Multitask methods for predicting molecular properties from heterogeneous data.

Data generation remains a bottleneck in training surrogate models to predict molecular properties. We demonstrate that multitask Gaussian process regression overcomes this limitation by leveraging both expensive and cheap data sources. In particular, we consider training sets constructed from coupled-cluster (CC) and density functional theory (DFT) data. We report that multitask surrogates can predict at CC-level accuracy with a reduction in data generation cost by over an order of magnitude. Of note, our approach allows the training set to include DFT data generated by a heterogeneous mix of exchange-correlation functionals without imposing any artificial hierarchy on functional accuracy. More generally, the multitask framework can accommodate a wider range of training set structures-including the full disparity between the different levels of fidelity-than existing kernel approaches based on Δ-learning although we show that the accuracy of the two approaches can be similar. Consequently, multitask regression can be a tool for reducing data generation costs even further by opportunistically exploiting existing data sources.

Development of a highly sensitive and specific intact proviral DNA assay for HIV-1 subtype B and C.

INTRODUCTION: HIV reservoir quantification is essential for evaluation of HIV curative strategies and may provide valuable insights about reservoir dynamics during antiretroviral therapy. The Intact Proviral DNA Assay (IPDA) provides the unique opportunity to quantify the intact and defective reservoir. The current IPDA is optimized for HIV-1 subtype B, the dominant subtype in resource-rich settings. However, subtype C is dominant in Sub-Saharan Africa, jointly accounting for around 60% of the pandemic. We developed an assay capable of quantifying intact and defective proviral HIV-1 DNA of subtype B and C. METHODS: Primer and probe sequences were strategically positioned at conserved regions in psi and env and adapted to subtype B&C. In silico analysis of 752 subtype B and 697 subtype C near-full length genome sequences (nFGS) was performed to predict  the specificity and sensitivity. Gblocks were used to determine the limit of blank (LoB), limit of detection (LoD), and different annealing temperatures were tested to address impact of sequence variability. RESULTS: The in silico analysis showed that the HIV-1 B&C IPDA correctly identified 100% of the intact subtype B, and 86% of the subtype C sequences. In contrast, the original IPDA identified 86% and 12% of these subtype B and C sequences as intact. Furthermore, the HIV-1 B&C IPDA correctly identified hypermutated (87% and 88%) and other defective sequences (73% and 66%) for subtype B and C with comparable specificity as the original IPDA for subtype B (59% and 63%). Subtype B cis-acting sequences were more frequently identified as intact by the HIV-1 B&C IPDA compared to the original IPDA (39% and 2%). The LoB for intact proviral DNA copies was 0, and the LoD for intact proviral DNA copies was 6 (> 95% certainty) at 60 °C. Quantification of 2-6 copies can be performed with > 80% certainty. Lowering the annealing temperature to 55 °C slightly lowered the specificity but prevented exclusion of samples with single mutations in the primer/probe region. CONCLUSIONS: We developed a robust and sensitive assay for the quantification of intact and defective HIV-1 subtype B and C proviral DNA, making this a suitable tool to monitor the impact of (large-scale) curative interventions.

Effects of atipamezole on selected physiologic parameters in cynomolgus macaques (Macaca fascicularis).

BACKGROUND: Atipamezole, an α-2 adrenergic receptor antagonist, reverses the α-2 agonist anesthetic effects. There is a dearth of information on the physiological effects of these drugs in cynomolgus macaques (Macaca fascicularis). We assessed atipamezole's physiologic effects. We hypothesized atipamezole administration would alter anesthetic parameters. METHODS: Five cynomolgus macaques were sedated with ketamine/dexmedetomidine intramuscularly, followed 45 min later with atipamezole (0.5 mg/kg). Anesthetic parameters (heart rate, blood pressure [systolic (SAP), diastolic (DAP), and mean (MAP) blood pressure], body temperature, respiratory rate, and %SpO2) were monitored prior to and every 10 min (through 60 min) post atipamezole injection. RESULTS: While heart rate was significantly increased for 60 min; SAP, DAP, MAP, and temperature were significantly decreased at 10 min. CONCLUSIONS: This study indicates subcutaneous atipamezole results in increased heart rate and transient blood pressure decrease. These findings are clinically important to ensure anesthetist awareness to properly support and treat patients as needed.

Ultratunable Quantum Frequency Conversion in Photonic Crystal Fiber.

Quantum frequency conversion of single photons between wavelength bands is a key enabler to realizing widespread quantum networks. We demonstrate the quantum frequency conversion of a heralded 1551 nm photon to any wavelength within an ultrabroad (1226-1408 nm) range in a group-velocity-symmetric photonic crystal fiber, covering over 150 independent frequency bins. The target wavelength is controlled by tuning only a single pump laser wavelength. We find internal, and total, conversion efficiencies of 12(1)% and 1.4(2)%, respectively. For the case of converting 1551 to 1300 nm we measure a heralded g^{(2)}(0)=0.25(6) for converted light from an input with g^{(2)}(0)=0.034(8). We expect that this photonic crystal fiber can be used for myriad quantum networking tasks.

An evaluation of the Chesapeake Bay management strategy to improve water quality in small agricultural watersheds.

Chesapeake Bay water quality has been a concern since 1970. In rural areas, agriculture is the dominant N and P source, and the voluntary application of best management practices (BMPs) is the primary management tool. Here we test the hypothesis that the current management approach of primarily voluntary, untargeted BMP implementation is insufficient to create detectable, widespread reductions in N, P, and total suspended solid (TSS) concentrations in agricultural watersheds of the Choptank basin, a tributary of Chesapeake Bay. To test this hypothesis, we assessed BMP implementation and sampled water quality on participating farms, at intermediate streams within each watershed, and at watershed outlets of four watersheds from 2013 to 2014. We also present water quality data from 2003 to 2014 at the outlets of 12 additional agricultural and one forested watershed and survey-directed interviews of farmers. By the end of 2014, large numbers of BMPs, both structural and cultural, had been implemented. Of the 16 agricultural watersheds, 50% showed significant decreases in baseflow N, 37.5% showed no changes, and 12.5% showed increasing TN. Baseflow P significantly decreased at just one watershed, increased at one, and remained stable at 14. Stormflow N was similar to baseflow, but stormflow P was 5 times higher than baseflow. These data partially support our hypothesis. Surveys suggested farmers considered themselves responsible for the quality of water leaving their farms, but out-of-pocket cost was the major impediment to further BMP adoption. We suggest that greater outreach and more financial support for farmers to implement BMPs is required to increase the types and densities of BMPs needed to achieve regional water quality goals.

Multichannel deconvolution of vibrational signals: A state-space inverse filtering approach.

Deconvolution of noisy measurements, especially when they are multichannel, has always been a challenging problem. The processing techniques developed range from simple Fourier methods to more sophisticated model-based parametric methodologies based on the underlying acoustics of the problem at hand. Methods relying on multichannel mean-squared error processors (Wiener filters) have evolved over long periods from the seminal efforts in seismic processing. However, when more is known about the acoustics, then model-based state-space techniques incorporating the underlying process physics can improve the processing significantly. The problems of interest are the vibrational response of tightly coupled acoustic test objects excited by an out-of-the-ordinary transient, potentially impairing their operational performance. Employing a multiple input/multiple output structural model of the test objects under investigation enables the development of an inverse filter by applying subspace identification techniques during initial calibration measurements. Feasibility applications based on a mass transport experiment and test object calibration test demonstrate the ability of the processor to extract the excitations successfully.

Transient recovery problem in acoustics: A multichannel model-based deconvolution approach.

Critical acoustical systems operating in complex environments contaminated with disturbances and noise offer an extreme challenge when excited by out-of-the-ordinary, impulsive, transient events that can be undetected and seriously affect their overall performance. Transient impulse excitations must be detected, extracted, and evaluated to determine any potential system damage that could have been imposed; therefore, the problem of recovering the excitation in an uncertain measurement environment becomes one of multichannel deconvolution. Recovering a transient and its initial energy has not been solved satisfactorily, especially when the measurement has been truncated and only a small segment of response data is available. The development of multichannel deconvolution techniques for both complete and incomplete excitation data is discussed, employing a model-based approach based on the state-space representation of an identified acoustical system coupled to a forward modeling solution and a Kalman-type processor for enhancement and extraction. Synthesized data are utilized to assess the feasibility of the various approaches, demonstrating that reasonable performance can be achieved even in noisy environments.

Multichannel spectral estimation in acoustics: A state-space approach.

Spectral estimation is a necessary methodology to analyze the frequency content of noisy data sets especially in acoustic applications. Many spectral techniques have evolved starting with the classical Fourier transform methods based on the well-known Wiener-Khintchine relationship relating the covariance-to-spectral density as a transform pair culminating with more elegant model-based parametric techniques that apply prior knowledge of the data to produce a high-resolution spectral estimate. Multichannel spectral representations are a class of both nonparametric, as well as parametric, estimators that provide improved spectral estimates. In any case, classical nonparametric multichannel techniques can provide reasonable estimates when coupled with peak-peaking methods as long as the signal levels are reasonably high. Parametric multichannel methods can perform quite well in low signal level environments even when applying simple peak-picking techniques. In this paper, the performance of both nonparametric (periodogram) and parametric (state-space) multichannel spectral estimation methods are investigated when applied to both synthesized noisy structural vibration data as well as data obtained from a sounding rocket flight. It is demonstrated that for the multichannel problem, state-space techniques provide improved performance, offering a parametric alternative compared to classical methods.

Vibrational processing of a dynamic structural flight system: A multichannel spectral estimation approach.

Dynamic testing of large flight vehicles (rockets) is not only complex, but also can be very costly. These flights are infrequent and can lead to disastrous effects if something were to fail during the flight. The development of sensors coupled to internal components offers a great challenge in reducing their size, yet still maintaining their precision. Sounding rockets provide both a viable and convenient alternative to the more costly vehicular flights. Some of the major objectives are to test various types of sensors for monitoring components of high interest as well as investigating real-time processing techniques. Signal processing presents an extreme challenge in this noisy multichannel environment. The estimation and tracking of modal frequencies from vibrating structures is an important set of features that can provide information about the components under test; therefore, high resolution multichannel spectral processing is required. The application of both single channel and multichannel techniques capable of producing reliable modal frequency estimates of a vibrating structure from uncertain accelerometer measurements is discussed.

Multichannel processing of vibrational measurements: A constrained subspace application.

Monitoring mechanical systems operating in uncertain environments contaminated with both environmental disturbances and noise lead directly to low signal-to-noise-ratios, creating an extremely challenging processing problem, especially in real-time. In order to estimate the performance of a particular system from uncertain vibrational data, it is necessary to identify its unique resonant (modal) frequency signature. The monitoring of structural modes to determine the condition of a device under investigation is essential, especially if it is a critical entity of an operational system. The development of a model-based scheme capable of the on-line tracking of the inherent structural modal frequencies by applying both constrained subspace identification techniques to extract the modal frequencies and state estimation methods to track the evolution is discussed. An application of this approach to a cylindrical structural device (pipe-in-air) is analyzed based on theoretical simulations along with controlled validation experiments, including injected anomalies illustrate the approach and performance. Statistics are gathered to bound potential processors for real-time performance employing these constrained techniques.

Intranasal midazolam and fentanyl for procedural sedation and analgesia in infants in the neonatal intensive care unit.

BACKGROUND: The intranasal route is a minimally invasive method for rapidly delivering midazolam and fentanyl to provide short-term analgesia and sedation in infants. However, intranasal use of midazolam and fentanyl is not labeled for infants and safety data are sparse. The objective of this study is to evaluate the safety of intranasal midazolam and intranasal fentanyl in infants admitted to the Neonatal Intensive Care Unit (NICU). METHODS: We retrospectively identified all infants receiving intranasal midazolam or fentanyl in the NICU from 2009 to 2015. We recorded indication for use and vital signs and determined the proportion of infants experiencing the following adverse events: death within 24 hours, hypotension, bradycardia, worsening respiratory status, and chest wall rigidity. Vital signs 4 hours before and after each dose were compared using the Wilcoxon signed-rank test. RESULTS: We identified 17 infants (gestational ages 23- 41 weeks) receiving 25 intranasal doses. None of the infants died or developed hypotension, bradycardia, or chest wall rigidity. Intranasal delivery was most commonly used for sedation during magnetic resonance imaging studies. Other indications include analgesia or sedation for retinopathy of prematurity surgery, intubation, and peripherally inserted central catheter placement. One infant receiving intranasal midazolam experienced worsening respiratory status. Vital signs before and after dosing were not significantly different. CONCLUSIONS: Intranasal midazolam and fentanyl use in term and preterm infants appeared safe and well-tolerated in this small cohort of infants. Larger, prospective studies evaluating the safety and efficacy of intranasal midazolam and fentanyl use in infants are warranted.

Direct Frequency-Comb-Driven Raman Transitions in the Terahertz Range.

We demonstrate the use of a femtosecond frequency comb to coherently drive stimulated Raman transitions between terahertz-spaced atomic energy levels. More specifically, we address the 3d ^{2}D_{3/2} and 3d ^{2}D_{5/2} fine structure levels of a single trapped ^{40}Ca^{+} ion and spectroscopically resolve the transition frequency to be ν_{D}=1,819,599,021,534±8 Hz. The achieved accuracy is nearly a factor of five better than the previous best Raman spectroscopy, and is currently limited by the stability of our atomic clock reference. Furthermore, the population dynamics of frequency-comb-driven Raman transitions can be fully predicted from the spectral properties of the frequency comb, and Rabi oscillations with a contrast of 99.3(6)% and millisecond coherence time have been achieved. Importantly, the technique can be easily generalized to transitions in the sub-kHz to tens of THz range and should be applicable for driving, e.g., spin-resolved rovibrational transitions in molecules and hyperfine transitions in highly charged ions.

Anesthetic considerations in a parturient with Freeman-Sheldon syndrome.

Freeman-Sheldon syndrome is a rare genetic disorder characterized by malformations of the face, oral cavity and musculoskeletal system. This case report describes the anesthetic management of a parturient with Freeman-Sheldon syndrome, kyphoscoliosis and a cardiac pacemaker for a cesarean delivery and tubal ligation. With a predicted difficult airway, our team decided to provide a combined spinal-epidural anesthetic. Problems encountered included difficult intravenous access, failure to identify the subarachnoid space and patient discomfort during surgery.

The role of the medial prefrontal cortex in updating reward value and avoiding perseveration.

The medial prefrontal cortex (mPFC) plays a major role in goal-directed behaviours, but it is unclear whether it plays a role in breaking away from a high-value reward in order to explore for better options. To address this question, we designed a novel 3-arm Bandit Task in which rats were required to choose one of three potential reward arms, each of which was associated with a different amount of food reward and time-out punishment. After a variable number of choice trials the reward locations were shuffled and animals had to disengage from the now devalued arm and explore the other options in order to optimise payout. Lesion and control groups' behaviours on the task were then analysed by fitting data with a reinforcement learning model. As expected, lesioned animals obtained less reward overall due to an inability to flexibly adapt their behaviours after a change in reward location. However, modelling results showed that lesioned animals were no more likely to explore than control animals. We also discovered that all animals showed a strong preference for certain maze arms, at the expense of reward. This tendency was exacerbated in the lesioned animals, with the strongest effects seen in a subset of animals with damage to dorsal mPFC. The results confirm a role for mPFC in goal-directed behaviours but suggest that rats rely on other areas to resolve the explore-exploit dilemma.

Review of the correlation between blood flow velocity and polycythemia in the fetus, neonate and adult: appropriate diagnostic levels need to be determined for twin anemia-polycythemia sequence.

Twin anemia-polycythemia sequence (TAPS) is recognized increasingly antenatally by the demonstration of an anemic twin and a polycythemic cotwin using the middle cerebral artery peak systolic velocity (MCA-PSV). While the MCA-PSV has been shown to correlate well with anemia in singleton fetuses, the evidence to support its use to diagnose fetal polycythemia appears to be less clear-cut. We aimed to evaluate fetal, neonatal and adult literature used to support the use of MCA-PSV for the diagnosis of polycythemia. Comprehensive literature searches were performed for ultrasound evidence of polycythemia in the human fetus, neonate and adult using key search terms. Only manuscripts in the English language with an abstract were considered for the review, performed in June 2014. Fifteen manuscripts were found for the human fetus, including 38 cases of TAPS. Nine of these defined fetal polycythemia as MCA-PSV < 0.8 multiples of the median (MoM), five used < 1.0 MoM and one used 0.8-1.0 MoM. Only two studies, involving a total of 15 cases, proposed a diagnostic level, acknowledging false-positive and -negative cases, though neither reported sensitivities or specificities. Six neonatal studies (96 neonates) demonstrated evidence of decreased cerebral velocities in polycythemia and a consequent increase with hemodilution. In the adult, five studies (57 polycythemic adults) demonstrated increased flow or velocity with hemodilution. Neither neonatal nor adult studies conclusively defined levels for screening for polycythemia. Despite widespread adoption of a cut-off of < 0.8 MoM in the published literature for the polycythemic fetus in TAPS, this is based upon minimal evidence, with unknown sensitivity and specificity. We recommend caution in excluding TAPS based purely upon the absence of a reduced MCA-PSV.

Fibronectin induction abrogates the BRAF inhibitor response of BRAF V600E/PTEN-null melanoma cells.

The mechanisms by which some melanoma cells adapt to Serine/threonine-protein kinase B-Raf (BRAF) inhibitor therapy are incompletely understood. In the present study, we used mass spectrometry-based phosphoproteomics to determine how BRAF inhibition remodeled the signaling network of melanoma cell lines that were BRAF mutant and PTEN null. Short-term BRAF inhibition was associated with marked changes in fibronectin-based adhesion signaling that were PTEN dependent. These effects were recapitulated through BRAF siRNA knockdown and following treatment with chemotherapeutic drugs. Increased fibronectin expression was also observed in mouse xenograft models as well as specimens from melanoma patients undergoing BRAF inhibitor treatment. Analysis of a melanoma tissue microarray showed loss of PTEN expression to predict for a lower overall survival, with a trend for even lower survival being seen when loss of fibronectin was included in the analysis. Mechanistically, the induction of fibronectin limited the responses of these PTEN-null melanoma cell lines to vemurafenib, with enhanced cytotoxicity observed following the knockdown of either fibronectin or its receptor α5ß1 integrin. This in turn abrogated the cytotoxic response to BRAF inhibition via increased AKT signaling, which prevented the induction of cell death by maintaining the expression of the pro-survival protein Mcl-1. The protection conveyed by the induction of FN expression could be overcome through combined treatment with a BRAF and PI3K inhibitor.

Soil Methane and Carbon Dioxide Fluxes from Cropland and Riparian Buffers in Different Hydrogeomorphic Settings.

Riparian buffers contribute to the mitigation of nutrient pollution in agricultural landscapes, but there is concern regarding their potential to be hot spots of greenhouse gas production. This study compared soil CO and CH fluxes in adjacent crop fields and riparian buffers (a flood-prone forest and a flood-protected grassland along an incised channel) and examined the impact of water table depth (WTD) and flood events on the variability of gas fluxes in riparian zones. Results showed significantly ( < 0.001) higher CO emission in riparian areas than in adjoining croplands (6.8 ± 0.6 vs. 3.6 ± 0.5 Mg CO-C ha yr; mean ± SE). Daily flux of CO and soil temperature were significantly related ( < 0.002), with Q values ranging between 1.75 and 2.53. Significant relationships ( < 0.05) were found between CH daily flux and WTD. Flood events resulted in enhanced CH emission (up to +44.5 mg CH-C m d in a swale) under warm soil conditions (>22°C), but the effect of flooding was less pronounced in early spring (emission <1.06 mg CH-C m d), probably due to low soil temperature. Although CH flux direction alternated at all sites, overall the croplands and the flood-affected riparian forest were CH sources, with annual emission averaging +0.04 ± 0.17 and +0.92 ± 1.6 kg CH-C ha, respectively. In the riparian forest, a topographic depression (<8% of the total area) accounted for 78% of the annual CH emission, underscoring the significance of landscape heterogeneity on CH dynamics in riparian buffers. The nonflooded riparian grassland, however, was a net CH sink (-1.08 ± 0.22 kg CH-C ha yr), probably due to the presence of subsurface tile drains and a dredged/incised channel at that study site. Although these hydrological alterations may have contributed to improvement in the CH sink strength of the riparian grassland, this must be weighed against the water quality maintenance functions and other ecological services provided by riparian buffers.

Complex ventral hernia repair with a human acellular dermal matrix.

PURPOSE: The ideal approach to complex ventral hernia repair is frequently debated. Differences in processing techniques among biologic materials may impact hernia repair outcomes. This study evaluates the outcomes of hernia repair with a terminally sterilized human acellular dermal matrix (TS-HADM) (AlloMax(®) Surgical Graft, by C. R. Bard/Davol, Inc., Warwick, RI, USA) treated with low-dose gamma irradiation. METHODS: A single-arm multi-center retrospective observational study of patients undergoing hernia repair with TS-HADM was performed. Data analyses were exploratory only; no formal hypothesis testing was pre-specified. RESULTS: Seventy-eight patients (43F, 35M) underwent incisional hernia repair with a TS-HADM. Mean follow-up was 20.5 months. Preoperative characteristics include age of 56.6 ± 11.1 years, BMI 36.7 ± 9.9 kg/m(2), and mean hernia defect size 187 cm(2). Sixty-five patients underwent component separation technique (CST) with a reinforcing graft. Overall, 21.8% developed recurrences. Recurrences occurred in 15% of patients repaired with CST. Major wound complications occurred in 31% of patients overall. Based upon CDC surgical wound classification, major wound complications were seen in 26, 40, 56, and 50% of Class 1, 2, 3, and 4 wounds, respectively. No grafts required removal. CONCLUSIONS: Hernia recurrences are not uncommon following complex abdominal wall reconstruction. Improved outcomes are seen when a TS-HADM is utilized as reinforcement to primary fascial closure.

Model-based failure detection for cylindrical shells from noisy vibration measurements.

Model-based processing is a theoretically sound methodology to address difficult objectives in complex physical problems involving multi-channel sensor measurement systems. It involves the incorporation of analytical models of both physical phenomenology (complex vibrating structures, noisy operating environment, etc.) and the measurement processes (sensor networks and including noise) into the processor to extract the desired information. In this paper, a model-based methodology is developed to accomplish the task of online failure monitoring of a vibrating cylindrical shell externally excited by controlled excitations. A model-based processor is formulated to monitor system performance and detect potential failure conditions. The objective of this paper is to develop a real-time, model-based monitoring scheme for online diagnostics in a representative structural vibrational system based on controlled experimental data.

Field study of growth and calcification rates of three species of articulated coralline algae in British Columbia, Canada.

Ocean acidification caused by rising atmospheric CO2 is predicted to negatively impact growth and calcification rates of coralline algae. Decreases in coralline abundance may have cascading effects on marine ecosystems and on carbon sequestration worldwide. In this study, we measured growth and calcification rates of three common species of articulated coralline algae (Bossiella plumosa, Calliarthron tuberculosum, and Corallina vancouveriensis) at an intertidal field site in British Columbia. Linear growth rates measured in the field were slow, although Bossiella grew significantly faster (0.22 cm mon⁻¹) than Calliarthron and Corallina (0.17 and 0.15 cm mon⁻¹, respectively). Growth rates in the field were generally slower than growth rates in the laboratory, suggesting that data generated in the laboratory may not be representative of natural field conditions. Growth rates did not decrease as fronds approached their maximum observed size, suggesting that maximum frond size might be determined not by intrinsic factors but by external factors such as wave-induced drag forces. Using growth data, we estimate that the largest observed Bossiella frond (20 cm²) and Calliarthron frond (40 cm²) were about 4- and 11-years-old, respectively, and had deposited approximately 1 and 6 g CaCO3 in that time. Given the great abundance of coralline algae along the coast of British Columbia, deposition rates of CaCO3 are expected to play a significant but poorly characterized role in carbon sequestration.