1  3785 115 INTERGENERATIONAL EFFECTS OF PRE-PREGNANCY CHRONIC LIPOPOLYSACCHARIDE FROM PORPHYROMONAS GINGIVALIS ON THE LEARNING, MEMORY AND SEIZURE SUSCEPTIBILITY OF OFFSPRING. OBJECTIVE: THE AIM OF THIS STUDY WAS TO INVESTIGATE THE EFFECTS OF PRE-PREGNANCY CHRONIC EXPOSURE TO PORPHYROMONAS GINGIVALIS LPS (PG LPS) ON THE LEARNING, MEMORY, AND SEIZURE SUSCEPTIBILITY OF THE OFFSPRING. DESIGN: TO ACHIEVE PERIODONTITIS, PG LPS (5 MUG/KG) WAS INJECTED INTO THE GINGIVAL OF FIVE FEMALE RATS EVERY 48 H FOR THREE WEEKS. FIVE CONTROL FEMALE RATS RECEIVED SALINE (0.9 %) AND FIVE FEMALE WERE KEPT INTACT. THE CONCENTRATIONS OF TNF-ALPHA AND IL-6 WERE MEASURED IN THE BLOOD SAMPLES. ONE WEEK AFTER THE FINAL INJECTION, FEMALES WERE MATED WITH INTACT MALES. FOLLOWING BIRTH AND WEANING, TWO MALE AND TWO FEMALE OFFSPRING WERE RANDOMLY SELECTED FROM EACH MOTHER, AND NEW GROUPS OF MALE AND FEMALE OFFSPRING WERE DEFINED FOR BEHAVIORAL ASSESSMENTS. MORRIS WATER MAZE WAS USED TO EVALUATE SPATIAL MEMORY, SHUTTLE BOX WAS USED TO INVESTIGATE AVOIDANCE MEMORY AND A PENTYLENETETRAZOLE-INDUCED SEIZURE WAS USED TO EVALUATE SEIZURE SUSCEPTIBILITY IN THE OFFSPRING. RESULTS: SPATIAL LEARNING AND AVOIDANCE MEMORY SIGNIFICANTLY DECREASED IN BOTH MALE AND FEMALE OFFSPRING OF PG LPS-EXPOSED FEMALE RATS, COMPARED TO THE CONTROL OFFSPRING. LATENCY TO REACH SEIZURE STAGES 1 AND 2 SIGNIFICANTLY INCREASED IN THE MALE OFFSPRING, BUT NOT THE FEMALE OFFSPRING OF PG LPS-EXPOSED FEMALE, COMPARED TO THE CONTROL OFFSPRING. HOWEVER, NO SIGNIFICANT DIFFERENCE WAS FOUND IN LATENCY TO REACH STAGES 3-5. CONCLUSION: PRE-PREGNANCY EXPOSURE TO PG LPS COULD AFFECT SOME BEHAVIORAL FUNCTIONS IN BOTH MALE AND FEMALE OFFSPRING INTERGENERATIONALLY.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
2  6693  19 VARIABLE INDUCTION OF PRDM1 AND DIFFERENTIATION IN CHRONIC LYMPHOCYTIC LEUKEMIA IS ASSOCIATED WITH ANERGY. DESPITE ANTIGEN ENGAGEMENT AND INTACT B-CELL-RECEPTOR (BCR) SIGNALING, CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) CELLS FAIL TO UNDERGO TERMINAL DIFFERENTIATION. WE HYPOTHESIZED THAT SUCH FAILURE MAY BE DUE TO ANERGY, AS CLL CELLS EXHIBIT VARIABLE LEVELS OF NONRESPONSIVENESS TO SURFACE IGM STIMULATION THAT IS REVERSIBLE IN VITRO. MOREOVER, ANERGY IS ASSOCIATED WITH REDUCED DIFFERENTIATION CAPACITY IN NORMAL B CELLS. WE INVESTIGATED RESPONSES OF CLL CELLS TO TWO POTENT DIFFERENTIATION-PROMOTING AGENTS, IL-21 AND CYTOSINE GUANINE DINUCLEOTIDE-ENRICHED OLIGO-DEOXYNUCLEOTIDES. THE INDUCTION OF PR DOMAIN-CONTAINING PROTEIN 1 (PRDM1; ALSO KNOWN AS BLIMP-1), A CRITICAL REGULATOR OF PLASMACYTIC DIFFERENTIATION, BY THESE AGENTS WAS CLOSELY CORRELATED BUT VARIED BETWEEN INDIVIDUAL CASES, DESPITE FUNCTIONALLY INTACT IL-21 RECEPTOR- AND TOLL-LIKE RECEPTOR 9-MEDIATED SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3, AND NUCLEAR FACTOR-KAPPAB PATHWAYS. PRDM1 INDUCTION WAS INVERSELY CORRELATED WITH THE EXTENT OF ANERGY AS MEASURED BY THE ABILITY TO MOBILIZE INTRACELLULAR CA(2+) FOLLOWING BCR CROSSLINKING. PRDM1 RESPONSIVENESS WAS ASSOCIATED WITH OTHER MARKERS OF DIFFERENTIATION AND PROLIFERATION BUT NOT WITH DIFFERENCES IN APOPTOSIS. THE ABILITY TO INDUCE PRDM1 DID CORRELATE WITH DIFFERENTIAL TRANSCRIPTIONAL AND EPIGENETIC REGULATION OF THE PRDM1 GENE. THESE STUDIES EXTEND OUR UNDERSTANDING OF CLL PATHOBIOLOGY, DEMONSTRATING THAT REDUCED DIFFERENTIATION CAPACITY MAY BE A CONSEQUENCE OF ANERGY. EPIGENETIC DRUGS MAY OFFER POSSIBILITIES TO REACTIVATE PRDM1 EXPRESSION AS PART OF NOVEL DIFFERENTIATION THERAPY APPROACHES.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
3   531  33 ASTROCYTE REACTIVITY FOLLOWING BLAST EXPOSURE INVOLVES ABERRANT HISTONE ACETYLATION. BLAST INDUCED NEUROTRAUMA (BINT) IS A PREVALENT INJURY WITHIN MILITARY AND CIVILIAN POPULATIONS. THE INJURY IS CHARACTERIZED BY PERSISTENT INFLAMMATION AT THE CELLULAR LEVEL WHICH MANIFESTS AS A MULTITUDE OF COGNITIVE AND FUNCTIONAL IMPAIRMENTS. EPIGENETIC REGULATION OF TRANSCRIPTION OFFERS AN IMPORTANT CONTROL MECHANISM FOR GENE EXPRESSION AND CELLULAR FUNCTION WHICH MAY UNDERLIE CHRONIC INFLAMMATION AND RESULT IN NEURODEGENERATION. WE HYPOTHESIZE THAT ALTERED HISTONE ACETYLATION PATTERNS MAY BE INVOLVED IN BLAST INDUCED INFLAMMATION AND THE CHRONIC ACTIVATION OF GLIAL CELLS. THIS STUDY AIMED TO ELUCIDATE CHANGES TO HISTONE ACETYLATION OCCURRING FOLLOWING INJURY AND THE ROLES THESE CHANGES MAY HAVE WITHIN THE PATHOLOGY. SPRAGUE DAWLEY RATS WERE SUBJECTED TO EITHER A 10 OR 17 PSI BLAST OVERPRESSURE WITHIN AN ADVANCED BLAST SIMULATOR (ABS). SHAM ANIMALS UNDERWENT THE SAME PROCEDURES WITHOUT BLAST EXPOSURE. MEMORY IMPAIRMENTS WERE MEASURED USING THE NOVEL OBJECT RECOGNITION (NOR) TEST AT 2 AND 7 DAYS POST-INJURY. TISSUES WERE COLLECTED AT 7 DAYS FOR WESTERN BLOT AND IMMUNOHISTOCHEMISTRY (IHC) ANALYSIS. SHAM ANIMALS SHOWED INTACT MEMORY AT EACH TIME POINT. THE NOVEL OBJECT DISCRIMINATION DECREASED SIGNIFICANTLY BETWEEN TWO AND 7 DAYS FOR EACH INJURY GROUP (P < 0.05). THIS IS INDICATIVE OF THE ONSET OF MEMORY IMPAIRMENT. WESTERN BLOT ANALYSIS SHOWED GLIAL FIBRILLARY ACIDIC PROTEIN (GFAP), A KNOWN MARKER OF ACTIVATED ASTROCYTES, WAS ELEVATED IN THE PREFRONTAL CORTEX (PFC) FOLLOWING BLAST EXPOSURE FOR BOTH INJURY GROUPS. ANALYSIS OF HISTONE PROTEIN EXTRACT SHOWED NO CHANGES IN THE LEVEL OF ANY TOTAL HISTONE PROTEINS WITHIN THE PFC. HOWEVER, ACETYLATION LEVELS OF HISTONE H2B, H3, AND H4 WERE DECREASED IN BOTH GROUPS (P < 0.05). CO-LOCALIZATION IMMUNOFLUORESCENCE WAS USED TO FURTHER INVESTIGATE ANY POTENTIAL CORRELATION BETWEEN DECREASED HISTONE ACETYLATION AND ASTROCYTE ACTIVATION. THESE EXPERIMENTS SHOWED A SIMILAR DECREASE IN H3 ACETYLATION IN ASTROCYTES EXPOSED TO A 17 PSI BLAST BUT NOT A 10 PSI BLAST. FURTHER INVESTIGATION OF GENE EXPRESSION BY POLYMERASE CHAIN REACTION (PCR) ARRAY, SHOWED DYSREGULATION OF SEVERAL CYTOKINE AND CYTOKINE RECEPTORS THAT ARE INVOLVED IN NEUROINFLAMMATORY PROCESSES. WE HAVE SHOWN ABERRANT HISTONE ACETYLATION PATTERNS INVOLVED IN BLAST INDUCED ASTROGLIOSIS AND COGNITIVE IMPAIRMENTS. FURTHER UNDERSTANDING OF THEIR ROLE IN THE INJURY PROGRESSION MAY LEAD TO NOVEL THERAPEUTIC TARGETS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
4   620  21 BIOCHEMISTRY AND MOLECULAR BIOLOGY OF GELATINASE B OR MATRIX METALLOPROTEINASE-9 (MMP-9): THE NEXT DECADE. RESEARCH ON MATRIX METALLOPROTEINASES (MMPS) AND IN PARTICULAR ON GELATINASE B, ALIAS MMP-9, HAS GROWN EXPONENTIALLY IN THE DECADE 2003-2012. STRUCTURAL DETAILS ABOUT FLEXIBILITY OF MMP-9 MONOMERS, TOGETHER WITH GLYCOSYLATION, OLIGOMERIZATION, HETEROGENEITY AND INSTABILITY OF THE WILDTYPE ENZYME EXPLAIN WHY CRYSTALLOGRAPHY EXPERIMENTS HAVE NOT YET BEEN SUCCESSFUL FOR THE INTACT ENZYME. MMP-9 MAY BE VIEWED AS A MULTIDOMAIN ENZYME IN WHICH THE HEMOPEXIN, THE O-GLYCOSYLATED AND THE CATALYTIC DOMAINS YIELD SUPPORT FOR ATTACHMENT, ARTICULATION AND CATALYSIS, RESPECTIVELY. THE STEPWISE PROTEOLYTIC ACTIVATION OF THE INACTIVE ZYMOGEN INTO A CATALYTICALLY ACTIVE FORM BECOMES GRADUALLY BETTER UNDERSTOOD. PRIMING OF ACTIVATION BY MMP-3 MAY BE EXECUTED BY MEPRINS THAT DESTABILIZE THE INTERACTION OF THE AMINOTERMINUS WITH THE THIRD FIBRONECTIN REPEAT. ALTERNATIVELY, AUTOCATALYTIC ACTIVATION MAY OCCUR IN THE PRESENCE OF MOLECULES THAT TIGHTLY BIND TO THE CATALYTIC SITE AND THAT PUSH THE CYSTEIN RESIDUE IN THE PRODOMAIN AWAY FROM THE CATALYTIC ZINC ION. THANKS TO THE DEVELOPMENT OF DEGRADOMICS TECHNOLOGIES, SUBSTRATE REPERTOIRES OF MMP-9 HAVE BEEN DEFINED, BUT IT REMAINS A CHALLENGE TO DETERMINE AND PROVE WHICH SUBSTRATES ARE BIOLOGICALLY RELEVANT. THE SUBSTRATE REPERTOIRE HAS BEEN ENLARGED FROM EXTRACELLULAR TO MEMBRANE-BOUND AND EFFICIENT INTRACELLULAR SUBSTRATES, SUCH AS CRYSTALLINS, TUBULINS AND ACTINS. BIOLOGICAL STUDIES OF MMP-9 HAVE TUNED THE FIELD FROM BEING PRIMARILY CANCER-ORIENTED TOWARDS VASCULAR AND INFLAMMATORY RESEARCH. IN TUMOR BIOLOGY, IT HAS BEEN INCREASINGLY APPRECIATED THAT MMP-9 FROM INFLAMMATORY CELLS, PARTICULARLY NEUTROPHILS, CO-DETERMINES PROGNOSIS AND OUTCOME. ASIDE FROM THE CATALYTIC FUNCTIONS EXECUTED BY AMINOTERMINAL DOMAINS OF MMP-9, THE CARBOXYTERMINAL HEMOPEXIN (PEX) DOMAIN OF GELATINASE B EXERTS NON-CATALYTIC ANTI-APOPTOTIC SIGNALING EFFECTS. THE RECOGNITION THAT GELATINASE B IS INDUCED BY MANY PRO-INFLAMMATORY CYTOKINES, WHEREAS ITS INHIBITORS ARE INCREASED BY ANTI-INFLAMMATORY CYTOKINES, HAS GENERATED INTEREST TO TARGET MMP-9 IN ACUTE LETHAL CONDITIONS, SUCH AS BACTERIAL MENINGITIS, SEPSIS AND ENDOTOXIN SHOCK, AND IN ACUTE EXACERBATIONS OF CHRONIC DISEASES. PREVIOUSLY DESCRIBED TRANSCRIPTIONAL REGULATION OF MMP-9 IS COMPLEMENTED BY EPIGENETIC CHECKPOINTS, INCLUDING HISTONE MODIFICATIONS AND MICRORNAS. BECAUSE ACTIVATION OF PROMMP-9 MAY BE EXECUTED BY OTHER MMPS, THE THERAPEUTIC DOGMA THAT MMP INHIBITORS NEED TO BE HIGHLY SELECTIVE MAY BE KEYED DOWN FOR THE TREATMENT OF LIFE-THREATENING CONDITIONS. WHEN INFLAMMATION AND MMP-9 FULFILL BENEFICIAL FUNCTIONS TO CLEAR DAMAGING PROTEIN COMPLEXES, SUCH AS IN SYSTEMIC AUTOIMMUNE DISEASES, THERAPEUTIC MMP INHIBITION HAS TO BE AVOIDED. IN MMP9 GENE KNOCKOUT MICE, SPECIFIC SPONTANEOUS PHENOTYPES EMERGED WITH EFFECTS ON THE SKELETAL, REPRODUCTIVE AND NERVOUS SYSTEMS. THESE FINDINGS NOT ONLY HAVE CLINICAL CORRELATES IN BONE GROWTH AND FERTILITY, BUT ALSO STIMULATE RESEARCH ON THE ROLES OF MMPS AND MMP-9 IN ENDOCRINOLOGY, IMMUNOLOGY AND THE NEUROSCIENCES. MMP9-DEFICIENT MICE ARE VALUABLE TOOLS TO DEFINE MMP-9 SUBSTRATES IN VIVO AND TO STUDY THE ROLE OF THIS ENZYME IN ANIMAL MODELS OF INFLAMMATORY, VASCULAR, NEOPLASTIC AND DEGENERATIVE DISEASES. FUTURE CHALLENGES INCLUDE SOLVING THE CRYSTAL STRUCTURE, DEFINITION OF THE FUNCTIONS OF COVALENT OLIGOMERS AND HETEROMERS IN BIOLOGY AND PATHOLOGY, LIFE-IMAGING OF MMP-9 ACTIVITY, SUBSTRATE DETERMINATION IN SITU AND THE STUDY OF INHIBITOR EFFECTS ON FERTILITY, CANCER AND INFLAMMATION AND IN NEUROBIOLOGY AND REGENERATIVE MEDICINE. SUCH STUDIES WILL BETTER DEFINE CONDITIONS IN WHICH INHIBITION OF MMP-9 IS BENEFICIAL OR HAS TO BE AVOIDED.	2013	

5   403  36 ANALYSIS OF EPIGENETIC AGE ACCELERATION AND HEALTHY LONGEVITY AMONG OLDER US WOMEN. IMPORTANCE: ACCELERATED BIOLOGICAL AGING IS ASSOCIATED WITH DECREASED PHYSICAL CAPABILITY AND COGNITIVE FUNCTIONING, WHICH ARE ASSOCIATED WITH INCREASED RISK OF MORBIDITY AND MORTALITY. OBJECTIVE: WE INVESTIGATED ASSOCIATIONS BETWEEN EPIGENETIC AGE ACCELERATION (EAA), A BIOMARKER ASSOCIATED WITH AGING, AND HEALTHY LONGEVITY AMONG OLDER WOMEN. DESIGN, SETTING, AND PARTICIPANTS: THIS COHORT STUDY WAS A SECONDARY ANALYSIS OF PARTICIPANTS IN THE WOMEN'S HEALTH INITIATIVE (WHI) WHO WERE ELIGIBLE TO SURVIVE TO AGE 90 YEARS BY SEPTEMBER 30, 2020. PARTICIPANTS WERE LOCATED IN MULTIPLE CENTERS. THIS STUDY WAS RESTRICTED TO WOMEN WITH GENOME-WIDE DNA METHYLATION DATA, GENERATED FROM BASELINE BLOOD SAMPLES WITHIN 3 WHI ANCILLARY STUDIES. MEDIAN (IQR) FOLLOW-UP TIMES FROM BASELINE WERE 21.6 (19.6-22.9) YEARS AND 21.4 (19.8-22.7) YEARS FOR WOMEN WHO SURVIVED TO AGE 90 YEARS WITH AND WITHOUT INTACT MOBILITY, RESPECTIVELY, AND 13.2 (8.8-16.7) FOR WOMEN WHO DID NOT SURVIVE TO AGE 90 YEARS. DATA WERE ANALYZED FROM DECEMBER 2020 TO JULY 2021. EXPOSURES: EAA WAS ESTIMATED USING 4 ESTABLISHED "CLOCKS": HORVATH PANTISSUE, HANNUM, PHENO, AND GRIM. MAIN OUTCOMES AND MEASURES: USING MULTINOMIAL LOGISTIC REGRESSION, ODDS RATIOS (ORS) AND 95% CIS WERE ESTIMATED FOR 3 HEALTHY LONGEVITY OUTCOMES FOR EACH CLOCK: SURVIVAL TO AGE 90 YEARS WITH INTACT MOBILITY, SURVIVAL TO AGE 90 YEARS WITHOUT INTACT MOBILITY, AND NO SURVIVAL TO AGE 90 YEARS. RESULTS: AMONG 1813 WOMEN, THERE WERE 464 WOMEN (MEAN [SD] AGE AT BASELINE, 71.6 [3.5] YEARS) WHO SURVIVED TO AGE 90 YEARS WITH INTACT MOBILITY AND COGNITIVE FUNCTIONING, 420 WOMEN (MEAN [SD] AGE AT BASELINE, 71.3 [3.2] YEARS) WHO SURVIVED TO AGE 90 YEARS WITHOUT INTACT MOBILITY AND COGNITIVE FUNCTIONING, AND 929 WOMEN (MEAN [SD] AGE AT BASELINE, 70.2 [3.4] YEARS) WHO DID NOT SURVIVE TO AGE 90 YEARS. WOMEN WHO SURVIVED TO AGE 90 YEARS WITH INTACT MOBILITY AND COGNITIVE FUNCTION WERE HEALTHIER AT BASELINE COMPARED WITH WOMEN WHO SURVIVED WITHOUT THOSE OUTCOMES OR WHO DID NOT SURVIVE TO AGE 90 YEARS (EG, 143 WOMEN [30.8%] VS 101 WOMEN [24.0%] AND 202 WOMEN [21.7%] WITH 0 CHRONIC CONDITIONS). THE ODDS OF SURVIVING TO AGE 90 YEARS WITH INTACT MOBILITY WERE LOWER FOR EVERY 1 SD INCREASE IN EAA COMPARED WITH THOSE WHO DID NOT SURVIVE TO AGE 90 YEARS AS MEASURED BY AGEACCELHORVATH (OR, 0.82; 95% CI, 0.69-0.96; P = .01), AGEACCELHANNUM (OR, 0.67; 95% CI, 0.56-0.80; P < .001), AGEACCELPHENO (OR, 0.60; 95% CI, 0.51-0.72; P < .001), AND AGEACCELGRIM (OR, 0.68; 95% CI, 0.55-0.84; P < .001). ORS WERE SIMILAR FOR WOMEN WHO SURVIVED TO AGE 90 YEARS WITH INTACT MOBILITY AND COGNITIVE FUNCTION (EG, AGEACCELHORVATH: OR PER 1 SD INCREASE IN EAA, 0.83; 95% CI, 0.71-0.98; P = .03) COMPARED WITH WOMEN WHO DID NOT SURVIVE TO AGE 90 YEARS. CONCLUSIONS AND RELEVANCE: THESE FINDINGS SUGGEST THAT EAA MAY BE A VALID BIOMARKER ASSOCIATED WITH HEALTHY LONGEVITY AMONG OLDER WOMEN AND MAY BE USED FOR RISK STRATIFICATION AND RISK ESTIMATION OF FUTURE FUNCTIONAL AND COGNITIVE AGING. OUTCOMES SUGGEST THAT FUTURE STUDIES MAY FOCUS ON THE POTENTIAL FOR PUBLIC HEALTH INTERVENTIONS TO COUNTERACT EAA AND ITS ASSOCIATION WITH POOR HEALTH OUTCOMES TO LOWER DISEASE BURDEN WHILE INCREASING LONGEVITY.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
6  5010  21 PEROXIDATION OF LINOLEIC, ARACHIDONIC AND OLEIC ACID IN RELATION TO THE INDUCTION OF OXIDATIVE DNA DAMAGE AND CYTOGENETIC EFFECTS. IN THE PRESENT STUDY, THE POSSIBLE ROLE OF THE POLYUNSATURATED FATTY ACIDS LINOLEIC AND ARACHIDONIC ACID IN THE CHEMICAL INDUCTION OF CARCINOGENESIS HAS BEEN INVESTIGATED. ANALYSIS OF 7,8-DIHYDRO-8-OXO-2'-DEOXYGUANOSINE (8-OXODG) LEVELS IN 2'-DEOXYGUANOSINE (DG) AND ISOLATED DNA HAS DEMONSTRATED THAT LINOLEIC AND ARACHIDONIC ACID ARE CAPABLE OF INDUCING THIS SPECIFIC GENOTOXIC DAMAGE. THIS EFFECT APPEARS TO BE RELATED TO THE DEGREE OF FATTY ACID UNSATURATION, SINCE IT WAS NOT INDUCED BY MONOUNSATURATED OLEIC ACID. ENZYMATIC PEROXIDATION OF LINOLEIC AND ARACHIDONIC ACID RESULTED IN A SIGNIFICANT INCREASE IN OXIDATIVE DNA DAMAGE. STUDIES ON THE INTERFERENCE OF RADICAL SCAVENGERS WITH THE INDUCTION OF 8-OXODG IN COMBINATION WITH ELECTRON SPIN RESONANCE SPECTROSCOPY DEMONSTRATED THAT THE SUPEROXIDE ANION WAS GENERATED DURING PEROXIDATION OF THESE FATTY ACIDS AND THAT SINGLET OXYGEN IS MOST LIKELY INVOLVED IN THE FORMATION OF OXIDATIVE DNA DAMAGE. THE LEVEL OF OXIDATIVE DAMAGE IN DG AND SINGLE-STRANDED DNA WAS HIGHER AS COMPARED TO THAT IN NATIVE DNA AFTER EQUIMOLAR TREATMENT. EXPOSURE OF HUMAN LYMPHOCYTES TO LINOLEIC OR ARACHIDONIC ACID DID NOT RESULT IN A SIGNIFICANT INCREASE IN LEVELS OF 8-OXODG. THIS MAY INDICATE THAT THE RATE OF INTRACELLULAR PEROXIDATION IS RELATIVELY LOW AND/OR THAT NUCLEAR DNA IN INTACT CELLS IS EFFECTIVELY PROTECTED AGAINST GENETIC DAMAGE INDUCED BY REACTIVE OXYGEN SPECIES. IT IS THEREFORE CONCLUDED THAT RELATIVELY SHORT PERIODS OF LINOLEIC OR ARACHIDONIC ACID ADMINISTRATION ARE NOT LIKELY TO IMPOSE A DIRECT GENOTOXIC RISK. IT CAN, HOWEVER, NOT BE EXCLUDED THAT CHRONIC EXPOSURE TO POLYUNSATURATED FATTY ACIDS INDUCES OXIDATIVE DNA DAMAGE OR IS RELATED TO CANCER RISK BY EPIGENETIC MECHANISMS, AS IS ALSO INDICATED BY THE OBSERVED CYTOTOXIC EFFECTS OF LINOLEIC AND ARACHIDONIC ACID.	1994	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
7  4092  22 MATERNAL REPETITIVE HYPOXIA PRIOR TO MATING CONFERS EPIGENETIC RESILIENCE TO MEMORY IMPAIRMENT IN MALE PROGENY. WE SHOWED PREVIOUSLY IN A MOUSE MODEL OF VASCULAR COGNITIVE IMPAIRMENT AND DEMENTIA INVOLVING CHRONIC CEREBRAL HYPOPERFUSION (CCH) THAT REPETITIVE HYPOXIC CONDITIONING (RHC) OF BOTH PARENTS RESULTS IN THE EPIGENETIC, INTERGENERATIONAL TRANSMISSION OF RESILIENCE TO RECOGNITION MEMORY LOSS IN ADULT PROGENY, AS ASSESSED BY THE NOVEL OBJECT RECOGNITION TEST. THE PRESENT STUDY WAS UNDERTAKEN IN THE SAME MODEL TO DETERMINE WHETHER RHC TREATMENT OF ONE OR BOTH PARENTS IS REQUIRED TO CONFER DEMENTIA RESILIENCE INTERGENERATIONALLY. WE FOUND INHERITED RESILIENCE TO 3 MONTHS OF CCH IN MALES IS MATERNALLY MEDIATED (P = .006). STATISTICALLY, WE OBSERVED A STRONG TREND FOR THE PATERNAL GERMLINE TO CONTRIBUTE AS WELL (P = .052). WE ALSO FOUND THAT, IN CONTRAST TO WHAT IS WIDELY OBSERVED IN MALES, FEMALES DISPLAY INTACT RECOGNITION MEMORY (P = .001) AFTER 3 MONTHS OF CCH, REVEALING A HERETOFORE UNIDENTIFIED SEXUAL DIMORPHISM WITH RESPECT TO COGNITIVE IMPACT DURING DISEASE PROGRESSION. OVERALL, RESULTS OF OUR STUDY STRONGLY IMPLICATE EPIGENETIC CHANGES IN MATERNAL GERM CELLS, INDUCED BY OUR REPETITIVE SYSTEMIC HYPOXIC STIMULUS, CONTRIBUTING TO A MODIFIED DIFFERENTIATION PROGRAM CAPABLE OF ESTABLISHING A DEMENTIA-RESILIENT PHENOTYPE IN ADULT MALE FIRST-GENERATION PROGENY. (PSYCINFO DATABASE RECORD (C) 2023 APA, ALL RIGHTS RESERVED).	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
8  5818  23 STRESS AND TRAUMA: BDNF CONTROL OF DENDRITIC-SPINE FORMATION AND REGRESSION. CHRONIC RESTRAINT STRESS LEADS TO INCREASES IN BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) MRNA AND PROTEIN IN SOME REGIONS OF THE BRAIN, E.G. THE BASAL LATERAL AMYGDALA (BLA) BUT DECREASES IN OTHER REGIONS SUCH AS THE CA3 REGION OF THE HIPPOCAMPUS AND DENDRITIC SPINE DENSITY INCREASES OR DECREASES IN LINE WITH THESE CHANGES IN BDNF. GIVEN THE POWERFUL INFLUENCE THAT BDNF HAS ON DENDRITIC SPINE GROWTH, THESE OBSERVATIONS SUGGEST THAT THE FUNDAMENTAL REASON FOR THE DIRECTION AND EXTENT OF CHANGES IN DENDRITIC SPINE DENSITY IN A PARTICULAR REGION OF THE BRAIN UNDER STRESS IS DUE TO THE CHANGES IN BDNF THERE. THE MOST LIKELY CAUSE OF THESE CHANGES IS PROVIDED BY THE STRESS INITIATED RELEASE OF STEROIDS, WHICH READILY ENTER NEURONS AND ALTER GENE EXPRESSION, FOR EXAMPLE THAT OF BDNF. OF PARTICULAR INTEREST IS HOW GLUCOCORTICOIDS AND MINERALOCORTICOIDS TEND TO HAVE OPPOSITE EFFECTS ON BDNF GENE EXPRESSION OFFERING THE POSSIBILITY THAT DIFFERENCES IN THE DISTRIBUTION OF THEIR RECEPTORS AND OF THEIR DOWNSTREAM EFFECTS MIGHT PROVIDE A BASIS FOR THE DIFFERENTIAL TRANSCRIPTION OF THE BDNF GENES. ALTERNATIVELY, DIFFERENCES IN THE EXTENT OF METHYLATION AND ACETYLATION IN THE EPIGENETIC CONTROL OF BDNF TRANSCRIPTION ARE POSSIBLE IN DIFFERENT PARTS OF THE BRAIN FOLLOWING STRESS. ALTHOUGH PRESENT EVIDENCE POINTS TO CHANGES IN BDNF TRANSCRIPTION BEING THE MAJOR CAUSAL AGENT FOR THE CHANGES IN SPINE DENSITY IN DIFFERENT PARTS OF THE BRAIN FOLLOWING STRESS, STEROIDS HAVE SIGNIFICANT EFFECTS ON DOWNSTREAM PATHWAYS FROM THE TRKB RECEPTOR ONCE IT IS ACTED UPON BY BDNF, INCLUDING THOSE THAT MODULATE THE DENSITY OF DENDRITIC SPINES. FINALLY, ALTHOUGH GLUCOCORTICOIDS PLAY A CANONICAL ROLE IN DETERMINING BDNF MODULATION OF DENDRITIC SPINES, RECENT STUDIES HAVE SHOWN A ROLE FOR CORTICOTROPHIN RELEASING FACTOR (CRF) IN THIS REGARD. THERE IS CONSIDERABLE IMPROVEMENT IN THE EXTENT OF CHANGES IN SPINE SIZE AND DENSITY IN RODENTS WITH FOREBRAIN SPECIFIC KNOCKOUT OF CRF RECEPTOR 1 (CRFR1) EVEN WHEN THE GLUCOCORTICOID PATHWAYS ARE LEFT INTACT. IT SEEMS THEN THAT CRF DOES HAVE A ROLE TO PLAY IN DETERMINING BDNF CONTROL OF DENDRITIC SPINES.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
9  6418  37 THE TEMPORAL EXPRESSION OF CIRCULATING MICRORNAS AFTER ACUTE EXPERIMENTAL PAIN IN HUMANS. BACKGROUND: MICRORNAS (MIRNAS) CAN MODULATE SEVERAL BIOLOGICAL SYSTEMS, INCLUDING THE PAIN SYSTEM. THIS STUDY AIMED TO EVALUATE THE TEMPORAL EXPRESSION OF CIRCULATING MIRNAS IN THE PLASMA OF HEALTHY VOLUNTEERS AS A MARKER FOR EPIGENETIC CHANGES BEFORE AND AFTER AN ACUTE, EXPERIMENTAL, PAIN PROVOCATION BY INTRAMUSCULAR HYPERTONIC SALINE INJECTION. METHODS: TWENTY VOLUNTEERS WERE RANDOMLY ALLOCATED INTO TWO GROUPS AND RECEIVED EITHER HYPERTONIC (PAIN) OR ISOTONIC (CONTROL) SALINE INJECTION IN THE FIRST DORSAL INTEROSSEOUS MUSCLE OF THEIR DOMINANT HAND. PAIN INTENSITY WAS CONTINUOUSLY RECORDED FOR 20 MINUTES AFTER INJECTION ON A VAS SCALE FROM 0 TO 100 (0 INDICATES NO PAIN AND 100 THE WORST IMAGINABLE PAIN). BLOOD SAMPLES WERE TAKEN AT BASELINE, 30 MINUTES, 3 HOURS, AND 24 HOURS POST-INJECTION, AND PLASMA WAS SEPARATED. MIRNA EXTRACTS WERE USED FOR RNA SEQUENCING WITH THE ILLUMINA NEXTSEQ PLATFORM. MIRNA TRANSCRIPTS WERE COMPARED BETWEEN THE PAIN AND THE NO-PAIN, CONTROL GROUP AT EVERY TIME POINT. SIGNIFICANT DIFFERENCES WERE CONSIDERED WHEN FOLDS WERE >2 AND THE FALSE DISCOVERY RATE WAS P < 0.05. RESULTS: AFTER 30 MINUTES, 4 MIRNAS WERE SIGNIFICANTLY ALTERED IN THE PAIN GROUP COMPARED TO CONTROLS, WHICH INCREASED TO 24 AFTER 3 HOURS AND TO 42 AFTER 24 HOURS FROM BASELINE (P < 0.0001). TWO MIRNAS WERE CONSISTENTLY UPREGULATED THROUGHOUT THE EXPERIMENT. ENRICHMENT ANALYSIS SHOWED SIGNIFICANT MIRNAS INVOLVED IN BRAIN PERCEPTION OF PAIN, BRAIN SIGNALLING AND RESPONSE TO STIMULI. CONCLUSIONS: THIS EXPLORATORY STUDY IS THE FIRST TO REPORT ON THE TEMPORAL EXPRESSION OF CIRCULATING MIRNAS AFTER AN ACUTE, HUMAN EXPERIMENTAL MUSCLE PAIN MODEL. SIGNIFICANCE: THIS EXPLORATORY STUDY EVALUATED THE TEMPORAL PROFILE OF CIRCULATING MIRNAS IN THE PLASMA OF HEALTHY SUBJECTS AFTER ACUTE EXPERIMENTAL PAIN. SEVERAL MIRNAS WERE ALTERED IN SUBJECTS AT THE TIMES OF FOLLOW-UP AFTER THE ACUTE PAIN MODEL WHEN COMPARED TO CONTROLS. MIRNAS PREVIOUSLY ASSOCIATED WITH PAIN PROCESSES WERE ALTERED IN THE PAIN GROUP. OUR RESULTS, BY SHOWING THE FAST AND PROLONGED MODIFICATIONS OF MIRNA ELICITED BY THE ACUTE EXPERIMENTAL PAIN MODEL, ADD NEW PERSPECTIVES TO THE TOPIC OF EPIGENETICS AND PAIN.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
10   219  31 ACUTE IMMOBILIZATION STRESS FOLLOWING CONTEXTUAL FEAR CONDITIONING REDUCES FEAR MEMORY: TIMING IS ESSENTIAL. BACKGROUND: HISTONE ACETYLATION IS REGULATED IN RESPONSE TO STRESS AND PLAYS AN IMPORTANT ROLE IN LEARNING AND MEMORY. CHRONIC STRESS IS KNOWN TO DETERIORATE COGNITION, WHEREAS ACUTE STRESS FACILITATES MEMORY FORMATION. HOWEVER, WHETHER ACUTE STRESS FACILITATES MEMORY FORMATION WHEN IT IS APPLIED AFTER FEAR STIMULATION IS NOT YET KNOWN. THEREFORE, THIS STUDY AIMED TO INVESTIGATE THE EFFECT OF ACUTE STRESS APPLIED AFTER FEAR TRAINING ON MEMORY FORMATION, MRNA EXPRESSION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), EPIGENETIC REGULATION OF BDNF EXPRESSION, AND CORTICOSTERONE LEVEL IN MICE IN VIVO. METHODS: MICE WERE SUBJECTED TO ACUTE IMMOBILIZATION STRESS FOR 30 MIN AT 60 OR 90 MIN AFTER CONTEXTUAL FEAR CONDITIONING TRAINING, AND ACETYLATION OF HISTONE 3 AT LYSINE 14 (H3K14) AND LEVEL OF CORTICOSTERONE WERE MEASURED USING WESTERN BLOT ANALYSIS AND ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA), RESPECTIVELY. A FREEZING BEHAVIOR TEST WAS PERFORMED 24 H AFTER TRAINING, AND MRNA EXPRESSION OF BDNF WAS MEASURED USING REAL-TIME POLYMERASE CHAIN REACTIONS. DIFFERENT GROUPS OF MICE WERE USED FOR EACH TEST. RESULTS: FREEZING BEHAVIOR SIGNIFICANTLY DECREASED WITH THE DOWN-REGULATION OF BDNF MRNA EXPRESSION CAUSED BY ACUTE IMMOBILIZATION STRESS AT 60 MIN AFTER FEAR CONDITIONING TRAINING OWING TO THE REDUCTION OF H3K14 ACETYLATION. HOWEVER, BDNF MRNA EXPRESSION AND H3K14 ACETYLATION WERE NOT REDUCED IN ANIMALS SUBJECTED TO IMMOBILIZATION STRESS AT 90 MIN AFTER THE TRAINING. FURTHER, THE CORTICOSTERONE LEVEL WAS SIGNIFICANTLY HIGH IN MICE SUBJECTED TO IMMOBILIZATION STRESS AT 60 MIN AFTER THE TRAINING. CONCLUSION: ACUTE IMMOBILIZATION STRESS FOR 30 MIN AT 60 MIN AFTER FEAR CONDITIONING TRAINING IMPAIRED MEMORY FORMATION AND REDUCED BDNF MRNA EXPRESSION AND H3K14 ACETYLATION IN THE HIPPOCAMPUS OF MICE OWING TO THE HIGH LEVEL OF CORTICOSTERONE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
11  3380  20 HIV-1 INFECTION OF GENETICALLY ENGINEERED IPSC-DERIVED CENTRAL NERVOUS SYSTEM-ENGRAFTED MICROGLIA IN A HUMANIZED MOUSE MODEL. THE CENTRAL NERVOUS SYSTEM (CNS) IS A MAJOR HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 RESERVOIR. MICROGLIA ARE THE PRIMARY TARGET CELL OF HIV-1 INFECTION IN THE CNS. CURRENT MODELS HAVE NOT ALLOWED THE PRECISE MOLECULAR PATHWAYS OF ACUTE AND CHRONIC CNS MICROGLIAL INFECTION TO BE TESTED WITH IN VIVO GENETIC METHODS. HERE, WE DESCRIBE A NOVEL HUMANIZED MOUSE MODEL UTILIZING HUMAN-INDUCED PLURIPOTENT STEM CELL-DERIVED MICROGLIA TO XENOGRAFT INTO MURINE HOSTS. THESE MICE ARE ADDITIONALLY ENGRAFTED WITH HUMAN PERIPHERAL BLOOD MONONUCLEAR CELLS THAT SERVED AS A MEDIUM TO ESTABLISH A PERIPHERAL INFECTION THAT THEN SPREAD TO THE CNS MICROGLIA XENOGRAFT, MODELING A TRANS-BLOOD-BRAIN BARRIER ROUTE OF ACUTE CNS HIV-1 INFECTION WITH HUMAN TARGET CELLS. THE APPROACH IS COMPATIBLE WITH IPSC GENETIC ENGINEERING, INCLUDING INSERTING TARGETED TRANSGENIC REPORTER CASSETTES TO TRACK THE XENOGRAFTED HUMAN CELLS, ENABLING THE TESTING OF NOVEL TREATMENT AND VIRAL TRACKING STRATEGIES IN A COMPARATIVELY SIMPLE AND COST-EFFECTIVE WAY VIVO MODEL FOR NEUROHIV. IMPORTANCE: OUR MOUSE MODEL IS A POWERFUL TOOL FOR INVESTIGATING THE GENETIC MECHANISMS GOVERNING CNS HIV-1 INFECTION AND LATENCY IN THE CNS AT A SINGLE-CELL LEVEL. A MAJOR ADVANTAGE OF OUR MODEL IS THAT IT USES IPSC-DERIVED MICROGLIA, WHICH ENABLES HUMAN GENETICS, INCLUDING GENE FUNCTION AND THERAPEUTIC GENE MANIPULATION, TO BE EXPLORED IN VIVO , WHICH IS MORE CHALLENGING TO STUDY WITH CURRENT HEMATOPOIETIC STEM CELL-BASED MODELS FOR NEUROHIV. OUR TRANSGENIC TRACING OF XENOGRAFTED HUMAN CELLS WILL PROVIDE A QUANTITATIVE MEDIUM TO DEVELOP NEW MOLECULAR AND EPIGENETIC STRATEGIES FOR REDUCING THE HIV-1 LATENT RESERVOIR AND TO TEST THE IMPACT OF THERAPEUTIC INFLAMMATION-TARGETING DRUG INTERVENTIONS ON CNS HIV-1 LATENCY.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
12  3419  12 HUMAN LINE-1 RETROTRANSPOSONS: IMPACTS ON THE GENOME AND REGULATION BY HOST FACTORS. GENOME SEQUENCING REVEALED THAT NEARLY HALF OF THE HUMAN GENOME IS COMPRISED OF TRANSPOSABLE ELEMENTS. ALTHOUGH MOST OF THESE ELEMENTS HAVE BEEN RENDERED INACTIVE DUE TO MUTATIONS, FULL-LENGTH INTACT LONG INTERSPERSED ELEMENT-1 (LINE-1 OR L1) COPIES RETAIN THE ABILITY TO MOBILIZE THROUGH RNA INTERMEDIATES BY A SO-CALLED "COPY-AND-PASTE" MECHANISM, TERMED RETROTRANSPOSITION. L1 IS THE ONLY KNOWN AUTONOMOUS MOBILE GENETIC ELEMENT IN THE GENOME, AND ITS RETROTRANSPOSITION CONTRIBUTES TO INTER- OR INTRA-INDIVIDUAL GENETIC VARIATION WITHIN THE HUMAN POPULATION. HOWEVER, L1 RETROTRANSPOSITION ALSO POSES A THREAT TO GENOME INTEGRITY DUE TO GENE DISRUPTION AND CHROMOSOMAL INSTABILITY. MOREOVER, RECENT STUDIES SUGGEST THAT ABERRANT L1 EXPRESSION CAN IMPACT HUMAN HEALTH BY CAUSING DISEASES SUCH AS CANCER AND CHRONIC INFLAMMATION THAT MIGHT LEAD TO AUTOIMMUNE DISORDERS. TO COUNTERACT THESE ADVERSE EFFECTS, THE HOST CELLS HAVE EVOLVED MULTIPLE LAYERS OF DEFENSE MECHANISMS AT THE EPIGENETIC, RNA AND PROTEIN LEVELS. INTRIGUINGLY, SEVERAL HOST FACTORS HAVE ALSO BEEN REPORTED TO FACILITATE L1 RETROTRANSPOSITION, SUGGESTING THAT THERE IS COMPETITION BETWEEN NEGATIVE AND POSITIVE REGULATION OF L1 BY HOST FACTORS. HERE, WE SUMMARIZE THE KNOWN HOST PROTEINS THAT REGULATE L1 ACTIVITY AT DIFFERENT STAGES OF THE REPLICATION CYCLE AND DISCUSS HOW THESE FACTORS MODULATE DISEASE-ASSOCIATED PHENOTYPES CAUSED BY L1.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
13  1699  24 DYNAMIC EPIGENETIC CHANGES DURING A RELAPSE AND RECOVERY CYCLE IN MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME. MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS) IS A COMPLEX DISEASE WITH VARIABLE SEVERITY. PATIENTS EXPERIENCE FREQUENT RELAPSES WHERE SYMPTOMS INCREASE IN SEVERITY, LEAVING THEM WITH A MARKED REDUCTION IN QUALITY OF LIFE. PREVIOUS WORK HAS INVESTIGATED MOLECULAR DIFFERENCES BETWEEN ME/CFS PATIENTS AND HEALTHY CONTROLS, BUT NOT THE DYNAMIC CHANGES SPECIFIC TO EACH INDIVIDUAL PATIENT. WE APPLIED PRECISION MEDICINE HERE TO MAP GENOMIC CHANGES IN TWO SELECTED ME/CFS PATIENTS THROUGH A PERIOD THAT CONTAINED A RELAPSE RECOVERY CYCLE. DNA WAS ISOLATED FROM TWO PATIENTS AND A HEALTHY AGE/GENDER MATCHED CONTROL AT REGULAR INTERVALS AND CAPTURED THE PATIENT RELAPSE IN EACH CASE. REDUCED REPRESENTATION DNA METHYLATION SEQUENCING PROFILES WERE OBTAINED SPANNING THE RELAPSE RECOVERY CYCLE. BOTH PATIENTS SHOWED A SIGNIFICANTLY LARGER METHYLOME VARIABILITY (10-20-FOLD) THROUGH THE PERIOD OF SAMPLING COMPARED WITH THE CONTROL. DURING THE RELAPSE, CHANGES IN THE METHYLOME PROFILES OF THE TWO PATIENTS WERE DETECTED IN REGULATORY-ACTIVE REGIONS OF THE GENOME THAT WERE ASSOCIATED, RESPECTIVELY, WITH 157 AND 127 DOWNSTREAM GENES, INDICATING DISTURBED METABOLIC, IMMUNE AND INFLAMMATORY FUNCTIONS. SEVERE HEALTH RELAPSES IN THE ME/CFS PATIENTS RESULTED IN FUNCTIONALLY IMPORTANT CHANGES IN THEIR DNA METHYLOMES THAT, WHILE DIFFERING BETWEEN THE TWO PATIENTS, LED TO VERY SIMILAR COMPROMISED PHYSIOLOGY. DNA METHYLATION AS A SIGNATURE OF DISEASE VARIABILITY IN ONGOING ME/CFS MAY HAVE PRACTICAL APPLICATIONS FOR STRATEGIES TO DECREASE RELAPSE FREQUENCY.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
14  6079  18 THE EFFECT OF CXCL12 PROCESSING ON CD34+ CELL MIGRATION IN MYELOPROLIFERATIVE NEOPLASMS. PRIMARY MYELOFIBROSIS (PMF) AND POLYCYTHEMIA VERA (PV) ARE CHRONIC MYELOPROLIFERATIVE NEOPLASMS. PMF AND, TO A LESSER DEGREE, PV ARE CHARACTERIZED BY CONSTITUTIVE MOBILIZATION OF HEMATOPOIETIC STEM CELLS (HSC) AND PROGENITOR CELLS (HPC) INTO THE PERIPHERAL BLOOD (PB). THE INTERACTION BETWEEN THE CHEMOKINE CXCL12 AND ITS RECEPTOR CXCR4 PLAYS A PIVOTAL ROLE IN DETERMINING THE TRAFFICKING OF CD34(+) CELLS BETWEEN THE BONE MARROW (BM) AND THE PB. PMF, BUT NOT PV, IS ASSOCIATED WITH DOWNREGULATION OF CXCR4 BY CD34(+) CELLS DUE TO EPIGENETIC EVENTS. BOTH PV AND PMF PATIENTS HAVE ELEVATED LEVELS OF IMMUNOREACTIVE FORMS OF CXCL12 IN THE BM AND PB. USING ELECTROSPRAY MASS SPECTROMETRY, THE PB AND BM PLASMA OF PV AND PMF PATIENTS WAS SHOWN TO CONTAIN REDUCED AMOUNTS OF INTACT CXCL12 BUT SIGNIFICANT AMOUNTS OF SEVERAL TRUNCATED FORMS OF CXCL12, WHICH ARE LACKING IN NORMAL PB AND BM PLASMA. THESE TRUNCATED FORMS OF CXCL12 ARE THE PRODUCT OF THE ACTION OF SEVERAL SERINE PROTEASES, INCLUDING DIPEPTIDYL PEPTIDASE-IV, NEUTROPHIL ELASTASE, MATRIX METALLOPROTEINASE-2 (MMP-2), MMP-9, AND CATHEPSIN G. UNLIKE CXCL12, THESE TRUNCATES EITHER LACK THE ABILITY TO ACT AS A CHEMOATTRACTANT FOR CD34(+) CELLS AND/OR ACT AS AN ANTAGONIST TO THE ACTION OF CXCL12. THESE DATA SUGGEST THAT PROTEOLYTIC DEGRADATION OF CXCL12 IS CHARACTERISTIC OF BOTH PV AND PMF AND THAT THE RESULTING TRUNCATED FORMS OF CXCL12, IN ADDITION TO THE REDUCED EXPRESSION OF CXCR4 BY CD34(+) CELLS, LEAD TO A PROFOUND MOBILIZATION OF HSC/HPC IN PMF.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
15  2889  21 GAIN-OF-FUNCTION STAT1 MUTATIONS IMPAIR STAT3 ACTIVITY IN PATIENTS WITH CHRONIC MUCOCUTANEOUS CANDIDIASIS (CMC). SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 (STAT3) TRIGGERED PRODUCTION OF TH-17 CYTOKINES MEDIATES PROTECTIVE IMMUNITY AGAINST FUNGI. MUTATIONS AFFECTING THE STAT3/INTERLEUKIN 17 (IL-17) PATHWAY CAUSE SELECTIVE SUSCEPTIBILITY TO FUNGAL (CANDIDA) INFECTIONS, A HALLMARK OF CHRONIC MUCOCUTANEOUS CANDIDIASIS (CMC). IN PATIENTS WITH AUTOSOMAL DOMINANT CMC, WE AND OTHERS PREVIOUSLY REPORTED DEFECTIVE TH17 RESPONSES AND UNDERLYING GAIN-OF-FUNCTION (GOF) STAT1 MUTATIONS, BUT HOW THIS AFFECTS STAT3 FUNCTION LEADING TO DECREASED IL-17 IS UNCLEAR. WE ALSO ASSESSED HOW GOF-STAT1 MUTATIONS AFFECT STAT3 ACTIVATION, DNA BINDING, GENE EXPRESSION, CYTOKINE PRODUCTION, AND EPIGENETIC MODIFICATIONS. WE EXCLUDED IMPAIRED STAT3 PHOSPHORYLATION, NUCLEAR TRANSLOCATION, AND SEQUESTRATION OF STAT3 INTO STAT1/STAT3 HETERODIMERS AND CONFIRM SIGNIFICANTLY REDUCED TRANSCRIPTION OF STAT3-INDUCIBLE GENES (RORC/IL-17/IL-22/IL-10/C-FOS/SOCS3/C-MYC) AS LIKELY UNDERLYING MECHANISM. STAT BINDING TO THE HIGH AFFINITY SIS-INDUCIBLE ELEMENT WAS INTACT BUT BINDING TO AN ENDOGENOUS STAT3 DNA TARGET WAS IMPAIRED. REDUCED STAT3-DEPENDENT GENE TRANSCRIPTION WAS REVERSED BY INHIBITING STAT1 ACTIVATION WITH FLUDARABINE OR ENHANCING HISTONE, BUT NOT STAT1 OR STAT3 ACETYLATION WITH HISTONE DEACETYLASE (HDAC) INHIBITORS TRICHOSTATIN A OR ITF2357. SILENCING HDAC1, HDAC2, AND HDAC3 INDICATED A ROLE FOR HDAC1 AND 2. REDUCED STAT3-DEPENDENT GENE TRANSCRIPTION UNDERLIES LOW TH-17 RESPONSES IN GOF-STAT1 CMC, WHICH CAN BE REVERSED BY INHIBITING ACETYLATION, OFFERING NOVEL TARGETS FOR FUTURE THERAPIES.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
16  3850  24 IS GENDER A FACTOR AFFECTING LONG-TERM HETEROTOPIC OSSIFICATION INCIDENCE AFTER SINGLE-LEVEL CERVICAL DISC ARTHROPLASTY? BACKGROUND: CERVICAL DISC DISEASES HAVE BEEN TREATED BY CERVICAL DISC ARTHROPLASTY (CDA). NEVERTHELESS, SOME PATIENTS WILL EXPERIENCE A MOBILITY FAILURE IN THEIR CERVICAL PROSTHESES OVER TIME BECAUSE OF HETEROTOPIC OSSIFICATION. THE AIM OF THIS STUDY WAS TO INVESTIGATE THE ROLE OF GENDER IN LONG-TERM OUTCOMES AFTER CDA. METHODS: A RETROSPECTIVE, SINGLE-CENTER STUDY OF PATIENTS WHO UNDERWENT SINGLE-LEVEL CDA WITH A BRYAN CERVICAL DISC PROSTHESIS WAS PERFORMED, INCLUDING A NARRATIVE REVIEW ABOUT GENDER DIFFERENCES IN BOTH STRUCTURAL AND BIOMECHANICAL FEATURES OF THE CERVICAL SPINE. RESULTS: STUDY PATIENTS (14 MEN, 30 WOMEN) HAD AN AVERAGE FOLLOW-UP OF 9.8 +/- 3.2 YEARS. SIGNIFICANT DIFFERENCES EMERGED BETWEEN GENDERS FOR SPECIFIC ITEMS IN NECK DISABILITY INDEX PREOPERATIVE EVALUATION, WITH WOMEN REPORTING WORSE PAIN SCORES (P = 0.05). AFTER STRATIFICATION BY AGE, WE FOUND A HIGHER PREOPERATIVE OVERALL NECK DISABILITY INDEX SCORE FOR FEMALE PATIENTS <36 YEARS OF AGE (P = 0.03). IN AN INTERGENDER, BODY MASS INDEX-SPECIFIC COMPARISON, WE ALSO FOUND A SIGNIFICANT DIFFERENCE IN NECK DISABILITY INDEX PREOPERATIVE SCORE WITH NORMAL-WEIGHT MALE PATIENTS FARING WORSE THAN OVERWEIGHT MALE PATIENTS (P = 0.05). AT A RADIOLOGICAL LEVEL, WE FOUND A TENDENCY TOWARD A HIGHER HETEROTOPIC OSSIFICATION INCIDENCE IN MALE PATIENTS (62% IN MEN, 17% IN WOMEN, P = 0.06). THE FEMALE CERVICAL SPINE HAS DISTINCTIVE FEATURES, INCLUDING BONE STRUCTURE, MUSCULAR ACTION, SOFT TISSUE RESPONSE, AND GENETIC AND EPIGENETIC RESPONSE TO OSTEOARTHRITIS. CONCLUSIONS: THE INCIDENCE OF MOBILITY FAILURE IN OUR SERIES OF SINGLE-LEVEL CDA WAS LOWER IN FEMALE PATIENTS. SEVERAL GENDER-SPECIFIC FACTORS BOTH IN STATIC AND IN DYNAMIC FEATURES MAY PLAY A SIGNIFICANT ROLE IN SPINAL PATHOLOGY AND CDA LONG-TERM RADIOLOGICAL OUTCOME.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
17  5207  29 PRENATAL STRESS INDUCES SPATIAL MEMORY DEFICITS AND EPIGENETIC CHANGES IN THE HIPPOCAMPUS INDICATIVE OF HETEROCHROMATIN FORMATION AND REDUCED GENE EXPRESSION. STRESS DURING PREGNANCY HAS A WIDE VARIETY OF NEGATIVE EFFECTS IN BOTH HUMAN [1] AND ANIMAL OFFSPRING [2]. THESE EFFECTS ARE ESPECIALLY APPARENT IN VARIOUS FORMS OF LEARNING AND MEMORY SUCH AS OBJECT RECOGNITION [3] AND SPATIAL MEMORY [4]. THE COGNITIVE EFFECTS OF PRENATAL STRESS (PNS) MAY BE MEDIATED THROUGH EPIGENETIC CHANGES SUCH AS HISTONE ACETYLATION AND DNA METHYLATION [5]. AS SUCH, THE PRESENT STUDY INVESTIGATED THE EFFECTS OF CHRONIC UNPREDICTABLE PNS ON MEMORY AND EPIGENETIC MEASURES IN ADULT OFFSPRING. MICE THAT UNDERWENT PNS EXHIBITED IMPAIRED SPATIAL MEMORY IN THE MORRIS WATER MAZE, AS WELL AS SEX-SPECIFIC CHANGES IN LEVELS OF DNA METHYLTRANSFERASE (DNMT) 1 PROTEIN, AND ACETYLATED HISTONE H3 (ACH3) IN THE HIPPOCAMPUS, AND SERUM CORTICOSTERONE. MALE MICE EXPOSED TO PNS EXHIBITED DECREASED HIPPOCAMPAL ACH3, WHEREAS FEMALE PNS MICE DISPLAYED A FURTHER REDUCTION IN ACH3, AS WELL AS HEIGHTENED HIPPOCAMPAL DNMT1 PROTEIN LEVELS AND CORTICOSTERONE LEVELS. THESE DATA SUGGEST THAT PNS MAY EPIGENETICALLY REDUCE TRANSCRIPTION IN THE HIPPOCAMPUS, PARTICULARLY IN FEMALES IN WHOM THIS EFFECT MAY BE RELATED TO INCREASED BASELINE STRESS HORMONE LEVELS, AND WHICH MAY UNDERLIE THE SEXUAL DIMORPHISM IN RATES OF MENTAL ILLNESS IN HUMANS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
18  4947  38 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
19  4081  27 MATERNAL MICRONUTRIENT SUPPLEMENTATION SUPPRESSES T CELL CHEMOKINE RECEPTOR EXPRESSION AND FUNCTION IN F1 MICE. PRENATAL ENVIRONMENTAL EXPOSURES PLAY A CRITICAL ROLE IN DETERMINING LATE-LIFE CHRONIC DISEASE SUSCEPTIBILITY. HOWEVER, THE MECHANISMS LINKING THE IN UTERO ENVIRONMENT AND DISEASE DEVELOPMENT IN THE OFFSPRING ARE POORLY UNDERSTOOD. RECENT INVESTIGATIONS HAVE CONFIRMED A CENTRAL PATHOGENIC ROLE OF T CELL CHEMOKINE RECEPTORS, PARTICULARLY C-C CHEMOKINE RECEPTOR (CCR) 2 AND CCR5, IN CHRONIC INFLAMMATORY CONDITIONS. THIS STUDY WAS DESIGNED TO DETERMINE THE EFFECT OF A SYNTHETIC PRENATAL MICRONUTRIENT SUPPLEMENTATION (MS) DIET RICH IN METHIONINE PATHWAY METABOLITES ON THE T CELL CHEMOKINE SYSTEM IN F1 C57BL/6 MICE. FEMALE MICE WERE FED EITHER AN MS OR CONTROL DIET 3 WK PRIOR TO MATING, DURING PREGNANCY, AND LACTATION. AT 4 WK OF AGE, F1 MICE WERE KILLED FOR EXPERIMENTS OR WERE FED THE STANDARD NIH-31 DIET AND ALLOWED TO AGE. FOOD CONSUMPTION, MATERNAL WEIGHT GAIN, AND LITTER SIZE WERE SIMILAR IN DAMS FED THE CONTROL AND MS DIETS. HOWEVER, THE F1 OFFSPRING OF DAMS FED THE MS DIET WERE SMALLER IN SIZE (P < 0.001). T CELLS FROM THE MS F1 OFFSPRING HAD GLOBAL HYPERMETHYLATION COMPARED WITH CONTROL F1 OFFSPRING (P < 0.005), CORRESPONDING TO LOWER T CELL CHEMOKINE RECEPTOR EXPRESSION [CCR2 (P < 0.001), CCR5 (P < 0.001), AND C-X-C CHEMOKINE RECEPTOR 3 (P < 0.01)] AND CYTOKINE EXPRESSION [TNFALPHA (P < 0.05), IL-2 (P < 0.001), AND IL-4 (P < 0.01)]. REDUCED T CELL CHEMOKINE RECEPTOR GENE EXPRESSION IN MS F1 MICE WAS ASSOCIATED WITH DECREASED CHEMOTAXIS IN VITRO TO C-C CHEMOKINE LIGAND (CCL) 2 AND C-X-C CHEMOKINE LIGAND 10 (P < 0.01) AND IN VIVO TO CCL2 (P < 0.01). TAKEN TOGETHER, THE RESULTS SUGGEST THAT EPIGENETIC ALTERATION THROUGH PRENATAL DIET MANIPULATION REDUCES THE RESPONSE TO PROINFLAMMATORY SIGNALS IN MICE.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
20  4035  23 MACHINE-LEARNED ANALYSIS OF GLOBAL AND GLIAL/OPIOID INTERSECTION-RELATED DNA METHYLATION IN PATIENTS WITH PERSISTENT PAIN AFTER BREAST CANCER SURGERY. BACKGROUND: GLIAL CELLS IN THE CENTRAL NERVOUS SYSTEM PLAY A KEY ROLE IN NEUROINFLAMMATION AND SUBSEQUENT CENTRAL SENSITIZATION TO PAIN. THEY ARE THEREFORE INVOLVED IN THE DEVELOPMENT OF PERSISTENT PAIN. ONE OF THE MAIN SITES OF INTERACTION OF THE IMMUNE SYSTEM WITH PERSISTENT PAIN HAS BEEN IDENTIFIED AS NEURO-IMMUNE CROSSTALK AT THE GLIAL-OPIOID INTERFACE. THE PRESENT STUDY EXAMINED A POTENTIAL ASSOCIATION BETWEEN THE DNA METHYLATION OF TWO KEY PLAYERS OF GLIAL/OPIOID INTERSECTION AND PERSISTENT POSTOPERATIVE PAIN. METHODS: IN A COHORT OF 140 WOMEN WHO HAD UNDERGONE BREAST CANCER SURGERY, AND WERE ASSIGNED BASED ON A 3-YEAR FOLLOW-UP TO EITHER A PERSISTENT OR NON-PERSISTENT PAIN PHENOTYPE, THE ROLE OF EPIGENETIC REGULATION OF KEY PLAYERS IN THE GLIAL-OPIOID INTERFACE WAS ASSESSED. THE METHYLATION OF GENES CODING FOR THE TOLL-LIKE RECEPTOR 4 (TLR4) AS A MAJOR MEDIATOR OF GLIAL CONTRIBUTIONS TO PERSISTENT PAIN OR FOR THE MU-OPIOID RECEPTOR (OPRM1) WAS ANALYZED AND ITS ASSOCIATION WITH THE PAIN PHENOTYPE WAS COMPARED WITH THAT CONFERRED BY GLOBAL GENOME-WIDE DNA METHYLATION ASSESSED VIA QUANTIFICATION OF THE METHYLATION IN THE RETROTRANSPOSON LINE1. RESULTS: TRAINING OF MACHINE LEARNING ALGORITHMS INDICATED THAT THE GLOBAL DNA METHYLATION PROVIDED A SIMILAR DIAGNOSTIC ACCURACY FOR PERSISTENT PAIN AS PREVIOUSLY ESTABLISHED NON-GENETIC PREDICTORS. HOWEVER, THE DIAGNOSIS CAN BE BASED ON A SINGLE DNA BASED MARKER. BY CONTRAST, THE METHYLATION OF TLR4 OR OPRM1 GENES COULD NOT CONTRIBUTE FURTHER TO THE ALLOCATION OF THE PATIENTS TO THE PAIN-RELATED PHENOTYPE GROUPS. CONCLUSIONS: WHILE CLEARLY SUPPORTING A PREDICTIVE UTILITY OF EPIGENETIC TESTING, THE PRESENT ANALYSIS CANNOT PROVIDE SUPPORT FOR SPECIFIC EPIGENETIC MODULATION OF PERSISTENT POSTOPERATIVE PAIN VIA METHYLATION OF TWO KEY GENES OF THE GLIAL-OPIOID INTERFACE.	2019