A Laboratory-Scale Evaluation of Smart Pebble Sensors Embedded in Geomaterials.

This paper introduces a novel approach to measure deformations in geomaterials using the recently developed 'Smart Pebble' sensors. Smart Pebbles were included in triaxial test specimens of unbound aggregates stabilized with geogrids. The sensors are equipped with an aggregate particle/position tracking algorithm that can manage uncertainty arising due to signal noise and random walk effects. Two Smart Pebbles were placed in each test specimen, one at specimen's mid-height, where a geogrid was installed in the mechanically stabilized specimen, and one towards the top of the specimen. Even with simple raw data processing, the trends on linear vertical acceleration indicated the ability of Smart Pebbles to assess the geomaterial configuration and applied stress states. Employing a Kalman filter-based algorithm, the Smart Pebble position coordinates were tracked during testing. The specimen's resilient deformations were simultaneously recorded. bender element shear wave transducer pairs were also installed on the specimens to further validate the Smart Pebble small-strain responses. The results indicate a close agreement between the BE sensors and Smart Pebbles estimates towards local stiffness enhancement quantification in the geogrid specimen. The study findings confirm the viability of using the Smart Pebbles in describing the resilient behavior of an aggregate material under repeated loading.

Physiological healing of chronic gastric ulcer is not impaired by the hydrogen sulphide (H2S)-releasing derivative of acetylsalicylic acid (ATB-340): functional and proteomic approaches.

Gastric ulcers affect approx. 10% of population. Non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid (ASA) predispose to or impair the physiologically complex healing of pre-existing ulcers. Since H2S is an endogenous cytoprotective molecule, we hypothesized that new H2S-releasing ASA-derivative (ATB-340) could overcome pathological impact of NSAIDs on GI regeneration.Clinically translational gastric ulcers were induced in Wistar rats using state-of-the-art microsurgical model employing serosal application of acetic acid. This was followed by 9 days long i.g. daily treatment with vehicle, ATB-340 (6-24 mg/kg) or equimolar ASA doses (4-14 mg/kg). Ulcer area was assessed macro- and microscopically. Prostaglandin (PG)E2  levels, indicating pharmacological activity of NSAIDs and 8-hydroxyguanozine content, reflecting nucleic acids oxidation in serum/gastric mucosa, were determined by ELISA. Qualitative and/or quantitative pathway-specific alterations at the ulcer margin were evaluated using real-time PCR and mass spectrometry-based proteomics.ASA, unlike ATB-340, dose-dependently delayed/impaired gastric tissue recovery, deregulating 310 proteins at the ulcer margin, including Ras signalling, wound healing or apoptosis regulators. ATB-340 maintained NSAIDs-specific cyclooxygenase-inhibiting capacity on systemic and GI level but in time-dependent manner. High dose of ATB-340 (24 mg/kg daily), but not ASA, decreased nucleic acids oxidation and upregulated anti-oxidative/anti-inflammatory heme oxygenase-1, 24-dehydrocholesterol reductase or suppressor of cytokine signalling (SOCS3) at the ulcer margin.Thus, ASA impairs the physiological healing of pre-existing gastric ulcers, inducing the extensive molecularly functional and proteomic alterations at the wound margin. H2S-releasing ATB-340 maintains the target activity of NSAIDs with limited impact on gastric PGE2 signalling and physiological GI regeneration, enhancing anti-inflammatory and anti-oxidative response, and providing the pharmacological advantage.

Mosquitoes provide a transmission route between possums and humans for Buruli ulcer in southeastern Australia.

Buruli ulcer, a chronic subcutaneous infection caused by Mycobacterium ulcerans, is increasing in prevalence in southeastern Australia. Possums are a local wildlife reservoir for M. ulcerans and, although mosquitoes have been implicated in transmission, it remains unclear how humans acquire infection. We conducted extensive field survey analyses of M. ulcerans prevalence among mosquitoes in the Mornington Peninsula region of southeastern Australia. PCR screening of trapped mosquitoes revealed a significant association between M. ulcerans and Aedes notoscriptus. Spatial scanning statistics revealed overlap between clusters of M. ulcerans-positive Ae. notoscriptus, M. ulcerans-positive possum excreta and Buruli ulcer cases, and metabarcoding analyses showed individual mosquitoes had fed on humans and possums. Bacterial genomic analysis confirmed shared single-nucleotide-polymorphism profiles for M. ulcerans detected in mosquitoes, possum excreta and humans. These findings indicate Ae. notoscriptus probably transmit M. ulcerans in southeastern Australia and highlight mosquito control as a Buruli ulcer prevention measure.

Hydrogen Sulfide-Releasing Indomethacin-Derivative (ATB-344) Prevents the Development of Oxidative Gastric Mucosal Injuries.

Hydrogen sulfide (H2S) emerged recently as an anti-oxidative signaling molecule that contributes to gastrointestinal (GI) mucosal defense and repair. Indomethacin belongs to the class of non-steroidal anti-inflammatory drugs (NSAIDs) and is used as an effective intervention in the treatment of gout- or osteoarthritis-related inflammation. However, its clinical use is strongly limited since indomethacin inhibits gastric mucosal prostaglandin (PG) biosynthesis, predisposing to or even inducing ulcerogenesis. The H2S moiety was shown to decrease the GI toxicity of some NSAIDs. However, the GI safety and anti-oxidative effect of a novel H2S-releasing indomethacin derivative (ATB-344) remain unexplored. Thus, we aimed here to compare the impact of ATB-344 and classic indomethacin on gastric mucosal integrity and their ability to counteract the development of oxidative gastric mucosal injuries. Wistar rats were pretreated intragastrically (i.g.) with vehicle, ATB-344 (7-28 mg/kg i.g.), or indomethacin (5-20 mg/kg i.g.). Next, animals were exposed to microsurgical gastric ischemia-reperfusion (I/R). Gastric damage was assessed micro- and macroscopically. The volatile H2S level was assessed in the gastric mucosa using the modified methylene blue method. Serum and gastric mucosal PGE2 and 8-hydroxyguanozine (8-OHG) concentrations were evaluated by ELISA. Molecular alterations for gastric mucosal barrier-specific targets such as cyclooxygenase-1 (COX)-1, COX-2, heme oxygenase-1 (HMOX)-1, HMOX-2, superoxide dismutase-1 (SOD)-1, SOD-2, hypoxia inducible factor (HIF)-1α, xanthine oxidase (XDH), suppressor of cytokine signaling 3 (SOCS3), CCAAT enhancer binding protein (C/EBP), annexin A1 (ANXA1), interleukin 1 beta (IL-1ß), interleukin 1 receptor type I (IL-1R1), interleukin 1 receptor type II (IL-1R2), inducible nitric oxide synthase (iNOS), tumor necrosis factor receptor 2 (TNFR2), or H2S-producing enzymes, cystathionine γ-lyase (CTH), cystathionine ß-synthase (CBS), or 3-mercaptopyruvate sulfur transferase (MPST), were assessed at the mRNA level by real-time PCR. ATB-344 (7 mg/kg i.g.) reduced the area of gastric I/R injuries in contrast to an equimolar dose of indomethacin. ATB-344 increased gastric H2S production, did not affect gastric mucosal PGE2 content, prevented RNA oxidation, and maintained or enhanced the expression of oxidation-sensitive HMOX-1 and SOD-2 in line with decreased IL-1ß and XDH. We conclude that due to the H2S-releasing ability, i.g., treatment with ATB-344 not only exerts dose-dependent GI safety but even enhances gastric mucosal barrier capacity to counteract acute oxidative injury development when applied at a low dose of 7 mg/kg, in contrast to classic indomethacin. ATB-344 (7 mg/kg) inhibited COX activity on a systemic level but did not affect cytoprotective PGE2 content in the gastric mucosa and, as a result, evoked gastroprotection against oxidative damage.

Repurposing sunscreen as an antibiotic: zinc-activated avobenzone inhibits methicillin-resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) is a major healthcare concern with associated healthcare costs reaching over ${\$}$1 billion in a single year in the USA. Antibiotic resistance in S. aureus is now observed against last line of defense antibiotics, such as vancomycin, linezolid, and daptomycin. Unfortunately, high throughput drug discovery approaches to identify new antibiotics effective against MRSA have not resulted in much tangible success over the last decades. Previously, we demonstrated the feasibility of an alternative drug discovery approach, the identification of metallo-antibiotics, compounds that gain antibacterial activity only after binding to a transition metal ion and as such are unlikely to be detected in standard drug screens. We now report that avobenzone, the primary active ingredient of most sunscreens, can be activated by zinc to become a potent antibacterial compound against MRSA. Zinc-activated avobenzone (AVB-Zn) potently inhibited a series of clinical MRSA isolates [minimal inhibitory concentration (MIC): 0.62-2.5 µM], without pre-existing resistance and activity without zinc (MIC: >10 µM). AVB-Zn was also active against clinical MRSA isolates that were resistant against the commonly used zinc-salt antibiotic bacitracin. We found AVB-Zn exerted no cytotoxicity on human cell lines and primary cells. Last, we demonstrate AVB-Zn can be deployed therapeutically as lotion preparations, which showed efficacy in a mouse wound model of MRSA infection. AVB-Zn thus demonstrates Zn-activated metallo-antibiotics are a promising avenue for future drug discovery.

Statistical modeling based on structured surveys of Australian native possum excreta harboring Mycobacterium ulcerans predicts Buruli ulcer occurrence in humans.

Background: Buruli ulcer (BU) is a neglected tropical disease caused by infection of subcutaneous tissue with Mycobacterium ulcerans. BU is commonly reported across rural regions of Central and West Africa but has been increasing dramatically in temperate southeast Australia around the major metropolitan city of Melbourne, with most disease transmission occurring in the summer months. Previous research has shown that Australian native possums are reservoirs of M. ulcerans and that they shed the bacteria in their fecal material (excreta). Field surveys show that locales where possums harbor M. ulcerans overlap with human cases of BU, raising the possibility of using possum excreta surveys to predict the risk of disease occurrence in humans. Methods: We thus established a highly structured 12 month possum excreta surveillance program across an area of 350 km2 in the Mornington Peninsula area 70 km south of Melbourne, Australia. The primary objective of our study was to assess using statistical modeling if M. ulcerans surveillance of possum excreta provided useful information for predicting future human BU case locations. Results: Over two sampling campaigns in summer and winter, we collected 2,282 possum excreta specimens of which 11% were PCR positive for M. ulcerans-specific DNA. Using the spatial scanning statistical tool SaTScan, we observed non-random, co-correlated clustering of both M. ulcerans positive possum excreta and human BU cases. We next trained a statistical model with the Mornington Peninsula excreta survey data to predict the future likelihood of human BU cases occurring in the region. By observing where human BU cases subsequently occurred, we show that the excreta model performance was superior to a null model trained using the previous year's human BU case incidence data (AUC 0.66 vs 0.55). We then used data unseen by the excreta-informed model from a new survey of 661 possum excreta specimens in Geelong, a geographically separate BU endemic area to the southwest of Melbourne, to prospectively predict the location of human BU cases in that region. As for the Mornington Peninsula, the excreta-based BU prediction model outperformed the null model (AUC 0.75 vs 0.50) and pinpointed specific locations in Geelong where interventions could be deployed to interrupt disease spread. Conclusions: This study highlights the One Health nature of BU by confirming a quantitative relationship between possum excreta shedding of M. ulcerans and humans developing BU. The excreta survey-informed modeling we have described will be a powerful tool for the efficient targeting of public health responses to stop BU. Funding: This research was supported by the National Health and Medical Research Council of Australia and the Victorian Government Department of Health (GNT1152807 and GNT1196396).

Prolonged COVID-19 symptom duration in people with systemic autoimmune rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance Vaccine Survey.

OBJECTIVE: We investigated prolonged COVID-19 symptom duration, defined as lasting 28 days or longer, among people with systemic autoimmune rheumatic diseases (SARDs). METHODS: We analysed data from the COVID-19 Global Rheumatology Alliance Vaccine Survey (2 April 2021-15 October 2021) to identify people with SARDs reporting test-confirmed COVID-19. Participants reported COVID-19 severity and symptom duration, sociodemographics and clinical characteristics. We reported the proportion experiencing prolonged symptom duration and investigated associations with baseline characteristics using logistic regression. RESULTS: We identified 441 respondents with SARDs and COVID-19 (mean age 48.2 years, 83.7% female, 39.5% rheumatoid arthritis). The median COVID-19 symptom duration was 15 days (IQR 7, 25). Overall, 107 (24.2%) respondents had prolonged symptom duration (≥28 days); 42/429 (9.8%) reported symptoms lasting ≥90 days. Factors associated with higher odds of prolonged symptom duration included: hospitalisation for COVID-19 vs not hospitalised and mild acute symptoms (age-adjusted OR (aOR) 6.49, 95% CI 3.03 to 14.1), comorbidity count (aOR 1.11 per comorbidity, 95% CI 1.02 to 1.21) and osteoarthritis (aOR 2.11, 95% CI 1.01 to 4.27). COVID-19 onset in 2021 vs June 2020 or earlier was associated with lower odds of prolonged symptom duration (aOR 0.42, 95% CI 0.21 to 0.81). CONCLUSION: Most people with SARDs had complete symptom resolution by day 15 after COVID-19 onset. However, about 1 in 4 experienced COVID-19 symptom duration 28 days or longer; 1 in 10 experienced symptoms 90 days or longer. Future studies are needed to investigate the possible relationships between immunomodulating medications, SARD type/flare, vaccine doses and novel viral variants with prolonged COVID-19 symptoms and other postacute sequelae of COVID-19 among people with SARDs.

Stress during pregnancy: An ecological momentary assessment of stressors among Black and White women with implications for maternal health.

BACKGROUND: Stress can lead to adverse physiological and psychological outcomes. Therefore, understanding stress during pregnancy provides insight into racial disparities in maternal health, particularly Black maternal health. OBJECTIVES: This study aimed to describe (1) daily exposure to self-reported stress levels during pregnancy, and (2) sources of stress among participants that identified as Black or White using data collected via ecological momentary assessment. METHODS: We leveraged survey data from the Postpartum Mothers Mobile Study, a prospective longitudinal study using ecological momentary assessment data collection methods to describe patterns of stress during pregnancy. This article is descriptive and documents patterns of self-reported stress levels and sources of stress. Frequencies and percentages of stress responses were computed to describe these patterns. RESULTS: The sample (n = 296) was 27% Black (n = 78) and 63% White (n = 184). Results were based on at least one measurement of that stress level during pregnancy. A similar number of Black and White participants reported no stress during pregnancy. White (85%-95%) and Black (60%-70%) participants reported low to moderate levels of stress. Black participants (38%) and White participants (35%) reported experiencing high stress. Black and White participants reported similar sources of stress: stress from a partner, too many things to do, a baby or other children, and financial concerns. White participants reported work as a top stressor, and Black participants reported financial issues as a top source of stress. CONCLUSION: This study provides insight into daily exposure to stress that has implications for maternal health. We described patterns of self-reported stress and sources of stress among Black and White participants. The daily exposures to stress reported by this sample exist within a context of root causes of structural inequities in education, health care, income, wealth, and housing that must be addressed to achieve maternal health equity.

Effects of Hydrogen Sulfide on the Microbiome: From Toxicity to Therapy.

Significance: Hydrogen sulfide (H2S), an important regulator of physiology and health, helps resolve inflammation and promotes tissue repair in the gastrointestinal tract. Recent Advances: Gut microbiota live as a multispecies biofilm in close interaction with the upper mucus layer lining the epithelium. The relative abundance, spatial organization, and function of these microorganisms affect a broad range of health outcomes. This article provides a state-of-the-art review of our understanding of the cross talk between H2S, the gut microbiota, and health. H2S can have toxic or therapeutic effects, depending on its concentration and source. When produced at excessive concentrations by local microbiota, H2S may cause mucus disruption and inflammation and contribute to development of cancer. In contrast, low levels of endogenous or exogenous H2S directly stabilize mucus layers, prevent fragmentation and adherence of the microbiota biofilm to the epithelium, inhibit the release of invasive pathobionts, and help resolve inflammation and tissue injury. Although scarce, research findings suggest that dietary H2S obtained from plants or ingestion of the H2S precursor, L-cysteine, may also modulate the abundance and function of microbiota. Critical Issues: A critical issue is the lack of understanding of the metagenomic, transcriptomic, and proteomic alterations that characterize the interactions between H2S and gut microbiota to shape health outcomes. Future Directions: The ambivalent roles of H2S in the gut offer a fertile ground for research on such critical issues. The findings will improve our understanding of how H2S modulates the microbiota to affect body function and will help identify novel therapeutic strategies. Antioxid. Redox Signal. 36, 211-219.

A need for null models in understanding disease transmission: the example of Mycobacterium ulcerans (Buruli ulcer disease).

Understanding the interactions of ecosystems, humans and pathogens is important for disease risk estimation. This is particularly true for neglected and newly emerging diseases where modes and efficiencies of transmission leading to epidemics are not well understood. Using a model for other emerging diseases, the neglected tropical skin disease Buruli ulcer (BU), we systematically review the literature on transmission of the etiologic agent, Mycobacterium ulcerans (MU), within a One Health/EcoHealth framework and against Hill's nine criteria and Koch's postulates for making strong inference in disease systems. Using this strong inference approach, we advocate a null hypothesis for MU transmission and other understudied disease systems. The null should be tested against alternative vector or host roles in pathogen transmission to better inform disease management. We propose a re-evaluation of what is necessary to identify and confirm hosts, reservoirs and vectors associated with environmental pathogen replication, dispersal and transmission; critically review alternative environmental sources of MU that may be important for transmission, including invertebrate and vertebrate species, plants and biofilms on aquatic substrates; and conclude with placing BU within the context of other neglected and emerging infectious diseases with intricate ecological relationships that lead to disease in humans, wildlife and domestic animals.

Dietary γ-Glutamylcysteine: Its Impact on Glutathione Status and Potential Health Outcomes.

Glutathione (GSH) is a tripeptide that is readily synthesized intracellularly in humans and other mammals. More than a century of research suggests that GSH has numerous biological functions, including protection from the potential adverse events associated with reactive oxygen species (ROS) and related redox reactions that may induce oxidative stress, and that may be linked to innate detoxification processes. Normal tissue and plasma levels of GSH decline through the aging process and decrease during various disease states. While the health value of dietary GSH remains controversial, there is evidence that some metabolic intermediates, such as γ-glutamylcysteine (GGC) may function to preserve adequate GSH levels when the synthetic pathways decline in activity, and the innate antioxidant system is challenged. It is also important to recognize that among the thousands of protein-coding human genes and their respective polymorphisms, at least two genes (Gclc and Gclm) are directly involved with GSH synthesis via glutamate-cysteine ligase. This commentary examines the classic biochemistry, toxicology, safety, and clinical value of GSH and its intermediates that may be modulated by dietary supplementation.

Microbiome Profile and Molecular Pathways Alterations in Gastrointestinal Tract by Hydrogen Sulfide-Releasing Nonsteroidal Anti-Inflammatory Drug (ATB-352): Insight into Possible Safer Polypharmacy.

Aims: Nonsteroidal anti-inflammatory drugs, including ketoprofen, induce adverse effects within the gastrointestinal (GI)-tract. Hydrogen sulfide (H2S) is an antioxidative gaseous mediator contributing to GI-protection. We aimed to evaluate the GI safety of a novel H2S-releasing derivative of ketoprofen (ATB-352) versus classic ketoprofen and the molecular mechanisms of their activity after chronic treatment in experimental animal models. Results: Ketoprofen (10 mg/kg/day) administered intragastrically for 7 days in contrast with ATB-352 (14 mg/kg/day) reduced mucosal H2S content inducing GI damage with significantly increased injury score, altered intestinal microbiome profile, and modulation of more than 50% of 36 investigated molecular sensors (e.g., mammalian target of rapamycin or suppressor of cytokine signaling 3 [SOCS3]). Polypharmacy with aspirin (10 mg/kg/day) enhanced ketoprofen toxicity not affecting GI safety of ATB-352. Omeprazole (20 mg/kg/day) decreased ketoprofen-induced injury to the level of ATB-352 alone. Both compounds combined or not with aspirin or omeprazole maintained the ability to inhibit cyclooxygenase (COX) activity manifested by decreased prostaglandin production. Innovation and Conclusions: Ketoprofen-induced H2S-production decrease and intestinal microbiome profile alterations lead to GI toxicity observed on macro-/microscopic and molecular levels. Ketoprofen but not ATB-352 requires concomitant treatment with omeprazole to eliminate GI adverse effects. ATB-352 applied alone or in a polypharmacy setting with aspirin effectively inhibited COX and maintained GI safety due to H2S-release. Neither compound affected DNA oxidation in the GI mucosa, but ATB-352 had lower impact on molecular oxidative/inflammatory response pathways and intestinal microbiome. The GI safety of ATB-352 could be due to the involvement of heme oxygenase 1 and SOCS3 pathway activation. Antioxid. Redox Signal. 36, 189-210.

SARS-CoV-2 infection in central North Carolina: Protocol for a population-based longitudinal cohort study and preliminary participant results.

Public health surveillance systems likely underestimate the true prevalence and incidence of SARS-CoV-2 infection due to limited access to testing and the high proportion of subclinical infections in community-based settings. This ongoing prospective, observational study aimed to generate accurate estimates of the prevalence and incidence of, and risk factors for, SARS-CoV-2 infection among residents of a central North Carolina county. From this cohort, we collected survey data and nasal swabs every two weeks and venous blood specimens every month. Nasal swabs were tested for the presence of SARS-CoV-2 virus (evidence of active infection), and serum specimens for SARS-CoV-2-specific antibodies (evidence of prior infection). As of June 23, 2021, we have enrolled a total of 153 participants from a county with an estimated 76,285 total residents. The anticipated study duration is at least 24 months, pending the evolution of the pandemic. Study data are being shared on a monthly basis with North Carolina state health authorities and future analyses aim to compare study data to state-wide metrics over time. Overall, the use of a probability-based sampling design and a well-characterized cohort will enable collection of critical data that can be used in planning and policy decisions for North Carolina and may be informative for other states with similar demographic characteristics.

Early experience of COVID-19 vaccination in adults with systemic rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance Vaccine Survey.

BACKGROUND: We describe the early experiences of adults with systemic rheumatic disease who received the COVID-19 vaccine. METHODS: From 2 April to 30 April 2021, we conducted an online, international survey of adults with systemic rheumatic disease who received COVID-19 vaccination. We collected patient-reported data on clinician communication, beliefs and intent about discontinuing disease-modifying antirheumatic drugs (DMARDs) around the time of vaccination, and patient-reported adverse events after vaccination. RESULTS: We analysed 2860 adults with systemic rheumatic diseases who received COVID-19 vaccination (mean age 55.3 years, 86.7% female, 86.3% white). Types of COVID-19 vaccines were Pfizer-BioNTech (53.2%), Oxford/AstraZeneca (22.6%), Moderna (21.3%), Janssen/Johnson & Johnson (1.7%) and others (1.2%). The most common rheumatic disease was rheumatoid arthritis (42.3%), and 81.2% of respondents were on a DMARD. The majority (81.9%) reported communicating with clinicians about vaccination. Most (66.9%) were willing to temporarily discontinue DMARDs to improve vaccine efficacy, although many (44.3%) were concerned about rheumatic disease flares. After vaccination, the most reported patient-reported adverse events were fatigue/somnolence (33.4%), headache (27.7%), muscle/joint pains (22.8%) and fever/chills (19.9%). Rheumatic disease flares that required medication changes occurred in 4.6%. CONCLUSION: Among adults with systemic rheumatic disease who received COVID-19 vaccination, patient-reported adverse events were typical of those reported in the general population. Most patients were willing to temporarily discontinue DMARDs to improve vaccine efficacy. The relatively low frequency of rheumatic disease flare requiring medications was reassuring.

Potent anti-inflammatory effects of an H2 S-releasing naproxen (ATB-346) in a human model of inflammation.

ATB-346 is a hydrogen sulfide-releasing non-steroidal anti-inflammatory drug (H2 S-NSAID) derived from naproxen, which in preclinical studies has been shown to have markedly reduced gastrointestinal adverse effects. However, its anti-inflammatory properties in humans compared to naproxen are yet to be confirmed. To test this, we used a dermal model of acute inflammation in healthy, human volunteers, triggered by ultraviolet-killed Escherichia coli. This robust model allows quantification of the cardinal signs of inflammation along with cellular and humoral factors accumulating within the inflamed skin. ATB-346 was non-inferior to naproxen in terms of its inhibition of cyclooxygenase activity as well as pain and tenderness. ATB-346 significantly inhibited neutrophil infiltration at the site of inflammation at 4 h, compared to untreated controls. Subjects treated with ATB-346 also experienced significantly reduced pain and tenderness compared to healthy controls. Furthermore, both classical and intermediate monocyte subsets infiltrating the site of inflammation at 48 h expressed significantly lower levels of CD14 compared to untreated controls, demonstrating a shift toward an anti-inflammatory phenotype. Collectively, we have shown for the first time in humans that ATB-346 is potently anti-inflammatory and propose that ATB-346 represents the next generation of H2 S-NSAIDs, as a viable alternative to conventional NSAIDs, with reduced adverse effects profile.

Microbial community succession on submerged vertebrate carcasses in a tidal river habitat: Implications for aquatic forensic investigations.

Death investigations in aquatic ecosystems are challenging due to abiotic and biotic factors that may influence the estimation of a postmortem submersion interval (PMSI). In this study, we examined bacterial changes throughout the decomposition process on porcine carcasses submerged in a tidal-influenced river and identified predictors of epinecrotic community succession. Fetal porcine (Sus scrofa) carcasses (N = 6) were submerged with epinecrotic samples collected every 3 days (6 collections) over a period of 19 days (~7415 accumulated degree hours (ADH)). Amplicon sequencing was performed using the Illumina MiSeq platform (16S V4 region, 2 × 250 bp format) to identify changes in bacterial relative abundance and diversity. To match bacterial succession with rough taphonomy, carcasses were visually assessed at each sampling time point to determine the decomposition stage. Notably, the three most abundant families were Moraxellaceae, Burkholderiaceae (Proteobacteria), and Clostridiaceae (Firmicutes), though communities composition varied significantly across decomposition stages. Greater bacterial phylogenetic diversity was observed in in latter decomposition stages (advanced floating decay, sunken remains). Random Forest Models were built to predict ADH and explained 77%-80.8% of variation in ADH with an error rate of +/-1943.2 ADH (Root Mean Square Error) or approx. ±2.7 days at the mean water temperature of this study. This study provided a useful model that could be used to estimate a PMSI in this river system utilizing bacterial community succession, and thus, potentially improve the accuracy of such estimations to be used in the court of law.

Organic fertility inputs synergistically increase denitrification-derived nitrous oxide emissions in agroecosystems.

Soil fertility in organic agriculture relies on microbial cycling of nutrient inputs from legume cover crops and animal manure. However, large quantities of labile carbon (C) and nitrogen (N) in these amendments may promote the production and emission of nitrous oxide (N2 O) from soils. Better ecological understanding of the N2 O emission controls may lead to new management strategies to reduce these emissions. We measured soil N2 O emission for two growing seasons in four corn-soybean-winter grain rotations with tillage, cover crop, and manure management variations typical of organic agriculture in temperate and humid North America. To identify N2 O production pathways and mitigation opportunities, we supplemented N2 O flux measurements with determinations of N2 O isotopomer composition and microbiological genomic DNA abundances in microplots where we manipulated cover crop and manure additions. The N input from legume-rich cover crops and manure prior to corn planting made the corn phase the main source of N2 O emissions, averaging 9.8 kg/ha of N2 O-N and representing 80% of the 3-yr rotations' total emissions. Nitrous oxide emissions increased sharply when legume cover crop and manure inputs exceeded 1.8 and 4 Mg/ha (dry matter), respectively. Removing the legume aboveground biomass before corn planting to prevent co-location of fresh biomass and manure decreased N2 O emissions by 60% during the corn phase. The co-occurrence of peak N2 O emission and high carbon dioxide emission suggests that oxygen (O2 ) consumption likely caused hypoxia and bacterial denitrification. This interpretation is supported by the N2 O site preference values trending towards denitrification during peak emissions with limited N2 O reduction, as revealed by the N2 O δ15 N and δ18 O and the decrease in clade I nosZ gene abundance following incorporation of cover crops and manure. Thus, accelerated microbial O2 consumption seems to be a critical control of N2 O emissions in systems with large additions of decomposable C and N substrates. Because many agricultural systems rely on combined fertility inputs from legumes and manures, our research suggests that controlling the rate and timing of organic input additions, as well as preventing the co-location of legume cover crops and manure, could mitigate N2 O emissions.