Modelling variation in test sensitivity for monitoring leptospirosis in beef cattle.

When Bayesian latent class analysis is used for diagnostic test data in the absence of a gold standard test, it is common to assume that any unknown test sensitivities and specificities are constant across different populations. Indeed this assumption is often necessary for model identifiability. However there are a number of practical situations, depending on the type of test and the nature of the disease, where this assumption may not be true. We present a case study of using a microscopic agglutination test to diagnose leptospiroris infection in beef cattle, which strongly suggests that sensitivity in particular varies among herds. We develop and fit an alternative model in which sensitivity is related to within-herd prevalence, and discuss the statistical and epidemiological implications.

Predicting anti-cancer drug combination responses with a temporal cell state network model.

Cancer chemotherapy combines multiple drugs, but predicting the effects of drug combinations on cancer cell proliferation remains challenging, even for simple in vitro systems. We hypothesized that by combining knowledge of single drug dose responses and cell state transition network dynamics, we could predict how a population of cancer cells will respond to drug combinations. We tested this hypothesis here using three targeted inhibitors of different cell cycle states in two different cell lines in vitro. We formulated a Markov model to capture temporal cell state transitions between different cell cycle phases, with single drug data constraining how drug doses affect transition rates. This model was able to predict the landscape of all three different pairwise drug combinations across all dose ranges for both cell lines with no additional data. While further application to different cell lines, more drugs, additional cell state networks, and more complex co-culture or in vivo systems remain, this work demonstrates how currently available or attainable information could be sufficient for prediction of drug combination response for single cell lines in vitro.

Molecular adsorption on coinage metal subnanoclusters: A DFT+D3 investigation.

Gold and silver subnanoclusters with few atoms are prominent candidates for catalysis-related applications, primarily because of the large fraction of lower-coordinated atoms exposed and ready to interact with external chemical species. However, an in-depth energetic analysis is necessary to characterize the relevant terms within the molecular adsorption process that can frame the interactions within the Sabatier principle. Herein, we investigate the interaction between Agn and Aun subnanoclusters (clu, n = 2-7) and N2 , NO, CO, and O2 molecules, using scalar-relativistic density functional theory calculations within van der Waals D3 corrections. The onefold top site is preferred for all chemisorption cases, with a predominance of linear (≈180°) and bent (≈120°) molecular geometries. A larger magnitude of adsorption energy is correlated with smaller distances between molecules and clusters and with the weakening of the adsorbates bond strength represented by the increase of the equilibrium distances and decrease of molecular stretching frequencies. From the energetic decomposition, the interaction energy term was established as an excellent descriptor to classify subnanoclusters in the adsorption/desorption process concomitant with the Sabatier principle. The limiting cases: (i) weak molecular adsorption on the subnanoclusters, which may compromise the reaction activation, where an interaction energy magnitude close to 0 eV is observed (e.g., physisorption in N2 /Ag6 ); and (ii) strong molecular interactions with the subnanoclusters, given the interaction energy magnitude is larger than at least one of the individual fragment binding energies (e.g., strong chemisorption in CO/Au4 and NO/Au4 ), conferring a decrease in the desorption rate and an increase in the possible poisoning rate. However, the intermediate cases are promising by involving interaction energy magnitudes between zero and fragment binding energies. Following the molecular closed-shell (open-shell) electronic configuration, we find a predominant electrostatic (covalent) nature of the physical interactions for N2 ⋯clu and CO ⋯clu (O2 ⋯clu and NO⋯clu), except in the physisorption case (N2 /Ag6 ) where dispersive interaction is dominant. Our results clarify questions about the molecular adsorption on subnanoclusters as a relevant mechanistic step present in nanocatalytic reactions.

Mesowestern Blot: Simultaneous Analysis of Hundreds of Submicroliter Lysates.

Western blotting is a widely used technique for molecular-weight-resolved analysis of proteins and their posttranslational modifications, but high-throughput implementations of the standard slab gel arrangement are scarce. The previously developed Microwestern requires a piezoelectric pipetting instrument, which is not available for many labs. Here, we report the Mesowestern blot, which uses a 3D-printable gel casting mold to enable high-throughput Western blotting without piezoelectric pipetting and is compatible with the standard sample preparation and small (∼1 µL) sample sizes. The main tradeoffs are reduced molecular weight resolution and higher sample-to-sample CV, making it suitable for qualitative screening applications. The casted polyacrylamide gel contains 336, ∼0.5 µL micropipette-loadable sample wells arranged within a standard microplate footprint. Polyacrylamide % can be altered to change molecular weight resolution profiles. Proof-of-concept experiments using both infrared-fluorescent molecular weight protein ladder and cell lysate (RIPA buffer) demonstrate that the protein loaded in Mesowestern gels is amenable to the standard Western blotting steps. The main difference between Mesowestern and traditional Western is that semidry horizontal instead of immersed vertical gel electrophoresis is used. The linear range of detection is at least 32-fold, and at least ∼500 attomols of ß-actin can be detected (∼29 ng of total protein from mammalian cell lysates: ∼100-300 cells). Because the gel mold is 3D-printable, users with access to additive manufacturing cores have significant design freedom for custom layouts. We expect that the technique could be easily adopted by any typical cell and molecular biology laboratory already performing Western blots.

Patterns of Sexual Activity and the Development of Sexual Pain Across the Menopausal Transition.

OBJECTIVE: To examine whether patterns of sexual intercourse frequency and demographic, menopausal status, genitourinary, health, and psychosocial factors are associated with developing sexual pain across the menopausal transition. METHODS: These were longitudinal analyses of questionnaire data from the multicenter, multiracial and ethnic prospective cohort SWAN (Study of Women's Health Across the Nation) (1995-2008). We used multivariable discrete-time proportional hazards models to examine whether incident sexual pain was associated with preceding long-term (up to 10 visits) or short-term (two and three visits) sexual intercourse frequency patterns or other factors (eg, menopause status, genitourinary symptoms, lifestyle factors, and mental health). RESULTS: Of the 2,247 women with no sexual pain at baseline, 1,087 (48.4%) developed sexual pain at least "sometimes" up to 10 follow-up visits over 13 years. We found no consistent association between prior patterns of sexual intercourse frequency and development of sexual pain. For example, neither decreases in intercourse frequency from baseline (adjusted hazard ratio [aHR] 0.93, 95% CI 0.73-1.19) nor decreases in frequency over three prior visits (aHR 1.00, 95% CI 0.72-1.41) were associated with incident pain. Reasons for interruptions in intercourse activity at the prior visit, including lack of interest (aHR 1.64, 95% CI 0.74-3.65) and relationship issues (aHR 0.36, 95% CI 0.04-2.88), were not associated with developing pain. Being postmenopausal using hormone therapy (aHR 3.16, 95% CI 1.46-6.85), and reported vaginal dryness (aHR 3.73, 95% CI 2.88-4.83) were most strongly associated with incident sexual pain. CONCLUSION: Long-term and short-term declines in sexual intercourse frequency across the menopausal transition were not associated with increased hazard of developing pain with intercourse. This empirical evidence does not support the common belief that a reduction in women's sexual frequency is responsible for their symptoms of sexual pain.

Comparative Genomics of Xylella fastidiosa Explores Candidate Host-Specificity Determinants and Expands the Known Repertoire of Mobile Genetic Elements and Immunity Systems.

Xylella fastidiosa causes diseases in many plant species. Originally confined to the Americas, infecting mainly grapevine, citrus, and coffee, X. fastidiosa has spread to several plant species in Europe causing devastating diseases. Many pathogenicity and virulence factors have been identified, which enable the various X. fastidiosa strains to successfully colonize the xylem tissue and cause disease in specific plant hosts, but the mechanisms by which this happens have not been fully elucidated. Here we present thorough comparative analyses of 94 whole-genome sequences of X. fastidiosa strains from diverse plant hosts and geographic regions. Core-genome phylogeny revealed clades with members sharing mostly a geographic region rather than a host plant of origin. Phylogenetic trees for 1605 orthologous CDSs were explored for potential candidates related to host specificity using a score of mapping metrics. However, no candidate host-specificity determinants were strongly supported using this approach. We also show that X. fastidiosa accessory genome is represented by an abundant and heterogeneous mobilome, including a diversity of prophage regions. Our findings provide a better understanding of the diversity of phylogenetically close genomes and expand the knowledge of X. fastidiosa mobile genetic elements and immunity systems.

Analysis of German BSE Surveillance Data: Estimation of the Prevalence of Confirmed Cases versus the Number of Infected, but Non-Detected, Cattle to Assess Confidence in Freedom from Infection.

Quantitative risk assessments for Bovine spongiform encephalopathy (BSE) necessitate estimates for key parameters such as the prevalence of infection, the probability of absence of infection in defined birth cohorts, and the numbers of BSE-infected, but non-detected cattle entering the food chain. We estimated three key parameters with adjustment for misclassification using the German BSE surveillance data using a Gompertz model for latent (i.e., unobserved) age-dependent detection probabilities and a Poisson response model for the number of BSE cases for birth cohorts 1999 to 2015. The models were combined in a Bayesian framework. We estimated the median true BSE prevalence between 3.74 and 0.216 cases per 100,000 animals for the birth cohorts 1990 to 2001 and observed a peak for the 1996 birth cohort with a point estimate of 16.41 cases per 100,000 cattle. For birth cohorts ranging from 2002 to 2013, the estimated median prevalence was below one case per 100,000 heads. The calculated confidence in freedom from disease (design prevalence 1 in 100,000) was above 99.5% for the birth cohorts 2002 to 2006. In conclusion, BSE surveillance in the healthy slaughtered cattle chain was extremely sensitive at the time, when BSE repeatedly occurred in Germany (2000-2009), because the entry of BSE-infected cattle into the food chain could virtually be prevented by the extensive surveillance program during these years and until 2015 (estimated non-detected cases/100.000 [95% credible interval] in 2000, 2009, and 2015 are 0.64 [0.5,0.8], 0.05 [0.01,0.14], and 0.19 [0.05,0.61], respectively).

Photoenhanced Degradation of Sarin at Cu/TiO2 Composite Aerogels: Roles of Bandgap Excitation and Surface Plasmon Excitation.

Multifunctional composites that couple high-capacity adsorbents with catalytic nanoparticles (NPs) offer a promising route toward the degradation of organophosphorus pollutants or chemical warfare agents (CWAs). We couple mesoporous TiO2 aerogels with plasmonic Cu nanoparticles (Cu/TiO2) and characterize the degradation of the organophosphorus CWA sarin under both dark and illuminated conditions. Cu/TiO2 aerogels combine high dark degradation rates, which are facilitated by hydrolytically active sites at the Cu||TiO2 interface, with photoenhanced degradation courtesy of semiconducting TiO2 and the surface plasmon resonance (SPR) of the Cu nanoparticles. The TiO2 aerogel provides a high surface area for sarin binding (155 m2 g-1), while the addition of Cu NPs increases the abundance of hydrolytically active OH sites. Degradation is accelerated on TiO2 and Cu/TiO2 aerogels with O2. Under broadband illumination, which excites the TiO2 bandgap and the Cu SPR, sarin degradation accelerates, and the products are more fully mineralized compared to those of the dark reaction. With O2 and broadband illumination, oxidation products are observed on the Cu/TiO2 aerogels as the hydrolysis products subsequently oxidize. In contrast, the photodegradation of sarin on TiO2 is limited by its slow initial hydrolysis, which limits the subsequent photooxidation. Accelerated hydrolysis occurs on Cu/TiO2 aerogels under visible illumination (>480 nm) that excites the Cu SPR but not the TiO2 bandgap, confirming that the Cu SPR excitation contributes to the broadband-driven activity. The high hydrolytic activity of the Cu/TiO2 aerogels combined with the photoactivity upon TiO2 bandgap excitation and Cu SPR excitation is a potent combination of hydrolysis and oxidation that enables the substantial chemical degradation of organophorphorus compounds.

Laponite-Incorporated UiO-66-NH2-Polyethylene Oxide Composite Membranes for Protection against Chemical Warfare Agent Simulants.

A strategy is developed to enhance the barrier protection of polyethylene oxide (PEO)-metal-organic framework (MOF) composite films against chemical warfare agent simulants. To achieve enhanced protection, an impermeable high-aspect-ratio filler in the form of Laponite RD (LRD) clay platelets was incorporated into a composite PEO film containing MOF UiO-66-NH2. The inclusion of the platelets aids in mitigating permeation of inert hydrocarbons (octane) and toxic chemicals (2-chloroethyl ethyl sulfide, 2-CEES) of dimensions/chemistry similar to prominent vesicant threats while still maintaining high water vapor transport rates (WVTR). By utilizing small-angle neutron scattering, small-angle X-ray scattering, and wide-angle X-ray scattering, the LRD platelet alignment of the films was determined, and the structure of the films was correlated with performance as a barrier material. Performance of the membranes against toxic chemical threats was assessed using permeation testing of octane and 2-CEES, a common simulant for the vesicant mustard gas, and breathability of the membranes was assessed using WVTR measurements. To assess their robustness, chemical exposure (in situ diffuse reflectance infrared Fourier transform spectroscopy) and mechanical (tensile strength) measurements were also performed. It was demonstrated that the barrier performance of the film upon inclusion of the LRD platelets exceeds that of other MOF-polymer composites found in the literature and that this approach establishes a new path for improving permselective materials for chemical protection applications.

Atomic resolution tracking of nerve-agent simulant decomposition and host metal-organic framework response in real space.

Gas capture and sequestration are valuable properties of metal-organic frameworks (MOFs) driving tremendous interest in their use as filtration materials for chemical warfare agents. Recently, the Zr-based MOF UiO-67 was shown to effectively adsorb and decompose the nerve-agent simulant, dimethyl methylphosphonate (DMMP). Understanding mechanisms of MOF-agent interaction is challenging due to the need to distinguish between the roles of the MOF framework and its particular sites for the activation and sequestration process. Here, we demonstrate the quantitative tracking of both framework and binding component structures using in situ X-ray total scattering measurements of UiO-67 under DMMP exposure, pair distribution function analysis, and theoretical calculations. The sorption and desorption of DMMP within the pores, association with linker-deficient Zr6 cores, and decomposition to irreversibly bound methyl methylphosphonate were directly observed and analyzed with atomic resolution.

A solvent-free solid catalyst for the selective and color-indicating ambient-air removal of sulfur mustard.

Bis(2-chloroethyl) sulfide or sulfur mustard (HD) is one of the highest-tonnage chemical warfare agents and one that is highly persistent in the environment. For decontamination, selective oxidation of HD to the substantially less toxic sulfoxide is crucial. We report here a solvent-free, solid, robust catalyst comprising hydrophobic salts of tribromide and nitrate, copper(II) nitrate hydrate, and a solid acid (NafionTM) for selective sulfoxidation using only ambient air at room temperature. This system rapidly removes HD as a neat liquid or a vapor. The mechanisms of these aerobic decontamination reactions are complex, and studies confirm reversible formation of a key intermediate, the bromosulfonium ion, and the role of Cu(II). The latter increases the rate four-fold by increasing the equilibrium concentration of bromosulfonium during turnover. Cu(II) also provides a colorimetric detection capability. Without HD, the solid is green, and with HD, it is brown. Bromine K-edge XANES and EXAFS studies confirm regeneration of tribromide under catalytic conditions. Diffuse reflectance infrared Fourier transform spectroscopy shows absorption of HD vapor and selective conversion to the desired sulfoxide, HDO, at the gas-solid interface.

Capture and Decomposition of the Nerve Agent Simulant, DMCP, Using the Zeolitic Imidazolate Framework (ZIF-8).

Understanding mechanisms of decontamination of chemical warfare agents (CWA) is an area of intense research aimed at developing new filtration materials to protect soldiers and civilians in case of state-sponsored or terrorist attack. In this study, we employed complementary structural, chemical, and dynamic probes and in situ data collection, to elucidate the complex chemistry, capture, and decomposition of the CWA simulant, dimethyl chlorophosphonate (DMCP). Our work reveals key details of the reactive adsorption of DMCP and demonstrates the versatility of zeolitic imidazolate framework (ZIF-8) as a plausible material for CWA capture and decomposition. The in situ synchrotron-based powder X-ray diffraction (PXRD) and pair distribution function (PDF) studies, combined with Fourier transform infrared (FT-IR) spectroscopy, X-ray photoelectron spectroscopy (XPS), zinc K-edge X-ray absorption near edge structure (XANES), and Raman spectroscopies, showed that the unique structure, chemical state, and topology of ZIF-8 enable accessibility, adsorption, and hydrolysis of DMCP into the pores and revealed the importance of linker chemistry and Zn2+ sites for nerve agent decomposition. DMCP decontamination and decomposition product(s) formation were observed by thermogravimetric analysis, FT-IR spectroscopy, and phosphorus (P) K-edge XANES studies. Differential PDF analysis indicated that the average structure of ZIF-8 (at the 30 Å scale) remains unchanged after DMCP dosing and provided information on the dynamics of interactions of DMCP with the ZIF-8 framework. Using in situ PXRD and diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS), we showed that nearly 90% regeneration of the ZIF-8 structure and complete liberation of DMCP and decomposition products occur upon heating.

Quantifying background nitrate removal mechanisms in an agricultural watershed with contrasting subcatchment baseflow concentrations.

Numerous studies have documented the linkages between agricultural nitrogen loads and surface water degradation. In contrast, potential water quality improvements due to agricultural best management practices are difficult to detect because of the confounding effect of background nitrate removal rates, as well as the groundwater-driven delay between land surface action and stream response. To characterize background controls on nitrate removal in two agricultural catchments, we calibrated groundwater travel time distributions with subsurface environmental tracer data to quantify the lag time between historic agricultural inputs and measured baseflow nitrate. We then estimated spatially distributed loading to the water table from nitrate measurements at monitoring wells, using machine learning techniques to extrapolate the loading to unmonitored portions of the catchment to subsequently estimate catchment removal controls. Multiple models agree that in-stream processes remove as much as 75% of incoming loads for one subcatchment while removing <20% of incoming loads for the other. The use of a spatially variable loading field did not result in meaningfully different optimized parameter estimates or model performance when compared with spatially constant loading derived directly from a county-scale agricultural nitrogen budget. Although previous studies using individual well measurements have shown that subsurface denitrification due to contact with a reducing argillaceous confining unit plays an important role in nitrate removal, the catchment-scale contribution of this process is difficult to quantify given the available data. Nonetheless, the study provides a baseline characterization of nitrate transport timescales and removal mechanisms that will support future efforts to detect water quality benefits from ongoing best management practice implementation.

Metal-Organic Framework- and Polyoxometalate-Based Sorbents for the Uptake and Destruction of Chemical Warfare Agents.

The threat of chemical warfare agents (CWAs), assured by their ease of synthesis and effectiveness as a terrorizing weapon, will persist long after the once-tremendous stockpiles in the U.S. and elsewhere are finally destroyed. As such, soldier and civilian protection, battlefield decontamination, and environmental remediation from CWAs remain top national security priorities. New chemical approaches for the fast and complete destruction of CWAs have been an active field of research for many decades, and new technologies have generated immense interest. In particular, our research team and others have shown metal-organic frameworks (MOFs) and polyoxometalates (POMs) to be active for sequestering CWAs and even catalyzing the rapid hydrolysis of agents. In this Forum Article, we highlight recent advancements made in the understanding and evaluation of POMs and Zr-based MOFs as CWA decontamination materials. Specifically, our aim is to bridge the gap between controlled, solution-phase laboratory studies and real-world or battlefield-like conditions by examining agent-material interactions at the gas-solid interface utilizing a multimodal experimental and computational approach. Herein, we report our progress in addressing the following research goals: (1) elucidating molecular-level mechanisms of the adsorption, diffusion, and reaction of CWA and CWA simulants within a series of Zr-based MOFs, such as UiO-66, MOF-808, and NU-1000, and POMs, including Cs8Nb6O19 and (Et2NH2)8[(α-PW11O39Zr(µ-OH)(H2O))2]·7H2O, (2) probing the effects that common ambient gases, such as CO2, SO2, and NO2, have on the efficacy of the MOF and POM materials for CWA destruction, and (3) using CWA simulant results to develop hypotheses for live agent chemistry. Key hypotheses are then tested with targeted live agent studies. Overall, our collaborative effort has provided insight into the fundamental aspects of agent-material interactions and revealed strategies for new catalyst development.

Development and Evaluation of a Cancer Literacy Intervention to Promote Mammography Screening Among Navajo Women: A Pilot Study.

PURPOSE: Develop and evaluate a mammography intervention that provides hope about cancer prevention and treatment. DESIGN: Pilot randomized controlled trial. SETTING: Two communities on the Navajo Nation. PARTICIPANTS: Navajo women and support persons. INTERVENTION: Both groups received standard care: one home visit discussing mammography pros/cons and barriers. The treatment group received an intervention based on Navajo language via an additional home visit with health education materials (written and oral) in English and Navajo, including a Navajo Cancer Glossary with a new descriptive phrase for cancer. ANALYSIS: Between control and intervention conditions, we compared baseline sociodemographics; changes from baseline to 3 months on mammography completion and breast cancer literacy scores. MEASURES: (1) intervention feasibility; (2) self- and clinic-reported mammography screening completion; (3) breast cancer literacy. RESULTS: A total of 25 participants were randomly assigned (13 treatment, 12 control), with 7 support persons in each arm. Mean age was 53 years, 90% had a high school degree or higher, 86% spoke Navajo and English. At 3 months, 44% had a clinically verified mammogram. Mammography completion was 57% among those with a support person and 27% among those without (P = .14). Intervention women reported more breast cancer beliefs consistent with mammography (P = .015). CONCLUSIONS: Increases in breast cancer beliefs consistent with mammography show promise. Findings highlight a need to tailor education materials to Navajo culture/language and focus on enhancing support.

Multimodal Characterization of Materials and Decontamination Processes for Chemical Warfare Protection.

This Review summarizes the recent progress made in the field of chemical threat reduction by utilizing new in situ analytical techniques and combinations thereof to study multifunctional materials designed for capture and decomposition of nerve gases and their simulants. The emphasis is on the use of in situ experiments that simulate realistic operating conditions (solid-gas interface, ambient pressures and temperatures, time-resolved measurements) and advanced synchrotron methods, such as in situ X-ray absorption and scattering methods, a combination thereof with other complementary measurements (e.g., XPS, Raman, DRIFTS, NMR), and theoretical modeling. The examples presented in this Review range from studies of the adsorption and decomposition of nerve agents and their simulants on Zr-based metal organic frameworks to Nb and Zr-based polyoxometalates and metal (hydro)oxide materials. The approaches employed in these studies ultimately demonstrate how advanced synchrotron-based in situ X-ray absorption spectroscopy and diffraction can be exploited to develop an atomic- level understanding of interfacial binding and reaction of chemical warfare agents, which impacts the development of novel filtration media and other protective materials.

Gold standards are out and Bayes is in: Implementing the cure for imperfect reference tests in diagnostic accuracy studies.

Bayesian mixture models, often termed latent class models, allow users to estimate the diagnostic accuracy of tests and true prevalence in one or more populations when the positive and/or negative reference standards are imperfect. Moreover, they allow the data analyst to show the superiority of a novel test over an old test, even if this old test is the (imperfect) reference standard. We use published data on Toxoplasmosis in pigs to explore the effects of numbers of tests, numbers of populations, and dependence structure among tests to ensure model (local) identifiability. We discuss and make recommendations about use of priors, sensitivity analysis, model identifiability and study design options, and strongly argue for the use of Bayesian mixture models as a logical and coherent approach for estimating the diagnostic accuracy of two or more tests.

Correlated Multimodal Approach Reveals Key Details of Nerve-Agent Decomposition by Single-Site Zr-Based Polyoxometalates.

Development of technologies for protection against chemical warfare agents (CWAs) is critically important. Recently, polyoxometalates have attracted attention as potential catalysts for nerve-agent decomposition. Improvement of their effectiveness in real operating conditions requires an atomic-level understanding of CWA decomposition at the gas-solid interface. We investigated decomposition of the nerve agent Sarin and its simulant, dimethyl chlorophosphate (DMCP), by zirconium polytungstate. Using a multimodal approach, we showed that upon DMCP and Sarin exposure the dimeric tungstate undergoes monomerization, making coordinatively unsaturated Zr(IV) centers available, which activate nucleophilic hydrolysis. Further, DMCP is shown to be a good model system of reduced toxicity for studies of CWA deactivation at the gas-solid interface.