DRESIS: the first comprehensive landscape of drug resistance information.

Widespread drug resistance has become the key issue in global healthcare. Extensive efforts have been made to reveal not only diverse diseases experiencing drug resistance, but also the six distinct types of molecular mechanisms underlying this resistance. A database that describes a comprehensive list of diseases with drug resistance (not just cancers/infections) and all types of resistance mechanisms is now urgently needed. However, no such database has been available to date. In this study, a comprehensive database describing drug resistance information named 'DRESIS' was therefore developed. It was introduced to (i) systematically provide, for the first time, all existing types of molecular mechanisms underlying drug resistance, (ii) extensively cover the widest range of diseases among all existing databases and (iii) explicitly describe the clinically/experimentally verified resistance data for the largest number of drugs. Since drug resistance has become an ever-increasing clinical issue, DRESIS is expected to have great implications for future new drug discovery and clinical treatment optimization. It is now publicly accessible without any login requirement at: https://idrblab.org/dresis/.

"One-Stone-Three-Birds" H2S-Photothermal Therapy for Enhanced Thrombolysis and Vascular Healing.

Thrombus causes a serious condition characterized by the formation of blood clots in blood vessels or heart, potentially leading to life-threatening emergencies. Photothermal therapy (PTT) serves as a treatment for thrombosis that provides noninvasive thrombus dissolution and fewer bleeding side effects. However, the high temperatures generated by PTT can exacerbate vascular inflammation and promote thrombus recurrence. In this study, a photothermal hydrogen sulfide (H2S) nanogenerator (PSA@ADT-OH) is constructed using a perylene-cored photothermal agent (PSA) coassembled with a H2S donor ADT-OH. The system PSA@ADT-OH demonstrates outstanding targeting and accumulation efficiency against blood flow shear forces. It also provides sustained H2S release at thrombus sites, contributing to antiplatelet aggregation, reactive oxygen species clearance, and vascular healing. This approach opens up new possibilities for advanced thrombus treatment.

Expression of myelin transcription factor 1 and lamin B receptor mediate neural progenitor fate transition in the zebrafish spinal cord pMN domain.

The pMN domain is a restricted domain in the ventral spinal cord, defined by the expression of the olig2 gene. Though it is known that the pMN progenitor cells can sequentially generate motor neurons and oligodendrocytes, the lineages of these progenitors are controversial and how their progeny are generated is not well understood. Using single-cell RNA sequencing, here, we identified a previously unknown heterogeneity among pMN progenitors with distinct fates and molecular signatures in zebrafish. Notably, we characterized two distinct motor neuron lineages using bioinformatic analysis. We then went on to investigate specific molecular programs that regulate neural progenitor fate transition. We validated experimentally that expression of the transcription factor myt1 (myelin transcription factor 1) and inner nuclear membrane integral proteins lbr (lamin B receptor) were critical for the development of motor neurons and neural progenitor maintenance, respectively. We anticipate that the transcriptome features and molecular programs identified in zebrafish pMN progenitors will not only provide an in-depth understanding of previous findings regarding the lineage analysis of oligodendrocyte progenitor cells and motor neurons but will also help in further understanding of the molecular programming involved in neural progenitor fate transition.

Landscape of drug-resistance mutations in kinase regulatory hotspots.

More than 48 kinase inhibitors (KIs) have been approved by Food and Drug Administration. However, drug-resistance (DR) eventually occurs, and secondary mutations have been found in the previously targeted primary-mutated cancer cells. Cancer and drug research communities recognize the importance of the kinase domain (KD) mutations for kinasopathies. So far, a systematic investigation of kinase mutations on DR hotspots has not been done yet. In this study, we systematically investigated four types of representative mutation hotspots (gatekeeper, G-loop, αC-helix and A-loop) associated with DR in 538 human protein kinases using large-scale cancer data sets (TCGA, ICGC, COSMIC and GDSC). Our results revealed 358 kinases harboring 3318 mutations that covered 702 drug resistance hotspot residues. Among them, 197 kinases had multiple genetic variants on each residue. We further computationally assessed and validated the epidermal growth factor receptor mutations on protein structure and drug-binding efficacy. This is the first study to provide a landscape view of DR-associated mutation hotspots in kinase's secondary structures, and its knowledge will help the development of effective next-generation KIs for better precision medicine.

Inhibition of Schwann cell pannexin 1 attenuates neuropathic pain through the suppression of inflammatory responses.

BACKGROUND: Neuropathic pain is still a challenge for clinical treatment as a result of the comprehensive pathogenesis. Although emerging evidence demonstrates the pivotal role of glial cells in regulating neuropathic pain, the role of Schwann cells and their underlying mechanisms still need to be uncovered. Pannexin 1 (Panx 1), an important membrane channel for the release of ATP and inflammatory cytokines, as well as its activation in central glial cells, contributes to pain development. Here, we hypothesized that Schwann cell Panx 1 participates in the regulation of neuroinflammation and contributes to neuropathic pain. METHODS: A mouse model of chronic constriction injury (CCI) in CD1 adult mice or P0-Cre transgenic mice, and in vitro cultured Schwann cells were used. Intrasciatic injection with Panx 1 blockers or the desired virus was used to knock down the expression of Panx 1. Mechanical and thermal sensitivity was assessed using Von Frey and a hot plate assay. The expression of Panx 1 was measured using qPCR, western blotting, and immunofluorescence. The production of cytokines was monitored through qPCR and enzyme-linked immunosorbent assay (ELISA). Panx1 channel activity was detected by ethidium bromide (EB) uptake. RESULTS: CCI induced persistent neuroinflammatory responses and upregulation of Panx 1 in Schwann cells. Intrasciatic injection of Panx 1 blockers, carbenoxolone (CBX), probenecid, and Panx 1 mimetic peptide (10Panx) effectively reduced mechanical and heat hyperalgesia. Probenecid treatment of CCI-induced mice significantly reduced Panx 1 expression in Schwann cells, but not in dorsal root ganglion (DRG). In addition, Panx 1 knockdown in Schwann cells with Panx 1 shRNA-AAV in P0-Cre mice significantly reduced CCI-induced neuropathic pain. To determine whether Schwann cell Panx 1 participates in the regulation of neuroinflammation and contributes to neuropathic pain, we evaluated its effect in LPS-treated Schwann cells. We found that inhibition of Panx 1 via CBX and Panx 1-siRNA effectively attenuated the production of selective cytokines, as well as its mechanism of action being dependent on both Panx 1 channel activity and its expression. CONCLUSION: In this study, we found that CCI-related neuroinflammation correlates with Panx 1 activation in Schwann cells, indicating that inhibition of Panx 1 channels in Schwann cells reduces neuropathic pain through the suppression of neuroinflammatory responses.

Highly sensitive gas sensor based on a parity-time-symmetric system.

Achieving extremely high sensitivity is an important indicator in the development of novel and stable gas concentration sensors. In this paper, we present a gas concentration sensor with parity-time symmetry for high sensitivity at low concentrations. The proposed sensor can detect toxic gases, such as benzene, bromine, and acetone, by probing the faint changing of the permittivity. Furthermore, the level of the sensitivity can be adjusted by the resistance segment, which is realized by various metallic formations. Our proposed structure provides a novel idea for the development of future gas concentration sensors, showing an exciting prospect for gas sensing technologies.

Improving quantitative analysis of spark-induced breakdown spectroscopy: Multivariate calibration of metal particles using machine learning.

We have recently developed a low-cost spark-induced breakdown spectroscopy (SIBS) instrument for in-situ analysis of toxic metal aerosol particles that we call TARTA (toxic-metal aerosol real time analyzer). In this work, we applied machine learning methods to improve the quantitative analysis of elemental mass concentrations measured by this instrument. Specifically, we applied least absolute shrinkage and selection operator (LASSO), partial least squares (PLS) regression, principal component regression (PCR), and support vector regression (SVR) to develop multivariate calibration models for 13 metals (e.g., Cr, Cu, Mn, Fe, Zn, Co, Al, K, Be, Hg, Cd, Pb, and Ni), some of which are included on the US EPA hazardous air pollutants (HAPS) list. The calibration performance, adjusted coefficient of determination (R2) and normalized root mean square error (RMSE), and limit of detection (LOD) of the proposed models were compared to those of univariate calibration models for each analyte. Our results suggest that machine learning models tend to have better prediction accuracy and lower LODs than conventional univariate calibration, of which the LASSO approach performs the best with R2 > 0.8 and LODs of 40-170 ng m-3 at a sampling time of 30 min and a flow rate of 15 l min -1. We then assessed the applicability of the LASSO model for quantifying elemental concentrations in mixtures of these metals, serving as independent validation datasets. Ultimately, the LASSO model developed in this work is a very promising machine learning approach for quantifying mass concentration of metals in aerosol particles using TARTA.

Color tuning in a compact core-shell nanocrystal based on intense and high-purity green and red photon upconversion.

To date, color-tunable photon upconversion (UC) in a single nanocrystal (NC) still suffers from cumbersome structures. Herein, we prepared a compact two-layer NC with bright and high-purity red and green UC emission upon 980 and 1530 nm excitation, respectively. The effects of trace Tm3+ doping and inert-shell coating on the UC color and intensity were discussed. In addition, the color tuning via various dual-excitation configurations and the color stability with temperature and excitation intensity were demonstrated. The proposed UC NC, featuring compact structure and high-quality color tuning, can lower the synthesis time cost and difficulty of its kind and can find wide applications in multi-channel imaging, display devices, anti-counterfeiting, and so on.

The performance of an inexpensive spark-induced breakdown spectroscopy instrument for near real-time analysis of toxic metal particles.

To meet the demand for identifying and controlling toxic air contaminants in environmental justice communities, we have recently developed a cost-effective spark-induced breakdown spectroscopy (SIBS) instrument for detecting and quantifying toxic metal air pollutants. We characterized the detection limit and linearity of this SIBS instrument by analyzing nebulized elemental standard solutions. The experimental parameters affecting SIBS performance were optimized, including the time delay to observation, the distance between electrodes, and the ablation voltage. The instrument successfully detected Cr, Cu, Mn, Fe, Zn, Co, and Ni, with limits of detection ranged from 0.05 µg m-3 to 0.81 µg m-3 at a flow rate of 15 l min-1 and a 30 min sampling duration. Similar to other investigations using ion breakdown spectroscopy, we did not observe strong emissions lines for As, Sb, Se, Hg, Pb, and Cd, which were likely due to spectral overlap, matrix effects, and the limited detection range of the optical components. Overall, SIBS is a promising technique for field measurements of toxic metals for environmental justice, industrial and urban applications.

Microconical silicon mid-IR concentrators: spectral, angular and polarization response.

It is widely discussed in the literature that a problem of reduction of thermal noise of mid-wave and long-wave infrared (MWIR and LWIR) cameras and focal plane arrays (FPAs) can be solved by using light-concentrating structures. The idea is to reduce the area and, consequently, the thermal noise of photodetectors, while still providing a good collection of photons on photodetector mesas that can help to increase the operating temperature of FPAs. It is shown that this approach can be realized using microconical Si light concentrators with (111) oriented sidewalls, which can be mass-produced by anisotropic wet etching of Si (100) wafers. The design is performed by numerical modeling in a mesoscale regime when the microcones are sufficiently large (several MWIR wavelengths) to resonantly trap photons, but still too small to apply geometrical optics or other simplified approaches. Three methods of integration Si microcone arrays with the focal plane arrays are proposed and studied: (i) inverted microcones fabricated in a Si slab, which can be heterogeneously integrated with the front illuminated FPA photodetectors made from high quantum efficiency materials to provide resonant power enhancement factors (PEF) up to 10 with angle-of-view (AOV) up to 10°; (ii) inverted microcones, which can be monolithically integrated with metal-Si Schottky barrier photodetectors to provide resonant PEFs up to 25 and AOVs up to 30° for both polarizations of incident plane waves; and iii) regular microcones, which can be monolithically integrated with near-surface photodetectors to provide a non-resonant power concentration on compact photodetectors with large AOVs. It is demonstrated that inverted microcones allow the realization of multispectral imaging with ∼100 nm bands and large AOVs for both polarizations. In contrast, the regular microcones operate similar to single-pass optical components (such as dielectric microspheres), producing sharply focused photonic nanojets.

Nanoheater-tuned whispering gallery mode lasing in liquid-filled hollow microcavities.

An all-optical tunable whispering gallery mode (WGM) lasing from the liquid-filled hollow glass microsphere (LFHGM) is proposed and experimentally verified. The LFHGM-based microlaser is prepared by injecting ${{\rm NaNdF}_4}/{\rm dye}$NaNdF4/dye co-doped liquid into the HGM, and WGM resonance is obtained under excitation of a 532 nm pulse laser. Since the high-efficiency absorption of the 793 nm continuous-wave laser by ${{\rm NaNdF}_4}$NaNdF4 nanocrystals (NCs) can result in photothermal effect-induced effective refractive index change of the microcavity, a secondary 793 nm laser is irradiated into the LFHGM to excite the ${{\rm NaNdF}_4}$NaNdF4 dispersed in the liquid core, thereby realizing a shift of resonant frequencies. The influence of the doping concentration of ${{\rm NaNdF}_4}$NaNdF4 NCs on the tuning range and the sensitivity over the power intensity range of $0{-}1.{68}\;{{\rm W/mm}^2}$0-1.68W/mm2 are investigated experimentally, obtaining maximum values of 4.95 and ${2}.{95}\;{\rm nm/}({\rm W}\;{{\rm mm}^{ - 2}})$2.95nm/(Wmm-2). The ability to generate stable lasing in a LFHGM cavity highlights the practical application of the microscale lasers in future all-optical networks.

Quantitative and sensitive detection of lipase using a liquid crystal microfiber biosensor based on the whispering-gallery mode.

In this study, we demonstrate a quantitative and sensitive strategy for monitoring the lipase concentration using a liquid crystal (LC) microfiber biosensor based on the whispering-gallery mode (WGM). An LC 4-cyano-4'-pentylbiphenyl (5CB) microfiber was doped with glycerol trioleate (GT) and used as both an optical microcavity and a sensing element. The self-assembled monolayer of a surfactant was formed at the LC/aqueous solution interface by the enzymatic reaction between lipase and GT, which resulted in the reorientation of the 5CB molecules from a planar to a homeotropic configuration. Interestingly, the structural change of the 5CB microfiber can be sensitively captured by the WGMs and quantitatively characterized by the wavelength shift. With this method, lipase with concentrations as low as 0.01 µg mL-1 in aqueous solution can be detected within 200 seconds, which is lower than the optimal value based on LC materials reported so far. In addition, our biodetection system is highly selective for lipase. We believe that the proposed biosensor has high potential for the detection of biochemical molecules.

Optical and Mass Spectrometric Measurements of the CH4-CO2 Dry Reforming Process in a Low Pressure, Very High Density, and Purely Inductive Plasma.

This paper presents a study of a CH4-CO2 plasma-reforming process carried out in a high power density (5-50 W/cm3), using toroidal transformer-coupled plasma, and operated at low pressure (0.2-0.7 Torr). Using the intermediate between a thermal and nonthermal plasma (electron density, ne ≈ 3 × 1012 cm-3 and a maximum gas temperature of ∼4000-6000 K along the center line), the low-pressure study provides a unique set of conditions to investigate reaction mechanisms, where three-body reactions can be ignored. Reactive species in the plasma were identified by optical emission spectroscopy. End products of the reforming process were measured by mass spectrometry. Quite high conversions of CO2 and CH4 were found (90%), with selectivities for CO and H2 of 80% at 300 sccm feed gas flow rate in a 0.5 Torr plasma, with a mole ratio CO2-CH4 of 1:1. A detailed reaction mechanism is presented, taking into account the combined detection of reactive intermediates in the plasma (H, O, CH, and C2) and stable product downstream.

Real-time monitoring of the enzymatic reaction of urease by using whispering gallery mode lasing.

A new strategy is reported here to monitor the enzymatic reactions in real time by using whispering gallery mode (WGM) lasing. The optical microcavity is formed via the self-assembly of an ultraviolet (UV)-treated nematic liquid crystal (LC) 4-cyano-4'-pentylbiphenyl (5CB). The single UV-treated 5CB microdroplet serves as both optical resonator and sensing reactor. The microdroplet configuration transitions induced wavelength shift in the WGM lasing spectra can be used as an indicator for the enzymatic reaction. The proposed sensor has a sub-microgram detection limit of urease (∼0.5 µg/ml), which is lower than the detection limit of currently available urease sensor based on LC materials. Our experimental results demonstrate that WGM lasing has unique advantages in the real-time monitoring of enzymatic reactions compared, for instance, with observation of the optical appearance under a polarized optical microscope.

Confined geometry and laser energy affect laser plasma propulsion.

The interaction of plasma (or shock waves) with the uniform sphere shape of polystyrene particles was investigated in this study to observe the effects of confined geometry and energy fluence on propulsion efficiency. The measurements indicate that propulsion efficiency first increases with energy fluence until reaching a maximum at 0.46 J/cm2, then decreases as energy fluency continues to increase. Compared to polystyrene particle propulsion without confined geometry, the propulsion efficiency of polystyrene particles improved due to multiple laser-induced shock wave reflections among the confined geometry internal face; the plasma propelling force also increased perpendicular to the target surface under confined geometry conditions. The results also show that the energy deposited on the plasma affects the energy distribution between the plasma and polystyrene particle. Moreover, a series of experiments was performed to roughly estimate the shock wave expansion shape through the motion direction of the polystyrene particle swarm, where the shock wave was observed to expand spherically.

Guanidine derivative polymer coated microbubble resonator for high sensitivity detection of CO2 gas concentration.

A carbon dioxide (CO2) gas sensor based on a polyhexamethylene biguanide (PHMB)-coated whispering gallery mode (WGM) microbubble resonator is proposed and verified experimentally in this work. Microbubbles were fabricated using two reverse arc discharges focused on microcapillaries. The inner wall of the microbubble was coated with a layer of PHMB using a filling and sintering process. A significant WGM resonance was observed by coupling with a tapered fiber. The experimental results show that as the concentration of carbon dioxide increases, a blue shift appears in the spectrum. Addition, a high sensitivity (0.46 pm /ppm) and a good linear relationship were obtained in the measurement range of 200-700 ppm with a detection limit of 50 ppm. The sensor features include high sensitivity, simple structure, easy manufacture, and low cost.

Highly efficient upconversion luminescence of Er heavily doped nanocrystals through 1530 nm excitation.

Improving luminescence efficiency is of vital importance for applications of rare-earth-doped upconversion materials. Herein, we present highly efficient upconversion nanocrystal, which is brighter than the state-of-the-art Er3+/Yb3+ co-doped core-shell material, through Er3+ heavily doping and 1530 nm excitation. Moreover, upconversion characteristics and mechanisms of Er3+ heavily doped core nanocrystals and their core-shell counterparts are investigated carefully.

Vector optical fiber magnetometer based on capillaries filled with magnetic fluid.

A novel and practical magnetic field sensor based on optical fiber optics is proposed in our work. We first demonstrate magnetic sensing with the structure that single-mode optical fibers are fused with capillaries in parallel in an experiment. We clearly show the aggregation and arrangement variation with the magnetic field of magnetic nanoparticles in capillaries. Based on the tunable effective refractive index of optical modes in a waveguide structure of a sensor, the optical properties and sensing mechanism in the sensing structure were simulated and further analyzed. We achieved the detection of a space magnetic field, including intensity and its direction. We obtained that the sensitivity of a sensor is 112 pm/mT, presenting good performance in the same kind of optical fiber magnetic field sensor.

Shrinkage Clustering: a fast and size-constrained clustering algorithm for biomedical applications.

BACKGROUND: Many common clustering algorithms require a two-step process that limits their efficiency. The algorithms need to be performed repetitively and need to be implemented together with a model selection criterion. These two steps are needed in order to determine both the number of clusters present in the data and the corresponding cluster memberships. As biomedical datasets increase in size and prevalence, there is a growing need for new methods that are more convenient to implement and are more computationally efficient. In addition, it is often essential to obtain clusters of sufficient sample size to make the clustering result meaningful and interpretable for subsequent analysis. RESULTS: We introduce Shrinkage Clustering, a novel clustering algorithm based on matrix factorization that simultaneously finds the optimal number of clusters while partitioning the data. We report its performances across multiple simulated and actual datasets, and demonstrate its strength in accuracy and speed applied to subtyping cancer and brain tissues. In addition, the algorithm offers a straightforward solution to clustering with cluster size constraints. CONCLUSIONS: Given its ease of implementation, computing efficiency and extensible structure, Shrinkage Clustering can be applied broadly to solve biomedical clustering tasks especially when dealing with large datasets.

Concentration dependent optical transition probabilities in ultra-small upconversion nanocrystals.

Transition probability is of vital importance for luminescence process, whereas the effects of doping concentration have not been explored in the Er3+:NaGdF4. In this work, we investigate the radiative transition probabilities of Er3+ highly doped NaGdF4 sub 10 nm nanocrystals using J-O theory. It is found that the transition probabilities vary with changing Er3+ concentration, especially altering the ratio of Er3+ 2H11/2 to 4S3/2 level, which is highly useful for optical thermometers as they are thermally coupled. To validate the concentration dependent transition probabilities, significant enhancements of upconversion luminescence are achieved by epitaxial growth of the inert shell, and thermal sensing behaviors are investigated using the improved samples.