1 5170 123 PREDATION RISK DETERMINES PIGMENTATION PHENOTYPE IN NUTHATCHES BY MELANIN-RELATED GENE EXPRESSION EFFECTS. PIGMENTS DETERMINE THE APPEARANCE OF ORGANISMS. HOWEVER, PIGMENT PRODUCTION CAN BE ASSOCIATED WITH PHYSIOLOGICAL CONSTRAINTS AS IN THE CASE OF PHEOMELANIN, THE SULPHURATED FORM OF MELANIN WHOSE SYNTHESIS IN MELANOCYTES CONSUMES CYSTEINE AND CONSEQUENTLY REDUCES THE AVAILABILITY OF GLUTATHIONE (GSH) TO EXERT ANTIOXIDANT PROTECTION. PHEOMELANOGENESIS MAY THUS INCREASE THE SUSCEPTIBILITY TO SUFFER CHRONIC OXIDATIVE STRESS. I INVESTIGATED THE POSSIBILITY THAT ENVIRONMENTAL LABILITY IN THE EXPRESSION OF GENES REGULATING PHEOMELANOGENESIS PROTECTS FROM OXIDATIVE STRESS, A SITUATION IN WHICH GSH IS MOST REQUIRED. BY BROADCASTING ADULT ALARM CALLS, I MANIPULATED THE PERCEPTION OF PREDATION RISK, A NATURAL SOURCE OF OXIDATIVE STRESS, IN FREE-LIVING EURASIAN NUTHATCH SITTA EUROPAEA NESTLINGS DEVELOPING PHEOMELANIN-PIGMENTED FLANK FEATHERS. THE MANIPULATION AFFECTED THE CONSUMPTION OF GSH THAT RESULTED FROM THE EXPRESSION OF TWO GENES (SLC7A11 AND SLC45A2) INFLUENCING CYSTEINE/GSH AVAILABILITY IN CELLS, AS THESE GENES WERE DOWN-REGULATED IN THE FEATHER MELANOCYTES OF THE NESTLINGS WITH LOWEST INTRACELLULAR ANTIOXIDANT CAPACITY (I.E. LOWEST GSH LEVELS). SYSTEMIC OXIDATIVE DAMAGE INCREASED WITH SLC7A11 EXPRESSION IN FEATHER MELANOCYTES, SUGGESTING THAT THE OBSERVED DOWN-REGULATION WAS PHYSIOLOGICALLY ADVANTAGEOUS. THE NESTLINGS EXPOSED TO AN INCREASED PERCEPTION OF PREDATION RISK DEVELOPED FLANK FEATHERS OF REDUCED COLOUR INTENSITY. THESE RESULTS INDICATE THAT PERCEIVED PREDATION RISK CAN DETERMINE THE PIGMENTATION PHENOTYPE BY (PROBABLY EPIGENETIC) EFFECTS ON GENE EXPRESSION THAT PROTECT FROM PHYSIOLOGICAL CONSTRAINTS IMPOSED BY PHEOMELANIN PRODUCTION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
2  681  28 BRAIN LIPOTOXICITY OF PHYTANIC ACID AND VERY LONG-CHAIN FATTY ACIDS. HARMFUL CELLULAR/MITOCHONDRIAL ACTIVITIES IN REFSUM DISEASE AND X-LINKED ADRENOLEUKODYSTROPHY. IT IS INCREASINGLY UNDERSTOOD THAT IN THE AGING BRAIN, ESPECIALLY IN THE CASE OF PATIENTS SUFFERING FROM NEURODEGENERATIVE DISEASES, SOME FATTY ACIDS AT PATHOLOGICALLY HIGH CONCENTRATIONS EXERT DETRIMENTAL ACTIVITIES. TO STUDY SUCH ACTIVITIES, WE HERE ANALYZE GENETIC DISEASES, WHICH ARE DUE TO COMPROMISED METABOLISM OF SPECIFIC FATTY ACIDS, EITHER THE BRANCHED-CHAIN PHYTANIC ACID OR VERY LONG-CHAIN FATTY ACIDS (VLCFAS). MICROMOLAR CONCENTRATIONS OF PHYTANIC ACID OR OF VLCFAS DISTURB THE INTEGRITY OF NEURAL CELLS BY IMPAIRING CA(2+) HOMEOSTASIS, ENHANCING OXIDATIVE STRESS OR DE-ENERGIZING MITOCHONDRIA. FINALLY, THESE COMBINED HARMFUL ACTIVITIES ACCELERATE CELL DEATH. MITOCHONDRIA ARE MORE SEVERELY TARGETED BY PHYTANIC ACID THAN BY VLCFAS. THE INSERTION OF VLCFAS INTO THE INNER MEMBRANE DISTORTS THE ARRANGEMENT OF MEMBRANE CONSTITUENTS AND THEIR FUNCTIONAL INTERACTIONS. PHYTANIC ACID EXERTS SPECIFIC PROTONOPHORIC ACTIVITY, INDUCES REACTIVE OXYGEN SPECIES (ROS) GENERATION, AND REDUCES ATP GENERATION. A CLEAR INHIBITION OF THE NA(+), K(+)-ATPASE ACTIVITY BY PHYTANIC ACID HAS ALSO BEEN REPORTED. IN ADDITION TO THE INSTANTANEOUS EFFECTS, A CHRONIC EXPOSURE OF BRAIN CELLS TO LOW MICROMOLAR CONCENTRATIONS OF PHYTANIC ACID MAY PRODUCE NEURONAL DAMAGE IN REFSUM DISEASE BY ALTERING EPIGENETIC TRANSCRIPTIONAL REGULATION. MYELIN-PRODUCING OLIGODENDROCYTES RESPOND WITH PARTICULAR SENSITIVITY TO VLCFAS. DELETERIOUS ACTIVITY OF VLCFAS ON ENERGY-DEPENDENT MITOCHONDRIAL FUNCTIONS DECLINES WITH INCREASING THE HYDROCARBON CHAIN LENGTH (C22:0 > C24:0 > C26:0). IN CONTRAST, THE REVERSE SEQUENCE HOLDS TRUE FOR CELL DEATH INDUCTION BY VLCFAS (C22:0 < C24:0 < C26:0). IN ADRENOLEUKODYSTROPHY, THE UPTAKE OF VLCFAS BY PEROXISOMES IS IMPAIRED BY DEFECTS OF THE ABCD1 TRANSPORTER. STUDYING MITOCHONDRIA FROM ABCD1-DEFICIENT AND WILD-TYPE MICE PROVES THAT THE ENERGY-DEPENDENT FUNCTIONS ARE NOT ALTERED IN THE DISEASE MODEL. THUS, A DEFECTIVE ABCD1 APPARENTLY EXERTS NO OBVIOUS ADAPTIVE PRESSURE ON MITOCHONDRIA. FURTHER RESEARCH HAS TO ELUCIDATE THE DETAILED MECHANISTIC BASIS FOR THE FAILURES CAUSING FATTY ACID-MEDIATED NEURODEGENERATION AND SHOULD HELP TO PROVIDE POSSIBLE THERAPEUTIC INTERVENTIONS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
3 1679  25 DRUG RESISTANCE IN GIARDIA DUODENALIS. GIARDIA DUODENALIS IS A MICROAEROPHILIC PARASITE OF THE HUMAN GASTROINTESTINAL TRACT AND A MAJOR CONTRIBUTOR TO DIARRHEAL AND POST-INFECTIOUS CHRONIC GASTROINTESTINAL DISEASE WORLD-WIDE. TREATMENT OF G. DUODENALIS INFECTION CURRENTLY RELIES ON A SMALL NUMBER OF DRUG CLASSES. NITROHETEROCYCLICS, IN PARTICULAR METRONIDAZOLE, HAVE REPRESENTED THE FRONT LINE TREATMENT FOR THE LAST 40 YEARS. NITROHETEROCYCLIC-RESISTANT G. DUODENALIS HAVE BEEN ISOLATED FROM PATIENTS AND CREATED IN VITRO, PROMPTING CONSIDERABLE RESEARCH INTO THE BIOMOLECULAR MECHANISMS OF RESISTANCE. THESE COMPOUNDS ARE REDOX-ACTIVE AND ARE BELIEVED TO DAMAGE PROTEINS AND DNA AFTER BEING ACTIVATED BY OXIDOREDUCTASE ENZYMES IN METABOLICALLY ACTIVE CELLS. IN THIS REVIEW, WE EXPLORE THE MOLECULAR PHENOTYPES OF NITROHETEROCYCLIC-RESISTANT G. DUODENALIS DESCRIBED TO DATE IN THE CONTEXT OF THE PROTIST'S UNUSUAL GLYCOLYTIC AND ANTIOXIDANT SYSTEMS. WE PROPOSE THAT RESISTANCE MECHANISMS ARE LIKELY TO EXTEND WELL BEYOND CURRENTLY DESCRIBED RESISTANCE-ASSOCIATED ENZYMES (I.E., PYRUVATE FERREDOXIN OXIDOREDUCTASES AND NITROREDUCTASES), TO INCLUDE NAD(P)H- AND FLAVIN-GENERATING PATHWAYS, AND POSSIBLY REDOX-SENSITIVE EPIGENETIC REGULATION. MECHANISMS THAT ALLOW G. DUODENALIS TO TOLERATE OXIDATIVE STRESS MAY LEAD TO RESISTANCE AGAINST BOTH OXYGEN AND NITROHETEROCYCLICS, WITH IMPLICATIONS FOR CLINICAL CONTROL. THE PRESENT REVIEW HIGHLIGHTS THE POTENTIAL FOR SYSTEMS BIOLOGY TOOLS AND ADVANCED BIOINFORMATICS TO FURTHER INVESTIGATE THE MULTIFACETED MECHANISMS OF NITROHETEROCYCLIC RESISTANCE IN THIS IMPORTANT PATHOGEN.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
4  238  27 ADENOSINE KINASE: A KEY REGULATOR OF PURINERGIC PHYSIOLOGY. ADENOSINE (ADO) IS AN ESSENTIAL BIOMOLECULE FOR LIFE THAT PROVIDES CRITICAL REGULATION OF ENERGY UTILIZATION AND HOMEOSTASIS. ADENOSINE KINASE (ADK) IS AN EVOLUTIONARY ANCIENT RIBOKINASE DERIVED FROM BACTERIAL SUGAR KINASES THAT IS WIDELY EXPRESSED IN ALL FORMS OF LIFE, TISSUES AND ORGAN SYSTEMS THAT TIGHTLY REGULATES INTRACELLULAR AND EXTRACELLULAR ADO CONCENTRATIONS. THE FACILE ABILITY OF ADK TO ALTER ADO AVAILABILITY PROVIDES A "SITE AND EVENT" SPECIFICITY TO THE ENDOGENOUS PROTECTIVE EFFECTS OF ADO IN SITUATIONS OF CELLULAR STRESS. IN ADDITION TO MODULATING THE ABILITY OF ADO TO ACTIVATE ITS COGNATE RECEPTORS (P1 RECEPTORS), NUCLEAR ADK ISOFORM ACTIVITY HAS BEEN LINKED TO EPIGENETIC MECHANISMS BASED ON TRANSMETHYLATION PATHWAYS. PREVIOUS DRUG DISCOVERY RESEARCH HAS TARGETED ADK INHIBITION AS A THERAPEUTIC APPROACH TO MANAGE EPILEPSY, PAIN, AND INFLAMMATION. THESE EFFORTS GENERATED MULTIPLE CLASSES OF HIGHLY POTENT AND SELECTIVE INHIBITORS. HOWEVER, CLINICAL DEVELOPMENT OF EARLY ADK INHIBITORS WAS STOPPED DUE TO APPARENT MECHANISTIC TOXICITY AND THE LACK OF SUITABLE TRANSLATIONAL MARKERS. NEW INSIGHTS REGARDING THE POTENTIAL ROLE OF THE NUCLEAR ADK ISOFORM (ADK-LONG) IN THE EPIGENETIC MODULATION OF MALADAPTIVE DNA METHYLATION OFFERS THE POSSIBILITY OF IDENTIFYING NOVEL ADK-ISOFORM SELECTIVE INHIBITORS AND NEW INTERVENTIONAL STRATEGIES THAT ARE INDEPENDENT OF ADO RECEPTOR ACTIVATION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
5  760  22 CASZ1: CURRENT IMPLICATIONS IN CARDIOVASCULAR DISEASES AND CANCERS. CASTOR ZINC FINGER 1 (CASZ1) IS A C2H2 ZINC FINGER FAMILY PROTEIN THAT HAS TWO SPLICING VARIANTS, CASZ1A AND CASZ1B. IT IS INVOLVED IN MULTIPLE PHYSIOLOGICAL PROCESSES, SUCH AS TISSUE DIFFERENTIATION AND ALDOSTERONE ANTAGONISM. GENETIC AND EPIGENETIC ALTERNATIONS OF CASZ1 HAVE BEEN CHARACTERIZED IN MULTIPLE CARDIOVASCULAR DISORDERS, SUCH AS CONGENITAL HEART DISEASES, CHRONIC VENOUS DISEASES, AND HYPERTENSION. HOWEVER, LITTLE IS KNOWN ABOUT HOW CASZ1 MECHANICALLY PARTICIPATES IN THE PATHOGENESIS OF THESE DISEASES. OVER THE PAST DECADES, AT FIRST GLANCE, PARADOXICAL INFLUENCES ON CELL BEHAVIORS AND PROGRESSIONS OF DIFFERENT CANCER TYPES HAVE BEEN DISCOVERED FOR CASZ1, WHICH MAY BE EXPLAINED BY A "DOUBLE-AGENT" ROLE FOR CASZ1. IN THIS REVIEW, WE DISCUSS THE PHYSIOLOGICAL FUNCTION OF CASZ1, AND FOCUS ON THE ASSOCIATION OF CASZ1 ABERRATIONS WITH THE PATHOGENESIS OF CARDIOVASCULAR DISEASES AND CANCERS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
6 2640  20 EPIGENOMIC AND TRANSCRIPTIONAL PROFILING IDENTIFIES IMPAIRED GLYOXYLATE DETOXIFICATION IN NAFLD AS A RISK FACTOR FOR HYPEROXALURIA. EPIGENETIC MODIFICATIONS (E.G. DNA METHYLATION) IN NAFLD AND THEIR CONTRIBUTION TO DISEASE PROGRESSION AND EXTRAHEPATIC COMPLICATIONS ARE POORLY EXPLORED. HERE, WE USE AN INTEGRATED EPIGENOME AND TRANSCRIPTOME ANALYSIS OF MOUSE NAFLD HEPATOCYTES AND IDENTIFY ALTERATIONS IN GLYOXYLATE METABOLISM, A PATHWAY RELEVANT IN KIDNEY DAMAGE VIA OXALATE RELEASE-A HARMFUL WASTE PRODUCT AND KIDNEY STONE-PROMOTING FACTOR. DOWNREGULATION AND HYPERMETHYLATION OF ALANINE-GLYOXYLATE AMINOTRANSFERASE (AGXT), WHICH DETOXIFIES GLYOXYLATE, PREVENTING EXCESSIVE OXALATE ACCUMULATION, IS ACCOMPANIED BY INCREASED OXALATE FORMATION AFTER METABOLISM OF THE PRECURSOR HYDROXYPROLINE. VIRAL-MEDIATED AGXT TRANSFER OR INHIBITING HYDROXYPROLINE CATABOLISM RESCUES EXCESSIVE OXALATE RELEASE. IN HUMAN STEATOTIC HEPATOCYTES, AGXT IS ALSO DOWNREGULATED AND HYPERMETHYLATED, AND IN NAFLD ADOLESCENTS, STEATOSIS SEVERITY CORRELATES WITH URINARY OXALATE EXCRETION. THUS, THIS WORK IDENTIFIES A REDUCED CAPACITY OF THE STEATOTIC LIVER TO DETOXIFY GLYOXYLATE, TRIGGERING ELEVATED OXALATE, AND PROVIDES A MECHANISTIC EXPLANATION FOR THE INCREASED RISK OF KIDNEY STONES AND CHRONIC KIDNEY DISEASE IN NAFLD PATIENTS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
7  582  21 BEHAVIORAL AND PHYSIOLOGICAL EFFECTS OF ACUTE AND CHRONIC KAVA EXPOSURE IN ADULT ZEBRAFISH. KAVA KAVA (PIPER METHYSTICUM) IS A MEDICINAL PLANT CONTAINING KAVALACTONES THAT EXERT POTENT SEDATIVE, ANALGESIC AND ANTI-STRESS ACTION. HOWEVER, THEIR PHARMACOLOGICAL EFFECTS AND MOLECULAR TARGETS REMAIN POORLY UNDERSTOOD. THE ZEBRAFISH (DANIO RERIO) HAS RECENTLY EMERGED AS A POWERFUL NEW MODEL ORGANISM FOR NEUROSCIENCE RESEARCH AND DRUG DISCOVERY. HERE, WE EVALUATE THE EFFECTS OF ACUTE AND CHRONIC EXPOSURE TO KAVA AND KAVALACTONES ON ADULT ZEBRAFISH ANXIETY, AGGRESSION AND SOCIALITY, AS WELL AS ON THEIR NEUROCHEMICAL, NEUROENDOCRINE AND GENOMIC RESPONSES. SUPPORTING EVOLUTIONARILY CONSERVED MOLECULAR TARGETS, ACUTE KAVA AND KAVALACTONES EVOKED DOSE-DEPENDENT BEHAVIORAL INHIBITION, UPREGULATED BRAIN EXPRESSION OF EARLY PROTOONCOGENES C-FOS AND C-JUN, ELEVATED BRAIN MONOAMINES AND LOWERED WHOLE-BODY CORTISOL. CHRONIC 7-DAY KAVA EXPOSURE EVOKED SIMILAR BEHAVIORAL EFFECTS, DID NOT ALTER CORTISOL LEVELS, AND FAILED TO EVOKE WITHDRAWAL-LIKE STATES UPON DISCONTINUATION. HOWEVER, CHRONIC KAVA UPREGULATED SEVERAL MICROGLIAL (INOS, EGR-2, CD11B), ASTROCYTAL (C3, C4B, S100A), EPIGENETIC (NCOA-1) AND PRO-INFLAMMATORY (IL-1BETA, IL-6, TNFA) BIOMARKER GENES, DOWNREGULATED CD206 AND IL-4, AND DID NOT AFFECT MAJOR APOPTOTIC GENES IN THE BRAIN. COLLECTIVELY, THIS STUDY SUPPORTS ROBUST, EVOLUTIONARILY CONSERVED BEHAVIORAL AND PHYSIOLOGICAL EFFECTS OF KAVA AND KAVALACTONES IN ZEBRAFISH, IMPLICATES BRAIN MONOAMINES IN THEIR ACUTE EFFECTS, AND PROVIDES NOVEL IMPORTANT INSIGHTS INTO POTENTIAL ROLE OF NEUROGLIAL AND EPIGENETIC MECHANISMS IN LONG-TERM KAVA USE.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
8 1791  23 EFFECT OF CHRONIC RADIATION ON THE FLAX (LINUM USITATISSIMUM L.) GENOME GROWN FOR SIX CONSECUTIVE GENERATIONS IN THE RADIOACTIVE CHERNOBYL AREA. THE GROWTH OF PLANTS UNDER CHRONIC RADIATION STRESS IN THE CHERNOBYL AREA MAY CAUSE CHANGES IN THE GENOME OF PLANTS. TO ASSESS THE EXTENT OF GENETIC AND EPIGENETIC CHANGES IN NUCLEAR DNA, SEEDS OF THE ANNUAL CROP FLAX (LINUM USITATISSIMUM L.) OF THE KYIVSKYI VARIETY, SOWN 21 YEARS AFTER THE ACCIDENT AND GROWN FOR SIX GENERATIONS IN RADIOACTIVE (RAD) AND REMEDIATED (REM) FIELDS WERE ANALYSED. FLAXSEED USED FOR SOWING FIRST GENERATION, WHICH SERVED AS A REFERENCE (REF), WAS ALSO ANALYSED. THE AFLP (AMPLIFIED FRAGMENT LENGTH POLYMORPHISM) REVEALED A HIGHER NUMBER OF SPECIFIC ECORI-MSEI LOCI (3.4-FOLD) IN POOLED FLAXSEED SAMPLES HARVESTED FROM THE RAD FIELD COMPARED WITH THE REM FIELD, INDICATING A LINK BETWEEN THE MUTATION PROCESS IN THE FLAX GENOME AND THE ONGOING ADAPTATION PROCESS. MSAP (METHYLATION-SENSITIVE AMPLIFIED POLYMORPHISM) DETECTING ECORI-MSPI AND ECORI-HPAII LOCI IN FLAX NUCLEAR DNA GENOME SHOWED NO SIGNIFICANT DIFFERENCES IN METHYLATION LEVEL, REACHING ABOUT 33% IN EACH OF THE GROUPS STUDIED. ON THE OTHER HAND, SIGNIFICANT CHANGES IN THE DNA METHYLATION PATTERN OF FLAXSEED SAMPLES HARVESTED FROM THE RAD FIELD COMPARED WITH CONTROLS WERE DETECTED. PAIRWISE F(ST) COMPARISON REVEALED WITHIN BOTH, ECORI-MSPI AND TRANSFORMED METHYLATION-SENSITIVE DATA SETS MORE THAN A 3-FOLD INCREASE OF GENETIC DIVERGENCE IN THE RAD FIELD COMPARED WITH BOTH CONTROLS. THESE RESULTS INDICATE THAT THE NUCLEAR GENOME OF FLAX EXPOSED TO CHRONIC RADIATION FOR SIX GENERATIONS HAS MORE MUTATIONS AND USES DNA METHYLATION AS ONE OF THE ADAPTATION MECHANISMS FOR SUSTAINABILITY UNDER ADVERSE CONDITIONS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
9 2819  20 FILARIAL AND WOLBACHIA GENOMICS. FILARIAL NEMATODE PARASITES, THE CAUSATIVE AGENTS FOR A SPECTRUM OF ACUTE AND CHRONIC DISEASES INCLUDING LYMPHATIC FILARIASIS AND RIVER BLINDNESS, THREATEN THE WELL-BEING AND LIVELIHOOD OF HUNDREDS OF MILLIONS OF PEOPLE IN THE DEVELOPING REGIONS OF THE WORLD. THE 2007 PUBLICATION ON A DRAFT ASSEMBLY OF THE 95-MB GENOME OF THE HUMAN FILARIAL PARASITE BRUGIA MALAYI- REPRESENTING THE FIRST HELMINTH PARASITE GENOME TO BE SEQUENCED - HAS BEEN FOLLOWED IN RAPID SUCCESSION BY PROJECTS THAT HAVE RESULTED IN THE GENOME SEQUENCING OF SIX ADDITIONAL FILARIAL SPECIES, SEVEN NONFILARIAL NEMATODE PARASITES OF ANIMALS AND NEARLY 30 PLANT PARASITIC AND FREE-LIVING SPECIES. PARALLEL TO THE GENOMIC SEQUENCING, TRANSCRIPTOMIC AND PROTEOMIC PROJECTS HAVE FACILITATED GENOME ANNOTATION, EXPANDED OUR UNDERSTANDING OF STAGE-ASSOCIATED GENE EXPRESSION AND PROVIDED A FIRST LOOK AT THE ROLE OF EPIGENETIC REGULATION OF FILARIAL GENOMES THROUGH MICRORNAS. THE EXPANSION IN FILARIAL GENOMICS WILL ALSO PROVIDE A SIGNIFICANT ENRICHMENT IN OUR KNOWLEDGE OF THE DIVERSITY AND VARIABILITY IN THE GENOMES OF THE ENDOSYMBIOTIC BACTERIUM WOLBACHIA LEADING TO A BETTER UNDERSTANDING OF THE GENETIC PRINCIPLES THAT GOVERN FILARIAL-WOLBACHIA MUTUALISM. THE GOAL HERE IS TO PROVIDE AN OVERVIEW OF THE TRENDS AND ADVANCES IN FILARIAL AND WOLBACHIA GENOMICS.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
10 5763  16 SOME COMMENTS ON MASOCHISM AND THE DELUSION OF OMNIPOTENCE FROM A DEVELOPMENTAL PERSPECTIVE. THIS PAPER EXPLORES THE RELATION OF THE DELUSION OF OMNIPOTENCE TO MASOCHISM AND SUGGESTS THAT THIS FANTASY CONSTITUTES A MAJOR COMPONENT OF THE RESISTANCE SO PROMINENT IN WORK WITH MASOCHISTIC PATIENTS. THE CONNECTIONS AMONG MASOCHISM, OMNIPOTENCE, NEGATIVE THERAPEUTIC REACTION, AND CLINGING TO PAIN ARE DISCUSSED. THE CLASSICAL VIEW HAS BEEN THAT THE FAILURE OF INFANTILE OMNIPOTENCE FORCES THE CHILD TO TURN TO REALITY. OUR EXPERIENCE WITH MASOCHISTIC PATIENTS SUGGESTS THAT IT IS THE REAL FAILURE TO ACHIEVE COMPETENT INTERACTIONS WITH OTHERS THAT FORCES THE CHILD TO TURN TO OMNIPOTENT SOLUTIONS. THE DISTINCTION IS MADE BETWEEN FANTASIES THAT ENHANCE THE REAL CAPACITIES OF THE SELF AND THOSE AIMED AT DENYING AND TRANSFORMING THE PAIN AND INADEQUACY OF THE MOTHER-CHILD RELATIONSHIP. THE EPIGENETIC TRANSFORMATIONS OF OMNIPOTENT FANTASIES THROUGH ALL LEVELS OF DEVELOPMENT ARE DESCRIBED. THE PATIENT'S NEED TO PROTECT THE OMNIPOTENT FANTASY IS DISCUSSED IN RELATION TO RESISTANCE AT EACH PHASE OF ANALYSIS.	1991	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
11 5511  22 RIBONUCLEASES IN TUMOR GROWTH. THIS REVIEW SUMMARIZES DATA ON AMBIGUOUS BIOLOGICAL FUNCTIONS OF RIBONUCLEASES (RNASES) AT TUMOR GROWTH. IN SOME CASES THE RAISED LEVEL OF ENZYME ACTIVITY IN BIOLOGICAL FLUIDS CAN BE REGARDED AS AN ADDITIONAL MARKER OF MALIGNANT GROWTH (PANCREAS CANCER, CHRONIC MYELOID LEUKEMIA, ETC.). AT THE SAME TIME THE ACTIVITY OF RNASES IS OFTEN LOWERED IN TUMOR TISSUE. HIGH SUBSTRATE SPECIFICITY OF PARTICULAR RNASES PROVIDES METABOLIC BALANCE BETWEEN VARIOUS KINDS OF RNAS WITH VARIOUS HALF-TIME EXCHANGE TURN. RNASES ARE THE IMPORTANT FACTORS OF EPIGENETIC REGULATION OF GENE ACTIVITY IN CELLS. THE ACTIVITY OF RNASES IS ADJUSTABLE BY INHIBITORS AND OTHER FACTORS, AND DEFINES TIME OF EXISTENCE OF DIFFERENT KINDS OF RNAS. RNASES (THE MODIFIED VARIANTS OF RNASE A, RNASES OF SEMEN FLUID OF THE CATTLE, RNASE OF AMPHIBIA OOCYTES) CAN BE USED AS ANTI-TUMOR THERAPEUTIC AGENTS. ON THE OTHER HAND, SOME INHIBITORS OF RNASES OF NATURAL OR SYNTHETIC ORIGIN WERE DEMONSTRATED TO BE PERSPECTIVE DRUGS THAT INHIBIT TUMOR GROWTH.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
12 3279  27 HERITABLE ALTERATION IN DNA METHYLATION INDUCED BY NITROGEN-DEFICIENCY STRESS ACCOMPANIES ENHANCED TOLERANCE BY PROGENIES TO THE STRESS IN RICE (ORYZA SATIVA L.). CYTOSINE METHYLATION IS RESPONSIVE TO VARIOUS BIOTIC- AND ABIOTIC-STRESSES, WHICH MAY PRODUCE HERITABLE EPIALLELES. NITROGEN (N)-DEFICIENCY IS AN ABIOTIC STRESS BEING REPEATEDLY EXPERIENCED BY PLANTS. TO ADDRESS POSSIBLE EPIGENETIC CONSEQUENCES OF N-DEFICIENCY-STRESS, WE INVESTIGATED THE STABILITY OF CYTOSINE METHYLATION IN RICE (ORYZA SATIVA L.) SUBSEQUENT TO A CHRONIC (A WHOLE-GENERATION) N-DEFICIENCY AT TWO LEVELS, MODERATE (20MG/L) AND SEVERE (10MG/L), UNDER HYDROPONIC CULTURE. MSAP ANALYSIS REVEALED THAT LOCUS-SPECIFIC METHYLATION ALTERATION OCCURRED IN LEAF-TISSUE OF THE STRESSED PLANTS (S(0)) EXPERIENCING EITHER LEVEL OF N-DEFICIENCY, WHICH WAS VALIDATED BY GEL-BLOTTING. ANALYSIS ON THREE NON-STRESSED SELF-FED PROGENIES (S(1), S(2) AND S(3)) BY GEL-BLOTTING INDICATED THAT CA. 50% OF THE ALTERED METHYLATION PATTERNS IN SOMATIC CELLS (LEAF) OF THE STRESSED S(0) PLANTS WERE RECAPTURED IN S(1), WHICH WERE THEN STABLY INHERITED TO S(2) AND S(3). BISULFITE SEQUENCING OF TWO VARIANT MSAP LOCI WITH HOMOLOGY TO LOW-COPY RETROTRANSPOSONS ON ONE STRESSED PLANT (S(0)) AND ITS NON-STRESSED PROGENIES (S(1) AND S(2)) SHOWED THAT WHEREAS ONE LOCUS EXHIBITED LIMITED AND NON-HERITABLE CHH METHYLATION ALTERATION, THE OTHER LOCUS MANIFESTED DRAMATIC HERITABLE HYPERMETHYLATION AT NEARLY ALL CYTOSINE SITES WITHIN THE ASSAYED REGION. INTRIGUINGLY, WHEN TWO GROUPS OF S(2) PLANTS DESCENDED FROM THE SAME N-DEFICIENCY-STRESSED S(0) PLANT WERE RE-SUBJECTED TO THE STRESS, THE GROUP INHERITING THE MODIFIED METHYLATION PATTERNS SHOWED ENHANCED TOLERANCE TO THE N-DEFICIENCY-STRESS COMPARED WITH THE GROUP BEARING THE ORIGINAL PATTERNS. OUR RESULTS THUS DEMONSTRATE HERITABILITY OF AN ACQUIRED ADAPTIVE TRAIT IN RICE, WHICH WAS ACCOMPANIED BY EPIGENETIC INHERITANCE OF MODIFIED CYTOSINE METHYLATION PATTERNS, IMPLICATING AN EPIGENETIC BASIS UNDERLYING THE INHERITANCE OF AN ACQUIRED TRAIT IN PLANTS.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
13 1016  31 CIITA EXPRESSION IS REGULATED BY HISTONE DEACETYLASE ENZYMES AND HAS A ROLE IN ALPHA-SYNUCLEIN PRE-FORMED FIBRIL-INDUCED ANTIGEN PRESENTATION IN MURINE MICROGLIAL CELL LINE. AIM: PARKINSON'S DISEASE (PD) IS A CHRONIC NEURODEGENERATIVE DISORDER RELATED WITH SEVERAL GENETIC AND EPIGENETIC FACTORS. IN THE CONTEXT OF EPIGENETIC FACTORS, HISTONE ACETYLATION IS ONE OF THE MOST ASSOCIATED MECHANISMS WITH PARKINSON'S DISEASE PROGRESSION. THIS STUDY INVESTIGATES THE EFFECTS OF THE INCREASED HISTONE ACETYLATION ON ANTIGEN PRESENTATION IN MICROGLIAL CELLS WHICH WERE INDUCED BY PRE-FORMED FIBRILS OF ALPHA-SYNUCLEIN (PFF ALPHA-SYNUCLEIN). METHODS: PARKINSON'S DISEASE MODEL WAS CREATED WITH PFF ALPHA-SYNUCLEIN ADMINISTRATION TO THE BV-2 MICROGLIAL CELLS. BV-2 CELLS WERE CO-TREATED WITH CUDC-907 AND TMP-195 TO INCREASE HISTONE ACETYLATION IN THE PRESENCE OF ALPHA-SYNUCLEIN. ANTIGEN REPRESENTATION WAS EVALUATED BY DETERMINING EXPRESSION LEVELS OF MAJOR HISTOCOMPATIBILITY COMPLEX-II (MHC-II) AND CLASS-II MAJOR HISTOCOMPATIBILITY COMPLEX (CIITA). RESULTS: OUR RESULTS SHOWED THAT PFF ALPHA-SYNUCLEIN SIGNIFICANTLY INCREASED MHC-II EXPRESSION, AND THAT EFFECT WAS MOST SEVERE AT 6 H OF ADMINISTRATION OF ALPHA-SYNUCLEIN. INCREASING HISTONE ACETYLATION VIA CUDC-907 AND TMP-195 ENHANCED MHC-II LEVELS EXPRESSION, WHICH WAS MORE SEVERE IN CUDC-907. ADDITIONALLY, CIITA EXPRESSION LEVELS WERE SIGNIFICANTLY INCREASED WITH PFF ALPHA-SYNUCLEIN ADMINISTRATION AND INTENSIFIED WITH THE CO-TREATMENT OF CUDC-907 AND TMP-195. FURTHERMORE, PFF ALPHA-SYNUCLEIN CAUSED A TIME-DEPENDENT INCREASE IN THE IFN-GAMMA (IFN-?) AND INTERLEUKIN-16(IL-16) LEVELS, AND THAT INCREASE WAS POTENTIATED WITH CUDC-907 AND TMP-195. CONCLUSION: CHANGES IN MHC-II AND CIITA EXPRESSION INDICATE THAT HISTONE ACETYLATION INCREASES THE ANTIGEN PRESENTATION PROPERTIES OF MICROGLIAL CELLS AFTER PFF ALPHA-SYNUCLEIN OR HISTONE DEACETYLASE INHIBITOR (HDACI) ADMINISTRATION. OUR RESULTS SHOW THAT MICROGLIAL ANTIGEN PRESENTATION MIGHT HAVE AN ESSENTIAL ROLE IN THE PATHOLOGY OF PARKINSON'S DISEASE, AND ALPHA-SYNUCLEIN LIKELY TO PLAY A PRIMARY ROLE IN THIS MECHANISM.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
14  768  27 CD47 (CLUSTER OF DIFFERENTIATION 47). CD47, ALSO KNOWN AS INTEGRIN-ASSOCIATED PROTEIN, IS A CONSTITUTIVELY AND UBIQUITOUSLY EXPRESSED TRANSMEMBRANE RECEPTOR. CD47 IS CONSERVED ACROSS AMNIOTES INCLUDING MAMMALS, REPTILES, AND BIRDS. EXPRESSION IS INCREASED IN MANY CANCERS AND, IN NON-MALIGNANT CELLS, BY STRESS AND WITH AGING. THE UP-REGULATION OF CD47 EXPRESSION IS GENERALLY EPIGENETIC, WHEREAS GENE AMPLIFICATION OCCURS WITH LOW FREQUENCY IN SOME CANCERS. CD47 IS A HIGH AFFINITY SIGNALING RECEPTOR FOR THE SECRETED PROTEIN THROMBOSPONDIN-1 (THBS1) AND THE COUNTER-RECEPTOR FOR SIGNAL REGULATORY PROTEIN-ALPHA (SIRPA, SIRPALPHA) AND SIRPGAMMA (SIRPG). CD47 INTERACTION WITH SIRPALPHA SERVES AS A MARKER OF SELF TO INNATE IMMUNE CELLS AND THEREBY PROTECTS CANCER CELLS FROM PHAGOCYTIC CLEARANCE. CONSEQUENTLY, HIGHER CD47 CORRELATES WITH A POOR PROGNOSIS IN SOME CANCERS, AND THERAPEUTIC BLOCKADE CAN SUPPRESS TUMOR GROWTH BY ENHANCING INNATE ANTITUMOR IMMUNITY. CD47 EXPRESSED ON CYTOTOXIC T CELLS, DENDRITIC CELLS, AND NK CELLS MEDIATES INHIBITORY THBS1 SIGNALING THAT FURTHER LIMITS ANTITUMOR IMMUNITY. CD47 LATERALLY ASSOCIATES WITH SEVERAL INTEGRINS AND THEREBY REGULATES CELL ADHESION AND MIGRATION. CD47 HAS ADDITIONAL LATERAL BINDING PARTNERS IN SPECIFIC CELL TYPES, AND LIGATION OF CD47 IN SOME CASES MODULATES THEIR FUNCTION. THBS1-CD47 SIGNALING IN NON-MALIGNANT CELLS INHIBITS NITRIC OXIDE/CGMP, CALCIUM, AND VEGF SIGNALING, MITOCHONDRIAL HOMEOSTASIS, STEM CELL MAINTENANCE, PROTECTIVE AUTOPHAGY, AND DNA DAMAGE RESPONSE, AND PROMOTES NADPH OXIDASE ACTIVITY. CD47 SIGNALING IS A PHYSIOLOGICAL REGULATOR OF PLATELET ACTIVATION, ANGIOGENESIS AND BLOOD FLOW. THBS1/CD47 SIGNALING IS FREQUENTLY DYSREGULATED IN CHRONIC DISEASES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
15 5487  26 REVERSIBLE ALTERATION IN THE EXPRESSION OF THE GAP JUNCTIONAL PROTEIN CONNEXIN 32 DURING TUMOR PROMOTION IN RAT LIVER AND ITS ROLE DURING CELL PROLIFERATION. ALTHOUGH NUMEROUS BIOCHEMICAL MARKERS CAN IDENTIFY PUTATIVE PRENEOPLASTIC ALTERED HEPATIC FOCI (AHF) IN RAT LIVER, NO CONSISTENT PATTERN OF EXPRESSION DURING HEPATOCARCINOGENESIS HAS EMERGED. USING QUANTITATIVE STEREOLOGIC ANALYSES WE DEMONSTRATED THAT DECREASED EXPRESSION OF THE MAJOR HEPATOCYTE GAP JUNCTION PROTEIN, CONNEXIN 32 (CX32), IN RAT AHF IS A CONSISTENT OBSERVATION IN SEVERAL PROTOCOLS OF MULTISTAGE HEPATOCARCINOGENESIS. THIS CHANGE WAS OBSERVED AFTER INITIATION BY EITHER ETHYLNITROSOUREA (ENU) OR DIETHYLNITROSAMINE (DEN), FOLLOWED BY PROMOTION WITH PHENOBARBITAL (PB), DIOXIN, CHLORENDIC ACID, C.I. SOLVENT YELLOW, OR TAMOXIFEN. AHF GENERATED BY WY-14,643, CIPROFIBRATE, AND A CHOLINE/METHIONINE-DEFICIENT DIETARY REGIMEN ALSO SHOWED DECREASED CX32 EXPRESSION. THE DECREASE OF CX32 IN AHF WAS RAPIDLY REVERSIBLE AFTER WITHDRAWAL OF PB, AND THIS CHANGE PRECEDED A REDUCTION IN PLACENTAL ISOZYME OF GLUTATHIONE-S-TRANSFERASE (GST) EXPRESSION IN THE SAME AHF. WITHIN 20 DAYS OF WITHDRAWAL, FEWER THAN 4% OF GST-POSITIVE AHF WERE CX32 DEFICIENT, WHILE THE VOLUME OF TOTAL AHF DECREASED 30%. CHRONIC PB TREATMENT ALSO RESULTED IN A REVERSIBLE DECREASE IN CX32 SPECIFICALLY IN MID- AND CENTRO-LOBULAR HEPATOCYTES. CONTINUOUS THYMIDINE LABELING DEMONSTRATED THAT CX32 COULD BE UNCOUPLED FROM THE CELL CYCLE, SUGGESTING THAT SOME LIVER PROMOTERS MAY ACT DIRECTLY TO ALTER THE EXPRESSION OF CX32. THESE OBSERVATIONS SUGGEST THAT A DECREASE IN CX32 CONTENT WAS A RELATIVELY COMMON EPIGENETIC CHANGE IN AHF INDUCED DURING HEPATOCARCINOGENESIS BY A NUMBER OF INITIATING AND PROMOTING AGENTS BUT THAT THIS CHANGE WAS NOT SUFFICIENT FOR CARCINOGENESIS. THIS CHANGE, HOWEVER, MAY BE NECESSARY FOR THE MECHANISM(S) OF TUMOR PROMOTION, SINCE CX32-POSITIVE AHF DID NOT PROLIFERATE AS READILY AS CX32-DEFICIENT AHF.	1990	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
16 2080  29 EPIGENETIC DNA METHYLATION OF EBI3 MODULATES HUMAN INTERLEUKIN-35 FORMATION VIA NFKB SIGNALING: A PROMISING THERAPEUTIC OPTION IN ULCERATIVE COLITIS. ULCERATIVE COLITIS (UC), A SEVERE CHRONIC DISEASE WITH UNCLEAR ETIOLOGY THAT IS ASSOCIATED WITH INCREASED RISK FOR COLORECTAL CANCER, IS ACCOMPANIED BY DYSREGULATION OF CYTOKINES. EPSTEIN-BARR VIRUS-INDUCED GENE 3 (EBI3) ENCODES A SUBUNIT IN THE UNIQUE HETERODIMERIC IL-12 CYTOKINE FAMILY OF EITHER PRO- OR ANTI-INFLAMMATORY FUNCTION. AFTER HAVING RECENTLY DEMONSTRATED THAT UPREGULATION OF EBI3 BY HISTONE ACETYLATION ALLEVIATES DISEASE SYMPTOMS IN A DEXTRAN SULFATE SODIUM (DSS)-TREATED MOUSE MODEL OF CHRONIC COLITIS, WE NOW AIMED TO EXAMINE A POSSIBLE FURTHER EPIGENETIC REGULATION OF EBI3 BY DNA METHYLATION UNDER INFLAMMATORY CONDITIONS. TREATMENT WITH THE DNA METHYLTRANSFERASE INHIBITOR (DNMTI) DECITABINE (DAC) AND TNFALPHA LED TO SYNERGISTIC UPREGULATION OF EBI3 IN HUMAN COLON EPITHELIAL CELLS (HCEC). USE OF DIFFERENT SIGNALING PATHWAY INHIBITORS INDICATED NFKAPPAB SIGNALING WAS NECESSARY AND PROPORTIONAL TO THE SYNERGISTIC EBI3 INDUCTION. MALDI-TOF/MS AND HPLC-ESI-MS/MS ANALYSIS OF DAC/TNFALPHA-TREATED HCEC IDENTIFIED IL-12P35 AS THE MOST PROBABLE BINDING PARTNER TO FORM A FUNCTIONAL PROTEIN. EBI3/IL-12P35 HETERODIMERS (IL-35) INDUCE THEIR OWN GENE UPREGULATION, SOMETHING THAT WAS INDEED OBSERVED IN HCEC CULTURED WITH MEDIA FROM PREVIOUSLY DAC/TNFALPHA-TREATED HCEC. THESE RESULTS SUGGEST THAT UNDER INFLAMMATORY AND DEMETHYLATING CONDITIONS THE UPREGULATION OF EBI3 RESULTS IN THE FORMATION OF ANTI-INFLAMMATORY IL-35, WHICH MIGHT BE CONSIDERED AS A THERAPEUTIC TARGET IN COLITIS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
17 5353  31 RE-EVALUATION OF POLIHEXANIDE USE IN WOUND ANTISEPSIS IN ORDER TO CLARIFY AMBIGUITIES OF TWO ANIMAL STUDIES. OBJECTIVE: DUE TO CLASSIFICATION OF THE AGENT POLIHEXANIDE (PHMB) IN CATEGORY 2 'MAY CAUSE CANCER' BY THE COMMITTEE FOR RISK ASSESSMENT OF THE EUROPEAN CHEMICALS AGENCY IN 2011, THE USERS OF WOUND ANTISEPTICS MAY BE HIGHLY CONFUSED. IN 2017, THIS STATEMENT WAS UPDATED, DEFINING PHMB UP TO 0.1% AS A PRESERVATIVE SAFE IN ALL COSMETIC PRODUCTS. IN THE INTEREST OF PATIENT SAFETY, A SCIENTIFIC CLARIFICATION OF THE POTENTIAL CARCINOGENICITY OF PHMB IS NECESSARY. METHODS: A MULTIDISCIPLINARY TEAM (MDT) OF MICROBIOLOGISTS, SURGEONS, DERMATOLOGISTS AND BIOCHEMISTS CONDUCTED A BENEFIT-RISK ASSESSMENT TO CLARIFY THE HAZARD OF ANTISEPTIC USE OF PHMB. RESULTS: IN TWO ANIMAL STUDIES, FROM WHICH THE ASSESSMENT OF A CARCINOGENIC RISK WAS DERIVED, PHMB WAS ADMINISTERED ORALLY OVER TWO YEARS IN EXTREMELY HIGH CONCENTRATIONS FAR ABOVE THE NO(A)EL (NO-OBSERVED-(ADVERSE-) EFFECT LEVEL) IN RATS AND MICE. FEEDING IN THE NO(A)EL RANGE RESULTED IN NO ABNORMAL EFFECTS. IN ONE MALE IN THE HIGHEST DOSE GROUP OF 4000PPM PHMB, AN ADENOCARCINOMA WAS FOUND, WHICH THE AUTHOR ATTRIBUTED TO CHRONIC INFLAMMATION OF THE COLON WITH SYSTEMIC ATYPICAL EXPOSURE. THE INCREASING INCIDENCE OF HEMANGIOSARCOMAS HIGHLY PROBABLY RESULTED FROM INCREASED ENDOTHELIAL PROLIFERATION, TRIGGERED BY THE EXCEEDINGLY HIGH DOSAGE FED, BECAUSE PHMB IS NOT GENOTOXIC AND THERE IS NO EVIDENCE FOR EPIGENETIC EFFECTS. DISCUSSION: IT IS WELL KNOWN THAT PHMB IS NOT ABSORBED WHEN APPLIED TOPICALLY. CONSIDERING THE ABSENCE OF GENOTOXICITY AND EPIGENETIC EFFECTS TOGETHER WITH THE INTERPRETATION OF THE ANIMAL STUDIES, IT IS THE CONSENSUS OF THE MULTIDISCIPLINARY EXPERTS THAT A CARCINOGENIC RISK FROM PHMB-USE FOR WOUND ANTISEPSIS CAN BE RULED OUT. CONCLUSION: ON THIS BASIS AND CONSIDERING THEIR EFFECTIVENESS, TOLERABILITY AND CLINICAL EVIDENCE, THE INDICATIONS FOR PHMB BASED WOUND ANTISEPTICS ARE JUSTIFIED.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
18 1109  27 COMMERCIAL PROCESSED SOY-BASED FOOD PRODUCT CONTAINS GLYCATED AND GLYCOXIDATED LUNASIN PROTEOFORMS. NUTRACEUTICALS HAVE BEEN PROPOSED TO EXERT POSITIVE EFFECTS ON HUMAN HEALTH AND CONFER PROTECTION AGAINST MANY CHRONIC DISEASES. A MAJOR BIOACTIVE COMPONENT OF SOY-BASED FOODS IS LUNASIN PEPTIDE, WHICH HAS POTENTIAL TO EXERT A MAJOR IMPACT ON THE HEALTH OF HUMAN CONSUMERS WORLDWIDE, BUT THE BIOCHEMICAL FEATURES OF DIETARY LUNASIN STILL REMAIN POORLY CHARACTERIZED. IN THIS STUDY, LUNASIN WAS PURIFIED FROM A SOY-BASED FOOD PRODUCT VIA STRONG ANION EXCHANGE SOLID PHASE EXTRACTION AND THEN SUBJECTED TO TOP-DOWN MASS SPECTROMETRY ANALYSIS THAT REVEALED IN DETAIL THE MOLECULAR DIVERSITY OF LUNASIN IN PROCESSED SOYBEAN FOODS. WE DETECTED MULTIPLE GLYCATED PROTEOFORMS TOGETHER WITH POTENTIALLY TOXIC ADVANCED GLYCATION END PRODUCTS (AGES) DERIVED FROM LUNASIN. IN BOTH CASES, MODIFICATION SITES WERE LYS24 AND LYS29 LOCATED AT THE HELICAL REGION THAT SHOWS STRUCTURAL HOMOLOGY WITH A CONSERVED REGION OF CHROMATIN-BINDING PROTEINS. THE IDENTIFIED POST-TRANSLATIONAL MODIFICATIONS MAY HAVE AN IMPORTANT REPERCUSSION ON LUNASIN EPIGENETIC REGULATORY CAPACITY. TAKING TOGETHER, OUR RESULTS DEMONSTRATE THE IMPORTANCE OF PROPER CHEMICAL CHARACTERIZATION OF COMMERCIAL PROCESSED FOOD PRODUCTS TO ASSESS THEIR IMPACT ON CONSUMER'S HEALTH AND RISK OF CHRONIC DISEASES.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
19 6636  38 UNRAVELING A NEW PLAYER IN MULTIPLE SCLEROSIS PATHOGENESIS: THE RNA-BINDING PROTEIN HUR. BACKGROUND: ELAV-LIKE PROTEINS ARE A SMALL FAMILY OF RNA-BINDING PROTEINS THAT ARE FUNDAMENTAL PLAYERS IN POST-TRANSCRIPTIONAL MECHANISMS AND ARE INVOLVED IN THE PATHOGENESIS OF NEUROLOGIC AND PSYCHIATRIC DISORDERS. HUR, THE UBIQUITOUSLY EXPRESSED MEMBER OF THE FAMILY, IS ALSO IMPLICATED IN SUSTAINING INFLAMMATION AND INFLAMMATORY DISEASES, SUPPORTING THE PRODUCTION OF PRO-INFLAMMATORY CYTOKINES. INFLAMMATION PLAYS A CENTRAL ROLE IN MULTIPLE SCLEROSIS (MS), WHICH REPRESENTS THE MOST COMMON CAUSE OF PERMANENT PHYSICAL DISABILITY IN YOUNG ADULTS. MS IS A CHRONIC AUTOIMMUNE DISEASE AFFECTING THE CENTRAL NERVOUS SYSTEM, WITH A COMPLEX AETIOLOGY INVOLVING GENETIC, ENVIRONMENTAL AND EPIGENETIC FACTORS. NO DATA ARE AVAILABLE ON THE POTENTIAL ENTANGLEMENT OF HUR IN MS PATHOGENESIS IN PATIENTS. IN THE PRESENT WORK, WE AIMED AT EXPLORING HUR PROTEIN LEVELS IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM MS PATIENTS, COMPARED TO HEALTHY CONTROLS. TO FURTHER ELUCIDATE THE POSSIBLE INVOLVEMENT OF HUR IN MS, WE ALSO INVESTIGATED THE RELATIONSHIP BETWEEN THIS SPECIFIC RNA-BINDING PROTEIN AND HSP70-2 PROTEIN, ALSO CONSIDERING THE HSP70-2 RS1061581 POLYMORPHISM, GIVEN THAT HSP70-2 MRNA HAS BEEN REPORTED AS A HUR TARGET AND THIS SPECIFIC POLYMORPHISM TO BE ASSOCIATED WITH MS RISK. METHODS: ALLELES AND GENOTYPES FOR HSP70-2 RS1061581 POLYMORPHISM WERE ASSESSED, BY USING A POLYMERASE CHAIN REACTION-RESTRICTION FRAGMENT LENGTH POLYMORPHISM, FOLLOWED BY DIGESTION WITH RESTRICTION ENZYME, IN MS PATIENTS AND HEALTHY CONTROLS. PBMCS FROM A SUBGROUP OF PATIENTS AND CONTROLS WERE USED TO EVALUATE HUR AND HSP70-2 PROTEIN CONTENT BY WESTERN BLOT. RESULTS: PBMCS FROM 52 MS PATIENTS HAD A LOWER HUR AND HIGHER HSP70-2 PROTEIN CONTENT COMPARED TO 43 HEALTHY CONTROLS. AN INCREASE OF 100 UNITS OF HUR SIGNIFICANTLY DECREASED THE RISK OF DEVELOPING MS BY 9.8% (OR: 0.902, 95% CI: 0.83-0.98), CONTROLLING FOR HSP70-2 PROTEIN EXPRESSION, HSP70-2 RS1061581 GENOTYPE, AGE AND SEX. MOREOVER, HOLDING HUR LEVELS, AN INCREASE OF 100 UNITS OF HSP70-2 PROTEIN SIGNIFICANTLY INCREASED THE MS RISK BY 18.1% (OR: 1.181, 95% CI: 1.03-1.36) AND THE GENETIC SUSCEPTIBILITY OF DEVELOPING MS FOR HSP70-2 RS1061581 GG CARRIERS IS CONFIRMED. OF INTEREST, MS PATIENTS WITH A MODERATE TO SEVERE FORM OF MS (MSSS >/= 3) SHOWED A TREND TOWARDS A REDUCTION OF HUR PROTEIN LEVELS COMPARED TO PATIENTS WITH MILD DISEASE SEVERITY (MSSS < 3). CONCLUSIONS: HUR PROTEIN LEVELS ARE REDUCED IN MS PATIENTS COMPARED TO HEALTHY SUBJECTS, AND THE PROTEIN AMOUNT MAY CONTINUE TO DECLINE WITH DISEASE PROGRESSION, SUGGESTING A PUTATIVE ROLE OF THIS RNA-BINDING PROTEIN. MOREOVER, OUR RESULTS SUGGEST THAT MS PATHOLOGY MAY HAVE DISRUPTED THE LINK BETWEEN HUR AND ITS TARGET TRANSCRIPT HSP70-2. IT WILL BE IMPORTANT TO FURTHER EXPLORE THE EXACT ROLE OF HUR IN MS, CONSIDERING THE COMPLEX INTERPLAY WITH OTHER RNA-BINDING FACTORS AND TARGET MRNAS.	2020	

20 3381  27 HLA AND AUTOIMMUNE DISEASES: TYPE 1 DIABETES (T1D) AS AN EXAMPLE. AUTOIMMUNE DISEASES NEED TO BE CONSIDERED AT A GENETIC AND MECHANISTIC LEVEL. T1D IS AN AUTOIMMUNE, CHRONIC, MULTIFACTORIAL AND POLYGENIC DISEASE CHARACTERIZED BY THE DESTRUCTION OF THE PANCREATIC BETA-CELLS ASSOCIATED WITH LONG TERM DYSFUNCTION OF SEVERAL ORGANS AND TISSUES. MECHANISMS OF SUSCEPTIBILITY INCLUDE EPI-GENETIC AND POST-TRANSCRIPTIONAL EFFECTS THAT REGULATE TRANSMISSION AND EXPRESSION OF THE INHERITED GENES. THE HLA COMPLEX, CONSTITUTES THE MOST RELEVANT REGION CONTRIBUTING 50% OF THE INHERITED RISK FOR T1D. AN ADDITIONAL 17 GENES WITH VARIABLE BUT SMALL EFFECTS HAVE BEEN DESCRIBED. IN NON-CAUCASIANS, THE PRESENCE OF E-DRBETA1-74 AND/OR D-DRBETA1-57 ARE RELEVANT IN PREDISPOSITION. THE "DIABETOGENIC HAPLOTYPES" IN MEXICANS WERE DRB1*0301-DQA1*0501-DQB1*0201 (OR = 21.4); DRB1*0405-DQA1-*0301-DQB1*0302 (OR = 44.5) AND THE SAME DQA1/DQB1 WITH DRB1*0404/*0401 CONFERRING LOWER RISK, INCREASING (OR = 61.3) WITH AN EARLY AGE AT ONSET AND A HETEROZYGOTE DR3/DR4 GENOTYPE. IN MOST POPULATIONS, THE ABSENCE OF D-57 AND THE PRESENCE OF R-52 ARE IMPORTANT TO THE SUSCEPTIBILITY, BUT IN HISPANICS, ALL DR4S (INCLUDING THE PROTECTIVE DRB1*0403/*0407/*0411) ARE IN LINKAGE DISEQUILIBRIUM WITH DQA1/DQB1 SUSCEPTIBILITY ALLELES. THUS, SUSCEPTIBILITY ALLELES IN LATIN AMERICAN MESTIZOS ARE OF MEDITERRANEAN ANCESTRY WHEREAS PROTECTIVE ALLELES ARE OF AMERINDIAN ORIGIN. IN THIS REVIEW, WE DISCUSS THE COMPLEXITY OF T1D AND SOME ASPECTS OF PREVENTION/INTERVENTION BASED ON IMMUNOGENETICS.	2006