Novel Insights into the Links between N6-Methyladenosine and Regulated Cell Death in Musculoskeletal Diseases.

Musculoskeletal diseases (MSDs), including osteoarthritis (OA), osteosarcoma (OS), multiple myeloma (MM), intervertebral disc degeneration (IDD), osteoporosis (OP), and rheumatoid arthritis (RA), present noteworthy obstacles associated with pain, disability, and impaired quality of life on a global scale. In recent years, it has become increasingly apparent that N6-methyladenosine (m6A) is a key regulator in the expression of genes in a multitude of biological processes. m6A is composed of 0.1-0.4% adenylate residues, especially at the beginning of 3'-UTR near the translation stop codon. The m6A regulator can be classified into three types, namely the "writer", "reader", and "eraser". Studies have shown that the epigenetic modulation of m6A influences mRNA processing, nuclear export, translation, and splicing. Regulated cell death (RCD) is the autonomous and orderly death of cells under genetic control to maintain the stability of the internal environment. Moreover, distorted RCDs are widely used to influence the course of various diseases and receiving increasing attention from researchers. In the past few years, increasing evidence has indicated that m6A can regulate gene expression and thus influence different RCD processes, which has a central role in the etiology and evolution of MSDs. The RCDs currently confirmed to be associated with m6A are autophagy-dependent cell death, apoptosis, necroptosis, pyroptosis, ferroptosis, immunogenic cell death, NETotic cell death and oxeiptosis. The m6A-RCD axis can regulate the inflammatory response in chondrocytes and the invasive and migratory of MM cells to bone remodeling capacity, thereby influencing the development of MSDs. This review gives a complete overview of the regulatory functions on the m6A-RCD axis across muscle, bone, and cartilage. In addition, we also discuss recent advances in the control of RCD by m6A-targeted factors and explore the clinical application prospects of therapies targeting the m6A-RCD in MSD prevention and treatment. These may provide new ideas and directions for understanding the pathophysiological mechanism of MSDs and the clinical prevention and treatment of these diseases.

Roles and mechanisms of copper homeostasis and cuproptosis in osteoarticular diseases.

Copper is an essential trace element in the human body that is extensively distributed throughout various tissues. The appropriate level of copper is crucial to maintaining the life activities of the human body, and the excess and deficiency of copper can lead to various diseases. The copper levels in the human body are regulated by copper homeostasis, which maintains appropriate levels of copper in tissues and cells by controlling its absorption, transport, and storage. Cuproptosis is a distinct form of cell death induced by the excessive accumulation of intracellular copper. Copper homeostasis and cuproptosis has recently elicited increased attention in the realm of human health. Cuproptosis has emerged as a promising avenue for cancer therapy. Studies concerning osteoarticular diseases have elucidated the intricate interplay among copper homeostasis, cuproptosis, and the onset of osteoarticular diseases. Copper dysregulation and cuproptosis cause abnormal bone and cartilage metabolism, affecting related cells. This phenomenon assumes a critical role in the pathophysiological processes underpinning various osteoarticular diseases, with implications for inflammatory and immune responses. While early Cu-modulating agents have shown promise in clinical settings, additional research and advancements are warranted to enhance their efficacy. In this review, we summarize the effects and potential mechanisms of copper homeostasis and cuproptosis on bone and cartilage, as well as their regulatory roles in the pathological mechanism of osteoarticular diseases (e.g., osteosarcoma (OS), osteoarthritis (OA), and rheumatoid arthritis (RA)). We also discuss the clinical-application prospects of copper-targeting strategy, which may provide new ideas for the diagnosis and treatment of osteoarticular diseases.

Facile Synthesis of Quinoline-Substituted 3-Hydroxy-2-oxindoles and 3-Amino-2-oxindoles via a Palladium-Catalyzed Cascade Intramolecular Cyclization/Intermolecular Nucleophilic Addition Reaction.

An efficient cascade intramolecular cyclization/intermolecular nucleophilic addition reaction of allenyl benzoxazinone with isatin or isatin-derived ketimine has been established by using Pd0-π-Lewis base catalysis. A series of 3-hydroxy-2-oxindoles and 3-amino-2-oxindoles with quaternary carbon atoms at the C3 position were synthesized in good yields under mild conditions through this protocol.

Lanthanum-doped magnetic biochar activating persulfate in the degradation of florfenicol.

In this study, lanthanum-doped magnetic biochar (LaMBC) was synthesized from bagasse by co-doping iron salt and lanthanum salt, and it was characterized for its application in the activation of persulfate (PS) in the degradation of Florfenicol (FLO). The results indicated that the LaMBC/PS system consistently achieved a degradation efficiency of over 99.5 %, with a reaction rate constant 4.71 times as that of MBC. The mechanism of FLO degradation suggested that O2•- and •OH played dominant roles, contributing 40.92 % and 36.96 %, respectively, during FLO degradation. Through physicochemical characterization and quenching experiments, it can be concluded that the key reasons for the enhancement of MBC activation performance are as follows: (1) Lanthanum doping in magnetized biochar increased the Fe(II) content in MBC. (2) Lanthanum doping significantly improved the adsorption capacity of LaMBC, increased the concentration of pollutants on the catalyst surface and effectively enhancing the reaction rate. (3) Lanthanum doping effectively increased the surface Fe(II) content during the reaction process in LaMBC, promoted the generation of active oxygen species in PS. This study delves into synthesizing and applying LaMBC for PS activation and FLO removal. The emphasis is on comprehensively characterizing and experimenting to elucidate the mechanism, proposing an innovative approach for efficiently degrading antibiotic wastewater.

Bactericidal efficacy of mobile ultraviolet-C disinfection devices in reducing contamination in biosafety laboratories.

INTRODUCTION: Biosafety research requires a wide range of microorganisms and thorough disinfection to prevent laboratory infection is often required. Ultraviolet-C (UV-C) exposure reduces bacterial and viral concentrations. Therefore, in this study, we aimed to evaluate the efficacy of a mobile UV-C device as a non-contact disinfection strategy. METHODOLOGY: The bactericidal efficacy of the UV-C device was determined based on log10 decreases in the relative abundances of bacterial indicators, including Escherichia coli, Staphylococcus aureus, Staphylococcus albus, and Pseudomonas aeruginosa at 0.5 and 1.0 m after irradiation for 30, 60, and 90 min. Next, the reduction of natural bacteria in air and on surface as a result of the UV-C device exposure in the laboratory were determined. RESULTS: Exposure to the UV-C disinfection device resulted in mean log10 decreases in microbial contamination of 3.55 and 5.85 following irradiation for 30 and 90 min, respectively, at a distance of 0.5 m. Further, P. aeruginosa and E. coli were the most and least sensitive to UV-C exposure, respectively. The bacterial load in air decreased by 65.53% after 60 min of irradiation, while those on surfaces decreased by 44.19% and 78.23% after 30 and 60 min of irradiation, respectively. CONCLUSIONS: The UV-C device effectively reduced bacterial load after irradiation for over 60 min. Further studies are encouraged to determine the effectiveness of the UV-C disinfection device in frequently occupied institutions, such as primary medical, health, and nursery, and its efficiency in infection control.

Characterization of Cancer Evolution Landscape Based on Accurate Detection of Somatic Mutations in Single Tumor Cells.

Accurate detection of somatic mutations in single tumor cells is greatly desired as it allows us to quantify the single-cell mutation burden and construct the mutation-based phylogenetic tree. Here we developed scNanoSeq chemistry and profiled 842 single cells from 21 human breast cancer samples. The majority of the mutation-based phylogenetic trees comprise a characteristic stem evolution followed by the clonal sweep. We observed the subtype-dependent lengths in the stem evolution. To explain this phenomenon, we propose that the differences are related to different reprogramming required for different subtypes of breast cancer. Furthermore, we reason that the time that the tumor-initiating cell took to acquire the critical clonal-sweep-initiating mutation by random chance set the time limit for the reprogramming process. We refer to this model as a reprogramming and critical mutation co-timing (RCMC) subtype model. Next, in the sweeping clone, we observed that tumor cells undergo a branched evolution with rapidly decreasing selection. In the most recent clades, effectively neutral evolution has been reached, resulting in a substantially large number of mutational heterogeneities. Integrative analysis with 522-713X ultra-deep bulk whole genome sequencing (WGS) further validated this evolution mode. Mutation-based phylogenetic trees also allow us to identify the early branched cells in a few samples, whose phylogenetic trees support the gradual evolution of copy number variations (CNVs). Overall, the development of scNanoSeq allows us to unveil novel insights into breast cancer evolution.

Chemical profiling and mechanistic studies of Zhi-Shang-Feng granules against influenza virus by high-performance liquid chromatography coupled with Q exactive focus hybrid quadrupole orbitrap high-resolution mass spectrometry in combination with network pharmacology analysis.

Zhi-Shang-Feng Granules are used in the clinical treatment of influenza to relieve headaches, chills and fever, bronchitis, nasal congestion, neuralgia and other symptoms. To decipher the components responsible for therapeutic effects of Zhi-Shang-Feng g ranules against influenza virus, an analytical method based on high-performance liquid chromatography coupled with Q exactive focus hybrid quadrupole orbitrap high resolution mass spectrometry was developed and the chemical profile of Zhi-Shang-Feng granules was characterized. Then, the identified components were used to conduct network pharmacological analysis and determine the potential mechanism of Zhi-Shang-Feng Granules. As a result, 177 compounds were putatively identified through comprehensive analysis by liquid chromatography coupled with high-resolution mass spectrometry, of which 23 compounds were unambiguously confirmed with reference standards. Components in Zhi-Shang-Feng Granules were found to specifically act on different enzymes, G-protein-coupled receptors, ion channels and transporters in the immune, endocrine, nervous, and circulatory systems. The potential mechanism was related to several biological processes, including cell growth and death, pattern recognition receptor signalling, signalling by interleukins, and lipid metabolism. The combination of chemical profile characterization and network construction provided useful insight into the overall chemical composition of Zhi-Shang-Feng granules and revealed their potential anti-infection, anti-inflammatory and immunoregulatory mechanisms against influenza virus infected disease.

Nitrogen-rich magnetic biochar prepared by urea was used as an efficient catalyst to activate persulfate to degrade organic pollutants.

In order to fully exploit the potential of magnetic biochar-based persulfate (PS) systems, N was utilized to modify the magnetic biochar-based catalysts through impregnation-pyrolysis method. A typical antifungal drug, metronidazole (MNZ), is selected as the target pollutant to score the reactivity of as-synthetic nitrogen-rich magnetic biochar (NMBC) catalysts. In the modified system, 99.6% of MNZ was removed, 13.6 times of that in the unmodified system. Active radical verification experiments showed that 1O2 was the key active radical. Various characterization showed that the nitrogen-rich significantly improved the persistent free radical, defect degree, content of oxygen-containing groups, electrochemical conductivity and other catalytic activity related properties. Physicochemical characterization, Fe(II) semi-quantitative analysis and masking experiments confirmed that the doping of magnetic biochar with nitrogen increased its Fe(II) content (23.79 mg/g), approximately 2.6 times higher than that of pristine magnetic biochar. Moreover, N induces strong electron accretion of Fe atom through coordination bond, which leads to the increase of electron density on the Fe atom, which increases the content of Fe (II) in the material, thus improving the ability of the material to activate PS to generate 1O2, and promoting the degradation reaction of MNZ. This paper provides a method to improve the activation performance of magnetic biochar.

Oral immunizations with Bacillus subtilis spores displaying VP19 protein provide protection against Singapore grouper iridovirus (SGIV) infection in grouper.

Disease caused by Singapore grouper iridovirus (SGIV) results in major economic losses in the global grouper aquaculture industry. Vaccination is considered to be the most effective way to protect grouper from SGIV. In this study, the spores of Bacillus subtilis (B.subtilis) WB600 were utilized as the vehicle that the VP19 protein was displayed on the spores surface. To further investigate the effect of oral vaccination, the grouper were orally immunized with B.s-CotC-19 spores. After challenged, the survival rate of grouper orally vaccinated with B.s-CotC-19 spores was 34.5% and the relative percent survival (RPS) was 28.7% compared to the PBS group. Moreover, the viral load in the tissues of the B.s-CotC-19 group was significantly lower than that of the PBS group. The histopathological sections of head kidney and liver tissue from the B.s-CotC-19 group showed significantly less histopathology compared to the PBS group. In addition, the specific IgM levels in serum in the B.s-CotC-19 group was higher than those in the PBS group. In the hindgut tissue, the immune-related gene expression detected by quantitative real-time PCR (qRT-PCR) exhibited an increasing trend in different degrees in the B.s-CotC-19 group, suggesting that the innate and adaptive immune responses were activated. These results indicated that the oral administration of recombinant B.subtilis spores was effective for preventing SGIV infection. This study provided a feasible strategy for the controlling of fish virus diseases.

Comparative cytotoxicity analyses of disinfection byproducts in drinking water using dimensionless parameter scaling method: Effect of halogen substitution type and number.

Up to date, over 700 disinfection byproducts (DBPs) have been detected and identified in drinking water. It has been recognized that cytotoxicity of DBPs varied significantly among groups. Even within the same group, cytotoxicity of different DBP species was also different due to different halogen substitution types and numbers. However, it is still difficult to quantitatively determine the inter-group cytotoxicity relationships of DBPs under the effect of halogen substitution in different cell lines, especially when a large number of DBP groups and multiple cytotoxicity cell lines are involved. In this study, a powerful dimensionless parameter scaling method was adopted to quantitatively determine the relationship of halogen substitution and the cytotoxicity of various DBP groups in three cell lines (i.e., the human breast carcinoma (MVLN), Chinese hamster ovary (CHO), and human hepatoma (Hep G2) cell cytotoxicity) with no need to consider their absolute values and other influences. By introducing the dimensionless parameters Dx-orn-speciescellline and D¯x-orn-speciescellline, as well as their corresponding linear regression equation coefficients ktypeornumbercellline and k¯typeornumbercellline, the strength and trend of halogen substitution influences on the relative cytotoxic potency could be determined. It was found that the effect of halogen substitution type and number on the cytotoxicity of DBPs followed the same patterns in the three cell lines. The CHO cell cytotoxicity was the most sensitive cell line to evaluate the effect of halogen substitution on the aliphatic DBPs, whereas the MVLN cell cytotoxicity was the most sensitive cell line to evaluate the effect of halogen substitution on the cyclic DBPs. Notably, seven quantitative structure activity relationship (QSAR) models were established, which could not only predict the cytotoxicity data of DBPs, but also help to explain and verify the patterns of halogen substitution effect on cytotoxicity of DBPs.

Effect of Mn-based magnetic biochar /PS reaction system on oxidation of metronidazole.

In order to fully exploit the potential of magnetic biochar-based persulfate (PS) systems, Mn was utilized to modify the magnetic biochar-based catalysts through impregnation-pyrolysis method. Taking metronidazole (MNZ), a typical antifungal drug, as the target contaminant, the reactivity of the synthesized magnetic biochar (MMBC) catalyst was evaluated. The degradation efficiency of MNZ in MMBC/persulfate system was 95.6%, which was 13.0 times higher than that in MBC/PS system. The characterization experiments confirmed the degradation of metronidazole by surface binding free radicals, the ·OH and 1O2 played the key role in remove of MNZ in the system of MMBC/PS. Physicochemical characterization, Fe(II) semi-quantitative analysis and masking experiments confirmed that the doping of MBC with Mn increased its Fe(II) content (43.0 mg/g), approximately 7.8 times higher than that of pristine MBC. The increase of Fe(II) content in MBC is the key reason to improve the optimization of MBC modified with Mn. Simultaneously, both Fe(II) and Mn(II) were the key components of PS activation by magnetic biochar. This paper presents a method to optimize the high efficiency of PS activation by magnetic biochar.

Few-Shot Learning-Based, Long-Term Stable, Sensitive Chemosensor for On-Site Colorimetric Detection of Cr(VI).

The rapid emergence of deep learning, e.g., deep convolutional neural networks (DCNNs) as one-click image analysis with super-resolution, has already revolutionized colorimetric determination. But it is severely limited by its data-hungry nature, which is overcome by combining the generative adversarial network (GAN), i.e., few-shot learning (FSL). Using the same amount of real sample data, i.e., 414 and 447 samples as training and test sets, respectively, the accuracy could be increased from 51.26 to 85.00% because 13,500 antagonistic samples are created and used by GAN as the training set. Meanwhile, the generated image quality with GAN is better than that with the commonly used convolution self-encoder method. The simple and rapid on-site determination of Cr(VI) with 1,5-diphenylcarbazide (DPC)-based test paper is a favorite for environment monitoring but is limited by unstable DPC, poor sensitivity, and narrow linear range. The chromogenic agent of DPC is protected by the blending of polyacrylonitrile (PAN) and then loaded onto thin chromatographic silica gel (SG) as a Cr(VI) colorimetric sensor (DPC/PAN/SG); its stability could be prolonged from 18 h to more than 30 days, and its repeatable reproducibility is realized via facile electrospinning. By replacing the traditional Ed method with DCNN, the detection limit is greatly improved from 1.571 mg/L to 50.00 µg/L, and the detection range is prolonged from 1.571-8.000 to 0.0500-20.00 mg/L. The complete test time is shortened to 3 min. Even without time-consuming and easily stained enrichment processing, its detection limit of Cr(VI) in the drinking water can meet on-site detection requirements by USEPA, WHO, and China.

[Quality evaluation of Commelina communis from different origins based on multicomponent content determination combined with chemometrics].

This research established a high-performance liquid chromatography(HPLC) method for simultaneous determination of isoorientin, orientin, vitexin, and isovitexin in Commelina communis to conduct content difference analysis and quality evaluation of 62 batches of C. communis from different origins. The HPLC content determination was performed on a Dikma Platisil ODS chromatographic column(4.6 mm×250 mm, 5 µm), with acetonitrile-0.1% formic acid(14∶86) as the mobile phase. The detection wavelength was set at 348 nm, the flow rate was 1.0 mL·min~(-1), and the column temperature was 35 ℃. The differences in origins and quality of 62 batches of C. communis were studied by chemometrics. The results showed that the determination of four components mani-fested a good linear relationship in the range of mass concentration(r>0.999 9), and the average recovery rate was 96.17%-103.0%. The relative standard deviations(RSDs) of precision, stability, and repeatability were all less than 2.0%. The content of four components from high to low was isoorientin>isovitexin>orientin>vitexin. Forty-seven batches of C. communis with clear origins were classified into six categories by chemometrics. C. communis from different origins had different qualities. Generally, C. communis from Western China, Central China, and South of China had superior qualities. The HPLC method established in this study is specific, simple, and efficient, which provides references for the comprehensive evaluation of the quality of C. communis. The chemometrics shows that the qualities of C. communis from different origins are largely different. Isoorientin can be used as an index to determine the content of C. communis, and its content limit should be set no less than 0.023%.

Droplet-based transcriptome profiling of individual synapses.

Synapses are crucial structures that mediate signal transmission between neurons in complex neural circuits and display considerable morphological and electrophysiological heterogeneity. So far we still lack a high-throughput method to profile the molecular heterogeneity among individual synapses. In the present study, we develop a droplet-based single-cell (sc) total-RNA-sequencing platform, called Multiple-Annealing-and-Tailing-based Quantitative scRNA-seq in Droplets, for transcriptome profiling of individual neurites, primarily composed of synaptosomes. In the synaptosome transcriptome, or 'synaptome', profiling of both mouse and human brain samples, we detect subclusters among synaptosomes that are associated with neuronal subtypes and characterize the landscape of transcript splicing that occurs within synapses. We extend synaptome profiling to synaptopathy in an Alzheimer's disease (AD) mouse model and discover AD-associated synaptic gene expression changes that cannot be detected by single-nucleus transcriptome profiling. Overall, our results show that this platform provides a high-throughput, single-synaptosome transcriptome profiling tool that will facilitate future discoveries in neuroscience.

Impacts of wet-dry alternations on cadmium and zinc immobilisation in soil remediated with iron oxides.

Chemical immobilisation is extensively used for in-situ remediation of heavy metals contaminated soil. Immobilised heavy metals could be reactivated by multiple factors such as pH, moisture, temperature, rainfall, etc., among which rainfall is very important, especially acid rain in southern China. Wet-dry alternations were used to simulate the leaching of metals by rainwater. The variation of cadmium (Cd) and zinc (Zn) speciation distribution in soil immobilised with iron oxides (goethite (GE) and 2-line ferrihydrite (GLS)) was investigated. The impacts of wet-dry alternations on the properties of the soil and amendments were also assessed. In the soil without amendments (OS) and amended with GE (GS), the stable fractions were reactivated and transformed into labile fractions under wet-dry alternations. In the soil amended with GLS (LS), the exchangeable and carbonate-bound Cd decreased while the soluble, Fe-Mn oxide bound and organic bound Cd increased. The carbonate-bound Zn was transformed into the Fe-Mn oxide-bound Zn. Transformation from the amorphous iron oxide into crystalline iron oxide in GS and LS were 4.9% and 5.3%. The Pearson correlation analysis showed that the soil pH and the iron-oxide speciation were strongly correlated with Cd/Zn fractions in the soil. The specific surface area, pore volume and adsorption capacity of the iron oxides decreased by 9.26%, 38.89% and 62-73% (for GE), 1.88%, 22.22% and 26-55% (for GLS). The altered soil properties and morphological differences between the two iron oxides under wet-dry alternations were important reasons for Cd/Zn reactivation.

Association between mixed aldehydes and bone mineral density based on four statistical models.

Aldehydes as an environmental pollutant may lead to oxidative stress, which is an important mechanism in the development of osteoporosis. This suggests a possible link between aldehyde exposure and osteoporosis. Considering the mixed nature of aldehyde exposure and the interactions between different aldehydes, we explored for the first time the associations between mixed six aldehydes (benzaldehyde, butyraldehyde, heptanal, hexanal, isovaleraldehyde, and propionaldehyde) and BMD in three populations (men, premenopausal women, and postmenopausal women) by applying four statistical models: quantile g-computation (qgcomp) model, Bayesian kernel machine regression (BKMR) model, generalized linear regression model (GLM), and generalized additive model (GAM), based on the National Health and Nutrition Examination Survey (NHANES) 2013-2014. We found that mixed aldehydes could significantly reduce BMD in men, with hexanaldehyde and propanaldehyde having the greatest negative qgcomp model and BKMR model weights, also confirmed by GLM. The associations between isopentanaldehyde and propanaldehyde and femoral BMD in men were non-linear and had threshold effects as derived from the BKMR model and GAM. The associations turned positive when the concentrations of isopentanaldehyde and propanaldehyde exceeded their respective inflection points. To conclude, our study might provide new ideas for the prevention and treatment of osteoporosis, and hexanaldehyde and propanaldehyde should be more regulated to prevent osteoporosis.

Impacts of anions on activated persulfate oxidation of Fe(II) - Rich potassium doped magnetic biochar.

The potassium-doped magnetic biochar (KMBC) preparation was inevitably introduced the different anions in the process of modifying magnetic biochar (MBC) with different potassium salts, but the effect and mechanism of different anion on KMBC activation properties has not been reported. Therefore, in this paper, five different KMBCs were prepared using several common potassium salts under the same dosage of K+ and Fe2+, and then was added in the presence of persulfate (PS) for the removal of metronidazole (MNZ). The removal rate of metronidazole was ordered as KMBCK2SO4 (98.40%) > KMBCKNO3 (76.84%) > KMBCKCl (20.79%) > KMBCK2CO3 (19.02%) > KMBCK2C2O4 (14.23%). However, the semi-quantitative of Fe(II) experiments results confirmed that the effectively increase of Fe(II) content by potassium salts modification played the dominant role in improvement of KMBC activation performance. The Fe(II) content of KMBC were ordered as KMBCK2CO3 > KMBCK2SO4 > KMBCKNO3 > KMBCKCl > KMBCK2C2O4, with the Fe(II) content of KMBC of 36.74, 17.70, 8.79, 5.24 and 4.85 mg/g, respectively. The indicated that the introduction of different anions would lead to different optimal Fe(Ⅱ) content in KMBC modified with different potassium salts, which was most directly reflected in 1O2 content in different KMBC/PS systems, and account for the difference in MNZ degradation efficiency. Meanwhile, when the Fe(II) content in KMBC reached the range of 13.7-28.8 mg/g, KMBC had the better performance of activating PS.

Plasma metabolomic analysis reveals the therapeutic effects of Jiashen tablets on heart failure.

Background: Heart failure is a chronic progressive condition that significantly affects the quality of life of patients with high hospitalization and mortality rates. Jiashen tablets (JST), a Chinese herbal formula, have been reported to be an effective treatment against heart failure, however the underlying mechanisms remain obscure. This study was designed to determine the effect of JST on the treatment of heart failure and delineate the underlying mechanisms by an untargeted metabolomics approach. Materials and methods: The chronic heart failure model was established by the permanent ligation of the left anterior descending coronary artery in rats. The cardiac functions of rats, including left ventricular ejection fraction (LVEF) and fractional shortening (LVFS), left ventricular internal diameter end diastole (LVIDd) and end systole (LVIDs), and interventricular septum thickness in diastole (IVSd) and in systole (IVSs), were measured by echocardiography. Biochemical analysis and histopathological examination were also performed to evaluate therapeutic effects of JST for treating heart failure. UHPLC-QTOF-MS/MS coupled with multivariate statistical analyses were applied for plasma metabolic profiling to identify biomarkers and potential mechanisms of JST in the treatment of heart failure. Results: Jiashen tablets could improve the cardiac function of heart failure rats and thus ameliorate heart failure via enhancing rat LVEF and LVFS and decreasing LVIDd, LVIDs, IVSd, and IVSs. Results of biochemical analysis and histopathological examination revealed that JST could reduce the serum lactate dehydrogenase (LDH) activity and the level of NT-pro BNP, markers of heart failure and myocardial damage, and inhibit myocardial fibrosis. Furthermore, in metabolomics analysis, a total of 210 metabolites with significant differences were identified between heart failure rats and normal rats, among which 29 metabolites were significantly restored after JST treatment. These metabolites were primarily involved in tryptophan metabolism, branched-chain amino acid metabolism, fatty acids ß-oxidation, and glycerophospholipid metabolism. Conclusion: The present study illustrated the therapeutic effect of JST for the treatment of heart failure and delineated the underlying mechanisms mainly relating to the regulation of amino acid metabolism and lipid metabolism in heart failure rats.

Evolution of sequence traits of prion-like proteins linked to amyotrophic lateral sclerosis (ALS).

Prions are proteinaceous particles that can propagate an alternative conformation to further copies of the same protein. They have been described in mammals, fungi, bacteria and archaea. Furthermore, across diverse organisms from bacteria to eukaryotes, prion-like proteins that have similar sequence characters are evident. Such prion-like proteins have been linked to pathomechanisms of amyotrophic lateral sclerosis (ALS) in humans, in particular TDP43, FUS, TAF15, EWSR1 and hnRNPA2. Because of the desire to study human disease-linked proteins in model organisms, and to gain insights into the functionally important parts of these proteins and how they have changed across hundreds of millions of years of evolution, we analyzed how the sequence traits of these five proteins have evolved across eukaryotes, including plants and metazoa. We discover that the RNA-binding domain architecture of these proteins is deeply conserved since their emergence. Prion-like regions are also deeply and widely conserved since the origination of the protein families for FUS, TAF15 and EWSR1, and since the last common ancestor of metazoa for TDP43 and hnRNPA2. Prion-like composition is uncommon or weak in any plant orthologs observed, however in TDP43 many plant proteins have equivalent regions rich in other amino acids (namely glycine and tyrosine and/or serine) that may be linked to stress granule recruitment. Deeply conserved low-complexity domains are identified that likely have functional significance.