1  1118 155 COMPARATIVE GENOTYPING AND PHENOTYPING OF ASPERGILLUS FUMIGATUS ISOLATES FROM HUMANS, DOGS AND THE ENVIRONMENT. BACKGROUND: ASPERGILLUS FUMIGATUS IS A UBIQUITOUS SAPROTROPHIC FUNGUS AND AN OPPORTUNISTIC PATHOGEN OF HUMANS AND ANIMALS. HUMANS AND ANIMALS CAN INHALE HUNDREDS OF A. FUMIGATUS SPORES DAILY. NORMALLY THIS IS HARMLESS FOR HUMANS, BUT IN CASE OF IMMUNODEFICIENCY, INVASIVE PULMONARY ASPERGILLOSIS (IPA) CAN DEVELOP WITH A HIGH MORTALITY RATE. A. FUMIGATUS ALSO CAUSES NON-INVASIVE MYCOSES LIKE SINO-NASAL ASPERGILLOSIS (SNA) IN DOGS. RESULTS: IN THIS STUDY WE COMPARED A. FUMIGATUS ISOLATES FROM HUMANS WITH SUSPECTED IPA, DOGS WITH SNA, AND A SET OF ENVIRONMENTAL ISOLATES. PHYLOGENETIC INFERENCE BASED ON CALMODULIN (CAM) AND BETA-TUBULIN (BENA) SEQUENCES DID NOT REVEAL A. FUMIGATUS SUB-GROUPS LINKED TO THE ORIGIN OF THE ISOLATES. GENOTYPING AND MICROSATELLITE ANALYSIS SHOWED THAT EACH DOG WAS INFECTED BY ONE A. FUMIGATUS GENOTYPE, WHEREAS HUMAN PATIENTS HAD MIXED INFECTIONS. AZOLE RESISTANCE WAS DETERMINED BY ANTIFUNGAL SUSCEPTIBILITY TESTING AND SEQUENCING OF THE CYP51A GENE. A TOTAL OF 12 OUT OF 29 HUMAN ISOLATES AND 1 OUT OF 27 ENVIRONMENTAL ISOLATES WERE AZOLE RESISTANT. OF THE AZOLE RESISTANT STRAINS, 11 HUMAN ISOLATES SHOWED TR(34)/L98H (N = 6) OR TR46/Y121F/T289A (N = 5). PHENOTYPICALLY, ISOLATES FROM DOGS WERE MORE VARIABLE IN GROWTH SPEED AND MORPHOLOGY WHEN COMPARED TO THOSE ISOLATED FROM HUMAN AND THE ENVIRONMENT. CONCLUSIONS: 1. A. FUMIGATUS FROM DOGS WITH SNA ARE PHENOTYPICALLY VERY DIVERSE IN CONTRAST TO THEIR ENVIRONMENTAL AND HUMAN COUNTERPARTS. 2. PHENOTYPIC VARIABILITY CAN BE INDUCED DURING THE CHRONIC INFECTION PROCESS IN THE SINUS OF THE DOGS. THE BASIS OF THIS HETEROGENEITY MIGHT BE DUE TO GENOMIC DIFFERENCES AND/OR EPIGENETIC VARIATIONS. 3. DIFFERENCES IN DOGS IS A COULD BE A RESULT OF WITHIN-HOST ADAPTION AND MIGHT BE TRIGGERED BY ENVIRONMENTAL FACTORS IN THE SINUS, HOWEVER THIS HYPOTHESIS STILL NEEDS TO BE TESTED.	2018	
                                                                                                                                                                                                                                                                                                                                     
2   513  26 ASSOCIATION OF SEROTONIN TRANSPORTER GENE ALUJB METHYLATION WITH MAJOR DEPRESSION, AMYGDALA RESPONSIVENESS, 5-HTTLPR/RS25531 POLYMORPHISM, AND STRESS. DNA METHYLATION PROFILES OF THE SEROTONIN TRANSPORTER GENE (SLC6A4) HAVE BEEN SHOWN TO ALTER SLC6A4 EXPRESSION, DRIVE ANTIDEPRESSANT TREATMENT RESPONSE AND MODIFY BRAIN FUNCTIONS. THIS STUDY INVESTIGATED WHETHER METHYLATION OF AN ALUJB ELEMENT IN THE SLC6A4 PROMOTOR WAS ASSOCIATED WITH MAJOR DEPRESSIVE DISORDER (MDD), AMYGDALA REACTIVITY TO EMOTIONAL FACES, 5-HTTLPR/RS25531 POLYMORPHISM, AND RECENT STRESS. MDD PATIENTS (N=122) AND HEALTHY CONTROLS (HC, N=176) UNDERWENT FMRI DURING AN EMOTIONAL FACE-MATCHING TASK. INDIVIDUAL SLC6A4 ALUJB METHYLATION PROFILES WERE ASCERTAINED AND ASSOCIATED WITH MDD, AMYGDALA REACTIVITY, 5-HTTLPR/RS25531, AND STRESS. SLC6A4 ALUJB METHYLATION WAS SIGNIFICANTLY LOWER IN MDD COMPARED TO HC AND IN STRESSED COMPARED TO LESS STRESSED PARTICIPANTS. LOWER ALUJB METHYLATION WAS PARTICULARLY FOUND IN 5-HTTLPR/RS25531 RISK ALLELE CARRIERS UNDER STRESS AND CORRELATED WITH LESS DEPRESSIVE EPISODES. FMRI ANALYSIS REVEALED A SIGNIFICANT INTERACTION OF ALUJB METHYLATION AND DIAGNOSIS IN THE AMYGDALA, WITH MDD PATIENTS SHOWING LOWER ALUJB METHYLATION ASSOCIATED WITH DECREASED AMYGDALA REACTIVITY. WHILE NO JOINT EFFECT OF ALUJB METHYLATION AND 5-HTTLPR/RS25531 EXISTED, RISK ALLELE CARRIERS SHOWED SIGNIFICANTLY INCREASED BILATERAL AMYGDALA ACTIVATION. THESE FINDINGS SUGGEST A ROLE OF SLC6A4 ALUJB METHYLATION IN MDD, AMYGDALA REACTIVITY, AND STRESS REACTION, PARTLY INTERWOVEN WITH 5-HTTLPR/RS25531 EFFECTS. PATIENTS WITH LOW METHYLATION IN CONJUNCTION WITH A SHORTER MDD HISTORY AND DECREASED AMYGDALA REACTIVITY MIGHT FEATURE A MORE STRESS-ADAPTIVE EPIGENETIC PROCESS, MAYBE VIA THEORETICALLY POSSIBLE ENDOGENOUS ANTIDEPRESSANT-LIKE EFFECTS. IN CONTRAST, PATIENTS WITH HIGHER METHYLATION MIGHT POSSIBLY SUFFER FROM IMPAIRED EPIGENETIC ADAPTION TO CHRONIC STRESS. FURTHER, THE 5-HTTLPR/RS25531 ASSOCIATION WITH AMYGDALA ACTIVATION WAS CONFIRMED IN OUR LARGE SAMPLE.	2018	
                                                                                                                                                                                                                                                         
3  2985  32 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	
                                                                                                                                                                                                                                                                               
4  2641  29 EPIGENOMIC AND TRANSCRIPTOMIC ANALYSES REVEAL DIFFERENCES BETWEEN LOW-GRADE INFLAMMATION AND SEVERE EXHAUSTION IN LPS-CHALLENGED MURINE MONOCYTES. EMERGING STUDIES SUGGEST THAT MONOCYTES CAN BE TRAINED BY BACTERIAL ENDOTOXIN TO ADOPT DISTINCT MEMORY STATES RANGING FROM LOW-GRADE INFLAMMATION TO IMMUNE EXHAUSTION. WHILE LOW-GRADE INFLAMMATION MAY CONTRIBUTE TO THE PATHOGENESIS OF CHRONIC DISEASES, EXHAUSTED MONOCYTES WITH PATHOGENIC AND IMMUNE-SUPPRESSIVE CHARACTERISTICS MAY UNDERLIE THE PATHOGENESIS OF POLYMICROBIAL SEPSIS INCLUDING COVID-19. HOWEVER, DETAILED PROCESSES BY WHICH THE DYNAMIC ADAPTION OF MONOCYTES OCCUR REMAIN POORLY UNDERSTOOD. HERE WE EXPOSED MURINE BONE-MARROW DERIVED MONOCYTES TO CHRONIC LIPOPOLYSACCHARIDE (LPS) STIMULATION AT LOW-DOSE OR HIGH-DOSE, AS WELL AS A PBS CONTROL. THE CELLS WERE PROFILED FOR GENOME-WIDE H3K27AC MODIFICATION AND GENE EXPRESSION. THE GENE EXPRESSION OF TRAM-DEFICIENT AND IRAK-M-DEFICIENT MONOCYTES WITH LPS EXPOSURE WAS ALSO ANALYZED. WE DISCOVER THAT LOW-GRADE INFLAMMATION PREFERENTIALLY UTILIZES THE TRAM-DEPENDENT PATHWAY OF TLR4 SIGNALING, AND INDUCES THE EXPRESSION OF INTERFERON RESPONSE GENES. IN CONTRAST, HIGH DOSE LPS UNIQUELY UPREGULATES EXHAUSTION SIGNATURES WITH METABOLIC AND PROLIFERATIVE PATHWAYS. THE EXTENSIVE DIFFERENCES IN THE EPIGENOMIC LANDSCAPE BETWEEN LOW-DOSE AND HIGH-DOSE CONDITIONS SUGGEST THE IMPORTANCE OF EPIGENETIC REGULATIONS IN DRIVING DIFFERENTIAL RESPONSES. OUR DATA PROVIDE POTENTIAL TARGETS FOR FUTURE MECHANISTIC OR THERAPEUTIC STUDIES.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
5  4185  24 METABOLIC ADAPTIONS/REPROGRAMMING IN ISLET BETA-CELLS IN RESPONSE TO PHYSIOLOGICAL STIMULATORS-WHAT ARE THE CONSEQUENCES. IRREVERSIBLE PANCREATIC BETA-CELL DAMAGE MAY BE A RESULT OF CHRONIC EXPOSURE TO SUPRAPHYSIOLOGICAL GLUCOSE OR LIPID CONCENTRATIONS OR CHRONIC EXPOSURE TO THERAPEUTIC ANTI-DIABETIC DRUGS. THE BETA-CELLS ARE ABLE TO RESPOND TO BLOOD GLUCOSE IN A NARROW CONCENTRATION RANGE AND RELEASE INSULIN IN RESPONSE, FOLLOWING ACTIVATION OF METABOLIC PATHWAYS SUCH AS GLYCOLYSIS AND THE TCA CYCLE. THE BETA-CELL CANNOT PROTECT ITSELF FROM GLUCOSE TOXICITY BY BLOCKING GLUCOSE UPTAKE, BUT INDEED RELIES ON ALTERNATIVE METABOLIC PROTECTION MECHANISMS TO AVOID DYSFUNCTION AND DEATH. ALTERATION OF NORMAL METABOLIC PATHWAY FUNCTION OCCURS AS A COUNTER REGULATORY RESPONSE TO HIGH NUTRIENT, INFLAMMATORY FACTOR, HORMONE OR THERAPEUTIC DRUG CONCENTRATIONS. METABOLIC REPROGRAMMING IS A TERM WIDELY USED TO DESCRIBE A CHANGE IN REGULATION OF VARIOUS METABOLIC ENZYMES AND TRANSPORTERS, USUALLY ASSOCIATED WITH CELL GROWTH AND PROLIFERATION AND MAY INVOLVE RESHAPING EPIGENETIC RESPONSES, IN PARTICULAR THE ACETYLATION AND METHYLATION OF HISTONE PROTEINS AND DNA. OTHER METABOLIC MODIFICATIONS SUCH AS MALONYLATION, SUCCINYLATION, HYDROXYBUTYRYLATION, ADP-RIBOSYLATION, AND LACTYLATION, MAY IMPACT REGULATORY PROCESSES, MANY OF WHICH NEED TO BE INVESTIGATED IN DETAIL TO CONTRIBUTE TO CURRENT ADVANCES IN METABOLISM. BY DESCRIBING MULTIPLE MECHANISMS OF METABOLIC ADAPTION THAT ARE AVAILABLE TO THE BETA-CELL ACROSS ITS LIFESPAN, WE HOPE TO IDENTIFY SITES FOR METABOLIC REPROGRAMMING MECHANISMS, MOST OF WHICH ARE INCOMPLETELY DESCRIBED OR UNDERSTOOD. MANY OF THESE MECHANISMS ARE RELATED TO PROMINENT ANTIOXIDANT RESPONSES. HERE, WE HAVE ATTEMPTED TO DESCRIBE THE KEY BETA-CELL METABOLIC ADAPTIONS AND CHANGES WHICH ARE REQUIRED FOR SURVIVAL AND FUNCTION IN VARIOUS PHYSIOLOGICAL, PATHOLOGICAL AND PHARMACOLOGICAL CONDITIONS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                    
6  6704  26 VHL GENE METHYLATION CONTRIBUTES TO EXCESSIVE ERYTHROCYTOSIS IN CHRONIC MOUNTAIN SICKNESS RAT MODEL BY UPREGULATING THE HIF-2ALPHA/EPO PATHWAY. AIMS: HYPOXIA-INDUCIBLE FACTORS (HIFS) PLAY IMPORTANT ROLES IN THE PATHOGENESIS OF ERYTHROCYTOSIS IN CHRONIC MOUNTAIN SICKNESS (CMS). VON HIPPEL-LINDAU (VHL) IS A KEY REGULATOR OF HYPOXIA THAT CAN DIRECT THE POLY-UBIQUITYLATION AND DEGRADATION OF HIFS. EPIGENETIC MECHANISMS ARE BELIEVED TO CONTRIBUTE TOWARD ADAPTION TO CHRONIC HYPOXIA. HERE, WE INVESTIGATED THE CONTRIBUTION AND MECHANISM OF VHL METHYLATION IN RATS WITH ERYTHROCYTOSIS IN CMS. MAIN METHODS: THE METHYLATION STATUS OF VHL WAS MEASURED VIA BISULFITE SEQUENCING PCR, WHILE VHL, DNMT1, DNMT3ALPHA, AND DNMT3BETA EXPRESSION WERE ASSESSED USING REAL-TIME REVERSE TRANSCRIPTION PCR AND WESTERN BLOTTING. HIF-2ALPHA AND EPO EXPRESSION LEVELS IN BONE MARROW WERE DETERMINED VIA IMMUNOHISTOCHEMICAL STAINING, AND ERYTHROID HYPERPLASIA IN BONE MARROW SECTIONS WERE OBSERVED WITH HEMATOXYLIN AND EOSIN STAINING. KEY FINDINGS: WE FOUND THAT CHRONIC HYPOXIA TRIGGERED ERYTHROID HYPERPLASIA IN THE BONE MARROW AND INCREASED THE QUANTITY OF PERIPHERAL RED BLOOD CELLS IN CMS RATS. CHRONIC HYPOXIA SIGNIFICANTLY INDUCED METHYLATION AT THE CPG SITE IN THE VHL PROMOTER, DECREASED VHL EXPRESSION, AND INCREASED HIF-2ALPHA AND EPO EXPRESSION. CHRONIC HYPOXIA INCREASED DNMT3ALPHA AND DNMT3BETA EXPRESSION, CONSISTENT WITH THE DECREASE IN VHL EXPRESSION. THE DNA METHYLTRANSFERASE INHIBITOR 5-AZACYTIDINE REDUCED CHRONIC HYPOXIA-INDUCED ERYTHROID PROLIFERATION IN THE BONE MARROW OF RATS WITH CMS BY SUPPRESSING VHL METHYLATION AND DNMTS EXPRESSION. SIGNIFICANCE: OUR STUDY SUGGESTS THAT VHL METHYLATION CONTRIBUTES TOWARD EXCESSIVE ERYTHROCYTOSIS IN CMS BY UPREGULATING THE HIF-2ALPHA/EPO PATHWAY IN THE BONE MARROW OF RATS. WE DEMONSTRATED THAT THE DNMT INHIBITOR 5-AZACYTIDINE CAN ATTENUATE ERYTHROID HYPERPLASIA IN THE BONE MARROW BY DEMETHYLATING THE VHL PROMOTER.	2021	
                                                                                                                                                                                                                                                                                                                                                   
7  6467  27 TISSUE-SPECIFIC EFFECTS OF EXERCISE AS NAD(+) -BOOSTING STRATEGY: CURRENT KNOWLEDGE AND FUTURE PERSPECTIVES. NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD(+) ) IS AN EVOLUTIONARILY HIGHLY CONSERVED COENZYME WITH MULTI-FACETED CELL FUNCTIONS, INCLUDING ENERGY METABOLISM, MOLECULAR SIGNALING PROCESSES, EPIGENETIC REGULATION, AND DNA REPAIR. SINCE THE DISCOVERY THAT LOWER NAD(+) LEVELS ARE A SHARED CHARACTERISTIC OF VARIOUS DISEASES AND AGING PER SE, SEVERAL NAD(+) -BOOSTING STRATEGIES HAVE EMERGED. OTHER THAN PHARMACOLOGICAL AND NUTRITIONAL APPROACHES, EXERCISE IS THOUGHT TO RESTORE NAD(+) HOMEOSTASIS THROUGH METABOLIC ADAPTION TO CHRONICALLY RECURRING STATES OF INCREASED ENERGY DEMAND. IN THIS REVIEW WE DISCUSS THE IMPACT OF ACUTE EXERCISE AND EXERCISE TRAINING ON TISSUE-SPECIFIC NAD(+) METABOLISM OF RODENTS AND HUMANS TO HIGHLIGHT THE POTENTIAL VALUE AS NAD(+) -BOOSTING STRATEGY. BY INTERCONNECTING RESULTS FROM DIFFERENT INVESTIGATIONS, WE AIM TO DRAW ATTENTION TO TISSUE-SPECIFIC ALTERATIONS IN NAD(+) METABOLISM AND THE ASSOCIATED IMPLICATIONS FOR WHOLE-BODY NAD(+) HOMEOSTASIS. ACUTE EXERCISE LED TO PROFOUND ALTERATIONS OF INTRACELLULAR NAD(+) METABOLISM IN VARIOUS INVESTIGATIONS, WITH THE MAGNITUDE AND DIRECTION OF CHANGES BEING STRONGLY DEPENDENT ON THE APPLIED EXERCISE MODALITY, CELL TYPE, AND INVESTIGATED ANIMAL MODEL OR HUMAN POPULATION. EXERCISE TRAINING ELEVATED NAD(+) LEVELS AND NAD(+) METABOLISM ENZYMES IN VARIOUS TISSUES. BASED ON THESE RESULTS, WE DISCUSS MOLECULAR MECHANISMS THAT MIGHT CONNECT ACUTE EXERCISE-INDUCED DISRUPTIONS OF NAD(+) /NADH HOMEOSTASIS TO CHRONIC EXERCISE ADAPTIONS IN NAD(+) METABOLISM. TAKING THIS HYPOTHESIS-DRIVEN APPROACH, WE HOPE TO INSPIRE FUTURE RESEARCH ON THE MOLECULAR MECHANISMS OF EXERCISE AS NAD(+) -MODIFYING LIFESTYLE INTERVENTION, THEREBY ELUCIDATING THE POTENTIAL THERAPEUTIC VALUE IN NAD(+) -RELATED PATHOLOGIES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                  
8  5839  32 STROKE RECOVERY ENHANCING THERAPIES: LESSONS FROM RECENT CLINICAL TRIALS. POSTSTROKE RECOVERY PROCESSES INCLUDE RESTORATION OR COMPENSATION OF FUNCTION, RESPECTIVELY FUNCTIONS INITIALLY LOST OR NEW FUNCTIONS ACQUIRED AFTER AN INJURY. THERAPEUTIC INTERVENTIONS CAN ENHANCE THESE PROCESSES AND/OR REDUCE PROCESSES IMPEDING REGENERATION. NUMEROUS EXPERIMENTAL STUDIES SUGGEST GREAT OPPORTUNITIES FOR SUCH TREATMENTS, BUT THE RESULTS FROM RECENT LARGE CLINICAL TRIALS USING NEUROMODULATORS SUCH AS DOPAMINE AND FLUOXETINE ARE DISAPPOINTING. THE REASONS FOR THIS ARE MANIFOLD AFFECTING FORWARD TRANSLATION OF RESULTS FROM ANIMALS MODELS INTO THE HUMAN SITUATION. THIS "TRANSLATIONAL ROAD BLOCK" IS DEFINED BY DIFFERENCES BETWEEN ANIMALS AND HUMANS WITH REGARD TO THE GENETIC AND EPIGENETIC BACKGROUND, SIZE AND ANATOMY OF THE BRAIN, CEREBRAL VASCULAR ANATOMY, IMMUNE SYSTEM, AS WELL AS CLINICAL FUNCTION AND BEHAVIOR. BACKWARD BLOCKADE INCLUDES THE INCOMPATIBLE ADAPTION OF TARGETS AND OUTCOMES IN CLINICAL TRIALS WITH REGARD TO PRIOR PRECLINICAL FINDINGS. FOR EXAMPLE, THE DESIGN OF CLINICAL RECOVERY TRIALS VARIES WIDELY AND WAS CHARACTERIZED BY THE SELECTION OF DIFFERENT CLINICAL ENDPOINTS, THE INCLUSION A BROAD SPECTRUM OF STROKE SUBTYPES AND CLINICAL SYNDROMES AS WELL AS DIFFERENT TIME WINDOWS FOR TREATMENT INITIATION AFTER INFARCT ONSET. THIS REVIEW WILL DISCUSS THESE ASPECTS BASED ON THE RESULTS OF THE RECENT STROKE RECOVERY TRIALS WITH THE GOAL TO CONTRIBUTE TO THE CURRENTLY BIGGEST UNMET NEED IN STROKE RESEARCH - THE DEVELOPMENT OF A RECOVERY ENHANCING THERAPY THAT IMPROVES THE FUNCTIONAL OUTCOME OF A CHRONIC STROKE PATIENT.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
9  2540  26 EPIGENETICS IN IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A LETHAL CHRONIC LUNG DISORDER WITH NO EFFECTIVE TREATMENT AND A PROGNOSIS WORSE THAN THAT OF LUNG CANCER. DESPITE EXTENSIVE RESEARCH EFFORTS, ITS ETIOLOGY AND PATHOGENESIS STILL REMAIN LARGELY UNKNOWN. CURRENT EXPERIMENTAL EVIDENCE HAS SHIFTED THE DISEASE PARADIGM FROM CHRONIC INFLAMMATION TOWARDS THE PREMISE OF ABNORMAL EPITHELIAL WOUND REPAIR IN RESPONSE TO REPEATED EPIGENETIC INJURIOUS STIMULI IN GENETICALLY PREDISPOSED INDIVIDUALS. EPIGENETICS IS DEFINED AS THE STUDY OF HERITABLE CHANGES IN GENE FUNCTION BY FACTORS OTHER THAN AN INDIVIDUAL'S DNA SEQUENCE, PROVIDING VALUABLE INFORMATION REGARDING ADAPTION OF GENES TO ENVIRONMENTAL CHANGES. ALTHOUGH CANCER IS THE MOST STUDIED DISEASE WITH RELEVANCE TO EPIGENETIC MODIFICATIONS, RECENT DATA SUPPORT THE IDEA THAT EPIGENOMIC ALTERATIONS MAY LEAD TO VARIABLE DISEASE PHENOTYPES, INCLUDING FIBROPROLIFERATIVE LUNG DISORDERS SUCH AS IPF. THIS REVIEW ARTICLE SUMMARIZES THE LATEST EXPERIMENTAL AND TRANSLATIONAL EPIGENETIC STUDIES IN THE RESEARCH FIELD OF CHRONIC LUNG DISORDERS, MAINLY FOCUSING ON IPF, HIGHLIGHTS CURRENT METHODOLOGY LIMITATIONS, AND UNDERLINES FUTURE DIRECTIONS AND PERSPECTIVES.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
10  4015  31 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
11  2711  21 EXERCISE TRAINING ALTERS THE GENOMIC RESPONSE TO ACUTE EXERCISE IN HUMAN ADIPOSE TISSUE. AIM: TO DETERMINE THE GENOMIC MECHANISMS BY WHICH ADIPOSE TISSUE RESPONDS TO ACUTE AND CHRONIC EXERCISE. METHODS: WE PROFILED THE TRANSCRIPTOMIC AND EPIGENETIC RESPONSE TO ACUTE EXERCISE IN HUMAN ADIPOSE TISSUE COLLECTED BEFORE AND AFTER ENDURANCE TRAINING. RESULTS: ALTHOUGH ACUTE EXERCISES WERE PERFORMED AT SAME RELATIVE INTENSITIES, THE MAGNITUDE OF TRANSCRIPTOMIC CHANGES AFTER ACUTE EXERCISE WAS REDUCED BY ENDURANCE TRAINING. DNA METHYLATION REMODELING INDUCED BY ACUTE EXERCISE WAS MORE PROMINENT IN TRAINED VERSUS UNTRAINED STATE. WE FOUND AN OVERLAP BETWEEN GENE EXPRESSION AND DNA METHYLATION CHANGES AFTER ACUTE EXERCISE FOR 32 GENES PRE-TRAINING AND SIX POST-TRAINING, NOTABLY AT ADIPOCYTE-SPECIFIC GENES. CONCLUSION: TRAINING STATUS DIFFERENTIALLY AFFECTS THE EPIGENETIC AND TRANSCRIPTOMIC RESPONSE TO ACUTE EXERCISE IN HUMAN ADIPOSE TISSUE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
12   169  32 ABNORMALITIES OF AMPK ACTIVATION AND GLUCOSE UPTAKE IN CULTURED SKELETAL MUSCLE CELLS FROM INDIVIDUALS WITH CHRONIC FATIGUE SYNDROME. BACKGROUND: POST EXERTIONAL MUSCLE FATIGUE IS A KEY FEATURE IN CHRONIC FATIGUE SYNDROME (CFS). ABNORMALITIES OF SKELETAL MUSCLE FUNCTION HAVE BEEN IDENTIFIED IN SOME BUT NOT ALL PATIENTS WITH CFS. TO TRY TO LIMIT POTENTIAL CONFOUNDERS THAT MIGHT CONTRIBUTE TO THIS CLINICAL HETEROGENEITY, WE DEVELOPED A NOVEL IN VITRO SYSTEM THAT ALLOWS COMPARISON OF AMP KINASE (AMPK) ACTIVATION AND METABOLIC RESPONSES TO EXERCISE IN CULTURED SKELETAL MUSCLE CELLS FROM CFS PATIENTS AND CONTROL SUBJECTS. METHODS: SKELETAL MUSCLE CELL CULTURES WERE ESTABLISHED FROM 10 SUBJECTS WITH CFS AND 7 AGE-MATCHED CONTROLS, SUBJECTED TO ELECTRICAL PULSE STIMULATION (EPS) FOR UP TO 24H AND EXAMINED FOR CHANGES ASSOCIATED WITH EXERCISE. RESULTS: IN THE BASAL STATE, CFS CULTURES SHOWED INCREASED MYOGENIN EXPRESSION BUT DECREASED IL6 SECRETION DURING DIFFERENTIATION COMPARED WITH CONTROL CULTURES. CONTROL CULTURES SUBJECTED TO 16 H EPS SHOWED A SIGNIFICANT INCREASE IN BOTH AMPK PHOSPHORYLATION AND GLUCOSE UPTAKE COMPARED WITH UNSTIMULATED CELLS. IN CONTRAST, CFS CULTURES SHOWED NO INCREASE IN AMPK PHOSPHORYLATION OR GLUCOSE UPTAKE AFTER 16 H EPS. HOWEVER, GLUCOSE UPTAKE REMAINED RESPONSIVE TO INSULIN IN THE CFS CELLS POINTING TO AN EXERCISE-RELATED DEFECT. IL6 SECRETION IN RESPONSE TO EPS WAS SIGNIFICANTLY REDUCED IN CFS COMPARED WITH CONTROL CULTURES AT ALL TIME POINTS MEASURED. CONCLUSION: EPS IS AN EFFECTIVE MODEL FOR ELICITING MUSCLE CONTRACTION AND THE METABOLIC CHANGES ASSOCIATED WITH EXERCISE IN CULTURED SKELETAL MUSCLE CELLS. WE FOUND FOUR MAIN DIFFERENCES IN CULTURED SKELETAL MUSCLE CELLS FROM SUBJECTS WITH CFS; INCREASED MYOGENIN EXPRESSION IN THE BASAL STATE, IMPAIRED ACTIVATION OF AMPK, IMPAIRED STIMULATION OF GLUCOSE UPTAKE AND DIMINISHED RELEASE OF IL6. THE RETENTION OF THESE DIFFERENCES IN CULTURED MUSCLE CELLS FROM CFS SUBJECTS POINTS TO A GENETIC/EPIGENETIC MECHANISM, AND PROVIDES A SYSTEM TO IDENTIFY NOVEL THERAPEUTIC TARGETS.	2015	
                                                                                                                                                                                                                              
13   287  32 AGING AND CHRONIC SUN EXPOSURE CAUSE DISTINCT EPIGENETIC CHANGES IN HUMAN SKIN. EPIGENETIC CHANGES ARE WIDELY CONSIDERED TO PLAY AN IMPORTANT ROLE IN AGING, BUT EXPERIMENTAL EVIDENCE TO SUPPORT THIS HYPOTHESIS HAS BEEN SCARCE. WE HAVE USED ARRAY-BASED ANALYSIS TO DETERMINE GENOME-SCALE DNA METHYLATION PATTERNS FROM HUMAN SKIN SAMPLES AND TO INVESTIGATE THE EFFECTS OF AGING, CHRONIC SUN EXPOSURE, AND TISSUE VARIATION. OUR RESULTS REVEAL A HIGH DEGREE OF TISSUE SPECIFICITY IN THE METHYLATION PATTERNS AND ALSO SHOWED VERY LITTLE INTERINDIVIDUAL VARIATION WITHIN TISSUES. DATA STRATIFICATION BY AGE REVEALED THAT DNA FROM OLDER INDIVIDUALS WAS CHARACTERIZED BY A SPECIFIC HYPERMETHYLATION PATTERN AFFECTING LESS THAN 1% OF THE MARKERS ANALYZED. INTERESTINGLY, STRATIFICATION BY SUN EXPOSURE PRODUCED A FUNDAMENTALLY DIFFERENT PATTERN WITH A SIGNIFICANT TREND TOWARDS HYPOMETHYLATION. OUR RESULTS THUS IDENTIFY DEFINED AGE-RELATED DNA METHYLATION CHANGES AND SUGGEST THAT THESE ALTERATIONS MIGHT CONTRIBUTE TO THE PHENOTYPIC CHANGES ASSOCIATED WITH SKIN AGING.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
14  4947  44 PATERNAL SEPSIS INDUCES ALTERATIONS OF THE SPERM METHYLOME AND DAMPENS OFFSPRING IMMUNE RESPONSES-AN ANIMAL STUDY. BACKGROUND: SEPSIS REPRESENTS THE UTMOST SEVERE CONSEQUENCE OF INFECTION, INVOLVING A DYSREGULATED AND SELF-DAMAGING IMMUNE RESPONSE OF THE HOST. WHILE DIFFERENT ENVIRONMENTAL EXPOSURES LIKE CHRONIC STRESS OR MALNUTRITION HAVE BEEN WELL DESCRIBED TO REPROGRAM THE GERMLINE AND SUBSEQUENTLY OFFSPRING ATTRIBUTES, THE INTERGENERATIONAL IMPACT OF SEPSIS AS A TREMENDOUS IMMUNOLOGICAL STRESSOR HAS NOT BEEN EXAMINED YET. METHODS: POLYMICROBIAL SEPSIS IN 12-WEEK-OLD MALE C57BL/6 MICE WAS INDUCED BY CECAL LIGATION AND PUNCTURE (CLP), FOLLOWED BY A MATING OF THE MALE SURVIVORS (OR APPROPRIATE SHAM CONTROL ANIMALS) 6 WEEKS LATER WITH HEALTHY FEMALES. ALVEOLAR MACROPHAGES OF OFFSPRING ANIMALS WERE ISOLATED AND STIMULATED WITH EITHER LPS OR ZYMOSAN, AND SUPERNATANT LEVELS OF TNF-ALPHA WERE QUANTIFIED BY ELISA. FURTHERMORE, SYSTEMIC CYTOKINE RESPONSE TO INTRAPERITONEALLY INJECTED LPS WAS ASSESSED AFTER 24 H. ALSO, MORPHOLOGY, MOTILITY, AND GLOBAL DNA METHYLATION OF THE SEPSIS SURVIVORS' SPERM WAS EXAMINED. RESULTS: COMPARATIVE REDUCED REDUCTION BISULFITE SEQUENCING (RRBS) OF SPERM REVEALED CHANGES OF DNA METHYLATION (N = 381), MOST PRONOUNCED IN THE INTERGENIC GENOME AS WELL AS WITHIN INTRONS OF DEVELOPMENTALLY RELEVANT GENES. OFFSPRING OF SEPSIS FATHERS EXHIBITED A SLIGHT DECREASE IN BODY WEIGHT, WITH A MORE PRONOUNCED WEIGHT DIFFERENCE IN MALE ANIMALS (CLP VS. SHAM). MALE DESCENDANTS OF SEPSIS FATHERS, BUT NOT FEMALE DESCENDANTS, EXHIBITED LOWER PLASMA CONCENTRATIONS OF IL-6, TNF-ALPHA, AND IL-10 24 H AFTER INJECTION OF LPS. IN LINE, ONLY ALVEOLAR MACROPHAGES OF MALE DESCENDANTS OF SEPSIS FATHERS PRODUCED LESS TNF-ALPHA UPON ZYMOSAN STIMULATION COMPARED TO SHAM DESCENDANTS, WHILE LPS RESPONSES KEPT UNCHANGED. CONCLUSION: WE CAN PROVE THAT MALE-BUT SURPRISINGLY NOT FEMALE-DESCENDANTS OF POST-SEPSIS FATHERS SHOW A DAMPENED SYSTEMIC AS WELL AS PULMONARY IMMUNE RESPONSE. BASED ON THIS OBSERVATION OF AN IMMUNE HYPO-RESPONSIVITY, WE PROPOSE THAT MALE DESCENDANTS OF SEPSIS FATHERS ARE AT RISK TO DEVELOP FUNGAL AND BACTERIAL INFECTIONS AND MIGHT BENEFIT FROM THERAPEUTIC IMMUNE MODULATION.	2018	
                                                                                
15  1009  38 CHRONIC VOLUNTARY ETHANOL DRINKING IN CYNOMOLGUS MACAQUES ELICITS GENE EXPRESSION CHANGES IN PREFRONTAL CORTICAL AREA 46. BACKGROUND: GENOME-WIDE PROFILING TO EXAMINE BRAIN TRANSCRIPTIONAL FEATURES ASSOCIATED WITH EXCESSIVE ETHANOL (ETOH) CONSUMPTION HAS BEEN APPLIED TO A VARIETY OF SPECIES INCLUDING RODENTS, NONHUMAN PRIMATES (NHPS), AND HUMANS. HOWEVER, THESE DATA WERE OBTAINED FROM CROSS-SECTIONAL SAMPLES WHICH ARE PARTICULARLY VULNERABLE TO INDIVIDUAL VARIATION WHEN OBTAINED FROM SMALL OUTBRED POPULATIONS TYPICAL OF HUMAN AND NHP STUDIES. IN THE CURRENT STUDY, A NOVEL WITHIN-SUBJECT DESIGN WAS USED TO EXAMINE THE EFFECTS OF VOLUNTARY ETOH CONSUMPTION ON PREFRONTAL CORTEX (PFC) GENE EXPRESSION IN A NHP MODEL. METHODS: TWO COHORTS OF CYNOMOLGUS MACAQUES (N = 23) UNDERWENT A SCHEDULE-INDUCED POLYDIPSIA PROCEDURE TO ESTABLISH ETOH SELF-ADMINISTRATION FOLLOWED BY 6 MONTHS OF DAILY OPEN ACCESS TO ETOH (4% W/V) AND WATER. INDIVIDUAL DAILY ETOH INTAKES RANGED FROM AN AVERAGE OF 0.7 TO 3.7 G/KG/D. DORSAL LATERAL PFC AREA 46 (A46) BRAIN BIOPSIES WERE COLLECTED IN ETOH-NAIVE AND CONTROL MONKEYS; CONTRALATERAL A46 BIOPSIES WERE COLLECTED FROM THE SAME MONKEYS FOLLOWING THE 6 MONTHS OF FLUID CONSUMPTION. GENE EXPRESSION CHANGES WERE ASSESSED USING RNA-SEQ PAIRED ANALYSIS, WHICH ALLOWED FOR CORRECTION OF INDIVIDUAL BASELINE DIFFERENCES IN GENE EXPRESSION. RESULTS: A TOTAL OF 675 GENES WERE SIGNIFICANTLY DOWN-REGULATED FOLLOWING ETOH CONSUMPTION; THESE WERE FUNCTIONALLY ENRICHED FOR IMMUNE RESPONSE, CELL ADHESION, PLASMA MEMBRANE, AND EXTRACELLULAR MATRIX. A TOTAL OF 567 GENES THAT WERE UP-REGULATED FOLLOWING ETOH CONSUMPTION WERE ENRICHED IN MICRORNA TARGET SITES AND INCLUDED TARGET SITES ASSOCIATED WITH TOLL-LIKE RECEPTOR PATHWAYS. THE DIFFERENTIALLY EXPRESSED GENES WERE ALSO SIGNIFICANTLY ENRICHED IN TRANSCRIPTION FACTOR BINDING SITES. CONCLUSIONS: THE DATA PRESENTED HERE ARE THE FIRST TO USE A LONGITUDINAL BIOPSY STRATEGY TO EXAMINE HOW CHRONIC ETOH CONSUMPTION AFFECTS GENE EXPRESSION IN THE PRIMATE PFC. PROMINENT EFFECTS WERE SEEN IN BOTH CELL ADHESION AND NEUROIMMUNE PATHWAYS; THE LATTER CONTAINED BOTH PRO- AND ANTIINFLAMMATORY GENES. THE DATA ALSO INDICATE THAT CHANGES IN MIRNAS AND TRANSCRIPTION FACTORS MAY BE IMPORTANT EPIGENETIC REGULATORS OF ETOH CONSUMPTION.	2020	

16  4252  25 METHYLOME CHANGES ASSOCIATED WITH FUNCTIONAL MOVEMENT/CONVERSION DISORDER: INFLUENCE OF BIOLOGICAL SEX AND CHILDHOOD ABUSE EXPOSURE. EPIGENETIC CHANGES, SUCH AS DNA METHYLATION (DNAM), MAY REPRESENT AN IMPORTANT MECHANISM IMPLICATED IN THE ETIOPATHOGENESIS OF FUNCTIONAL MOVEMENT/CONVERSION DISORDER (FMD). HERE, WE AIMED TO IDENTIFY METHYLOMIC VARIATIONS IN A CASE-CONTROL COHORT OF FMD AND TO UNCOVER SPECIFIC EPIGENETIC SIGNATURES ASSOCIATED WITH FEMALE SEX AND CHILDHOOD ABUSE, TWO KEY RISK FACTORS FOR FMD AND OTHER FUNCTIONAL NEUROLOGICAL DISORDERS. GENOME-WIDE DNAM ANALYSIS WAS PERFORMED FROM PERIPHERAL BLOOD IN 57 PATIENTS WITH FMD AND 47 HEALTHY CONTROLS WITH AND WITHOUT CHILDHOOD ABUSE. USING PRINCIPAL COMPONENT ANALYSIS, WE EXAMINED THE ASSOCIATION OF PRINCIPAL COMPONENTS WITH FMD STATUS IN ABUSED AND NON-ABUSED INDIVIDUALS, IN THE ENTIRE STUDY SAMPLE AND IN FEMALE SUBJECTS ONLY. NEXT, WE USED ENRICHMENT PATHWAY ANALYSIS TO INVESTIGATE THE BIOLOGICAL SIGNIFICANCE OF DNAM CHANGES AND EXPLORED DIFFERENCES IN METHYLATION LEVELS OF GENES ANNOTATED TO THE TOP ENRICHED BIOLOGICAL PATHWAYS SHARED ACROSS COMPARISONS. WE FOUND THAT FMD WAS ASSOCIATED WITH DNAM VARIATION ACROSS THE GENOME AND IDENTIFIED A COMMON EPIGENETIC 'SIGNATURE' ENRICHED FOR BIOLOGICAL PATHWAYS IMPLICATED IN CHRONIC STRESS AND CHRONIC PAIN. HOWEVER, METHYLATION LEVELS OF GENES INCLUDED IN THE TOP TWO SHARED PATHWAYS HARDLY OVERLAPPED, SUGGESTING THAT TRANSCRIPTIONAL PROFILES MAY DIFFER AS A FUNCTION OF CHILDHOOD ABUSE EXPOSURE AND SEX AMONG SUBJECTS WITH FMD. THIS STUDY IS UNIQUE IN PROVIDING GENOME-WIDE EVIDENCE OF DNAM CHANGES IN FMD AND IN INDICATING A POTENTIAL MECHANISM LINKING CHILDHOOD ABUSE EXPOSURE AND FEMALE SEX TO DIFFERENCES IN FMD PATHOPHYSIOLOGY. FUTURE STUDIES ARE NEEDED TO REPLICATE OUR FINDINGS IN INDEPENDENT COHORTS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
17  5682  29 SHORT-TERM CHANGES IN GLOBAL METHYLATION AND HYDROXYMETHYLATION DURING ALCOHOL DETOXIFICATION. ALCOHOL DEPENDENCE IS A COMMON PUBLIC HEALTH PROBLEM AND EPIGENETICS MAY OFFER NEW ASPECTS IN UNDERSTANDING THE BIOLOGICAL AND GENETIC UNDERPINNINGS AND IMPROVE TREATMENT OF THIS COMPLEX DISEASE. SUPPOSEDLY, METHYLATION AND HYDROXYMETHYLATION ARE ALTERED IN BRAIN TISSUES AND IN SYNAPSE-RELATED GENES DUE TO CHRONIC ALCOHOL INTAKE AND DURING WITHDRAWAL. TO ASSESS POTENTIAL EPIGENETIC CHANGES AFTER CESSATION OF CHRONIC ALCOHOL INTAKE, WE COMPARED 23 ALCOHOL-DEPENDENT INDIVIDUALS DURING INPATIENT ALCOHOL DETOXIFICATION WITH 13 CAREFULLY MATCHED CONTROLS. BLOOD SAMPLES WERE TAKEN ON THE DAY OF ADMISSION, AFTER ONE AND AFTER TWO WEEKS AT THE END OF INPATIENT TREATMENT. GENOME-WIDE GLOBAL METHYLATION AND GLOBAL DNA HYDROXYMETHYLATION WERE COMPARED ACROSS GROUPS. THERE WERE SIGNIFICANT DIFFERENCES IN GLOBAL METHYLATION ACROSS TIME FROM ADMISSION TO ONE AND TWO WEEKS OF INPATIENT WITHDRAWAL (P < 0.001). THESE FINDINGS WERE PARALLELED TO CHANGES IN GLOBAL DNA HYDROXYMETHYLATION ACROSS TIME WHEN AGE WAS EMPLOYED AS A COFACTOR (P < 0.001). SEVERAL POTENTIALLY INFLUENCING VARIABLES LIKE SEVERITY OF WITHDRAWAL, DOSE OF WITHDRAWAL MEDICATION AND ALCOHOL INTAKE BEFORE ADMISSION DID NOT YIELD SIGNIFICANT INFLUENCE ON EPIGENETIC CHANGES. THE RESULTS CONFIRM PREVIOUS FINDINGS OF SIGNIFICANT ALTERATIONS OF EPIGENETIC PATTERNS DURING ALCOHOL INTOXICATION AND PRESENT FOR THE FIRST TIME HYDROXYMETHYLATION CHANGES IN THESE INDIVIDUALS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
18   524  28 ASSOCIATIONS OF BDNF GENOTYPE AND PROMOTER METHYLATION WITH ACUTE AND LONG-TERM STROKE OUTCOMES IN AN EAST ASIAN COHORT. BACKGROUND: BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) HAS BEEN SHOWN TO PLAY AN IMPORTANT ROLE IN POSTSTROKE RECOVERY. BDNF SECRETION IS INFLUENCED BY GENETIC AND EPIGENETIC PROFILES. THIS STUDY AIMED TO INVESTIGATE WHETHER BDNF VAL66MET POLYMORPHISM AND PROMOTER METHYLATION STATUS WERE ASSOCIATED WITH OUTCOMES AT TWO WEEKS AND ONE YEAR AFTER STROKE. METHODS AND FINDINGS: A TOTAL OF 286 PATIENTS WERE EVALUATED AT THE TIME OF ADMISSION AND TWO WEEKS AFTER STROKE, AND 222 (78%) WERE FOLLOWED ONE YEAR LATER IN ORDER TO EVALUATE CONSEQUENCES OF STROKE AT BOTH ACUTE AND CHRONIC STAGES. STROKE OUTCOMES WERE DICHOTOMISED INTO GOOD AND POOR BY THE MODIFIED RANKIN SCALE. STROKE SEVERITY (NATIONAL INSTITUTES OF HEALTH STROKE SCALE), PHYSICAL DISABILITY (BARTHEL INDEX), AND COGNITIVE FUNCTION (MINI-MENTAL STATE EXAMINATION) WERE MEASURED. ASSOCIATIONS OF BDNF GENOTYPE AND METHYLATION STATUS ON STROKE OUTCOMES AND ASSESSMENT SCALE SCORES WERE INVESTIGATED USING LOGISTIC REGRESSION, REPEATED MEASURES ANOVA AND PARTIAL CORRELATION TESTS. BDNF VAL66MET POLYMORPHISM WAS INDEPENDENTLY ASSOCIATED WITH POOR OUTCOME AT 2 WEEKS AND AT 1 YEAR, AND WITH WORSENING PHYSICAL DISABILITY AND COGNITIVE FUNCTION OVER THAT PERIOD. HIGHER BDNF PROMOTER METHYLATION STATUS WAS INDEPENDENTLY ASSOCIATED WITH WORSE OUTCOMES AT 1 YEAR, AND WITH THE WORSENING OF PHYSICAL DISABILITY AND COGNITIVE FUNCTION. NO SIGNIFICANT GENOTYPE-METHYLATION INTERACTIONS WERE FOUND. CONCLUSIONS: A ROLE FOR BDNF IN POSTSTROKE RECOVERY WAS SUPPORTED, AND CLINICAL UTILITY OF BDNF GENETIC AND EPIGENETIC PROFILE AS PROGNOSTIC BIOMARKERS AND A TARGET FOR DRUG DEVELOPMENT WAS SUGGESTED.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
19   228  36 ADAPTATION OF THE HUMAN POPULATION TO THE ENVIRONMENT: CURRENT KNOWLEDGE, CLUES FROM CZECH CYTOGENETIC AND "OMICS" BIOMONITORING STUDIES AND POSSIBLE MECHANISMS. THE HUMAN POPULATION IS CONTINUALLY EXPOSED TO NUMEROUS HARMFUL ENVIRONMENTAL STRESSORS, CAUSING NEGATIVE HEALTH EFFECTS AND/OR DEREGULATION OF BIOMARKER LEVELS. HOWEVER, STUDIES REPORTING NO OR EVEN POSITIVE IMPACTS OF SOME STRESSORS ON HUMANS ARE ALSO SOMETIMES PUBLISHED. THE MAIN AIM OF THIS REVIEW IS TO PROVIDE A COMPREHENSIVE OVERVIEW OF THE LAST DECADE OF CZECH BIOMONITORING RESEARCH, CONCERNING THE EFFECT OF VARIOUS LEVELS OF AIR POLLUTION (BENZO[A]PYRENE) AND RADIATION (URANIUM, X-RAY EXAMINATION AND NATURAL RADON BACKGROUND), ON THE DIFFERENTLY EXPOSED POPULATION GROUPS. BECAUSE SOME RESULTS OBTAINED FROM CYTOGENETIC STUDIES WERE OPPOSITE THAN HYPOTHESIZED, WE HAVE SEARCHED FOR A MEANINGFUL INTERPRETATION IN GENOMIC/EPIGENETIC STUDIES. A DETAILED ANALYSIS OF OUR DATA SUPPORTED BY THE STUDIES OF OTHERS AND CURRENT EPIGENETIC KNOWLEDGE, LEADS TO A HYPOTHESIS OF THE VERSATILE MECHANISM OF ADAPTATION TO ENVIRONMENTAL STRESSORS VIA DNA METHYLATION SETTINGS WHICH MAY EVEN ORIGINATE IN PRENATAL DEVELOPMENT, AND HELP TO REDUCE THE RESULTING DNA DAMAGE LEVELS. THIS HYPOTHESIS IS FULLY IN AGREEMENT WITH UNEXPECTED DATA FROM OUR STUDIES (E.G. LOWER LEVELS OF DNA DAMAGE IN SUBJECTS FROM HIGHLY POLLUTED REGIONS THAN IN CONTROLS OR IN SUBJECTS EXPOSED REPEATEDLY TO A POLLUTANT THAN IN THOSE WITHOUT PREVIOUS EXPOSURE), AND IS ALSO SUPPORTED BY DIFFERENCES IN DNA METHYLATION PATTERNS IN GROUPS FROM REGIONS WITH VARIOUS LEVELS OF POLLUTION. IN LIGHT OF THE ADAPTATION HYPOTHESIS, THE FOLLOWING POINTS MAY BE SUGGESTED FOR FUTURE RESEARCH: (I) THE CHRONIC AND ACUTE EXPOSURE OF STUDY SUBJECTS SHOULD BE DISTINGUISHED; (II) THE EXPOSURE HISTORY SHOULD BE MAPPED INCLUDING PLACE OF RESIDENCE DURING THE LIFE AND PRENATAL DEVELOPMENT; (III) CHANGES OF EPIGENETIC MARKERS SHOULD BE MONITORED OVER TIME. IN SUMMARY, INVESTIGATION OF HUMAN ADAPTATION TO THE ENVIRONMENT, ONE OF THE MOST IMPORTANT PROCESSES OF SURVIVAL, IS A NEW CHALLENGE FOR FUTURE RESEARCH IN THE FIELD OF HUMAN BIOMONITORING THAT MAY CHANGE OUR VIEW ON THE RESULTS OF BIOMARKER ANALYSES AND POTENTIAL NEGATIVE HEALTH IMPACTS OF THE ENVIRONMENT.	2017	
              
20  1058  27 CLINICAL MEASURES OF ALLOSTATIC LOAD IN CHILDREN AND ADOLESCENTS WITH FOOD ALLERGY, DEPRESSION, OR ANXIETY. PURPOSE: SUSTAINED HIGH STRESS EXPOSURE RESULTS IN CHRONIC ACTIVATION OF THE STRESS RESPONSE SYSTEM, DYSREGULATED STRESS RESPONSES, HIGH ALLOSTATIC LOAD, AND POOR LATER-LIFE HEALTH. CHILDREN AND ADOLESCENTS WITH CHRONIC HEALTH CONDITIONS FACE STRESSORS RELATED TO THEIR CONDITION IN ADDITION TO THOSE TYPICAL OF CHILDHOOD AND ADOLESCENCE, PLACING THEM AT RISK OF HIGH ALLOSTATIC LOAD. THE PURPOSE OF THIS SECONDARY ANALYSIS WAS TO EXAMINE WHETHER YOUTH WITH CHRONIC HEALTH CONDITIONS DIFFER FROM CONTROLS ON CLINICAL MEASURES OF ALLOSTATIC LOAD. DESIGN AND METHODS: A SECONDARY ANALYSIS OF TWO DATASETS, THE ELECTRONIC HEALTH RECORD OF A TERTIARY CHILDREN'S HOSPITAL AND DATA FROM THE SURVEY OF THE HEALTH OF WISCONSIN, COMPARED YOUTH WITH CHRONIC HEALTH CONDITIONS TO CONTROLS ON CLINICAL MEASURES OF ALLOSTATIC LOAD. ADDITIONAL ANALYSES EXPLORED WHETHER PARENTAL STRESS AND MENTAL HEALTH INFLUENCED THESE RELATIONSHIPS. RESULTS: ANALYSES IDENTIFIED DIFFERENCES IN BMI, BLOOD PRESSURE, AND WAIST CIRCUMFERENCE BETWEEN YOUTH WITH FOOD ALLERGY, ANXIETY, OR DEPRESSION, AND CONTROLS. THESE RELATIONSHIPS DIFFERED FOR MALES AND FEMALES AND FOR THOSE WITH COMORBID MENTAL AND PHYSICAL CONDITIONS, AND WERE INFLUENCED BY PARENT STRESS AND MENTAL HEALTH. CONCLUSIONS: RESULTS SUPPORT FUTURE STUDIES EXPLORING WHETHER HIGH STRESS IN YOUTH WITH CHRONIC HEALTH CONDITIONS LEADS TO INCREASED ALLOSTATIC LOAD. INCORPORATING BIOMARKERS AS WELL AS GENETIC AND EPIGENETIC FACTORS WILL PROVIDE CRITICAL INSIGHTS. PRACTICE IMPLICATIONS: YOUTH WITH MENTAL AND PHYSICAL CHCS MAY BE AT INCREASED RISK OF HIGH ALLOSTATIC LOAD, REFLECTED IN CLINICAL MEASURES OF METABOLISM, AND SHOULD HAVE REGULAR ASSESSMENTS OF THEIR METABOLIC HEALTH.	2021