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The ability of Cu-H complexes to undergo selective insertion of unsaturated hydrocarbons under mild conditions has rendered them valuable, versatile catalysts. The direct formation of Cu allyl intermediates from unfunctionalized 1,3-dienes and transient Cu hydrides is an appealing strategy for upgrading conjugated diene feedstocks. However, empirical mechanistic studies of the underlying elementary steps and characterization of key intermediates in Cu-H catalysis are sparse. Using [(NHC)CuH]

An intraneuronal parasite infecting approximately one-third of the world’s population, Toxoplasma gondii has been associated with markers of cardiovascular disease. In this study, we used data from the Center for Disease Control and Prevention’s National Health and Nutrition Examination Survey to investigate associations between T. gondii and blood pressure and hypertension. Multiple regression modelling adjusted for a range of covariates showed that T. gondii was associated with lowered probability of elevated blood pressure, with lower probability of Stages 1 and 2 hypertension, and with lower systolic and diastolic blood pressure. These findings suggest that T. gondii might alter hemodynamic regulation, although the clinical relevance of these associations requires additional investigation.

As of May 10, 2021, according to SPAC Alpha, there were 315 special purpose acquisition company (SPAC) IPOs completed YTD – more than 100 per cent higher than the number of SPAC IPOs in the previous four years combined. David Erickson, Itamar Drechsler and Nikolai Roussanov explore how the SPAC market exploded in 2020 and what may happen in the future.

IntroductionThere are concerns about microorganisms present on cannabis materials used in clinical settings by individuals whose health status is already compromised and are likely more susceptible to opportunistic infections from microbial populations present on the materials. Most concerning is administration by inhalation where cannabis plant material is heated in a vaporizer, aerosolized, and inhaled to receive the bioactive ingredients. Heating to high temperatures is known to kill microorganisms including bacteria and fungi; however, microbial death is dependent upon exposure time and temperature. It is unknown whether the heating of cannabis at temperatures and times designated by a commercial vaporizer utilized in clinical settings will significantly decrease the microbial loads in cannabis plant material.MethodsTo assess this question, bulk cannabis plant material supplied by National Institute on Drug Abuse (NIDA) was used to assess the impact of heating by a commercial vaporizer. Initial method development studies using a cannabis placebo spiked with Escherichia coli were performed to optimize culture and recovery parameters. Subsequent studies were carried out using the cannabis placebo, low delta-9 tetrahydrocannabinol (THC) potency and high THC potency cannabis materials exposed to either no heat or heating for 30 or 70 seconds at 190°C. Phosphate-buffered saline was added to the samples and the samples agitated to suspend the microorganism. Microbial growth after no heat or heating was evaluated by plating on growth media and determining the total aerobic microbial counts and total yeast and mold counts.Results and discussionOverall, while there were trends of reductions in microbial counts with heating, these reductions were not statistically significant, indicating that heating using standard vaporization parameters of 70 seconds at 190°C may not eliminate the existing microbial bioburden, including any opportunistic pathogens. When cultured organisms were identified by DNA sequence analyses, several fungal and bacterial taxa were detected in the different products that have been associated with opportunistic infections or allergic reactions including Enterobacteriaceae, Staphylococcus, Pseudomonas, and Aspergillus.

Moral injury is a complex phenomenon characterized by spiritual, psychological, and moral distress caused by actions or acts of omission inconsistent with an individual’s moral and ethical values. We present two cases from an ongoing randomized controlled trial of a spiritually integrated structured intervention delivered by chaplains for individuals suffering from moral injury. Chaplains met with Veterans for twelve 50-min sessions that each focused on a specific domain of moral injury. Participants were asked to complete validated scales assessing symptoms of moral injury and PTSD, including the PTSD Checklist for DSM-5 (PCL-5), Moral Injury Symptom Scale-Military Version Short Form, and Moral Injury Symptom Scale-Military Version Long Form. We report on two Veterans who completed the intervention and demonstrated significant improvement in moral injury and PTSD symptoms.

Determining the distribution and environmental preferences of rare species threatened by global change has long been a focus of conservation. Typical minimum suggested number of occurrences ranges from ∼5 to 30, but many species are represented by even fewer occurrences. However, several newer methods may be able to accommodate such low samples sizes. These include Bayesian joint species distribution models (JSDMs) which allow rare species to statistically “borrow strength” from more common species with similar niches, and ensembles of small models (ESMs), which reduce the number of parameters by averaging smaller models. Here we explore how niche breadth and niche position relative to other species influence model performance at low sample sizes (N=2, 4, 8, 16, 32, 64) using virtual species within a community of real species. ESMs were better at discrimination tasks for most species, and yielded better-than-random accuracy even for N=2. In contrast, “traditional” single species or JSDMs were better able to estimate the underlying response curves of variables that influenced the niche, but at low sample sizes also were more likely to incorrectly identify unimportant factors as influential. Species with niches that were narrow and peripheral to the available environmental space yielded models with better discrimination capacity than species with broad niches or niches that were similar to those of other species, regardless of whether the modeling algorithm allowed for borrowing of strength. Our study suggests that some rare species may be able to be modeled reliably at very low sample sizes, although the best algorithm depends on number of occurrences and whether the niche or distribution is the focus.

Recent work by our group and others have shown individuals with IgE to the oligosaccharide allergen present in mammalian products (α-gal) have increased atheroma burden with increased necrosis and calcification compared to those without α -gal specific IgE. These data suggest α -gal specific IgE increase plaque severity and vulnerability, yet the mechanisms that promote production of IgE to α -gal are unknown. Previous work from our group utilized multi-omics single cell analysis of circulating PBMCs from subjects with coronary angiography at UVA and showed subjects with IgE α -gal sensitization had a higher frequency of CCR6hi switched memory (SWM) B cells and that the CCR6 ligand, CCL20, increased class switching to IgE. To determine mechanisms whereby CCR6 may mediated class switching to IgE, we enriched total B cells from healthy donor peripheral blood mononuclear cells and stimulated with 20ng/ml human IL-4 and 10μg/ml agnostic anti-human CD40 with or without 20ng/ml CCL20 for 3 days. After 3 days of treatment, cells were collected and stained with a 15-color panel and analyzed via flow cytometry. Cells were analyzed for surface expression of CD20 and CD3 to gate total B cells. Gated B cells were further separated into CD27+/IgM-/IgD- to define SWM B cell population. CCL20 treatment did not increase the total percent of SWM B cells; however, there was a 2-3-fold increase in CCR6+ SWM B cells compared to CCR6- SWM B cells. CCL20 treated CCR6+ SWM B cells have an average of 7% increase of phosphorylated mTOR in total SWM B cells compared to nonCCL20 treated CCR6+ SWM B cells. These results suggest CCL20 stimulation induces mTOR phosphorylation and activation. Thus, mTOR activation and downstream mediators may be necessary for α -gal induced B cell class switching. From these preliminary studies, we conclude that CCL20 stimulation increases the percent pmTOR+ SWM B cells. We will continue to investigate downstream mTOR mediators in regard to B cell class switching after CCL20 stimulation and how α-gal sensitization augments B cell IgE class switching and increases atherosclerosis with our novel α -gal-/- Apoe-/- mouse.

Gout is one of the most common and complex causes of arthritis that can affect anyone.1,2 It is one of the most ancient medical conditions known going back to references in Egypt in 2640 BC and Hippocrates writing about it in 400 BC.3–5 Gout occurs when there are deposits of urate monosodium crystals in the synovial fluid and other tissues causing the inflammation and intense pain of a gout attack. Urate monosodium crystals usually are associated with long-term hyperuricemia that is triggered by several genetic factors as well as environmental factors such as the overconsumption of rich purine diets, alcohol, obesity, obesity-related disease, kidney disease, and certain medications.1,6–13 Risk factors for older patients include low-dose aspirin, alcohol abuse, decreased renal function, and prolonged use of diuretics.14,15 Advanced gout, also known as gouty tophi, are large, visible (masses) made up of urate crystals.5,16,17 The tophus is a cardinal sign and usually develops after 5–10 years of chronic undertreated gout with the olecranon bursa being one of the most affected areas.5,16,17 Formation is caused by elevated serum uric acid levels due to neglected and poorly controlled gout.18,19 Gouty tophi can develop anywhere. It can develop in peri-articular soft tissues, sub-articular regions around bones, tendon sheaths, bursas, articular cartilage, and synovial tissues around flexor tendons.17,20 Gouty tophi have been identified in vocal cords, myocardium, heart valves, eyes, spinal cord, pancreatic tail, breast, penis, with a propensity to affect the helix of the ear.17,21,22 However, patients with multiple gouty tophi rarely are encountered because hyperuricemia can be treated effectively. The differential diagnosis of gouty tophi is broad, even though gout can be diagnosed clinically by elevated serum uric acid level; however, the concentration of serum uric acid may be within the normal limits and yet gouty tophi still can be developed.23–25 This case was a patient who developed multiple gouty tophi over an extended period of time with increasing size of the masses while on medical treatment for his gout. The one mass of unique interest developed over the superficial anterior tibia just distal to the tibial tubercle and not in the patellar tendon, which is uncommon.

Most ligand designs for reactions catalyzed by (NHC)Cu–H (NHC = N-heterocyclic carbene ligand) have focused on introducing steric bulk near the Cu center. Here, we evaluate the effect of remote ligand modification in a series of [(NHC)CuH]2 in which the para substituent (R) on the N-aryl groups of the NHC is Me, Et, tBu, OMe or Cl. Although the R group is distant (6 bonds away) from the reactive Cu center, the complexes have different spectroscopic signatures. Kinetics studies of the insertion of ketone, aldimine, alkyne, and unactivated α-olefin substrates reveal that Cu–H complexes with bulky or electron-rich R groups undergo faster substrate insertion. The predominant cause of this phenomenon is destabilization of the [(NHC)CuH]2 dimer relative to the (NHC)Cu–H monomer, resulting in faster formation of Cu–H monomer. These findings indicate that remote functionalization of NHCs is a compelling strategy for accelerating the rate of substrate insertion with Cu–H species.

We report the hydrogenation of CO2 to MeOH by a Ru(triphos) catalyst containing a cationic tetraalkylammonium moiety in the outer coordination sphere. This catalyst affords higher TON and TOF value...

Carbon Capture and Storage (CCS) has seen growing momentum as a crucial strategy for meeting CO2 emission reduction targets. However, it comes with different technical and strategical challenges. One of the major challenges associated with CCS is the multi-actor value chain, which based on individual actor requirements, may not be necessarily aligned with each other and therefore requires coordination and agreement.An important design consideration is the quality of the CO2 stream as it moves through the CCS process. Various industries still consider CO2 as a waste stream and as such it only has limited quality control based on local regulations. This paper will discuss the various issues associated with CO2 quality in the various elements of the CCS chain, from collection, through transportation to storage.There are various technologies providing discrete solutions for different elements of the CCS chain. However, for a cost-effective CCS design, a holistic approach should be applied.At custody transfer points within a CCS chain, CO2 will need to meet specification criteria for type and quantity of allowable impurities. Impurities may be inherent in the captured CO2 or carried over from processes or reaction by-products. Some impurities may have significant impact on the behaviour of CO2 rich fluid even in small ppm quantities and adversely affect the CCS chain integrity or operation. CO2 not meeting specification criteria risks non-acceptance at custody transfer points. This paper shall address the critical considerations for CO2 quality at each of the CCS chain interface points.This paper will provide a high-level overview of how impurities can significantly affect the calculation of CO2 rich fluid properties and behaviour, chemical reactions, corrosion risk, etc. Additionally, some of the gaps in the current understanding and standards will be addressed and their possible economic impact on CCS chain design and operation.The novel part of this work is holistically looking at the whole CCUS chain and addressing how CO2 quality and specification can affect each part of the chain and their impact on the economics and viability of the solution.

Objectives/Scope Many midstream operators are developing plans to introduce Hydrogen (H2) into natural gas networks in concentrations of 0 to 20%. It is important to keep the concentration in all locations in the network within these limits, to reduce H2 induced cracking of pipelines and because most burners in the US are not designed for the different heating values (Wobbe Index) associated with the H2 mixtures, and flame speed present with H2 flames. This paper presents a model which dynamically tracks H2 concentrations, and associated Wobbe Index, in a complex delivery network and discusses the operational challenges associated with the introduction of H2 in these systems. Methods, Procedures, Process The model is based on proven technology which has been used on gases of variable quality for 30 years. The key item currently however is the new addition of H2 to the composition mix. The model is dynamic and responds to changes in the H2 concentration and flowrate. It is envisioned that the H2 supply to these networks will be variable (for example solar generated H2). This paper will present several case studies showing how H2 affects an existing gas distribution network and the paper will also discuss how H2 impacts the thermodynamics used in the calculation engine. Results, Observations, Conclusions The case studies will show that for even simple events like a customer trip, high concentration H2 packets can travel into pipelines that normally do not receive H2. As H2 travels through the pipeline, parameters within the system start to change such as the pipeline pressure drop increases and the compressor duty and outlet temperature increase. Novel / Additive Information The model tracks gas packets dynamically in the network (packet size is based on dispersion length) and calculates the density and energy content based on the local concentration. It then has a built in EOS (equation of state) based on GERG 2008 to calculate the density. Even with this complexity the model can run at speeds 100 times real-timefor a network that has approximately over 1,000 km of pipe.

Epileptogenic seizures, or status epilepticus (SE), leads to excitotoxic injury in hippocampal and limbic neurons in the kainic acid (KA) animal model of temporal lobe epilepsy (TLE). Here, we have further characterized neural activity regulated methylaminoisobutryic acid (MeAIB)/glutamine transport activity in mature rat hippocampal neurons in vitro that is inhibited by riluzole (IC50=1 μM), an anti-convulsant benzothiazole agent. We screened a library of riluzole derivatives and identified SKA-41 followed by a second screen and synthesized several novel chlorinated aminothiazoles (SKA-377, SKA-378, SKA-379) that are also potent MeAIB transport inhibitors in vitro, and brain penetrant following systemic administration. When administered before KA, SKA-378 did not prevent seizures but still protected the hippocampus and several other limbic areas against SE-induced neurodegeneration at 3d. When SKA-377 - 379, (30mg/kg) were administered after KA-induced SE, acute neural injury in the CA3, CA1 and CA4/hilus was also largely attenuated. Riluzole (10mg/kg) blocks acute neural injury. Kinetic analysis of SKA-378 and riluzoles' blockade of Ca2+-regulated MeAIB transport in neurons in vitro indicates that inhibition occurs via a non-competitive, indirect mechanism. Sodium channel NaV1.6 antagonism blocks neural activity regulated MeAIB/Gln transport in vitro (IC50=60nM) and SKA-378 is the most potent inhibitor of NaV1.6 (IC50=28μM) compared to NaV1.2 (IC50=118μM) in heterologous cells. However, pharmacokinetic analysis suggests that sodium channel blockade may not be the predominant mechanism of neuroprotection here. Riluzole and our novel aminothiazoles are agents that attenuate acute neural hippocampal injury following KA-induced SE and may help to understand mechanisms involved in the progression of epileptic disease.

Background: Recent studies have suggested that IgE sensitization to α-gal is associated with coronary artery disease (CAD). However, the B cell subtype(s) responsible for production of IgE to α-gal and mechanisms mediating this production remain elusive.Methods: Single cell multi-omics sequencing, was utilized to phenotype B cells obtained from 60 subjects that had undergone coronary angiography in whom serum IgE was evaluated by ImmunoCAP. Bioinformatics approaches were used to identify B cell subtype(s) and transcriptomic signatures associated with α-gal sensitization. In vitro characterization of chemokine/chemokine receptor pairs on switched memory B cells associated with IgE to α-gal was performed.Results: Of the 60 patients, 17 (28%) were positive for IgE to α-gal. CITESeq identified CCR6+ class-switched memory (SWM) B cells and CXCR4 expresssion on these CCR6+ SWM B cells as significantly associated with IgE sensitization to α-gal but not to other common allergens (peanut or inhalants). In vitro studies of enriched human B cells revealed significantly greater IgE on SWM B cells with high CCR6 and CXCR4 expression 10 days after cells were treated with IL-4 and CD40 to stimulate class switch recombination. Both CCL20 (CCR6 ligand) and CXCL12 (ligand for CXCR4) increased the expression of IgE on SWM B cells expressing their receptors. However, they appeared to have unique pathways mediating this effect as only CCL20 increased activation-induced cytidine deaminase (AID), while CXCL12 drove proliferation of CXCR4+ SWM B cells. Lastly, correlation analysis indicated an association between CAD severity and the frequency of both CCR6+ SWM and CXCR4+ SWM B cells.Conclusions: CCR6+ SWM B cells were identified as potential producers of IgE to α-gal in CAD patients. Additionally, our findings highlighted non-chemotaxis roles of CCL20/CCR6 and CXCL12/CXCR4 signaling in mediating IgE class switching and cell proliferation of SWM B cells respectively. Results may have important implications for a better understanding and better therapeutic approaches for subjects with IgE sensitization to α-gal.

We propose and demonstrate a protocol for high-fidelity indirect readout of trapped ion hyperfine qubits, where the state of a $^9\text{Be}^+$ qubit ion is mapped to a $^{25}\text{Mg}^+$ readout ion using laser-driven Raman transitions. By partitioning the $^9\text{Be}^+$ ground state hyperfine manifold into two subspaces representing the two qubit states and choosing appropriate laser parameters, the protocol can be made robust to spontaneous photon scattering errors on the Raman transitions, enabling repetition for increased readout fidelity. We demonstrate combined readout and back-action errors for the two subspaces of $1.2^{+1.1}_{-0.6} \times 10^{-4}$ and $0^{+1.9}_{-0} \times 10^{-5}$ with 68% confidence while avoiding decoherence of spectator qubits due to stray resonant light that is inherent to direct fluorescence detection., 7 + 6 pages, 3 + 1 figures

Background: tumor-infiltrating lymphocytes are prognostic in many human cancers. However, the prognostic value of lymphocytes infiltrating glioblastoma (GBM), and roles in tumor control or progression are unclear. We hypothesized that B and T cell density, and markers of their activity, proliferation, differentiation, or function, would have favorable prognostic significance for patients with GBM. Methods: initial resection specimens from 77 patients with IDH1/2 wild type GBM who received standard-of-care treatment were evaluated with multiplex immunofluorescence histology (mIFH), for the distribution, density, differentiation, and proliferation of T cells and B cells, as well as for the presence of tertiary lymphoid structures (TLS), and IFNγ expression. Immune infiltrates were evaluated for associations with overall survival (OS) by univariate and multivariate Cox proportional hazards modeling. Results: in univariate analyses, improved OS was associated with high densities of proliferating (Ki67+) CD8+ cells (HR 0.36, p = 0.001) and CD20+ cells (HR 0.51, p = 0.008), as well as CD8+Tbet+ cells (HR 0.46, p = 0.004), and RORγt+ cells (HR 0.56, p = 0.04). Conversely, IFNγ intensity was associated with diminished OS (HR 0.59, p = 0.036). In multivariable analyses, adjusting for clinical variables, including age, resection extent, Karnofsky Performance Status (KPS), and MGMT methylation status, improved OS was associated with high densities of proliferating (Ki67+) CD8+ cells (HR 0.15, p < 0.001), and higher ratios of CD8+ cells to CD4+ cells (HR 0.31, p = 0.005). Diminished OS was associated with increases in patient age (HR 1.21, p = 0.005) and higher mean intensities of IFNγ (HR 2.13, p = 0.027). Conclusions: intratumoral densities of proliferating CD8 T cells and higher CD8/CD4 ratios are independent predictors of OS in patients with GBM. Paradoxically, higher mean intensities of IFNγ in the tumors were associated with shorter OS. These findings suggest that survival may be enhanced by increasing proliferation of tumor-reactive CD8+ T cells and that approaches may be needed to promote CD8+ T cell dominance in GBM, and to interfere with the immunoregulatory effects of IFNγ in the tumor microenvironment.

Agricultural nitrous oxide (N2O) emission accounts for a non-trivial fraction of global greenhouse gas (GHG) budget. To date, estimating N2O fluxes from cropland remains a challenging task because the related microbial processes (e.g., nitrification and denitrification) are controlled by complex interactions among climate, soil, plant and human activities. Existing approaches such as process-based (PB) models have well-known limitations due to insufficient representations of the processes or uncertainties of model parameters, and due to leverage recent advances in machine learning (ML) a new method is needed to unlock the “black box” to overcome its limitations such as low interpretability, out-of-sample failure and massive data demand. In this study, we developed a first-of-its-kind knowledge-guided machine learning model for agroecosystems (KGML-ag) by incorporating biogeophysical and chemical domain knowledge from an advanced PB model, ecosys, and tested it by comparing simulating daily N2O fluxes with real observed data from mesocosm experiments. The gated recurrent unit (GRU) was used as the basis to build the model structure. To optimize the model performance, we have investigated a range of ideas, including (1) using initial values of intermediate variables (IMVs) instead of time series as model input to reduce data demand; (2) building hierarchical structures to explicitly estimate IMVs for further N2O prediction; (3) using multi-task learning to balance the simultaneous training on multiple variables; and (4) pre-training with millions of synthetic data generated from ecosys and fine-tuning with mesocosm observations. Six other pure ML models were developed using the same mesocosm data to serve as the benchmark for the KGML-ag model. Results show that KGML-ag did an excellent job in reproducing the mesocosm N2O fluxes (overall r2=0.81, and RMSE=3.6 mgNm-2d-1 from cross validation). Importantly, KGML-ag always outperforms the PB model and ML models in predicting N2O fluxes, especially for complex temporal dynamics and emission peaks. Besides, KGML-ag goes beyond the pure ML models by providing more interpretable predictions as well as pinpointing desired new knowledge and data to further empower the current KGML-ag. We believe the KGML-ag development in this study will stimulate a new body of research on interpretable ML for biogeochemistry and other related geoscience processes.