Anti-neuroinflammatory effect of hydroxytyrosol: a potential strategy for anti-depressant development.

Introduction: Depression is a complex psychiatric disorder with substantial societal impact. While current antidepressants offer moderate efficacy, their adverse effects and limited understanding of depression's pathophysiology hinder the development of more effective treatments. Amidst this complexity, the role of neuroinflammation, a recognized but poorly understood associate of depression, has gained increasing attention. This study investigates hydroxytyrosol (HT), an olive-derived phenolic antioxidant, for its antidepressant and anti-neuroinflammatory properties based on mitochondrial protection. Methods: In vitro studies on neuronal injury models, the protective effect of HT on mitochondrial ultrastructure from inflammatory damage was investigated in combination with high-resolution imaging of mitochondrial substructures. In animal models, depressive-like behaviors of chronic restraint stress (CRS) mice and chronic unpredictable mild stress (CUMS) rats were examined to investigate the alleviating effects of HT. Targeted metabolomics and RNA-Seq in CUMS rats were used to analyze the potential antidepressant pathways of HT. Results: HT protected mitochondrial ultrastructure from inflammatory damage, thus exerting neuroprotective effects in neuronal injury models. Moreover, HT reduced depressive-like behaviors in mice and rats exposed to CRS and CUMS, respectively. HT's influence in the CRS model included alleviating hippocampal neuronal damage and modulating cytokine production, mitochondrial dysfunction, and brain-derived neurotrophic factor (BDNF) signaling. Targeted metabolomics in CUMS rats revealed HT's effect on neurotransmitter levels and tryptophan-kynurenine metabolism. RNA-Seq data underscored HT's antidepressant mechanism through the BDNF/TrkB signaling pathways, key in nerve fiber functions, myelin formation, microglial differentiation, and neural regeneration. Discussion: The findings underscore HT's potential as an anti-neuroinflammatory treatment for depression, shedding light on its antidepressant effects and its relevance in nutritional psychiatry. Further investigations are warranted to comprehensively delineate its mechanisms and optimize its clinical application in depression treatment.

Decoding the Identification Mechanism of an SAM-III Riboswitch on Ligands through Multiple Independent Gaussian-Accelerated Molecular Dynamics Simulations.

S-Adenosyl-l-methionine (SAM)-responsive riboswitches play a central role in the regulation of bacterial gene expression at the level of transcription attenuation or translation inhibition. In this study, multiple independent Gaussian-accelerated molecular dynamics simulations were performed to decipher the identification mechanisms of SAM-III (SMK) on ligands SAM, SAH, and EEM. The results reveal that ligand binding highly affects the structural flexibility, internal dynamics, and conformational changes of SAM-III. The dynamic analysis shows that helices P3 and P4 as well as two junctions J23 and J24 of SAM-III are highly susceptible to ligand binding. Analyses of free energy landscapes suggest that ligand binding induces different free energy profiles of SAM-III, which leads to the difference in identification sites of SAM-III on ligands. The information on ligand-nucleotide interactions not only uncovers that the π-π, cation-π, and hydrogen bonding interactions drive identification of SAM-III on the three ligands but also reveals that different electrostatic properties of SAM, SAH, and EEM alter the active sites of SAM-III. Meanwhile, the results also verify that the adenine group of SAM, SAH, and EEM is well recognized by conserved nucleotides G7, A29, U37, A38, and G48. We expect that this study can provide useful information for understanding the applications of SAM-III in chemical, synthetic RNA biology, and biomedical fields.

Exploring the deactivation mechanism of human ß 2 adrenergic receptor by accelerated molecular dynamic simulations.

The ß 2 adrenergic receptor (ß2AR), one of important members of the G protein coupled receptors (GPCRs), has been suggested as an important target for cardiac and asthma drugs. Two replicas of Gaussian accelerated molecular dynamics (GaMD) simulations are performed to explore the deactivation mechanism of the active ß2AR bound by three different substrates, including the agonist (P0G), antagonist (JTZ) and inverse agonist (JRZ). The simulation results indicate that the Gs protein is needed to stabilize the active state of the ß2AR. Without the Gs protein, the receptor could transit from the active state toward the inactive state. During the transition process, helix TM6 moves toward TM3 and TM5 in geometric space and TM5 shrinks upwards. The intermediate state is captured during the transition process of the active ß2AR toward the inactive one, moreover the changes in hydrophobic interaction networks between helixes TM3, TM5, and TM6 and the formation of a salt bridge between residues Arg3.50 and Glu6.30 drive the transition process. We expect that this finding can provide energetic basis and molecular mechanism for further understanding the function and target roles of the ß2AR.

Free Energy Profiles Relating With Conformational Transition of the Switch Domains Induced by G12 Mutations in GTP-Bound KRAS.

Mutations of G12 in KRAS have been involved in different cancers. Multiple replica-Gaussian accelerated molecular dynamics (MR-GaMD) simulations are applied to investigate conformational changes of the switch domains caused by G12C, G12D and G12R. Free energy landscapes suggest that G12C, G12D and G12R induce more energetic states compared to the GTP-bound WT KRAS and make the conformations of the switch domains more disordered, which disturbs bindings of KRAS to effectors. Dynamics analyses based on MR-GaMD trajectory show that G12C, G12D and G12R not only change structural flexibility of the switch domains but also affect their motion behavior, indicating that these three mutations can be used to tune the activity of KRAS. The analyses of interaction networks verify that the instability in interactions of the GTP with the switch SⅠ plays an important role in the high disorder states of the switch domain. This work is expected to provide useful information for deeply understanding the function of KRAS.

Q61 mutant-mediated dynamics changes of the GTP-KRAS complex probed by Gaussian accelerated molecular dynamics and free energy landscapes.

Understanding the molecular mechanism of the GTP-KRAS binding is significant for improving the target roles of KRAS in cancer treatment. In this work, multiple replica Gaussian accelerated molecular dynamics (MR-GaMD) simulations were applied to decode the effect of Q61A, Q61H and Q61L on the activity of KRAS. Dynamics analyses based on MR-GaMD trajectory reveal that motion modes and dynamics behavior of the switch domain in KRAS are heavily affected by the three Q61 mutants. Information of free energy landscapes (FELs) shows that Q61A, Q61H and Q61L induce structural disorder of the switch domain and disturb the activity of KRAS. Analysis of the interaction network uncovers that the decrease in the stability of hydrogen bonding interactions (HBIs) of GTP with residues V29 and D30 induced by Q61A, Q61H and Q61L is responsible for the structural disorder of the switch-I and that in the occupancy of the hydrogen bond between GTP and residue G60 leads to the structural disorder of the switch-II. Thus, the high disorder of the switch domain caused by three current Q61 mutants produces a significant effect on binding of KRAS to its effectors. This work is expected to provide useful information for further understanding function and target roles of KRAS in anti-cancer drug development.

Synthesis of a novel aminobenzene-containing hemicucurbituril and its fluorescence spectral properties with ions.

A novel hemicucurbituril-based macrocycle, alternately consisting of amidobenzene and 2-imidazolidione moieties was designed and synthesized. Based on the fragment coupling strategy, nitrobenzene-containing hemicucurbituril was firstly prepared facilely under alkaline environment, and reduction of the nitro groups produced the desired amidobenzene-containing hemicucurbituril. As an original fluorescent chemosensor, it exhibited strong interactions with Fe3+ over other metal cations. The experimental evidence of fluorescence spectra suggested that a 1:1 complex was formed between this macrocycle and Fe3+ with an association constant up to (2.1 ± 0.3) × 104 M-1. Meanwhile, this macrocycle showed no obvious or only slight enhancement of the fluorescence intensity with selected anions.

Pathogenic infection and immune-related gene expression of Chinese sturgeon (Acipenser sinensis) challenged by Citrobacter freundii.

Citrobacter freundii is one of the important bacterial diseases responsible for disease outbreaks to wild and cultured fishes globally. However, no known empirical research has focused on exploring relationships between immune response after C. freundii infection in sturgeons. In this study, C. freundii was isolated and identified from artificially breeding Chinese sturgeon, and global measurement of transcriptome response to C. freundii infection in head-kidney and spleen of A. sinensis were conducted to the acknowledgement of the potential mechanisms of pathogen-host interaction triggered by the bacterial infection. In total, differentially expressed genes which significantly associated with immune responses were found to be participated in antigen processing and presentation (MHC I, MHC II, HspA1, Hsp90A, Hsp70, CTSL, and CTSE), and acute phase response (serotransferrin and CP), as well as changing of other immune-related cytokine, such as chemokine and interferon, which proving their reacting and regulatory role during the response of thehost against C. freundii infection in fish. C. freundii can cause serious disease in sturgeon species was first reported in this study, and innate immune responses to C. freundii infection in this study will be conducive to understand the defense mechanisms and making appropriate prevention strategies in A. sinensis aquaculture operations.

Biomedical Knowledge Graphs Construction From Conditional Statements.

Conditions play an essential role in biomedical statements. However, existing biomedical knowledge graphs (BioKGs) only focus on factual knowledge, organized as a flat relational network of biomedical concepts. These BioKGs ignore the conditions of the facts being valid, which loses essential contexts for knowledge exploration and inference. We consider both facts and their conditions in biomedical statements and proposed a three-layered information-lossless representation of BioKG. The first layer has biomedical concept nodes, attribute nodes. The second layer represents both biomedical fact and condition tuples by nodes of the relation phrases, connecting to the subject and object in the first layer. The third layer has nodes of statements connecting to a set of fact tuples and/or condition tuples in the second layer. We transform the BioKG construction problem into a sequence labeling problem based on a novel designed tag schema. We design a Multi-Input Multi-Output sequence labeling model (MIMO) that learns from multiple input signals and generates proper number of multiple output sequences for tuple extraction. Experiments on a newly constructed dataset show that MIMO outperforms the existing methods. Further case study demonstrates that the BioKGs constructed provide a good understanding of the biomedical statements.

Effects of feeding frequency on juvenile Chinese sturgeon Acipenser sinensis.

In this study, the effects of different feeding frequencies on the growth and the expression of genes in the GH/IGF axis were assessed in juvenile Chinese sturgeon. The newly hatched Chinese sturgeons were bred for 38 days at three different feeding frequencies groups (feeding frequency of two times a day, TWD; three times a day, THD; and four times a day, FOD), and the expression levels of the GH/IGF axis responses to feeding frequency were determined by quantitative real-time PCR. In addition, the full-length of the Coding Sequences of IGF I and IGF II genes (489-bp and 660-bp, respectively), were cloned and analyzed from Chinese sturgeon the first time. Multiple sequence alignments of IGFs revealed that Chinese sturgeon are high sequence identity to IGFs from other species. The phylogenetic relationships based on the IGF I and IGF II amino acid sequences were consistent with the traditional classification. After 38 days of growth, the three different feeding frequencies groups of Chinese sturgeon had no significant difference of body length, body weight, specific growth rate, the survival rate, the rate of weight gain and the condition factor. However, the relative expression of Chinese sturgeon GH in the pituitary decreased with increasing feeding frequency. The relative expression of Chinese sturgeon GHR in liver and skeletal muscle was deceased with increasing feeding frequency, while the relative expression of GHR in stomach and intestines at THD group was significantly higher than that of at TWD group and FOD group (p < 0.05). The relative expression of Chinese sturgeon IGF I in liver increased significantly with increasing feeding frequency (p < 0.05). The relative expression of IGF I in stomach and skeletal muscle was similar at the three groups. The relative expression of IGF I in intestines was significantly higher at FOD group than at TWD group and THD group (p < 0.05). The relative expression of Chinese sturgeon IGF II in liver at TWD group was significantly higher than that at THD group and FOD group (p < 0.05). However, the relative expression of IGF II in stomach, intestines and skeletal muscle at THD group was higher than that at TWD group and FOD group. Based on these previous studies that liver IGF I is regarded as a biomarker of growth performance, this result suggested that the juvenile Chinese sturgeon is better for growth when feeding four times daily compared to twice and thrice daily.

MnS@N,S Co-Doped Carbon Core/Shell Nanocubes: Sulfur-Bridged Bonds Enhanced Na-Storage Properties Revealed by In Situ Raman Spectroscopy and Transmission Electron Microscopy.

Rational structure and morphology design are of great significance to realize excellent Na storage for advanced electrode materials in sodium-ion batteries (SIBs). Herein, a cube-like core/shell composite of single MnS nanocubes (≈50 nm) encapsulated in N, S co-doped carbon (MnS@NSC) with strong CSMn bond interactions is successfully prepared as outstanding anode material for SIBs. The carbon shell significantly restricts the expansion of the MnS volume in successive sodiation/desodiation processes, as demonstrated by in situ transmission electron microscopy (TEM) of one single MnS@NSC nanocube. Moreover, the in situ generated CSMn bonds between the MnS core and carbon shell play a significant role in improving the Na-storage stability and reversibility of MnS@NSC, as revealed by in situ Raman and TEM. As a result, MnS@NSC exhibits a high reversible specific capacity of 594.2 mAh g-1 at a current density of 100 mA g-1 and an excellent rate performance. It also achieves a remarkable cycling stability of 329.1 mAh g-1 after 3000 charge/discharge cycles at 1 A g-1 corresponding to a low capacity attenuation rate of 0.0068% per cycle, which is superior to that of pristine MnS and most of the reported Mn-based anode materials in SIBs.

Establishment and characterization of a cell line derived from fin of the endangered Yangtze sturgeon (Acipenser dabryanus).

Yangtze sturgeon (Acipenser dabryanus) is an endangered endemic freshwater fish of China. Cell-line is a potential means used for long-term preservation of germplasm resources and an ideal in vitro model in place of living organisms for biological studies. Here, culture condition and characterization of fin-derived cell in Yangtze sturgeon were carried out. Tissue explant techniques have been efficiently used in the Yangtze sturgeon caudal fin (YSCF) culture. The YSCF cell line showed a fibroblast-like morphology and stable growth in minimum essential medium eagle's (MEME) supplemented with 10-20% fetal bovine serum at 25°C. Cells were cryopreserved with preservative DMSO in liquid nitrogen and grew normally after recovery. No bacterial, fungal, or mycoplasma contamination was detected in the YSCF cells. Karyotype analysis of the YSCF cells showed that the chromosome numbers of the YSCF ranged from 242 to 273, and the modal chromosome number was identified as 264 at passage 9. The YSCF cells were confirmed from A. dabryanus by assay of 16S rRNA and COI. Furthermore, GFP reporter gene was successfully transferred into YSCF cells and expressed. The established YSCF cell lines will contribute to the preservation of germplasm resources and provide a useful vitro tool for further biological studies in sturgeon species.

Physicochemical properties and potential beneficial effects of porphyran from Porphyra haitanensis on intestinal epithelial cells.

This study examined the beneficial effects of porphyran from Porphyra haitanensis (PHP) on intestinal epithelial cells, in terms of cell proliferation and migration and elucidated the potential molecular mechanism of action of PHP. Purified PHP is a homogenous polysaccharide with a molecular weight of 2.01 × 105 Da, intrinsic viscosity [η] of 463.76 mL/g, and radius of gyration of 61.2 nm. When the intestinal epithelial wound healing activity of PHP was investigated in vitro using the IEC-6 cell line (intestinal epithelial cells-6), it was found that PHP could promote cell migration and proliferation. PHP enhanced the protein expression of cell division control protein 42, paxillin, and focal adhesion kinase, which suggest that PHP might modulate the expression of these proteins to improve intestinal epithelial healing. Thus, this study indicated that PHP could serve as a potential source of functional food constituents for intestinal epithelial protection and restoration.

Genome-wide analysis of the Chinese sturgeon sox gene family: identification, characterisation and expression profiles of different tissues.

The sox family is assumed to be responsible for a number of developmental systems. Genome sequencing technology makes it possible to scan sox genes and conduct characteristic analyses of different species. In fish, full characterisation of sox genes at the genome-wide level has been reported for pufferfish Takifugu rubripes, medaka Oryzias latipes, tilapia Oreochromis niloticus and channel catfish Ictalurus punctatus. However, no systematic investigation of the sox family in sturgeons (Acipenseridae) has been reported to date. This study conducted genome-wide identification of the sox genes in the Chinese sturgeon Acipenser sinensis and profiled their tissue distribution between male and female individuals. In total, 19 sox genes were identified, including soxb1, b2, c, d, e, f and h, in the Chinese sturgeon. Genomic structure analysis indicated relatively conserved exon-intron structures in each sox group and phylogenetic analysis supported the previous classification of the sox family. Most of the sox genes showed a tissue-specific expression pattern, indicating the possible involvement of Chinese sturgeon sox genes at different developmental processes such as cardiac and gonadal development. This study provides a comprehensive resource of Chinese sturgeon sox genes and enables a better understanding of the evolution and function of the sox family.

Effects of Angle of Epiglottis on Aerodynamic and Acoustic Parameters in Excised Canine Larynges.

OBJECTIVES: The aim of this study is to explore the effects of the angle of epiglottis (Aepi) on phonation and resonance in excised canine larynges. METHODS: The anatomic Aepi was measured for 14 excised canine larynges as a control. Then, the Aepis were manually adjusted to 60° and 90° in each larynx. Aerodynamic and acoustic parameters, including mean flow rate, sound pressure level, jitter, shimmer, fundamental frequency (F0), and formants (F1'-F4'), were measured with a subglottal pressure of 1.5 kPa. Simple linear regression analysis between acoustic and aerodynamic parameters and the Aepi of the control was performed, and an analysis of variance comparing the acoustic and aerodynamic parameters of the three treatments was carried out. RESULTS: The results of the study are as follows: (1) the larynges with larger anatomic Aepi had significantly lower jitter, shimmer, formant 1, and formant 2; (2) phonation threshold flow was significantly different for the three treatments; and (3) mean flow rate and sound pressure level were significantly different between the 60° and the 90° treatments of the 14 larynges. CONCLUSIONS: The Aepi was proposed for the first time in this study. The Aepi plays an important role in phonation and resonance of excised canine larynges.

Establishment and Analysis of False Vocal Folds Hypertrophy Model in Excised Canine Larynges.

OBJECTIVE: This study aimed to investigate the role of false vocal folds (FVFs) medialization in phonation and the acoustic impact of ventricular hypertrophy by establishing an FVF hypertrophy model. STUDY DESIGN: A prospective in vitro experiment was carried out. SETTING: The study was carried out using a pseudolung platform with high-speed camera in a soundproof room. MATERIALS AND METHODS: Control, degree I, and degree II FVFs hypertrophy were simulated in 10 excised larynges via fructose injection of 0.1 mL for degree I and 0.25 mL for degree II. Mean flow rate (MFR), fundamental frequencies (F0), formants, and sound pressure level were measured with a subglottal pressure of 1.5 kPa and 2.5 kPa, respectively. RESULTS: When the subglottal pressure was controlled at both at 1.5 kPa and at 2.5 kPa, the degree of FVF hypertrophy significantly influenced the distribution of the formants, F0, and MFR in excised canine larynges. Increasing the degree of hypertrophy was associated with a decrease in F0 and an increase in MFR. In degree II FVF hypertrophy models, the sound pressure level and the first formant were significantly higher (P < 0.05) than in normal models. CONCLUSION: Hypertrophy of the FVFs has a significant influence on the distribution of sound energy and is associated with changes in sound quality.

Construction of a high-density linkage map and mapping of sex determination and growth-related loci in the mandarin fish (Siniperca chuatsi).

BACKGROUND: The mandarin fish (Siniperca chuatsi) is an important and widely cultured fish in China. However, the lack of selective breeding of mandarin fish in previous decades has resulted in a decline in the growth rate of pond-cultured fish, a shortened period of sexual maturity, and reduced disease resistance; these issues seriously affect the quality and safety of the fish products. Therefore, it is necessary to establish a selective breeding program for the mandarin fish to improve the economical traits of the fish and to sustain the development of the mandarin fish industry. RESULTS: We constructed a high-density linkage map for it based on double digest restriction site associated DNA sequencing (ddRAD-Sequencing). This map contained 3283 dimorphic single nucleotide polymorphism markers and 24 linkage groups (LGs). The total map-length was 1972.01 cM, with an average interlocus distance of 0.61 cM. One significant quantitative trait locus (QTL) for sex determination trait was detected on LG23, which was supported by five markers, clustered between 60.27 and 68.71 cM. The highest logarithm of odds value (17.73) was located at 60.27 cM, near the marker r1_73194, accounting for 53.3% of the phenotypic variance. Genotypes of all the male fish on r1_33008 were homozygous, whereas those of all females were heterozygous. Thus, LG23 was considered a sex-related linkage group. Eleven significant QTLs, for three growth traits, at two growth stages and the increased values were distributed on four LGs; their contributions to the phenotypic variation were quite low (12.4-17.2%), suggesting that multiple genes affected the growth traits. CONCLUSION: This high-resolution genetic map provides a valuable resource for fine-mapping of important traits and for identification of sex-related markers that should facilitate breeding of all-female mandarin fish for aquaculture and mechanistic studies on sex determination.