Advances in structure-based drug design: The potential for precision therapeutics in psychiatric disorders.

Over the years, the field of GPCR drug design has undergone a remarkable evolution, fueled by advancements in science and technology. This evolution has given rise to a diverse range of ideas and approaches in structure-based drug design, bolstering the versatility and strength of the GPCR drug design toolbox. This review encapsulates the iterative development process, navigating challenges and opportunities in structure-based drug design within GPCRs. With a focused emphasis on its impact on psychiatric disorders, the review accentuates recent advancements and delves into the potentials unlocked by emerging technologies. The review explores the intricate interplay between scientific progress and iterative refinement, offering profound insights into the potential pathways that lie ahead for GPCR drug design.

The pan-plastome of Hemerocallis citrina reveals new insights into the genetic diversity and cultivation history of an economically important food plant.

BACKGROUND: Hemerocallis citrina Baroni (Huang hua cai in Chinese) is a perennial herbaceous plant grown for its flower buds that are eaten fresh or dried and is known as the vegetarian three treasures. The nuclear genome of H. citrina has been reported, but the intraspecific variation of the plastome (plastid genome) has not yet been studied. Therefore, the panplastome of this species collected from diverse locations is reported here for the first time. RESULTS: In this study, 65 H. citrina samples were resequenced, de novo assembled, and aligned with the published plastome of H. citrina to resolve the H. citrina panplastome. The sizes of the 65 newly assembled complete plastomes of H. citrina ranged from 156,048 bp to 156,263 bp, and the total GC content ranged from 37.31 to 37.34%. The structure of the complete plastomes showed a typical tetrameric structure, including a large single copy (LSC), a small single copy (SSC), and a pair of inverted repeat regions (IRA and IRB). Many nucleotide variants were identified between plastomes, among which the variants in the intergenic spacer region were the most abundant, with the highest number of variants concentrated in the LSC region. Based on the phylogenetic tree constructed using the ML method, population structure analysis, and principal component analysis (PCA), the panplastome data were subdivided into five genetic clusters. The C5 genetic cluster was mostly represented by samples from Qidong, Hunan Province, while samples from Shanxi and Shaanxi Provinces were classified into the C4 genetic cluster. The greatest genetic diversity was found in the C1 genetic cluster, and the greatest genetic distance between any two clusters was found between the C4 and C5 clusters. CONCLUSION: The resolution of the panplastome and the analysis of the population structure of H. citrina plastomes provide important data for future breeding projects and germplasm preservation.

Dual-mode self-powered photoelectrochemical and colorimetric determination of procalcitonin accomplished by multienzyme-expressed Ni4Cu2 bimetallic hollow nanospheres and spherical nanoflower-MoS2/Cu2ZnSnS4/Bi2S3.

Bacterial infections, viral infections and autoimmune diseases pose a considerable threat to human health. Procalcitonin (PCT) has emerged as a biomarker for the detection of these diseases. To ensure accurate and reliable results, we propose a dual-mode approach that incorporates self-validation and self-correction mechanisms. Herein, we develop a dual-mode self-powered photoelectrochemical (PEC) and colorimetric sensor to determine PCT. The self-powered PEC sensor was constructed with a photoanode of spherical nanoflower-MoS2/Cu2ZnSnS4/Bi2S3 material and a photocathode of CuInS2 material. Ni4Cu2 bimetallic hollow nanospheres (BHNs) possess superoxide dismutase and catalase performance, which facilitate superoxide anion radical (·O2-) and H2O2 circulating generation, promoting the separation of photogenerated electrons and holes to amplify photocurrent signal. Thus Ni4Cu2 BHNs is used as a marker material for PEC sensor. Meanwhile, in colorimetric mode, Ni4Cu2 BHNs converts blue oxTMB to a colourless TMB for colorimetric detection of PCT. Based on this principle, dual-mode determination of PCT with high sensitivity is achieved. The dual-mode method not only demonstrates outstanding properties and practicability, but also presents an effective, highly efficient and reliable method for detecting PCT.

Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants.

Psychedelics make up a group of psychoactive compounds that induce hallucinogenic effects by activating the serotonin 2A receptor (5-HT2AR). Clinical trials have demonstrated the traditional psychedelic substances like psilocybin as a class of rapid-acting and long-lasting antidepressants. However, there is a pressing need for rationally designed 5-HT2AR agonists that possess optimal pharmacological profiles in order to fully reveal the therapeutic potential of these agonists and identify safer drug candidates devoid of hallucinogenic effects. This Perspective provides an overview of the structure-activity relationships of existing 5-HT2AR agonists based on their chemical classifications and discusses recent advancements in understanding their molecular pharmacology at a structural level. The encouraging clinical outcomes of psychedelics in depression treatment have sparked drug discovery endeavors aimed at developing novel 5-HT2AR agonists with improved subtype selectivity and signaling bias properties, which could serve as safer and potentially nonhallucinogenic antidepressants. These efforts can be significantly expedited through the utilization of structure-based methods and functional selectivity-directed screening.

Fructose overconsumption impairs hepatic manganese homeostasis and ammonia disposal.

Arginase, a manganese (Mn)-dependent enzyme, is indispensable for urea generation and ammonia disposal in the liver. The potential role of fructose in Mn and ammonia metabolism is undefined. Here we demonstrate that fructose overconsumption impairs hepatic Mn homeostasis and ammonia disposal in male mice. Fructose overexposure reduces liver Mn content as well as its activity of arginase and Mn-SOD, and impairs the clearance of blood ammonia under liver dysfunction. Mechanistically, fructose activates the Mn exporter Slc30a10 gene transcription in the liver in a ChREBP-dependent manner. Hepatic overexpression of Slc30a10 can mimic the effect of fructose on liver Mn content and ammonia disposal. Hepatocyte-specific deletion of Slc30a10 or ChREBP increases liver Mn contents and arginase activity, and abolishes their responsiveness to fructose. Collectively, our data establish a role of fructose in hepatic Mn and ammonia metabolism through ChREBP/Slc30a10 pathway, and postulate fructose dietary restriction for the prevention and treatment of hyperammonemia.

Tandem Hydroperoxyl-Alkylperoxyl Radical Quenching by an Engineered Nanoporous Cerium Oxide Nanoparticle Macrostructure (NCeONP): Toward Efficient Solid-State Autoxidation Inhibitors.

The use of nanomaterials as inhibitors of the autoxidation of organic materials is attracting tremendous interest in petrochemistry, food storage, and biomedical applications. Metal oxide materials and CeO2 in particular represent one of the most investigated inorganic materials with promising radical trapping and antioxidant abilities. However, despite the importance, examples of the CeO2 material's ability to retard the autoxidation of organic substrates are still lacking, together with a plausible chemical mechanism for radical trapping. Herein, we report the synthesis of a new CeO2-derived nanoporous material (NCeONP) with excellent autoxidation inhibiting properties due to its ability to catalyze the cross-dismutation of alkyl peroxyl (ROO•) and hydroperoxyl (HOO•) radicals, generated in the system by the addition of the pro-aromatic hydrocarbon γ-terpinene. The antioxidant ability of NCeONP is superior to that of other nanosized metal oxides, including TiO2, ZnO, ZrO2, and pristine CeO2 nanoparticles. Studies of the reaction with a sacrificial reductant allowed us to propose a mechanism of inhibition consisting of H atom transfer from HOO• to the metal oxides (MOx + HOO• → MOx-H• + O2), followed by the release of the H atom to an ROO• radical (MOx-H• + ROO• → MOx + ROOH). Besides identifying NCeONP as a promising material for developing effective antioxidants, our study provides the first evidence of a radical mechanism that can be exploited to develop novel solid-state autoxidation inhibitors.

Dual-signal ratiometric electrochemical immunosensor constructed with snowflake-like FeSe2-AuNPs and PAA-ZIF@TB for sensitive detection of CYFRA21-1.

In this study, a ratiometric electrochemical immunosensor has been developed to detect the cytokeratin 19 fragment 21-1 (CYFRA21-1) biomarker in a highly sensitive manner through a dual-signal output model. As one of signal indicators, snowflake-like FeSe2 loaded with AuNPs (FeSe2-AuNPs) as sensing substrate with good conductivity and large active sites provides a differential pulse voltammetry (DPV) signal at +0.4 V. Another signal indicator, toluidine blue (TB) with the water-solubility property is an excellent redox probe that can generate DPV signal at -0.3 V. To solve the water-solubility problem, the TB is absorbed with polyacrylic acid (PAA) functionalized ZIF-67 (PAA-ZIF-67), which retains the properties of ZIF-67 that are large specific surface area and strong adsorption properties. The ratio of signals, stemmed from PAA-ZIF@TB and FeSe2-AuNPs (IPAA-ZIF@TB/IFeSe2-AuNPs), increases with the CYFRA21-1 concentration. Under optimal experimental conditions, CYFRA21-1 was detected in a wide dynamic range from 0.1 pg/mL to 100 ng/mL, with a lower limit of detection of 0.02 pg/mL. Looking ahead, this ratio based strategy provides prospective clinical applications for detecting other biomarkers.

How and when can job-insecure employees prevent psychological distress against the COVID-19 pandemic? The role of cognitive appraisal and reappraisal.

The COVID-19 pandemic has greatly affected economies around the world, causing record unemployment rates that have exacerbated the already prevalent job insecurity, thereby leading to psychological distress among many individuals. The present study aims to reveal the underlying mechanisms of psychological distress induced by the COVID-19 pandemic among job-insecure employees and to identify one of the emotion regulation strategies (i.e., cognitive reappraisal) as a protective factor that mitigates psychological distress. Drawing upon transactional theory, we proposed and tested a moderated mediation model, wherein cognitive reappraisal serves as a moderator of the direct and indirect relationship between job insecurity and psychological distress via stress appraisals (i.e., threat appraisal and challenge appraisal) based on data from 922 employees. Results show that threat appraisal and challenge appraisal positively and negatively mediate the relationship between job insecurity and psychological distress, respectively. Furthermore, as an emotion regulation strategy, cognitive reappraisal mitigates psychological distress among job-insecure employees, weakens the positive indirect effect of threat appraisal, but intensifies the negative indirect effect of challenge appraisal. Our findings suggest that cognition plays an important role in individuals' emotional reactions to COVID-19-related stress, and cognition reappraisal is an effective emotion regulation strategy in mitigating psychological distress. Therefore, cognition reappraisal skills should be improved to reduce psychological distress induced by COVID-19 pandemic.

Nutrient transfer and antioxidant effect of adzuki bean before and after GABA enrichment.

In order to study the nutritional changes of γ-aminobutyric acid (GABA) enrichment in adzuki bean germination, vacuum combined with monosodium glutamate (MSG) was used as the germination stress of adzuki bean. The nutrient transfer before and after GABA enrichment in adzuki bean germination under vacuum combined with MSG stress were studied by means of chromatography and scanning electron microscope (SEM). The antioxidant activity and hypoglycemic effect of different solvent extracts before and after germination of adzuki bean were evaluated by experiments in vitro. The results showed that the nutritional characteristics of adzuki bean rich in GABA changed significantly (P < 0.05), the total fatty acids decreased significantly (P < 0.05), and the 21 amino acids detected increased significantly. After germination, the starch granules of adzuki bean became smaller and the surface was rough Germination stress significantly increased the antioxidant and hypoglycemic activities of the extracts from different solvents (P < 0.05), and the water extracts had the best effect on DPPH and ⋅OH radical scavenging rates of 88.52 and 83.56%, respectively. The results indicated that the germinated adzuki bean rich in GABA was more nutritious than the raw adzuki bean and had good antioxidant activity. It hoped to provide technical reference for rich food containing GABA.

Does "lottery culture" affect household financial decisions? Evidence from China.

In recent years, China's "lottery culture" has developed vigorously. Moreover, the investment participation rate of Chinese families in the formal financial market is low, whereas that in the informal financial market is high. Is there a certain relationship between "lottery culture" and family financial decision-making? If so, what is the underlying mechanism? Based on the 2017 CHFS data and lottery sales data of provinces, this study explores the impact of "lottery culture" on household participation in the formal and informal financial markets and the diversity of household financial portfolios. Results show that "lottery culture" can impede household participation in the formal financial market and the diversity of household financial portfolios while promoting household participation in the informal financial market in China. Furthermore, we analyze two channels of "lottery culture" impacts on household financial decisions: (1) risk attitude and (2) human capital. Results illustrate that "lottery culture" can influence household financial decisions by increasing risk tolerance and reducing the human capital of households.

ZBTB20 Regulates Prolactin Expression and Lactotrope Function in Adult Mice.

Lactotropes are prolactin (PRL)-secreting endocrine cells in the anterior pituitary. We have established the zinc finger protein ZBTB20 as an essential transcription factor for lactotrope specification, the disruption of which results in complete loss of lactotropes in mice. However, the potential role of ZBTB20 in mature lactotropes remains unclear. Here we demonstrate that ZBTB20 acts as a critical cell-autonomous regulator for PRL expression in mature lactotropes in adult mice. Via a CRISPR/Cas9 approach, we first generated a tamoxifen-inducible Prl-CreER knockin mouse line that could efficiently mediate gene recombination specifically in lactotropes. Conditional deletion of the Zbtb20 gene specifically in mature lactotropes at adulthood led to a substantial decrease in PRL levels both in the pituitary and in plasma, without significant alterations of lactotrope relative density in the pituitary from male or female mice. Furthermore, conditional disruption of Zbtb20 in adult female mice did not significantly change pregnancy-elicited lactotrope expansion, but caused an impaired mammary gland expansion and lactation due to the PRL defect. Thus, our data point to an important role of ZBTB20 in regulating PRL expression and lactotrope function at adulthood.

Identification and verification of a 4-gene signature predicting the overall survival of cervical cancer.

Cervical cancer (CC) is one of the most common gynecological malignancies, ranking fourth in both incidence and mortality in women worldwide. Early screening and treatment are of great significance in reducing the incidence and mortality of CC. Due to the complex molecular mechanisms of tumor progression, the predictive power of traditional clinical information is limited. In this study, an effective molecular model is established to assess prognosis of patients with CC and guide clinical treatment so as to improve their survival rate. Three high quality datasets (GSE138080, GSE52904, GSE67522) of expression profiling were obtained from gene expression omnibus (GEO) database. Another mRNA expression and clinicopathological data of CC were obtained from The Cancer Genome Atlas (TCGA) dataset. The bioinformatic analyses such as univariate analysis, multivariate Cox proportional-hazards model (Cox) analysis and lasso regression analysis were conducted to select survival-related differentially expressed genes (DEGs) and further establish a prognostic gene signature. Moreover, the performance of prognostic gene signature was evaluated based on Kaplan-Meier curve and receiver operating characteristic (ROC) curve. Gene set enrichment analysis (GSEA) and tumor immunity analysis were carried out to elucidate the molecular mechanisms and immune relevance. A 4-gene signature comprising procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2), spondin1 (SPON1), secreted phosphoprotein 1 (SPP1), ribonuclease H2 subunit A (RNASEH2A) was established to predict overall survival (OS) of CC. The ROC curve indicated good performance of the 4-gene signature in predicting OS of CC based on the TCGA dataset. The 4-gene signature classified the patients into high-risk and low-risk groups with distinct OS rates of CC. Univariate analysis and multivariate Cox regression analysis revealed that the 4-gene signature was an independent factor affecting the prognosis of patients with CC. Our study developed a 4-gene signature capable of predicting the OS of CC. The findings may be beneficial to individualized clinical treatment and timely follow-up for patients with CC.

CoNi-RGO and NiCo2S4-ZIF/g-C3N4 signal amplified electrochemical immunosensors for sensitive detection of CYFRA 21-1.

Herein, a signal amplified electrochemical immunosensor for the sensitive detection of cytokeratin 19 fragments (CYFRA 21-1) in human serum was discussed. The CoNi-RGO was used as a substrate for the sensor with excellent specific surface area and strong electrical conductivity, which enables more efficient attachment of antibodies. The introduction of the bimetallic sulfide NiCo2S4 composite ZIF material provides strong catalytic performance for the immunosensor. It is worth noting that, in addition to these satisfactory advantages, these two materials also show amazing signal amplification capacity. When the immunosensor works, the increase in electrical impedance decreases the electron transfer rate, making the electrochemical signal change obvious. The signal enhancement of immunosensors was emphasized by the marker during construction, and the experimental results were satisfactory. The proposed signal enhanced immunosensor had a linear relationship in the range of 0.001-10 ng/mL for CYFRA 21-1, and the minimum detection limit was 0.33 pg/mL for △I = 95.22 + 23.27 lg c. This demonstrates that the electrochemical immunosensor we constructed is successful and has a great developing potential.

Fungal Diversity in Barley Under Different Storage Conditions.

The diversity of fungi in barley in simulated storage environments was analyzed. Barley was stored at different temperatures (15, 25, 35°C) and relative humidity (55, 65, 75, 85 RH) for 180 and 360 days. Alpha diversity, beta diversity, species composition, and species differences were analyzed using Illumina HiSeq technology. The fungal communities in all barley samples before and after storage belonged to 3 phyla, 18 classes, 39 orders, 71 families, 103 genera, and 152 species. The relative abundance of the dominant phylum Ascomycota was 77.98-99.19%. The relative abundance of Basidiomycota was 0.77-21.96%. At the genus level, the dominant genera of fungi in barley initially included Fusarium, Aspergillus, Microdochium, Alternaria, and Epicoccum. After 360 days of storage, the dominant genera became Epicoccum, Alternaria, Bipolar, Cladosporium, Fusarium, and Aspergillus. According to Venn diagrams and principal coordinates analysis, the fungal community diversity in barley initially was much higher than in barley stored at different temperatures and humidity. The application of PLS-DA could accurately distinguish between barley stored for 180 and 360 days. Some high-temperature and high-humidity environments accelerated storage. The dominant genera differed in different storage conditions and constantly changed with increasing storage duration. Epicoccum was one of the dominant genera after longer storage periods. This study provides theoretical support for optimizing safe storage conditions in barley.

The unconventional activation of the muscarinic acetylcholine receptor M4R by diverse ligands.

Muscarinic acetylcholine receptors (mAChRs) respond to the neurotransmitter acetylcholine and play important roles in human nervous system. Muscarinic receptor 4 (M4R) is a promising drug target for treating neurological and mental disorders, such as Alzheimer's disease and schizophrenia. However, the lack of understanding on M4R's activation by subtype selective agonists hinders its therapeutic applications. Here, we report the structural characterization of M4R selective allosteric agonist, compound-110, as well as agonist iperoxo and positive allosteric modulator LY2119620. Our cryo-electron microscopy structures of compound-110, iperoxo or iperoxo-LY2119620 bound M4R-Gi complex reveal their different interaction modes and activation mechanisms of M4R, and the M4R-ip-LY-Gi structure validates the cooperativity between iperoxo and LY2119620 on M4R. Through the comparative structural and pharmacological analysis, compound-110 mostly occupies the allosteric binding pocket with vertical binding pose. Such a binding and activation mode facilitates its allostersic selectivity and agonist profile. In addition, in our schizophrenia-mimic mouse model study, compound-110 shows antipsychotic activity with low extrapyramidal side effects. Thus, this study provides structural insights to develop next-generation antipsychotic drugs selectively targeting on mAChRs subtypes.

The Effects of GABA-Rich Adzuki Beans on Glycolipid Metabolism, as Well as Intestinal Flora, in Type 2 Diabetic Mice.

OBJECTIVES: In this study, the effects of γ-aminobutyric acid (GABA)-rich sprouted adzuki beans on the glycolipid metabolism and gastrointestinal health were investigated in mice with type 2 diabetes mellitus (T2DM). METHODS: Mice with T2DM were subjected to dietary intervention with different doses of GABA-rich sprouted adzuki beans for 6 consecutive weeks, during which growth indicators, glycolipid metabolism, and the composition and diversity of the gut microbiota changes were observed. RESULTS: A high dietary intake of GABA-rich sprouted adzuki beans had a preventive effect against weight gain, significantly reduced serum levels of FBG, TG, and TC. Additionally, high dietary intake of GABA-rich sprouted adzuki beans increased the abundances of Firmicutes, Bacteroidetes, Verrucomicrobia, and Akkermansia, leading to a shift in the structure of the gut microbiota toward the dominance of probiotics with regulatory effects on glycolipid metabolism. CONCLUSIONS: GABA-rich sprouted adzuki beans can effectively control the bodyweight of mice with T2DM, maintain a balanced blood glucose level, improve glycolipid metabolism and the changes in the microbiota may mediate the anti-diabetic effect of sprouted adzuki beans.

Ratiometric electrochemical immunoassay for procalcitonin based on dual signal probes: Ag NPs and Nile blue A.

In order to determine procalcitonin, a sandwich-type ratiometic electrochemical immunosensor was developed by differential pulse voltammetry (DPV). Due to high chemical stability and good biocompatibility, graphitic carbon nitride (g-C3N4) could be used as feasible supporter to carry silver nanoparticles (Ag NPs) with an obvious oxidative peak (measured typically at + 0.3 V vs. SCE). Ag NPs loaded onto g-C3N4 were not only beneficial to prevent the agglomeration of Ag NPs, but also favorable to improve the electron transfer velocity of g-C3N4. Moreover, the g-C3N4-Ag NPs as the matrix could immobilize primary antibody by Ag-N bond. Nile blue A (NBA), an excellent redox probe based on the redox reaction with two-electrons, provides a current signal at - 0.38 V (vs. SCE). Zr-based metal organic framework (UiO-67), an ideal framework material with large specific surface area and high porosity, could absorb the substantial water-soluble NBA by electrostatic adsorption. The UiO-67 modified by NBA (NBA-UiO-67) owned admirable biocompatibility and was a qualifying marker to load the secondary antibody. For the immunosensor, the current ratio of NBA to Ag NPs (INBA/IAg NPs) was increased as the concentrations of PCT increased. Under the optimum conditions, the linear range of the immunosensor was 0.005 to 50 ng/mL; the detection limit was 1.67 pg/mL (S/N = 3), which reflected the excellent analytical performance of the sensor. The proposed immunosensor strategy is a simple and dependable platform, with great application potential in biometric analysis.

Queen Bees: How Is Female Managers' Happiness Determined?

This paper aims to study the determinants of subjective happiness among working females with a focus on female managers. Drawn on a large social survey data set (N = 10470) in China, this paper constructs gender development index at sub-national levels to study how institutional settings are related to female managers' happiness. We find that female managers report higher levels of happiness than non-managerial employees. However, the promoting effect is contingent on individual characteristics and social-economic settings. The full sample regression suggests that female managers behaving in a masculine way generally report a high level of happiness. Meanwhile, female managers who refuse to support gender equality report low happiness levels. Sub-sample analysis reveals that these causalities are conditioned on regional culture. Masculine behavior and gender role orientation significantly predict subjective happiness only in gender-egalitarian regions. This study is one of the first to consider both internal (individual traits) and external (social-economic environment) factors when investigating how female managers' happiness is impacted. Also, this study challenges the traditional wisdom on the relationship between female managers' job satisfaction and work-home conflict. This study extends the literature by investigating the impacts of female managers' masculine behavior on their happiness. This study is useful for promoting female managers' leadership effectiveness and happiness.

Structure-based discovery of nonhallucinogenic psychedelic analogs.

Drugs that target the human serotonin 2A receptor (5-HT2AR) are used to treat neuropsychiatric diseases; however, many have hallucinogenic effects, hampering their use. Here, we present structures of 5-HT2AR complexed with the psychedelic drugs psilocin (the active metabolite of psilocybin) and d-lysergic acid diethylamide (LSD), as well as the endogenous neurotransmitter serotonin and the nonhallucinogenic psychedelic analog lisuride. Serotonin and psilocin display a second binding mode in addition to the canonical mode, which enabled the design of the psychedelic IHCH-7113 (a substructure of antipsychotic lumateperone) and several 5-HT2AR ß-arrestin-biased agonists that displayed antidepressant-like activity in mice but without hallucinogenic effects. The 5-HT2AR complex structures presented herein and the resulting insights provide a solid foundation for the structure-based design of safe and effective nonhallucinogenic psychedelic analogs with therapeutic effects.