3% IN THE UNITED STATES. RESEARCH SHOWS THAT EXPOSURE TO CANNABIS IS ASSOCIATED WITH HYPODOPAMINERGIC ANHEDONIA (DEPRESSION), COGNITIVE DECLINE, POOR MEMORY, INATTENTION, IMPAIRED LEARNING PERFORMANCE, REDUCED DOPAMINE BRAIN RESPONSE-ASSOCIATED EMOTIONALITY, AND INCREASED ADDICTION SEVERITY IN YOUNG ADULTS. THE ADDICTION MEDICINE COMMUNITY IS INCREASING CONCERN BECAUSE OF THE HIGH CONTENT OF DELTA-9-TETRAHYDROCANNABINOL (THC) CURRENTLY FOUND IN ORAL AND VAPING CANNABIS PRODUCTS, THE COGNITIVE EFFECTS OF CANNABIS MAY BECOME MORE PRONOUNCED IN YOUNG ADULTS WHO USE THESE CANNABIS PRODUCTS. PRELIMINARY RESEARCH SUGGESTS THAT IT IS POSSIBLE TO INDUCE 'DOPAMINE HOMEOSTASIS,' THAT IS, RESTORE DOPAMINE FUNCTION WITH DOPAMINE UPREGULATION WITH THE PROPOSED COMPOUND AND NORMALIZE BEHAVIOR IN CHRONIC CANNABIS USERS WITH CANNABIS-INDUCED HYPODOPAMINERGIC ANHEDONIA (DEPRESSION) AND COGNITIVE DECLINE. THIS PSYCHOLOGICAL, NEUROBIOLOGICAL, ANATOMICAL, GENETIC, AND EPIGENETIC RESEARCH ALSO COULD PROVIDE EVIDENCE TO USE FOR THE DEVELOPMENT OF AN APPROPRIATE POLICY REGARDING THE DECRIMINALIZATION OF CANNABIS FOR RECREATIONAL USE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
18   242  50 ADOLESCENT CANNABINOID EXPOSURE MODULATES THE VULNERABILITY TO COCAINE-INDUCED CONDITIONED PLACE PREFERENCE AND DNMT3A EXPRESSION IN THE PREFRONTAL CORTEX IN SWISS MICE. RATIONALE: CANNABIS SATIVA IS THE MOST WIDELY USED DRUG BY ADOLESCENTS GLOBALLY. THE RECREATIONAL USE OF SYNTHETIC CANNABINOIDS BY TEENAGERS HAS ALSO GROWN IN RECENT YEARS. DESPITE THE WRONG PERCEPTION THAT EXPOSURE TO THESE DRUGS DOES NOT CAUSE HARM, REPEATED EXPOSURE TO CANNABINOIDS AT EARLY STAGES OF LIFE COMPROMISES IMPORTANT MATURATION PROCESSES AND BRAIN DEVELOPMENT. CHRONIC EARLY CANNABINOID USE HAS BEEN RELATED TO A HIGHER RISK OF PSYCHIATRIC OUTCOMES, INCLUDING COCAINE ADDICTION. EVIDENCE SUGGESTS THAT EXPOSURE TO NATURAL AND SYNTHETIC CANNABINOIDS DURING ADOLESCENCE MODIFIES MOLECULAR AND BEHAVIORAL EFFECTS OF COCAINE IN ADULTHOOD. RESPONSES TO COCAINE ARE REGULATED BY EPIGENETIC MECHANISMS, SUCH AS DNA METHYLATION, IN THE BRAIN'S REWARD REGIONS. HOWEVER, THE INVOLVEMENT OF THESE PROCESSES IN MODULATION OF THE VULNERABILITY TO THE EFFECTS OF COCAINE INDUCED BY PRIOR EXPOSURE TO CANNABINOIDS REMAINS POORLY UNDERSTOOD. OBJECTIVES: INVESTIGATE WHETHER EXPOSURE TO THE SYNTHETIC CANNABINOID WIN55,212-2 DURING ADOLESCENCE MODULATES ANXIETY- AND DEPRESSION-LIKE BEHAVIOR, MEMORY, AND COCAINE REWARD IN ADULT MICE. WE ALSO EVALUATED WHETHER EXPOSURE TO CANNABINOIDS DURING ADOLESCENCE MODULATES THE EXPRESSION OF ENZYMES THAT ARE INVOLVED IN DNA METHYLATION. RESULTS: EXPOSURE TO WIN55,212-2 DURING ADOLESCENCE DID NOT ALTER ANXIETY- OR DEPRESSIVE-LIKE BEHAVIOR. HOWEVER, PRIOR EXPOSURE TO CANNABINOIDS INHIBITED COCAINE-INDUCED CONDITIONED PLACE PREFERENCE WITHOUT MODULATING COCAINE-INDUCED HYPERLOCOMOTION, ACCOMPANIED BY AN INCREASE IN EXPRESSION OF THE ENZYME DNA METHYLTRANSFERASE 3A (DNMT3A) IN THE PREFRONTAL CORTEX. CONCLUSIONS: OUR FINDINGS SUGGEST THAT EXPOSURE TO WIN55,212-2 DURING ADOLESCENCE LEADS TO CHANGES IN DNMT3A EXPRESSION, AND THIS PATHWAY APPEARS TO BE RELEVANT TO MODULATING THE REWARDING EFFECTS OF COCAINE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
19  5368  29 RECENT ADVANCES IN THE STUDY OF HEPATITIS B VIRUS COVALENTLY CLOSED CIRCULAR DNA. CHRONIC HEPATITIS B INFECTION IS CAUSED BY HEPATITIS B VIRUS (HBV) AND A TOTAL CURE IS YET TO BE ACHIEVED. THE VIRAL COVALENTLY CLOSED CIRCULAR DNA (CCCDNA) IS THE KEY TO ESTABLISH A PERSISTENT INFECTION WITHIN HEPATOCYTES. CURRENT ANTIVIRAL STRATEGIES HAVE NO EFFECT ON THE PRE-EXISTING CCCDNA RESERVOIR. THEREFORE, THE STUDY OF THE MOLECULAR MECHANISM OF CCCDNA FORMATION IS BECOMING A MAJOR FOCUS OF HBV RESEARCH. THIS REVIEW SUMMARIZES THE CURRENT ADVANCES IN CCCDNA MOLECULAR BIOLOGY AND THE LATEST STUDIES ON THE ELIMINATION OR INACTIVATION OF CCCDNA, INCLUDING THREE MAJOR AREAS: (1) EPIGENETIC REGULATION OF CCCDNA BY HBV X PROTEIN, (2) IMMUNE-MEDIATED DEGRADATION, AND (3) GENOME-EDITING NUCLEASES. ALL THESE ASPECTS PROVIDE CLUES ON HOW TO FINALLY ATTAIN A CURE FOR CHRONIC HEPATITIS B INFECTION.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
20  4055  44 MAPPING OF HISTONE MODIFICATIONS IN EPISOMAL HBV CCCDNA UNCOVERS AN UNUSUAL CHROMATIN ORGANIZATION AMENABLE TO EPIGENETIC MANIPULATION. CHRONIC HEPATITIS B VIRUS (HBV) INFECTION AFFECTS 240 MILLION PEOPLE WORLDWIDE AND IS A MAJOR RISK FACTOR FOR LIVER FAILURE AND HEPATOCELLULAR CARCINOMA. CURRENT ANTIVIRAL THERAPY INHIBITS CYTOPLASMIC HBV GENOMIC REPLICATION, BUT IS NOT CURATIVE BECAUSE IT DOES NOT DIRECTLY AFFECT NUCLEAR HBV CLOSED CIRCULAR DNA (CCCDNA), THE GENOMIC FORM THAT TEMPLATES VIRAL TRANSCRIPTION AND SUSTAINS VIRAL PERSISTENCE. NOVEL APPROACHES THAT DIRECTLY TARGET CCCDNA REGULATION WOULD THEREFORE BE HIGHLY DESIRABLE. CCCDNA IS ASSEMBLED WITH CELLULAR HISTONE PROTEINS INTO CHROMATIN, BUT LITTLE IS KNOWN ABOUT THE REGULATION OF HBV CHROMATIN BY HISTONE POSTTRANSLATIONAL MODIFICATIONS (PTMS). HERE, USING A NEW CCCDNA CHIP-SEQ APPROACH, WE REPORT, TO OUR KNOWLEDGE, THE FIRST GENOME-WIDE MAPS OF PTMS IN CCCDNA-CONTAINING CHROMATIN FROM DE NOVO INFECTED HEPG2 CELLS, PRIMARY HUMAN HEPATOCYTES, AND FROM HBV-INFECTED LIVER TISSUE. WE FIND HIGH LEVELS OF PTMS ASSOCIATED WITH ACTIVE TRANSCRIPTION ENRICHED AT SPECIFIC SITES WITHIN THE HBV GENOME AND, SURPRISINGLY, VERY LOW LEVELS OF PTMS LINKED TO TRANSCRIPTIONAL REPRESSION EVEN AT SILENT HBV PROMOTERS. WE SHOW THAT TRANSCRIPTION AND ACTIVE PTMS IN HBV CHROMATIN ARE REDUCED BY THE ACTIVATION OF AN INNATE IMMUNITY PATHWAY, AND THAT THIS EFFECT CAN BE RECAPITULATED WITH A SMALL MOLECULE EPIGENETIC MODIFYING AGENT, OPENING THE POSSIBILITY THAT CHROMATIN-BASED REGULATION OF CCCDNA TRANSCRIPTION COULD BE A NEW THERAPEUTIC APPROACH TO CHRONIC HBV INFECTION.	2015