Studies on the in vitro mechanism and in vivo therapeutic effect of the antimicrobial peptide ACP5 against Trichophyton mentagrophytes.

Trichophyton mentagrophytes is a zoophilic dermatophyte that can cause dermatophytosis in humans and animals. Antimicrobial peptides (AMPs) are considered as a promising agent to overcome the drug-resistance of T. mentagrophytes. Our findings suggest that cationic antimicrobial peptide (ACP5) not only possesses stronger activity against T. mentagrophytes than fluconazole, but also shows lower toxicity to L929 mouse fibroblast cells than terbinafine. Notably, its resistance development rate after resistance induction was lower than terbinafine. The present study aimed to evaluate the fungicidal mechanism of ACP5 in vitro and its potential to treat dermatophyte infections in vivo. ACP5 at 1 ×MIC completely inhibited T. mentagrophytes spore germination in vitro. ACP5 severely disrupts the mycelial morphology, leading to mycelial rupture. Mechanistically, ACP5 induces excessive ROS production, damaging the integrity of the cell membrane and decreasing the mitochondrial membrane potential, causing irreversible damage in T. mentagrophytes. Furthermore, 1% ACP5 showed similar efficacy to the commercially available drug 1% terbinafine in a guinea pig dermatophytosis model, and the complete eradication of T. mentagrophytes from the skin by ACP5 was verified by tissue section observation. These results indicate that ACP5 is a promising candidate for the development of new agent to combat dermatophyte resistance.

Response Surface Optimization of Polysaccharides from Jaboticaba (Myrciaria cauliflora [Mart.] O.Berg) Fruits: Ultrasound-Assisted Extraction, Structure Properties, and Antioxidant/Hypoglycemic Activities.

Ultrasound-assisted extraction (UAE) method proves to be more effective compared to traditional extraction methods. In the present study, response surface methodology (RSM) was used to determine the optimal process parameters for extracting polysaccharides (U-MCP) from jaboticaba fruit using UAE. The optimum extraction conditions were ultrasonic time 70 min, extraction temperature 60 °C, and power 350 W. Under these conditions, the sugar content of U-MCP was 52.8 %. The molecular weights of the ultrasound-assisted extracted U-MCP ranged from 9.52×102 to 3.27×103  Da, and consisted of five monosaccharides including mannose, galacturonic acid, glucose, galactose, and arabinose. Moreover, in vitro antioxidant and hypoglycaemic assay revealed that U-MCP has prominent anti-oxidant activities (1,1-diphenyl-2-picryl-hydrazyl (DPPH) radicals, hydroxyl radicals and 2,2'-Azinobis (3-ethylbenzothiazoline-6-sulfonic Acid Ammonium Salt) (ABTS) radicals scavenging activities) and hypoglycemic activities (α-amylase and α-glucosidase inhibition activities).

Machine Learning Accelerates De Novo Design of Antimicrobial Peptides.

Efficient and precise design of antimicrobial peptides (AMPs) is of great importance in the field of AMP development. Computing provides opportunities for peptide de novo design. In the present investigation, a new machine learning-based AMP prediction model, AP_Sin, was trained using 1160 AMP sequences and 1160 non-AMP sequences. The results showed that AP_Sin correctly classified 94.61% of AMPs on a comprehensive dataset, outperforming the mainstream and open-source models (Antimicrobial Peptide Scanner vr.2, iAMPpred and AMPlify) and being effective in identifying AMPs. In addition, a peptide sequence generator, AP_Gen, was devised based on the concept of recombining dominant amino acids and dipeptide compositions. After inputting the parameters of the 71 tridecapeptides from antimicrobial peptides database (APD3) into AP_Gen, a tridecapeptide bank consisting of de novo designed 17,496 tridecapeptide sequences were randomly generated, from which 2675 candidate AMP sequences were identified by AP_Sin. Chemical synthesis was performed on 180 randomly selected candidate AMP sequences, of which 18 showed high antimicrobial activities against a wide range of the tested pathogenic microorganisms, and 16 of which had a minimal inhibitory concentration of less than 10 µg/mL against at least one of the tested pathogenic microorganisms. The method established in this research accelerates the discovery of valuable candidate AMPs and provides a novel approach for de novo design of antimicrobial peptides.

Adaptive feature extraction method for capsule endoscopy images.

The traditional feature-extraction method of oriented FAST and rotated BRIEF (ORB) detects image features based on a fixed threshold; however, ORB descriptors do not distinguish features well in capsule endoscopy images. Therefore, a new feature detector that uses a new method for setting thresholds, called the adaptive threshold FAST and FREAK in capsule endoscopy images (AFFCEI), is proposed. This method, first constructs an image pyramid and then calculates the thresholds of pixels based on the gray value contrast of all pixels in the local neighborhood of the image, to achieve adaptive image feature extraction in each layer of the pyramid. Subsequently, the features are expressed by the FREAK descriptor, which can enhance the discrimination of the features extracted from the stomach image. Finally, a refined matching is obtained by applying the grid-based motion statistics algorithm to the result of Hamming distance, whereby mismatches are rejected using the RANSAC algorithm. Compared with the ASIFT method, which previously had the best performance, the average running time of AFFCEI was 4/5 that of ASIFT, and the average matching score improved by 5% when tracking features in a moving capsule endoscope.

Localized Anion-Cation Aggregated Aqueous Electrolytes with Accelerated Kinetics for Low-Temperature Zinc Metal Batteries.

Aqueous zinc metal batteries hold great promise for large-scale energy storage because of their high safety, rich material resources and low cost. However, the freeze of aqueous electrolytes hinders low-temperature operation of the batteries. Here, aqueous localized anion-cation aggregated electrolytes composed of Zn(BF4 )2 as the salt and tetrahydrofuran (THF) as the diluent, are developed to improve the low-temperature performance of the Zn anode. THF promotes the inclusion of BF4 - in the solvation sheath of Zn2+ , facilitating the formation of ZnF2 -rich solid-electrolyte-interphase. THF also affects the hydrogen bonding between neighboring H2 O molecules, effectively lowering the freezing point. Therefore, the full cells of Zn||polyaniline (PANI) exhibit an ultralong cycle life of 8000 cycles with an average Coulombic efficiency of 99.99 % at -40 °C. Impressively, the pouch cells display a high capacity retention of 86.2 % after 500 cycles at -40 °C, which demonstrates the great prospect of such electrolytes in cold regions. This work provides new insights for the design of low-temperature aqueous electrolytes.

Diagnostic Significance of DCE-MRI-Related Quantitative Parameters for Nasal Cavity and Sinus Tumors.

Objective: Our aim was to explore the diagnostic value of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)-related quantitative parameters for benign and malignant nasal cavity and sinus tumors. Methods: A total of 78 patients with nasal sinus tumors admitted to People's Hospital of Qingdao Chengyang District in China were enrolled in our study, Of the patients, 41 were diagnosed as having benign tumors and 37 as having malignant tumors by pathological diagnosis. All patients received DCE-MRI scans before surgery to derive time-intensity curves (TICs) and related quantitative parameters (flux rate constant [Kep], transfer constant [Ktrans], extravascular volume fraction [Ve]). The diagnostic surgical pathology results were used as the gold standard to analyze the diagnostic effect of TIC and related quantitative parameters of DCE-MRI, and the receiver operating characteristic (ROC) curves were plotted to determine the values of each parameter in predicting nasal sinus tumors. Results: The percentage of class I in the benign group was significantly higher than in the malignant group (P < .05); the percentage of class III in the benign group was significantly lower than in the malignant group (P < .05); the percentage of class II in the 2 groups was comparable (P > .05). Kep, Ktrans and Ve in the benign group were 0.338±0.124, 0.061±0.035 and 0.532±0.138, respectively; Kep, Ktrans and Ve in the malignant group were 0.785±0.211, 0.441±0.125 and 0.327±0.048, respectively. The levels of Kep and Ktrans were significantly lower in the benign group than in the malignant group (all P < .05); the levels of Ve were significantly higher in the benign group than in the malignant group (P < .05). The optimal Kep cut-off value for predicting malignant nasal sinus tumors was 0.510 min-1, with a sensitivity of 81.4% and specificity of 89.5%; the optimal Ktrans cut-off value for predicting malignant nasal sinus tumors was 0.206 min-1, with a sensitivity of 84.3% and specificity of 89.7%; the optimal Ve cut-off value for predicting malignant nasal sinus tumors was 0.384 min-1, with a sensitivity of 71.8% and specificity of 82.4%. Conclusion: DCE-MRI-related quantitative parameters are ideal for the diagnosis of benign and malignant nasal sinus tumors. This modality provides more data for the identification of the nature of the tumor, and thus merits clinical promotion and application.

Fast and accurate local ancestry inference with Recomb-Mix.

The availability of large genotyped cohorts brings new opportunities for revealing high-resolution genetic structure of admixed populations, via local ancestry inference (LAI), the process of identifying the ancestry of each segment of an individual haplotype. Though current methods achieve high accuracy in standard cases, LAI is still challenging when reference populations are more similar (e.g., intra-continental), when the number of reference populations is too numerous, or when the admixture events are deep in time, all of which are increasingly unavoidable in large biobanks. Here, we present a new LAI method, Recomb-Mix. Adopting the commonly used site-based formulation based on the classic Li and Stephens' model, Recomb-Mix integrates the elements of existing methods and introduces a new graph collapsing to simplify counting paths with the same ancestry label readout. Through comprehensive benchmarking on various simulated datasets, we show that Recomb-Mix is more accurate than existing methods in diverse sets of scenarios while being competitive in terms of resource efficiency. We expect that Recomb-Mix will be a useful method for advancing genetics studies of admixed populations.

Zwitterionic Covalent Organic Framework Based Electrostatic Field Electrocatalysts for Durable Lithium-Sulfur Batteries.

Lithium-sulfur batteries (LSBs) are one of the most promising candidates for next-generation energy storage systems. To develop long-life LSBs, there is an urgent need to develop functional materials with higher catalytic activity toward polysulfides and reduced dendritic lithium growth. Herein, an electrostatic field electrocatalyst is designed in a zwitterionic covalent organic framework (COF) with a "two birds with one stone" ability for simultaneously overcoming obstacles in the lithium metal anode and sulfur cathode. The synergism between cationic and anionic moieties in the zwitterionic COF creates an electrostatic field for bidirectionally catalyzing S cathode conversion. Besides, the rational design of zwitterionic COF as a separator modification layer allows lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) dissociation and fast lithium-ion conduction, which alleviates lithium dendrite growth and thus improves the cycling life of LSBs. This contribution not only pioneers the application of zwitterionic COF in the field of LSBs but also highlights the potential of electrostatic field electrocatalysts.

Chaenomeles sinensis polysaccharide and its carboxymethylated derivative alleviate dextran sulfate sodium-induced ulcerative colitis via suppression of inflammation and oxidative stress.

Chaenomeles sinensis fruit polysaccharide (CSP) and carboxymethylated CSP (CSP-M) were prepared using ultrasound extraction and the sodium hydroxide-chloroacetic acid method. Structural analysis revealed that both CSP and CSP-M mainly consisted of glucose, arabinose, rhamnose, glucuronic acid, galactose, and xylose, and the introduction of carboxymethyl did not damage the polymer chain of CSP. In vivo studies verified that both CSP and CSP-M could remarkably alleviate the symptoms of ulcerative colitis (UC) mice and reduce intestinal epithelial cell depletion, along with the infiltration of inflammatory cells in colon tissue, by mediating the expression of myeloperoxidase (MPO), inflammatory factors [tumour necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and IL-6], and oxidative stress factors [malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and nitric oxide (NO)]. Most importantly, the introduction of carboxymethyl significantly enhanced the anti-UC activity of CSP, confirming the efficacy of carboxymethylation as a method to enhance the biological activities of CSP, thereby suggesting the potential of CSP-M as a therapeutic option for UC.

Exploring the micromorphological characteristics of adult lower cervical vertebrae based on micro-computed tomography.

We will use micro-computed tomography to scan 31 sets of the adult lower cervical vertebrae (155 vertebrae) to observe the morphological characteristics and direction of trabeculae in the lower cervical vertebrae by outlining and reconstructing the regions of interest and to calculate the variation laws of the microstructure in the regions of interest to reveal their structural characteristics and weak areas. As a result, the images showed that the trabeculae in the lower cervical pedicle near the medial and lateral cortices were relatively dense, and their bone plates were lamellar. There were cavities between the superior and inferior articular processes where the ossification centers had not been absorbed after ossified. The lamellar trabeculae in the vertebral plates near the cortical bones were only 1-2 layers, extended and transformed into rod-shaped trabeculae in a radial shape toward the medullary space. The lamellar trabeculae of the vertebral plate extend over the spinous process near the cortical bone. The statistical results of the trabeculae's morphological parameters showed significant differences in bone volume fraction values among the four parts (P < 0.05). There were substantial differences in BS/BV, except for no differences between the pedicle and the vertebral plate (P < 0.05). There was a significant difference in trabecular pattern factor values between the articular process, the spinous process, and the vertebral plate (P < 0.05) and a significant difference between the pedicle, the spinous process, and the vertebral plate (P < 0.05). There were no significant differences in trabecular bone thickness and trabecular space values among the four parts (P < 0.05). The anatomical microstructural perspective confirms that the optimal choice is internal fixation via the pedicle. If using pedicle screws, the nail tract needs to be placed into the spinous process to increase its holding power and resistance to extraction.

A zinc-modified Anemarrhena asphodeloides polysaccharide complex enhances immune activity via the NF-κB and MAPK signaling pathways.

Anemarrhena asphodeloides polysaccharide (AAP70-1) was reported to have immunomodulatory effects in our previous report. To further improve the immunomodulatory effects of AAP70-1, an A. asphodeloides polysaccharide-zinc complex (AAP-Zn) was synthesized using a ZnCl2 modification method, and the potential mechanisms by which AAP-Zn activates macrophages were investigated. The results showed that the structural features of AAP-Zn were similar to those of AAP70-1 with a Zn content of 0.2 %, confirming that Zn mainly interacted with AAP70-1 by forming ZnO coordination bonds and Zn…OH bonds. In addition, the administration of AAP70-1 and AAP-Zn effectively improved the immunomodulatory effects by enhancing phagocytosis and upregulating the mRNA expression of cytokines (TNF-α, IL-6, IL-1ß, and IL-18), as well as increasing the production levels of nitric oxide (NO) and reactive oxygen species (ROS) in zebrafish embryos. The intracellular mechanism by which AAP-Zn activates macrophages was found to involve activation of the NF-κB and MAPK signaling pathways. Our findings suggested that AAP-Zn may be a potential immunopotentiator in the field of biomedicine or functional foods.

High-Efficiency Separator Capacity-Compensation Strategy Applied to Sodium-Ion Batteries.

Sodium-ion batteries (SIBs) are expected to replace partial reliance on lithium-ion batteries (LIBs) in the field of large-scale energy storage as well as low-speed electric vehicles due to the abundance, wide distribution, and easy availability of sodium metal. Unfortunately, a certain amount of sodium ions are irreversibly trapped in the solid electrolyte interface (SEI) layer during the initial charging process, causing the initial capacity loss (ICL) of the SIBs. A separator capacity-compensation strategy is proposed, where the capacity compensator on the separator oxidizes below the high cut-off voltage of the cathode to provide additional sodium ions. This strategy shows attractive advantages, including adaptability to current production processes, no impairment of cell long-cycle life, controlled pre-sodiation degree, and strategy universality. The separator capacity-compensation strategy is applied in the NaNi1/3 Fe1/3 Mn1/3 O2 (NMFO)||HC full cell and achieve a compensated capacity ratio of 18.2%. In the Na3 V2 (PO4 )3 (NVP)||HC full cell, the initial reversible specific capacity is increased from 61.0 mAh g-1 to 83.1 mAh g-1 . The separator capacity-compensation strategy is proven to be universal and provides a new perspective to enhance the energy density of SIBs.

The Effects of Social Status and Imposition on the Comprehension of Refusals in Chinese: An ERP Study.

This study aims to examine how real-time processing of information about the social status of interlocutors (high vs. low) and the imposition of making a refusal by manipulating the indirectness of invitation forms (declining direct invitations vs. declining indirect invitations) affects the interpretation of refusals in Chinese. The event-related potentials results showed that high-status invitees who decline invitations from low-status inviters elicited weaker N400 effects followed by late mitigated negative effects, while high imposition refusals elicited stronger N400 effects followed by increased late negativities. The two factors of social status and imposition functioned independently during the comprehension of refusal utterances. These findings suggest that individuals take the social status of interlocutors and the imposition of making a refusal into consideration as an utterance unfolds, while face-threatening contexts create inferential difficulties for reinterpreting the pragmatic implications of an utterance.

RNAMotifComp: a comprehensive method to analyze and identify structurally similar RNA motif families.

MOTIVATION: The 3D structures of RNA play a critical role in understanding their functionalities. There exist several computational methods to study RNA 3D structures by identifying structural motifs and categorizing them into several motif families based on their structures. Although the number of such motif families is not limited, a few of them are well-studied. Out of these structural motif families, there exist several families that are visually similar or very close in structure, even with different base interactions. Alternatively, some motif families share a set of base interactions but maintain variation in their 3D formations. These similarities among different motif families, if known, can provide a better insight into the RNA 3D structural motifs as well as their characteristic functions in cell biology. RESULTS: In this work, we proposed a method, RNAMotifComp, that analyzes the instances of well-known structural motif families and establishes a relational graph among them. We also have designed a method to visualize the relational graph where the families are shown as nodes and their similarity information is represented as edges. We validated our discovered correlations of the motif families using RNAMotifContrast. Additionally, we used a basic Naïve Bayes classifier to show the importance of RNAMotifComp. The relational analysis explains the functional analogies of divergent motif families and illustrates the situations where the motifs of disparate families are predicted to be of the same family. AVAILABILITY AND IMPLEMENTATION: Source code publicly available at https://github.com/ucfcbb/RNAMotifFamilySimilarity.

Minimal positional substring cover is a haplotype threading alternative to Li and Stephens model.

The Li and Stephens (LS) hidden Markov model (HMM) models the process of reconstructing a haplotype as a mosaic copy of haplotypes in a reference panel. For small panels, the probabilistic parameterization of LS enables modeling the uncertainties of such mosaics. However, LS becomes inefficient when sample size is large, because of its linear time complexity. Recently the PBWT, an efficient data structure capturing the local haplotype matching among haplotypes, was proposed to offer a fast method for giving some optimal solution (Viterbi) to the LS HMM. Previously, we introduced the minimal positional substring cover (MPSC) problem as an alternative formulation of LS whose objective is to cover a query haplotype by a minimum number of segments from haplotypes in a reference panel. The MPSC formulation allows the generation of a haplotype threading in time constant to sample size (O(N)). This allows haplotype threading on very large biobank-scale panels on which the LS model is infeasible. Here, we present new results on the solution space of the MPSC. In addition, we derived a number of optimal algorithms for MPSC, including solution enumerations, the length maximal MPSC, and h-MPSC solutions. In doing so, our algorithms reveal the solution space of LS for large panels. We show that our method is informative in terms of revealing the characteristics of biobank-scale data sets and can improve genotype imputation.

Fast inference of genetic recombination rates in biobank scale data.

Although rates of recombination events across the genome (genetic maps) are fundamental to genetic research, the majority of current studies only use one standard map. There is evidence suggesting population differences in genetic maps, and thus estimating population-specific maps, are of interest. Although the recent availability of biobank-scale data offers such opportunities, current methods are not efficient at leveraging very large sample sizes. The most accurate methods are still linkage disequilibrium (LD)-based methods that are only tractable for a few hundred samples. In this work, we propose a fast and memory-efficient method for estimating genetic maps from population genotyping data. Our method, FastRecomb, leverages the efficient positional Burrows-Wheeler transform (PBWT) data structure for counting IBD segment boundaries as potential recombination events. We used PBWT blocks to avoid redundant counting of pairwise matches. Moreover, we used a panel-smoothing technique to reduce the noise from errors and recent mutations. Using simulation, we found that FastRecomb achieves state-of-the-art performance at 10-kb resolution, in terms of correlation coefficients between the estimated map and the ground truth. This is mainly because FastRecomb can effectively take advantage of large panels comprising more than hundreds of thousands of haplotypes. At the same time, other methods lack the efficiency to handle such data. We believe further refinement of FastRecomb would deliver more accurate genetic maps for the genetics community.

RaPID-Query for fast identity by descent search and genealogical analysis.

MOTIVATION: Due to the rapid growth of the genetic database size, genealogical search, a process of inferring familial relatedness by identifying DNA matches, has become a viable approach to help individuals finding missing family members or law enforcement agencies locating suspects. A fast and accurate method is needed to search an out-of-database individual against millions of individuals. Most existing approaches only offer all-versus-all within panel match. Some prototype algorithms offer one-versus-all query from out-of-panel individual, but they do not tolerate errors. RESULTS: A new method, random projection-based identity-by-descent (IBD) detection (RaPID) query, is introduced to make fast genealogical search possible. RaPID-Query identifies IBD segments between a query haplotype and a panel of haplotypes. By integrating matches over multiple PBWT indexes, RaPID-Query manages to locate IBD segments quickly with a given cutoff length while allowing mismatched sites. A single query against all UK biobank autosomal chromosomes was completed within 2.76 seconds on average, with the minimum length 7 cM and 700 markers. RaPID-Query achieved a 0.016 false negative rate and a 0.012 false positive rate simultaneously on a chromosome 20 sequencing panel having 86 265 sites. This is comparable to the state-of-the-art IBD detection method TPBWT(out-of-sample) and Hap-IBD. The high-quality IBD segments yielded by RaPID-Query were able to distinguish up to fourth degree of the familial relatedness for a given individual pair, and the area under the receiver operating characteristic curve values are at least 97.28%. AVAILABILITY AND IMPLEMENTATION: The RaPID-Query program is available at https://github.com/ucfcbb/RaPID-Query.

RNA-NRD: a non-redundant RNA structural dataset for benchmarking and functional analysis.

The significance of RNA functions and their role in evolution and disease control have remarkably increased the research scope in the field of RNA science. Though the availability of RNA structure data in PBD has been growing tremendously, maintaining their quality and integrity has become the greater challenge. Since the data available in PDB are results of different independent research, they might contain redundancy. As a result, there remains a possibility of data bias for both protein and RNA chains. Quite a few studies have been conducted to remove the redundancy of protein structures by introducing high-quality representatives. However, the amount of research done to remove the redundancy of RNA structures is still very low. To remove RNA chain redundancy in PDB, we have introduced RNA-NRD, a non-redundant dataset of RNA chains based on sequence and 3D structural similarity. We compared RNA-NRD with the existing non-redundant RNA structure dataset RS-RNA and showed that it has better-formed clusters of redundant RNA chains with lower average RMSD and higher average PSI, thus improving the overall quality of the dataset.

Discovery of novel, potent, and orally bioavailable HDACs inhibitors with LSD1 inhibitory activity for the treatment of solid tumors.

Histone deacetylases (HDACs) and lysine-specific demethylase 1 (LSD1) are attractive targets for epigenetic cancer therapy. There is an intimate interplay between the two enzymes. HDACs inhibitors have shown synergistic anticancer effects in combination with LSD1 inhibitors in several types of cancer. Herein, we describe the discovery of compound 5e, a highly potent HDACs inhibitor (HDAC1/2/6/8; IC50 = 2.07/4.71/2.40/107 nM) with anti-LSD1 potency (IC50 = 1.34 µM). Compound 5e exhibited marked antiproliferative activity in several cancer cell lines. 5e effectively induced mitochondrial apoptosis with G2/M phase arrest, inhibiting cell migration and invasion in MGC-803 and HCT-116 cancer cells. It also showed good liver microsomal stability and acceptable pharmacokinetic parameters in SD rats. More importantly, orally administered compound 5e demonstrated higher in vivo antitumor efficacy than SAHA in the MGC-803 (TGI = 71.5%) and HCT-116 (TGI = 57.6%) xenograft tumor models accompanied by good tolerability. This study provides a novel lead compound with dual inhibitory activity against HDACs and LSD1 to further develop epigenetic drugs for solid tumor therapy. Further optimization is needed to improve the LSD1 activity to achieve dual inhibitors with balanced potency on LSD1 and HDACs.