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Current treatments for deep tissue burns are limited, and most serve only to enhance hydration or prevent bacterial growth. This leaves burn healing dependent on slow natural processes to debride the wound and reestablish the epidermal and dermal layers of the skin. Infections are well known to destabilize this process through a variety of mechanisms, most notably through increased inflammation and the resulting oxidative stress. In this study, we show that ARAG (an antioxidant-rich antimicrobial gel) can suppress the growth of multiple bacteria commonly found to infect burns (Klebsiella pneumoniae, Proteus vulgaris, Pseudomonas aeruginosa, and Staphylococcus aureus). This inhibition is comparable to that conferred by silver ion release from burn dressings such as Mepilex-Ag. We further show, using a porcine model for deep partial-thickness burns, that ARAG allows for enhanced wound healing over Mepilex-Ag, the current standard of care. Histological findings indicate this is likely due to increased wound debridement and dampening of late inflammatory processes, leading to more balanced physiologic healing. Taken together, these findings show promise for ARAG as a superior alternative to the current standard of care.

For the first time, we present a comparison of atmospheric transport models for Carbonyl Sulfide (COS), a promising photosynthesis tracer, within the framework of the ongoing Atmospheric Tracer Transport Model Intercomparison Project (TransCom). Seven atmospheric transport models participated in the inter-comparison experiment and provided simulations of COS mixing ratios in the troposphere over a 10-year period (2010–2019), using prescribed state of the art surface fluxes for each component of the atmospheric COS budget (i.e., linked to vegetation, soil, ocean, fire and industry). The main goals of TransCom-COS are (a) to investigate the roles of the transport uncertainty and emission distribution in simulating the spatio-temporal variability of COS mixing ratio in the troposphere and (b) to assess the sensitivity of simulated tropospheric COS mixing ratio to the seasonal variability of the COS terrestrial fluxes. Models were run with the same prior emissions and without chemistry to isolate differences due to transport. Two COS flux scenarios were compared: one using a biospheric flux with a monthly time resolution and the other one using a biospheric flux with a tri-hourly time resolution. In addition, we investigated the sensitivity of the simulated concentrations to different biospheric fluxes and to indirect oceanic emissions through DMS. The modelled COS mixing ratios were assessed against observations from in situ surface stations, aircraft and ground based FTIR stations. Using the state of the art surface fluxes for each component of the COS budget, preliminary results indicate that all transport models fail to capture the surface latitudinal distribution of COS. The COS mixing ratios are underestimated by at least 50 ppt in the tropics, pointing to a missing tropical source. In summer, the mixing ratios are overestimated by at least 50 ppt above 40N, pointing to a likely missing sink in the high northern latitudes during this period. The surface variability of COS mixing ratios is more sensitive to transport models than to a change in biospheric fluxes (two estimates based on different global Land Surface Models). Regarding the seasonal mean latitudinal profiles, the model spread is greater than 60 ppt above 40N in boreal summer and in the vicinity of anthropogenic sources. Regarding the seasonal amplitude, the model spread reaches 50 ppt at 6 sites out of 15, compared to an observed seasonal amplitude of 100 ppt. All models simulated a too late minimum by 2 to 3 months at northern sites ALT, BRW owing to likely errors in the seasonal cycle in the ocean emissions. Finally, the temporal resolution of the biospheric fluxes (monthly versus tri-hourly) has a small impact (less than 20 ppt) on the mean seasonal cycle at stations from the NOAA network.

Periurethral human mesenchymal stem cell (hMSC) injections are associated with functional improvement in animal models of postpartum stress urinary incontinence (SUI). However, limited data exist on the role of hMSCs in modulating gene expression in tissue repair after urethral injury. To this end, we quantified temporal gene expression modulation in hMSCs, and in injured rat urethral tissue, using RNA-seq in an animal model of SUI, over a 3-day period following urethral injury, and local hMSC injection. We injected PKH fluorescent-labeled hMSC into the periurethral space of rats following a 4 h vaginal distention (VD) (three rats per time point). Control rats underwent VD injury only, and all animals were euthanized at 12, 24, 36, 72 h postinjury. Rat urethral and vaginal tissues were frozen and sectioned. Fluorescent labeled hMSCs were distinguished from adjacent, unlabeled rat urethral tissue. RNA was prepared from hMSCs and urethral tissue obtained by laser dissection of frozen tissue sections and sequenced on an Illumina HiSeq 2500. Differentially expressed genes (DEGs) over 72 h were evaluated using a two-group t-test (p

The diverse bacterial communities that colonize the gastrointestinal tract play an essential role in maintaining immune homeostasis through the production of critical metabolites such as short-chain fatty acids (SCFAs) and this can be disrupted by antibiotic use. However, few studies have addressed the effects of specific antibiotics longitudinally on the microbiome and immunity. We evaluated the effects of four specific antibiotics: enrofloxacin, cephalexin, paromomycin, and clindamycin, in healthy female rhesus macaques. All antibiotics disrupted the microbiome, including reduced abundances of fermentative bacteria and increased abundances of potentially pathogenic bacteria, including Enterobacteriaceae in the stool, and decreased Helicobacteraceae in the colon. This was associated with decreased SCFAs, indicating altered bacterial metabolism. Importantly, antibiotic use also substantially altered local immune responses, including increased neutrophils and Th17 cells in the colon. Furthermore, we observed increased soluble CD14 in plasma, indicating microbial translocation. These data provide a longitudinal evaluation of antibiotic-induced changes to the composition and function of colonic bacterial communities associated with specific alterations in mucosal and systemic immunity.

People infected with severe acute respiratory syndrome coronavirus 2 display a wide range of illness, from asymptomatic infection to severe respiratory distress resulting in death. We measured serum biomarkers in uninfected individuals and in individuals with mild, moderate, or critical coronavirus disease 2019 (COVID-19) disease. Levels of monocyte activation (soluble CD14 and fatty acid–binding protein 4) and inflammation (tumor necrosis factor receptors 1 and 2 [TNFR1 and TNFR2]) were increased in COVID-19 individuals, regardless of disease severity. Among patients with critical disease, individuals who recovered from COVID-19 had lower levels of TNFR1 and TNFR2 at hospital admission compared to these levels in patients with critical disease who ultimately died.

People with HIV (PWH) are at increased risk for atherosclerotic cardiovascular disease (ASCVD). Proportions of vascular homing monocytes are enriched in PWH; however, little is known regarding monocyte-derived macrophages (MDMs) that may drive atherosclerosis in this population. We isolated PBMCs from people with and without HIV, and cultured these cells for 5 days in medium containing autologous serum to generate MDMs. Differential gene expression (DGE) analysis of MDMs from PWH identified broad alterations in innate immune signaling (IL-1β, TLR expression, PPAR βδ) and lipid processing (LXR/RXR, ACPP, SREBP1). Transcriptional changes aligned with the functional capabilities of these cells. Expression of activation markers and innate immune receptors (CD163, TLR4, and CD300e) was altered on MDMs from PWH, and these cells produced more TNFα, reactive oxygen species (ROS), and matrix metalloproteinases (MMPs) than did cells from people without HIV. MDMs from PWH also had greater lipid accumulation and uptake of oxidized LDL. PWH had increased serum levels of free fatty acids (FFAs) and ceramides, with enrichment of saturated FAs and a reduction in polyunsaturated FAs. Levels of lipid classes and species that are associated with CVD correlated with unique DGE signatures and altered metabolic pathway activation in MDMs from PWH. Here, we show that MDMs from PWH display a pro-atherogenic phenotype; they readily form foam cells, have altered transcriptional profiles, and produce mediators that likely contribute to accelerated ASCVD., Author summary People with HIV (PWH) are at greater risk for developing cardiovascular disease (CVD) than the general public, but the mechanisms underlying this increased risk are poorly understood. Macrophages play key roles in the pathogenesis of atherosclerosis, and are potential targets for therapeutic intervention. Here, we investigate phenotypic and functional abnormalities in monocyte-derived macrophages (MDMs) isolated from PWH that may drive CVD risk in this population. MDMs were differentiated in the presence of autologous serum, enabling us to explore the contributions of serum components (lipids, inflammatory cytokines, microbial products) as drivers of altered MDM function. We link serum levels of inflammatory biomarkers and CVD-associated lipid species to MDM activation. Our study provides new insight into drivers of pro-atherogenic MDM phenotype in PWH, and identifies directions for future study and potential intervention strategies to mitigate CVD risk.

Immune checkpoint inhibitor (ICI) therapy continues to revolutionize melanoma treatment, but only a subset of patients respond. Major efforts are underway to develop minimally invasive predictive assays of ICI response. Using single-cell transcriptomics, we discovered a unique CD8 T cell blood/tumor-shared subpopulation in melanoma patients with high levels of oxidative phosphorylation (OXPHOS), the ectonucleotidases CD38 and CD39, and both exhaustion and cytotoxicity markers. We called this population with high levels of OXPHOS “CD8+ TOXPHOS cells.” We validated that higher levels of OXPHOS in tumor- and peripheral blood–derived CD8+ TOXPHOS cells correlated with ICI resistance in melanoma patients. We then developed an ICI therapy response predictive model using a transcriptomic profile of CD8+ TOXPHOS cells. This model is capable of discerning responders from nonresponders using either tumor or peripheral blood CD8 T cells with high accuracy in multiple validation cohorts. In sum, CD8+ TOXPHOS cells represent a critical immune population to assess ICI response with the potential to be a new target to improve outcomes in melanoma patients.

Background Coexpression of the immune checkpoint receptors PD-1 and TIM-3 is associated with dysfunction of tumor infiltrating lymphocytes in melanoma (MEL) and squamous cell carcinoma (SCC). To identify the mechanisms underlying this dysfunctional phenotype and to identify targets to rescue immune function, we performed transcriptional profiling of PD-1+TIM-3+CD8+ TILs sorted directly from MEL and SCC tumors in conjunction with immunologic phenotyping. We identified a number of novel dysregulated pathways and associated gene signatures in the PD-1+TIM-3+ subset that have not previously been reported in TILs, including bile acid metabolism, and demonstrated that these pathways are highly correlated not only to immune checkpoint receptor expression but also to MTOR pathway activation. Methods Surgically excised melanoma tumors were dissociated and mononuclear cells were isolated by Ficoll gradient separation and cryopreserved. For sorting based on immune checkpoint receptor expression, a cocktail of monoclonal antibodies to the following targets, including viability dye was used: CD3, CD4, CD8, CD45RA, CD27, CCR7 PE, CD14, CD19, Live/Dead, BTLA, TIM-3, PD-1, CTLA-4, TIGIT and LAG-3. RNA was purified from 10,000 sorted cells using RNeasy Mini Kits (Qiagen), followed by RNASeq library generation using TruSeq Stranded Total RNA HT Kits (Illumina). Gene set variation analysis (GSVA) was used for pathway analysis, as well as linear regression modelling using limma (Bioconductor). Results Transcriptomic analysis of CD8+ TILs revealed 4,228 genes (P Conclusions Transcriptomic analysis of PD-1+TIM-3+ CD8+ TILs identified novel candidate mechanisms of immune dysfunction in CD8+ TILs from patients with metastatic melanoma who fail immunotherapy. Our study identifies the bile acid and MTOR metabolic pathways as a potential novel therapeutic targets for complementary therapy to restore immune function in melanoma and SCC patients. Ethics Approval This study was performed under an IRB approved protocol.

Gamma spectroscopy was used to quantify the accumulation of the uranyl ion (UO22+) into mesoporous silica gel in an aqueous solution under static and pressure-driven flow conditions. The amount of uranyl accumulated into silica gel under static conditions does not trend with the surface area reported by the manufacturer, but it is controlled by the silica gel permeability. Under flow conditions, the amount of uranyl deposited within mesoporous silica gel increases with pore size and ion removal efficiencies ranging from 1.8 to 7.0% were observed. Uranium transport and accumulation within mesoporous silicates is important in environmental monitoring, waste management and remediation.

Summary Tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) are used for HIV treatment and prevention. Previously, we found that topical rectal tenofovir gel caused immunological changes in the mucosa. Here, we assess the effect of oral TDF/FTC in three HIV pre-exposure prophylaxis trials, two with gastrointestinal and one with cervicovaginal biopsies. TDF/FTC induces type I/III interferon-related (IFN I/III) genes in the gastrointestinal tract, but not blood, with strong correlations between the two independent rectal biopsy groups (Spearman r = 0.91) and between the rectum and duodenum (r = 0.81). Gene set testing also indicates stimulation of the type I/III pathways in the ectocervix and of cellular proliferation in the duodenum. mRNA sequencing, digital droplet PCR, proteomics, and immunofluorescence confirm IFN I/III pathway stimulation in the gastrointestinal tract. Thus, oral TDF/FTC stimulates an IFN I/III signature throughout the gut, which could increase antiviral efficacy but also cause chronic immune activation in HIV prevention and treatment settings., Graphical Abstract, Highlights Tenofovir (TDF) and emtricitabine (FTC) are used for HIV treatment and prevention TDF/FTC induce a type I/III interferon-associated signature throughout the gut IFN I/III induction is confirmed in independent clinical cohorts and 5 assay types IFN I/III induction may contribute to anti-HIV efficacy and chronic immune activation, Many people take the antiretroviral drugs tenofovir and emtricitabine to prevent and treat HIV infection. Hughes et al. show that these medications induce genes and proteins associated with type I/III interferon pathways in the gut. This effect may contribute to HIV inhibition but could also cause chronic immune activation.

ObjectiveTo test the hypothesis that patients with amyotrophic lateral sclerosis (ALS) inheriting the common interleukin 6 receptor (IL6R) coding variant (Asp358Ala, rs2228145, C allele) have associated increases in interleukin 6 (IL6) and IL6R levels in serum and CSF and faster disease progression than noncarriers.MethodsAn observational, case-control study of paired serum and CSF of 47 patients with ALS, 46 healthy, and 23 neurologic disease controls from the Northeastern ALS Consortium Biofluid Repository (cohort 1) was performed to determine serum levels of IL6, sIL6R, and soluble glycoprotein 130 and compared across groups and IL6R genotype. Clinical data regarding disease progression from a separate cohort of 35 patients with ALS from the Wake Forest ALS Center (cohort 2) were used to determine change in ALSFRS-R scores by genotype.ResultsPatients with ALS had increased CSF IL6 levels compared with healthy (p < 0.001) and neurologic (p = 0.021) controls. Patients with ALS also had increased serum IL6 compared with healthy (p = 0.040) but not neurologic controls. Additive allelic increases in serum IL6R were observed in all groups (average increase of 52% with the presence of the IL6R C allele; p < 0.001). However, only subjects with ALS had significantly increased CSF sIL6R levels compared with controls (p < 0.001). When compared across genotypes, only patients with ALS inheriting the IL6R C allele exhibit increased CSF IL6. ALSFRS-R scores decreased more in patients with ALS with the IL6R C allele than in those without (p = 0.019).ConclusionsTheses results suggest that for individuals inheriting the IL6R C allele, the cytokine exerts a disease- and location-specific role in ALS. Follow-up, prospective studies are necessary, as this subgroup of patients may be identified as ideally responsive to IL6 receptor–blocking therapies.

There is a desire from the radiation detection community to develop a low-cost method to detect neutron radiation. One potential solution is to measure the 478 keV gamma-ray from the 10B(n, α ) reaction using a spectroscopic gamma-ray detector. Experiments and Monte Carlo N-Particle 6.2 radiation transport simulations were performed for a NaI(Tl) detector surrounded with natural isotopic composition boron carbide powder. The neutron source for the experimental measurements was 241Am–Be.​ Additional MCNP simulations were performed using a 240Pu spontaneous fission neutron source. The experimental results were compared against 3He based measurements and found to be 70% as efficient as the 3He system. The total cost of this modification to an existing NaI(Tl) detector was $65.12. The optimal 10B-NaI(Tl) system design when measuring 240Pu was determined to consist of a 0.5 cm endcap of boron carbide and 6 cm of high-density polyethylene for neutron moderation.

The diverse bacterial communities that colonize the gastrointestinal tract play an essential role in maintaining immune homeostasis through the production of critical metabolites such as short chain fatty acids (SCFA), and this can be disrupted by antibiotic use. However, few studies have addressed the effects of specific antibiotics longitudinally on the microbiome and immunity. We evaluated the effects of four specific antibiotics; enrofloxacin, cephalexin, paromomycin, and clindamycin; in healthy female rhesus macaques. All antibiotics disrupted the microbiome, including reduced abundances of fermentative bacteria and increased abundances of potentially pathogenic bacteria, including Enterobacteriaceae in stool, and decreased Helicobacteraceae in the colon. This was associated with decreased SCFAs, indicating altered bacterial metabolism. Importantly, antibiotic use also substantially altered local immune responses, including increased neutrophils and Th17 cells in the colon. Furthermore, we observed increased soluble-CD14 in plasma, indicating microbial translocation. These data provide a longitudinal evaluation of antibiotic-induced changes to the composition and function of colonic bacterial communities, associated with specific alterations in mucosal and systemic immunity.

Individuals with chronic diseases are reported to have increased classical monocytes (CD14++CD16neg) which can be activated by an infectious agent and/or inflammatory milieu. Both psoriasis and HIV are considered chronic inflammatory diseases and affected individuals display alterations in monocyte phenotype and function. Moreover, individuals with either psoriasis or HIV demonstrate a significantly increased risk of developing cardiovascular disease (CVD). We sorted classical monocytes from psoriatic and healthy controls and compared them to classical monocytes from PLHIV individuals (elite controllers (EC) and non-controllers (NC, cART suppressed). Using RNA-Seq, we identified significant differentially expressed genes (DEG, p

In an attempt to overcome the inconsistencies of plastic explosive–filled shape charges in EOD operations we have explored the use of sensitized gelled nitromethane liquid as a filling for a number of shaped charge devices. The ability to penetrate munition casings and induce deflagration is not only dependent on the velocity of detonation of the mixture, investigated in previous papers, but also on the geometry of the devices used and in some cases the confinement present in the device. In this article a range of nitromethane-based explosive fillings, with a range of velocities of detonation, was used to investigate the performance, in terms of target penetration, of both conical and dished metal liners and flat-bottomed cup liners mounted in cylindrical tubes. A number of unexpected results were obtained when copper dish devices were mounted in metal tubes and demonstrated a penetration dependence on standoff to the target. These observations were confirmed by flash X-ray investigation of the functionin...

Disposal of time-expired and unexploded ordnance has proved problematical in the past because of the procedures adopted; i.e., attach an explosive charge and cause the munition to function or long-range projectile attack. Improvements used explosively driven metallic liners to impact on the munition but detonation occurred with the standard plastic explosive fillings. If the munition can be persuaded to burn or at worst deflagrate, then the region of collateral damage could be reduced, even though the extended detonation safety zone would still be required. This article describes some work performed on the initiation of munitions ranging from simulated mortar shells, filled with plastic explosive PE4, via NATO standard 81-mm mortar shells to 1000-lb (450-kg) bombs by either copper cone or dish liners devices filled with various sensitized nitromethane formulations. Most of these formulations initiated deflagrations in the attacked munitions. Detonations resulted in some cases when plastic explosive, PE 4,...

Aging leads to dysregulation of multiple components of the immune system that results in increased susceptibility to infections and poor response to vaccines in the aging population. The dysfunctions of adaptive B and T cells are well documented, but the effect of aging on innate immunity remains incompletely understood. Using a heterogeneous population of peripheral blood mononuclear cells (PBMCs), we first undertook transcriptional profiling and found that PBMCs isolated from old individuals (≥ 65 years) exhibited a delayed and altered response to stimulation with TLR4, TLR7/8, and RIG-I agonists compared to cells obtained from adults (≤ 40 years). This delayed response to innate immune agonists resulted in the reduced production of pro-inflammatory and antiviral cytokines and chemokines including TNFα, IL-6, IL-1β, IFNα, IFNγ, CCL2, and CCL7. While the major monocyte and dendritic cell subsets did not change numerically with aging, activation of specific cell types was altered. PBMCs from old subjects also had a lower frequency of CD40+ monocytes, impaired up-regulation of PD-L1 on monocytes and T cells, and increased expression of PD-L2 and B7-H4 on B cells. The defective immune response to innate agonists adversely affected adaptive immunity as TLR-stimulated PBMCs (minus CD3 T cells) from old subjects elicited significantly lower levels of adult T-cell proliferation than those from adult subjects in an allogeneic mixed lymphocyte reaction (MLR). Collectively, these age-associated changes in cytokine, chemokine and interferon production, as well as co-stimulatory protein expression could contribute to the blunted memory B- and T-cell immune responses to vaccines and infections.

A fuel processor was constructed which incorporated two burners with direct steam generation by water injection into the burner exhaust. These burners with direct water vaporization enabled rapid fuel processor start-up for automotive fuel cell systems. The fuel processor consisted of a conventional chain of reactors: auto-thermal reformer (ATR), water gas shift (WGS) reactor and preferential oxidation (PrOx) reactor. The criticality of steam to the fuel reforming process was illustrated. By utilizing direct vaporization of water, and hydrogen for catalyst light-off, excellent start performance was obtained with a start time of 20 s to 30% power and 140 s to full power.

Cationic allyldicarbonyl derivatives of molybdenum and tungsten of the types [M(CO) 2 (η 3 -allyl)(L 3 )PF 6 (M = W, allyl = C 3 H 5 or 2-MeC 3 H 4 , L 3 =bis(2-pyridylmethyl)amine, bpma) and [M(CO) 2 (η 3 -allyl)(L 4 )]PF 6 (M = Mo or W, allyl = C 3 H 5 or 2-MeC 3 H 4 , L4 = tris(2-pyridylmethyl)amine, tpma) have been prepared, and their isomerism and dynamic behaviour in solution examined. In the solid state, [W(CO) 2 (η 3 -C 3 H 5 )(bpma)]PF 6 ( 1a ) exhibits an unsymmetric, and [Mo(CO) 2 (η 3 -C 3 H 5 )(tpma)]PF 6 ( 3 ) a symmetric, orientation of the N-donor set, which comprises two pyridyl rings and the central, exocyclic N of each ligand, with respect to the π-allyl group. The third bipyridyl ring of tpma in the latter complex is orientated away from the metal centre in the solid, but undergoes rapid exchange with N-donors within the coordination sphere at elevated temperatures in solution. Neither of the 2-MeC 3 H 4 analogues of 3 are dynamic under similar conditions, whereas the 2-MeC 3 H 4 analogue of 1 undergoes a facile trigonal twist rearrangement.