Deficiency of MMP1a (Matrix Metalloprotease 1a) Collagenase Suppresses Development of Atherosclerosis in Mice: Translational Implications for Human Coronary Artery Disease.

[Figure: see text].

PAR1 (Protease-Activated Receptor 1) Pepducin Therapy Targeting Myocardial Necrosis in Coronary Artery Disease and Acute Coronary Syndrome Patients Undergoing Cardiac Catheterization: A Randomized, Placebo-Controlled, Phase 2 Study.

OBJECTIVE: Arterial thrombosis leading to ischemic injury worsens the prognosis of many patients with cardiovascular disease. PZ-128 is a first-in-class pepducin that reversibly inhibits PAR1 (protease-activated receptor 1) on platelets and other vascular cells by targeting the intracellular surface of the receptor. The TRIP-PCI (Thrombin Receptor Inhibitory Pepducin in Percutaneous Coronary Intervention) trial was conducted to assess the safety and efficacy of PZ-128 in patients undergoing cardiac catheterization with intent to perform percutaneous coronary intervention. Approach and Results: In this randomized, double-blind, placebo-controlled, phase 2 trial, 100 patients were randomly assigned (2:1) to receive PZ-128 (0.3 or 0.5 mg/kg), or placebo in a 2-hour infusion initiated just before the start of cardiac catheterization, on top of standard oral antiplatelet therapy. Rates of the primary end point of bleeding were not different between the combined PZ-128 doses (1.6%, 1/62) and placebo group (0%, 0/35). The secondary end points of major adverse coronary events at 30 and 90 days did not significantly differ but were numerically lower in the PZ-128 groups (0% and 2% in the PZ-128 groups, 6% and 6% with placebo, p=0.13, p=0.29, respectively). In the subgroup of patients with elevated baseline cardiac troponin I, the exploratory end point of 30-day major adverse coronary events + myocardial injury showed 83% events in the placebo group versus 31% events in the combined PZ-128 drug groups, an adjusted relative risk of 0.14 (95% CI, 0.02-0.75); P=0.02. CONCLUSIONS: In this first-in-patient experience, PZ-128 added to standard antiplatelet therapy appeared to be safe, well tolerated, and potentially reduced periprocedural myonecrosis, thus providing the basis for further clinical trials. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02561000.

Transitioning into the Community: Perceptions of Barriers and Facilitators Experienced By Formerly Incarcerated, Homeless Women During Reentry-A Qualitative Study.

Formerly incarcerated, homeless women on parole or probation experience individual-and structural-level barriers and facilitators as they prepare to transition into the community during reentry. A qualitative study was undertaken using focus group methods with formerly incarcerated, currently homeless women (N = 18, Mage = 37.67, SD 10.68, 23-53 years of age) exiting jail or prison. Major themes which emerged included the following: (1) access to resources-barriers and facilitators during community transition, (2) familial reconciliation and parenting during community transition, and (3) trauma and self-care support during community transition. These findings suggest a need to develop multi-level interventions at the individual, program and institutional/societal level with a gender-sensitive lens for women who are transitioning to community reentry. It is hoped that providing such resources will reduce the likelihood of homelessness and reincarceration.

Noncanonical Matrix Metalloprotease 1-Protease-Activated Receptor 1 Signaling Drives Progression of Atherosclerosis.

OBJECTIVE: Protease-activated receptor-1 (PAR1) is classically activated by thrombin and is critical in controlling the balance of hemostasis and thrombosis. More recently, it has been shown that noncanonical activation of PAR1 by matrix metalloprotease-1 (MMP1) contributes to arterial thrombosis. However, the role of PAR1 in long-term development of atherosclerosis is unknown, regardless of the protease agonist. APPROACH AND RESULTS: We found that plasma MMP1 was significantly correlated (R=0.33; P=0.0015) with coronary atherosclerotic burden as determined by angiography in 91 patients with coronary artery disease and acute coronary syndrome undergoing cardiac catheterization or percutaneous coronary intervention. A cell-penetrating PAR1 pepducin, PZ-128, currently being tested as an antithrombotic agent in the acute setting in the TRIP-PCI study (Thrombin Receptor Inhibitory Pepducin-Percutaneous Coronary Intervention), caused a significant decrease in total atherosclerotic burden by 58% to 70% (P<0.05) and reduced plaque macrophage content by 54% (P<0.05) in apolipoprotein E-deficient mice. An MMP1 inhibitor gave similar beneficial effects, in contrast to the thrombin inhibitor bivalirudin that gave no improvement on atherosclerosis end points. Mechanistic studies revealed that inflammatory signaling mediated by MMP1-PAR1 plays a critical role in amplifying tumor necrosis factor α signaling in endothelial cells. CONCLUSIONS: These data suggest that targeting the MMP1-PAR1 system may be effective in tamping down chronic inflammatory signaling in plaques and halting the progression of atherosclerosis.

Cell-Penetrating Pepducin Therapy Targeting PAR1 in Subjects With Coronary Artery Disease.

OBJECTIVE: Pepducins are membrane-tethered, cell-penetrating lipopeptides that target the cytoplasmic surface of their cognate receptor. Here, we report the first human use of a protease-activated receptor-1-based pepducin, which is intended as an antiplatelet agent to prevent ischemic complications of percutaneous coronary interventions. APPROACH AND RESULTS: PZ-128 was administered by 1 to 2 hours continuous intravenous infusion (0.01-2 mg/kg) to 31 subjects with coronary artery disease or multiple coronary artery disease risk factors. Safety, antiplatelet efficacy, and pharmacokinetics were assessed at baseline and 0.5, 1, 2, 6, 24 hours, and 7 to 10 days postdosing. The inhibitory effects of PZ-128 on platelet aggregation stimulated by the protease-activated receptor-1 agonist SFLLRN (8 µmol/L) at 30 minutes to 6 hours were dose dependent with 20% to 40% inhibition at 0.3 mg/kg, 40% to 60% at 0.5 mg/kg, and ≥ 80% to 100% at 1 to 2 mg/kg. The subgroup receiving aspirin in the 0.5 and 1-mg/kg dose cohorts had 65% to 100% inhibition of final aggregation to SFLLRN at 30 minutes to 2 hours and 95% to 100% inhibition by 6 hours. The inhibitory effects of 0.5 mg/kg PZ-128 were reversible with 50% recovery of aggregation to SFLLRN by 24 hours. There were no significant effects of PZ-128 on aggregation induced by AYPGKF, ADP, or collagen, indicating that the observed effects were specific to protease-activated receptor-1. The plasma half-life was 1.3 to 1.8 hours, and PZ-128 was nondetectable in urine. There were no effects on bleeding, coagulation, clinical chemistry, or ECG parameters. CONCLUSIONS: PZ-128 is a promising antiplatelet agent that provides rapid, specific, dose dependent, and reversible inhibition of platelet protease-activated receptor-1 through a novel intracellular mechanism. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01806077.

Achieving Drug and Alcohol Abstinence Among Recently Incarcerated Homeless Women: A Randomized Controlled Trial Comparing Dialectical Behavioral Therapy-Case Management With a Health Promotion Program.

BACKGROUND: Homeless female ex-offenders (homeless female offenders) exiting jail and prison are at a critical juncture during reentry and transitioning into the community setting. OBJECTIVE: The purpose of the study was to compare the effect of a dialectical behavioral therapy-case management (DBT-CM) program with a health promotion (HP) program on achieving drug and alcohol abstinence among female parolees/probationers residing in the community. METHODS: We conducted a multicenter parallel randomized controlled trial with 130 female parolees/probationers (aged 19-64 years) residing in the community randomly assigned to either DBT-CM (n = 65) or HP (n = 65). The trial was conducted in four community-based partner sites in Los Angeles and Pomona, California, from February 2015 to November 2016. Treatment assignment was carried out using a computer-based urn randomization program. The primary outcome was drug and alcohol use abstinence at 6-month follow up. RESULTS: Analysis was based on data from 116 participants with complete outcome data. Multivariable logistic regression revealed that the DBT-CM program remained an independent positive predictor of decrease in drug use among the DBT-CM participants at 6 months (p = .01) as compared with the HP program participants. Being non-White (p < .05) and having higher depressive symptom scores (p < .05) were associated with lower odds of drug use abstinence (i.e., increased the odds of drug use) at 6 months. DISCUSSION: DBT-CM increased drug and alcohol abstinence at 6-month follow-up, compared to an HP program.

Violent Crime in the Lives of Homeless Female Ex-Offenders.

The cyclical pattern of violence in the lives of homeless female ex-offenders may precipitate ongoing substance use and recidivism; all of which have shown to be mounting public health issues affecting successful reentry. This paper, which analyzed baseline data from a longitudinal study of 126 female ex-offenders in Los Angeles and Pomona, California, highlighted the factors found to be associated with violent crime among homeless female ex-offenders. A multiple logistic regression model for whether or not the last conviction was for a violent offense indicated that poor housing (p = .011) and self-reported anger or hostility (p < .001) were significant correlates. An ordinal regression model for the number of violent offenses also indicated that affectionate support was associated with committing fewer number of violent crimes (p = .001), while positive social interactions (p = .007), and anger/hostility (p = .015) were associated with greater number of violent crimes. Implications for developing a comprehensive array of strategies that can mitigate the pattern of violence often seen in the lives of homeless female who have recently exited jails and prisons is discussed.

Genomic and phenotypic insights into the ecology of Arthrobacter from Antarctic soils.

BACKGROUND: Members of the bacterial genus Arthrobacter are both readily cultured and commonly identified in Antarctic soil communities. Currently, relatively little is known about the physiological traits that allow these bacteria to survive in the harsh Antarctic soil environment. The aim of this study is to investigate if Antarctic strains of Arthrobacter owe their resilience to substantial genomic changes compared to Arthrobacter spp. isolated from temperate soil environments. RESULTS: Quantitative PCR-based analysis revealed that up to 4% of the soil bacterial communities were comprised of Arthrobacter spp. at four locations in the Ross Sea Region. Genome analysis of the seven Antarctic Arthrobacter isolates revealed several features that are commonly observed in psychrophilic/psychrotolerant bacteria. These include genes primarily associated with sigma factors, signal transduction pathways, the carotenoid biosynthesis pathway and genes induced by cold-shock, oxidative and osmotic stresses. However, these genes were also identified in genomes of seven temperate Arthrobacter spp., suggesting that these mechanisms are beneficial for growth and survival in a range of soil environments. Phenotypic characterisation revealed that Antarctic Arthrobacter isolates demonstrate significantly lower metabolic versatility and a narrower salinity tolerance range compared to temperate Arthrobacter species. Comparative analyses also revealed fewer protein-coding sequences and a significant decrease in genes associated with transcription and carbohydrate transport and metabolism in four of the seven Antarctic Arthrobacter isolates. Notwithstanding genome incompleteness, these differences together with the decreased metabolic versatility are indicative of genome content scaling. CONCLUSIONS: The genomes of the seven Antarctic Arthrobacter isolates contained several features that may be beneficial for growth and survival in the Antarctic soil environment, although these features were not unique to the Antarctic isolates. These genome sequences allow further investigations into the expression of physiological traits that enable survival under extreme conditions and, more importantly, into the ability of these bacteria to respond to future perturbations including climate change and human impacts.

Methylchloroisothiazolinone and methylisothiazolinone contact allergy: an occupational perspective.

BACKGROUND: Sensitivity to either methylchloroisothiazolinone (MCI)/methylisothiazolinone (MI) or MI has increased, with a reported frequency of up to 11.1% among dermatitis patients, the main context being allergic contact dermatitis caused by MCI or MCI/MI in personal care products. Case reports have described occupational allergic contact dermatitis caused by MI in paints and within the beauty industry. PATIENTS/MATERIALS/METHODS: This study identified incident cases of occupational allergic contact dermatitis caused by MCI/MI and or MI reported from 1996 to 2012 to a UK-wide surveillance scheme (EPIDERM), with the aim of identifying changes in incidence over the study period. RESULTS: The data show an increase in occupational allergic contact dermatitis caused by MCI/MI and or MI from 1996 to 2012 of 4.1% [95% confidence interval (CI) 1.6-6.9] per annum. Analysis by industry showed a 3.8% (95% CI: -0.3 to 8.0) per annum increase in those exposed to personal care products in the workplace as a primary exposure [healthcare workers, 8.1% (95% CI: 2.1-14.4) per annum; beauty workers, 6.6% (95% CI: -2.2 to 16.2) per annum; hairdressers, 1.5% (95% CI: -4.7 to 8.1) per annum]. There was a 6.3% (95% CI: 1.8-10.9) per annum increase for manufacturing workers. A statistically significant rise in the frequency of occupational allergic contact dermatitis was shown to be attributable to MCI/MI and or MI between 1996 and 2012. CONCLUSION: The findings support recommendations for a review of the regulations relating to MCI/MI and/or MI in cosmetic and personal care products and in industrial settings.

UK rates of occupational skin disease attributed to rubber accelerators, 1996-2012.

BACKGROUND: Natural and synthetic rubbers containing rubber accelerators are well-known causes of allergic contact dermatitis (ACD). Latex contact urticaria (CU) has been widely reported, especially when powdered latex glove use was commonplace. Consequently, interventions to reduce latex exposure by altering glove manufacture were introduced. OBJECTIVE: This study aimed to analyse trends in UK-reported incidence of occupational skin disease associated with rubber accelerators. METHOD: We analysed cases reported to EPIDERM (part of The Health and Occupation Research network) of occupational ACD caused by natural and synthetic rubber products, between 1996 and 2012. RESULTS: For the studied period, a decreasing incidence of ACD associated with rubber products was found, with an average annual change of -1.2% [95% confidence interval (CI) -3.1 to 0.7]. The number of cases of latex CU (n = 580) significantly declined. The number of cases of ACD caused by mercapto mix and mercaptobenzothiazole (n = 177) and thiuram mix (n = 603) also declined. Reports of ACD associated with carba mix and its constituents (n = 219) increased significantly, by an average annual percentage of 10.1% (95%CI: 6.1-14.2). Twenty-six cases of ACD caused by rarer rubber compounds were identified, highlighting skin disease attributable to less widely recognized chemicals. CONCLUSIONS: These data show a falling reported incidence of occupational ACD attributed to rubber chemicals, but within this a significant rise attributable to the constituents of the carba mix. Clinicians should recognize the changing diversity of chemicals used in rubber manufacturing, and consider including carba mix in their baseline series and testing beyond this in suspect cases to avoid false-negative results.

Paenibacillus darwinianus sp. nov., isolated from gamma-irradiated Antarctic soil.

A novel bacterium, strain Br(T), was isolated from gamma-irradiated soils of the Britannia drift, Lake Wellman Region, Antarctica. This isolate was rod-shaped, endospore forming, Gram-stain-variable, catalase-positive, oxidase-negative and strictly aerobic. Cells possessed a monotrichous flagellum. Optimal growth was observed at 18 °C, pH 7.0 in PYGV or R2A broth. The major cellular fatty acid was anteiso-C15 : 0 (63.4 %). Primary identified lipids included phosphatidylethanolamine, diphosphatidylglycerol and phosphatidylglycerol. Total phospholipid was 60 % (w/w) of the total lipid extract. MK-7 was the dominant isoprenoid quinone. The genomic DNA G+C content was 55.6 mol%. Based on 16S rRNA gene sequence similarity, strain Br(T) clusters within the genus Paenibacillus with similarity values ranging from 93.9 to 95.1 %. Phylogenetic analyses by maximum-likelihood, maximum-parsimony and neighbour-joining methods revealed that strain Br(T) clusters with Paenibacillus daejeonensis (AF290916), Paenibacillus tarimensis (EF125184) and Paenibacillus pinihumi (GQ423057), albeit with weak bootstrap support. On the basis of phenotypic, chemotaxonomic and phylogenetic characteristics, we propose that strain Br(T) represents a novel species, Paenibacillus darwinianus sp. nov. The type strain is Br(T) ( = DSM 27245(T) = ICMP 19912(T)).

Successional development of biofilms in moving bed biofilm reactor (MBBR) systems treating municipal wastewater.

Biofilm-based technologies, such as moving bed biofilm reactor (MBBR) systems, are widely used to treat wastewater. Biofilm development is important for MBBR systems as much of the microbial biomass is retained within reactors as biofilm on suspended carriers. Little is known about this process of biofilm development and the microorganisms upon which MBBRs rely. We documented successional changes in microbial communities as biofilms established in two full-scale MBBR systems treating municipal wastewater over two seasons. 16S rRNA gene-targeted pyrosequencing and clone libraries were used to describe microbial communities. These data indicate a successional process that commences with the establishment of an aerobic community dominated by Gammaproteobacteria (up to 52 % of sequences). Over time, this community shifts towards dominance by putatively anaerobic organisms including Deltaproteobacteria and Clostridiales. Significant differences were observed between the two wastewater treatment plants (WWTPs), mostly due to a large number of sequences (up to 55 %) representing Epsilonproteobacteria (mostly Arcobacter) at one site. Archaea in young biofilms included several lineages of Euryarchaeota and Crenarchaeota. In contrast, the mature biofilm consisted entirely of Methanosarcinaceae (Euryarchaeota). This study provides new insights into the community structure of developing biofilms at full-scale WWTPs and provides the basis for optimizing MBBR start-up and operational parameters.

dsrAB-based analysis of sulphate-reducing bacteria in moving bed biofilm reactor (MBBR) wastewater treatment plants.

Sulphate-reducing bacteria (SRB) are important members of the sulphur cycle in wastewater treatment plants (WWTPs). In this study, we investigate the diversity and activity of SRB within the developing and established biofilm of two moving bed biofilm reactor (MBBR) systems treating municipal wastewater in New Zealand. The larger of the two WWTPs (Moa Point) generates high levels of sulphide relative to the smaller Karori plant. Clone libraries of the dissimilatory (bi)sulphite reductase (dsrAB) genes and quantitative real-time PCR targeting dsrA transcripts were used to compare SRB communities between the two WWTPs. Desulfobulbus (35-53 % of total SRB sequences) and genera belonging to the family Desulfobacteraceae (27-41 %) dominated the SRB fraction of the developing biofilm on deployed plastic carriers at both sites, whereas Desulfovibrio and Desulfomicrobium were exclusively found at Moa Point. In contrast, the established biofilms from resident MBBR carriers were largely dominated by Desulfomonile tiedjei-like organisms (58-100 % of SRB sequences). The relative transcript abundance of dsrA genes (signifying active SRBs) increased with biofilm weight yet remained low overall, even in the mature biofilm stage. Our results indicate that although SRB are both present and active in the microbial community at both MBBR study sites, differences in the availability of sulphate may be contributing to the observed differences in sulphide production at these two plants.

Effect of Fenton reagent shock and recovery periods on anaerobic microbial community structure and degradation of chlorinated aliphatics.

This study investigates the effect of Fenton reagent on the structure and function of a microbial consortium during the anaerobic degradation of hexachloroethane (HCA) and tetrachloroethene (PCE). Anaerobic biodegradation tests of HCA and PCE were performed in batch reactors using an anaerobic microbial consortium that had been exposed to Fenton reagent for durations of 0, 0.04, and 2 days and then allowed to recover for periods of 0, 3, and 7 days. The bacterial community structure was determined using culture-independent methods of 16S rRNA gene sequencing and automated ribosomal intergenic spacer analysis. Larger recovery periods partially restored the microbial community structure; however, the recovery periods did not restore the loss of ability to degrade HCA and PCE in cultures shocked for 0.04 days, and PCE in cultures shocked for 2 days. Overall the exposure to Fenton reagent had an impact on bacterial community structure with downstream effects on HCA and PCE degradation. This study highlights that the impacts of short- and long-term shocks on microbial community structure and function can be correlated using a combination of biodegradation tests and community structure analysis tools.

Bacterial composition of soils of the Lake Wellman area, Darwin Mountains, Antarctica.

The aim of this study was to examine the bacterial composition of high latitude soils from the Darwin-Hatherton glacier region of Antarctica. Four soil pits on each of four glacial drift sheets were sampled for chemical and microbial analyses. The four drifts-Hatherton, Britannia, Danum, and Isca-ranged, respectively, from early Holocene (10 ky) to mid-Quaternary (ca 900 ky). Numbers of culturable bacteria were low, with highest levels detected in soils from the younger Hatherton drift. DNA was extracted and 16S rRNA gene clone libraries prepared from samples below the desert pavement for each of the four drift sheets. Between 31 and 262 clones were analysed from each of the Hatherton, Britannia, and Danum drifts. Bacterial sequences were dominated by members of the phyla Deinococcus-Thermus, Actinobacteria, and Bacteroidetes. Culturable bacteria, including some that clustered with soil clones (e.g., members of the genera Arthrobacter, Adhaeribacter, and Pontibacter), belonged to Actinobacteria and Bacteroidetes. The isolated bacteria are ideal model organisms for genomic and phenotypic investigations of those attributes that allow bacteria to survive and/or grow in Antarctic soils because they have close relatives that are not tolerant of these conditions.

Mortality in a cohort of Staffordshire pottery workers: follow-up to December 2008.

OBJECTIVES: To examine mortality from lung cancer, chronic obstructive pulmonary disease (COPD) and chronic non-malignant renal disease (cNMRD) in pottery workers exposed to silica. METHODS: A cohort of Stoke-on-Trent pottery workers (N=5115), previously followed to 1992, was traced for vital status and cause of death to December 2008. Standardised mortality ratio (SMR) analyses, comparing deaths to England and Wales and Stoke-on-Trent, examined underlying cause in 1985-1992 and 1993-2008 and mentioned cause for 1993-2008. Survival analysis considered exposure duration and concentration of respirable silica for lung cancer, COPD and cNMRD, using Cox regression. RESULTS: Excess risks of lung cancer, COPD and cNMRD were seen against both England and Wales and Stoke-on-Trent for 1985-2008. SMRs for lung cancer and COPD were lower in 1993-2008 and non-significant for lung cancer against Stoke-on-Trent in that period (SMR 1.07 95% CI 0.92 to 1.25). Exposure concentration, estimated for 1943 subjects, was related to lung cancer in smokers for early but not later deaths with mean silica concentration >200 µg/m(3) among deaths to June 1992 (HR 2.80 95% CI 1.21 to 6.50). For COPD an increasing trend with duration and (non-significantly) with mean concentration was seen for early but not later deaths in smokers. No relation was observed between estimated exposures and cNMRD. CONCLUSIONS: Excess rates of death from COPD and lung cancer were more marked in the period of the first follow-up (1985-1992) than in the second, with any relation to estimated exposure being limited to the earlier period. Conclusions about COPD and exposure were limited by an early selective destruction of files.

Time trends in the incidence of work-related mental ill-health and musculoskeletal disorders in the UK.

OBJECTIVES: To determine UK trends (from 1996 to 2009) in incidence of work-related mental ill-health and musculoskeletal disorders, for all industry as well as for health and social care employees. Second, to investigate whether there may have been a recent shift from a physical to psychological perspective in how patients present their illness by comparing reporting trends for back pain and 'other work stress'. METHODS: Multilevel models were used to investigate changes in incidence of work-related illness, as diagnosed by specialist physicians. The dependent variable comprised case reports to The Health and Occupation Research network. Comparisons were made between medical specialties, industry (health and social care vs all other employees), gender and diagnosis. RESULTS: Trends for Occupational Physicians' (OP) reporting mental ill-health (average annual increase +3.7% (95% CI +2.2% to +5.2%)) differed significantly (p<0.001) from psychiatrists' reporting over the same time period (-5.9% (95% CI -7.6% to -4.2%)). For OPs' reporting, the rate of increase was greater for females and for health and social care employees. A fall in incidence of musculoskeletal disorders for OPs of -5.8% (95% CI -7.3% to -4.3%) and rheumatologists' reporting -6.6% (95% CI -8.3% to -4.8%) was found, with little variation by gender or industry. Within health and social care, an increase in incidence of 'other work stress' was accompanied by a similar decrease in 'spine/back pain'. CONCLUSIONS: The evidence presented is consistent with a shift in the presentation of ill-health from a physical to psychological perspective, although changes in hazards, prevention measures and physician awareness should also be considered as explanations.

Triggers of aggregation and extracellular polysaccharide polymer production in Acidovorax temperans.

Bacterial aggregation has important implications for the maintenance of bacteria in engineered environments. The triggers for aggregation, however, are poorly understood. A strain of Acidovorax temperans CB2Hn isolated from activated sludge was found to exhibit transient aggregation and was applied as a model to investigate factors that regulate biological aggregation. Growth kinetic studies indicate CB2Hn has exponential growth rates (µ(max)) ranging from 0.11 to 0.75 (log(CFU mL(-1))h(-1)) depending on nutrient conditions. CB2Hn exhibited variable aggregation in growth media that differed in the type of available carbon. Aggregation indices and extracellular polysaccharide polymer levels showed transient maxima which occurred at different points in the growth curve for each medium type. Maximum aggregation points were detected at the beginning of log phase in media containing complex carbon sources. In contrast, maximum values were detected in early log phase and mid-to-late log phase in media containing both simple and complex carbon sources. The results suggest that aggregation is regulated by nutritional cues and is possibly triggered by the switch to utilisation of complex carbon substrates.

Suppression of Heart Failure With PAR1 Pepducin Technology in a Pressure Overload Model in Mice.

BACKGROUND: PAR1 (protease-activated receptor-1) contributes to acute thrombosis, but it is not clear whether the receptor is involved in deleterious inflammatory and profibrotic processes in heart failure. Here, we employ the pepducin technology to determine the effects of targeting PAR1 in a mouse heart failure with reduced ejection fraction model. METHODS: After undergoing transverse aortic constriction pressure overload or sham surgery, C57BL/6J mice were randomized to daily sc PZ-128 pepducin or vehicle, and cardiac function, inflammation, fibrosis, and molecular analyses conducted at 7 weeks RESULTS: After 7 weeks of transverse aortic constriction, vehicle mice had marked increases in macrophage/monocyte infiltration and fibrosis of the left ventricle as compared with Sham mice. PZ-128 treatment significantly suppressed the inflammatory cell infiltration and cardiac fibrosis. Despite no effect on myocyte cell hypertrophy, PZ-128 afforded a significant reduction in overall left ventricle weight and completely protected against the transverse aortic constriction-induced impairments in left ventricle ejection fraction. PZ-128 significantly suppressed transverse aortic constriction-induced increases in an array of genes involved in myocardial stress, fibrosis, and inflammation. CONCLUSIONS: The PZ-128 pepducin is highly effective in protecting against cardiac inflammation, fibrosis, and loss of left ventricle function in a mouse model.