1  6736 239 WHAT IS A PSYCHOSIS AND WHERE IS IT LOCATED? KRAEPELIN'S DICHOTOMY, MANIC-DEPRESSIVE INSANITY AND DEMENTIA PRAECOX, ARE CONTRASTING AND TRUE ENDOGENOUS DISEASE ENTITIES WHICH AFFECT EXCITABILITY, THE FUNDAMENTAL PROPERTY OF THE CNS. KRAEPELIN WANTED TO ESTABLISH A VALID CLASSIFICATION AND HIT THE EXTREMES IN BRAIN STRUCTURE AND FUNCTION AT A TIME WHEN WE HAD NO KNOWLEDGE OF BRAIN DYSFUNCTION IN "FUNCTIONAL" PSYCHOSES. THE AETIOLOGY IS NOW KNOWN: THE PSYCHOSES ARE PART OF HUMAN GROWTH AND MATURATION AND MIGHT BE CLASSIFIED ACCORDING TO THEIR BRAIN DYSFUNCTION, WHICH IS EXACTLY WHAT KRAEPELIN WANTED. HOWEVER, PRESUMABLY TO REDUCE THE STIGMA ATTACHED TO THE WORD "PSYCHOSIS", THERE IS CURRENTLY A STRONG INITIATIVE TO ELIMINATE THE CONCEPT. BUT KNOWLEDGE OF WHAT IS HAPPENING IN THE BRAIN IN A PSYCHOSIS MIGHT BE MORE HELPFUL IN REDUCING STIGMA. IT IS SUGGESTED THAT PSYCHOSIS IS DUE TO AN AFFECTION OF THE SUPPLEMENTARY MOTOR AREA (SMA), LOCATED AT THE CENTRE OF THE MEDIAL FRONTAL LOBE NETWORK. THE SMA IS ONE OF THE RARE UNIVERSALLY CONNECTED AREAS OF THE BRAIN, AS SHOULD BE THE CASE FOR SUCH A KEY STRUCTURE THAT MAKES DECISIONS AS TO THE RIGHT MOMENT FOR ACTION. THIS IMPORTANT NETWORK, WHICH PARTLY HAS CONTINUOUS NEUROGENESIS, HAS SUFFICIENTLY WIDESPREAD CONNECTIONS. THE SMA, A PREMOTOR AREA LOCATED ON THE MEDIAL SIDE OF THE FRONTAL LOBES, IS ONE OF THE LAST REGIONS TO REACH A CONCURRENCE OF SYNAPTOGENESIS. AN AFFECTION OF THE SMA, A DEFICIENT OR ABOLISHED DELAYED RESPONSE TASK, SERIOUSLY DISTURBS OUR RELATION AND ADAPTATION TO THE SURROUNDINGS. WE USUALLY MASTER THE DELAYED RESPONSE TASK AROUND THE AGE OF 7 MONTHS, A TIME AT WHICH THE SECOND CNS REGRESSIVE EVENT TAKES PLACE, WHICH PROCEEDS FROM THE POSTERIOR TO THE ANTERIOR OF THE BRAIN. IN VERY LATE MATURATION, A PERSISTENT AFFECTION OF THE SMA MIGHT OCCUR. WE EXPERIENCE A CHRONIC PSYCHOSIS: INFANTILE AUTISM (IA), A CHRONIC INABILITY TO ACT CONSCIOUSLY, WHICH CONTRASTS WITH THE EPISODIC SMA AFFECTION POST-PUBERTY, WHEN EXCITATION IS REDUCED DUE TO EXCESSIVE PRUNING OF EXCITATORY SYNAPSES. SILENT SPOTS ARE THE RESULT OF INSUFFICIENT FILL-IN MECHANISMS FOLLOWING A BREAKDOWN OF CIRCUITRY. THEY MAY AFFECT THE SMA IN THE CASE OF VERY LATE PUBERTY. AN ACUTE REDUCTION IN EXCITATION AND CONCOMITANTLY A MARKED INCREASE IN SILENT SPOTS MIGHT LEAD TO AN ACUTE PSYCHOSIS. A FRONTAL PREFERENCE IS LIKELY, GIVEN THAT A REDUCTION MIGHT OCCUR ANYWHERE IN THE CORTEX, BUT PARTICULARLY IN THE AREAS MATURING LATEST. THE VARYING LOCALISATIONS PROBABLY EXPLAIN THE DIFFICULTY IN ACCEPTING SCHIZOPHRENIA AS A DISEASE ENTITY. THE MULTIFACTORIAL INHERITANCE OF THE DICHOTOMY IMPLIES THAT THE GENETICS ARE NOT FATE, A PSYCHOTIC DEVELOPMENT MIGHT BE PREVENTED GIVEN ENOUGH EPIGENETIC FACTORS: BRAIN FOOD (OMEGA 3). MIGHT THE PRESENT DIETARY ADVERSITY, WITH ITS LACK OF BRAIN FOOD, BE RESPONSIBLE FOR A RISING INCIDENCE IN PSYCHOSIS? A PSYCHOSIS IS AN UNDERSTANDABLE AND PREVENTABLE DYSFUNCTION OF THE BRAIN, AND ITS MECHANISMS ARE KNOWN. PRIMARILY A DISORDER OF REDUCED EXCITATION IN AN ATTENUATED CNS, THIS EXPLAINS WHY ALL THE NEUROLEPTICS ARE CONVULSANTS, RAISING EXCITATION, IN CONTRAST TO ALL ANTIDEPRESSIVES, WHICH ARE ANTI-EPILEPTIC.	2008	

2  5306  28 PROTEOMICS PROFILING WITH SWATH-MS QUANTITATIVE ANALYSIS OF CHANGES IN THE HUMAN BRAIN WITH HIV INFECTION REVEALS A DIFFERENTIAL IMPACT ON THE FRONTAL AND TEMPORAL LOBES. THE CHRONIC IRREVERSIBLE REGRESSION OF COGNITIVE ABILITY AND MEMORY FUNCTION IN HUMAN IMMUNODEFICIENCY VIRUS (HIV)-ASSOCIATED DEMENTIA (HAND) IS LINKED WITH LATE-STAGE HIV INFECTION IN THE BRAIN. THE MOLECULAR-LEVEL SIGNATURES OF NEUROINFLAMMATION AND NEURODEGENERATION ARE LINKED WITH DYSFUNCTION IN HAND PATIENTS. PROTEIN EXPRESSION CHANGES AND POSTTRANSLATIONAL MODIFICATION ARE EPIGENETIC CUES FOR DEMENTIA AND NEURODEGENERATIVE DISEASE. IN THIS STUDY QUANTITATIVE PROTEOME ANALYSIS WAS PERFORMED TO COMPREHENSIVELY ELUCIDATE CHANGES IN PROTEIN PROFILES IN HIV-POSITIVE (HIV+) HUMAN BRAINS. FRONTAL AND TEMPORAL LOBES OF NORMAL AND HIV+ BRAINS WERE SUBJECTED TO LABEL-FREE LIQUID CHROMATOGRAPHY-TANDEM MASS SPECTROMETRY (LC-MS/MS) ANALYSIS USING THE DATA-INDEPENDENT ACQUISITION METHOD. COMPREHENSIVE PROTEOMIC IDENTIFICATION AND QUANTIFICATION ANALYSIS REVEALED THAT 3294 TOTAL PROTEINS AND 251 PROTEINS WERE DIFFERENTIALLY EXPRESSED IN HIV+ BRAINS; SPECIFICALLY, HIV+ FRONTAL AND TEMPORAL LOBES HAD 132 AND 119 DIFFERENTIALLY EXPRESSED PROTEINS, RESPECTIVELY. PROTEOMIC AND BIOINFORMATIC ANALYSES REVEALED PROTEIN ALTERATIONS PREDOMINANTLY IN THE HIV+ FRONTAL LOBE REGION. THE EXPRESSION OF GOLPH3, IMPDH2, DYNLL1, RPL11, AND GPNMB PROTEINS WAS SIGNIFICANTLY ALTERED IN HIV+ FRONTAL LOBES COMPARED TO THAT IN NORMAL BRAINS. THESE PROTEINS ARE ASSOCIATED WITH METABOLIC PATHWAYS, NEURODEGENERATIVE DISORDERS, AND DEMENTIA. THESE PROTEOMIC-LEVEL CHANGES MAY BE POTENTIAL BIOLOGICAL MARKERS AND THERAPEUTIC TARGETS TO RELIEVE THE DEMENTIA-ASSOCIATED SYMPTOMS IN INDIVIDUALS WITH HAND.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
3  5324  33 PULMONARY MICRORNA PROFILING: IMPLICATIONS IN UPPER LOBE PREDOMINANT LUNG DISEASE. BACKGROUND: NUMEROUS PULMONARY DISEASES MANIFEST WITH UPPER LOBE PREDOMINANCE INCLUDING CYSTIC FIBROSIS, SMOKING-RELATED CHRONIC OBSTRUCTIVE PULMONARY DISEASE, AND TUBERCULOSIS. ZONAL HYPOXIA, CHARACTERISTIC OF THESE PULMONARY MALADIES, AND OXYGEN STRESS IN GENERAL IS KNOWN TO EXERT PROFOUND EFFECTS ON VARIOUS IMPORTANT ASPECTS OF CELL BIOLOGY. LUNG MACROPHAGES ARE MAJOR PARTICIPANTS IN THE PULMONARY INNATE IMMUNE RESPONSE AND REGIONAL DIFFERENCES IN MACROPHAGE RESPONSIVENESS TO HYPOXIA MAY CONTRIBUTE IN THE DEVELOPMENT OF LUNG DISEASE. MICRORNAS ARE UBIQUITOUS REGULATORS OF HUMAN BIOLOGY AND EMERGING EVIDENCE INDICATES ALTERED MICRORNA EXPRESSION MODULATES RESPIRATORY DISEASE PROCESSES. THE OBJECTIVE OF THIS STUDY IS TO GAIN INSIGHT INTO THE EPIGENETIC AND CELLULAR MECHANISMS INFLUENCING REGIONAL DIFFERENCES IN LUNG DISEASE BY INVESTIGATING EFFECT OF HYPOXIA ON REGIONAL MICRORNA EXPRESSION IN THE LUNG. ALL STUDIES WERE PERFORMED USING PRIMARY ALVEOLAR MACROPHAGES (N = 10) OR BRONCHOALVEOLAR LAVAGE FLUID (N = 16) ISOLATED FROM HUMAN SUBJECTS. MICRORNA WAS ASSAYED VIA THE NANOSTRING NCOUNTER MICRORNA ASSAY. RESULTS: DIVERGENT MOLECULAR PATTERNS OF MICRORNA EXPRESSION WERE OBSERVED IN ALTERNATE LUNG LOBES, SPECIFICALLY NOTED WAS DISPARATE EXPRESSION OF MIR-93 AND MIR-4454 IN ALVEOLAR MACROPHAGES ALONG WITH ALTERED EXPRESSION OF MIR-451A AND MIR-663A IN BRONCHOALVEOLAR LAVAGE FLUID. GENE ONTOLOGY WAS USED TO IDENTIFY POTENTIAL DOWNSTREAM TARGETS OF DIVERGENT MICRORNAS. TARGETS INCLUDE CYTOKINES AND MATRIX METALLOPROTEINASES, MOLECULES THAT COULD HAVE A SIGNIFICANT IMPACT ON PULMONARY INFLAMMATION AND FIBROSIS. CONCLUSIONS: OUR FINDINGS SHOW VARIANT REGIONAL MICRORNA EXPRESSION ASSOCIATED WITH HYPOXIA IN ALVEOLAR MACROPHAGES AND BAL FLUID IN THE LUNG-UPPER VS LOWER LOBE. FUTURE STUDIES SHOULD ADDRESS WHETHER THESE SPECIFIC MICRORNAS MAY ACT INTRACELLULARLY, IN A PARACRINE/ENDOCRINE MANNER TO DIRECT THE INNATE IMMUNE RESPONSE OR MAY ULTIMATELY BE INVOLVED IN PULMONARY HOST-TO-PATHOGEN TRANS-KINGDOM CROSS-TALK.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
4   808  20 CHANGED HISTONE ACETYLATION PATTERNS IN NORMAL-APPEARING WHITE MATTER AND EARLY MULTIPLE SCLEROSIS LESIONS. THE EPIGENETIC IDENTITY OF OLIGODENDROCYTES IS MODULATED BY POSTTRANSLATIONAL MODIFICATIONS OF HISTONES. ACETYLATION OF HISTONE H3 RESULTS FROM THE BALANCE BETWEEN THE ACTIVITY OF HISTONE ACETYLTRANSFERASES (HATS) AND HISTONE DEACETYLASES AND MODULATES TRANSCRIPTIONAL ACTIVATION. WE HAVE PREVIOUSLY SHOWN THAT, IN RODENTS, HISTONE DEACETYLATION FAVORS OLIGODENDROCYTE DIFFERENTIATION, WHEREAS ACETYLATION IS ASSOCIATED WITH INCREASED LEVELS OF TRANSCRIPTIONAL INHIBITORS OF OLIGODENDROCYTE DIFFERENTIATION. HERE, WE REPORT, IN HUMANS BRAINS, A SHIFT TOWARD HISTONE ACETYLATION IN THE WHITE MATTER OF THE FRONTAL LOBES OF AGED SUBJECTS AND IN PATIENTS WITH CHRONIC MULTIPLE SCLEROSIS (MS). INCREASED IMMUNOREACTIVITY FOR ACETYLATED HISTONE H3 WAS OBSERVED IN THE NUCLEI OF NOGOA+ OLIGODENDROCYTES IN A SUBSET OF MS SAMPLES. THESE CHANGES WERE ASSOCIATED WITH HIGH LEVELS OF TRANSCRIPTIONAL INHIBITORS OF OLIGODENDROCYTE DIFFERENTIATION (I.E., TCF7L2, ID2, AND SOX2) AND HIGHER HAT TRANSCRIPT LEVELS (I.E., CBP, P300) IN FEMALE MS PATIENTS COMPARED WITH NON-NEUROLOGICAL CONTROLS AND CORRELATED WITH DISEASE DURATION. CHROMATIN IMMUNOPRECIPITATION FROM SAMPLES OF MS PATIENTS REVEALED ENRICHMENT OF ACETYL-HISTONE H3 AT THE PROMOTER OF THE INCREASED TARGET GENES (I.E., TCF7L2). THE DATA IN CHRONIC LESIONS CONTRASTED WITH FINDINGS IN EARLY MS LESIONS, WHERE A MARKED OLIGODENDROGLIAL HISTONE DEACETYLATION WAS OBSERVED. TOGETHER, THESE DATA SUGGEST THAT HISTONE DEACETYLATION IS A PROCESS THAT OCCURS AT THE EARLY STAGES OF THE DISEASE AND WHOSE EFFICIENCY DECREASES WITH DISEASE DURATION.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
5  4275  29 MICROGLIA ACTIVATION IN THE MIDBRAIN OF THE HUMAN NEONATE: THE EFFECT OF PERINATAL HYPOXIC-ISCHEMIC INJURY. PERINATAL HYPOXIA-ISCHEMIA (PHI) IS A MAJOR RISK FACTOR FOR THE DEVELOPMENT OF NEUROPSYCHIATRIC DEFICITS LATER IN LIFE. WE PREVIOUSLY REPORTED THAT AFTER PROLONGED PHI, THE DOPAMINERGIC NEURONS OF THE HUMAN NEONATE SHOWED A DRAMATIC REDUCTION OF TYROSINE HYDROXYLASE (TH) IN THE SUBSTANTIA NIGRA, WITHOUT IMPORTANT SIGNS OF NEURONAL DEGENERATION DESPITE THE SIGNIFICANT REDUCTION IN THEIR CELL SIZE. SINCE MICROGLIA ACTIVATION COULD PRECEDE NEURONAL DEATH, WE NOW INVESTIGATED 2 MICROGLIA ACTIVATION MARKERS, IONIZED CALCIUM-BINDING ADAPTER MOLECULE 1 (IBA1), AND THE PHAGOCYTOSIS MARKER CD68. THE HIGHEST IBA1 IMMUNOREACTIVITY WAS FOUND IN NEONATES WITH NEUROPATHOLOGICAL LESIONS OF SEVERE/ABRUPT PHI, WHILE THE LOWEST IN SUBJECTS WITH MODERATE/PROLONGED OR OLDER PHI. SUBJECTS WITH VERY SEVERE/PROLONGED OR CHRONIC PHI SHOWED AN INCREASED IBA1 EXPRESSION AND VERY ACTIVATED MICROGLIAL MORPHOLOGY. HEAVY ATTACHMENT OF MICROGLIA ON TH NEURONS AND REMARKABLE EXPRESSION OF CD68 WERE ALSO OBSERVED INDICATING PHAGOCYTOSIS IN THIS GROUP. FEMALES APPEAR TO EXPRESS MORE IBA1 THAN MALES, SUGGESTING A GENDER DIFFERENCE IN MICROGLIA MATURATION AND IMMUNE REACTIVITY AFTER PHI INSULT. PHI-INDUCED MICROGLIAL "PRIMING" DURING THE SENSITIVE FOR BRAIN DEVELOPMENT PERINATAL/NEONATAL PERIOD, IN COMBINATION WITH GENETIC OR OTHER EPIGENETIC FACTORS, COULD PREDISPOSE THE SURVIVORS TO NEUROPSYCHIATRIC DISORDERS LATER IN LIFE, POSSIBLY THROUGH A SEXUALLY DIMORPHIC WAY.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
6  1610  40 DNA METHYLATION/DEMETHYLATION NETWORK EXPRESSION IN PSYCHOTIC PATIENTS WITH A HISTORY OF ALCOHOL ABUSE. BACKGROUND: RECENT STUDIES SUGGEST THAT PROTRACTED AND EXCESSIVE ALCOHOL USE INDUCES AN EPIGENETIC DYSREGULATION IN HUMAN AND RODENT BRAINS. WE RECENTLY REPORTED THAT DNA METHYLATION DYNAMICS ARE ALTERED IN BRAINS OF PSYCHOTIC (PS) PATIENTS, INCLUDING SCHIZOPHRENIA AND BIPOLAR DISORDER PATIENTS. BECAUSE PS PATIENTS ARE OFTEN COMORBID WITH CHRONIC ALCOHOL ABUSE, WE EXAMINED WHETHER THE ALTERED EXPRESSION OF MULTIPLE MEMBERS OF THE DNA METHYLATION/DEMETHYLATION NETWORK OBSERVED IN POSTMORTEM BRAINS OF PS PATIENTS WAS MODIFIED IN PS PATIENTS WITH A HISTORY OF CHRONIC ALCOHOL ABUSE. METHODS: DNA-METHYLTRANSFERASE-1 (DNMT1) MRNA-POSITIVE NEURONS WERE COUNTED IN SITU IN PREFRONTAL CORTEX SAMPLES OBTAINED FROM THE HARVARD BRAIN TISSUE RESOURCE CENTER, BELMONT, MA. 10-11-TRANSLOCATION (TETS 1, 2, 3), APOLIPOPROTEIN B EDITING COMPLEX ENZYME (APOBEC-3C), GROWTH AND DNA-DAMAGE-INDUCIBLE PROTEIN 45BETA (GADD45BETA), AND METHYL-BINDING DOMAIN PROTEIN-4 (MBD4) MRNAS WERE MEASURED BY QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION IN INFERIOR PARIETAL CORTICAL LOBULE SAMPLES OBTAINED FROM THE STANLEY FOUNDATION NEUROPATHOLOGY CONSORTIUM, BETHESDA, MD. RESULTS: WE OBSERVED AN INCREASE IN DNMT1 MRNA-POSITIVE NEURONS IN PS PATIENTS COMPARED WITH NON-PS SUBJECTS. IN ADDITION, THERE WAS A PRONOUNCED DECREASE IN APOBEC-3C AND A PRONOUNCED INCREASE IN GADD45BETA AND TET1 MRNAS IN PS PATIENTS WITH NO HISTORY OF ALCOHOL ABUSE. IN PS PATIENTS WITH A HISTORY OF CHRONIC ALCOHOL ABUSE, THE NUMBERS OF DNMT1-POSITIVE NEURONS WERE NOT INCREASED SIGNIFICANTLY. FURTHERMORE, THE DECREASE IN APOBEC-3C MRNA WAS LESS PRONOUNCED, WHILE THE INCREASE IN TET1 MRNA HAD A TENDENCY TO BE POTENTIATED IN THOSE PS PATIENTS THAT WERE CHRONIC ALCOHOL ABUSERS. GADD45BETA AND MBD4 MRNAS WERE NOT INFLUENCED BY ALCOHOL ABUSE. THE EFFECT OF CHRONIC ALCOHOL ABUSE ON DNA METHYLATION/DEMETHYLATION NETWORK ENZYMES CANNOT BE ATTRIBUTED TO CONFOUNDING DEMOGRAPHIC VARIABLES OR TO THE TYPE AND DOSE OF MEDICATION USED. CONCLUSIONS: BASED ON THESE RESULTS, WE HYPOTHESIZE THAT PS PATIENTS MAY ABUSE ALCOHOL AS A POTENTIAL ATTEMPT AT SELF-MEDICATION TO NORMALIZE ALTERED DNA METHYLATION/DEMETHYLATION NETWORK PATHWAYS. HOWEVER, BEFORE ACCEPTING THIS CONCLUSION, WE NEED TO STUDY ALTERATIONS IN THE DNA METHYLATION/DEMETHYLATION PATHWAYS AND THE DNA METHYLATION DYNAMICS IN A SUBSTANTIAL NUMBER OF ALCOHOLIC PS AND NON-PS PATIENTS. ADDITIONAL INVESTIGATION MAY ALSO BE NECESSARY TO DETERMINE WHETHER THE ALTERED DNA METHYLATION DYNAMICS ARE DIRECT OR THE CONSEQUENCE OF AN INDIRECT INTERACTION OF ALCOHOL WITH THE NEUROPATHOGENETIC MECHANISMS UNDERLYING PSYCHOSIS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
7    83  29 A NOVEL EPIGENETIC MARKER, TEN-ELEVEN TRANSLOCATION FAMILY MEMBER 2 (TET2), IS IDENTIFIED IN THE INTRACTABLE EPILEPTIC BRAIN AND REGULATES ATP BINDING CASSETTE SUBFAMILY B MEMBER 1 (ABCB1) IN THE BLOOD-BRAIN BARRIER. DRUG-RESISTANT EPILEPSY (DRE) IS A CHRONIC CONDITION DERIVED FROM SPONTANEOUS CHANGES AND REGULATORY EFFECTS IN THE EPILEPTIC BRAIN. AS DEMETHYLATION FACTORS, TEN-ELEVEN TRANSLOCATION (TET) FAMILY MEMBERS HAVE BECOME A FOCUS IN RECENT STUDIES OF NEUROLOGICAL DISORDERS. HERE, WE QUANTIFIED AND LOCALIZED TET1, TET2 AND 5-HYDROXYMETHYLCYTOSINE (5-HMC) IN THE TEMPORAL LOBE CORTEX OF DRE PATIENTS (N = 27) AND TRAUMATIC BRAIN HEMORRHAGE CONTROLS (N = 10) BY IMMUNOCHEMICAL STAINING. TET2 AND ATP BINDING CASSETTE SUBFAMILY B MEMBER 1 (ABCB1) EXPRESSION PATTERNS WERE DETERMINED IN THE ISOLATED BRAIN CAPILLARIES OF DRE PATIENTS. TET2 EXPRESSION WAS SIGNIFICANTLY INCREASED IN THE TEMPORAL CORTICAL TISSUE OF DRE PATIENTS WITH OR WITHOUT HIPPOCAMPAL SCLEROSIS (HS) COMPARED TO CONTROL PATIENTS, WHILE TET1 AND 5-HMC SHOWED NO DIFFERENCES IN EXPRESSION. WE ALSO FOUND THAT A PARTICULARLY STRONG EXPRESSION OF TET2 IN THE VASCULAR TISSUE OF DRE PATIENTS. ABCB1 AND TET2 HAVE EVIDENTLY HIGHER EXPRESSION IN THE VASCULAR ENDOTHELIUM FROM THE NEOCORTEX OF DRE PATIENTS. IN BLOOD-BRAIN BARRIER (BBB) MODEL, TET2 DEPLETION CAN CAUSE ATTENUATED EXPRESSION AND FUNCTION OF ABCB1. DATA FROM A COHORT STUDY AND EXPERIMENTS IN A BBB MODEL SUGGEST THAT TET2 HAS A SPECIFIC REGULATORY EFFECT ON ABCB1, WHICH MAY SERVE AS A POTENTIAL MECHANISM AND TARGET IN DRE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
8  1528  29 DNA METHYLATION CHANGES IN REGIONAL LUNG MACROPHAGES ARE ASSOCIATED WITH METABOLIC DIFFERENCES. A NUMBER OF PULMONARY DISEASES OCCUR WITH UPPER LOBE PREDOMINANCE, INCLUDING CYSTIC FIBROSIS AND SMOKING-RELATED CHRONIC OBSTRUCTIVE PULMONARY DISEASE. IN THE HEALTHY LUNG, SEVERAL PHYSIOLOGIC AND METABOLIC FACTORS EXHIBIT DISPARITY WHEN COMPARING THE UPPER LOBE OF THE LUNG TO LOWER LOBE, INCLUDING DIFFERENCES IN OXYGENATION, VENTILATION, LYMPHATIC FLOW, PH, AND BLOOD FLOW. IN THIS STUDY, WE ASKED WHETHER THESE REGIONAL DIFFERENCES IN THE LUNG ARE ASSOCIATED WITH DNA METHYLATION CHANGES IN LUNG MACROPHAGES THAT COULD POTENTIALLY LEAD TO ALTERED CELL RESPONSIVENESS UPON SUBSEQUENT ENVIRONMENTAL CHALLENGE. ALL ANALYSES WERE PERFORMED USING PRIMARY LUNG MACROPHAGES COLLECTED VIA BRONCHOALVEOLAR LAVAGE FROM HEALTHY HUMAN SUBJECTS WITH NORMAL PULMONARY FUNCTION. EPIGENOME-WIDE DNA METHYLATION WAS EXAMINED VIA INFINIUM METHYLATIONEPIC (850K) ARRAY AND VALIDATED BY TARGETED NEXT-GENERATION BISULFITE SEQUENCING. WE OBSERVED 95 CPG LOCI WITH SIGNIFICANT DIFFERENTIAL METHYLATION IN LUNG MACROPHAGES, COMPARING UPPER LOBE TO LOWER LOBE (ALL FALSE DISCOVERY RATE < 0.05). SEVERAL OF THESE GENES, INCLUDING CLIP4, HSH2D, NR4A1, SNX10, AND TYK2, HAVE BEEN IMPLICATED AS PARTICIPANTS IN INFLAMMATORY/IMMUNE-RELATED BIOLOGICAL PROCESSES. FUNCTIONALLY, WE IDENTIFIED PHENOTYPIC DIFFERENCES IN OXYGEN USE, COMPARING UPPER VERSUS LOWER LUNG MACROPHAGES. OUR RESULTS SUPPORT A HYPOTHESIS THAT EPIGENETIC CHANGES, SPECIFICALLY DNA METHYLATION, AT A MULTITUDE OF GENE LOCI IN LUNG MACROPHAGES ARE ASSOCIATED WITH METABOLIC DIFFERENCES REGIONALLY IN LUNG.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
9  1633  34 DO EPIGENETIC EVENTS TAKE PLACE IN THE VASTUS LATERALIS OF PATIENTS WITH MILD CHRONIC OBSTRUCTIVE PULMONARY DISEASE? MUSCLE DYSFUNCTION IS A MAJOR COMORBIDITY IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). SEVERAL BIOLOGICAL MECHANISMS INCLUDING EPIGENETIC EVENTS REGULATE MUSCLE MASS AND FUNCTION IN MODELS OF MUSCLE ATROPHY. INVESTIGATIONS CONDUCTED SO FAR HAVE FOCUSED ON THE ELUCIDATION OF BIOLOGICAL MECHANISMS INVOLVED IN MUSCLE DYSFUNCTION IN ADVANCED COPD. WE ASSESSED WHETHER THE EPIGENETIC PROFILE MAY BE ALTERED IN THE VASTUS LATERALIS OF PATIENTS WITH MILD COPD, NORMAL BODY COMPOSITION, AND MILDLY IMPAIRED MUSCLE FUNCTION AND EXERCISE CAPACITY. IN VASTUS LATERALIS (VL) OF MILD COPD PATIENTS WITH WELL-PRESERVED BODY COMPOSITION AND IN HEALTHY AGE-MATCHED CONTROLS, EXPRESSION OF DNA METHYLATION, MUSCLE-ENRICHED MICRORNAS, HISTONE ACETYLTRANSFERASES (HTAS) AND DEACETYLASES (HDACS), PROTEIN ACETYLATION, SMALL UBIQUITIN-RELATED MODIFIER (SUMO) LIGASES, AND MUSCLE STRUCTURE WERE EXPLORED. ALL SUBJECTS WERE CLINICALLY EVALUATED. COMPARED TO HEALTHY CONTROLS, IN THE VL OF MILD COPD PATIENTS, MUSCLE FUNCTION AND EXERCISE CAPACITY WERE MODERATELY REDUCED, DNA METHYLATION LEVELS DID NOT DIFFER, MIR-1 EXPRESSION LEVELS WERE INCREASED AND POSITIVELY CORRELATED WITH BOTH FORCED EXPIRATORY VOLUME IN ONE SECOND (FEV1) AND QUADRICEPS FORCE, HDAC4 PROTEIN LEVELS WERE INCREASED, AND MUSCLE FIBER TYPES AND SIZES WERE NOT DIFFERENT. MODERATE SKELETAL MUSCLE DYSFUNCTION IS A RELEVANT FEATURE IN PATIENTS WITH MILD COPD AND PRESERVED BODY COMPOSITION. SEVERAL EPIGENETIC EVENTS ARE DIFFERENTIALLY EXPRESSED IN THE LIMB MUSCLES OF THESE PATIENTS, PROBABLY AS AN ATTEMPT TO COUNTERBALANCE THE UNDERLYING MECHANISMS THAT ALTER MUSCLE FUNCTION AND MASS. THE STUDY OF PATIENTS AT EARLY STAGES OF THEIR DISEASE IS OF INTEREST AS THEY ARE A TARGET FOR TIMELY THERAPEUTIC INTERVENTIONS THAT MAY SLOW DOWN THE COURSE OF THE DISEASE AND PREVENT THE DELETERIOUS EFFECTS OF MAJOR COMORBIDITIES.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
10   351  31 ALTERED ENDOTHELIAL DYSFUNCTION-RELATED MIRS IN PLASMA FROM ME/CFS PATIENTS. MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS) IS A COMPLEX DISEASE CHARACTERIZED BY UNEXPLAINED DEBILITATING FATIGUE. ALTHOUGH THE ETIOLOGY IS UNKNOWN, EVIDENCE SUPPORTS IMMUNOLOGICAL ABNORMALITIES, SUCH AS PERSISTENT INFLAMMATION AND IMMUNE-CELL ACTIVATION, IN A SUBSET OF PATIENTS. SINCE THE INTERPLAY BETWEEN INFLAMMATION AND VASCULAR ALTERATIONS IS WELL-ESTABLISHED IN OTHER DISEASES, ENDOTHELIAL DYSFUNCTION HAS EMERGED AS ANOTHER PLAYER IN ME/CFS PATHOGENESIS. ENDOTHELIAL NITRIC OXIDE SYNTHASE (ENOS) GENERATES NITRIC OXIDE (NO) THAT MAINTAINS ENDOTHELIAL HOMEOSTASIS. ENOS IS ACTIVATED BY SILENT INFORMATION REGULATOR 1 (SIRT1), AN ANTI-INFLAMMATORY PROTEIN. DESPITE ITS RELEVANCE, NO STUDY HAS ADDRESSED THE SIRT1/ENOS AXIS IN ME/CFS. THE INTEREST IN CIRCULATING MICRORNAS (MIRS) AS POTENTIAL BIOMARKERS IN ME/CFS HAS INCREASED IN RECENT YEARS. ACCORDINGLY, WE ANALYZE A SET OF MIRS REPORTED TO MODULATE THE SIRT1/ENOS AXIS USING PLASMA FROM ME/CFS PATIENTS. OUR RESULTS SHOW THAT MIR-21, MIR-34A, MIR-92A, MIR-126, AND MIR-200C ARE JOINTLY INCREASED IN ME/CFS PATIENTS COMPARED TO HEALTHY CONTROLS. A SIMILAR FINDING WAS OBTAINED WHEN ANALYZING PUBLIC MIR DATA ON PERIPHERAL BLOOD MONONUCLEAR CELLS. BIOINFORMATICS ANALYSIS SHOWS THAT ENDOTHELIAL FUNCTION-RELATED SIGNALING PATHWAYS ARE ASSOCIATED WITH THESE MIRS, INCLUDING OXIDATIVE STRESS AND OXYGEN REGULATION. INTERESTINGLY, HISTONE DEACETYLASE 1, A PROTEIN RESPONSIBLE FOR EPIGENETIC REGULATIONS, REPRESENTED THE MOST RELEVANT NODE WITHIN THE NETWORK. IN CONCLUSION, OUR STUDY PROVIDES A BASIS TO FIND ENDOTHELIAL DYSFUNCTION-RELATED BIOMARKERS AND EXPLORE NOVEL TARGETS IN ME/CFS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
11  5010  29 PEROXIDATION OF LINOLEIC, ARACHIDONIC AND OLEIC ACID IN RELATION TO THE INDUCTION OF OXIDATIVE DNA DAMAGE AND CYTOGENETIC EFFECTS. IN THE PRESENT STUDY, THE POSSIBLE ROLE OF THE POLYUNSATURATED FATTY ACIDS LINOLEIC AND ARACHIDONIC ACID IN THE CHEMICAL INDUCTION OF CARCINOGENESIS HAS BEEN INVESTIGATED. ANALYSIS OF 7,8-DIHYDRO-8-OXO-2'-DEOXYGUANOSINE (8-OXODG) LEVELS IN 2'-DEOXYGUANOSINE (DG) AND ISOLATED DNA HAS DEMONSTRATED THAT LINOLEIC AND ARACHIDONIC ACID ARE CAPABLE OF INDUCING THIS SPECIFIC GENOTOXIC DAMAGE. THIS EFFECT APPEARS TO BE RELATED TO THE DEGREE OF FATTY ACID UNSATURATION, SINCE IT WAS NOT INDUCED BY MONOUNSATURATED OLEIC ACID. ENZYMATIC PEROXIDATION OF LINOLEIC AND ARACHIDONIC ACID RESULTED IN A SIGNIFICANT INCREASE IN OXIDATIVE DNA DAMAGE. STUDIES ON THE INTERFERENCE OF RADICAL SCAVENGERS WITH THE INDUCTION OF 8-OXODG IN COMBINATION WITH ELECTRON SPIN RESONANCE SPECTROSCOPY DEMONSTRATED THAT THE SUPEROXIDE ANION WAS GENERATED DURING PEROXIDATION OF THESE FATTY ACIDS AND THAT SINGLET OXYGEN IS MOST LIKELY INVOLVED IN THE FORMATION OF OXIDATIVE DNA DAMAGE. THE LEVEL OF OXIDATIVE DAMAGE IN DG AND SINGLE-STRANDED DNA WAS HIGHER AS COMPARED TO THAT IN NATIVE DNA AFTER EQUIMOLAR TREATMENT. EXPOSURE OF HUMAN LYMPHOCYTES TO LINOLEIC OR ARACHIDONIC ACID DID NOT RESULT IN A SIGNIFICANT INCREASE IN LEVELS OF 8-OXODG. THIS MAY INDICATE THAT THE RATE OF INTRACELLULAR PEROXIDATION IS RELATIVELY LOW AND/OR THAT NUCLEAR DNA IN INTACT CELLS IS EFFECTIVELY PROTECTED AGAINST GENETIC DAMAGE INDUCED BY REACTIVE OXYGEN SPECIES. IT IS THEREFORE CONCLUDED THAT RELATIVELY SHORT PERIODS OF LINOLEIC OR ARACHIDONIC ACID ADMINISTRATION ARE NOT LIKELY TO IMPOSE A DIRECT GENOTOXIC RISK. IT CAN, HOWEVER, NOT BE EXCLUDED THAT CHRONIC EXPOSURE TO POLYUNSATURATED FATTY ACIDS INDUCES OXIDATIVE DNA DAMAGE OR IS RELATED TO CANCER RISK BY EPIGENETIC MECHANISMS, AS IS ALSO INDICATED BY THE OBSERVED CYTOTOXIC EFFECTS OF LINOLEIC AND ARACHIDONIC ACID.	1994	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
12  3767  24 INTEGRATIVE EPIGENOMIC ANALYSIS IN DIFFERENTIATED HUMAN PRIMARY BRONCHIAL EPITHELIAL CELLS EXPOSED TO CIGARETTE SMOKE. CIGARETTE SMOKE (CS) IS ONE OF THE MAJOR RISK FACTORS FOR MANY PULMONARY DISEASES, INCLUDING CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND LUNG CANCER. THE FIRST LINE OF DEFENSE FOR CS EXPOSURE IS THE BRONCHIAL EPITHELIAL CELLS. ELUCIDATION OF THE EPIGENETIC CHANGES DURING CS EXPOSURE IS KEY TO GAINING A MECHANISTIC UNDERSTANDING INTO HOW MATURE AND DIFFERENTIATED BRONCHIAL EPITHELIAL CELLS RESPOND TO CS. THEREFORE, WE PERFORMED EPIGENOMIC PROFILING IN CONJUNCTION WITH TRANSCRIPTIONAL PROFILING IN WELL-DIFFERENTIATED HUMAN BRONCHIAL EPITHELIAL (HBE) CELLS CULTURED IN AIR-LIQUID INTERFACE (ALI) EXPOSED TO THE VAPOR PHASE OF CS. THE GENOME-WIDE ENRICHMENT OF HISTONE 3 LYSINE 27 ACETYLATION WAS DETECTED BY CHROMATIN IMMUNOPRECIPITATION FOLLOWED BY NEXT GENERATION SEQUENCING (CHIP-SEQ) IN HBE CELLS AND SUGGESTED THE PLAUSIBLE BINDING OF SPECIFIC TRANSCRIPTION FACTORS RELATED TO CS EXPOSURE. ADDITIONALLY, INTERROGATION OF CHIP-SEQ DATA WITH GENE EXPRESSION PROFILING OF HBE CELLS AFTER CS EXPOSURE FOR DIFFERENT DURATIONS (3 HOURS, 2 DAYS, 4 DAYS) SUGGESTED THAT EARLIER EPIGENETIC CHANGES (3 HOURS AFTER CS EXPOSURE) MAY BE ASSOCIATED WITH LATER GENE EXPRESSION CHANGES INDUCED BY CS EXPOSURE (4 DAYS). THE INTEGRATION OF EPIGENETICS AND GENE EXPRESSION DATA REVEALED SIGNALING PATHWAYS RELATED TO CS-INDUCED EPIGENETIC CHANGES IN HBE CELLS THAT MAY IDENTIFY NOVEL REGULATORY PATHWAYS RELATED TO CS-INDUCED COPD.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
13  3493  28 IDENTIFICATION OF KEY GENES, PATHWAYS, AND MIRNA/MRNA REGULATORY NETWORKS OF CUMS-INDUCED DEPRESSION IN NUCLEUS ACCUMBENS BY INTEGRATED BIOINFORMATICS ANALYSIS. INTRODUCTION: MAJOR DEPRESSIVE DISORDER (MDD) IS A RECURRENT, DEVASTATING MENTAL DISORDER, WHICH AFFECTS >350 MILLION PEOPLE WORLDWIDE, AND EXERTS SUBSTANTIAL PUBLIC HEALTH AND FINANCIAL COSTS TO SOCIETY. THUS, THERE IS A SIGNIFICANT NEED TO DISCOVER INNOVATIVE THERAPEUTICS TO TREAT DEPRESSION EFFICIENTLY. STRESS-INDUCED DYSFUNCTION IN THE SUBTYPE OF NEURONAL CELLS AND THE CHANGE OF SYNAPTIC PLASTICITY AND STRUCTURAL PLASTICITY OF NUCLEUS ACCUMBENS (NAC) ARE IMPLICATED IN DEPRESSION SYMPTOMOLOGY. HOWEVER, THE MOLECULAR AND EPIGENETIC MECHANISMS AND STRESSES TO THE NAC PATHOLOGICAL CHANGES IN DEPRESSION REMAIN ELUSIVE. MATERIALS AND METHODS: IN THIS STUDY, TREATMENT GROUP MICE WERE TREATED CONTINUALLY WITH THE CHRONIC UNPREDICTABLE MILD STRESS (CUMS) UNTIL EXPRESSION OF DEPRESSION-LIKE BEHAVIORS WERE FOUND. DEPRESSION WAS CONFIRMED WITH SUCROSE PREFERENCE, NOVELTY-SUPPRESSED FEEDING, FORCED SWIMMING, AND TAIL SUSPENSION TESTS. WE APPLIED HIGH-THROUGHPUT RNA SEQUENCING TO ASSESS MICRORNA EXPRESSION AND TRANSCRIPTIONAL PROFILES IN THE NAC TISSUE FROM DEPRESSION-LIKE BEHAVIORS MICE AND CONTROL MICE. THE REGULATORY NETWORK OF MIRNAS/MRNAS WAS CONSTRUCTED BASED ON THE HIGH-THROUGHPUT RNA SEQUENCE AND BIOINFORMATICS SOFTWARE PREDICTIONS. RESULTS: A TOTAL OF 17 MIRNAS AND 10 MRNAS WERE SIGNIFICANTLY UPREGULATED IN THE NAC OF CUMS-INDUCED MICE WITH DEPRESSION-LIKE BEHAVIORS, AND 12 MIRNAS AND 29 MRNAS WERE DOWNREGULATED. A SERIES OF BIOINFORMATICS ANALYSES SHOWED THAT THESE ALTERED MIRNAS PREDICTED TARGET MRNA AND DIFFERENTIALLY EXPRESSED MRNAS WERE SIGNIFICANTLY ENRICHED IN THE MAPK SIGNALING PATHWAY, GABAERGIC SYNAPSE, DOPAMINERGIC SYNAPSE, CYTOKINE-CYTOKINE RECEPTOR INTERACTION, AXON GUIDANCE, REGULATION OF AUTOPHAGY, AND SO ON. FURTHERMORE, DUAL LUCIFERASE REPORT ASSAY AND QRT-PCR RESULTS VALIDATED THE MIRNA/MRNA REGULATORY NETWORK. CONCLUSION: THE DETERIORATIONS OF GABAERGIC SYNAPSES, DOPAMINERGIC SYNAPSES, NEUROTRANSMITTER SYNTHESIS, AS WELL AS AUTOPHAGY-ASSOCIATED APOPTOTIC PATHWAY ARE ASSOCIATED WITH THE MOLECULAR PATHOLOGICAL MECHANISM OF CUMS-INDUCED DEPRESSION.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
14  4989  30 PCSK9 IS INCREASED IN CEREBROSPINAL FLUID OF INDIVIDUALS WITH ALCOHOL USE DISORDER. BACKGROUND: RECENT STUDIES HAVE SHOWN THAT ALCOHOL USE AFFECTS THE REGULATION AND EXPRESSION OF PROPROTEIN CONVERTASE SUBTILISIN/KEXIN 9 (PCSK9). WHILE A MAJOR ROLE OF PCSK9 IN HEPATIC FUNCTION AND LIPID REGULATION HAS BEEN CLEARLY ESTABLISHED, OTHER PLEIOTROPIC EFFECTS REMAIN POORLY UNDERSTOOD. EXISTING RESEARCH SUGGESTS A POSITIVE ASSOCIATION BETWEEN PCSK9 EXPRESSION IN THE BRAIN AND PSYCHOPATHOLOGY, WITH INCREASED LEVELS OF PCSK9 IN THE CEREBROSPINAL FLUID (CSF) OF INDIVIDUALS WITH DEMENTIA AND EPIGENETIC MODIFICATIONS OF PCSK9 ASSOCIATED WITH ALCOHOL USE DISORDER (AUD). IN THIS STUDY, WE HYPOTHESIZED THAT CHRONIC ALCOHOL USE WOULD INCREASE PCSK9 EXPRESSION IN CSF. METHODS: PCSK9 LEVELS IN CSF WERE MEASURED IN INDIVIDUALS WITH AUD (N = 42) ADMITTED TO AN INPATIENT REHABILITATION PROGRAM AND CONTROLS (N = 25). CSF SAMPLES IN AUD WERE ASSESSED AT 2 TIME POINTS, AT DAY 5 AND DAY 21 AFTER ADMISSION. FURTHERMORE, PLASMA SAMPLES WERE COLLECTED AND MEASURED FROM THE INDIVIDUALS WITH AUD. RESULTS: PCSK9 IN CSF WAS SIGNIFICANTLY INCREASED IN THE AUD GROUP AT DAY 5 AND DAY 21 COMPARED TO THE CONTROLS (P < 0.0001). PLASMA PCSK9 LEVELS WERE CORRELATED POSITIVELY WITH CSF PCSK9 LEVELS IN AUD (P = 0.0493). CONCLUSIONS: OUR DATA SUGGEST THAT PCSK9 IS ELEVATED IN THE CSF OF INDIVIDUALS WITH AUD, WHICH MAY INDICATE A POTENTIAL ROLE OF PCSK9 IN AUD. ADDITIONAL STUDIES ARE NECESSARY TO FURTHER ELUCIDATE THE FUNCTIONS OF PCSK9 IN THE BRAIN.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
15  2755  38 EXPRESSION OF CLASS II HISTONE DEACETYLASES IN TWO MOUSE MODELS OF TEMPORAL LOBE EPILEPSY. EPIGENETIC MECHANISMS LIKE ALTERED HISTONE ACETYLATION MAY HAVE A CRUCIAL ROLE IN EPILEPTOGENESIS. IN TWO MOUSE MODELS OF TEMPORAL LOBE EPILEPSY, WE INVESTIGATED CHANGES IN THE EXPRESSION OF CLASS II HISTONE DEACETYLASES (HDAC), A GROUP OF SIGNAL TRANSDUCERS THAT SHUTTLE BETWEEN NUCLEUS AND CYTOPLASM. INTRAHIPPOCAMPAL INJECTION OF KAINIC ACID (KA) INDUCED A STATUS EPILEPTICUS, DEVELOPMENT OF SPONTANEOUS SEIZURES (AFTER 3 DAYS), AND FINALLY CHRONIC EPILEPSY AND GRANULE CELL DISPERSION. EXPRESSION OF CLASS II HDAC MRNAS WAS INVESTIGATED AT DIFFERENT TIME INTERVALS AFTER KA INJECTION IN THE GRANULE CELL LAYERS AND IN SECTORS CA1 AND CA3 CONTRALATERAL TO THE SITE OF KA INJECTION LACKING NEURODEGENERATION. INCREASED EXPRESSION OF HDAC5 AND 9 MRNAS COINCIDED WITH PRONOUNCED GRANULE CELL DISPERSION IN THE KA-INJECTED HIPPOCAMPUS AT LATE INTERVALS (14-28 DAYS AFTER KA) AND EQUALLY AFFECTED BOTH HDAC9 SPLICE VARIANTS. IN CONTRAST, IN THE PILOCARPINE MODEL (SHOWING NO GRANULE CELL DISPERSION), WE OBSERVED DECREASES IN THE EXPRESSION OF HDAC5 AND 9 AT THE SAME TIME INTERVALS. BEYOND THIS, STRIKING SIMILARITIES BETWEEN BOTH TEMPORAL LOBE EPILEPSY MODELS SUCH AS FAST DECREASES IN HDAC7 AND 10 MRNAS DURING THE ACUTE STATUS EPILEPTICUS WERE OBSERVED, NOTABLY ALSO IN THE CONTRALATERAL HIPPOCAMPUS NOT AFFECTED BY NEURODEGENERATION. THE PARTICULAR PATTERNS OF HDAC MRNA EXPRESSION SUGGEST A ROLE IN EPILEPTOGENESIS AND GRANULE CELL DISPERSION. REDUCED EXPRESSION OF HDACS MAY RESULT IN INCREASED EXPRESSION OF PRO- AND ANTICONVULSIVE PROTEINS. ON THE OTHER HAND, EXPORT OF HDACS FROM THE NUCLEUS INTO THE CYTOPLASM COULD ALLOW FOR DEACETYLATION OF CYTOPLASMATIC PROTEINS INVOLVED IN AXONAL AND DENDRITIC REMODELING, LIKE GRANULE CELL DISPERSION. HDAC 5 AND HDAC 9 EXPRESSION IS HIGHLY INCREASED IN GRANULE CELLS OF THE KA-INJECTED HIPPOCAMPUS AND PARALLELS GRANULE CELL DISPERSION. BOTH HDACS ARE THOUGHT TO BE TARGETED TO THE CYTOPLASM AND TO ACT THERE BY DEACETYLATING CYTOPLASMATIC (E.G. CYTOSCELETON-RELATED) PROTEINS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
16  6748  30 WHOLE GENOME METHYLATION ARRAY ANALYSIS REVEALS NEW ASPECTS IN BALKAN ENDEMIC NEPHROPATHY ETIOLOGY. BACKGROUND: BALKAN ENDEMIC NEPHROPATHY (BEN) REPRESENTS A CHRONIC PROGRESSIVE INTERSTITIAL NEPHRITIS IN STRIKING CORRELATION WITH UROEPITHELIAL TUMOURS OF THE UPPER URINARY TRACT. THE DISEASE HAS ENDEMIC DISTRIBUTION IN THE DANUBE RIVER REGIONS IN SEVERAL BALKAN COUNTRIES.DNA METHYLATION IS A PRIMARY EPIGENETIC MODIFICATION THAT IS INVOLVED IN MAJOR PROCESSES SUCH AS CANCER, GENOMIC IMPRINTING, GENE SILENCING, ETC. THE SIGNIFICANCE OF CPG ISLAND METHYLATION STATUS IN NORMAL DEVELOPMENT, CELL DIFFERENTIATION AND GENE EXPRESSION IS WIDELY RECOGNIZED, ALTHOUGH STILL STAYS POORLY UNDERSTOOD. METHODS: WE PERFORMED WHOLE GENOME DNA METHYLATION ARRAY ANALYSIS ON DNA POOL SAMPLES FROM PERIPHERAL BLOOD FROM 159 AFFECTED INDIVIDUALS AND 170 HEALTHY INDIVIDUALS. THIS TECHNIQUE ALLOWED US TO DETERMINE THE METHYLATION STATUS OF 27 627 CPG ISLANDS THROUGHOUT THE WHOLE GENOME IN HEALTHY CONTROLS AND BEN PATIENTS. THUS WE OBTAINED THE METHYLATION PROFILE OF BEN PATIENTS FROM BULGARIAN AND SERBIAN ENDEMIC REGIONS. RESULTS: USING SPECIFICALLY DEVELOPED SOFTWARE WE COMPARED THE METHYLATION PROFILES OF BEN PATIENTS AND CORRESPONDING CONTROLS AND REVEALED THE DIFFERENTLY METHYLATED REGIONS. WE THEN COMPARED THE DMRS BETWEEN ALL PATIENT-CONTROL PAIRS TO DETERMINE COMMON CHANGES IN THE EPIGENETIC PROFILES.SEC61G, IL17RA, HDAC11 PROVED TO BE DIFFERENTLY METHYLATED THROUGHOUT ALL PATIENT-CONTROL PAIRS. THE CPG ISLANDS OF ALL 3 GENES WERE HYPOMETHYLATED COMPARED TO CONTROLS. THIS SUGGESTS THAT DYSREGULATION OF THESE GENES INVOLVED IN IMMUNOLOGICAL RESPONSE COULD BE A COMMON MECHANISM IN BEN PATHOGENESIS IN BOTH ENDEMIC REGIONS AND IN BOTH GENDERS. CONCLUSION: OUR DATA PROPOSE A NEW HYPOTHESIS THAT IMMUNOLOGIC DYSREGULATION HAS A PLACE IN BEN ETIOPATHOGENESIS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
17  4015  32 LOW-DOSE EXPOSURE TO BISPHENOLS A, F AND S OF HUMAN PRIMARY ADIPOCYTE IMPACTS CODING AND NON-CODING RNA PROFILES. BISPHENOL A (BPA) EXPOSURE HAS BEEN SUSPECTED TO BE ASSOCIATED WITH DELETERIOUS EFFECTS ON HEALTH INCLUDING OBESITY AND METABOLICALLY-LINKED DISEASES. ALTHOUGH BISPHENOLS F (BPF) AND S (BPS) ARE BPA STRUCTURAL ANALOGS COMMONLY USED IN MANY MARKETED PRODUCTS AS A REPLACEMENT FOR BPA, ONLY SPARSE TOXICOLOGICAL DATA ARE AVAILABLE YET. OUR OBJECTIVE WAS TO COMPREHENSIVELY CHARACTERIZE BISPHENOLS GENE TARGETS IN A HUMAN PRIMARY ADIPOCYTE MODEL, IN ORDER TO DETERMINE WHETHER THEY MAY INDUCE CELLULAR DYSFUNCTION, USING CHRONIC EXPOSURE AT TWO CONCENTRATIONS: A "LOW-DOSE" SIMILAR TO THE DOSE USUALLY ENCOUNTERED IN HUMAN BIOLOGICAL FLUIDS AND A HIGHER DOSE. THEREFORE, BPA, BPF AND BPS HAVE BEEN ADDED AT 10 NM OR 10 MUM DURING THE DIFFERENTIATION OF HUMAN PRIMARY ADIPOCYTES FROM SUBCUTANEOUS FAT OF THREE NON-DIABETIC CAUCASIAN FEMALE PATIENTS. GENE EXPRESSION (MRNA/LNCRNA) ARRAYS AND MICRORNA ARRAYS, HAVE BEEN USED TO ASSESS CODING AND NON-CODING RNA CHANGES. WE DETECTED SIGNIFICANTLY DEREGULATED MRNA/LNCRNA AND MIRNA AT LOW AND HIGH DOSES. ENRICHMENT IN "CANCER" AND "ORGANISMAL INJURY AND ABNORMALITIES" RELATED PATHWAYS WAS FOUND IN RESPONSE TO THE THREE PRODUCTS. SOME LONG INTERGENIC NON-CODING RNAS AND SMALL NUCLEOLAR RNAS WERE DIFFERENTIALLY EXPRESSED SUGGESTING THAT BISPHENOLS MAY ALSO ACTIVATE MULTIPLE CELLULAR PROCESSES AND EPIGENETIC MODIFICATIONS. THE ANALYSIS OF UPSTREAM REGULATORS OF DEREGULATED GENES HIGHLIGHTED HORMONES OR HORMONE-LIKE CHEMICALS SUGGESTING THAT BPS AND BPF CAN BE SUSPECTED TO INTERFERE, JUST LIKE BPA, WITH HORMONAL REGULATION AND HAVE TO BE CONSIDERED AS ENDOCRINE DISRUPTORS. ALL THESE RESULTS SUGGEST THAT AS BPA, ITS SUBSTITUTES BPS AND BPF SHOULD BE USED WITH THE SAME RESTRICTIONS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
18  5345  34 RAPID CHANGES IN EXPRESSION OF CLASS I AND IV HISTONE DEACETYLASES DURING EPILEPTOGENESIS IN MOUSE MODELS OF TEMPORAL LOBE EPILEPSY. A PROMINENT ROLE OF EPIGENETIC MECHANISMS IN MANIFESTATION OF EPILEPSY HAS BEEN PROPOSED. THUS ALTERED HISTONE H3 AND H4 ACETYLATION HAS BEEN DEMONSTRATED IN EXPERIMENTAL MODELS OF TEMPORAL LOBE EPILEPSY (TLE). WE NOW INVESTIGATED CHANGES IN THE EXPRESSION OF THE CLASS I AND CLASS IV HISTONE DEACETYLASES (HDAC) IN TWO COMPLEMENTARY MOUSE TLE MODELS. UNILATERAL INTRAHIPPOCAMPAL INJECTION OF KAINIC ACID (KA) INDUCED A STATUS EPILEPTICUS LASTING 6 TO 24H, DEVELOPMENT OF SPONTANEOUS LIMBIC SEIZURES (2 TO 3 DAYS AFTER KA INJECTION) AND CHRONIC EPILEPSY, AS REVEALED BY TELEMETRIC RECORDINGS OF THE EEGS. MICE WERE KILLED AT DIFFERENT INTERVALS AFTER KA INJECTION AND EXPRESSION OF HDAC MRNAS WAS INVESTIGATED BY IN SITU HYBRIDIZATION. WE OBSERVED MARKED DECREASES IN THE EXPRESSION OF HDACS 1, 2 AND 11 (BY UP TO 75%) IN THE GRANULE CELL AND PYRAMIDAL CELL LAYERS OF THE HIPPOCAMPUS DURING THE ACUTE STATUS EPILEPTICUS (2 TO 6H AFTER KA INJECTION). THIS WAS FOLLOWED BY INCREASED EXPRESSION OF ALL CLASS I HDAC MRNAS IN ALL PRINCIPAL CELL LAYERS OF THE HIPPOCAMPUS AFTER 12 TO 48 H. IN THE CHRONIC PHASE, 14 AND 28 DAYS AFTER KA, ONLY MODEST INCREASES IN THE EXPRESSION OF HDAC1 MRNA WERE OBSERVED IN GRANULE AND PYRAMIDAL CELLS. IMMUNOHISTOCHEMISTRY USING AN ANTIBODY DETECTING HDAC2 REVEALED RESULTS CONSISTENT WITH THE MRNA DATA AND INDICATES ALSO EXPRESSION IN GLIAL CELLS ON THE INJECTION SIDE. SIMILAR CHANGES AS SEEN IN THE KA MODEL WERE OBSERVED AFTER A PILOCARPINE-INDUCED STATUS EPILEPTICUS EXCEPT THAT DECREASES IN HDACS 2, 3 AND 8 WERE ALSO SEEN AT THE CHRONIC 28 DAY INTERVAL. THE PROMINENT DECREASES IN HDAC EXPRESSION DURING STATUS EPILEPTICUS ARE CONSISTENT WITH THE PREVIOUSLY DEMONSTRATED INCREASED EXPRESSION OF NUMEROUS PROTEINS AND WITH THE AUGMENTED ACETYLATION OF HISTONE H4. IT IS SUGGESTED THAT RESPECTIVE PUTATIVE GENE PRODUCTS COULD FACILITATE PROCONVULSIVE AS WELL AS ANTICONVULSIVE MECHANISMS. THE INCREASED EXPRESSION OF ALL CLASS I HDACS DURING THE "SILENT PHASE", ON THE OTHER HAND, MAY BE RELATED TO DECREASED HISTONE ACETYLATION, WHICH COULD CAUSE A DECREASE IN EXPRESSION OF CERTAIN PROTEINS, A MECHANISM THAT COULD ALSO PROMOTE EPILEPTOGENESIS. THUS, ADDRESSING HDAC EXPRESSION MAY HAVE A THERAPEUTIC POTENTIAL IN INTERFERING WITH A STATUS EPILEPTICUS AND WITH THE MANIFESTATION OF TLE.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
19   972  30 CHRONIC OBSTRUCTIVE PULMONARY DISEASE IS ASSOCIATED WITH EPIGENOME-WIDE DIFFERENTIAL METHYLATION IN BAL LUNG CELLS. DNA METHYLATION PATTERNS IN CHRONIC PULMONARY OBSTRUCTIVE DISEASE (COPD) MIGHT OFFER NEW INSIGHTS INTO DISEASE PATHOGENESIS. TO ASSESS METHYLATION PROFILES IN THE MAIN COPD TARGET ORGAN, WE PERFORMED AN EPIGENOME-WIDE ASSOCIATION STUDY ON BAL CELLS. BRONCHOSCOPIES WERE PERFORMED IN 18 SUBJECTS WITH COPD AND 15 CONTROL SUBJECTS (EX- AND CURRENT SMOKERS). DNA METHYLATION WAS MEASURED USING THE ILLUMINA METHYLATIONEPIC BEADCHIP KIT, COVERING MORE THAN 850,000 CPGS. DIFFERENTIALLY METHYLATED POSITIONS (DMPS) WERE EXAMINED FOR 1) ENRICHMENT IN PATHWAYS AND FUNCTIONAL GENE RELATIONSHIPS USING THE KYOTO ENCYCLOPEDIA OF GENES AND GENOMES AND GENE ONTOLOGY, 2) ACCELERATED AGING USING HORVATH'S EPIGENETIC CLOCK, 3) CORRELATION WITH GENE EXPRESSION, AND 4) COLOCALIZATION WITH GENETIC VARIATION. WE FOUND 1,155 BONFERRONI-SIGNIFICANT (P < 6.74 X 10(-8)) DMPS ASSOCIATED WITH COPD, MANY WITH LARGE EFFECT SIZES. FUNCTIONAL ANALYSIS IDENTIFIED BIOLOGICALLY PLAUSIBLE PATHWAYS AND GENE RELATIONSHIPS, INCLUDING ENRICHMENT FOR TRANSCRIPTION FACTOR ACTIVITY. STRONG CORRELATION WAS FOUND BETWEEN DNA METHYLATION AND CHRONOLOGICAL AGE BUT NOT BETWEEN COPD AND ACCELERATED AGING. FOR 79 UNIQUE DMPS, DNA METHYLATION CORRELATED SIGNIFICANTLY WITH GENE EXPRESSION IN BAL CELLS. THIRTY-NINE PERCENT OF DMPS WERE COLOCALIZED WITH COPD-ASSOCIATED SNPS. TO THE BEST OF OUR KNOWLEDGE, THIS IS THE FIRST EPIGENOME-WIDE ASSOCIATION STUDY OF COPD ON BAL CELLS, AND OUR ANALYSES REVEALED MANY DIFFERENTIAL METHYLATION SITES. INTEGRATION WITH MRNA DATA SHOWED A STRONG FUNCTIONAL READOUT FOR RELEVANT GENES, IDENTIFYING SITES WHERE DNA METHYLATION MIGHT DIRECTLY AFFECT EXPRESSION. ALMOST HALF OF DMPS WERE COLOCATED WITH SNPS IDENTIFIED IN PREVIOUS GENOME-WIDE ASSOCIATION STUDIES OF COPD, SUGGESTING JOINT GENETIC AND EPIGENETIC PATHWAYS RELATED TO DISEASE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
20  3553  33 IMMUNOTOLERANCE OF DAIRY HEIFERS IN RESPONSE TO REPEATED EXPOSURE TO BACTERIAL LIPOPOLYSACCHARIDE ENDOTOXIN. DAIRY CATTLE FACE A VARIETY OF STRESSFUL EVENTS ON A DAILY BASIS. MORE SPECIFICALLY, CLIMATE CHANGE HAS RESULTED IN MORE FREQUENT HEAT STRESS EVENTS THAT INCREASE THE INCIDENCE OF CHRONIC BACTERIAL INFECTIONS BY INDUCING CONDITIONS LIKE LEAKY GUT SYNDROME, WHEREBY THE INTEGRITY OF THE INTESTINAL EPITHELIUM IS COMPROMISED ALLOWING FOR LUMINAL BACTERIAL LIPOPOLYSACCHARIDE (LPS) ENDOTOXIN TO INFILTRATE THE HOST'S BLOODSTREAM RESULTING IN ACUTE OR CHRONIC SYSTEMIC STIMULATION OF THE INNATE IMMUNE SYSTEM. REPEATED EXPOSURE TO LPS OVER A SHORT PERIOD OF TIME IS REPORTED TO INDUCE IMMUNOTOLERANCE WITHIN THE HOST. THIS LPS TOLERANCE IS AN ESSENTIAL IMMUNOHOMEOSTATIC RESPONSE THAT CAN PROTECT AGAINST OVER ACTIVATION OF THE INFLAMMATORY RESPONSE DURING SUBSEQUENT EXPOSURE TO LPS. IN THE PRESENT STUDY, HOLSTEIN CALVES (N = 20) WERE INITIALLY STRESS CHALLENGED WITH EITHER SALINE, OR 100, 200 OR 400 NG/KG OF LPS ADMINISTERED INTRAMUSCULAR, AND AGAIN RE-CHALLENGED WITH 200 NG/KG OF LPS 2-WEEKS LATER. SERUM WAS COLLECTED EVERY 2 HR FOR 6 HR TO PROFILE CHANGES IN CIRCULATORY STRESS BIOMARKERS AFTER THE REPEATED LPS EXPOSURES. HEIFERS THAT WERE INITIALLY CHALLENGED WITH 100, 200 AND 400 NG/KG OF LPS DEMONSTRATED SIGNIFICANTLY ATTENUATED CORTISOL RESPONSES IN THE SECOND CHALLENGE (P < 0.01, 0.01 AND 0.05, RESPECTIVELY), WHEREAS CONTROL ANIMALS WHO PREVIOUSLY RECEIVED SALINE DEMONSTRATED A STRONG CORTISOL RESPONSE AT 2 HR AFTER RECEIVING 200 NG/KG OF LPS (P < 0.05). THE CYTOKINE/CHEMOKINE (IL-6, CCL2, CCL3 AND CCL4) RESPONSES WERE ALSO ATTENUATED DURING THE LPS RECHALLENGE (P < 0.05). FINALLY, MICRORNA EXPRESSION PROFILES WERE DETERMINED TO ASSESS THE EPIGENETIC RESPONSE TO REPEATED LPS EXPOSURE. INTERESTINGLY, MIR-31 AND MIR-223 WERE DOWNREGULATED IN RESPONSE TO THE SECOND LPS CHALLENGE. THE PRESENT STUDY DEMONSTRATES THE DYNAMIC NATURE OF THE STRESS RESPONSE IN DAIRY CATTLE AS IT RELATES TO THE DEVELOPMENT OF LPS TOLERANCE. UNDERSTANDING THE ROLES OF VARIOUS STRESS BIOMARKERS IN THE CONTEXT OF INNATE IMMUNE CELL TOLERANCE IS ESSENTIAL FOR EVALUATING THEIR IMPACT ON IMMUNE SYSTEM HOMEOSTASIS.	2023