Re-analysis and meta-analysis of summary statistics from gene-environment interaction studies.

MOTIVATION: statistics from genome-wide association studies enable many valuable downstream analyses that are more efficient than individual-level data analysis while also reducing privacy concerns. As growing sample sizes enable better-powered analysis of gene-environment interactions, there is a need for gene-environment interaction-specific methods that manipulate and use summary statistics. RESULTS: We introduce two tools to facilitate such analysis, with a focus on statistical models containing multiple gene-exposure and/or gene-covariate interaction terms. REGEM (RE-analysis of GEM summary statistics) uses summary statistics from a single, multi-exposure genome-wide interaction study to derive analogous sets of summary statistics with arbitrary sets of exposures and interaction covariate adjustments. METAGEM (META-analysis of GEM summary statistics) extends current fixed-effects meta-analysis models to incorporate multiple exposures from multiple studies. We demonstrate the value and efficiency of these tools by exploring alternative methods of accounting for ancestry-related population stratification in genome-wide interaction study in the UK Biobank as well as by conducting a multi-exposure genome-wide interaction study meta-analysis in cohorts from the diabetes-focused ProDiGY consortium. These programs help to maximize the value of summary statistics from diverse and complex gene-environment interaction studies. AVAILABILITY AND IMPLEMENTATION: REGEM and METAGEM are open-source projects freely available at https://github.com/large-scale-gxe-methods/REGEM and https://github.com/large-scale-gxe-methods/METAGEM.

Sparsity-guided multiple functional connectivity patterns for classification of schizophrenia via convolutional network.

The explorations of brain functional connectivity network (FCN) using resting-state functional magnetic resonance imaging can provide crucial insights into discriminative analysis of neuropsychiatric disorders, such as schizophrenia (SZ). Pearson's correlation (PC) is widely used to construct a densely connected FCN which may overlook some complex interactions of paired regions of interest (ROIs) under confounding effect of other ROIs. Although the method of sparse representation takes into account this issue, it penalizes each edge equally, which often makes the FCN look like a random network. In this paper, we establish a new framework, called convolutional neural network with sparsity-guided multiple functional connectivity, for SZ classification. The framework consists of two components. (1) The first component constructs a sparse FCN by integrating PC and weighted sparse representation (WSR). The FCN retains the intrinsic correlation between paired ROIs, and eliminates false connection simultaneously, resulting in sparse interactions among multiple ROIs with the confounding effect regressed out. (2) In the second component, we develop a functional connectivity convolution to learn discriminative features for SZ classification from multiple FCNs by mining the joint spatial mapping of FCNs. Finally, an occlusion strategy is employed to explore the contributive regions and connections, to derive the potential biomarkers in identifying associated aberrant connectivity of SZ. The experiments on SZ identification verify the rationality and advantages of our proposed method. This framework also can be used as a diagnostic tool for other neuropsychiatric disorders.

A formula and numerical study on Ewald 1D summation.

Ewald summation is famous for its successful applications in molecular simulations for systems under 2 dimensional periodic boundary condition (2D PBC, e.g., planar interfaces) and systems under 3D PBC (e.g., bulk). However, the extension to systems under 1D PBC (like porous structures and tubes) is largely hindered by the special functions in the formula. In this work, a simple approximation of Ewald 1D sum is introduced with its error rigorously controlled. To investigate the impacts on the efficiency and accuracy by different parts, a pairwise potential is calculated for a series of screening parameters ( α ) and radial distances ( ρ ) between two point charges. A mapping between the sum of trigonometric functions in Ewald 1D method and the sum of specific vectors further reveals the different converging speeds of different Fourier parts. When choosing α = 0.2 Å-1 , it is appropriate to ignore the insignificant parts in the sum to accelerate the method.

Ru(III)-Periodate for High Performance and Selective Degradation of Aqueous Organic Pollutants: Important Role of Ru(V) and Ru(IV).

In this study, Ru(III) ions were utilized to activate periodate (PI) for oxidation of trace organic pollutants (TOPs, e.g., carbamazepine (CBZ)). The Ru(III)/PI system can significantly promote the oxidation of CBZ in a wide initial pH range (3.0-11.0) at 1 µM Ru(III), showing much higher performance than transition metal ions (i.e., Fe(II), Co(II), Zn(II), Fe(III), Cu(II), Ni(II), Mn(II), and Ce(III)) and noble metal ion (i.e., Ag(I), Pd(II), Pt(II), and Ir(III)) activated PI systems. Probe experiments, UV-vis spectra, and X-ray absorption near-edge structure (XANES) spectra confirmed high-valent Ru-oxo species (Ru(V)=O) as the dominant oxidant in the process. Because of the dominant role of Ru(V)=O, the Ru(III)/PI process exhibited a remarkable selectivity and strong anti-interference in the oxidation of TOPs in complex water matrices. The Ru(V)=O species can undertake 1-e- and 2-e- transfer reactions via the catalytic cycles of Ru(V)=O → Ru(IV) → Ru(III) and Ru(V)=O → Ru(III), respectively. The utilization efficiency of PI in the Ru(III)/PI process for the oxidation of TOPs can approach 100% under optimal conditions. PI stoichiometrically transformed into IO3- without production of undesired iodine species (e.g., HOI and I2). This study developed an efficient and environmentally benign advanced oxidation process for rapid removal of TOPs and enriched understandings on reactivity of Ru(V)=O and Ru catalytic cycles.

Highly Stable and Selective Sensing of Hydrogen Sulfide in Living Mouse Brain with NiN4 Single-Atom Catalyst-Based Galvanic Redox Potentiometry.

Hydrogen sulfide (H2S) is recognized as a gasotransmitter and multifunctional signaling molecule in the central nervous system. Despite its essential neurofunctions, the chemical dynamics of H2S during physiological and pathological processes remains poorly understood, emphasizing the significance of H2S sensor development. However, the broadly utilized electrochemical H2S sensors suffer from low stability and sensitivity loss in vivo due to sulfur poisoning-caused electrode passivation. Herein, we report a high-performance H2S sensor that combines single-atom catalyst strategy and galvanic redox potentiometry to overcome the issue. Atomically dispersed NiN4 active sites on the sensing interface promote electrochemical H2S oxidation at an extremely low potential to drive spontaneous bipolarization of a single carbon fiber. Bias-free potentiometric sensing at open-circuit condition minimizes sulfur accumulation on the electrode surface, thus significantly enhancing the stability and sensitivity. The resulting sensor displays high selectivity to H2S against physiological interferents and enables real-time accurate quantification of H2S-releasing behavior in the living mouse brain.

A Novel Multi-Agent Model for Robustness with Component Failure and Malware Propagation in Wireless Sensor Networks.

A wireless sensor network (WSN) is a group of sensors connected with a wireless communications infrastructure designed to monitor and send collected data to the primary server. The WSN is the cornerstone of the Internet of Things (IoT) and Industry 4.0. Robustness is an essential characteristic of WSN that enables reliable functionalities to end customers. However, existing approaches primarily focus on component reliability and malware propagation, while the robustness and security of cascading failures between the physical domain and the information domain are usually ignored. This paper proposes a cross-domain agent-based model to analyze the connectivity robustness of a system in the malware propagation process. The agent characteristics and transition rules are also described in detail. To verify the practicality of the model, three scenarios based on different network topologies are proposed. Finally, the robustness of the scenarios and the topologies are discussed.

Single-Atom Co-N4 Electrocatalyst Enabling Four-Electron Oxygen Reduction with Enhanced Hydrogen Peroxide Tolerance for Selective Sensing.

Electrocatalysis of the four-electron oxygen reduction reaction (ORR) provides a promising approach for energy conversion, storage, and oxygen monitoring. However, it is always accompanied by the reduction of hydrogen peroxide (H2O2) on most employed catalysts, which brings down the electrocatalytic selectivity. Here, we report a single-atom Co-N4 electrocatalyst for the four-electron ORR at an onset potential of 0.68 V (vs RHE) in neutral media while with high H2O2 tolerance, outperforming commercial Pt electrocatalysts. Electrochemical kinetic analysis confirms that the Co-N4 catalytic sites dominantly promote the direct four-electron pathway of the ORR rather than the two sequential two-electron reduction pathways with H2O2 as the intermediate. Density functional theory calculations reveal that H2O2 reduction is hampered by the weak adsorption of H2O2 on the porphyrin-like Co centers. This endows the electrocatalyst with improved resistance to current interference from H2O2, enabling highly selective O2 sensing as validated by the reliable sensing performance in vivo. Our study demonstrates the intriguing advantage of single-atom catalysts with high capacity for tailoring metal-adsorbate interactions, broadening their applications in environmental and life monitoring.

Three-site and five-site fixed-charge water models compatible with AMOEBA force field.

In a typical biomolecular simulation using Atomic Multipole Optimized Energetics for Biomolecular Applications (AMOEBA) force field, the vast majority molecules in the simulation box consist of water, and these water molecules consume the most CPU power due to the explicit mutual induction effect. To improve the computational efficiency, we here develop two new nonpolarizable water models (with flexible bonds and fixed charges) that are compatible with AMOEBA solute: the 3-site AW3C and 5-site AW5C. To derive the force-field parameters for AW3C and AW5C, we fit to six experimental liquid thermodynamic properties: liquid density, enthalpy of vaporization, dielectric constant, isobaric heat capacity, isothermal compressibility and thermal expansion coefficient, at a broad range of temperatures from 261.15 to 353.15 K under 1.0 atm pressure. We further validate our AW3C and AW5C water models by showing that they can well reproduce the radial distribution function g(r), self-diffusion constant D, and hydration free energy from the AMOEBA03 water model and the experimental observations. Furthermore, we show that our AW3C and AW5C water models can greatly accelerate (>5 times) the bulk water as well as biomolecular simulations when compared to AMOEBA water. Specifically, we demonstrate that the applications of AW3C and AW5C water models to simulate a DNA duplex lead to a threefold acceleration, and in the meanwhile well maintain the structural properties as the fully polarizable AMOEBA water. We expect that our AW3C and AW5C water models hold great promise to be widely applied to simulate complex bio-molecules using the AMOEBA force field.

Tmem30a Plays Critical Roles in Ensuring the Survival of Hematopoietic Cells and Leukemia Cells in Mice.

The fundamental structure of eukaryotic cell plasma membrane is the phospholipid bilayer, which contains four major phospholipids. These phospholipids are asymmetrically distributed between the outer and inner leaflets. P4-ATPase flippase complexes play essential roles in ensuring this asymmetry. We found that conditional deletion of Tmem30a, the ß subunit of P4-ATPase flippase complex, caused pancytopenia in mice. Tmem30a deficiency resulted in depletion of lineage-committed blood cells in the peripheral blood, spleen, and bone marrow. Ablation of Tmem30a also caused the depletion of hematopoietic stem cells (HSCs). HSC RNA sequencing results revealed that multiple biological processes and signal pathways were involved in the event, including mammalian target of rapamycin signaling, genes for HSC stemness, and genes responding to interferons. Our results also revealed that targeting Tmem30a signaling had therapeutic utility in BCR/ABL1-induced chronic myeloid leukemia.

Analytic theory of finite-size effects in supercell modeling of charged interfaces.

The Ewald3D sum with the tinfoil boundary condition (e3dtf) evaluates the electrostatic energy of a finite unit cell inside an infinitely periodic supercell. Although it has been used as a de facto standard treatment of electrostatics for simulations of extended polar or charged interfaces, the finite-size effect on simulated properties has yet to be fully understood. There is, however, an intuitive way to quantify the average effect arising from the difference between the e3dtf and Coulomb potentials on the response of mobile charges to contact surfaces with fixed charges and/or to an applied external electric field. Although any charged interface formed by mobile countercharges that compensate the fixed charges fluctuates upon a change in the acting electric field, the distance between a pair of oppositely charged interfaces is found to be nearly stationary, which allows an analytic finite-size correction to the amount of countercharges. Application of the theory to solvated electric double layers (insulator/electrolyte interfaces) predicts that the state of complete charge compensation is invariant with respect to solvent permittivities, which is confirmed by a proper analysis of simulation data in the literature.

Piezoluminescence from ferroelectric Ca3Ti2O7:Pr3+ long-persistent phosphor.

A variety of up-and-coming applications of piezoluminescence in artificial skins, structural health diagnosis, and mechano-driven lightings and displays recently have triggered an intense research effort to design and develop new piezoluminescent materials. In this work, we deduced and verified an efficient piezoluminescence in ferroelectric Ca3Ti2O7:Pr3+ long-persistent phosphor, in view of three fundamental elements forming piezoluminescence - piezoelectricity, luminescent centers and carrier traps. Under the stimulation of mechanical actions including compression and friction, Ca3Ti2O7:Pr3+ shows an intense red emission from 1D2-3H4 transition of Pr3+. On the basis of investigations on structural and optical characteristics especially photoluminescence, persistent luminescence and thermoluminescence, we finally proposed a possible piezoluminescent mechanism in Ca3Ti2O7:Pr3+. Our research is expected to expand the horizon of existing piezoluminescent materials, accelerating the development and application of new materials.

The effect of electrostatic boundaries in molecular simulations: symmetry matters.

Artifacts arise when the long-ranged electrostatic interaction is inappropriately treated in molecular simulations of electrolytes. When the usual Ewald3D sum method with the tinfoil boundary condition (e3dtf) is used for simulations of an interfacial liquid under an external electric field, a straightforward analysis of the liquid structure often suggests unphysical dielectric properties as a consequence of the inaccurate treatment of the electrostatics. In order to understand the underlying mechanism that leads to this apparent violation of thermodynamics, we now derive a new equation in the weak-field limit that, in a mean field view, accounts for the average effect arising from the difference between e3dtf and the sophisticated Ewald2D sum method (e2d). Numerical simulations of a water system in slab geometry confirm the validity of the weak-field limit equation for a series of parameter setup associated with e3dtf. Moreover, a similar procedure applied to a spherically confined water system suggests that corrections to the seemingly inappropriate treatment of the electrostatics in fact vanish. This cancellation of the boundary effect due to symmetry immediately sheds light on the long-lasting problem of the validity of the ad hoc application of e3dtf for bulk systems. In total, we argue that artifacts arising from e3dtf are often predictable and analytical corrections to the straightforward analysis might be applied to reveal consistent thermodynamic properties in liquid simulations.

On the connections and differences among three mean-field approximations: a stringent test.

This letter attempts to clarify the meaning of three closely related mean-field approximations: random phase approximation (RPA), local molecular field (LMF) approximation, and symmetry-preserving mean-field (SPMF) approximation, and their use of reliability and validity in the field of theory and simulation of liquids when the long-ranged component of the intermolecular interaction plays an important role in determining density fluctuations and correlations. The RPA in the framework of classical density functional theory (DFT) neglects the higher order correlations in the bulk and directly applies the long-ranged part of the potential to correct the pair direct correlation function of the short-ranged system while the LMF approach introduces a nonuniform mimic system under a reconstructed static external potential that accounts for the average effect arising from the long-ranged component of the interaction. Furthermore, the SPMF approximation takes the viewpoint of LMF but instead instantaneously averages the long-ranged component of the potential over the degrees of freedom in the direction with preserved symmetry. The formal connections and the particular differences of the viewpoint among the three approximations are explained and their performances in producing structural properties of liquids are stringently tested using an exactly solvable model. We demonstrate that the RPA treatment often yields uncontrolled poor results for pair distribution functions of the bulk system. On the other hand, the LMF theory produces quite reasonably structural correlations when the pair distribution in the bulk is converted to the singlet particle distribution in the nonuniform system. It turns out that the SPMF approach outperforms the other two at all densities and under extreme conditions where the long-ranged component significantly contributes to the structural correlations.

Note: A pairwise form of the Ewald sum for non-neutral systems.

Using an example of a mixed discrete-continuum representation of charges under the periodic boundary condition, we show that the exact pairwise form of the Ewald sum, which is well-defined even if the system is non-neutral, provides a natural starting point for deriving unambiguous Coulomb energies that must remove all spurious dependence on the choice of the Ewald screening factor.

Single-shot angular compounded optical coherence tomography angiography by splitting full-space B-scan modulation spectrum for flow contrast enhancement.

We proposed a single-shot spatial angular compounded optical coherence tomography angiography (AC-Angio-OCT) for blood flow contrast enhancement. By encoding incident angles in B-scan modulation frequencies and splitting the modulation spectrum in the spatial frequency domain, angle-resolved independent subangiograms were obtained and compounded to improve the flow contrast. A full space of the spatial frequency domain allows a wide modulation spectrum. To get access to the full space of the spatial frequency domain and avoid the complex-conjugate ambiguity of the modulation spectrum, a complex-valued OCT spectral interferogram was retrieved by removing one of the conjugate terms in the depth space. To validate the proposed concept, both flow phantom and live animal experiments were performed. The proposed AC-Angio-OCT offers a ∼50% decrease of misclassification errors, and an improved flow contrast and vessel connectivity, which contributes to the interpretation of OCT angiograms.

Hybrid averaging offers high-flow contrast by cost apportionment among imaging time, axial, and lateral resolution in optical coherence tomography angiography.

The current temporal, wavelength, angular, and spatial averaging approaches trade imaging time and resolution for multiple independent measurements that improve the flow contrast in optical coherence tomography angiography (OCTA). We find that these averaging approaches are equivalent in principle, offering almost the same flow contrast enhancement as the number of averages increases. Based on this finding, we propose a hybrid averaging strategy for contrast enhancement by cost apportionment. We demonstrate that, compared with any individual approach, the hybrid averaging is able to offer a desired flow contrast without severe degradation of imaging time and resolution. Making use of the extended range of a VCSEL-based swept-source OCT, an angular averaging approach by path length encoding is also demonstrated for flow contrast enhancement.

[Multi-Element Detection in Molten Steel with Laser-Induced Breakdown Spectroscopy].

On-line element content detection in iron and steel industry is one of the key techniques to ensure the quality in iron and steel metallurgy. Laser Induced Breakdown Spectroscopy (LIBS) has been applied to on-line components detection in molten steel. We have built LIBS system for components detection of molten steel in laboratory. The system consists of a Q-switched Nd∶YAG laser (repetition rate 10 Hz, wavelength 1 064 nm, pulse length 10 ns, pulse energy about 120 mJ), high frequency induction furnace (temperature 1 600 ℃), spectrometer (wavelength range 186～310 nm, spectral resolution 0.1 nm), laser focusing and spectral signal collecting system. Multi-elements were detected in molten steel with the application of deep-UV detector coating and solarization resistant fibers. According to the calibration curves of C, S, Mn and Cr, the limit of detections are 169, 15, 58.9 and 210 µg·g-1 respectively. The R-squares of calibration curves of C, S, Mn, and Cr are better than 0.96 by using appropriate analytical lines and reference lines. At the same time, through the comparison of different elements, we find the best calibration curve of different element need different delay conditions.

A novel acidic matrix protein, PfN44, stabilizes magnesium calcite to inhibit the crystallization of aragonite.

Magnesium is widely used to control calcium carbonate deposition in the shell of pearl oysters. Matrix proteins in the shell are responsible for nucleation and growth of calcium carbonate crystals. However, there is no direct evidence supporting a connection between matrix proteins and magnesium. Here, we identified a novel acidic matrix protein named PfN44 that affected aragonite formation in the shell of the pearl oyster Pinctada fucata. Using immunogold labeling assays, we found PfN44 in both the nacreous and prismatic layers. In shell repair, PfN44 was repressed, whereas other matrix proteins were up-regulated. Disturbing the function of PfN44 by RNAi led to the deposition of porous nacreous tablets with overgrowth of crystals in the nacreous layer. By in vitro circular dichroism spectra and fluorescence quenching, we found that PfN44 bound to both calcium and magnesium with a stronger affinity for magnesium. During in vitro calcium carbonate crystallization and calcification of amorphous calcium carbonate, PfN44 regulated the magnesium content of crystalline carbonate polymorphs and stabilized magnesium calcite to inhibit aragonite deposition. Taken together, our results suggested that by stabilizing magnesium calcite to inhibit aragonite deposition, PfN44 participated in P. fucata shell formation. These observations extend our understanding of the connections between matrix proteins and magnesium.

Association between single nucleotide polymorphism of vitamin D receptor gene FokI polymorphism and clinical progress of benign prostatic hyperplasia.

BACKGROUND: The aim of the study was to investigate the association between single nucleotide polymorphism (SNP) of vitamin D receptor (VDR) gene and clinical progress of benign prostatic hyperplasia (BPH) in Chinese men. METHODS: The DNA was extracted from blood of 200 BPH patients with operation (progression group) and 200 patients without operation (control group), respectively. The genotypes of VDR gene FokI SNP represented by "F/f" were identified by PCR-restriction fragment length polymorphism. The odds ratio (OR) of having progression of BPH for having the genotype were calculated. RESULTS: Our date indicated that the f alleles of the VDR gene FokI SNP associated with the progression of BPH (P = 0.009). CONCLUSION: For the first time, our study demonstrated that VDR gene FokI SNP may be associated with the risk of BPH progress.