Boosting Photocatalytic Hydrogen Production by MOF-derived Metal Oxide Heterojunctions with a 10.0% Apparent Quantum Yield.

Photocatalytic hydrogen production offers an alternative pathway to establish a sustainable energy economy. While numerous photoactive materials exhibit potential for generating hydrogen from water, the synergy achieved by combining two different materials with complementary properties in the form of heterojunctions can significantly their photocatalytic activity. Our study describes the design and generation of the metal-organic framework-derived (MOF) metal oxide heterojunction composed of RuO2/N,S-TiO2. The RuO2/N,S-TiO2 is generated through the pyrolysis of MOFs, Ru- HKUST-1, and the amino-functionalized MIL-125-NH2. Among the various RuO2/N,S- TiO2 materials tested, the material characterized by the lowest RuO2 content, exhibited the highest hydrogen evolution rate, producing 10,761 µmol·hr-1·g-1 of hydrogen with an apparent quantum-yield of 10.0% in pure water. In addition to RuO2/N,S-TiO2, we generated two other MOF-derived metal-oxide heterojunctions, ZnO/N,S-TiO2 and In2O3/N,S-TiO2, leading to apparent quantum yields of 0.7% and 0.3%, respectively. The remarkable photocatalytic activity observed in RuO2/N,S-TiO2 is thought to be attributed to the synergistic effects arising from the combination of metallic properties inherent in the metal oxides, their band alignment, porosity, and surface properties inherited from the parent MOFs. The photocatalytic efficiency of RuO2/N,S-TiO2 was further demonstrated in actual water samples, producing hydrogen with a rate of 8,190 µmol·hr-1·g-1 in tap water.

A role for the dorsolateral striatum in prospective action control.

The dorsolateral striatum (DLS) is important for performing actions persistently, even when it becomes suboptimal, reflecting a function that is reflexive and habitual. However, there are also ways in which persistent behaviors can result from a more prospective, planning mode of behavior. To help tease apart these possibilities for DLS function, we trained animals to perform a lever press for reward and then inhibited the DLS in key test phases: as the task shifted from a 1-press to a 3-press rule (upshift), as the task was maintained, as the task shifted back to the one-press rule (downshift), and when rewards came independent of pressing. During DLS inhibition, animals always favored their initially learned strategy to press just once, particularly so during the free-reward period. DLS inhibition surprisingly changed performance speed bidirectionally depending on the task shifts. DLS inhibition thus encouraged habitual behavior, suggesting it could normally help adapt to changing conditions.

Exercise-induced ß2-adrenergic Receptor Activation Enhances the Antileukemic Activity of Expanded γδ T-Cells via DNAM-1 Upregulation and PVR/Nectin-2 Recognition.

Exercise mobilizes cytotoxic lymphocytes to blood which may allow superior cell products to be harvested and manufactured for cancer therapy. Gamma-Delta (γδ) T-cells have shown promise for treating solid tumors, but there is a need to increase their potency against hematologic malignancies. Here, we show that human γδ T-cells mobilized to blood in response to just 20 minutes of graded exercise have surface phenotypes and transcriptomic profiles associated with cytotoxicity, adhesion, migration, and cytokine signaling. Following 14 days ex vivo expansion with zoledronic acid and IL2, exercise mobilized γδ T-cells had surface phenotypes and transcriptomic profiles associated with enhanced effector functions and demonstrated superior cytotoxic activity against multiple hematologic tumors in vitro and in vivo in leukemia-bearing xenogeneic mice. Infusing humans with the ß1+ß2-agonist isoproterenol and administering ß1 or ß1+ß2 antagonists prior to exercise revealed these effects to be ß2-adrenergic receptor (AR) dependent. Antibody blocking of DNAM-1 on expanded γδ T-cells, as well as the DNAM-1 ligands PVR and Nectin-2 on leukemic targets, abolished the enhanced antileukemic effects of exercise. These findings provide a mechanistic link between exercise, ß2-AR activation, and the manufacture of superior γδ T-cell products for adoptive cell therapy against hematologic malignancies. SIGNIFICANCE: Exercise mobilizes effector γδ T-cells to blood via ß2-adrenergic signaling which allows for generation of a potent expanded γδ T-cell product that is highly cytotoxic against hematologic malignancies.

Enteric glia regulate Paneth cell secretion and intestinal microbial ecology.

Glial cells of the enteric nervous system (ENS) interact closely with the intestinal epithelium and secrete signals that influence epithelial cell proliferation and barrier formation in vitro. Whether these interactions are important in vivo, however, is unclear because previous studies reached conflicting conclusions [1]. To better define the roles of enteric glia in steady state regulation of the intestinal epithelium, we characterized the glia in closest proximity to epithelial cells and found that the majority express PLP1 in both mice and humans. To test their functions using an unbiased approach, we genetically depleted PLP1+ cells in mice and transcriptionally profiled the small and large intestines. Surprisingly, glial loss had minimal effects on transcriptional programs and the few identified changes varied along the gastrointestinal tract. In the ileum, where enteric glia had been considered most essential for epithelial integrity, glial depletion did not drastically alter epithelial gene expression but caused a modest enrichment in signatures of Paneth cells, a secretory cell type important for innate immunity. In the absence of PLP1+ glia, Paneth cell number was intact, but a subset appeared abnormal with irregular and heterogenous cytoplasmic granules, suggesting a secretory deficit. Consistent with this possibility, ileal explants from glial-depleted mice secreted less functional lysozyme than controls with corresponding effects on fecal microbial composition. Collectively, these data suggest that enteric glia do not exert broad effects on the intestinal epithelium but have an essential role in regulating Paneth cell function and gut microbial ecology.

SAXS/MC studies of the mixed-folded protein Cdt1 reveal monomeric, folded over conformations.

Cdt1 is a protein critical for DNA replication licensing and is well-established to be a binding partner of the minichromosome maintenance (MCM) complex. Cdt1 has also been demonstrated to have an emerging, "moonlighting" role at the kinetochore via direct binding to microtubules and to the Ndc80 complex. However, it is not known how the structure and conformations of Cdt1 could allow for these multiple, completely unique sets of protein complexes. And while there exist multiple robust methods to study entirely folded or entirely unfolded proteins, structure-function studies of combined, mixed folded/disordered proteins remain challenging. It this work, we employ multiple orthogonal biophysical and computational techniques to provide a detailed structural characterization of human Cdt1 92-546. DSF and DSCD show both folded winged helix (WH) domains of Cdt1 are relatively unstable. CD and NMR show the N-terminal and the linker regions are intrinsically disordered. Using DLS and SEC-MALS, we show that Cdt1 is polydisperse, monomeric at high concentrations, and without any apparent inter-molecular self-association. SEC-SAXS of the monomer in solution enabled computational modeling of the protein in silico. Using the program SASSIE, we performed rigid body Monte Carlo simulations to generate a conformational ensemble. Using experimental SAXS data, we filtered for conformations which did and did not fit our data. We observe that neither fully extended nor extremely compact Cdt1 conformations are consistent with our SAXS data. The best fit models have the N-terminal and linker regions extended into solution and the two folded domains close to each other in apparent "folded over" conformations. The best fit Cdt1 conformations are consistent with a function as a scaffold protein which may be sterically blocked without the presence of binding partners. Our studies also provide a template for combining experimental and computational biophysical techniques to study mixed-folded proteins.

COVID-19 vaccination produces exercise-responsive SARS-CoV-2 specific T-cells regardless of infection history.

BACKGROUND: The mobilization and redistribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) specific T-cells and neutralizing antibodies (nAbs) during exercise is purported to increase immune surveillance and protect against severe coronavirus disease 2019 (COVID-19). We sought to determine if COVID-19 vaccination would elicit exercise-responsive SARS-CoV-2 T-cells and transiently alter nAb titers. METHODS: Eighteen healthy participants completed a 20-min bout of graded cycling exercise before and/or after receiving a COVID-19 vaccine. All major leukocyte subtypes were enumerated before, during, and after exercise by flow cytometry, and immune responses to SARS-CoV-2 were determined using whole blood peptide stimulation assays, T-cell receptor (TCR)-ß sequencing, and SARS-CoV-2 nAb serology. RESULTS: COVID-19 vaccination had no effect on the mobilization or egress of major leukocyte subsets in response to intensity-controlled graded exercise. However, non-infected participants had a significantly reduced mobilization of CD4+ and CD8+ naive T-cells, as well as CD4+ central memory T-cells, after vaccination (synthetic immunity group); this was not seen after vaccination in those with prior SARS-CoV-2 infection (hybrid immunity group). Acute exercise after vaccination robustly mobilized SARS-CoV-2 specific T-cells to blood in an intensity-dependent manner. Both groups mobilized T-cells that reacted to spike protein; however, only the hybrid immunity group mobilized T-cells that reacted to membrane and nucleocapsid antigens. nAbs increased significantly during exercise only in the hybrid immunity group. CONCLUSION: These data indicate that acute exercise mobilizes SARS-CoV-2 specific T-cells that recognize spike protein and increases the redistribution of nAbs in individuals with hybrid immunity.

Interspecific killing of wolverines by one wolf pack.

Interactions between different species of predators are not uncommon, yet they are generally understudied in North America. Across their range, gray wolves (Canis lupus) and wolverines (Gulo gulo) occupy similar habitats and dietary niches. However, due to the elusiveness and relatively low density of these two species, interactions between them are not well documented. Here, we describe three instances of a single wolf pack killing a wolverine in the span of 13 months. None of the wolverines killed by wolves were consumed, suggesting that food was not the primary motivation behind the killings. Alternatively, defense of a food resource, territoriality, interspecific competitive killing, or some combination of those behaviors appear to be the cause of these actions. Documentation of these occurrences improves our understanding of wolf and wolverine ecology, interspecific predator interactions, and potential future changes to this aspect of community ecology.

Multivariate metal-organic frameworks generated through post-synthetic modification: impact and future directions.

Reticular chemistry has proven to be invaluable over time, thanks to the structural versatility, and tailored porosity observed in structures like metal-organic frameworks (MOFs), covalent-organic frameworks (COFs), and metal-organic polyhedra (MOPs). Despite the wide array of ligands and metals available for synthesizing MOFs, they are still somewhat constrained by the reliance on de novo conditions and the focus on generating MOFs with single ligand and metal. To surpass these limitations, researchers have established strategies to generate multivariate (MTV) MOF structures incorporating more than one ligand/metal into the crystal lattice. MTV-MOFs have demonstrated enhanced properties by virtue of the additional functionalities incorporated within their structures. One approach to developing MTV-MOFs is through post-synthetic modification (PSM), where new functionalities are introduced after the initial synthesis, thereby achieving the enhanced properties of MTV-MOFs even in cases where the new functionalities are incompatible with MOF synthesis.

Uracil-DNA glycosylase of murine gammaherpesvirus 68 binds cognate viral replication factors independently of its catalytic residues.

Herpesviruses are large double-stranded DNA viruses that encode core replication proteins and accessory factors involved in nucleotide metabolism and DNA repair. Mammalian uracil-DNA glycosylases (UNG) excise deleterious uracil residues from their genomic DNA. Each herpesvirus UNG studied to date has demonstrated conservation of the enzymatic function to excise uracil residues from DNA. We previously reported that a murine gammaherpesvirus (MHV68) with a stop codon in ORF46 (ORF46.stop) that encodes for vUNG was defective in lytic replication and latency in vivo. However, a mutant virus that expressed a catalytically inactive vUNG (ORF46.CM) had no replication defect unless coupled with additional mutations in the catalytic motif of the viral dUTPase (ORF54.CM). The disparate phenotypes observed in the vUNG mutants led us to explore the non-enzymatic properties of vUNG. Immunoprecipitation of vUNG followed by mass spectrometry in MHV68-infected fibroblasts identified a complex comprising the cognate viral DNA polymerase, vPOL, encoded by ORF9, and the viral DNA polymerase processivity factor, vPPF, encoded by ORF59. MHV68 vUNG co-localized with vPOL and vPPF in subnuclear structures consistent with viral replication compartments. In reciprocal co-immunoprecipitations, the vUNG formed a complex with the vPOL and vPPF upon transfection with either factor alone or in combination. Lastly, we determined that key catalytic residues of vUNG are not required for interactions with vPOL and vPPF upon transfection or in the context of infection. We conclude that the vUNG of MHV68 associates with vPOL and vPPF independently of its catalytic activity. IMPORTANCE Gammaherpesviruses encode a uracil-DNA glycosylase (vUNG) that is presumed to excise uracil residues from viral genomes. We previously identified the vUNG enzymatic activity, but not the protein itself, as dispensable for gammaherpesvirus replication in vivo. In this study, we report a non-enzymatic role for the viral UNG of a murine gammaherpesvirus in forming a complex with two key components of the viral DNA replication machinery. Understanding the role of the vUNG in this viral DNA replication complex may inform the development of antiviral drugs that combat gammaherpesvirus-associated cancers.

The role of sex on sign-tracking acquisition and outcome devaluation sensitivity in Long Evans rats.

Cues that predict rewards can trigger reward-seeking behaviors but also can, in some cases, become targets of motivation themselves. One behavioral phenomenon that captures this idea is sign-tracking in which animals, including humans, interact with reward-predictive cues even though it is not necessary to do so. Sign-tracking in rats has been studied in the domain of motivation and in how motivated behaviors can or cannot become excessive and habit-like over time. Many prior studies look at sign-tracking examine this behavior in male subjects, but there are few papers that look at this behavior in female subjects. Moreover, it is unknown where there might be sex-related variation in how flexible sign-tracking is when faced with changing reward values. Therefore, we asked if there were sex differences in the acquisition of sign-tracking behavior and if there were any sex differences in how sensitive animals were in their sign-tracking following reward devaluation. In contrast to previous reports, we found that males and females show no differences in how they acquire sign-tracking and in ultimate sign-tracking levels following training. Additionally, we found no difference in how quickly males and females learned to devalue the food reward, and we found no differences in sign-tracking levels by sex following outcome devaluation. We believe that this is primarily due to our experiment being performed in the Long Evans strain but also believe that there are many other factors contributing to differences between our study and previous work.

Ultrasonography for Skin and Soft Tissue Infections, Noninfectious Cysts, Foreign Bodies, and Burns in the Critical Care Setting.

There are multiple opportunities for the use of ultrasonography in the diagnosis of skin and soft tissue differentials. Ultrasonography is inexpensive, easily reproducible, and able to provide real-time data in situations where condition changes and progression are common. Not only does bedside ultrasonography provide the clinician an in-depth look beyond epidermal structures into body cavities, it remains a safe, nonionizing radiating, effective, cost-efficient, reliable, and accessible tool for the emergency management of life- and limb-threatening integumentary infections. Unnecessary invasive procedures are minimized, providing improved patient outcomes. Integumentary abnormalities secondary to trauma, surgery, and hospitalization are common among critical care patients. This article provides a brief overview and evidence-based recommendations for the use of ultrasonography in the critical care setting for integumentary system conditions, including common skin and soft tissue differentials, foreign bodies, and burn depth assessment.

The Impact of a Digital Weight Loss Intervention on Health Care Resource Utilization and Costs Compared Between Users and Nonusers With Overweight and Obesity: Retrospective Analysis Study.

BACKGROUND: The Noom Weight program is a smartphone-based weight management program that uses cognitive behavioral therapy techniques to motivate users to achieve weight loss through a comprehensive lifestyle intervention. OBJECTIVE: This retrospective database analysis aimed to evaluate the impact of Noom Weight use on health care resource utilization (HRU) and health care costs among individuals with overweight and obesity. METHODS: Electronic health record data, insurance claims data, and Noom Weight program data were used to conduct the analysis. The study included 43,047 Noom Weight users and 14,555 non-Noom Weight users aged between 18 and 80 years with a BMI of ≥25 kg/m² and residing in the United States. The index date was defined as the first day of a 3-month treatment window during which Noom Weight was used at least once per week on average. Inverse probability treatment weighting was used to balance sociodemographic covariates between the 2 cohorts. HRU and costs for inpatient visits, outpatient visits, telehealth visits, surgeries, and prescriptions were analyzed. RESULTS: Within 12 months after the index date, Noom Weight users had less inpatient costs (mean difference [MD] -US $20.10, 95% CI -US $30.08 to -US $10.12), less outpatient costs (MD -US $124.33, 95% CI -US $159.76 to -US $88.89), less overall prescription costs (MD -US $313.82, 95% CI -US $565.42 to -US $62.21), and less overall health care costs (MD -US $450.39, 95% CI -US $706.28 to -US $194.50) per user than non-Noom Weight users. In terms of HRU, Noom Weight users had fewer inpatient visits (MD -0.03, 95% CI -0.04 to -0.03), fewer outpatient visits (MD -0.78, 95% CI -0.93 to -0.62), fewer surgeries (MD -0.01, 95% CI -0.01 to 0.00), and fewer prescriptions (MD -1.39, 95% CI -1.76 to -1.03) per user than non-Noom Weight users. Among a subset of individuals with 24-month follow-up data, Noom Weight users incurred lower overall prescription costs (MD -US $1139.52, 95% CI -US $1972.21 to -US $306.83) and lower overall health care costs (MD -US $1219.06, 95% CI -US $2061.56 to -US $376.55) per user than non-Noom Weight users. The key differences were associated with reduced prescription use. CONCLUSIONS: Noom Weight use is associated with lower HRU and costs than non-Noom Weight use, with potential cost savings of up to US $1219.06 per user at 24 months after the index date. These findings suggest that Noom Weight could be a cost-effective weight management program for individuals with overweight and obesity. This study provides valuable evidence for health care providers and payers in evaluating the potential benefits of digital weight loss interventions such as Noom Weight.

Tracking and curating putative SARS-CoV-2 recombinants with RIVET.

MOTIVATION: Identifying and tracking recombinant strains of SARS-CoV-2 is critical to understanding the evolution of the virus and controlling its spread. But confidently identifying SARS-CoV-2 recombinants from thousands of new genome sequences that are being shared online every day is quite challenging, causing many recombinants to be missed or suffer from weeks of delay in being formally identified while undergoing expert curation. RESULTS: We present RIVET-a software pipeline and visual platform that takes advantage of recent algorithmic advances in recombination inference to comprehensively and sensitively search for potential SARS-CoV-2 recombinants and organize the relevant information in a web interface that would help greatly accelerate the process of identifying and tracking recombinants. AVAILABILITY AND IMPLEMENTATION: RIVET-based web interface displaying the most updated analysis of potential SARS-CoV-2 recombinants is available at https://rivet.ucsd.edu/. RIVET's frontend and backend code is freely available under the MIT license at https://github.com/TurakhiaLab/rivet and the documentation for RIVET is available at https://turakhialab.github.io/rivet/. The inputs necessary for running RIVET's backend workflow for SARS-CoV-2 are available through a public database maintained and updated daily by UCSC (https://hgdownload.soe.ucsc.edu/goldenPath/wuhCor1/UShER_SARS-CoV-2/).

Temporal partitioning and the potential for avoidance behaviour within South African carnivore communities.

Carnivora occupy many ecological niches fundamental to ecosystem functioning. Within this diverse order, carnivore species compete to establish dominance, ensure survival and maintain fitness. Subordinate carnivores must, therefore, adapt their behaviour to coexist with dominant species. One such strategy is the partitioning of temporal activity patterns. We aim to determine interspecific avoidance patterns among sympatric carnivores by examining coexistence along a temporal axis. We compared the temporal activity patterns of 13 carnivore species using multi-seasonal camera trapping data from four protected areas across South Africa: Associated Private Nature Reserves, Madikwe Game Reserve, Mountain Zebra National Park and Tswalu Kalahari Reserve. Interspecific coefficients of overlap in diel and core activity periods were calculated over the study period and during the wet and dry seasons. Furthermore, interspecific spatiotemporal behaviour was examined using time-to-event analyses. Our results showed that complete avoidance of diel activity patterns was rare among South African carnivore species. Most species were predominantly nocturnal and, therefore, diel activity overlap was high, whereas core activity overlap was significantly lower (p < .001). Diel activity overlap was significantly lower during the dry than wet seasons (p = .045). Lastly, evidence of spatiotemporal aggregation revolved around scavenging species. We show the importance of seasonality in the temporal avoidance behaviours of South African carnivores while highlighting the need for fine-scaled behavioural analyses. Overall, we show that the daily activity patterns of most subordinate South African carnivore species are not influenced by top-down forces in the form of competitional suppression and risk exerted by dominant species. If avoidance is required, it is more likely to manifest as fine-scaled avoidance of core activity periods. We suggest that the focus on core activity periods might be a more suitable tool for interspecific temporal partitioning research.

Nucleus accumbens core acetylcholine receptors modulate the balance of flexible and inflexible cue-directed motivation.

Sign-tracking is a conditioned response where animals interact with reward-predictive cues due to the cues having motivational value, or incentive salience. The nucleus accumbens core (NAc) has been implicated in mediating the sign-tracking response. Additionally, acetylcholine (ACh) transmission throughout the striatum has been attributed to both incentive motivation and behavioral flexibility. Here, we demonstrate a role for NAc ACh receptors in the flexibility of sign-tracking. Sign-tracking animals were exposed to an omission contingency, in which vigorous sign-tracking was punished by reward omission. Animals rapidly adjusted their behavior, but they maintained sign-tracking in a less vigorous manner that did not cancel reward. Within this context of sign-tracking being persistent yet flexible in structure, blockade of NAc nicotinic receptors (nAChRs) led to a persistence in the initial sign-tracking response during omission followed by a period of change in the makeup of sign-tracking, whereas blockade of muscarinic receptors (mAChRs) oppositely enhanced the omission-related development of the new sign-tracking behaviors. Later, once omission learning had occurred, nAChR blockade uniquely led to reduced sign-tracking and elevated reward-directed behaviors instead. These results indicate that NAc ACh receptors have opposing roles in maintaining learned patterns of sign-tracking, with nAChRs having a special involvement in regulating the structure of the sign-tracking response.

Uracil-DNA Glycosylase of Murine Gammaherpesvirus 68 Binds Cognate Viral Replication Factors Independently of its Catalytic Residues.

Herpesviruses are large double-stranded DNA viruses that encode core replication proteins and accessory factors involved in nucleotide metabolism and DNA repair. Mammalian Uracil-DNA glycosylases (UNG) excise deleterious uracil residues from their genomic DNA. Each herpesvirus UNG studied to date has demonstrated conservation of the enzymatic function to excise uracil residues from DNA. We previously reported that a murine gammaherpesvirus (MHV68) with a stop codon in ORF46 (ORF46.stop) that encodes for vUNG was defective in lytic replication and latency in vivo. However, a mutant virus that expressed a catalytically inactive vUNG (ORF46.CM) had no replication defect, unless coupled with additional mutations in the catalytic motif of the viral dUTPase (ORF54.CM). The disparate phenotypes observed in the vUNG mutants led us to explore the non-enzymatic properties of vUNG. Immunoprecipitation of vUNG followed by mass spectrometry in MHV68-infected fibroblasts identified a complex comprised of the cognate viral DNA polymerase, vPOL encoded by ORF9 , and the viral DNA polymerase processivity factor, vPPF encoded by ORF59 . MHV68 vUNG colocalized with vPOL and vPPF in subnuclear structures consistent with viral replication compartments. In reciprocal co-immunoprecipitations, the vUNG formed a complex with the vPOL and vPPF upon transfection with either factor alone, or in combination. Last, we determined that key catalytic residues of vUNG are not required for interactions with vPOL and vPPF upon transfection or in the context of infection. We conclude that the vUNG of MHV68 associates with vPOL and vPPF independently of its catalytic activity. IMPORTANCE: Gammaherpesviruses encode a uracil-DNA glycosylase (vUNG) that is presumed to excise uracil residues from viral genomes. We previously identified the vUNG enzymatic activity, but not the protein itself, as dispensable for gammaherpesvirus replication in vivo . In this study, we report a non-enzymatic role for the viral UNG of a murine gammaherpesvirus to form a complex with two key components of the viral DNA replication machinery. Understanding the role of the vUNG in this viral DNA replication complex may inform the development of antiviral drugs that combat gammaherpesvirus associated cancers.

The impacts of the 340B Program on health care quality for low-income patients.

OBJECTIVE: To assess the effects of hospital 340B eligibility on quality of inpatient care provided to Medicaid and uninsured patients and for all patients. DATA: Agency for Health Care Research and Quality's Healthcare Cost and Utilization Project State Inpatient Data, Hospital Cost Reporting Information System Data, Office of Pharmacy Affairs Information System Data, and American Hospital Association Annual Survey. DESIGN: Regression discontinuity design comparing hospitals just above the DSH percentage program eligibility threshold to those just below. Quality measures include all-cause mortality and 30-day readmission rates as well as condition-specific measures. DATA EXTRACTION: Inpatient data from general acute care hospitals from 2008 to 2014 in 15 states. Data linked on hospital 340B eligibility and participation. PRINCIPAL FINDINGS: We did not find discontinuities in inpatient care quality across the Program eligibility threshold for Medicaid and uninsured patients; specifically, on all-cause mortality (beta = -0.04 percentage points, 95% CI: -0.16, 0.08), 30-day readmission rates (beta = -0.16 percentage points, 95% CI: -0.81, 0.5), or other measures. Among insured and non-Medicaid patients, we found discontinuities for acute myocardial infarction (beta = -0.87 percentage points, 95% CI: -1.55, -0.2) and postoperative sepsis (beta = -0.15 percentage points, 95% CI: -0.23, -0.07) mortality. CONCLUSIONS: 340B Program participation has not demonstrated improved quality of inpatient care among Medicaid or uninsured patients.

Difference in acute and chronic stage ischemic stroke metabolic markers with controls.

BACKGROUND: Acute Ischemic Stroke (AIS), a major cause of disability, was previously associated with multiple metabolomic changes, but many findings were contradictory. Case-control and longitudinal study designs could have played a role in that. To clarify metabolomic changes, we performed a simultaneous comparison of ischemic stroke metabolome in acute, chronic stages of stroke and controls. METHODS: Through the nuclear magnetic resonance (NMR) platform, we evaluated 271 serum metabolites from a cohort of 297 AIS patients in acute and chronic stages and 159 controls. We used Sparse Partial Least Squares-Discriminant analysis (sPLS-DA) to evaluate group disparity; multivariate regression to compare metabolome in acute, chronic stages of stroke and controls; and mixed regression to compare metabolome acute and chronic stages of stroke. We applied false discovery rate (FDR) to our calculations. RESULTS: The sPLS-DA revealed separation of the metabolome in acute, chronic stages of stroke and controls. Regression analysis identified 38 altered metabolites. Ketones, branched-chain amino acids (BCAAs), energy, and inflammatory compounds were mostly elevated, while alanine and glutamine were decreased in the acute stage. These metabolites declined/increased in the chronic stage, often to the same levels as in controls. Levels of fatty acids, phosphatidylcholines, phosphoglycerides, and sphingomyelins did not change between acute and chronic stages, but were different comparing to controls. CONCLUSION: Our pilot study identified metabolites associated with acute stage of ischemic stroke and those that are altered in stroke patients comparing to controls regardless of stroke acuity. Future investigation in a larger independent cohort is needed to validate these findings.

Measuring and modeling macrophage proliferation in a lab-on-CMOS capacitance sensing microsystem.

We report on the use of a lab-on-CMOS biosensor platform for quantitatively tracking the proliferation of RAW 264.7 murine Balb/c macrophages. We show that macrophage proliferation correlates linearly with an average capacitance growth factor resulting from capacitance measurements at a plurality of electrodes dispersed in a sensing area of interest. We further show a temporal model that captures the cell number evolution in the area over long periods (e.g., 30 h). The model links the cell numbers and the average capacitance growth factor to describe the observed cell proliferation.

Human lymphocytes mobilized with exercise have an anti-tumor transcriptomic profile and exert enhanced graft-versus-leukemia effects in xenogeneic mice.

Background: Every bout of exercise mobilizes and redistributes large numbers of effector lymphocytes with a cytotoxic and tissue migration phenotype. The frequent redistribution of these cells is purported to increase immune surveillance and play a mechanistic role in reducing cancer risk and slowing tumor progression in physically active cancer survivors. Our aim was to provide the first detailed single cell transcriptomic analysis of exercise-mobilized lymphocytes and test their effectiveness as a donor lymphocyte infusion (DLI) in xenogeneic mice engrafted with human leukemia. Methods: Peripheral blood mononuclear cells (PBMCs) were collected from healthy volunteers at rest and at the end of an acute bout of cycling exercise. Flow cytometry and single-cell RNA sequencing was performed to identify phenotypic and transcriptomic differences between resting and exercise-mobilized cells using a targeted gene expression panel curated for human immunology. PBMCs were injected into the tail vein of xenogeneic NSG-IL-15 mice and subsequently challenged with a luciferase tagged chronic myelogenous leukemia cell line (K562). Tumor growth (bioluminescence) and xenogeneic graft-versus-host disease (GvHD) were monitored bi-weekly for 40-days. Results: Exercise preferentially mobilized NK-cell, CD8+ T-cell and monocyte subtypes with a differentiated and effector phenotype, without significantly mobilizing CD4+ regulatory T-cells. Mobilized effector lymphocytes, particularly effector-memory CD8+ T-cells and NK-cells, displayed differentially expressed genes and enriched gene sets associated with anti-tumor activity, including cytotoxicity, migration/chemotaxis, antigen binding, cytokine responsiveness and alloreactivity (e.g. graft-versus-host/leukemia). Mice receiving exercise-mobilized PBMCs had lower tumor burden and higher overall survival (4.14E+08 photons/s and 47%, respectively) at day 40 compared to mice receiving resting PBMCs (12.1E+08 photons/s and 22%, respectively) from the same donors (p<0.05). Human immune cell engraftment was similar for resting and exercise-mobilized DLI. However, when compared to non-tumor bearing mice, K562 increased the expansion of NK-cell and CD3+/CD4-/CD8- T-cells in mice receiving exercise-mobilized but not resting lymphocytes, 1-2 weeks after DLI. No differences in GvHD or GvHD-free survival was observed between groups either with or without K562 challenge. Conclusion: Exercise in humans mobilizes effector lymphocytes with an anti-tumor transcriptomic profile and their use as DLI extends survival and enhances the graft-versus-leukemia (GvL) effect without exacerbating GvHD in human leukemia bearing xenogeneic mice. Exercise may serve as an effective and economical adjuvant to increase the GvL effects of allogeneic cell therapies without intensifying GvHD.