Phylobook: a tool for display, clade annotation and extraction of sequences from molecular phylogenies.

As the volume of sequence data from variable pathogens increases, means of analyzing, annotating and extracting specific taxa for study becomes more difficult. To meet these challenges for datasets with hundreds to thousands of taxa, 'Phylobook' was developed. Starting with a sequence alignment file, Phylobook generates and displays phylogenetic trees adjacent to highlighter plots showing the position of mutations, and allows the user to identify lineages and recombinants, annotate and export selected subsets of sequences for downstream analysis. Accurate lineage assignment, which is difficult to automate, is aided using annotations created by different clustering methods. Phylobook provides web-based display combined with automated clustering and manual editing to allow for expert assessment and correction of lineage assignments and extraction for downstream analysis.

Optimized SMRT-UMI protocol produces highly accurate sequence datasets from diverse populations-Application to HIV-1 quasispecies.

Pathogen diversity resulting in quasispecies can enable persistence and adaptation to host defenses and therapies. However, accurate quasispecies characterization can be impeded by errors introduced during sample handling and sequencing, which can require extensive optimizations to overcome. We present complete laboratory and bioinformatics workflows to overcome many of these hurdles. The Pacific Biosciences single molecule real-time platform was used to sequence polymerase-chain reaction (PCR) amplicons derived from cDNA templates tagged with unique molecular identifiers (SMRT-UMI). Optimized laboratory protocols were developed through extensive testing of different sample preparation conditions to minimize between-template recombination during PCR. The use of UMI allowed accurate template quantitation as well as removal of point mutations introduced during PCR and sequencing to produce a highly accurate consensus sequence from each template. Production of highly accurate sequences from the large datasets produced from SMRT-UMI sequencing is facilitated by a novel bioinformatic pipeline, Probabilistic Offspring Resolver for Primer IDs (PORPIDpipeline). PORPIDpipeline automatically filters and parses circular consensus reads by sample, identifies and discards reads with UMIs likely created from PCR and sequencing errors, generates consensus sequences, checks for contamination within the dataset, and removes any sequence with evidence of PCR recombination, heteroduplex formation, or early cycle PCR errors. The optimized SMRT-UMI sequencing and PORPIDpipeline methods presented here represent a highly adaptable and established starting point for accurate sequencing of diverse pathogens. These methods are illustrated through characterization of human immunodeficiency virus quasispecies in a virus transmitter-recipient pair of individuals.

Unravelling the Photoelectrochemical Water Splitting of Nanometer-Thick Carbon Nitride Layer.

Matching the thickness of the graphitic carbon nitride (CN) nanolayer with the charge diffusion length is expected to compensate for the poor intrinsic conductivity and charge recombination in CN for photoelectrochemical cells (PEC). Herein, the compact CN nanolayer with tunable thickness is in situ coated on carbon fibers. The compact packing along with good contact with the substrate improves the electron transport and alleviates the charge recombination. The PEC investigation shows CN nanolayer of 93 nm-thick yields an optimum photocurrent of 116 µA cm-2 at 1.23 V versus RHE, comparable to most micrometer-thick CN layers, with a low onset potential of 0.2 V in 1 m KOH under 1 sun illumination. This optimum performance suggests the electron diffusion length matches with the thickness of the CN nanolayer. Further deposition of NiFe-layered double hydroxide enhanced the surface water oxidation kinetics, delivering an improved photocurrent of 210 µA cm-2 with IPCE of 12.8% at 400 nm. The CN nanolayer also shows extended potential in PEC organic synthesis. This work experimentally reveals the PEC behavior of the nanometer-thick CN layer, providing new insights into CN in the application of energy and environment-related fields.

Development and Validation of a Genotypic Assay to Quantify CXCR4- and CCR5-Tropic Human Immunodeficiency Virus Type-1 (HIV-1) Populations and a Comparison to Trofile®.

HIV-1 typically infects cells via the CD4 receptor and CCR5 or CXCR4 co-receptors. Maraviroc is a CCR5-specific viral entry inhibitor; knowledge of viral co-receptor specificity is important prior to usage. We developed and validated an economical V3-env Illumina-based assay to detect and quantify the frequency of viruses utilizing each co-receptor. Plasma from 54 HIV+ participants (subtype B) was tested. The viral template cDNA was generated from plasma RNA with unique molecular identifiers (UMIs). The sequences were aligned and collapsed by the UMIs with a custom bioinformatics pipeline. Co-receptor usage, determined by codon analysis and online phenotype predictors PSSM and Geno2pheno, were compared to existing Trofile® data. The cost of V3-UMI was tallied. The sequences interpreted by Geno2pheno using the most conservative cut-off, a 2% false-positive-rate (FPR), predicted CXCR4 usage with the greatest sensitivity (76%) and specificity (100%); PSSM and codon analysis had similar sensitivity and lower specificity. Discordant Trofile® and genotypic results were more common when participants had specimens from different dates analyzed by either assay. V3-UMI reagents cost USD$62/specimen. A batch of ≤20 specimens required 5 h of technical time across 1.5 days. V3-UMI predicts HIV tropism at a sensitivity and specificity similar to those of Trofile®, is relatively inexpensive, and could be performed by most central laboratories. The adoption of V3-UMI could expand HIV drug therapeutic options in lower-resource settings that currently do not have access to phenotypic HIV tropism testing.

Antiproliferative piperidine alkaloids from the leaves of Alocasia macrorrhiza.

Seventeen piperidine alkaloids, including 15 previously undescribed 2-substituted-6-(9-phenylnonyl)-piperidine-3,4-diol alkaloids and a previously undescribed 2-substituted-6-(9-phenylnonyl)-piperidine-3-ol alkaloid, were isolated from the leaves of Alocasia macrorrhiza (L.) Schott. Their planar structures and configurations were elucidated based on HR-ESI-MS, 1D and 2D NMR, Snatzke's method, modified Mosher method, single-crystal X-ray crystallography, as well as quantum chemical calculation. It was found that ΔδH5b-H5a can be used to elucidate the relative configuration of 2,3,4,6-tetrasubstituted piperidine, by analyzing the NMR data of 2-substituted-6-(9-phenylnonyl)-piperidine-3,4-diol. Antiproliferative activity was evaluated for all of the alkaloids, and compounds 6-8 showed considerable inhibitory activity against K562 cell line, with the IC50 values of 17.24 ± 1.62, 19.31 ± 0.9 and 18.77 ± 1.09µM, respectively. Furthermore, compounds 6 and 7 exerted an antiproliferative effect by inducing apoptosis.

A Spiking Artificial Vision Architecture Based on Fully Emulating the Human Vision.

Intelligent vision necessitates the deployment of detectors that are always-on and low-power, mirroring the continuous and uninterrupted responsiveness characteristic of human vision. Nonetheless, contemporary artificial vision systems attain this goal by the continuous processing of massive image frames and executing intricate algorithms, thereby expending substantial computational power and energy. In contrast, biological data processing, based on event-triggered spiking, has higher efficiency and lower energy consumption. Here, this work proposes an artificial vision architecture consisting of spiking photodetectors and artificial synapses, closely mirroring the intricacies of the human visual system. Distinct from previously reported techniques, the photodetector is self-powered and event-triggered, outputting light-modulated spiking signals directly, thereby fulfilling the imperative for always-on with low-power consumption. With the spiking signals processing through the integrated synapse units, recognition of graphics, gestures, and human action has been implemented, illustrating the potent image processing capabilities inherent within this architecture. The results prove the 90% accuracy rate in human action recognition within a mere five epochs utilizing a rudimentary artificial neural network. This novel architecture, grounded in spiking photodetectors, offers a viable alternative to the extant models of always-on low-power artificial vision system.

Prevention efficacy of the broadly neutralizing antibody VRC01 depends on HIV-1 envelope sequence features.

In the Antibody Mediated Prevention (AMP) trials (HVTN 704/HPTN 085 and HVTN 703/HPTN 081), prevention efficacy (PE) of the monoclonal broadly neutralizing antibody (bnAb) VRC01 (vs. placebo) against HIV-1 acquisition diagnosis varied according to the HIV-1 Envelope (Env) neutralization sensitivity to VRC01, as measured by 80% inhibitory concentration (IC80). Here, we performed a genotypic sieve analysis, a complementary approach to gaining insight into correlates of protection that assesses how PE varies with HIV-1 sequence features. We analyzed HIV-1 Env amino acid (AA) sequences from the earliest available HIV-1 RNA-positive plasma samples from AMP participants diagnosed with HIV-1 and identified Env sequence features that associated with PE. The strongest Env AA sequence correlate in both trials was VRC01 epitope distance that quantifies the divergence of the VRC01 epitope in an acquired HIV-1 isolate from the VRC01 epitope of reference HIV-1 strains that were most sensitive to VRC01-mediated neutralization. In HVTN 704/HPTN 085, the Env sequence-based predicted probability that VRC01 IC80 against the acquired isolate exceeded 1 µg/mL also significantly associated with PE. In HVTN 703/HPTN 081, a physicochemical-weighted Hamming distance across 50 VRC01 binding-associated Env AA positions of the acquired isolate from the most VRC01-sensitive HIV-1 strain significantly associated with PE. These results suggest that incorporating mutation scoring by BLOSUM62 and weighting by the strength of interactions at AA positions in the epitope:VRC01 interface can optimize performance of an Env sequence-based biomarker of VRC01 prevention efficacy. Future work could determine whether these results extend to other bnAbs and bnAb combinations.

Mid-Infrared Bipolar and Unipolar Linear Polarization Detections in Nb2 GeTe4 /MoS2 Heterostructures.

Detecting and distinguishing light polarization states, one of the most basic elements of optical fields, have significant importance in both scientific studies and industry applications. Artificially fabricated structures, e.g., metasurfaces with anisotropic absorptions, have shown the capabilities of detecting polarization light and controlling. However, their operations mainly rely on resonant absorptions based on structural designs that are usually narrow bands. Here, a mid-infrared (MIR) broadband polarization photodetector with high PRs and wavelength-dependent polarities using a 2D anisotropic/isotropic Nb2 GeTe4 /MoS2 van der Waals (vdWs) heterostructure is demonstrated. It is shown that the photodetector exhibits high PRs of 48 and 34 at 4.6  and 11.0 µm wavelengths, respectively, and even a negative PR of -3.38 for 3.7 µm under the zero bias condition at room temperature. Such interesting results can be attributed to the superimposed effects of a photovoltaic (PV) mechanism in the Nb2 GeTe4 /MoS2 hetero-junction region and a bolometric mechanism in the MoS2 layer. Furthermore, the photodetector demonstrates its effectiveness in bipolar and unipolar polarization encoding communications and polarization imaging enabled by its unique and high PRs.

An all-two-dimensional Fe-FET retinomorphic sensor based on the novel gate dielectric In2Se3-xOx.

Two-dimensional (2D) ferroelectric field-effect transistors (Fe-FETs) have attracted extensive interest as a competitive platform for implementing future-generation functional electronics, including digital memory and brain-inspired computing circuits. In 2D Fe-FETs, the 2D ferroelectric materials are more suitable as gate dielectric materials compared to 3D ferroelectric materials. However, the current 2D ferroelectric materials (represented by α-In2Se3) need to be integrated with other 3D gate dielectric layers because of their high conductivity as a ferroelectric semiconductor. This 2D/3D hybrid structure can lead to compatibility problems in practical devices. In this study, a new 2D gate dielectric material that is compatible with the complementary metal-oxide semiconductor process was found by using oxygen plasma treatment. The 2D gate dielectric material obtained shows excellent performance, with an equivalent oxide thickness of less than 0.15 nm, and excellent insulation, with a leakage current of less than 2 × 10-5 A cm-2 (under a 1 V gate voltage). Based on this dielectric layer and the α-In2Se3 ferroelectric gate material, we fabricated an all-2D Fe-FET high-performance photodetector with a high on/off ratio (∼105) and detectivity (>1013 Jones). Moreover, the photoelectric device integrates perception, memory and computing characteristics, indicating that it can be applied to an artificial neural network for visual recognition.

Neutralization profiles of HIV-1 viruses from the VRC01 Antibody Mediated Prevention (AMP) trials.

The VRC01 Antibody Mediated Prevention (AMP) efficacy trials conducted between 2016 and 2020 showed for the first time that passively administered broadly neutralizing antibodies (bnAbs) could prevent HIV-1 acquisition against bnAb-sensitive viruses. HIV-1 viruses isolated from AMP participants who acquired infection during the study in the sub-Saharan African (HVTN 703/HPTN 081) and the Americas/European (HVTN 704/HPTN 085) trials represent a panel of currently circulating strains of HIV-1 and offer a unique opportunity to investigate the sensitivity of the virus to broadly neutralizing antibodies (bnAbs) being considered for clinical development. Pseudoviruses were constructed using envelope sequences from 218 individuals. The majority of viruses identified were clade B and C; with clades A, D, F and G and recombinants AC and BF detected at lower frequencies. We tested eight bnAbs in clinical development (VRC01, VRC07-523LS, 3BNC117, CAP256.25, PGDM1400, PGT121, 10-1074 and 10E8v4) for neutralization against all AMP placebo viruses (n = 76). Compared to older clade C viruses (1998-2010), the HVTN703/HPTN081 clade C viruses showed increased resistance to VRC07-523LS and CAP256.25. At a concentration of 1µg/ml (IC80), predictive modeling identified the triple combination of V3/V2-glycan/CD4bs-targeting bnAbs (10-1074/PGDM1400/VRC07-523LS) as the best against clade C viruses and a combination of MPER/V3/CD4bs-targeting bnAbs (10E8v4/10-1074/VRC07-523LS) as the best against clade B viruses, due to low coverage of V2-glycan directed bnAbs against clade B viruses. Overall, the AMP placebo viruses represent a valuable resource for defining the sensitivity of contemporaneous circulating viral strains to bnAbs and highlight the need to update reference panels regularly. Our data also suggests that combining bnAbs in passive immunization trials would improve coverage of global viruses.

A two-dimensional mid-infrared optoelectronic retina enabling simultaneous perception and encoding.

Infrared machine vision system for object perception and recognition is becoming increasingly important in the Internet of Things era. However, the current system suffers from bulkiness and inefficiency as compared to the human retina with the intelligent and compact neural architecture. Here, we present a retina-inspired mid-infrared (MIR) optoelectronic device based on a two-dimensional (2D) heterostructure for simultaneous data perception and encoding. A single device can perceive the illumination intensity of a MIR stimulus signal, while encoding the intensity into a spike train based on a rate encoding algorithm for subsequent neuromorphic computing with the assistance of an all-optical excitation mechanism, a stochastic near-infrared (NIR) sampling terminal. The device features wide dynamic working range, high encoding precision, and flexible adaption ability to the MIR intensity. Moreover, an inference accuracy more than 96% to MIR MNIST data set encoded by the device is achieved using a trained spiking neural network (SNN).

Optimized SMRT-UMI protocol produces highly accurate sequence datasets from diverse populations - application to HIV-1 quasispecies.

Pathogen diversity resulting in quasispecies can enable persistence and adaptation to host defenses and therapies. However, accurate quasispecies characterization can be impeded by errors introduced during sample handling and sequencing which can require extensive optimizations to overcome. We present complete laboratory and bioinformatics workflows to overcome many of these hurdles. The Pacific Biosciences single molecule real-time platform was used to sequence PCR amplicons derived from cDNA templates tagged with universal molecular identifiers (SMRT-UMI). Optimized laboratory protocols were developed through extensive testing of different sample preparation conditions to minimize between-template recombination during PCR and the use of UMI allowed accurate template quantitation as well as removal of point mutations introduced during PCR and sequencing to produce a highly accurate consensus sequence from each template. Handling of the large datasets produced from SMRT-UMI sequencing was facilitated by a novel bioinformatic pipeline, Probabilistic Offspring Resolver for Primer IDs (PORPIDpipeline), that automatically filters and parses reads by sample, identifies and discards reads with UMIs likely created from PCR and sequencing errors, generates consensus sequences, checks for contamination within the dataset, and removes any sequence with evidence of PCR recombination or early cycle PCR errors, resulting in highly accurate sequence datasets. The optimized SMRT-UMI sequencing method presented here represents a highly adaptable and established starting point for accurate sequencing of diverse pathogens. These methods are illustrated through characterization of human immunodeficiency virus (HIV) quasispecies.

Human-Level Control Through Directly Trained Deep Spiking Q-Networks.

As the third-generation neural networks, spiking neural networks (SNNs) have great potential on neuromorphic hardware because of their high energy efficiency. However, deep spiking reinforcement learning (DSRL), that is, the reinforcement learning (RL) based on SNNs, is still in its preliminary stage due to the binary output and the nondifferentiable property of the spiking function. To address these issues, we propose a deep spiking Q -network (DSQN) in this article. Specifically, we propose a directly trained DSRL architecture based on the leaky integrate-and-fire (LIF) neurons and deep Q -network (DQN). Then, we adapt a direct spiking learning algorithm for the DSQN. We further demonstrate the advantages of using LIF neurons in DSQN theoretically. Comprehensive experiments have been conducted on 17 top-performing Atari games to compare our method with the state-of-the-art conversion method. The experimental results demonstrate the superiority of our method in terms of performance, stability, generalization and energy efficiency. To the best of our knowledge, our work is the first one to achieve state-of-the-art performance on multiple Atari games with the directly trained SNN.

Anti-Corrosion Reinforcements Using Coating Technologies-A Review.

Coated reinforcements are expected to improve the performance of reinforced concrete in aggressive environments, but different kinds of coated reinforcements can express a variety of properties, which can confuse researchers and engineers. This paper reviews the manufacture, corrosion mechanisms, behaviors, and applications of popular or promising coated reinforcements, incorporating galvanized reinforcements (GRs), epoxy coated reinforcements (ECRs), stainless cladding reinforcements (SCRs), and steel-fiber reinforced polymer composite bars (SFCBs). In terms of manufacture, GRs and ECRs should focus on minimizing the negative effect of manufacture on performance, while SCRs and SFCBs should reduce the cost and increase the production capacity. Behaviors of GRs and ECRs are primarily determined by the steel substrate, but the behaviors of SCRs and SFCBs are primarily affected by the coat and core, and their interaction. The corrosion mechanism of GRs and SCRs is about oxidation, while that of SFCBs is about hydrolysis. ECRs are usually corroded under film, which can be a cause of premature failure. Corrosion embrittles SCRs, as well as bare bars, but corrosion of SFCBs usually causes a reduction in maximum strength. The investigation of the corrosion behaviors of GRs and ECRs focuses on bond strength. GRs have controversial performance. ECRs have been proven to have drawbacks regarding bond strength. The use of anti-corrosion reinforcement is uneven in regions, which may correlate with the development of technology and the economy.

Low-frequency pre-treatment HIV drug resistance: effects on 2-year outcome of first-line efavirenz-based antiretroviral therapy.

OBJECTIVES: Assess the impact of pre-treatment high-frequency and low-frequency drug-resistant HIV variants on long-term outcomes of first-line efavirenz-based antiretroviral therapy (ART). DESIGN: Prospective observational study. METHODS: Participants' pre-treatment plasma RNA had two sections of HIV pol encoding reverse transcriptase sequenced (Illumina, MiSeq) using unique molecular identifiers to detect wild-type (pre-treatment drug-resistant variants less than 1% of viral quasispecies), low-frequency (1-9%) or high-frequency drug-resistant variants (10-100%). Associations between pre-treatment drug resistance and virologic outcomes over 24 months of efavirenz-based ART were assessed for the number and frequency of mutations by drug class and other resistance parameters. RESULTS: Virologic failure was detected in 30 of 352 (9%) and pre-treatment drug-resistant variants were detected in the viral quasispecies of 31 of 352 (9%) participants prescribed efavirenz-based ART. Survival analyses revealed statistically significant associations between pre-treatment drug resistance at low (P < 0.0001) and high (P < 0.001) frequencies, at oligonucleotide ligation assay (OLA) (P < 0.00001) and non-OLA (P < 0.01) codons, to a single-antiretroviral class (P < 0.00001), and a shorter time to virologic failure of efavirenz-based ART. Regression analyses detected independent effects across resistance categories, including both low-frequency (P < 0.01) and high-frequency (P < 0.001) drug-resistant variants. CONCLUSION: We observed that pre-treatment HIV drug resistance detected at low frequencies increased the risk of virologic failure over 24 months of efavirenz-based ART, but that most failures, regardless of drug-resistant variants' frequencies, were detected within a year of ART initiation. These observations suggest that when efavirenz-based ART is prescribed, screening for pre-treatment drug resistance by an assay capable of detecting low-frequency variants, including OLA, may guide clinicians to prescribe more effective ART.

Electrically tunable two-dimensional heterojunctions for miniaturized near-infrared spectrometers.

Miniaturized spectrometers are of considerable interest for their portability. Most designs to date employ a photodetector array with distinct spectral responses or require elaborated integration of micro & nano optic modules, typically with a centimeter-scale footprint. Here, we report a design of a micron-sized near-infrared ultra-miniaturized spectrometer based on two-dimensional van der Waals heterostructure (2D-vdWH). By introducing heavy metal atoms with delocalized electronic orbitals between 2D-vdWHs, we greatly enhance the interlayer coupling and realize electrically tunable infrared photoresponse (1.15 to 1.47 µm). Combining the gate-tunable photoresponse and regression algorithm, we achieve spectral reconstruction and spectral imaging in a device with an active footprint < 10 µm. Considering the ultra-small footprint and simple fabrication process, the 2D-vdWHs with designable bandgap energy and enhanced photoresponse offer an attractive solution for on-chip infrared spectroscopy.

Switchable Unipolar-Barrier Van der Waals Heterostructures with Natural Anisotropy for Full Linear Polarimetry Detection.

Polarization-resolved photodetection in a compact footprint is of great interest for ultraminiaturized polarimeters to be used in a wide range of applications. However, probing the states of polarization (SOP) in materials with natural anisotropy are usually weak, limited by the material's natural dichroism or diattenuation. Here, a twisted unipolar-barrier van der Waals heterostructure (vdWH) to construct a bias-switchable polarization detection for retrieval of full SOP (from 0 to 180°) for linear polarized incident light is reported. As a demonstration example, this study realizes the concept in a b-AsP/WS2 /b-AsP vdWH relying on the natural anisotropic properties of the materials without using additional plasmonic/metasurface nanostructures to realize linear polarimetry in the mid-infrared range. Polarimetric imaging is further demonstrated with the developed linear polarimetry by directly displaying the Jones-vector-described SOP distribution of certain target object. This method, with the capabilities of detecting full linear SOP, is promising for the next-generation on-chip miniaturized polarimeters.

Limiting Factors of Detectivity in Near-Infrared Colloidal Quantum Dot Photodetectors.

Lead sulfide colloidal quantum dots (PbS CQDs) have shown great potential in photodetectors owing to their promising optical properties, especially their strong and tunable absorption. However, the limitation of the specific detectivity (D*) in CQD near-infrared (NIR) photodetectors remains unknown due to the ambiguous noise analysis. Therefore, a clear understanding of the noise current is critically demanded. Here, we elucidate that the noise current is the predominant factor limiting D*, and the noise is highly dependent on the trap densities in halide-passivated PbS films and the carriers injected from the Schottky contact (EDT-passivated PbS films/metal). It is found that the thickness of CQDs is proportional to their interface trap density, while it is inversely proportional to their minimal bulk trap density. A balance point can be reached at a certain thickness (136 nm) to minimize the trap density, giving rise to the improvement of D*. Utilizing thicker PbS-EDT films broadens the width of the tunneling barrier and thereby reduces the carrier injection, contributing to a further enhancement of D*. The limiting factors of D* determined in this work not only explain the physical mechanism of the influence on detection sensitivity but also give guidance to the design of high-performance CQD photodetectors.

Colloidal Systems in Concentrated Electrolyte Solutions Exhibit Re-entrant Long-Range Electrostatic Interactions due to Underscreening.

Surface force measurements have revealed that at very high electrolyte concentrations as well as in neat and diluted ionic liquids and deep eutectic solvents, the range of electrostatic interactions is far greater than the Debye length. Here, we explore the consequences of this underscreening for soft-matter and colloidal systems by investigating the stability of nanoparticle dispersions, the self-assembly of ionic surfactants, and the thickness of soap films. In each case, we find clear evidence of re-entrant properties due to underscreening at high salt concentrations. Our results show that underscreening in concentrated electrolytes is a general phenomenon and is not dependent on confinement by macroscopic surfaces. The stability of systems at very high salinity due to underscreening may be beneficially applied to processes that currently use low-salinity water.