Community frailty response service: the ED at your front door.

We describe the expansion and adaptation of a frailty response team to assess older people in their usual place of residence. The team had commenced a weekend service to a limited area in February 2020. As a consequence of demand related to the COVID-19 pandemic, we expanded it and adapted the model of care to provide a 7-day service to our entire catchment area. Five hundred and ninety two patient reviews have been completed in the first 105 days of operation with 43 patients transferred to hospital for further investigation or management following assessment.

Environmental and Sensor Integration Influences on Temperature Measurements by Rotary-Wing Unmanned Aircraft Systems.

Obtaining thermodynamic measurements using rotary-wing unmanned aircraft systems (rwUAS) requires several considerations for mitigating biases from the aircraft and its environment. In this study, we focus on how the method of temperature sensor integration can impact the quality of its measurements. To minimize non-environmental heat sources and prevent any contamination coming from the rwUAS body, two configurations with different sensor placements are proposed for comparison. The first configuration consists of a custom quadcopter with temperature and humidity sensors placed below the propellers for aspiration. The second configuration incorporates the same quadcopter design with sensors instead shielded inside of an L-duct and aspirated by a ducted fan. Additionally, an autopilot algorithm was developed for these platforms to face them into the wind during flight for kinematic wind estimations. This study will utilize in situ rwUAS observations validated against tower-mounted reference instruments to examine how measurements are influenced both by the different configurations as well as the ambient environment. Results indicate that both methods of integration are valid but the below-propeller configuration is more susceptible to errors from solar radiation and heat from the body of the rwUAS.

Moving towards a Network of Autonomous UAS Atmospheric Profiling Stations for Observations in the Earth's Lower Atmosphere: The 3D Mesonet Concept.

The deployment of small unmanned aircraft systems (UAS) to collect routine in situ vertical profiles of the thermodynamic and kinematic state of the atmosphere in conjunction with other weather observations could significantly improve weather forecasting skill and resolution. High-resolution vertical measurements of pressure, temperature, humidity, wind speed and wind direction are critical to the understanding of atmospheric boundary layer processes integral to air-surface (land, ocean and sea ice) exchanges of energy, momentum, and moisture; how these are affected by climate variability; and how they impact weather forecasts and air quality simulations. We explore the potential value of collecting coordinated atmospheric profiles at fixed surface observing sites at designated times using instrumented UAS. We refer to such a network of autonomous weather UAS designed for atmospheric profiling and capable of operating in most weather conditions as a 3D Mesonet. We outline some of the fundamental and high-impact science questions and sampling needs driving the development of the 3D Mesonet and offer an overview of the general concept of operations. Preliminary measurements from profiling UAS are presented and we discuss how measurements from an operational network could be realized to better characterize the atmospheric boundary layer, improve weather forecasts, and help to identify threats of severe weather.

Intercomparison of Small Unmanned Aircraft System (sUAS) Measurements for Atmospheric Science during the LAPSE-RATE Campaign.

Small unmanned aircraft systems (sUAS) are rapidly transforming atmospheric research. With the advancement of the development and application of these systems, improving knowledge of best practices for accurate measurement is critical for achieving scientific goals. We present results from an intercomparison of atmospheric measurement data from the Lower Atmospheric Process Studies at Elevation-a Remotely piloted Aircraft Team Experiment (LAPSE-RATE) field campaign. We evaluate a total of 38 individual sUAS with 23 unique sensor and platform configurations using a meteorological tower for reference measurements. We assess precision, bias, and time response of sUAS measurements of temperature, humidity, pressure, wind speed, and wind direction. Most sUAS measurements show broad agreement with the reference, particularly temperature and wind speed, with mean value differences of 1.6 ± 2 . 6 ∘ C and 0.22 ± 0 . 59 m/s for all sUAS, respectively. sUAS platform and sensor configurations were found to contribute significantly to measurement accuracy. Sensor configurations, which included proper aspiration and radiation shielding of sensors, were found to provide the most accurate thermodynamic measurements (temperature and relative humidity), whereas sonic anemometers on multirotor platforms provided the most accurate wind measurements (horizontal speed and direction). We contribute both a characterization and assessment of sUAS for measuring atmospheric parameters, and identify important challenges and opportunities for improving scientific measurements with sUAS.

Enhanced Acidity of Acetic and Pyruvic Acids on the Surface of Water.

Understanding the acid-base behavior of carboxylic acids on aqueous interfaces is a fundamental issue in nature. Surface processes involving carboxylic acids such as acetic and pyruvic acids play roles in (1) the transport of nutrients through cell membranes, (2) the cycling of metabolites relevant to the origin of life, and (3) the photooxidative processing of biogenic and anthropogenic emissions in aerosols and atmospheric waters. Here, we report that 50% of gaseous acetic acid and pyruvic acid molecules transfer a proton to the surface of water at pH 2.8 and 1.8 units lower than their respective acidity constants p Ka = 4.6 and 2.4 in bulk water. These findings provide key insights into the relative Bronsted acidities of common carboxylic acids versus interfacial water. In addition, the work estimates the reactive uptake coefficient of gaseous pyruvic acid by water to be γPA = 0.06. This work is useful to interpret the interfacial behavior of pyruvic acid under low water activity conditions, typically found in haze aerosols, clouds, and fog waters.

Implications of guidelines for osteoporosis and its treatment.

The development of clinical guidelines is now a more uniform process, with formalised methods to ensure that recommendations are based on current best available evidence from randomised controlled trials and systematic reviews. Over the past 20 years we have seen a growth in guidelines including those relating to osteoporosis, with recommendations varying between and within countries. Some guidelines are concerned with case finding and primary or secondary prevention, such as those produced by the National Institute for Health and Care Excellence (NICE CG146, TA-160, -161, -464), while others focus on specific conditions or risk factors associated with osteoporosis, such as the menopause, coeliac disease and eating disorder. Clinicians can be confused as to which to follow in any particular clinical scenario. International guidelines, such as those from North America (NOF, CAROC, AACE) and Scotland (SIGN 142), differ from those of England, Wales and Northern Ireland, with recent recommendations from NICE (TA464) shifting the focus of treatment from those at greatest fracture risk to an apparent blanket approach, based on cost-effectiveness, rather than clinical effectiveness.Osteoporosis treatment should be targeted at those who can benefit most, outweighing the potential for harm. If the low health economic threshold of NICE TA464 were adopted as a clinical threshold, the most important group-older people at greatest risk of fracture, would not be prioritised. We risk overwhelming clinical services, while causing harm to some at low fracture risk from adverse effects of treatment, yet failing to treat the older population at highest fracture risk.

Whole tumor section quantitative image analysis maximizes between-pathologists' reproducibility for clinical immunohistochemistry-based biomarkers.

Pathologists have had increasing responsibility for quantitating immunohistochemistry (IHC) biomarkers with the expectation of high between-reader reproducibility due to clinical decision-making especially for patient therapy. Digital imaging-based quantitation of IHC clinical slides offers a potential aid for improvement; however, its clinical adoption is limited potentially due to a conventional field-of-view annotation approach. In this study, we implemented a novel solely morphology-based whole tumor section annotation strategy to maximize image analysis quantitation results between readers. We first compare the field-of-view image analysis annotation approach to digital and manual-based modalities across multiple clinical studies (~120 cases per study) and biomarkers (ER, PR, HER2, Ki-67, and p53 IHC) and then compare a subset of the same cases (~40 cases each from the ER, PR, HER2, and Ki-67 studies) using whole tumor section annotation approach to understand incremental value of all modalities. Between-reader results for each biomarker in relation to conventional scoring modalities showed similar concordance as manual read: ER field-of-view image analysis: 95.3% (95% CI 92.0-98.2%) vs digital read: 92.0% (87.8-95.8%) vs manual read: 94.9% (91.4-97.8%); PR field-of-view image analysis: 94.1% (90.3-97.2%) vs digital read: 94.0% (90.2-97.1%) vs manual read: 94.4% (90.9-97.2%); Ki-67 field-of-view image analysis: 86.8% (82.1-91.4%) vs digital read: 76.6% (70.9-82.2%) vs manual read: 85.6% (80.4-90.4%); p53 field-of-view image analysis: 81.7% (76.4-86.8%) vs digital read: 80.6% (75.0-86.0%) vs manual read: 78.8% (72.2-83.3%); and HER2 field-of-view image analysis: 93.8% (90.0-97.2%) vs digital read: 91.0 (86.6-94.9%) vs manual read: 87.2% (82.1-91.9%). Subset implementation and analysis on the same cases using whole tumor section image analysis approach showed significant improvement between pathologists over field-of-view image analysis and manual read (HER2 100% (97-100%), P=0.013 field-of-view image analysis and 0.013 manual read; Ki-67 100% (96.9-100%), P=0.040 and 0.012; ER 98.3% (94.1-99.5%), p=0.232 and 0.181; and PR 96.6% (91.5-98.7%), p=0.012 and 0.257). Overall, whole tumor section image analysis significantly improves between-pathologist's reproducibility and is the optimal approach for clinical-based image analysis algorithms.

Oxidation of Substituted Catechols at the Air-Water Interface: Production of Carboxylic Acids, Quinones, and Polyphenols.

Anthropogenic activities contribute benzene, toluene, and anisole to the environment, which in the atmosphere are converted into the respective phenols, cresols, and methoxyphenols by fast gas-phase reaction with hydroxyl radicals (HO•). Further processing of the latter species by HO• decreases their vapor pressure as a second hydroxyl group is incorporated to accelerate their oxidative aging at interfaces and in aqueous particles. This work shows how catechol, pyrogallol, 3-methylcatechol, 4-methylcatechol, and 3-methoxycatechol (all proxies for oxygenated aromatics derived from benzene, toluene, and anisole) react at the air-water interface with increasing O3(g) during τc ≈ 1 µs contact time and contrasts their potential for electron transfer and in situ production of HO• using structure-activity relationships. A unifying mechanism is provided to explain the oxidation of the five proxies, which includes the generation of semiquinone radicals. Functionalization in the presence of HO• results in the formation of polyphenols and hydroxylated quinones. Instead, fragmentation produces polyfunctional low molecular weight carboxylic acids after oxidative cleavage of the aromatic bond with two vicinal hydroxy groups to yield substituted cis,cis-muconic acids. The generation of maleinaldehydic, maleic, pyruvic, glyoxylic, and oxalic acids confirms the potential of oxy aromatics to produce light-absorbing aqueous secondary organic aerosols in the troposphere.

The inducible costimulator augments Tc17 cell responses to self and tumor tissue.

The inducible costimulator (ICOS) plays a key role in the development of Th17 cells, but its role in the development and antitumor activity of IL-17-producing CD8(+) T cells (Tc17) remains unknown. We found that ICOS costimulation was important for the functional maintenance, but not differentiation, of Tc17 cells in vitro. Blocking the ICOS pathway using an antagonist mAb or by using recipient mice genetically deficient in the ICOS ligand reduced the antitumor activity of adoptively transferred Tc17 cells. Conversely, activating Tc17 cells with an ICOS agonist in vitro enhanced their capacity to eradicate melanoma and induce autoimmune vitiligo when infused into mice. However, ICOS stimulation did not augment the antitumor activity of IL-2 expanded T cells. Additional investigation revealed that ICOS stimulation not only increased IL-2Rα, CXCR3, and IL-23R expression on Tc17 cells, but also dampened their expression of suppressive molecule CD39. Although Tc17 cells activated with an ICOS agonist cosecreted heightened IL-17A, IL-9, and IFN-γ, their therapeutic effectiveness was critically dependent on IFN-γ production. Depletion of IL-17A and IL-9 had little impact on antitumor Tc17 cells activated with an ICOS agonist. Collectively, our work reveals that the ICOS pathway potentiates the antitumor activity of adoptively transferred Tc17 cells. This work has major implications for the design of vaccine, Ab and cell-based therapies for autoimmunity, infectious disease, and cancer.

PAX3 and FOXD3 Promote CXCR4 Expression in Melanoma.

Metastatic melanoma is an aggressive and deadly disease. The chemokine receptor CXCR4 is active in melanoma metastasis, although the mechanism for the promotion and maintenance of CXCR4 expression in these cells is mostly unknown. Here, we find melanoma cells express two CXCR4 isoforms, the common version and a variant that is normally restricted to cells during development or to mature blood cells. CXCR4 expression is driven through a highly conserved intronic enhancer element by the transcription factors PAX3 and FOXD3. Inhibition of these transcription factors slows melanoma cell growth, migration, and motility, as well as reduces CXCR4 expression. Overexpression of these transcription factors drives the production of increased CXCR4 levels. Loss of PAX3 and FOXD3 transcription factor activity results in a reduction in cell motility, migration, and chemotaxis, all of which are rescued by CXCR4 overexpression. Here, we discover a molecular pathway wherein PAX3 and FOXD3 promote CXCR4 gene expression in melanoma.

FOXD3 Promotes PAX3 Expression in Melanoma Cells.

Several key transcription factors regulate cell growth, survival, and differentiation during neural crest and melanoblast development in the embryo, and these same pathways may be reactivated in tumors arising from the progenitors of these cells. The transcription factors PAX3 and FOXD3 have essential roles in melanoblasts and melanoma. In this study, we define a regulatory pathway where FOXD3 promotes the expression of PAX3. Both factors are expressed in melanoma cells and there is a positive correlation between the transcript levels of PAX3 and FOXD3. The PAX3 gene contains two FOX binding motifs within highly conserved enhancer regulatory elements that are essential for neural crest development. FOXD3 binds to both of these motifs in vitro but only one of these sites is preferentially utilized in melanoma cells. Overexpression of FOXD3 upregulates PAX3 levels while inhibition of FOXD3 function does not alter PAX3 protein levels, supporting that FOXD3 is sufficient but not necessary to drive PAX3 expression in melanoma cells. Here, we identify a molecular pathway where FOXD3 upregulates PAX3 expression and therefore contributes to melanoma progression.

Heterogeneous Oxidation of Catechol.

Natural and anthropogenic emissions of aromatic hydrocarbons from biomass burning, agro-industrial settings, and fossil fuel combustion contribute precursors to secondary aerosol formation (SOA). How these compounds are processed under humid tropospheric conditions is the focus of current attention to understand their environmental fate. This work shows how catechol thin films, a model for oxygenated aromatic hydrocarbons present in biomass burning and combustion aerosols, undergo heterogeneous oxidation at the air-solid interface under variable relative humidity (RH = 0-90%). The maximum reactive uptake coefficient of O3(g) by catechol γO3 = (7.49 ± 0.35) × 10(-6) occurs for 90% RH. Upon exposure of ca. 104-µm thick catechol films to O3(g) mixing ratios between 230 ppbv and 25 ppmv, three main reaction pathways are observed. (1) The cleavage of the 1,2 carbon-carbon bond at the air-solid interface resulting in the formation of cis,cis-muconic acid via primary ozonide and hydroperoxide intermediates. Further direct ozonolysis of cis,cis-muconic yields glyoxylic, oxalic, crotonic, and maleic acids. (2) A second pathway is evidenced by the presence of Baeyer-Villiger oxidation products including glutaconic 4-hydroxy-2-butenoic and 5-oxo-2-pentenoic acids during electrospray ionization mass spectrometry (MS) and ion chromatography MS analyses. (3) Finally, indirect oxidation by in situ produced hydroxyl radical (HO(•)) results in the generation of semiquinone radical intermediates toward the synthesis of polyhydoxylated aromatic rings such as tri-, tetra-, and penta-hydroxybenzene. Remarkably, heavier polyhydroxylated biphenyl and terphenyl products present in the extracted oxidized films result from coupling reactions of semiquinones of catechol and its polyhydroxylated rings. The direct ozonolysis of 1,2,3- and 1,2,4-trihydroxybenezene yields 2- and 3-hydroxy-cis,cis-muconic acid, respectively. The production of 2,4- or 3,4-dihdroxyhex-2-enedioic acid is proposed to result from the sequential processing of cis,cis-muconic acid, 2- and 3-hydroxy-cis,cis-muconic acid. Overall, these reactions contribute precursors to form aqueous SOA from aromatics in atmospheric aerosols and brown clouds.

Catechol oxidation by ozone and hydroxyl radicals at the air-water interface.

Anthropogenic emissions of aromatic hydrocarbons promptly react with hydroxyl radicals undergoing oxidation to form phenols and polyphenols (e.g., catechol) typically identified in the complex mixture of humic-like substances (HULIS). Because further processing of polyphenols in secondary organic aerosols (SOA) can continue mediated by a mechanism of ozonolysis at interfaces, a better understanding about how these reactions proceed at the air-water interface is needed. This work shows how catechol, a molecular probe of the oxygenated aromatic hydrocarbons present in SOA, can contribute interfacial reactive species that enhance the production of HULIS under atmospheric conditions. Reactive semiquinone radicals are quickly produced upon the encounter of 40 ppbv-6.0 ppmv O3(g) with microdroplets containing [catechol] = 1-150 µM. While the previous pathway results in the instantaneous formation of mono- and polyhydroxylated aromatic rings (PHA) and chromophoric mono- and polyhydroxylated quinones (PHQ), a different channel produces oxo- and dicarboxylic acids of low molecular weight (LMW). The cleavage of catechol occurs at the 1,2 carbon-carbon bond at the air-water interface through the formation of (1) an ozonide intermediate, (2) a hydroperoxide, and (3) cis,cis-muconic acid. However, variable [catechol] and [O3(g)] can affect the ratio of the primary products (cis,cis-muconic acid and trihydroxybenzenes) and higher order products observed (PHA, PHQ, and LMW oxo- and dicarboxylic acids). Secondary processing is confirmed by mass spectrometry, showing the production of crotonic, maleinaldehydic, maleic, glyoxylic, and oxalic acids. The proposed pathway can contribute precursors to aqueous SOA (AqSOA) formation, converting aromatic hydrocarbons into polyfunctional species widely found in tropospheric aerosols with light-absorbing brown carbon.

Practical Lessons on Antimicrobial Therapy for Critically Ill Patients.

Sepsis stands as a formidable global health challenge, with persistently elevated mortality rates in recent decades. Each year, sepsis not only contributes to heightened morbidity but also imposes substantial healthcare costs on survivors. This narrative review aims to highlight the targeted measures that can be instituted to alleviate the incidence and impact of sepsis in intensive care. Here we discuss measures to reduce nosocomial infections and the prevention of equipment and patient colonisation by resilient pathogens. The overarching global crisis of bacterial resistance to newly developed antimicrobial agents intensifies the imperative for antimicrobial stewardship and de-escalation. This urgency has been accentuated in recent years, notably during the COVID-19 pandemic, as high-dose steroids and opportunistic infections presented escalating challenges. Ongoing research into airway colonisation's role in influencing disease outcomes among critically ill patients underscores the importance of tailoring treatments to disease endotypes within heterogeneous populations, which are important lessons for intensivists in training. Looking ahead, the significance of novel antimicrobial delivery systems and drug monitoring is poised to increase. This narrative review delves into the multifaceted barriers and facilitators inherent in effectively treating critically ill patients vulnerable to nosocomial infections. The future trajectory of intensive care medicine hinges on the meticulous implementation of vigilant stewardship programs, robust infection control measures, and the continued exploration of innovative and efficient technological solutions within this demanding healthcare landscape.

A polygenic risk score added to a QRISK®2 cardiovascular disease risk calculator demonstrated robust clinical acceptance and clinical utility in the primary care setting.

AIMS: The aim of the study was to assess the real-world feasibility, acceptability, and impact of an integrated risk tool for cardiovascular disease (CVD IRT, combining the standard QRISK®2 risk algorithm with a polygenic risk score), implemented within routine primary practice in the UK National Health Service. METHODS AND RESULTS: The Healthcare Evaluation of Absolute Risk Testing Study (NCT05294419) evaluated participants undergoing primary care health checks. Both QRISK2 and CVD IRT scores were returned to the healthcare providers (HCPs), who then communicated the results to participants. The primary outcome of the study was feasibility of CVD IRT implementation. Secondary outcomes included changes in CVD risk (QRISK2 vs. CVD IRT) and impact of the CVD IRT on clinical decision-making. A total of 832 eligible participants (median age 55 years, 62% females, 97.5% White ethnicity) were enrolled across 12 UK primary care practices. Cardiovascular disease IRT scores were obtained on 100% of the blood samples. Healthcare providers stated that the CVD IRT could be incorporated into routine primary care in a straightforward manner in 90.7% of reports. Participants stated they were 'likely' or 'very likely' to recommend the use of this test to their family or friends in 86.9% of reports. Participants stated that the test was personally useful (98.8%) and that the results were easy to understand (94.6%). When CVD IRT exceeded QRISK2, HCPs planned changes in management for 108/388 (27.8%) of participants and 47% (62/132) of participants with absolute risk score changes of >2%. CONCLUSION: Amongst HCPs and participants who agreed to the trial of genetic data for refinement of clinical risk prediction in primary care, we observed that CVD IRT implementation was feasible and well accepted. The CVD IRT results were associated with planned changes in prevention strategies.

When a standard cardiovascular risk tool, as currently used in National Health Service Health Checks, was expanded to include genetic risk information, it was well accepted by both participants and healthcare providers and generated impactful changes in planned clinical decision-making.Most participants found the test useful and easy to understand, and healthcare providers found it straightforward to use in most cases.When risk was increased by the addition of genetic information, this influenced planned management decisions.

Domain swapping in allosteric modulation of DNA specificity.

SgrAI is a type IIF restriction endonuclease that cuts an unusually long recognition sequence and exhibits allosteric self-modulation of cleavage activity and sequence specificity. Previous studies have shown that DNA bound dimers of SgrAI oligomerize into an activated form with higher DNA cleavage rates, although previously determined crystal structures of SgrAI bound to DNA show only the DNA bound dimer. A new crystal structure of the type II restriction endonuclease SgrAI bound to DNA and Ca(2+) is now presented, which shows the close association of two DNA bound SgrAI dimers. This tetrameric form is unlike those of the homologous enzymes Cfr10I and NgoMIV and is formed by the swapping of the amino-terminal 24 amino acid residues. Two mutations predicted to destabilize the swapped form of SgrAI, P27W and P27G, have been made and shown to eliminate both the oligomerization of the DNA bound SgrAI dimers as well as the allosteric stimulation of DNA cleavage by SgrAI. A mechanism involving domain swapping is proposed to explain the unusual allosteric properties of SgrAI via association of the domain swapped tetramer of SgrAI bound to DNA into higher order oligomers.

Conversion of iodide to hypoiodous acid and iodine in aqueous microdroplets exposed to ozone.

Halides are incorporated into aerosol sea spray, where they start the catalytic destruction of ozone (O3) over the oceans and affect the global troposphere. Two intriguing environmental problems undergoing continuous research are (1) to understand how reactive gas phase molecular halogens are directly produced from inorganic halides exposed to O3 and (2) to constrain the environmental factors that control this interfacial process. This paper presents a laboratory study of the reaction of O3 at variable iodide (I(-)) concentration (0.010-100 µM) for solutions aerosolized at 25 °C, which reveal remarkable differences in the reaction intermediates and products expected in sea spray for low tropospheric [O3]. The ultrafast oxidation of I(-) by O3 at the air-water interface of microdroplets is evidenced by the appearance of hypoiodous acid (HIO), iodite (IO2(-)), iodate (IO3(-)), triiodide (I3(-)), and molecular iodine (I2). Mass spectrometry measurements reveal an enhancement (up to 28%) in the dissolution of gaseous O3 at the gas-liquid interface when increasing the concentration of NaI or NaBr from 0.010 to 100 µM. The production of iodine species such as HIO and I2 from NaI aerosolized solutions exposed to 50 ppbv O3 can occur at the air-water interface of sea spray, followed by their transfer to the gas-phase, where they contribute to the loss of tropospheric ozone.

Novel immunocompetent murine models representing advanced local and metastatic pancreatic cancer.

BACKGROUND: The development of novel therapeutics for pancreatic cancer has been hindered by a lack of relevant preclinical models. The purpose of this study was to evaluate the clinical relevancy of two pancreatic cancer models using standard-of-care therapeutic agent gemcitabine. MATERIALS AND METHODS: Murine Panc02 cells were injected directly into the spleen or pancreas of C57BL/6 mice to respectively create models of metastatic and locally advanced pancreatic cancer. Beginning 7 d post-Panc02 injection, treated mice received 20 mg/kg gemcitabine i.p. every 3 d. Animals were sacrificed when the untreated mice became moribund and tumor/liver weight used to assess tumor burden. RESULTS: Untreated mice became moribund 22 d after pancreatic Panc02 injection. Gross analysis revealed localized pancreatic tumors weighing 1.063 g. Intrasplenic Panc02 injection produced extensive liver metastasis by d 15 when the untreated mice first became moribund. Liver weights at this time averaged 3.6 g compared with the average non-tumor-bearing weight of 1.23 g. Gemcitabine therapy resulted in a 54% decrease in localized pancreatic tumor weight and 62.5% decrease in metastatic liver weight. Additionally, gemcitabine therapy extended animal survival to 20.5 d compared with 18.0 d average for the untreated mice. CONCLUSIONS: We describe two models depicting both locally advanced and metastatic pancreatic cancer in immunocompetent mice. In efforts to establish baseline therapeutic efficacy, we determined that gemcitabine reduces tumor burden in both models and enhances survival in the metastatic model. These clinically relevant models provide valuable tools to evaluate novel therapeutics in pancreatic cancer.

Interfacial Oxidative Oligomerization of Catechol.

The heterogeneous reaction between thin films of catechol exposed to O3(g) creates hydroxyl radicals (HO•) in situ, which in turn generate semiquinone radical intermediates in the path to form heavier polyhydroxylated biphenyl, terphenyl, and triphenylene products. Herein, the alteration of catechol aromatic surfaces and their chemical composition are studied during the heterogeneous oxidation of catechol films by O3(g) molar ratios ≥ 230 ppbv at variable relative humidity levels (0% ≤ RH ≤ 90%). Fourier transform infrared micro-spectroscopy, atomic force microscopy, electrospray ionization mass spectrometry, and reverse-phase liquid chromatography with UV-visible and mass spectrometry detection provide new physical insights into understanding the surface reaction. A Langmuir-Hinshelwood mechanism is accounted to report reaction rates, half-lives, and reactive uptake coefficients for the system under variable relative humidity levels. The reactions reported explain how the oligomerization of polyphenols proceeds at interfaces to contribute to the formation of brown organic carbon in atmospheric aerosols.

New clues in the allosteric activation of DNA cleavage by SgrAI: structures of SgrAI bound to cleaved primary-site DNA and uncleaved secondary-site DNA.

SgrAI is a type II restriction endonuclease that cuts an unusually long recognition sequence and exhibits allosteric self-activation with expansion of DNA-sequence specificity. The three-dimensional crystal structures of SgrAI bound to cleaved primary-site DNA and Mg²(+) and bound to secondary-site DNA with either Mg²(+) or Ca²(+) are presented. All three structures show a conformation of enzyme and DNA similar to the previously determined dimeric structure of SgrAI bound to uncleaved primary-site DNA and Ca²(+) [Dunten et al. (2008), Nucleic Acids Res. 36, 5405-5416], with the exception of the cleaved bond and a slight shifting of the DNA in the SgrAI/cleaved primary-site DNA/Mg²(+) structure. In addition, a new metal ion binding site is located in one of the two active sites in this structure, which is consistent with proposals for the existence of a metal-ion site near the 3'-O leaving group.