Real experience of caregivers of patients with HIV/AIDS from the perspective of iceberg theory: a qualitative research.

OBJECTIVE: This study aimed to investigate the caregiving behaviours and supportive needs of caregivers of patients with HIV/AIDS and provide a basis for healthcare institutions to carry out caregiver interventions. DESIGN: A purposive sampling method was used to select 11 caregivers of patients with HIV/AIDS in the Infectious Disease Department of a tertiary hospital in Nanjing, China, to conduct semistructured interviews. Colaizzi analysis was used to collate and analyse the interview data. SETTING: All interviews were conducted at a tertiary hospital specialising in infectious diseases in Nanjing, Jiangsu Province. PARTICIPANTS: We purposively sampled 11 caregivers of people with HIV/AIDS, including nine women and two men. RESULTS: Analysing the results from the perspective of iceberg theory, three thematic layers were identified: behavioural, value and belief. The behavioural layer includes a lack of awareness of the disease, physical and mental coping disorders, and an increased sense of stigma; the values layer includes a heightened sense of responsibility, the constraints of traditional gender norms, the influence of strong family values and the oppression of public opinion and morality and the belief layer includes the faith of standing together through storms and stress. CONCLUSION: Healthcare professionals should value the experiences of caregivers of patients with HIV/AIDS and provide professional support to improve their quality of life.

Regulating the Electrode-Electrolyte Interfaces of Lithium-High Nickel Batteries via a Multifunctional Additive.

Lithium metal batteries with high nickel ternary (LiNixCoyMn1-x-yO2, x ≥ 0.8) as the cathode hold the promise to meet the demand of next-generation high energy density batteries. However, the unsatisfactory stability of electrode-electrolyte interfaces limits their practical applications. In this work, N-methyl-N-trimethylsilyltrifluoroacetamide (NMTFA) is suggested as a new functional electrolyte additive to stabilize the Li∥LiNi0.9Co0.05Mn0.05O2 chemistry by forming robust and effective electrode-electrolyte interphases, namely the anode-electrolyte interphase (AEI, or conventionally called SEI) and cathode-electrolyte interphase (CEI). The NMTFA-derived SEI/CEI greatly enhances the battery performance that a capacity retention of 82.1% after 200 cycles at 1C charge/discharge is achieved, significantly higher than that without NMTFA addition (52.5%). Moreover, the NMTFA also improves the thermal stability of the electrolyte and inhibits the hydrolysis of LiPF6. This work provides new clues for the optimization of electrolyte formulation for lithium-high nickel batteries through modulating interfaces.

Body composition phase angle: A potential predictor of vitamin D status in early pregnancy.

Phase angle and vitamin D can reflect the state of the body cells, and the two may interact with each other. Therefore, this study was conducted to find out the relationship between PA and vitamin D. Taking women in early pregnancy as our study subjects, we found that PA had a positive effect on vitamin D levels. Body composition phase angle, as a noninvasive, easy-to-operate, and easy-to-monitor indicator, can be used an early screening index for vitamin D nutrition levels in early pregnancy, and the cutoff value was 4.95°.

Miao sour soup influences serum lipid via regulation of high-fat diet-induced intestinal flora in obese rats.

Obesity is associated with the gut microbiota and has been shown to cause gut microbiota disturbances. Our previous studies have demonstrated that Miao sour soup (SS) contains abundant short-chain fatty acids (SCFAs) which can be used as energy substrates of intestinal flora to selectively stimulate their growth and reproduction. Therefore, we explored whether the intestinal microbiota of rats with high-fat diet-induced obesity could be restored to normal by SS intervention. Male obese rats were divided into five groups randomly after successful modeling of obese rats: normal diet, high-fat diet (HDF), HFD + SS, HFD with antibiotic, and HFD with antibiotic + SS. After 12 weeks of intervention, the weight and serum lipid of obese rats decreased. Furthermore, 16S rRNA analysis showed an imbalance and a decrease in the abundance and diversity of intestinal flora in obese rats, which improved after SS intervention. At the phylum level, Firmicutes increased while Proteobacteria decreased. The composition of the intestinal flora recovered at the genus level, inhibiting the reproduction of pathogenic bacteria, while the levels of SCFA-producing bacteria such as Blautia and Lactococcus and the levels of SCFAs in cecal contents increased. In addition, SS reduced the levels of TNF-α and IL-6 in the intestinal mucosa of obese rats, increased the contents of PYY and GLP-1 in colon tissue, and increased the expression of tight junction protein Occludin and ZO-1 in the intestinal epithelium. Taken together, SS can regulate the intestinal flora of obese rats and improve the intestinal flora to facilitate weight loss and lipid reduction.

Enantioseparation and mechanism study on baclofen by capillary electrophoresis and molecular modeling.

Enantioselective analysis of chiral drugs plays a significant role in chemistry, biology and pharmacology. Baclofen, an antispasmodic chiral drug, has been widely studied due to the obvious differences in toxicity and medical activity between enantiomers. Herein, a simple and efficient method for separation of baclofen enantiomers by capillary electrophoresis was established without complicated sample derivatization and expensive instruments. Then, the molecular modeling and density functional theory were used to simulate and investigate the chiral resolution mechanism of electrophoresis, the calculated intermolecular forces were directly presented by visualization softwares. Moreover, the theoretical and experimental electronic circular dichroism (ECD) spectra of ionized baclofen were compared, and the configuration of dominant enantiomer in the nonracemic mixture can be determined by ECD signal intensity, which was proportional to the electrophoresis peak area difference of the corresponding enantiomer excess experiments. In this way, the peak order identification and configuration quantification of baclofen enantiomers in electrophoretic separation were successfully achieved without relying on a single standard.

Quantitative assessment of the in-vitro binding kinetics of antisickling aromatic aldehydes with hemoglobin A: A universal HPLC-UV/Vis method to quantitate Schiff-base adduct formation.

Aromatic aldehydes act as allosteric effectors of hemoglobin (AEH), forming Schiff-base adducts with the protein to increase its oxygen (O2) affinity; a desirable property in sickle cell disease (SCD) treatment, as the high-O2 affinity hemoglobin (Hb) does not polymerize and subsequently prevents erythrocytes sickling. This study reports the development, validation, and application of a weak cation-exchange HPLC assay - quantifying the appearance of Hb-AEH adduct - as a "universal" method, allowing for the prioritization of AEH candidates through an understanding of their Hb binding affinity and kinetics. Concentration- and time-dependent Hb binding profiles of ten AEHs were determined with HPLC, followed by the appropriate non-linear modeling to characterize their steady-state binding affinity (KDss), and binding kinetics second-order association (kon) and first-order dissociation (koff) rate constants. Vanillin-derived AEHs exhibited enhanced binding affinity to Hb, primarily due to their faster kon. Across AEH, kon and koff values are strongly correlated (r = 0.993, n = 7), suggesting that modifications of the AEH scaffold enhanced their interactions with Hb as intended, but inadvertently increased their Hb-AEH adduct dissociation. To our knowledge, the present study is the first to provide valuable insight into Hb binding kinetics of antisickling aromatic aldehydes, and the assay will be a useful platform in screening/prioritizing drug candidates for SCD treatment.

iDARTS: Improving DARTS by Node Normalization and Decorrelation Discretization.

Differentiable ARchiTecture Search (DARTS) uses a continuous relaxation of network representation and dramatically accelerates Neural Architecture Search (NAS) by almost thousands of times in GPU-day. However, the searching process of DARTS is unstable, which suffers severe degradation when training epochs become large, thus limiting its application. In this article, we claim that this degradation issue is caused by the imbalanced norms between different nodes and the highly correlated outputs from various operations. We then propose an improved version of DARTS, namely iDARTS, to deal with the two problems. In the training phase, it introduces node normalization to maintain the norm balance. In the discretization phase, the continuous architecture is approximated based on the similarity between the outputs of the node and the decorrelated operations rather than the values of the architecture parameters. Extensive evaluation is conducted on CIFAR-10 and ImageNet, and the error rates of 2.25% and 24.7% are reported within 0.2 and 1.9 GPU-day for architecture search, respectively, which shows its effectiveness. Additional analysis also reveals that iDARTS has the advantage in robustness and generalization over other DARTS-based counterparts.

Integrative proteomics and metabolomics of Guizhou Miao Sour Soup affecting simple obese rats.

Miao Sour Soup (MSS) is a fermented product from the Qiandongnan region of Guizhou Province, which enrich many beneficial ingredients and is widely consumed in the whole China. Fermented food is beneficial to physical health with the potential positive regulating affection on simple obesity. In this study, we analyzed the mechanism of action of MSS to prevent simple obesity induced by high-fat diet by proteomics and metabolomics. Quantitative proteomics with tandem mass tagging labeling and liquid chromatography-mass spectrometry was used to analyze the changes of liver proteins and metabolites after the MSS intervention. MSS intervention upregulated 33 proteins and 9 metabolites and downregulated 19 proteins and 10 metabolites. Bioinformatics analysis showed that MSS could prevent simple obesity by acting on the PPAR signaling pathway, retinol metabolism, fatty acid ß-oxidation, fatty acid degradation, fatty acid biosynthesis, glycine, serine and threonine metabolism, pyruvate metabolism, citrate cycle (TCA cycle) and other signaling pathways. This study provides new insights into the use of MSS to prevent simple obesity caused by high-fat diets and the search for healthy eating patterns with MSS.

Lysophosphatidic acid signaling via LPA6 : A negative modulator of developmental oligodendrocyte maturation.

The developmental process of central nervous system (CNS) myelin sheath formation is characterized by well-coordinated cellular activities ultimately ensuring rapid and synchronized neural communication. During this process, myelinating CNS cells, namely oligodendrocytes (OLGs), undergo distinct steps of differentiation, whereby the progression of earlier maturation stages of OLGs represents a critical step toward the timely establishment of myelinated axonal circuits. Given the complexity of functional integration, it is not surprising that OLG maturation is controlled by a yet fully to be defined set of both negative and positive modulators. In this context, we provide here first evidence for a role of lysophosphatidic acid (LPA) signaling via the G protein-coupled receptor LPA6 as a negative modulatory regulator of myelination-associated gene expression in OLGs. More specifically, the cell surface accessibility of LPA6 was found to be restricted to the earlier maturation stages of differentiating OLGs, and OLG maturation was found to occur precociously in Lpar6 knockout mice. To further substantiate these findings, a novel small molecule ligand with selectivity for preferentially LPA6 and LPA6 agonist characteristics was functionally characterized in vitro in primary cultures of rat OLGs and in vivo in the developing zebrafish. Utilizing this approach, a negative modulatory role of LPA6 signaling in OLG maturation could be corroborated. During development, such a functional role of LPA6 signaling likely serves to ensure timely coordination of circuit formation and myelination. Under pathological conditions as seen in the major human demyelinating disease multiple sclerosis (MS), however, persistent LPA6 expression and signaling in OLGs can be seen as an inhibitor of myelin repair. Thus, it is of interest that LPA6 protein levels appear elevated in MS brain samples, thereby suggesting that LPA6 signaling may represent a potential new druggable pathway suitable to promote myelin repair in MS.

Elucidating the binding mechanism of LPA species and analogs in an LPA4 receptor homology model.

Lysophosphatidic acid receptor 4 (LPA4) has emerged as a potential therapeutic target for the treatment of a variety of diseases, including cancer and obesity-induced diabetes, but its structure remains to be revealed. In the present work, a homology model of LPA4 was built for studying the binding mechanism of LPA species and analogs. Then five selected LPA species and analogs with structural variations in their phosphate groups, substitutions on the glycerol backbone, and fatty acyl chains were docked into the LPA4 model, followed by molecular dynamics simulations and energy analyses. The computational results revealed that the aliphatic residues located at the vertical cleft of LPA4 may form a hydrophobic environment for the fatty acyl moiety of LPA species and their analogs. Meanwhile, the positively charged residues in the central cavity of LPA4 may form ionic interactions with the negatively charged hydrophilic head group of LPA species and their analogs. In addition, it was noted that a different binding mode of the hydrophilic head group in each species with the central cavity of the LPA4 might lead to a special rearrangement of the fatty acyl moiety. Taken together, these results may facilitate understanding of the activation mechanism of LPA4 and help design selective ligands to modulate its function for therapeutic purposes.

Novel bivalent ligands carrying potential antinociceptive effects by targeting putative mu opioid receptor and chemokine receptor CXCR4 heterodimers.

The functional interactions between opioid and chemokine receptors have been implicated in the pathological process of chronic pain. Mounting studies have indicated the possibility that a MOR-CXCR4 heterodimer may be involved in nociception and related pharmacologic effects. Herein we have synthesized a series of bivalent ligands containing both MOR agonist and CXCR4 antagonist pharmacophores with an aim to investigate the functional interactions between these two receptors. In vitro studies demonstrated reasonable recognition of designed ligands at both respective receptors. Further antinociceptive testing in mice revealed compound 1a to be the most promising member of this series. Additional molecular modeling studies corroborated the findings observed. Taken together, we identified the first bivalent ligand 1a showing promising antinociceptive effect by targeting putative MOR-CXCR4 heterodimers, which may serve as a novel chemical probe to further develop more potent bivalent ligands with potential application in analgesic therapies for chronic pain management.

Impact of selenium on cerebellar injury and mRNA expression in offspring of rat exposed to methylmercury.

During the fetal development stage, the Central Nervous System (CNS) is particularly sensitive to methylmercury (MeHg). However, the mechanism underlying the antagonistic effect of selenium (Se) on MeHg toxicity is still not fully understood. In this study, female rat models with MeHg and Se co-exposure were developed. Pathological changes in the cerebellum and differential mRNA expression profiles in offspring rats were studied. In the MeHg-exposed group, a large number of Purkinje cells showed pathological changes and mitochondria were significantly swollen; co-exposure with Se significantly improved the structure and organization of the cerebellum. In total, 378 differentially expressed genes (DEGs) (including 284 up-regulated genes and 94 down-regulated genes) in the cerebellum of the MeHg-exposed group and 210 DEGs (including 84 up-regulated genes and 126 down-regulated genes) in the cerebellum of the MeHg+Se co-exposed group were identified. The genes involved in neurotransmitter synthesis and release and calcium ion balance in the cerebellum were significantly up-regulated in the MeHg-exposed group. These genes in the MeHg+Se co-exposed group were not changed or down-regulated. These findings demonstrate that the neurotoxicity caused by MeHg exposure is related to the up-regulation of multiple genes in the nerve signal transduction and calcium ion signal pathways, which are closely related to impairments in cell apoptosis and learning and memory. Supplementation with Se can mitigate the changes to related genes and protect neurons in the mammalian brain (especially the developing cerebellum) from MeHg toxicity. Se provides a potential intervention strategy for MeHg toxicity.

Effects of Miao sour soup on hyperlipidemia in high-fat diet-induced obese rats via the AMPK signaling pathway.

Hyperlipidemia is a common characteristic of obese animals. Identifying the factors involved in the regulation of dietary lipid metabolism is the most beneficial way to improve health. Miao sour soup (MSS) is a fermented food made from tomato and red pepper that contains lycopene, capsaicin, and organic acids. We conducted this study to investigate the regulatory functions and mechanisms of MSS on the blood lipid levels of high-fat diet-induced obese rats. In our preventive study, rats were fed normal diet (ND1), high-fat diet (HFD1), HFD + 4 g/kg BW MSS (HFD + LS1), and HFD + 8 g/kg BW MSS (HFD + HS1). We found that MSS significantly reduced the body weight and fat accumulation and improved the blood lipid levels of rats. MSS significantly increased the expression of AMP-activated protein kinase-alpha (AMPKα), attenuated the expression of the adipogenic transcription factor sterol regulatory element-binding protein-1c (SREBP-1c), and suppressed the expression of fatty acid synthase (FAS) and acetyl-CoA carboxylase alpha (ACCα), the critical regulators of hepatic lipid metabolism. Additionally, we also conducted a treatment study, and we grouped rats to receive ND2, HFD2, PC2, HFD + LS2, and HFD + HS2 for another 10 weeks. MSS treatment reduced the body weight, fat deposition, and percentage of lipid droplets and regulated the plasma lipid content. MSS significantly increased the expression of AMPK and alleviated the expression of SREBP-1c, ACC, and FAS. Taken together, these findings suggest that MSS prevents and treats hyperlipidemia in obese rats by regulating the AMPK signaling pathway.

Insight into the drug resistance mechanisms of GS-9669 caused by mutations of HCV NS5B polymerase via molecular simulation.

GS-9669 is a non-nucleos(t)ide inhibitor (NNI) binding to the thumb site II of the Hepatitis C virus (HCV) NS5B polymerase and has advanced into phase II trials. To clarify the drug resistance mechanisms of GS-9669 caused by M423T/I/V, L419M, R422K, and I482L mutations of NS5B polymerase (GT1b) and the receptor-ligand interactions during the binding process, a series of molecular simulation methods including molecular dynamics (MD) simulations and adaptive steered molecular dynamics (ASMD) simulations were performed for the wild-type (WT) and six mutant NS5B/GS-9669 complexes. The calculated results indicate that the binding free energies of the mutant systems are less negative than that of the WT system, indicating that these mutations will indeed cause NS5B to produce different degrees of resistance to GS-9669. The mutation-induced drug resistances are mainly caused by the loss of binding affinities of Leu419 and Trp528 with GS-9669 or the formation of multiple solvent bridges. Moreover, the ASMD calculations show that GS-9669 binds to the thumb II sites of the seven NS5B polymerases in distinct pathways without any obvious energy barriers. Although the recognition methods and binding pathways are distinct, the binding processes of GS-9669 with the WT and mutant NS5B polymerases are basically controlled thermodynamically. This study clearly reveals the resistance mechanisms of GS-9669 caused by M423T/I/V, L419M, R422K, and I482L mutations of HCV NS5B polymerase and provides some valuable clues for further optimization and design of novel NS5B inhibitors.

Effects of Low-dose Mercury Exposure in Newborns on mRNA Expression Profiles.

This study was designed to investigate the molecular mechanism of mercury (Hg) toxicity in the newborns by mRNA sequencing (mRNA-seq). A questionnaire survey, routine blood parameters of pregnant women, and umbilical cord blood (UCB) of newborns were collected. The median (25th percentile, 75th percentile) of total Hg (THg) concentrations in UCB of newborns was 3.63 (2.50, 6.19) µg/L. A total of 504 differentially expressed genes of mRNA were revealed between the case and control group, including 456 upregulated and 48 downregulated genes. The Gene Ontology (GO) analysis showed that differentially expressed genes were primarily involved in mitophagy, hemoglobin complex, and oxygen carrier activity. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis demonstrated that the most differentially expressed genes were annotated in Huntington's disease, Parkinson's disease, and Alzheimer's disease. The qRT-PCR was used to validate the results of mRNA-seq. Low-dose Hg exposure could increase blood NE# and WBC in the pregnant women. This study provides scientific evidences on mechanism of Hg toxicity in newborns.

Structure-Based Design and Development of Chemical Probes Targeting Putative MOR-CCR5 Heterodimers to Inhibit Opioid Exacerbated HIV-1 Infectivity.

Crystal structures of ligand-bound G-protein-coupled receptors provide tangible templates for rationally designing molecular probes. Herein, we report the structure-based design, chemical synthesis, and biological investigations of bivalent ligands targeting putative mu opioid receptor C-C motif chemokine ligand 5 (MOR-CCR5) heterodimers. The bivalent ligand VZMC013 possessed nanomolar level binding affinities for both the MOR and CCR5, inhibited CCL5-stimulated calcium mobilization, and remarkably improved anti-HIV-1BaL activity over previously reported bivalent ligands. VZMC013 inhibited viral infection in TZM-bl cells coexpressing CCR5 and MOR to a greater degree than cells expressing CCR5 alone. Furthermore, VZMC013 blocked human immunodeficiency virus (HIV)-1 entry in peripheral blood mononuclear cells (PBMC) cells in a concentration-dependent manner and inhibited opioid-accelerated HIV-1 entry more effectively in phytohemagglutinin-stimulated PBMC cells than in the absence of opioids. A three-dimensional molecular model of VZMC013 binding to the MOR-CCR5 heterodimer complex is constructed to elucidate its mechanism of action. VZMC013 is a potent chemical probe targeting MOR-CCR5 heterodimers and may serve as a pharmacological agent to inhibit opioid-exacerbated HIV-1 entry.

Exploring naltrexamine derivatives featuring azaindole moiety via nitrogen-walk approach to investigate their in vitro pharmacological profiles at the mu opioid receptor.

In the present work, we reported the application of a nitrogen-walk approach on developing a series of novel opioid ligands containing an azaindole moiety at the C6-position of the epoxymorphinan skeleton. In vitro study results showed that introducing a nitrogen atom around the indole moiety not only retained excellent binding affinity, but also led to significant functional switch at the mu opioid receptor (MOR). Further computational investigations provided corroborative evidence and plausible explanations of the results of the in vitro studies. Overall, our current work implemented a series of novel MOR ligands with high binding affinity and considerably low efficacy, which may shed light on rational design of low efficacy MOR ligands for opioid use disorder therapeutics.

Verifying the role of 3-hydroxy of 17-cyclopropylmethyl-4,5α-epoxy-3,14ß-dihydroxy-6ß-[(4'-pyridyl) carboxamido]morphinan derivatives via their binding affinity and selectivity profiles on opioid receptors.

In the present study, the role of 3-hydroxy group of a series of epoxymorphinan derivatives in their binding affinity and selectivity profiles toward the opioid receptors (ORs) has been investigated. It was found that the 3-hydroxy group was crucial for the binding affinity of these derivatives for all three ORs due to the fact that all the analogues 1a-e exhibited significantly higher binding affinities compared to their counterpart 3-dehydroxy ones 6a-e. Meanwhile most compounds carrying the 3-hydroxy group possessed similar selectivity profiles for the kappa opioid receptor over the mu opioid receptor as their corresponding 3-dehydroxy derivatives. [35S]-GTPγS functional assay results indicated that the 3-hydroxy group of these epoxymorphinan derivatives was important for maintaining their potency on the ORs with various effects. Further molecular modeling studies helped comprehend the remarkably different binding affinity and functional profiles between compound 1c (NCP) and its 3-dehydroxy analogue 6c.

Exploring the putative mechanism of allosteric modulations by mixed-action kappa/mu opioid receptor bitopic modulators.

The modulation and selectivity mechanisms of seven mixed-action kappa opioid receptor (KOR)/mu opioid receptor (MOR) bitopic modulators were explored. Molecular modeling results indicated that the 'message' moiety of seven bitopic modulators shared the same binding mode with the orthosteric site of the KOR and MOR, whereas the 'address' moiety bound with different subdomains of the allosteric site of the KOR and MOR. The 'address' moiety of seven bitopic modulators bound to different subdomains of the allosteric site of the KOR and MOR may exhibit distinguishable allosteric modulations to the binding affinity and/or efficacy of the 'message' moiety. Moreover, the 3-hydroxy group on the phenolic moiety of the seven bitopic modulators induced selectivity to the KOR over the MOR.

IOX1 Suppresses Wnt Target Gene Transcription and Colorectal Cancer Tumorigenesis through Inhibition of KDM3 Histone Demethylases.

Epigenetic activation of Wnt/ß-catenin signaling plays a critical role in Wnt-induced tumorigenesis, notably in colorectal cancers. KDM3 and KDM4 histone demethylases have been reported to promote oncogenic Wnt signaling through demethylation of H3K9 on Wnt target gene promoters and are suggested to be potential therapeutic targets. However, potent inhibitors for these regulators are still not available. In addition, which family is most responsible for activation of Wnt target genes and Wnt-induced oncogenesis is not well documented, specifically in colorectal cancer. In this study, we characterized the functional redundancy and differences between KDM3 and KDM4 in regard to regulating Wnt signaling. Our data suggest that KDM3 may play a more essential role than KDM4 in regulating oncogenic Wnt signaling in human colorectal cancer. We also identified that IOX1, a known histone demethylase inhibitor, significantly suppresses Wnt target gene transcription and colorectal cancer tumorigenesis. Mechanistically, IOX1 inhibits the enzymatic activity of KDM3 by binding to the Jumonji C domain and thereby preventing the demethylation of H3K9 on Wnt target gene promoters. Taken together, our data not only identified the critical mechanisms by which IOX1 suppressed Wnt/ß-catenin signaling and colorectal cancer tumorigenesis through inhibition of KDM3, but also suggested that IOX1 may represent an attractive small molecule lead for future drug design and discovery.