bluuebunny/crossref_metadata_2025 huggingface dataset:
High-Resolution Magic-Angle Spinning NMR Spectroscopy for Evaluation of Cell Shielding by Virucidal Composites Based on Biogenic Silver Nanoparticles, Flexible Cellulose Nanofibers and Graphene Oxide
Authors: Stanisic Danijela , Cruz Guilherme C. F. , Elias Leonardo Abdala , Tsukamoto Junko , Arns Clarice W. , Soares da Silva Douglas , Mochkalev Stanislav , Savu Raluca , Tasic Ljubica
Published: May 2022

Antiviral and non-toxic effects of silver nanoparticles onto in vitro cells infected with coronavirus were evaluated in this study using High-Resolution Magic-Angle Spinning Nuclear Magnetic Resonance (HR-MAS NMR) spectroscopy. Silver nanoparticles were designed and synthesized using an orange flavonoid—hesperetin (HST)—for reduction of silver(I) and stabilization of as obtained nanoparticles. The bio-inspired process is a simple, clean, and sustainable way to synthesize biogenic silver nanoparticles (AgNP@HST) with diameters of ∼20 nm and low zeta potential (−40 mV), with great colloidal stability monitored for 2 years. The nanoparticles were used for the fabrication of two types of antiviral materials: colloids (AgNP@HST spray) and 3D flexible nanostructured composites. The composites, decorated with AgNP@HST (0.05 mmol L−1), were made using cellulose nanofibers (CNF) obtained from orange peel and graphene oxide (GO), being denominated CNF@GO@AgNP@HST. Both materials showed high virucidal activity against coronaviruses in cell infection in vitro models and successfully inhibited the viral activity in cells. HR-MAS 1H-NMR technique was used for determining nanomaterials’ effects on living cells and their influences on metabolic pathways, as well as to study viral effects on cells. It was proven that none of the manufactured materials showed toxicity towards the intact cells used. Furthermore, viral infection was reverted when cells, infected with the coronavirus, were treated using the as-fabricated nanomaterials. These significant results open possibilities for antiviral application of 3D flexible nanostructured composite such as packaging papers and filters for facial masks, while the colloidal AgNP@HST spray can be used for disinfecting surfaces, as well as a nasal, mouth, and eye spray.
Predicting the Internal Knee Abduction Impulse During Walking Using Deep Learning
Authors: Boukhennoufa Issam , Altai Zainab , Zhai Xiaojun , Utti Victor , McDonald-Maier Klaus D , Liew Bernard X. W.
Published: May 2022

Knee joint moments are commonly calculated to provide an indirect measure of knee joint loads. A shortcoming of inverse dynamics approaches is that the process of collecting and processing human motion data can be time-consuming. This study aimed to benchmark five different deep learning methods in using walking segment kinematics for predicting internal knee abduction impulse during walking. Three-dimensional kinematic and kinetic data used for the present analyses came from a publicly available dataset on walking (participants n = 33). The outcome for prediction was the internal knee abduction impulse over the stance phase. Three-dimensional (3D) angular and linear displacement, velocity, and acceleration of the seven lower body segment’s center of mass (COM), relative to a fixed global coordinate system were derived and formed the predictor space (126 time-series predictors). The total number of observations in the dataset was 6,737. The datasets were split into training (75%, n = 5,052) and testing (25%, n = 1685) datasets. Five deep learning models were benchmarked against inverse dynamics in quantifying knee abduction impulse. A baseline 2D convolutional network model achieved a mean absolute percentage error (MAPE) of 10.80%. Transfer learning with InceptionTime was the best performing model, achieving the best MAPE of 8.28%. Encoding the time-series as images then using a 2D convolutional model performed worse than the baseline model with a MAPE of 16.17%. Time-series based deep learning models were superior to an image-based method when predicting knee abduction moment impulse during walking. Future studies looking to develop wearable technologies will benefit from knowing the optimal network architecture, and the benefit of transfer learning for predicting joint moments.
High Cell Density Cultivation of Paracoccus sp. on Sugarcane Juice for Poly(3-hydroxybutyrate) Production
Authors: Moungprayoon Ayyapruk , Lunprom Siriporn , Reungsang Alissara , Salakkam Apilak
Published: May 2022

High cell density cultivation is a promising approach to reduce capital and operating costs of poly (3-hydroxybutyrate) (PHB) production. To achieve high cell concentration, it is necessary that the cultivation conditions are adjusted and controlled to support the best growth of the PHB producer. In the present study, carbon to nitrogen (C/N) ratio of a sugarcane juice (SJ)-based medium, initial sugar concentration, and dissolved oxygen (DO) set point, were optimized for batch cultivation of Paracoccus sp. KKU01. A maximum biomass concentration of 55.5 g/L was attained using the C/N ratio of 10, initial sugar concentration of 100 g/L, and 20% DO set point. Fed-batch cultivation conducted under these optimum conditions, with two feedings of SJ-based medium, gave the final cell concentration of 87.9 g/L, with a PHB content, concentration, and yield of 36.2%, 32.1 g/L, and 0.13 g/g-sugar, respectively. A medium-based economic analysis showed that the economic yield of PHB on nutrients was 0.14. These results reveal the possibility of using SJ for high cell density cultivation of Paracoccus sp. KKU01 for PHB production. However, further optimization of the process is necessary to make it more efficient and cost-effective.
Regulating Acidosis and Relieving Hypoxia by Platelet Membrane-Coated Nanoparticle for Enhancing Tumor Chemotherapy
Authors: Luo Xingyu , Cao Jian , Yu Jianming , Dai Dongqing , Jiang Wei , Feng Yahui , Hu Yong
Published: May 2022

Acidosis and hypoxia of tumor remain a great challenge for cancer therapy. Herein, we developed Hb-LOX-DOX-ZIF8@platelet membrane nanoparticles (H-L-D-Z@PM NPs) to address this problem. Lactate oxidase (LOX) could deplete intratumoral lactate adequately and amplify oxidative stress efficiently. In the meantime, hemoglobin (Hb) was intended to deliver oxygen, relieve hypoxia, and boost the catalytic activity of LOX. The coated PM bestowed active tumor-targeting ability and good biocompatibility to these nanoparticles. Moreover, the encapsulation of zeolitic imidazolate framework-8 (ZIF8) offered the acid response capacity to nanoparticles. With the synergism of chemotherapy drug doxorubicin (DOX), these H-L-D-Z@PM NPs appeared to have excellent antitumor competence. Collectively, this study offered a new strategy for enhancing tumor chemotherapy by regulating acidosis and relieving hypoxia.
System Principles Governing the Organization, Architecture, Dynamics, and Evolution of Gene Regulatory Networks
Authors: Freyre-González Julio A. , Escorcia-Rodríguez Juan M. , Gutiérrez-Mondragón Luis F. , Martí-Vértiz Jerónimo , Torres-Franco Camila N. , Zorro-Aranda Andrea
Published: May 2022

Synthetic biology aims to apply engineering principles for the rational, systematical design and construction of biological systems displaying functions that do not exist in nature or even building a cell from scratch. Understanding how molecular entities interconnect, work, and evolve in an organism is pivotal to this aim. Here, we summarize and discuss some historical organizing principles identified in bacterial gene regulatory networks. We propose a new layer, the concilion, which is the group of structural genes and their local regulators responsible for a single function that, organized hierarchically, coordinate a response in a way reminiscent of the deliberation and negotiation that take place in a council. We then highlight the importance that the network structure has, and discuss that the natural decomposition approach has unveiled the system-level elements shaping a common functional architecture governing bacterial regulatory networks. We discuss the incompleteness of gene regulatory networks and the need for network inference and benchmarking standardization. We point out the importance that using the network structural properties showed to improve network inference. We discuss the advances and controversies regarding the consistency between reconstructions of regulatory networks and expression data. We then discuss some perspectives on the necessity of studying regulatory networks, considering the interactions’ strength distribution, the challenges to studying these interactions’ strength, and the corresponding effects on network structure and dynamics. Finally, we explore the ability of evolutionary systems biology studies to provide insights into how evolution shapes functional architecture despite the high evolutionary plasticity of regulatory networks.
Novel Cell Therapy Using Mesenchymal Stromal Cell Sheets for Medication-Related Osteonecrosis of the Jaw
Authors: Kaibuchi Nobuyuki , Iwata Takanori , Koga Yoko Kawase , Okamoto Toshihiro
Published: May 2022

Despite medication-related osteonecrosis of the jaw (MRONJ) being first reported in 2003, the optimal treatment and prevention modalities for MRONJ are not clear. As a result, dentistry, oral surgery, and departments involved in the treatment of cancer and bone diseases are struggling with the management of MRONJ. Several cases of MRONJ cannot be managed by conventional treatment strategies recommended in various position papers. Therefore, studies have been conducted to investigate the efficacy of novel therapies for MRONJ. However, the optimal treatment is unknown. Several cell therapies including autologous cell transplantation have been reported for MRONJ. Although the efficacy of cell therapy for MRONJ has been demonstrated, large, statistically accurate clinical trials are lacking. We have been investigating the efficacy of MRONJ treatment using mesenchymal stromal cell (MSC) sheets since 2013 and confirmed its efficacy through various experiments, wherein MSC sheets were transplanted in model rats and beagle dogs with MRONJ-like lesions. Based on these results, we are planning to conduct a clinical trial of MRONJ therapy using periodontal ligament-derived MSC sheets.
Detecting Key Functional Components Group and Speculating the Potential Mechanism of Xiao-Xu-Ming Decoction in Treating Stroke
Authors: Chen Yu-peng , Wang Ke-xin , Cai Jie-qi , Li Yi , Yu Hai-lang , Wu Qi , Meng Wei , Wang Handuo , Yin Chuan-hui , Wu Jie , Huang Mian-bo , Li Rong , Guan Dao-gang
Published: May 2022

Stroke is a cerebrovascular event with cerebral blood flow interruption which is caused by occlusion or bursting of cerebral vessels. At present, the main methods in treating stroke are surgical treatment, statins, and recombinant tissue-type plasminogen activator (rt-PA). Relatively, traditional Chinese medicine (TCM) has widely been used at clinical level in China and some countries in Asia. Xiao-Xu-Ming decoction (XXMD) is a classical and widely used prescription in treating stroke in China. However, the material basis of effect and the action principle of XXMD are still not clear. To solve this issue, we designed a new system pharmacology strategy that combined targets of XXMD and the pathogenetic genes of stroke to construct a functional response space (FRS). The effective proteins from this space were determined by using a novel node importance calculation method, and then the key functional components group (KFCG) that could mediate the effective proteins was selected based on the dynamic programming strategy. The results showed that enriched pathways of effective proteins selected from FRS could cover 99.10% of enriched pathways of reference targets, which were defined by overlapping of component targets and pathogenetic genes. Targets of optimized KFCG with 56 components can be enriched into 166 pathways that covered 80.43% of 138 pathways of 1,012 pathogenetic genes. A component potential effect score (PES) calculation model was constructed to calculate the comprehensive effective score of components in the components-targets-pathways (C-T-P) network of KFCGs, and showed that ferulic acid, zingerone, and vanillic acid had the highest PESs. Prediction and docking simulations show that these components can affect stroke synergistically through genes such as MEK, NFκB, and PI3K in PI3K-Akt, cAMP, and MAPK cascade signals. Finally, ferulic acid, zingerone, and vanillic acid were tested to be protective for PC12 cells and HT22 cells in increasing cell viabilities after oxygen and glucose deprivation (OGD). Our proposed strategy could improve the accuracy on decoding KFCGs of XXMD and provide a methodologic reference for the optimization, mechanism analysis, and secondary development of the formula in TCM.
Identification of A Risk Signature Based on Lactic Acid Metabolism-Related LncRNAs in Patients With Esophageal Squamous Cell Carcinoma
Authors: Zhao Fangchao , Li Yishuai , Dong Zefang , Zhang Dengfeng , Guo Pengfei , Li Zhirong , Li Shujun
Published: May 2022

Lactic acid, formerly thought of as a byproduct of glycolysis or a metabolic waste produced, has now been identified as a key regulator of cancer growth, maintenance, and progression. However, the results of investigations on lactic acid metabolism-related long non-coding RNAs (LRLs) in esophageal squamous cell carcinoma (ESCC) remain inconclusive. In this study, univariate Cox regression analysis was carried out in the TCGA cohort, and 9 lncRNAs were shown to be significantly associated with prognosis. Least absolute shrinkage and selection operator (LASSO) regression analysis and multivariate Cox regression analysis were then used in the GEO cohort. 6 LRLs were identified as independent prognostic factors for ESCC patients used to construct a prognostic risk-related signature subsequently. Two groups were formed based on the middle value of risk scores: a low-risk group and a high-risk group. Following that, we conducted Kaplan-Meier survival analysis, which revealed that the high-risk group had a lower survival probability than the low-risk group in both GEO and TCGA cohorts. On multivariate Cox regression analysis, the prognostic signature was shown to be independent prognostic factor, and it was found to be a better predictor of the prognosis of ESCC patients than the currently widely used grading and staging approaches. The established nomogram can be conveniently applied in the clinic to predict the 1-, 3-, and 5- year survival rates of patients. There was a significant link found between the 6 LRLs-based prognostic signature and immune-cell infiltration, tumor microenvironment (TME), tumor somatic mutational status, and chemotherapeutic treatment sensitivity in the study population. Finally, we used GTEx RNA-seq data and qRT-PCR experiments to verify the expression levels of 6 LRLs. In conclusion, we constructed a prognostic signature which could predict the prognosis and immunotherapy response of ESCC patients.
Two Pex5 Proteins With Different Cargo Specificity Are Critical for Peroxisome Function in Ustilago maydis
Authors: Ast Julia , Bäcker Nils , Bittner Elena , Martorana Domenica , Ahmad Humda , Bölker Michael , Freitag Johannes
Published: May 2022

Peroxisomes are dynamic multipurpose organelles with a major function in fatty acid oxidation and breakdown of hydrogen peroxide. Many proteins destined for the peroxisomal matrix contain a C-terminal peroxisomal targeting signal type 1 (PTS1), which is recognized by tetratricopeptide repeat (TPR) proteins of the Pex5 family. Various species express at least two different Pex5 proteins, but how this contributes to protein import and organelle function is not fully understood. Here, we analyzed truncated and chimeric variants of two Pex5 proteins, Pex5a and Pex5b, from the fungus Ustilago maydis. Both proteins are required for optimal growth on oleic acid-containing medium. The N-terminal domain (NTD) of Pex5b is critical for import of all investigated peroxisomal matrix proteins including PTS2 proteins and at least one protein without a canonical PTS. In contrast, the NTD of Pex5a is not sufficient for translocation of peroxisomal matrix proteins. In the presence of Pex5b, however, specific cargo can be imported via this domain of Pex5a. The TPR domains of Pex5a and Pex5b differ in their affinity to variations of the PTS1 motif and thus can mediate import of different subsets of matrix proteins. Together, our data reveal that U. maydis employs versatile targeting modules to control peroxisome function. These findings will promote our understanding of peroxisomal protein import also in other biological systems.
Reciprocal Regulation of Mitofusin 2-Mediated Mitophagy and Mitochondrial Fusion by Different PINK1 Phosphorylation Events
Authors: Li Jiajia , Dang Xiawei , Franco Antonietta , Dorn Gerald W
Published: May 2022

Mitochondrial repair is essential to metabolic homeostasis. Outer mitochondrial membrane mitofusin (MFN) proteins orchestrate mitochondrial fusion that opposes mitochondrial degeneration caused by senescence. Depending upon physiological context, MFN2 can either mediate mitochondrial fusion or recruit cytosolic Parkin to initiate mitophagic elimination. Because it is not clear how these events are counter-regulated we engineered and expressed MFN2 mutants that mimic phosphorylated or non-phosphorylatable MFN2 at its PINK1 phosphorylation sites: T111, S378, and S442. By interrogating mitochondrial fusion, polarization status, and Parkin binding/mitophagy as a function of inferred MFN2 phosphorylation, we discovered that individual MFN2 phosphorylation events act as a biological “bar-code”, directing mitochondrial fate based on phosphorylation site state. Experiments in Pink1 deficient cells supported a central role for PINK1 kinase as the pivotal regulator of MFN2 functionality. Contrary to popular wisdom that Parkin-mediated ubiquitination regulates MFN-mediated mitochondrial fusion, results in Prkn null cells demonstrated the dispensability of Parkin for MFN2 inactivation. These data demonstrate that PINK1-mediated phosphorylation is necessary and sufficient, and that Parkin is expendable, to switch MFN2 from fusion protein to mitophagy effector.
Ferrochelatase: Mapping the Intersection of Iron and Porphyrin Metabolism in the Mitochondria
Authors: Obi Chibuike David , Bhuiyan Tawhid , Dailey Harry A. , Medlock Amy E.
Published: May 2022

Porphyrin and iron are ubiquitous and essential for sustaining life in virtually all living organisms. Unlike iron, which exists in many forms, porphyrin macrocycles are mostly functional as metal complexes. The iron-containing porphyrin, heme, serves as a prosthetic group in a wide array of metabolic pathways; including respiratory cytochromes, hemoglobin, cytochrome P450s, catalases, and other hemoproteins. Despite playing crucial roles in many biological processes, heme, iron, and porphyrin intermediates are potentially cytotoxic. Thus, the intersection of porphyrin and iron metabolism at heme synthesis, and intracellular trafficking of heme and its porphyrin precursors are tightly regulated processes. In this review, we discuss recent advances in understanding the physiological dynamics of eukaryotic ferrochelatase, a mitochondrially localized metalloenzyme. Ferrochelatase catalyzes the terminal step of heme biosynthesis, the insertion of ferrous iron into protoporphyrin IX to produce heme. In most eukaryotes, except plants, ferrochelatase is localized to the mitochondrial matrix, where substrates are delivered and heme is synthesized for trafficking to multiple cellular locales. Herein, we delve into the structural and functional features of ferrochelatase, as well as its metabolic regulation in the mitochondria. We discuss the regulation of ferrochelatase via post-translational modifications, transportation of substrates and product across the mitochondrial membrane, protein-protein interactions, inhibition by small-molecule inhibitors, and ferrochelatase in protozoal parasites. Overall, this review presents insight on mitochondrial heme homeostasis from the perspective of ferrochelatase.
Selective Photocatalytic Oxidation of Glycerol and 3-Pyridinemethanol by Nanotube/Nanowire-Structured TiO2 Powders Obtained by Breakdown Anodization
Authors: Çetinkaya Sıdıka , Khamidov Gofur , Özcan Levent , Palmisano Leonardo , Yurdakal Sedat
Published: May 2022

Nanotube/nanowire-structured TiO2 was formed on the Ti surface by an anodic oxidation method performed at different potential values (50 or 60 V) and for different times (3 or 5 h). The TiO2 photocatalysts were taken in powder form using the ultrasonic treatment from the Ti electrodes, calcined at different temperatures, and characterized by XRD and SEM techniques, and BET surface area analyses. Both the crystallinity and the size of the primary TiO2 particles increased by increasing the heat treatment temperature. While all the photocatalysts heat treated up to 500°C were only in the anatase phase, the particles heat-treated at 700°C consisted of both anatase and rutile phases. The BET specific surface area of the samples decreased drastically after heat treatment of 700°C because of partial sinterization. SEM analyses indicated that the prepared materials were structured in both nanotubes and nanowires. They were tested as photocatalysts for the selective oxidation of glycerol and 3-pyridinemethanol under UVA irradiation in water at room temperature and ambient pressure. Glyceraldehyde, 1,3-dihydroxyacetone, and formic acid were determined as products in glycerol oxidation, while the products of 3-pyridinemethanol oxidation were 3-pyridinemethanal and vitamin B3. Non-nanotube/nanowire-structured commercial (Degussa P25 and Merck TiO2) photocatalysts were used for the sake of comparison. Low selectivity values towards the products obtained by partial oxidation were determined for glycerol. On the contrary, higher selectivity values towards the products were obtained (total 3-pyridinemethanal and vitamin B3 selectivity up to ca. 90%) for the photocatalytic oxidation of 3-pyridinemethanol. TiO2 photocatalysts must be highly crystalline (calcined at 700°C) for effective oxidation of glycerol, while for the selective oxidation of 3-pyridinemethanol it was not necessary to obtain a high crystallinity, and the optimal heat treatment temperature was 250°C. Glycerol and its oxidation products could more easily desorb from highly crystalline and less hydroxylated surfaces, which would justifies their higher activity. The prepared photocatalysts showed lower activity than Degussa P25, but a greater selectivity towards the products found.
Deciphering the Structure and Formation of Amyloids in Neurodegenerative Diseases With Chemical Biology Tools
Authors: Landrieu Isabelle , Dupré Elian , Sinnaeve Davy , El Hajjar Léa , Smet-Nocca Caroline
Published: May 2022

Protein aggregation into highly ordered, regularly repeated cross-β sheet structures called amyloid fibrils is closely associated to human disorders such as neurodegenerative diseases including Alzheimer’s and Parkinson’s diseases, or systemic diseases like type II diabetes. Yet, in some cases, such as the HET-s prion, amyloids have biological functions. High-resolution structures of amyloids fibrils from cryo-electron microscopy have very recently highlighted their ultrastructural organization and polymorphisms. However, the molecular mechanisms and the role of co-factors (posttranslational modifications, non-proteinaceous components and other proteins) acting on the fibril formation are still poorly understood. Whether amyloid fibrils play a toxic or protective role in the pathogenesis of neurodegenerative diseases remains to be elucidated. Furthermore, such aberrant protein-protein interactions challenge the search of small-molecule drugs or immunotherapy approaches targeting amyloid formation. In this review, we describe how chemical biology tools contribute to new insights on the mode of action of amyloidogenic proteins and peptides, defining their structural signature and aggregation pathways by capturing their molecular details and conformational heterogeneity. Challenging the imagination of scientists, this constantly expanding field provides crucial tools to unravel mechanistic detail of amyloid formation such as semisynthetic proteins and small-molecule sensors of conformational changes and/or aggregation. Protein engineering methods and bioorthogonal chemistry for the introduction of protein chemical modifications are additional fruitful strategies to tackle the challenge of understanding amyloid formation.
Adsorption and Sensing Performances of Pristine and Au-Decorated Gallium Nitride Monolayer to Noxious Gas Molecules: A DFT Investigation
Authors: Li Zhihui , Jia Lufen , Chen Jianxing , Cui Xiaosen , Zhou Qu
Published: May 2022

In this study, the adsorption of noxious gas molecules (NO, Cl2, and O3) on GaN and Au-decorated GaN was systematically scrutinized, and the adsorption energy, bond length, charge, density of state (DOS), partial density of state (PDOS), electron deformation density (EDD), and orbitals were analyzed by the density functional theory (DFT) method. It is found that the interaction between NO and pristine GaN is physical adsorption, while GaN chemically reacts with Cl2 and O3. These observations suggest that pristine GaN may be a candidate for the detection of Cl2 and O3. The highly activated Au-decorated GaN can enhance the adsorption performance toward NO and convert the physical adsorption for NO into chemical adsorption, explaining the fact that precious metal doping is essential for regulating the electronic properties of the substrate material. This further confirms the well-established role of Au-decorated GaN in NO gas-sensing applications. In addition, the adsorption performance of Au-decorated GaN for Cl2 and O3 molecules is highly improved, which provides guidance to scavenge toxic gases such as Cl2 and O3 by the Au-decorated GaN material.
Gas Sensing Mechanism and Adsorption Properties of C2H4 and CO Molecules on the Ag3–HfSe2 Monolayer: A First-Principle Study
Authors: Jia Lufen , Chen Jianxing , Cui Xiaosen , Wang Zhongchang , Zeng Wen , Zhou Qu
Published: May 2022

The detection of dissolved gases in oil is an important method for the analysis of transformer fault diagnosis. In this article, the potential-doped structure of the Ag3 cluster on the HfSe2 monolayer and adsorption behavior of CO and C2H4 upon Ag3–HfSe2 were studied theoretically. Herein, the binding energy, adsorption energy, band structure, density of state (DOS), partial density of state (PDOS), Mulliken charge analysis, and frontier molecular orbital were investigated. The results showed that the adsorption effect on C2H4 is stronger than that on CO. The electrical sensitivity and anti-interference were studied based on the bandgap and adsorption energy of gases. In particular, there is an increase of 55.49% in the electrical sensitivity of C2H4 after the adsorption. Compared to the adsorption energy of different gases, it was found that only the adsorption of the C2H4 system is chemisorption, while that of the others is physisorption. It illustrates the great anti-interference in the detection of C2H4. Therefore, the study explored the potential of HfSe2-modified materials for sensing and detecting CO and C2H4 to estimate the working state of power transformers.
Exploring the Binding Mechanism of a Supramolecular Tweezer CLR01 to 14-3-3σ Protein via Well-Tempered Metadynamics
Authors: Zhou Xin , Shi Mingsong , Wang Xin , Xu Dingguo
Published: May 2022

Using supramolecules for protein function regulation is an effective strategy in chemical biology and drug discovery. However, due to the presence of multiple binding sites on protein surfaces, protein function regulation via selective binding of supramolecules is challenging. Recently, the functions of 14-3-3 proteins, which play an important role in regulating intracellular signaling pathways via protein–protein interactions, have been modulated using a supramolecular tweezer, CLR01. However, the binding mechanisms of the tweezer molecule to 14-3-3 proteins are still unclear, which has hindered the development of novel supramolecules targeting the 14-3-3 proteins. Herein, the binding mechanisms of the tweezer to the lysine residues on 14-3-3σ (an isoform in 14-3-3 protein family) were explored by well-tempered metadynamics. The results indicated that the inclusion complex formed between the protein and supramolecule is affected by both kinetic and thermodynamic factors. In particular, simulations confirmed that K214 could form a strong binding complex with the tweezer; the binding free energy was calculated to be −10.5 kcal·mol−1 with an association barrier height of 3.7 kcal·mol−1. In addition, several other lysine residues on 14-3-3σ were identified as being well-recognized by the tweezer, which agrees with experimental results, although only K214/tweezer was co-crystallized. Additionally, the binding mechanisms of the tweezer to all lysine residues were analyzed by exploring the representative conformations during the formation of the inclusion complex. This could be helpful for the development of new inhibitors based on tweezers with more functions against 14-3-3 proteins via modifications of CLR01. We also believe that the proposed computational strategies can be extended to understand the binding mechanism of multi-binding sites proteins with supramolecules and will, thus, be useful toward drug design.
Pneumococcal Surface Proteins as Virulence Factors, Immunogens, and Conserved Vaccine Targets
Authors: Aceil Javid , Avci Fikri Y.
Published: May 2022

Streptococcus pneumoniae is an opportunistic pathogen that causes over 1 million deaths annually despite the availability of several multivalent pneumococcal conjugate vaccines (PCVs). Due to the limitations surrounding PCVs along with an evolutionary rise in antibiotic-resistant and unencapsulated strains, conserved immunogenic proteins as vaccine targets continue to be an important field of study for pneumococcal disease prevention. In this review, we provide an overview of multiple classes of conserved surface proteins that have been studied for their contribution to pneumococcal virulence. Furthermore, we discuss the immune responses observed in response to these proteins and their promise as vaccine targets.
Emergence of Plasmids Co-Harboring Carbapenem Resistance Genes and tmexCD2-toprJ2 in Sequence Type 11 Carbapenem Resistant Klebsiella pneumoniae Strains
Authors: Li Xi , Wang Weizhong , Jin Xi , Zhang Xiaofan , Zou Xuehan , Ma Qiang , Hu Qingfeng , Huang Haijun , Tu Yuexing
Published: May 2022

Objectives

To characterize two plasmids co-harboring carbapenem resistance genes and tmexCD2-toprJ2 in carbapenem-resistant Klebsiella pneumoniae (CRKP) strains.

Methods

Two clinical CRKP strains were isolated and characterized by antimicrobial susceptibility testing, conjugation assays, whole-genome sequencing, and bioinformatics analysis.

Results

The two CRKP strains NB4 and NB5 were both resistant to imipenem, meropenem and tigecycline. Whole-genome sequencing revealed that two CRKP strains belonged to the ST11 type and carried multiple resistance genes. The tmexCD2-toprJ2 clusters in both strains were located on the IncFIB(Mar)-like/HI1B-like group of hybrid plasmids, which co-harbored the metallo-β-lactamase gene blaNDM-1. In addition, the co-existence of blaNDM-1 and blaKPC-2 and the presence of tmexCD2-toprJ2 in CRKP strain NB5 was observed.

Conclusions

In this study, tmexCD2-toprJ2 gene clusters were identified in two NDM-1-producing CRKP ST11 strains. These gene clusters will likely spread into clinical high-risk CRKP clones and exacerbate the antimicrobial resistance crisis. In addition, we detected the co-occurrence of blaNDM-1, blaKPC-2 and tmexCD2-toprJ2 in a single strain, which will undoubtedly accelerate the formation of a “superdrug resistant” bacteria. Hence, effective control measures should be implemented to prevent the further dissemination of such organisms in clinical settings.
Rethinking Figurative Language in Autism: What Evidence Can We Use for Interventions?
Authors: Vulchanova Mila , Vulchanov Valentin
Published: May 2022

Problems with the processing and understanding of figurative language have been systematically observed in individuals on the autism spectrum despite preserved structural language skills. In this qualitative review we discuss theoretical considerations of relevance for figurative language processing in neurotypical individuals and individuals with autism across the life-span. We address the factors which influence figurative language processing and their role in the processing of different types of figurative language, with a focus on idioms and metaphors. We address critically the evidence from research, including findings in our own research and recent systematic reviews and the extent to which they offer a reliable picture of potential deficits in figurative language processing in autism and their possible sources. This evidence is discussed from the point of view of insights it offers for interventions targeting non-literal language skills in children and adults with autism.
Predicting the Prognosis of Patients in the Coronary Care Unit: A Novel Multi-Category Machine Learning Model Using XGBoost
Authors: Wang Xingchen , Zhu Tianqi , Xia Minghong , Liu Yu , Wang Yao , Wang Xizhi , Zhuang Lenan , Zhong Danfeng , Zhu Jun , He Hong , Weng Shaoxiang , Zhu Junhui , Lai Dongwu
Published: May 2022

Background

Early prediction and classification of prognosis is essential for patients in the coronary care unit (CCU). We applied a machine learning (ML) model using the eXtreme Gradient Boosting (XGBoost) algorithm to prognosticate CCU patients and compared XGBoost with traditional classification models.

Methods

CCU patients' data were extracted from the MIMIC-III v1.4 clinical database, and divided into four groups based on the time to death: <30 days, 30 days−1 year, 1–5 years, and ≥5 years. Four classification models, including XGBoost, naïve Bayes (NB), logistic regression (LR), and support vector machine (SVM) were constructed using the Python software. These four models were tested and compared for accuracy, F1 score, Matthews correlation coefficient (MCC), and area under the curve (AUC) of the receiver operating characteristic curves. Subsequently, Local Interpretable Model-Agnostic Explanations method was performed to improve XGBoost model interpretability. We also constructed sub-models of each model based on the different categories of death time and compared the differences by decision curve analysis. The optimal model was further analyzed using a clinical impact curve. At last, feature ablation curves of the XGBoost model were conducted to obtain the simplified model.

Results

Overall, 5360 CCU patients were included. Compared to NB, LR, and SVM, the XGBoost model showed better accuracy (0.663, 0.605, 0.632, and 0.622), micro-AUCs (0.873, 0.811, 0.841, and 0.818), and MCC (0.337, 0.317, 0.250, and 0.182). In subgroup analysis, the XGBoost model had a better predictive performance in acute myocardial infarction subgroup. The decision curve and clinical impact curve analyses verified the clinical utility of the XGBoost model for different categories of patients. Finally, we obtained a simplified model with thirty features.

Conclusions

For CCU physicians, the ML technique by XGBoost is a potential predictive tool in patients with different conditions, and it may contribute to improvements in prognosis.
Nicorandil Improves Left Ventricular Myocardial Strain in Patients With Coronary Chronic Total Occlusion
Authors: Chen Shaomin , Ma Chen , Feng Xinheng , Cui Ming
Published: May 2022

Background

Nicorandil is recommended as a second-line treatment for stable angina; however, randomized-controlled trials to evaluate the benefit of nicorandil for patients with chronic total occlusion (CTO) are lacking.

Objective

To determine whether nicorandil can improve left ventricular (LV) myocardial strain in patients with CTO.

Methods

Patients with CTO were included and randomized to the nicorandil group (n = 31) and the control group (n = 30). Nicorandil was given orally at 15 mg/day for 3 months in the nicorandil group. Three-dimensional speckle-tracking echocardiography and the Seattle Angina Questionnaire (SAQ) survey were performed at baseline and at 3 months. The primary study endpoint was the LV global area strain (GAS) at 3 months.

Results

The nicorandil and the control groups were well-matched at baseline, including the mean GAS and SAQ scores. At 3 months, GAS in the nicorandil group was significantly higher than that in the control group (−23.7 ± 6.3% vs. −20.3 ± 5.6%, respectively; p = 0.033). There were no significant differences in LV global longitudinal strain, global circumferential strain, global radial strain, LV ejection fraction, LV end-diastolic volume, and LV end-systolic volume at 3 months between the two groups. At 3 months, the SAQ scores for angina stability, angina frequency, and treatment satisfaction in the nicorandil group were significantly higher than those in the control group.

Conclusion

Nicorandil treatment can improve GAS and angina symptoms in patients with CTO.

Clinical Trial Registration

www.ClinicalTrials.gov, identifier: NCT05087797.
Cardiac Shockwave Therapy – A Novel Therapy for Ischemic Cardiomyopathy?
Authors: Graber Michael , Nägele Felix , Hirsch Jakob , Pölzl Leo , Schweiger Victor , Lechner Sophia , Grimm Michael , Cooke John P. , Gollmann-Tepeköylü Can , Holfeld Johannes
Published: May 2022

Over the past decades, shockwave therapy (SWT) has gained increasing interest as a therapeutic approach for regenerative medicine applications, such as healing of bone fractures and wounds. More recently, pre-clinical studies have elucidated potential mechanisms for the regenerative effects of SWT in myocardial ischemia. The mechanical stimulus of SWT may induce regenerative effects in ischemic tissue via growth factor release, modulation of inflammatory response, and angiogenesis. Activation of the innate immune system and stimulation of purinergic receptors by SWT appears to enhance vascularization and regeneration of injured tissue with functional improvement. Intriguingly, small single center studies suggest that SWT may improve angina, exercise tolerance, and hemodynamics in patients with ischemic heart disease. Thus, SWT may represent a promising technology to induce cardiac protection or repair in patients with ischemic heart disease.
Longitudinal Associations Between Cumulative Physical Activity and Change in Structure and Function of the Left Side of the Heart: The Tromsø Study 2007–2016
Authors: Heitmann Kim Arne , Welde Boye , Løchen Maja-Lisa , Stylidis Michael , Schirmer Henrik , Morseth Bente
Published: May 2022

Background

Current knowledge about the relationship between physical activity (PA) and cardiac remodeling is mainly derived from cross-sectional studies of athletes, and there is a knowledge gap of this association in the general adult and elderly population. Therefore, we aimed to explore the longitudinal association between cumulative PA and change in cardiac structure and function in a general adult and elderly population.

Methods

This longitudinal study includes 594 participants from the sixth (Tromsø6, 2007–08) and seventh (Tromsø7, 2015–16) survey of the Tromsø Study. Cardiac structure and function were assessed by echocardiography at two time points, and PA was self-reported by questionnaire at both time points. PA volume was expressed as cumulative PA (Low, Moderate, and Hard) and the association with left atrial (LA) and left ventricular (LV) structure and function was assessed using ANCOVA.

Results

Overall, LA diameter index (LADi) increased significantly more in Hard compared to Moderate PA (+0.08 cm/m2, 95% CI 0.01–0.15, p = 0.020) from Tromsø6 to Tromsø7. When stratified by sex or age, higher levels of cumulative PA were associated with increased LADi in males and in participants <65 years only. Indexed LV mass (LVMi) increased significantly more in Moderate than in Low PA (+3.9 g/m2.7, 95% CI 0.23–7.57, p = 0.037). When stratified by sex or age, these changes in LVMi and indexed LV diameter (LVDi) were only significant in females. No significant associations were observed between cumulative PA and change in relative wall thickness, E/e' ratio, e' velocity, LV ejection fraction, and LADi/LVDi ratio.

Conclusion

Higher levels of cumulative PA were associated with increased LADi in males and participants <65 years, and with increased LVMi and LVDi in females. Despite cardiac chamber enlargement, the pump function of the heart did not change with higher levels of PA, and the atrioventricular ratio was unchanged. Our results indicate that cardiac chamber enlargement is a physiological response to PA.
Association Between a Novel Metabolic Score for Insulin Resistance and Mortality in People With Diabetes
Authors: Wang Zhenwei , Xie Jing , Wang Junjie , Feng Wei , Liu Naifeng , Liu Yun
Published: May 2022

Background

Growing studies have shown that insulin resistance (IR) is associated with poor prognoses among patients with diabetes, whereas the association between IR and mortality has not been determined. Hence we aimed to evaluate the associations between IR and all-cause, cardiovascular diseases (CVDs) and cancer-related mortality in patients with diabetes.

Methods

We enrolled 2,542 participants with diabetes with an average age of 57.12 ± 0.39 years and 52.8% men from the 1999–2014 National Health and Nutrition Examination Survey (NHANES 1999–2014). A novel metabolic score for insulin resistance (METS-IR) was considered as alternative marker of IR. Mortality data were obtained from the National Death Index records and all participants were followed up until December 31, 2015. Cox proportional hazards regression, restricted cubic spline and Kaplan-Meier survival curves were performed to evaluate the associations between METS-IR and all-cause and cause-specific mortality in patients with diabetes.

Results

During 17,750 person-years of follow-up [median (months), 95% CI: 90, 87–93], 562 deaths were documented, including 133 CVDs-related deaths and 90 cancer-related deaths. Multivariate Cox regression showed that compared with Quintile 1 (METS-IR ≤ 41), METS-IR in Quintile 2, 3, and 4 was all associated with all-cause mortality (Q2 vs. Q1: HR 0.65, 95% CI 0.49–0.87, P = 0.004; Q3 vs. Q1: HR 0.69, 95% CI 0.50–0.96, P = 0.029; Q4 vs. Q1: HR 0.57, 95% CI 0.36–0.91, P = 0.019; respectively). Restricted cubic spline indicated that METS-IR was non-linearly associated with all-cause and CVDs-related mortality. Threshold effect analyses determined that threshold values of METS-IR for all-cause and CVDs-related mortality were both 33.33. Only METS-IR below the threshold was negatively associated with all-cause and CVDs-related mortality (HR 0.785, 95% CI 0.724–0.850, P < 0.001; HR 0.722, 95% CI 0.654–0.797, P < 0.001; respectively). Sensitivity analyses showed that when excluding participants who died within 1 years of follow-up, the results of threshold effect analyses remained consistent, whereas excluding participants with CVDs, METS-IR below the threshold was only negatively correlated with all-cause mortality. Subgroup analyses indicated that for all-cause mortality, the results were still stable in all subgroups except newly diagnosed diabetes, but for CVDs-related mortality, the association persisted only in participants who were ≤ 65 years, male, White, non-White, already diagnosed diabetes, or uesd oral drugs, insulin, insulin sensitizing drugs.

Conclusion

METS-IR was non-linearly associated with all-cause and CVDs-related mortality in patients with diabetes, and METS-IR below the threshold was negatively associated with all-cause and CVDs-related mortality.
Successful Therapy for Myocarditis Concomitant With Complete Heart Block After Pembrolizumab Treatment for Head and Neck Squamous Cell Carcinoma: A Case Report With Literature Review
Authors: Su Lina , Liu Chuanfen , Wu Wenjie , Cui Yuxia , Wu Manyan , Chen Hong
Published: May 2022

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy over the past decade. Despite their beneficial effects on treating numerous types of tumors, cardiotoxicity resulting from ICIs is a rare side effect but a concerning one due to its high mortality rate. We herein describe a case of an 80-year-old woman with recurrent head and neck squamous cell cancer (HNSCC), who presented with myocarditis complicated by complete atrioventricular block (CAVB) after second infusion of pembrolizumab. After quickly ruling out myocardial infarction and viral myocarditis, the strong relationship between the onset time and pembrolizumab therapy suggested that ICI-induced myocarditis was the most possible diagnosis. Though CAVB frequently presents with fulminant myocarditis in the setting of ICI-related cardiotoxicity, the patients kept a stable hemodynamic status and had normal myocardial function with just a slightly low global longitudinal strain (GLS) at−16.4%, which implied myocardial injury but was highly related to good prognosis based on the existing literature. Besides, elderly patients are vulnerable to adverse outcomes of steroid therapy, notably opportunistic infections. To balance beneficial effects and adverse effects of immune suppression, she accepted high-dose steroids without pulse methylprednisolone. Excitingly, she had a dramatic clinical and laboratory improvement, and heart block quickly returned to normal sinus rhythm. Another interesting finding was that the patient's tumor remained stable during the half-year follow-up from the termination of immunotherapy. Besides, we here firstly review previously reported cases in terms of their clinical characteristics and prognosis of ICI-induced myocarditis with CAVB, in particular the reversibility of heart block. In conclusion, ICI-induced myocarditis can be life-threatening and it therefore warrants efforts to increase awareness, facilitate early detection, and initiate prompt intervention. Importantly, CAVB secondary to ICIs-induced myocarditis may not always present with fulminant myocarditis and more than 50% of these surviving patients might recover to normal sinus rhythm. For patients with ICI-induced myocarditis with contraindication for cardiac magnetic resonance (CMR), speckle-tracking echocardiography is a reliable and sensitive alternative to CMR for detecting myocardial injury, and GLS may be an important prognostic indicator.