Deep generative modeling for single-cell transcriptomics.

Single-cell transcriptome measurements can reveal unexplored biological diversity, but they suffer from technical noise and bias that must be modeled to account for the resulting uncertainty in downstream analyses. Here we introduce single-cell variational inference (scVI), a ready-to-use scalable framework for the probabilistic representation and analysis of gene expression in single cells ( https://github.com/YosefLab/scVI ). scVI uses stochastic optimization and deep neural networks to aggregate information across similar cells and genes and to approximate the distributions that underlie observed expression values, while accounting for batch effects and limited sensitivity. We used scVI for a range of fundamental analysis tasks including batch correction, visualization, clustering, and differential expression, and achieved high accuracy for each task

Remote physiological monitoring: Clinical, financial, and behavioral outcomes in a heart failure population

This article reports on the outcomes associated with remote physiological monitoring (RPM) conducted as part of a heart failure disease management program. Claims data, medical records, data transmission records, and survey results for 91 individuals ages 50–92 (mean 74 years) successfully completing a heart failure RPM program were analyzed for time periods before, during, and after the monitoring intervention. The program was associated with significant reductions in per member per month costs and emergency room and hospital utilization. More detailed analyses were performed for specific gender and age subgroups. Participant surveys indicated high levels of satisfaction, and improvements in self-perceived health status, self-efficacy, and self-management behaviors. This study is the first to assess the impact of a RPM program following removal of the monitoring equipment. The results indicate that RPM, as a component of a traditional disease management program, has a sustained, beneficial effect on participants’ lifestyles after the monitoring period has ended

Discovery and Validation of a New Class of Small Molecule Toll-Like Receptor 4 (TLR4) Inhibitors

Many inflammatory diseases may be linked to pathologically elevated signaling via the receptor for lipopolysaccharide (LPS), toll-like receptor 4 (TLR4). There has thus been great interest in the discovery of TLR4 inhibitors as potential anti-inflammatory agents. Recently, the structure of TLR4 bound to the inhibitor E5564 was solved, raising the possibility that novel TLR4 inhibitors that target the E5564-binding domain could be designed. We utilized a similarity search algorithm in conjunction with a limited screening approach of small molecule libraries to identify compounds that bind to the E5564 site and inhibit TLR4. Our lead compound, C34, is a 2-acetamidopyranoside (MW 389) with the formula C17H27NO9, which inhibited TLR4 in enterocytes and macrophages in vitro, and reduced systemic inflammation in mouse models of endotoxemia and necrotizing enterocolitis. Molecular docking of C34 to the hydrophobic internal pocket of the TLR4 co-receptor MD-2 demonstrated a tight fit, embedding the pyran ring deep inside the pocket. Strikingly, C34 inhibited LPS signaling ex-vivo in human ileum that was resected from infants with necrotizing enterocolitis. These findings identify C34 and the β-anomeric cyclohexyl analog C35 as novel leads for small molecule TLR4 inhibitors that have potential therapeutic benefit for TLR4-mediated inflammatory diseases. © 2013 Neal et al

Repeated Quantum Error Detection in a Surface Code

The realization of quantum error correction is an essential ingredient for reaching the full potential of fault-tolerant universal quantum computation. Using a range of different schemes, logical qubits can be redundantly encoded in a set of physical qubits. One such scalable approach is based on the surface code. Here we experimentally implement its smallest viable instance, capable of repeatedly detecting any single error using seven superconducting qubits, four data qubits and three ancilla qubits. Using high-fidelity ancilla-based stabilizer measurements we initialize the cardinal states of the encoded logical qubit with an average logical fidelity of 96.1%. We then repeatedly check for errors using the stabilizer readout and observe that the logical quantum state is preserved with a lifetime and coherence time longer than those of any of the constituent qubits when no errors are detected. Our demonstration of error detection with its resulting enhancement of the conditioned logical qubit coherence times in a 7-qubit surface code is an important step indicating a promising route towards the realization of quantum error correction in the surface code.Comment: 12 pages, 11 figure

A Prospective Randomized Controlled Trial of the Effects of Vitamin D Supplementation on Cardiovascular Disease Risk

Vitamin D (VitD) supplementation has been advocated for cardiovascular risk reduction; however, supporting data are sparse. The objective of this study was to determine whether VitD supplementation reduces cardiovascular risk. Subjects in this prospective, randomized, double-blind, placebo-controlled trial of post-menopausal women with serum 25-hydroxyvitamin D concentrations >10 and <60 ng/mL were randomized to Vitamin D3 2500 IU or placebo, daily for 4 months. Primary endpoints were changes in brachial artery flow-mediated vasodilation (FMD), carotid-femoral pulse wave velocity (PWV), and aortic augmentation index (AIx). The 114 subjects were mean (standard deviation) 63.9 (3.0) years old with a 25-hydroxyvitamin D level of 31.3 (10.6) ng/mL. Low VitD (<30 ng/mL) was present in 47% and was associated with higher body-mass index, systolic blood pressure, glucose, CRP, and lower FMD (all p<0.05). After 4 months, 25-hydroxyvitamin D levels increased by 15.7 (9.3) ng/mL on vitamin D3 vs. −0.2 (6.1) ng/mL on placebo (p<0.001). There were no significant differences between groups in changes in FMD (0.3 [3.4] vs. 0.3 [2.6] %, p = 0.77), PWV (0.00 [1.06] vs. 0.05 [0.92] m/s, p = 0.65), AIx (2.7 [6.3] vs. 0.9 [5.6] %, p = 0.10), or CRP (0.3 [1.9] vs. 0.3 [4.2] mg/L, p = 0.97). Multivariable models showed no significant interactions between treatment group and low VitD status (<30 ng/mL) for changes in FMD (p = 0.65), PWV (p = 0.93), AIx (p = 0.97), or CRP (p = 0.26).In conclusion, VitD supplementation did not improve endothelial function, arterial stiffness, or inflammation. These observations do not support use of VitD supplementation to reduce cardiovascular disease risk

Full Sequence and Comparative Analysis of the Plasmid pAPEC-1 of Avian Pathogenic E. coli χ7122 (O78∶K80∶H9)

(APEC), are very diverse. They cause a complex of diseases in Human, animals, and birds. Even though large plasmids are often associated with the virulence of ExPEC, their characterization is still in its infancy., are also present in the sequence of pAPEC-1. The comparison of the pAPEC-1 sequence with the two available plasmid sequences reveals more gene loss and reorganization than previously appreciated. The presence of pAPEC-1-associated genes is assessed in human ExPEC by PCR. Many patterns of association between genes are found.The pathotype typical of pAPEC-1 was present in some human strains, which indicates a horizontal transfer between strains and the zoonotic risk of APEC strains. ColV plasmids could have common virulence genes that could be acquired by transposition, without sharing genes of plasmid function

The Sound Generated by Mid-Ocean Ridge Black Smoker Hydrothermal Vents

Hydrothermal flow through seafloor black smoker vents is typically turbulent and vigorous, with speeds often exceeding 1 m/s. Although theory predicts that these flows will generate sound, the prevailing view has been that black smokers are essentially silent. Here we present the first unambiguous field recordings showing that these vents radiate significant acoustic energy. The sounds contain a broadband component and narrowband tones which are indicative of resonance. The amplitude of the broadband component shows tidal modulation which is indicative of discharge rate variations related to the mechanics of tidal loading. Vent sounds will provide researchers with new ways to study flow through sulfide structures, and may provide some local organisms with behavioral or navigational cues

Resting-State Multi-Spectrum Functional Connectivity Networks for Identification of MCI Patients

In this paper, a high-dimensional pattern classification framework, based on functional associations between brain regions during resting-state, is proposed to accurately identify MCI individuals from subjects who experience normal aging. The proposed technique employs multi-spectrum networks to characterize the complex yet subtle blood oxygenation level dependent (BOLD) signal changes caused by pathological attacks. The utilization of multi-spectrum networks in identifying MCI individuals is motivated by the inherent frequency-specific properties of BOLD spectrum. It is believed that frequency specific information extracted from different spectra may delineate the complex yet subtle variations of BOLD signals more effectively. In the proposed technique, regional mean time series of each region-of-interest (ROI) is band-pass filtered ( Hz) before it is decomposed into five frequency sub-bands. Five connectivity networks are constructed, one from each frequency sub-band. Clustering coefficient of each ROI in relation to the other ROIs are extracted as features for classification. Classification accuracy was evaluated via leave-one-out cross-validation to ensure generalization of performance. The classification accuracy obtained by this approach is 86.5%, which is an increase of at least 18.9% from the conventional full-spectrum methods. A cross-validation estimation of the generalization performance shows an area of 0.863 under the receiver operating characteristic (ROC) curve, indicating good diagnostic power. It was also found that, based on the selected features, portions of the prefrontal cortex, orbitofrontal cortex, temporal lobe, and parietal lobe regions provided the most discriminant information for classification, in line with results reported in previous studies. Analysis on individual frequency sub-bands demonstrated that different sub-bands contribute differently to classification, providing extra evidence regarding frequency-specific distribution of BOLD signals. Our MCI classification framework, which allows accurate early detection of functional brain abnormalities, makes an important positive contribution to the treatment management of potential AD patients

Analyzing the Impacts of Dams on Riparian Ecosystems: A Review of Research Strategies and Their Relevance to the Snake River Through Hells Canyon

River damming provides a dominant human impact on river environments worldwide, and while local impacts of reservoir flooding are immediate, subsequent ecological impacts downstream can be extensive. In this article, we assess seven research strategies for analyzing the impacts of dams and river flow regulation on riparian ecosystems. These include spatial comparisons of (1) upstream versus downstream reaches, (2) progressive downstream patterns, or (3) the dammed river versus an adjacent free-flowing or differently regulated river(s). Temporal comparisons consider (4) pre- versus post-dam, or (5) sequential post-dam conditions. However, spatial comparisons are complicated by the fact that dams are not randomly located, and temporal comparisons are commonly limited by sparse historic information. As a result, comparative approaches are often correlative and vulnerable to confounding factors. To complement these analyses, (6) flow or sediment modifications can be implemented to test causal associations. Finally, (7) process-based modeling represents a predictive approach incorporating hydrogeomorphic processes and their biological consequences. In a case study of Hells Canyon, the upstream versus downstream comparison is confounded by a dramatic geomorphic transition. Comparison of the multiple reaches below the dams should be useful, and the comparison of Snake River with the adjacent free-flowing Salmon River may provide the strongest spatial comparison. A pre- versus post-dam comparison would provide the most direct study approach, but pre-dam information is limited to historic reports and archival photographs. We conclude that multiple study approaches are essential to provide confident interpretations of ecological impacts downstream from dams, and propose a comprehensive study for Hells Canyon that integrates multiple research strategies

Calculation of the relative metastabilities of proteins using the CHNOSZ software package

<p>Abstract</p> <p>Background</p> <p>Proteins of various compositions are required by organisms inhabiting different environments. The energetic demands for protein formation are a function of the compositions of proteins as well as geochemical variables including temperature, pressure, oxygen fugacity and pH. The purpose of this study was to explore the dependence of metastable equilibrium states of protein systems on changes in the geochemical variables.</p> <p>Results</p> <p>A software package called CHNOSZ implementing the revised Helgeson-Kirkham-Flowers (HKF) equations of state and group additivity for ionized unfolded aqueous proteins was developed. The program can be used to calculate standard molal Gibbs energies and other thermodynamic properties of reactions and to make chemical speciation and predominance diagrams that represent the metastable equilibrium distributions of proteins. The approach takes account of the chemical affinities of reactions in open systems characterized by the chemical potentials of basis species. The thermodynamic database included with the package permits application of the software to mineral and other inorganic systems as well as systems of proteins or other biomolecules.</p> <p>Conclusion</p> <p>Metastable equilibrium activity diagrams were generated for model cell-surface proteins from archaea and bacteria adapted to growth in environments that differ in temperature and chemical conditions. The predicted metastable equilibrium distributions of the proteins can be compared with the optimal growth temperatures of the organisms and with geochemical variables. The results suggest that a thermodynamic assessment of protein metastability may be useful for integrating bio- and geochemical observations.</p