1  4947 181 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	
                                                                                                                                  
2  1118  44 COMPARATIVE GENOTYPING AND PHENOTYPING OF ASPERGILLUS FUMIGATUS ISOLATES FROM HUMANS, DOGS AND THE ENVIRONMENT. BACKGROUND: ASPERGILLUS FUMIGATUS IS A UBIQUITOUS SAPROTROPHIC FUNGUS AND AN OPPORTUNISTIC PATHOGEN OF HUMANS AND ANIMALS. HUMANS AND ANIMALS CAN INHALE HUNDREDS OF A. FUMIGATUS SPORES DAILY. NORMALLY THIS IS HARMLESS FOR HUMANS, BUT IN CASE OF IMMUNODEFICIENCY, INVASIVE PULMONARY ASPERGILLOSIS (IPA) CAN DEVELOP WITH A HIGH MORTALITY RATE. A. FUMIGATUS ALSO CAUSES NON-INVASIVE MYCOSES LIKE SINO-NASAL ASPERGILLOSIS (SNA) IN DOGS. RESULTS: IN THIS STUDY WE COMPARED A. FUMIGATUS ISOLATES FROM HUMANS WITH SUSPECTED IPA, DOGS WITH SNA, AND A SET OF ENVIRONMENTAL ISOLATES. PHYLOGENETIC INFERENCE BASED ON CALMODULIN (CAM) AND BETA-TUBULIN (BENA) SEQUENCES DID NOT REVEAL A. FUMIGATUS SUB-GROUPS LINKED TO THE ORIGIN OF THE ISOLATES. GENOTYPING AND MICROSATELLITE ANALYSIS SHOWED THAT EACH DOG WAS INFECTED BY ONE A. FUMIGATUS GENOTYPE, WHEREAS HUMAN PATIENTS HAD MIXED INFECTIONS. AZOLE RESISTANCE WAS DETERMINED BY ANTIFUNGAL SUSCEPTIBILITY TESTING AND SEQUENCING OF THE CYP51A GENE. A TOTAL OF 12 OUT OF 29 HUMAN ISOLATES AND 1 OUT OF 27 ENVIRONMENTAL ISOLATES WERE AZOLE RESISTANT. OF THE AZOLE RESISTANT STRAINS, 11 HUMAN ISOLATES SHOWED TR(34)/L98H (N = 6) OR TR46/Y121F/T289A (N = 5). PHENOTYPICALLY, ISOLATES FROM DOGS WERE MORE VARIABLE IN GROWTH SPEED AND MORPHOLOGY WHEN COMPARED TO THOSE ISOLATED FROM HUMAN AND THE ENVIRONMENT. CONCLUSIONS: 1. A. FUMIGATUS FROM DOGS WITH SNA ARE PHENOTYPICALLY VERY DIVERSE IN CONTRAST TO THEIR ENVIRONMENTAL AND HUMAN COUNTERPARTS. 2. PHENOTYPIC VARIABILITY CAN BE INDUCED DURING THE CHRONIC INFECTION PROCESS IN THE SINUS OF THE DOGS. THE BASIS OF THIS HETEROGENEITY MIGHT BE DUE TO GENOMIC DIFFERENCES AND/OR EPIGENETIC VARIATIONS. 3. DIFFERENCES IN DOGS IS A COULD BE A RESULT OF WITHIN-HOST ADAPTION AND MIGHT BE TRIGGERED BY ENVIRONMENTAL FACTORS IN THE SINUS, HOWEVER THIS HYPOTHESIS STILL NEEDS TO BE TESTED.	2018	
                                                                                                                                                                                                                                                                                                                                                                                      
3  1053  30 CLINICAL IMPLICATIONS OF INTERFERON-GAMMA GENETIC AND EPIGENETIC VARIANTS. INTERFERON-GAMMA (IFN-GAMMA) IS AN INTEGRAL AND CRITICAL MOLECULE OF THE IMMUNE SYSTEM, WITH MULTIPLE FUNCTIONS, MOSTLY RELATED TO THE T HELPER TYPE 1 (TH1) RESPONSE TO INFECTION. IT IS CRITICAL FOR DEFENCE AGAINST MYCOBACTERIAL INFECTION AND IS OF INCREASING INTEREST IN DEFENCE AGAINST FUNGI. IN THIS ARTICLE, WE REVIEW THE GENETIC AND EPIGENETIC VARIANTS AFFECTING IFN-GAMMA EXPRESSION AND INVESTIGATE ITS ROLE IN DISEASE, WITH AN EMPHASIS ON FUNGAL DISEASES SUCH AS INVASIVE AND CHRONIC PULMONARY ASPERGILLOSIS. OVER 347 IFN-GAMMA GENE VARIANTS HAVE BEEN DESCRIBED, IN MULTIPLE ETHNIC POPULATIONS. MANY APPEAR TO CONFER A SUSCEPTIBILITY TO DISEASE, ESPECIALLY TUBERCULOSIS (TB) AND HEPATITIS, BUT ALSO SOME NON-INFECTIOUS CONDITIONS SUCH AS APLASTIC ANAEMIA, CERVICAL CANCER AND PSORIASIS. SEVERAL EPIGENETIC MODIFICATIONS ARE ALSO DESCRIBED, INCREASING IFN-GAMMA EXPRESSION IN TH1 LYMPHOCYTES AND REDUCING IFN-GAMMA EXPRESSION IN TH2 LYMPHOCYTES. RECOMBINANT IFN-GAMMA ADMINISTRATION IS LICENSED FOR THE PROPHYLAXIS OF INFECTION (BACTERIAL AND FUNGAL) IN PATIENTS WITH THE PHAGOCYTE FUNCTIONAL DEFICIENCY SYNDROME CHRONIC GRANULOMATOUS DISEASE, ALTHOUGH THE BENEFITS APPEAR LIMITED. INTERFERON-GAMMA THERAPY IS GIVEN TO PATIENTS WITH PROFOUND DEFECTS IN IFN-GAMMA AND INTERLEUKIN-12 PRODUCTION AND APPEARS TO BE BENEFICIAL FOR PATIENTS WITH INVASIVE ASPERGILLOSIS AND CRYPTOCOCCAL MENINGITIS, BUT THE STUDIES ARE NOT DEFINITIVE. A HIGH PROPORTION OF PATIENTS WITH CHRONIC PULMONARY ASPERGILLOSIS ARE POOR PRODUCERS OF IFN-GAMMA IN RESPONSE TO MULTIPLE STIMULI AND COULD ALSO BENEFIT FROM IFN-GAMMA ADMINISTRATION. THE INVESTIGATION AND MANAGEMENT OF PATIENTS WITH POSSIBLE OR DEMONSTRATED IFN-GAMMA DEFICIENCY IN ADULTHOOD IS POORLY STUDIED AND COULD BE GREATLY ENHANCED WITH THE INTEGRATION OF GENETIC DATA.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
4  6302  33 THE PUTATIVE ROLE OF VIRUSES, BACTERIA, AND CHRONIC FUNGAL BIOTOXIN EXPOSURE IN THE GENESIS OF INTRACTABLE FATIGUE ACCOMPANIED BY COGNITIVE AND PHYSICAL DISABILITY. PATIENTS WHO PRESENT WITH SEVERE INTRACTABLE APPARENTLY IDIOPATHIC FATIGUE ACCOMPANIED BY PROFOUND PHYSICAL AND OR COGNITIVE DISABILITY PRESENT A SIGNIFICANT THERAPEUTIC CHALLENGE. THE EFFECT OF PSYCHOLOGICAL COUNSELING IS LIMITED, WITH SIGNIFICANT BUT VERY SLIGHT IMPROVEMENTS IN PSYCHOMETRIC MEASURES OF FATIGUE AND DISABILITY BUT NO IMPROVEMENT ON SCIENTIFIC MEASURES OF PHYSICAL IMPAIRMENT COMPARED TO CONTROLS. SIMILARLY, EXERCISE REGIMES EITHER PRODUCE SIGNIFICANT, BUT PRACTICALLY UNIMPORTANT, BENEFIT OR PROVOKE SYMPTOM EXACERBATION. MANY SUCH PATIENTS ARE AFFORDED THE EXCLUSIONARY, NON-SPECIFIC DIAGNOSIS OF CHRONIC FATIGUE SYNDROME IF RUDIMENTARY TESTING FAILS TO DISCOVER THE CAUSE OF THEIR SYMPTOMS. MORE SOPHISTICATED INVESTIGATIONS OFTEN REVEAL THE PRESENCE OF A RANGE OF PATHOGENS CAPABLE OF ESTABLISHING LIFE-LONG INFECTIONS WITH SOPHISTICATED IMMUNE EVASION STRATEGIES, INCLUDING PARVOVIRUSES, HHV6, VARIANTS OF EPSTEIN-BARR, CYTOMEGALOVIRUS, MYCOPLASMA, AND BORRELIA BURGDORFERI. OTHER PATIENTS HAVE A HISTORY OF CHRONIC FUNGAL OR OTHER BIOTOXIN EXPOSURE. HEREIN, WE EXPLAIN THE EPIGENETIC FACTORS THAT MAY RENDER SUCH INDIVIDUALS SUSCEPTIBLE TO THE CHRONIC PATHOLOGY INDUCED BY SUCH AGENTS, HOW SUCH AGENTS INDUCE PATHOLOGY, AND, INDEED, HOW SUCH PATHOLOGY CAN PERSIST AND EVEN AMPLIFY EVEN WHEN INFECTIONS HAVE CLEARED OR WHEN BIOTOXIN EXPOSURE HAS CEASED. THE PRESENCE OF ACTIVE, REACTIVATED, OR EVEN LATENT HERPES VIRUS COULD BE A POTENTIAL SOURCE OF INTRACTABLE FATIGUE ACCOMPANIED BY PROFOUND PHYSICAL AND OR COGNITIVE DISABILITY IN SOME PATIENTS, AND THE SAME MAY BE TRUE OF PERSISTENT PARVOVIRUS B12 AND MYCOPLASMA INFECTION. A HISTORY OF CHRONIC MOLD EXPOSURE IS A FEASIBLE EXPLANATION FOR SUCH SYMPTOMS, AS IS THE PRESENCE OF B. BURGDORFERI. THE COMPLEX TROPISM, LIFE CYCLES, GENETIC VARIABILITY, AND LOW TITER OF MANY OF THESE PATHOGENS MAKES THEIR DETECTION IN BLOOD A CHALLENGE. EXAMINATION OF LYMPHOID TISSUE OR CSF IN SUCH CIRCUMSTANCES MAY BE WARRANTED.	2016	
                                                                                                                                                                                                    
5  2692  26 EVOLUTION OF THE CONCEPTS OF ENDOMETROSIS, POST BREEDING ENDOMETRITIS, AND SUSCEPTIBILITY OF MARES. IN THIS PAPER, THE EVOLUTION OF OUR UNDERSTANDING ABOUT POST BREEDING ENDOMETRITIS (PBE), THE SUSCEPTIBILITY OF MARES, AND EVENTS LEADING TO ENDOMETROSIS ARE REVIEWED. WHEN SPERM ARRIVE IN THE UTERUS, PRO-INFLAMMATORY CYTOKINES AND CHEMOKINES ARE RELEASED. THEY ATTRACT NEUTROPHILS AND INDUCE MODULATORY CYTOKINES WHICH CONTROL INFLAMMATION. IN SUSCEPTIBLE MARES, THIS PHYSIOLOGICAL DEFENSE CAN BE PROLONGED SINCE THE PATTERN OF CYTOKINE RELEASE DIFFERS FROM THAT OF RESISTANT MARES BEING DELAYED AND WEAKER FOR ANTI-INFLAMMATORY CYTOKINES. DELAYED UTERINE CLEARANCE DUE TO CONFORMATIONAL DEFECTS, DEFICIENT MYOMETRIAL CONTRACTIONS, AND FAILURE OF THE CERVIX TO RELAX IS DETECTED BY INTRAUTERINE FLUID ACCUMULATION AND IS AN IMPORTANT REASON FOR SUSCEPTIBILITY TO ENDOMETRITIS. MULTIPAROUS AGED MARES ARE MORE LIKELY TO BE SUSCEPTIBLE. UNTREATED PROLONGED PBE CAN LEAD TO BACTERIAL OR FUNGAL ENDOMETRITIS CALLED PERSISTENT OR CHRONIC ENDOMETRITIS. EXUBERANT OR PROLONGED NEUTROPHILIA AND CYTOKINE RELEASE CAN HAVE DELETERIOUS AND PERMANENT EFFECTS IN INDUCING ENDOMETROSIS. INTERACTIONS OF NEUTROPHILS, CYTOKINES, AND PROSTAGLANDINS IN THE FORMATION OF COLLAGEN AND EXTRACELLULAR MATRIX IN THE PATHOGENESIS OF FIBROSIS ARE DISCUSSED. ENDOMETRITIS AND ENDOMETROSIS ARE INTERCONNECTED, INFLUENCING EACH OTHER. IT IS SUGGESTED THAT THEY REPRESENT EPIGENETIC CHANGES INDUCED BY AGE AND HOSTILE UTERINE ENVIRONMENT.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
6  2008  43 EPIGENETIC BASIS FOR MONOCYTE DYSFUNCTION IN PATIENTS WITH SEVERE ALCOHOLIC HEPATITIS. BACKGROUND & AIMS: SEVERE FORMS OF ALCOHOL-RELATED LIVER DISEASE ARE ASSOCIATED WITH INCREASED SUSCEPTIBILITY TO INFECTIONS WHICH ARE ASSOCIATED WITH POOR PROGNOSIS. THE CELLULAR AND MOLECULAR MECHANISMS RESPONSIBLE FOR THIS ALTERED HOST DEFENSE ARE INCOMPLETELY UNDERSTOOD. METHODS: WE PERFORMED WHOLE BLOOD PHENOTYPIC ANALYSIS AND EX VIVO STIMULATION WITH VARIOUS PATHOGEN-ASSOCIATED MOLECULAR PATTERNS (PAMPS). WE INCLUDED 34 PATIENTS WITH ALCOHOL-RELATED CIRRHOSIS (18 OF WHOM HAD BIOPSY-PROVEN SEVERE ALCOHOLIC HEPATITIS [SAH]), 12 HEALTHY CONTROLS AND 11 PATIENTS WITH CHRONIC ALCOHOL CONSUMPTION WITHOUT SIGNIFICANT LIVER DISEASE. WE ALSO EVALUATED THE TRANSCRIPTOMIC (RNA-SEQ) AND CHROMATIN ACCESSIBILITY (ATAC-SEQ) PROFILES OF CD14(+) MONOCYTES FROM A SUBSET OF PATIENTS. RESULTS: CIRCULATING MONOCYTES AND CONVENTIONAL DENDRITIC CELLS (DCS) FROM PATIENTS WITH SAH DISPLAYED COMPLEX ALTERATIONS CHARACTERIZED BY INCREASED EXPRESSION OF BOTH ACTIVATING AND INHIBITORY SURFACE MARKERS AND AN IMPAIRED PRO-INFLAMMATORY RESPONSE UPON STIMULATION WITH PAMPS REPRESENTATIVE OF GRAM-NEGATIVE BACTERIA (LIPOPOLYSACCHARIDE, PAM3CSK4) OR FUNGAL PATHOGENS (ZYMOSAN). THEIR DECREASED ABILITY TO PRODUCE MORE THAN 1 CYTOKINE (POLYFUNCTIONALITY) UPON PAMP STIMULATION CORRELATED WITH THE RISK OF DEVELOPING INFECTION AT 28 DAYS OR MORTALITY AT 90 DAYS. THE PRESENCE OF ACUTE-ON-CHRONIC LIVER FAILURE IN PATIENTS WITH SAH DID NOT SIGNIFICANTLY MODIFY THE IMMUNE PROFILE OF MONOCYTES AND DCS. MOREOVER, CD14(+) MONOCYTES OF PATIENTS WITH SAH DISPLAYED ALTERED TRANSCRIPTIONAL AND EPIGENOMIC PROFILES CHARACTERIZED BY DOWNREGULATION OF KEY INNATE IMMUNE AND METABOLIC PATHWAYS AND UPREGULATION OF IMPORTANT IMMUNOMODULATORY FACTORS. CONCLUSIONS: IN PATIENTS WITH SAH, THE ALTERED TRANSCRIPTIONAL PROGRAM AND FUNCTIONAL PROPERTIES OF MONOCYTES THAT CONTRIBUTE TO PATIENTS' SUSCEPTIBILITY TO INFECTION HAVE STRONG EPIGENETIC DETERMINANTS. LAY SUMMARY: PATIENTS WITH SEVERE ALCOHOLIC HEPATITIS ARE AT INCREASED RISK OF INFECTIONS, WHICH CONTRIBUTE TO THE POOR PROGNOSIS ASSOCIATED WITH THE DISEASE. HEREIN, WE SHOW THAT EPIGENETIC DETERMINANTS UNDERLY THE IMMUNE CELL DYSFUNCTION AND INAPPROPRIATE RESPONSES TO PATHOGENS THAT ARE ASSOCIATED WITH SEVERE ALCOHOLIC HEPATITIS.	2020	

7  2889  29 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
8  3553  48 IMMUNOTOLERANCE OF DAIRY HEIFERS IN RESPONSE TO REPEATED EXPOSURE TO BACTERIAL LIPOPOLYSACCHARIDE ENDOTOXIN. DAIRY CATTLE FACE A VARIETY OF STRESSFUL EVENTS ON A DAILY BASIS. MORE SPECIFICALLY, CLIMATE CHANGE HAS RESULTED IN MORE FREQUENT HEAT STRESS EVENTS THAT INCREASE THE INCIDENCE OF CHRONIC BACTERIAL INFECTIONS BY INDUCING CONDITIONS LIKE LEAKY GUT SYNDROME, WHEREBY THE INTEGRITY OF THE INTESTINAL EPITHELIUM IS COMPROMISED ALLOWING FOR LUMINAL BACTERIAL LIPOPOLYSACCHARIDE (LPS) ENDOTOXIN TO INFILTRATE THE HOST'S BLOODSTREAM RESULTING IN ACUTE OR CHRONIC SYSTEMIC STIMULATION OF THE INNATE IMMUNE SYSTEM. REPEATED EXPOSURE TO LPS OVER A SHORT PERIOD OF TIME IS REPORTED TO INDUCE IMMUNOTOLERANCE WITHIN THE HOST. THIS LPS TOLERANCE IS AN ESSENTIAL IMMUNOHOMEOSTATIC RESPONSE THAT CAN PROTECT AGAINST OVER ACTIVATION OF THE INFLAMMATORY RESPONSE DURING SUBSEQUENT EXPOSURE TO LPS. IN THE PRESENT STUDY, HOLSTEIN CALVES (N = 20) WERE INITIALLY STRESS CHALLENGED WITH EITHER SALINE, OR 100, 200 OR 400 NG/KG OF LPS ADMINISTERED INTRAMUSCULAR, AND AGAIN RE-CHALLENGED WITH 200 NG/KG OF LPS 2-WEEKS LATER. SERUM WAS COLLECTED EVERY 2 HR FOR 6 HR TO PROFILE CHANGES IN CIRCULATORY STRESS BIOMARKERS AFTER THE REPEATED LPS EXPOSURES. HEIFERS THAT WERE INITIALLY CHALLENGED WITH 100, 200 AND 400 NG/KG OF LPS DEMONSTRATED SIGNIFICANTLY ATTENUATED CORTISOL RESPONSES IN THE SECOND CHALLENGE (P < 0.01, 0.01 AND 0.05, RESPECTIVELY), WHEREAS CONTROL ANIMALS WHO PREVIOUSLY RECEIVED SALINE DEMONSTRATED A STRONG CORTISOL RESPONSE AT 2 HR AFTER RECEIVING 200 NG/KG OF LPS (P < 0.05). THE CYTOKINE/CHEMOKINE (IL-6, CCL2, CCL3 AND CCL4) RESPONSES WERE ALSO ATTENUATED DURING THE LPS RECHALLENGE (P < 0.05). FINALLY, MICRORNA EXPRESSION PROFILES WERE DETERMINED TO ASSESS THE EPIGENETIC RESPONSE TO REPEATED LPS EXPOSURE. INTERESTINGLY, MIR-31 AND MIR-223 WERE DOWNREGULATED IN RESPONSE TO THE SECOND LPS CHALLENGE. THE PRESENT STUDY DEMONSTRATES THE DYNAMIC NATURE OF THE STRESS RESPONSE IN DAIRY CATTLE AS IT RELATES TO THE DEVELOPMENT OF LPS TOLERANCE. UNDERSTANDING THE ROLES OF VARIOUS STRESS BIOMARKERS IN THE CONTEXT OF INNATE IMMUNE CELL TOLERANCE IS ESSENTIAL FOR EVALUATING THEIR IMPACT ON IMMUNE SYSTEM HOMEOSTASIS.	2023	
                                                                                                                                 
9  3781  30 INTERFERON SIGNATURE IN PATIENTS WITH STAT1 GAIN-OF-FUNCTION MUTATION IS EPIGENETICALLY DETERMINED. STAT1 GAIN-OF-FUNCTION (GOF) VARIANTS LEAD TO DEFECTIVE TH17 CELL DEVELOPMENT AND CHRONIC MUCOCUTANEOUS CANDIDIASIS (CMC), BUT FREQUENTLY ALSO TO AUTOIMMUNITY. STIMULATION OF CELLS WITH STAT1 INDUCING CYTOKINES LIKE INTERFERONS (IFN) RESULT IN HYPERPHOSPHORYLATION AND DELAYED DEPHOSPHORYLATION OF GOF STAT1. HOWEVER, THE MECHANISM HOW THE DELAYED DEPHOSPHORYLATION EXACTLY CAUSES THE INCREASED EXPRESSION OF STAT1-DEPENDENT GENES, AND HOW THE INTRACELLULAR SIGNAL TRANSDUCTION FROM CYTOKINE RECEPTORS IS AFFECTED, REMAINS UNKNOWN. IN THIS STUDY WE SHOW THAT THE CIRCULATING LEVELS OF IFN-ALPHA WERE NOT PERSISTENTLY ELEVATED IN STAT1 GOF PATIENTS. NEVERTHELESS, THE EXPRESSION OF INTERFERON SIGNATURE GENES WAS EVIDENT EVEN IN THE PATIENT WITH LOW OR UNDETECTABLE SERUM IFN-ALPHA LEVELS. CHROMATIN IMMUNOPRECIPITATION (CHIP) EXPERIMENTS REVEALED THAT THE ACTIVE CHROMATIN MARK TRIMETHYLATION OF LYSINE 4 OF HISTONE 3 (H3K4ME3), WAS SIGNIFICANTLY ENRICHED IN AREAS ASSOCIATED WITH INTERFERON-STIMULATED GENES IN STAT1 GOF CELLS IN COMPARISON TO CELLS FROM HEALTHY DONORS. THIS SUGGESTS THAT THE CHROMATIN BINDING OF GOF STAT1 VARIANT PROMOTES EPIGENETIC CHANGES COMPATIBLE WITH HIGHER GENE EXPRESSION AND ELEVATED REACTIVITY TO TYPE I INTERFERONS, AND POSSIBLY PREDISPOSES FOR INTERFERON-RELATED AUTOIMMUNITY. THE RESULTS ALSO SUGGEST THAT EPIGENETIC REWIRING MAY BE RESPONSIBLE FOR TREATMENT FAILURE OF JANUS KINASE 1/2 (JAK1/2) INHIBITORS IN CERTAIN PATIENTS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
10   169  40 ABNORMALITIES OF AMPK ACTIVATION AND GLUCOSE UPTAKE IN CULTURED SKELETAL MUSCLE CELLS FROM INDIVIDUALS WITH CHRONIC FATIGUE SYNDROME. BACKGROUND: POST EXERTIONAL MUSCLE FATIGUE IS A KEY FEATURE IN CHRONIC FATIGUE SYNDROME (CFS). ABNORMALITIES OF SKELETAL MUSCLE FUNCTION HAVE BEEN IDENTIFIED IN SOME BUT NOT ALL PATIENTS WITH CFS. TO TRY TO LIMIT POTENTIAL CONFOUNDERS THAT MIGHT CONTRIBUTE TO THIS CLINICAL HETEROGENEITY, WE DEVELOPED A NOVEL IN VITRO SYSTEM THAT ALLOWS COMPARISON OF AMP KINASE (AMPK) ACTIVATION AND METABOLIC RESPONSES TO EXERCISE IN CULTURED SKELETAL MUSCLE CELLS FROM CFS PATIENTS AND CONTROL SUBJECTS. METHODS: SKELETAL MUSCLE CELL CULTURES WERE ESTABLISHED FROM 10 SUBJECTS WITH CFS AND 7 AGE-MATCHED CONTROLS, SUBJECTED TO ELECTRICAL PULSE STIMULATION (EPS) FOR UP TO 24H AND EXAMINED FOR CHANGES ASSOCIATED WITH EXERCISE. RESULTS: IN THE BASAL STATE, CFS CULTURES SHOWED INCREASED MYOGENIN EXPRESSION BUT DECREASED IL6 SECRETION DURING DIFFERENTIATION COMPARED WITH CONTROL CULTURES. CONTROL CULTURES SUBJECTED TO 16 H EPS SHOWED A SIGNIFICANT INCREASE IN BOTH AMPK PHOSPHORYLATION AND GLUCOSE UPTAKE COMPARED WITH UNSTIMULATED CELLS. IN CONTRAST, CFS CULTURES SHOWED NO INCREASE IN AMPK PHOSPHORYLATION OR GLUCOSE UPTAKE AFTER 16 H EPS. HOWEVER, GLUCOSE UPTAKE REMAINED RESPONSIVE TO INSULIN IN THE CFS CELLS POINTING TO AN EXERCISE-RELATED DEFECT. IL6 SECRETION IN RESPONSE TO EPS WAS SIGNIFICANTLY REDUCED IN CFS COMPARED WITH CONTROL CULTURES AT ALL TIME POINTS MEASURED. CONCLUSION: EPS IS AN EFFECTIVE MODEL FOR ELICITING MUSCLE CONTRACTION AND THE METABOLIC CHANGES ASSOCIATED WITH EXERCISE IN CULTURED SKELETAL MUSCLE CELLS. WE FOUND FOUR MAIN DIFFERENCES IN CULTURED SKELETAL MUSCLE CELLS FROM SUBJECTS WITH CFS; INCREASED MYOGENIN EXPRESSION IN THE BASAL STATE, IMPAIRED ACTIVATION OF AMPK, IMPAIRED STIMULATION OF GLUCOSE UPTAKE AND DIMINISHED RELEASE OF IL6. THE RETENTION OF THESE DIFFERENCES IN CULTURED MUSCLE CELLS FROM CFS SUBJECTS POINTS TO A GENETIC/EPIGENETIC MECHANISM, AND PROVIDES A SYSTEM TO IDENTIFY NOVEL THERAPEUTIC TARGETS.	2015	
                                                                                                                                                                                                                                                                               
11  5912  25 TARGETED THERAPIES IN SYSTEMIC LUPUS ERYTHEMATOSUS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC, MULTISYSTEM DISORDER CHARACTERISED BY LOSS OF TOLERANCE TO ENDOGENOUS NUCLEAR ANTIGENS AND AUTOANTIBODY FORMATION. RECENT INSIGHT INTO THE IMMUNOPATHOGENESIS OF LUPUS HAS PROVIDED THE FOUNDATION FOR A NOVEL CLASS OF AGENTS WHICH TARGET SPECIFIC, DYSREGULATED COMPONENTS OF THE IMMUNE SYSTEM. EFFORTS HAVE FOCUSED PREDOMINANTLY ON B-CELL DEPLETING THERAPIES, OF WHICH BELIMUMAB WAS THE FIRST TO DEMONSTRATE SUCCESS IN PHASE III STUDIES AND THUS RECEIVE MARKETING AUTHORISATION. OFF-LABEL PRESCRIBING OF RITUXIMAB IN REFRACTORY CASES IS COMMON AND SUPPORTED BY UNCONTROLLED STUDIES, WHICH SUGGEST A FAVOURABLE RISK:BENEFIT PROFILE. HOWEVER, TWO PLACEBO-CONTROLLED TRIALS FAILED TO SHOW BENEFIT, POSSIBLY BECAUSE OF INAPPROPRIATE PATIENT SELECTION AND OTHER ASPECTS OF TRIAL METHODOLOGY. INHIBITION OF DYSREGULATED CO-STIMULATORY SIGNALS AND CYTOKINES ARE OTHER THERAPEUTIC STRATEGIES CURRENTLY UNDER INVESTIGATION. SOME CANDIDATE DRUGS FAILED TO MEET PRIMARY ENDPOINTS IN EARLY-PHASE CLINICAL TRIALS, YET DEMONSTRATED CLINICAL BENEFIT WHEN ALTERNATIVE ASSESSMENT CRITERIA WERE APPLIED OR SPECIFIC PATIENT SUB-GROUPS ANALYSED. WELL-DESIGNED STUDIES OF GREATER SIZE AND DURATION ARE NEEDED TO CLARIFY THE THERAPEUTIC UTILITY OF THESE AGENTS. FUTURE IMMUNOMODULATORY STRATEGIES TARGETING INTERFERON-ALPHA, T CELLS, OXIDATIVE STRESS AND EPIGENETIC ABNORMALITIES MAY REDUCE MULTISYSTEM DISEASE ACTIVITY AND PROLONG SURVIVAL IN THIS COMPLEX AND HETEROGENEIC DISEASE.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
12  5760  46 SOLUBLE URIC ACID PRIMES TLR-INDUCED PROINFLAMMATORY CYTOKINE PRODUCTION BY HUMAN PRIMARY CELLS VIA INHIBITION OF IL-1RA. OBJECTIVES: THE STUDY OF THE PROINFLAMMATORY ROLE OF URIC ACID HAS FOCUSED ON THE EFFECTS OF ITS CRYSTALS OF MONOSODIUM URATE (MSU). HOWEVER, LITTLE IS KNOWN WHETHER URIC ACID ITSELF CAN DIRECTLY HAVE PROINFLAMMATORY EFFECTS. IN THIS STUDY, WE INVESTIGATE THE PRIMING EFFECTS OF URIC ACID EXPOSURE ON THE CYTOKINE PRODUCTION OF PRIMARY HUMAN CELLS UPON STIMULATION WITH GOUT-RELATED STIMULI. METHODS: PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) WERE HARVESTED FROM PATIENTS WITH GOUT AND HEALTHY VOLUNTEERS. CELLS WERE PRETREATED WITH OR WITHOUT URIC ACID IN SOLUBLE FORM FOR 24 H AND THEN STIMULATED FOR 24 H WITH TOLL-LIKE RECEPTOR (TLR)2 OR TLR4 LIGANDS IN THE PRESENCE OR ABSENCE OF MSU CRYSTALS. CYTOKINE PRODUCTION WAS MEASURED BY ELISA; MRNA LEVELS WERE ASSESSED USING QPCR. RESULTS: THE PRODUCTION OF INTERLEUKIN (IL)-1BETA AND IL-6 WAS HIGHER IN PATIENTS COMPARED WITH CONTROLS AND THIS CORRELATED WITH SERUM URATE LEVELS. PROINFLAMMATORY CYTOKINE PRODUCTION WAS SIGNIFICANTLY POTENTIATED WHEN CELLS FROM HEALTHY SUBJECTS WERE PRETREATED WITH URIC ACID. SURPRISINGLY, THIS WAS ASSOCIATED WITH A SIGNIFICANT DOWNREGULATION OF THE ANTI-INFLAMMATORY CYTOKINE IL-1 RECEPTOR ANTAGONIST (IL-1RA). THIS EFFECT WAS SPECIFIC TO STIMULATION BY URIC ACID AND WAS EXERTED AT THE LEVEL OF GENE TRANSCRIPTION. EPIGENETIC REPROGRAMMING AT THE LEVEL OF HISTONE METHYLATION BY URIC ACID WAS INVOLVED IN THIS EFFECT. CONCLUSIONS: IN THIS STUDY WE DEMONSTRATE A MECHANISM THROUGH WHICH HIGH CONCENTRATIONS OF URIC ACID (UP TO 50 MG/DL) INFLUENCE INFLAMMATORY RESPONSES BY FACILITATING IL-1BETA PRODUCTION IN PBMCS. WE SHOW THAT A MECHANISM FOR THE AMPLIFICATION OF IL-1BETA CONSISTS IN THE DOWNREGULATION OF IL-1RA AND THAT THIS EFFECT COULD BE EXERTED VIA EPIGENETIC MECHANISMS SUCH AS HISTONE METHYLATION. HYPERURICAEMIA CAUSES A SHIFT IN THE IL-1BETA/IL-1RA BALANCE PRODUCED BY PBMCS AFTER EXPOSURE TO MSU CRYSTALS AND TLR-MEDIATED STIMULI, AND THIS PHENOMENON IS LIKELY TO REINFORCE THE ENHANCED STATE OF CHRONIC INFLAMMATION.	2016	
                                                                                                                                                                                                               
13  6540  39 TRANSCRIPTIONAL, EPIGENETIC, AND FUNCTIONAL REPROGRAMMING OF MONOCYTES FROM NON-HUMAN PRIMATES FOLLOWING CHRONIC ALCOHOL DRINKING. CHRONIC HEAVY DRINKING (CHD) OF ALCOHOL IS A KNOWN RISK FACTOR FOR INCREASED SUSCEPTIBILITY TO BACTERIAL AND VIRAL INFECTION AS WELL AS IMPAIRED WOUND HEALING. EVIDENCE SUGGESTS THAT THESE DEFECTS ARE MEDIATED BY A DYSREGULATED INFLAMMATORY RESPONSE ORIGINATING FROM MYELOID CELLS, NOTABLY MONOCYTES AND MACROPHAGES, BUT THE MECHANISMS REMAIN POORLY UNDERSTOOD. OUR ABILITY TO STUDY CHD IS IMPACTED BY THE COMPLEXITIES OF HUMAN DRINKING PATTERNS AND BEHAVIOR AS WELL AS COMORBIDITIES AND CONFOUNDING RISK FACTORS FOR PATIENTS WITH ALCOHOL USE DISORDERS. TO OVERCOME THESE CHALLENGES, WE UTILIZED A TRANSLATIONAL RHESUS MACAQUE MODEL OF VOLUNTARY ETHANOL SELF-ADMINISTRATION THAT CLOSELY RECAPITULATES HUMAN DRINKING PATTERNS AND CHRONICITY. IN THIS STUDY, WE EXAMINED THE EFFECTS OF CHD ON BLOOD MONOCYTES IN CONTROL AND CHD FEMALE MACAQUES AFTER 12 MONTHS OF DAILY ETHANOL CONSUMPTION. WHILE MONOCYTES FROM CHD FEMALE MACAQUES GENERATED A HYPER-INFLAMMATORY RESPONSE TO EX VIVO LPS STIMULATION, THEIR RESPONSE TO E. COLI WAS DAMPENED. IN DEPTH SCRNA-SEQ ANALYSIS OF PURIFIED MONOCYTES REVEALED SIGNIFICANT SHIFTS IN CLASSICAL MONOCYTE SUBSETS WITH ACCUMULATION OF CELLS EXPRESSING MARKERS OF HYPOXIA (HIF1A) AND INFLAMMATION (NFKB SIGNALING PATHWAY) IN CHD MACAQUES. THE INCREASED PRESENCE OF MONOCYTE SUBSETS SKEWED TOWARDS INFLAMMATORY PHENOTYPES WAS COMPLEMENTED BY EPIGENETIC ANALYSIS, WHICH REVEALED HIGHER ACCESSIBILITY OF PROMOTER REGIONS THAT REGULATE GENES INVOLVED IN CYTOKINE SIGNALING PATHWAYS. COLLECTIVELY, DATA PRESENTED IN THIS MANUSCRIPT DEMONSTRATE THAT CHD SHIFTS CLASSICAL MONOCYTE SUBSET COMPOSITION AND PRIMES THE MONOCYTES TOWARDS A MORE HYPER-INFLAMMATORY RESPONSE TO LPS, BUT COMPROMISED PATHOGEN RESPONSE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
14  6568  38 TRANSMATERNAL HELICOBACTER PYLORI EXPOSURE REDUCES ALLERGIC AIRWAY INFLAMMATION IN OFFSPRING THROUGH REGULATORY T CELLS. BACKGROUND: TRANSMATERNAL EXPOSURE TO TOBACCO, MICROBES, NUTRIENTS, AND OTHER ENVIRONMENTAL FACTORS SHAPES THE FETAL IMMUNE SYSTEM THROUGH EPIGENETIC PROCESSES. THE GASTRIC MICROBE HELICOBACTER PYLORI REPRESENTS AN ANCESTRAL CONSTITUENT OF THE HUMAN MICROBIOTA THAT CAUSES GASTRIC DISORDERS ON THE ONE HAND AND IS INVERSELY ASSOCIATED WITH ALLERGIES AND CHRONIC INFLAMMATORY CONDITIONS ON THE OTHER. OBJECTIVE: HERE WE INVESTIGATE THE CONSEQUENCES OF TRANSMATERNAL EXPOSURE TO H PYLORI IN UTERO AND/OR DURING LACTATION FOR SUSCEPTIBILITY TO VIRAL AND BACTERIAL INFECTION, PREDISPOSITION TO ALLERGIC AIRWAY INFLAMMATION, AND DEVELOPMENT OF IMMUNE CELL POPULATIONS IN THE LUNGS AND LYMPHOID ORGANS. METHODS: WE USE EXPERIMENTAL MODELS OF HOUSE DUST MITE- OR OVALBUMIN-INDUCED AIRWAY INFLAMMATION AND INFLUENZA A VIRUS OR CITROBACTER RODENTIUM INFECTION ALONG WITH METAGENOMICS ANALYSES, MULTICOLOR FLOW CYTOMETRY, AND BISULFITE PYROSEQUENCING, TO STUDY THE EFFECTS OF H PYLORI ON ALLERGY SEVERITY AND IMMUNOLOGIC AND MICROBIOME CORRELATES THEREOF. RESULTS: PERINATAL EXPOSURE TO H PYLORI EXTRACT OR ITS IMMUNOMODULATOR VACUOLATING CYTOTOXIN CONFERS ROBUST PROTECTIVE EFFECTS AGAINST ALLERGIC AIRWAY INFLAMMATION NOT ONLY IN FIRST- BUT ALSO SECOND-GENERATION OFFSPRING BUT DOES NOT INCREASE SUSCEPTIBILITY TO VIRAL OR BACTERIAL INFECTION. IMMUNE CORRELATES OF ALLERGY PROTECTION INCLUDE SKEWING OF REGULATORY OVER EFFECTOR T CELLS, EXPANSION OF REGULATORY T-CELL SUBSETS EXPRESSING CXCR3 OR RETINOIC ACID-RELATED ORPHAN RECEPTOR GAMMAT, AND DEMETHYLATION OF THE FORKHEAD BOX P3 (FOXP3) LOCUS. THE COMPOSITION AND DIVERSITY OF THE GASTROINTESTINAL MICROBIOTA IS MEASURABLY AFFECTED BY PERINATAL H PYLORI EXPOSURE. CONCLUSION: WE CONCLUDE THAT EXPOSURE TO H PYLORI HAS CONSEQUENCES NOT ONLY FOR THE CARRIER BUT ALSO FOR SUBSEQUENT GENERATIONS THAT CAN BE EXPLOITED FOR INTERVENTIONAL PURPOSES.	2019	
                                                                                                                                                                                                                                                                                                                                                   
15  3037  41 GENOME AND METHYLOME VARIATION IN HELICOBACTER PYLORI WITH A CAG PATHOGENICITY ISLAND DURING EARLY STAGES OF HUMAN INFECTION. BACKGROUND & AIMS: HELICOBACTER PYLORI IS REMARKABLE FOR ITS GENETIC VARIATION; YET, LITTLE IS KNOWN ABOUT ITS GENETIC CHANGES DURING EARLY STAGES OF HUMAN INFECTION, AS THE BACTERIA ADAPT TO THEIR NEW ENVIRONMENT. WE ANALYZED GENOME AND METHYLOME VARIATIONS IN A FULLY VIRULENT STRAIN OF H PYLORI DURING EXPERIMENTAL INFECTION. METHODS: WE PERFORMED A RANDOMIZED PHASE I/II, OBSERVER-BLIND, PLACEBO-CONTROLLED STUDY OF 12 HEALTHY, H PYLORI-NEGATIVE ADULTS IN GERMANY FROM OCTOBER 2008 THROUGH MARCH 2010. THE VOLUNTEERS WERE GIVEN A PROPHYLACTIC VACCINE CANDIDATE (N = 7) OR PLACEBO (N = 5) AND THEN CHALLENGED WITH H PYLORI STRAIN BCM-300. BIOPSY SAMPLES WERE COLLECTED AND H PYLORI WERE ISOLATED. GENOMES OF THE CHALLENGE STRAIN AND 12 REISOLATES, OBTAINED 12 WEEKS AFTER (OR IN 1 CASE, 62 WEEKS AFTER) INFECTION WERE SEQUENCED BY SINGLE-MOLECULE, REAL-TIME TECHNOLOGY, WHICH, IN PARALLEL, PERMITTED DETERMINATION OF GENOME-WIDE METHYLATION PATTERNS FOR ALL STRAINS. FUNCTIONAL EFFECTS OF GENETIC CHANGES OBSERVED IN H PYLORI STRAINS DURING HUMAN INFECTION WERE ASSESSED BY MEASURING RELEASE OF INTERLEUKIN 8 FROM AGS CELLS (TO DETECT CAG PATHOGENICITY ISLAND FUNCTION), NEUTRAL RED UPTAKE (TO DETECT VACUOLATING CYTOTOXIN ACTIVITY), AND ADHESION ASSAYS. RESULTS: THE OBSERVED MUTATION RATE WAS IN AGREEMENT WITH RATES PREVIOUSLY DETERMINED FROM PATIENTS WITH CHRONIC H PYLORI INFECTIONS, WITHOUT EVIDENCE OF A MUTATION BURST. A LOSS OF CAG PATHOGENICITY ISLAND FUNCTION WAS OBSERVED IN 3 REISOLATES. IN ADDITION, 3 REISOLATES FROM THE VACCINE GROUP ACQUIRED MUTATIONS IN THE VACUOLATING CYTOTOXIN GENE VACA, RESULTING IN LOSS OF VACUOLIZATION ACTIVITY. WE OBSERVED INTERSTRAIN VARIATION IN METHYLOMES DUE TO PHASE VARIATION IN GENES ENCODING METHYLTRANSFERASES. CONCLUSIONS: WE ANALYZED ADAPTATION OF A FULLY VIRULENT STRAIN OF H PYLORI TO 12 DIFFERENT VOLUNTEERS TO OBTAIN A ROBUST ESTIMATE OF THE FREQUENCY OF GENETIC AND EPIGENETIC CHANGES IN THE ABSENCE OF INTERSTRAIN RECOMBINATION. OUR FINDINGS INDICATE THAT THE LARGE AMOUNT OF GENETIC VARIATION IN H PYLORI POSES A CHALLENGE TO VACCINE DEVELOPMENT. CLINICALTRIALS.GOV NO: NCT00736476.	2018	
                                                                            
16   295  34 AGING INDUCES B CELL DEFECTS AND DECREASED ANTIBODY RESPONSES TO INFLUENZA INFECTION AND VACCINATION. BACKGROUND: AGING IS CHARACTERIZED BY A PROGRESSIVE DECLINE IN THE CAPACITY OF THE IMMUNE SYSTEM TO FIGHT INFLUENZA VIRUS INFECTION AND TO RESPOND TO VACCINATION. AMONG THE SEVERAL FACTORS INVOLVED, IN ADDITION TO INCREASED FRAILTY AND HIGH-RISK CONDITIONS, THE AGE-ASSOCIATED DECREASE IN CELLULAR AND HUMORAL IMMUNE RESPONSES PLAYS A RELEVANT ROLE. THIS IS IN LARGE PART DUE TO INFLAMMAGING, THE CHRONIC LOW-GRADE INFLAMMATORY STATUS OF THE ELDERLY, ASSOCIATED WITH INTRINSIC INFLAMMATION OF THE IMMUNE CELLS AND DECREASED IMMUNE FUNCTION. RESULTS: AGING IS USUALLY ASSOCIATED WITH REDUCED INFLUENZA VIRUS-SPECIFIC AND INFLUENZA VACCINE-SPECIFIC ANTIBODY RESPONSES BUT SOME ELDERLY INDIVIDUALS WITH HIGHER PRE-EXPOSURE ANTIBODY TITERS, DUE TO A PREVIOUS INFECTION OR VACCINATION, HAVE LESS PROBABILITY TO GET INFECTED. EXAMPLES OF THIS EXCEPTION ARE THE ELDERLY INDIVIDUALS INFECTED DURING THE 2009 PANDEMIC SEASON WHO MADE ANTIBODIES WITH BROADER EPITOPE RECOGNITION AND HIGHER AVIDITY THAN THOSE MADE BY YOUNGER INDIVIDUALS. SEVERAL STUDIES HAVE ALLOWED THE IDENTIFICATION OF B CELL INTRINSIC DEFECTS ACCOUNTING FOR SUB-OPTIMAL ANTIBODY RESPONSES OF ELDERLY INDIVIDUALS. THESE DEFECTS INCLUDE 1) REDUCED CLASS SWITCH RECOMBINATION, RESPONSIBLE FOR THE GENERATION OF A SECONDARY RESPONSE OF CLASS SWITCHED ANTIBODIES, 2) REDUCED DE NOVO SOMATIC HYPERMUTATION OF THE ANTIBODY VARIABLE REGION, 3) REDUCED BINDING AND NEUTRALIZATION CAPACITY, AS WELL AS BINDING SPECIFICITY, OF THE SECRETED ANTIBODIES, 4) INCREASED EPIGENETIC MODIFICATIONS THAT ARE ASSOCIATED WITH LOWER ANTIBODY RESPONSES, 5) INCREASED FREQUENCIES OF INFLAMMATORY B CELL SUBSETS, AND 6) SHORTER TELOMERES. CONCLUSIONS: ALTHOUGH INFLUENZA VACCINATION REPRESENTS THE MOST EFFECTIVE WAY TO PREVENT INFLUENZA INFECTION, VACCINES WITH GREATER IMMUNOGENICITY ARE NEEDED TO IMPROVE THE RESPONSE OF ELDERLY INDIVIDUALS. RECENT ADVANCES IN TECHNOLOGY HAVE MADE POSSIBLE A BROAD APPROACH TO BETTER UNDERSTAND THE AGE-ASSOCIATED CHANGES IN IMMUNE CELLS, NEEDED TO DESIGN TAILORED VACCINES AND EFFECTIVE THERAPEUTIC STRATEGIES THAT WILL BE ABLE TO IMPROVE THE IMMUNE RESPONSE OF VULNERABLE INDIVIDUALS.	2020	
                                                                                        
17  5592  35 ROLE OF TUMOR NECROSIS FACTOR-ALPHA IN THE HUMAN SYSTEMIC ENDOTOXIN-INDUCED TRANSCRIPTOME. TNFALPHA HAS BEEN IMPLICATED IN THE PATHOGENESIS OF VARIOUS INFLAMMATORY DISEASES. DIFFERENT STRATEGIES TO INHIBIT TNFALPHA IN PATIENTS WITH SEPSIS AND CHRONIC INFLAMMATORY CONDITIONS HAVE SHOWN CONTRASTING OUTCOMES. ALTHOUGH TNFALPHA INHIBITORS ARE WIDELY USED IN CLINICAL PRACTICE, THE IMPACT OF TNFALPHA ANTAGONISM ON WHITE BLOOD CELL GENE EXPRESSION PROFILES DURING ACUTE INFLAMMATION IN HUMANS IN VIVO HAS NOT BEEN ASSESSED. WE HERE LEVERAGED THE ESTABLISHED MODEL OF HUMAN ENDOTOXEMIA TO EXAMINE THE EFFECT OF THE TNFALPHA ANTAGONIST, ETANERCEPT, ON THE GENOME-WIDE TRANSCRIPTIONAL RESPONSES IN CIRCULATING LEUKOCYTES INDUCED BY INTRAVENOUS LPS ADMINISTRATION IN MALE SUBJECTS. ETANERCEPT PRE-TREATMENT RESULTED IN A MARKEDLY DAMPENED TRANSCRIPTIONAL RESPONSE TO LPS. GENE CO-EXPRESSION NETWORK ANALYSIS REVEALED THIS LPS-INDUCED TRANSCRIPTOME CAN BE CATEGORIZED AS TNFALPHA RESPONSIVE AND NON-RESPONSIVE MODULES. HIGHLY SIGNIFICANT TNFALPHA RESPONSIVE MODULES INCLUDE NF-KB SIGNALING, ANTIVIRAL RESPONSES AND T-CELL MEDIATED RESPONSES. WITHIN THESE TNFALPHA RESPONSIVE MODULES WE DELINEATE FUNDAMENTAL GENES INVOLVED IN EPIGENETIC MODIFICATIONS, TRANSCRIPTIONAL INITIATION AND ELONGATION. THUS, WE PROVIDE COMPREHENSIVE INFORMATION ABOUT MOLECULAR PATHWAYS THAT MIGHT BE TARGETED BY THERAPEUTIC INTERVENTIONS THAT SEEK TO INHIBIT TNFALPHA ACTIVITY DURING HUMAN INFLAMMATORY DISEASES.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
18   537  19 ASYMPTOMATIC HYPERURICEMIA: IS IT REALLY ASYMPTOMATIC? PURPOSE OF REVIEW: HYPERURICEMIA IS HIGHLY PREVALENT, AFFECTING APPROXIMATELY 38 MILLION INDIVIDUALS IN THE UNITED STATES. HOWEVER, THE SIGNIFICANCE OF ASYMPTOMATIC HYPERURICEMIA - HYPERURICEMIA IN THE ABSENCE OF GOUT - CONTINUES TO BE DEBATED. RECENT FINDINGS: ASYMPTOMATIC HYPERURICEMIA RESULTS IN MONOSODIUM URATE CRYSTAL DEPOSITION IN TISSUES, WHICH MAY PROMOTE CHRONIC INFLAMMATION. INTRACELLULARLY, HYPERURICEMIA INHIBITS THE MASTER REGULATOR ADENOSINE MONOPHOSPHATE (AMP)-ASSOCIATED PROTEIN KINASE AND MAY CONDITION INNATE IMMUNE RESPONSES THROUGH DURABLE EPIGENETIC MODIFICATIONS. AT THE POPULATION LEVEL, ASYMPTOMATIC HYPERURICEMIA IS ASSOCIATED WITH MULTIPLE COMORBIDITIES, INCLUDING HYPERTENSION, CHRONIC KIDNEY DISEASE, CORONARY ARTERY DISEASE, AND DIABETES; LIMITATIONS OF THESE STUDIES INCLUDE THAT MOST ARE RETROSPECTIVE AND SOME DO NOT RIGOROUSLY DISTINGUISH BETWEEN ASYMPTOMATIC HYPERURICEMIA AND GOUT. TREATMENT STUDIES SUGGEST THAT URATE LOWERING MAY REDUCE THE RISK OF INCIDENCE OR PROGRESSION OF SOME OF THESE COMORBIDITIES; UNFORTUNATELY, MANY OF THESE TREATMENT STUDIES ARE SMALL OR FLAWED, AND NOT ALL STUDY RESULTS ARE CONSISTENT. SUMMARY: ACCUMULATING EVIDENCE SUGGESTS THAT ASYMPTOMATIC HYPERURICEMIA CONTRIBUTES TO THE COMORBIDITIES WITH WHICH IT ASSOCIATES AND THAT PROPER ASYMPTOMATIC HYPERURICEMIA TREATMENT MAY REDUCE FUTURE RISK. ADDITIONAL PROSPECTIVE TRIALS ARE NEEDED TO DEFINITELY ESTABLISH CAUSALITY AND SUPPORT DECISION-MAKING AS TO WHETHER, AND WHICH PATIENTS WITH ASYMPTOMATIC HYPERURICEMIA WOULD WARRANT URATE-LOWERING TREATMENT.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
19  3635  33 INCREASED DNA METHYLATION, CELLULAR SENESCENCE AND PREMATURE EPIGENETIC AGING IN GUINEA PIGS AND HUMANS WITH TUBERCULOSIS. BACKGROUND: TUBERCULOSIS (TB) IS THE ARCHETYPICAL CHRONIC INFECTION, WITH PATIENTS HAVING MONTHS OF SYMPTOMS BEFORE DIAGNOSIS. IN THE TWO YEARS AFTER SUCCESSFUL THERAPY, SURVIVORS OF TB HAVE A THREE-FOLD INCREASED RISK OF DEATH. METHODS: GUINEA PIGS WERE INFECTED WITH MYCOBACTERIUM TUBERCULOSIS (MTB) FOR 45 DAYS, FOLLOWED BY RRBS DNA METHYLATION ANALYSIS. IN HUMANS, NETWORK ANALYSIS OF DIFFERENTIALLY EXPRESSED GENES ACROSS THREE TB COHORTS WERE VISUALIZED AT THE PATHWAY-LEVEL. SERUM LEVELS OF INFLAMMATION WERE MEASURED BY ELISA. HORVATH (DNA METHYLATION) AND RNA-SEQ BIOLOGICAL CLOCKS WERE USED TO INVESTIGATE SHIFTS IN CHRONOLOGICAL AGE AMONG HUMANS WITH TB. RESULTS: GUINEA PIGS WITH TB DEMONSTRATED DNA HYPERMETHYLATION AND SHOWED SYSTEM-LEVEL SIMILARITY TO HUMANS WITH TB (P-VALUE = 0.002). THE TRANSCRIPTOME IN TB IN MULTIPLE COHORTS WAS ENRICHED FOR DNA METHYLATION AND CELLULAR SENESCENCE. SENESCENCE ASSOCIATED PROTEINS CXCL9, CXCL10, AND TNF WERE ELEVATED IN TB PATIENTS COMPARED TO HEALTHY CONTROLS. HUMANS WITH TB DEMONSTRATE 12.7 YEARS (95% CI: 7.5, 21.9) AND 14.38 YEARS (95% CI: 10.23-18.53) OF CELLULAR AGING AS MEASURED BY EPIGENETIC AND GENE EXPRESSION BASED CELLULAR CLOCKS, RESPECTIVELY. CONCLUSIONS: IN BOTH GUINEA PIGS AND HUMANS, TB PERTURBS EPIGENETIC PROCESSES, PROMOTING PREMATURE CELLULAR AGING AND INFLAMMATION, A PLAUSIBLE MEANS TO EXPLAIN THE LONG-TERM DETRIMENTAL HEALTH OUTCOMES AFTER TB.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
20   846  42 CHILDHOOD EXPOSURE TO AMBIENT POLYCYCLIC AROMATIC HYDROCARBONS IS LINKED TO EPIGENETIC MODIFICATIONS AND IMPAIRED SYSTEMIC IMMUNITY IN T CELLS. BACKGROUND: EVIDENCE SUGGESTS THAT EXPOSURE TO POLYCYCLIC AROMATIC HYDROCARBONS (PAHS) INCREASES ATOPY; IT IS UNCLEAR HOW PAH EXPOSURE IS LINKED TO INCREASED SEVERITY OF ATOPIC DISEASES. OBJECTIVE: WE HYPOTHESIZED THAT AMBIENT PAH EXPOSURE IS LINKED TO IMPAIRMENT OF IMMUNITY IN ATOPIC CHILDREN (DEFINED AS CHILDREN WITH ASTHMA AND/OR ALLERGIC RHINITIS) FROM FRESNO, CALIFORNIA, AN AREA WITH ELEVATED AMBIENT PAHS. METHODS: WE RECRUITED 256 SUBJECTS FROM FRESNO, CA. AMBIENT PAH CONCENTRATIONS (NG/M(3) ) WERE MEASURED USING A SPATIAL-TEMPORAL REGRESSION MODEL OVER MULTIPLE TIME PERIODS. ASTHMA DIAGNOSIS WAS DETERMINED BY CURRENT NHLBI CRITERIA. PHENOTYPING AND FUNCTIONAL IMMUNE MEASUREMENTS WERE PERFORMED FROM ISOLATED CELLS. FOR EPIGENETIC MEASUREMENTS, DNA WAS ISOLATED AND PYROSEQUENCED. RESULTS: WE SHOW THAT HIGHER AVERAGE PAH EXPOSURE WAS SIGNIFICANTLY ASSOCIATED WITH IMPAIRED TREG FUNCTION AND INCREASED METHYLATION IN THE FORKHEAD BOX PROTEIN 3 (FOXP3) LOCUS (P < 0.05), CONDITIONAL ON ATOPIC STATUS. THESE EPIGENETIC MODIFICATIONS WERE SIGNIFICANTLY LINKED TO DIFFERENTIAL PROTEIN EXPRESSION OF FOXP3 (P < 0.001). METHYLATION WAS ASSOCIATED WITH CELLULAR FUNCTIONAL CHANGES, SPECIFICALLY TREG DYSFUNCTION, AND AN INCREASE IN TOTAL PLASMA IGE LEVELS. PROTEIN EXPRESSION OF IL-10 DECREASED AND IFN-GAMMA INCREASED AS THE EXTENT OF PAH EXPOSURE INCREASED. THE STRENGTH OF THE ASSOCIATIONS GENERALLY INCREASED AS THE TIME WINDOW FOR AVERAGE PAH EXPOSURE INCREASED FROM 24 HR TO 1 YEAR, SUGGESTING MORE OF A CHRONIC RESPONSE. SIGNIFICANT ASSOCIATIONS WITH CHRONIC PAH EXPOSURE AND IMMUNE OUTCOMES WERE ALSO OBSERVED IN SUBJECTS WITH ALLERGIC RHINITIS. CONCLUSIONS AND CLINICAL RELEVANCE: COLLECTIVELY, THESE RESULTS DEMONSTRATE THAT INCREASED AMBIENT PAH EXPOSURE IS ASSOCIATED WITH IMPAIRED SYSTEMIC IMMUNITY AND EPIGENETIC MODIFICATIONS IN A KEY LOCUS INVOLVED IN ATOPY: FOXP3, WITH A HIGHER IMPACT ON ATOPIC CHILDREN. THE RESULTS SUGGEST THAT INCREASED ATOPIC CLINICAL SYMPTOMS IN CHILDREN COULD BE LINKED TO INCREASED PAH EXPOSURE IN AIR POLLUTION.	2015