Miracle-dz/UniFAR-FTUs huggingface dataset:
Comparative Analysis on Single- and Multiherb Strategies in Coronary Artery Atherosclerosis Therapy

Herbal medicine unswervingly serves human health by modernizing preparation and administration. Coronary artery atherosclerosis is a serious threat to human health and survival all over the world. Following experimental and clinical evidence, we collected four herbal treatments containing herbal strategy I (San Qi), II (Injectio Salvia Miltiorrhizae), III (Danhong injection), and IV (Taoren Honghua Jian granule) against coronary artery disease. In order to analyze their similarities and differences in controlling coronary artery atherosclerosis, we investigated each herb of four strategies and revealed that the number of active components and molecule targets is increasing with the herb category of herbal strategy. Nitric oxide-associated carbonate dehydratase activity and nitrogen metabolism are tacitly enriched by target corresponding genes with statistical significance in four strategies. The herbal strategy with multiherb not merely possesses more amounts and interactions of target proteins than the strategy with single-herb but also enlarges interaction partners of target proteins like PTPN11 and STAT3 in strategy II, III, and IV. Whereas single-herb also involves regulating network core proteins in consistent with compatibility, such as SRC and PIK3R1 that are mostly targeted by strategy I, III, and IV. Comparing the targets of the herbal strategies and three existing drugs (atenolol, pravastatin and propranolol) and the symbols of coronary artery atherosclerosis, we discovered that MAOA, HTR1A, and ABCG2 are overlapping in the three groups. Hence, our work enables people to better understand the connections and distinctions of single- and multiherb on the healing of coronary artery atherosclerosis.
Modelling sudden cardiac death risks factors in patients with coronavirus disease of 2019: the hydroxychloroquine and azithromycin case

Abstract Aims Coronavirus disease of 2019 (COVID-19) has rapidly become a worldwide pandemic. Many clinical trials have been initiated to fight the disease. Among those, hydroxychloroquine and azithromycin had initially been suggested to improve clinical outcomes. Despite any demonstrated beneficial effects, they are still in use in some countries but have been reported to prolong the QT interval and induce life-threatening arrhythmia. Since a significant proportion of the world population may be treated with such COVID-19 therapies, evaluation of the arrhythmogenic risk of any candidate drug is needed. Methods and results Using the O'Hara-Rudy computer model of human ventricular wedge, we evaluate the arrhythmogenic potential of clinical factors that can further alter repolarization in COVID-19 patients in addition to hydroxychloroquine (HCQ) and azithromycin (AZM) such as tachycardia, hypokalaemia, and subclinical to mild long QT syndrome. Hydroxychloroquine and AZM drugs have little impact on QT duration and do not induce any substrate prone to arrhythmia in COVID-19 patients with normal cardiac repolarization reserve. Nevertheless, in every tested condition in which this reserve is reduced, the model predicts larger electrocardiogram impairments, as with dofetilide. In subclinical conditions, the model suggests that mexiletine limits the deleterious effects of AZM and HCQ. Conclusion By studying the HCQ and AZM co-administration case, we show that the easy-to-use O'Hara-Rudy model can be applied to assess the QT-prolongation potential of off-label drugs, beyond HCQ and AZM, in different conditions representative of COVID-19 patients and to evaluate the potential impact of additional drug used to limit the arrhythmogenic risk.
Encoding of Partially Occluded and Occluding Objects in Primate Inferior Temporal Cortex

Object segmentation—the process of parsing visual scenes—is essential for object recognition and scene understanding. We investigated how responses of neurons in macaque inferior temporal (IT) cortex contribute to object segmentation under partial occlusion. Specifically, we asked whether IT responses to occluding and occluded objects are bound together as in the visual image or linearly separable reflecting their segmentation. We recorded the activity of 121 IT neurons while two male animals performed a shape discrimination task under partial occlusion. We found that for a majority (60%) of neurons, responses were enhanced by partial occlusion, but they were only weakly shape selective for the discriminanda at all levels of occlusion. Enhancement of IT responses in these neurons depended largely on the area of occlusion but only minimally on the color and shape of the occluding dots. In contrast to the above group of neurons, a sizable minority responded best to the unoccluded stimulus and showed strong selectivity for the shape of the discriminanda. In these neurons, response magnitude and shape selectivity declined with increasing levels of occlusion. Simulations revealed that the response characteristics of both classes of neurons were consistent with a model in which the responses to the occluded shape and the occluders are weighted separately and linearly combined. Overall, our results support the hypothesis that information about occluded and occluding stimuli are linearly separable and easily decodable from IT responses and that IT neurons encode a segmented representation of the visual scene. SIGNIFICANCE STATEMENT Recognizing partially occluded objects can be challenging, yet the primate visual system achieves it rapidly and effortlessly. For successful recognition in the face of occlusion, segmentation of the occluded and occluding objects is a critical first step. Using a combination of experimental data and simulations, here we demonstrate that responses of neurons in macaque IT cortex, the highest stage of the form processing pathway, reflect occluded and occluding stimuli as segmented components and are not bound together as they appear in the visual image. These results support the idea that segmentation and perception of occluded and occluding stimuli are directly mirrored in the responses of neurons in the highest form processing stages.
Combined Action of Guard Cell Plasma Membrane Rapid- and Slow-Type Anion Channels in Stomatal Regulation.

Initiation of stomatal closure by various stimuli requires activation of guard cell plasma membrane anion channels, which are defined as rapid (R)- and slow (S)-type. The single-gene loss-of-function mutants of these proteins are well characterized. However, the impact of suppressing both the S- and R-type channels has not been studied. Here, by generating and studying double and triple Arabidopsis thaliana mutants of SLOW ANION CHANNEL1 (SLAC1), SLAC1 HOMOLOG3 (SLAH3) and ALUMINUM-ACTIVATED MALATE TRANSPORTER 12 (ALMT12)/QUICK-ACTIVATING ANION CHANNEL 1 (QUAC1), we show that impairment of R- and S-type channels gradually increased whole-plant steady-state stomatal conductance. Ozone-induced cell death also increased gradually in higher-order mutants with the highest levels observed in the quac1 slac1 slah3 triple mutant. Strikingly, while single mutants retained stomatal responsiveness to abscisic acid, darkness, reduced air humidity, and elevated CO2, the double mutant lacking SLAC1 and QUAC1 was nearly insensitive to these stimuli, indicating the need for coordinated activation of both R- and S-type anion channels in stomatal closure.
An Automated Methodology for Non-targeted Compositional Analysis of Small Molecules in High Complexity Environmental Matrices Using Coupled Ultra Performance Liquid Chromatography Orbitrap Mass Spectrometry

The life-critical matrices of air and water are among the most complex chemical mixtures that are ever encountered. Ultrahigh-resolution mass spectrometers, such as the Orbitrap, provide unprecedented analytical capabilities to probe the molecular composition of such matrices, but the extraction of non-targeted chemical information is impractical to perform via manual data processing. Automated non-targeted tools rapidly extract the chemical information of all detected compounds within a sample dataset. However, these methods have not been exploited in the environmental sciences. Here, we provide an automated and (for the first time) rigorously tested methodology for the non-targeted compositional analysis of environmental matrices using coupled liquid chromatography–mass spectrometric data. First, the robustness and reproducibility was tested using authentic standards, evaluating performance as a function of concentration, ionization potential, and sample complexity. The method was then used for the compositional analysis of particulate matter and surface waters collected from worldwide locations. The method detected >9600 compounds in the individual environmental samples, arising from critical pollutant sources, including carcinogenic industrial chemicals, pesticides, and pharmaceuticals among others. This methodology offers considerable advances in the environmental sciences, providing a more complete assessment of sample compositions while significantly increasing throughput.
Chromatin architecture transitions from zebrafish sperm through early embryogenesis

Chromatin architecture mapping in 3D formats has increased our understanding of how regulatory sequences and gene expression are connected and regulated in a genome. The 3D chromatin genome shows extensive remodeling during embryonic development, and although the cleavage-stage embryos of most species lack structure before zygotic genome activation (pre-ZGA), zebrafish has been reported to have structure. Here, we aimed to determine the chromosomal architecture in paternal/sperm zebrafish gamete cells to discern whether it either resembles or informs early pre-ZGA zebrafish embryo chromatin architecture. First, we assessed the higher-order architecture through advanced low-cell in situ Hi-C. The structure of zebrafish sperm, packaged by histones, lacks topological associated domains and instead displays “hinge-like” domains of ∼150 kb that repeat every 1–2 Mbs, suggesting a condensed repeating structure resembling mitotic chromosomes. The pre-ZGA embryos lacked chromosomal structure, in contrast to prior work, and only developed structure post-ZGA. During post-ZGA, we find chromatin architecture beginning to form at small contact domains of a median length of ∼90 kb. These small contact domains are established at enhancers, including super-enhancers, and chemical inhibition of Ep300a (p300) and Crebbpa (CBP) activity, lowering histone H3K27ac, but not transcription inhibition, diminishes these contacts. Together, this study reveals hinge-like domains in histone-packaged zebrafish sperm chromatin and determines that the initial formation of high-order chromatin architecture in zebrafish embryos occurs after ZGA primarily at enhancers bearing high H3K27ac.
Preparation of silk fibroin/hyaluronic acid hydrogels with enhanced mechanical performance by a combination of physical and enzymatic crosslinking

Abstract Silk fibroin (SF) from Bombyx mori is a natural polymer with exceptional biocompatibility, low immunogenicity, and ease of processability. SF-based hydrogels have been identified as one of the most attractive candidate scaffolds for tissue engineering and can be fabricated through various physical or chemical crosslinking approaches. However, conventional SF hydrogels may suffer from several major drawbacks, such as structural inhomogeneity, poor mechanical properties or utilization of cytotoxic reagents. Herein, a dually crosslinked SF-based composite hydrogel with enhanced strength and elasticity was fabricated by inducing the formation of uniform and small β-sheet structures by sonication in a restricted enzymatic precrosslinked network. The composite hydrogel not only demonstrated concentration-dependent stiffness variation but also exhibited time-dependent changes in toughness behavior. Moreover, subsequent experimental results revealed that the hydrogels exhibit other advantages, including high water retention capacity and long-term stability under physiological conditions. Finally, a three-dimensional (3 D) construct of the cell-laden hydrogel was fabricated, confirming that the composite hydrogel could provide a biocompatible microenvironment with dynamically changing mechanical properties. The combination of physical and enzymatic crosslinking strategies contributes to a biocompatible composite hydrogel with unique mechanical properties that holds great potential for use in tissue engineering and regenerative medicine.
WRKY53 Integrates Classic Brassinosteroid Signaling and the Mitogen-Activated Protein Kinase Pathway to Regulate Rice Architecture and Seed Size.

In rice (Oryza sativa) and other plants, plant architecture and seed size are closely related to yield. Brassinosteroid (BR) signaling and the mitogen-activated protein kinase (MAPK) pathway (MAPKKK10-MAPKK4-MAPK6) are two major regulatory pathways that control rice architecture and seed size. However, their possible relationship and crosstalk remain elusive. Here, we show that WRKY53 mediated the crosstalk between BR signaling and the MAPK pathway. Biochemical and genetic assays demonstrated that GSK2 phosphorylates WRKY53 and lowers its stability, indicating that WRKY53 is a substrate of GSK2 in BR signaling. WRKY53 interacted with BZR1; they function synergistically to regulate BR-related developmental processes. We also provide genetic evidence showing that WRKY53 functions in a common pathway with the MAPKKK10-MAPKK4-MAPK6 cascade in leaf angle and seed size control, suggesting that WRKY53 is a direct substrate of this pathway. Moreover, GSK2 phosphorylated MAPKK4 to suppress MAPK6 activity, suggesting that GSK2-mediated BR signaling might also regulated MAPK pathway. Together, our results revealed a critical role for WRKY53 and uncovered sophisticated levels of interplay between BR signaling and the MAPK pathway in regulating rice architecture and seed size.
Heparin-binding VEGFR1 variants as long-acting VEGF inhibitors for treatment of intraocular neovascular disorders

Significance Vascular endothelial growth factor (VEGF) inhibitors have transformed the treatment of intraocular vascular disorders. However, the burden of frequent intravitreal injections reduces patient compliance such that the impact in the “real world” is less than in clinical trials. Thus, there is a need to discover VEGF inhibitors than can be administered less frequently. We hypothesized that the ability to bind heparan-sulfate proteoglycans may be a strategy to promote intraocular retention and increase half-life. We designed a series of VEGF receptor 1 variants and identified some with strong heparin-binding characteristics that are more effective and durable in action in animal models of intraocular neovascularization than a standard of care like aflibercept. The work should fulfill an unmet medical need and advance therapy. Neovascularization is a key feature of ischemic retinal diseases and the wet form of age-related macular degeneration (AMD), all leading causes of severe vision loss. Vascular endothelial growth factor (VEGF) inhibitors have transformed the treatment of these disorders. Millions of patients have been treated with these drugs worldwide. However, in real-life clinical settings, many patients do not experience the same degree of benefit observed in clinical trials, in part because they receive fewer anti-VEGF injections. Therefore, there is an urgent need to discover and identify novel long-acting VEGF inhibitors. We hypothesized that binding to heparan-sulfate proteoglycans (HSPG) in the vitreous, and possibly other ocular structures, may be a strategy to promote intraocular retention, ultimately leading to a reduced burden of intravitreal injections. We designed a series of VEGF receptor 1 variants and identified some with strong heparin-binding characteristics and ability to bind to vitreous matrix. Our data indicate that some of our variants have longer duration and greater efficacy in animal models of intraocular neovascularization than current standard of care. Our study represents a systematic attempt to exploit the functional diversity associated with heparin affinity of a VEGF receptor.
Droplet generation in cross-flow for cost-effective 3D-printed “plug-and-play” microfluidic devices

Droplet-based microfluidics is a rapidly growing field of research and involves various applications from chemistry to biology. Droplet generation techniques become the pre-requisite focus. Additive manufacturing (3D printing) technology has recently been exploited in microfluidics due to its simplicity and low cost. However, only relatively large droplets can be produced in current 3D-printed droplet generators, due to the channel dimension limitations on how fine a channel can be 3D-printed. Here we report a novel design of a 3D-printed “plug-and-play” device for the generation of monodisperse microdroplets with sizes down to ∼50 μm. This device combines a 3D-printed generator, a commercial tubing and a fingertight fitting, which can be easily assembled and disassembled. Different emulsions, water-in-oil and oil-in-water, can be generated in the same device. Scaling laws for droplet sizes generated in our device have been successfully proposed and verified. Furthermore, the feasibility of 3D printing technology used in droplet-based engineering applications has been demonstrated by two novel 3D-printed devices, as well as by using the device for producing magnetically responsive microparticles.
Overexpression of an ALS-associated FUS mutation in C. elegans disrupts NMJ morphology and leads to defective neuromuscular transmission.

The amyotrophic lateral sclerosis (ALS) neurodegenerative disorder has been associated with multiple genetic lesions, including mutations in the gene for FUS (Fused in Sarcoma), a nuclear-localized RNA/DNA-binding protein. Neuronal expression of the pathological form of FUS proteins in C. elegans results in mislocalization and aggregation of FUS in the cytoplasm, and leads to impairment of motility. However, the mechanisms by which the mutant FUS disrupts neuronal health and function remain unclear. Here we investigated the impact of ALS-associated FUS on motor neuron health using correlative light and electron microscopy, electron tomography, and electrophysiology. We show that ectopic expression of wild-type or ALS-associated human FUS impairs synaptic vesicle docking at neuromuscular junctions. ALS-associated FUS led to the emergence of a population of large, electron-dense, and filament-filled endosomes. Electrophysiological recording revealed reduced transmission from motor neurons to muscles. Together, these results suggest a pathological effect of ALS-causing FUS at synaptic structure and function organization.
Cost sharing for breast cancer hormone therapy: How do dual eligible patients’ copayment impact adherence

Objective To examine the different levels of copayment assistance and treatment adherence among Medicare and Medicaid dual eligible beneficiaries with breast cancer in the U.S. Research design Propensity Score methodology was adopted to minimize potential selection bias from the nonrandom allocation of the treatment group (i.e., full Medicaid beneficiaries) and control group (i.e., Medicare Savings Programs [MSPs] beneficiaries). Longitudinal hierarchical model and Cox proportional-hazard model were adopted to examine patients’ adherence over their full five-year course of adjuvant hormone therapy. Results Our study cohort consisted of 1,133 dual eligible beneficiaries diagnosed with hormone receptor-positive early stage breast cancer in years 2007 –mid 2009. About 80.5% of them received MSPs benefits, while the rest received full Medicaid benefits. On average for a standardized 30-day hormone therapy medication, full Medicaid beneficiaries spent $0.5-$2.0 and MSP beneficiaries spent $1.4-$4.8 in copayment. After adjusting for other factors, this copayment reduction wasn’t associated with a significantly better adherence. However, when the catastrophic coverage threshold was reached (copayments reduced to zero), significant improvement in adherence was found in both groups. Conclusions Our study found that small amount of cost-sharing reduction did not affect Medicare and Medicaid dual eligible patients’ medication treatment adherence, however, the elimination of cost-sharing (even a minimal amount) was associated with improved adherence. Future legislative and advocacy efforts should be paid on eliminating cost sharing for dual eligibles, and possibly even a broader group of financially vulnerable patients.
Microwave assisted green synthesis of silver nanoparticles for optical, catalytic, biological and electrochemical applications

Abstract Plant-derived nanoparticles have multi-functionalities owing to their ecological origin and biocompatible nature. A novel and stable silver nanoparticle (AgNP) was reported here using Cyanthillium cinereum (C. cinereum) as a reducing as well as capping agent by rapid microwave-assisted green method. The synthesized nanoparticles revealed their crystalline and spherical nature with an average size of 19.25 ± 0.44 nm in HR-TEM analysis. The excitation of electrons from occupied d-bands to states above the Fermi level while employing photoluminescence studies of AgNP indicated their awesome optical properties. Rapid decomposition of dangerous organic dyes like methylene blue and fuchsine in the catalytic presence of AgNP was evidenced from simple UV–visible spectral analysis. In vitro antioxidant potential assessed by DPPH assay indicated an IC50 value of 40.80 ± 0.14 μg/mL for the new AgNP. A substantial control on the growth of pathogenic bacteria such as Staphylococcus aureus and Klebsiella pneumonia can be achieved by synthesized nanoparticles as demonstrated by the well diffusion method. AgNP was also functioned as a non-enzymatic electrochemical sensor with a sharp oxidation peak with peak potentials at 0.366 V and it has a wide application as a bio sensor in neurobiology especially in the detection of neurotransmitters like dopamine with high sensitivity.