Novel Bifunctional Conjugates Targeting PD-L1/PARP7 as Dual Immunotherapy for Potential Cancer Treatment.

Bifunctional conjugates targeting PD-L1/PARP7 were designed, synthesized, and evaluated for the first time. Compounds B3 and C6 showed potent activity against PD-1/PD-L1 interaction (IC50 = 0.426 and 0.342 µM, respectively) and PARP7 (IC50 = 2.50 and 7.05 nM, respectively). They also displayed excellent binding affinity with hPD-L1, approximately 100-200-fold better than that of hPD-1. Both compounds restored T-cell function, leading to the increase of IFN-γ secretion. In the coculture assay, B3 and C6 enhanced the killing activity of MDA-MB-231 cells by Jurkat T cells in a concentration-dependent manner. Furthermore, B3 and C6 displayed significant in vivo antitumor efficacy in a melanoma B16-F10 tumor mouse model, more than 5.3-fold better than BMS-1 (a PD-L1 inhibitor) and RBN-2397 (a PARP7i clinical candidate) at the dose of 25 mg/kg, without observable side effects. These results provide valuable insight and understanding for developing bifunctional conjugates for potential anticancer therapy.

Development and Validation of a High-Performance Liquid Chromatography Coupled With Ultraviolet Detection Method for Quantification of Bictegravir in Human Plasma.

BACKGROUND: To establish a method for determining the bictegravir (BIC) concentration in human plasma using high-performance liquid chromatography coupled with ultraviolet detection. METHODS: The analysis was performed on a CLC-octadecylsilane column (150 × 6.0 mm, 5 µm) using a mixture of phosphate buffer and acetonitrile (62:38, v/v) as the mobile phase at the flow rate of 1.4 mL/min. The column temperature was maintained at 40°C. Using triamcinolone acetonide as the internal standard, 100 µL of plasma sample was extracted by methyl tert-butyl ether, followed by evaporating under nitrogen stream, redissolving with 100 µL mobile phase, and injection of 20-40 µL of supernatant into the chromatographic system. Ultraviolet detection was performed at 260 nm, and the total run time for each sample was 14 minutes. RESULTS: The method exhibited good linearity within the range from 0.10 to 10.0 mcg/mL (r = 0.9995, n = 5). The intraday and interday relative standard deviations for low-, medium-, and high-concentration quality control samples (0.20, 4.00, 8.00 mcg/mL) and the lower limit of quantification (0.10 mcg/mL) were 1.31%-6.20% (n = 10) and 1.18%-2.87% (n = 5), respectively. The intraday and interday accuracies were 100.53%-102.32% and 97.96%-103.84%, respectively. The extraction recovery rates ranged from 80.00% to 88.09% (n = 3). The stability tests showed that the BIC concentration changed by <15%. CONCLUSIONS: This study successfully established a high-performance liquid chromatography coupled with ultraviolet detection method for determining plasma BIC concentrations. This method is simple, selective, sensitive, and accurate, making it suitable for clinical monitoring and pharmacokinetic studies of BIC.

Perioperative management of a patient with unexpectedly detected early-stage ovarian mucinous carcinoma combined with progressive bulbar paralysis: a case report and literature review.

BACKGROUND: Giant ovarian cysts (GOCs)complicated with progressive bulbar paralysis (PBP) are very rare, and no such literature about these cases have been reported. Through the diagnosis and treatment of this case, the perioperative related treatment of such patients was analyzed in detail, and early-stage ovarian mucinous carcinoma was unexpectedly found during the treatment, which provided reference for clinical diagnosis and treatment of this kind of diseases. CASE PRESENTATION: In this article, we reported a 38-year-old female patient. The patient was diagnosed with PBP 2 years ago. Examination revealed a large fluid-dominated cystic solid mass in the pelvis measuring approximately 28.6×14.2×8.0 cm. Carbohydrate antigen19-9(CA19-9) 29.20 IU/mL and no other significant abnormalities were observed. The patient eventually underwent transabdominal right adnexal resection under regional anesthesia, epidural block. Postoperative pathology showed mucinous carcinoma in some areas of the right ovary. The patient was staged as stage IA, and surveillance was chosen. With postoperative follow-up 1 month later, her CA19-9 decreased to 14.50 IU/ml. CONCLUSIONS: GOCs combined with PBP patients require a multi-disciplinary treatment. Preoperative evaluation of the patient's PBP progression, selection of the surgical approach in relation to the patient's fertility requirements, the nature of the ovarian cyst and systemic condition are required. Early mucinous ovarian cancer accidentally discovered after operation and needs individualized treatment according to the guidelines and the patient's situation. The patient's dysphagia and respiratory function should be closely monitored during the perioperative period. In addition, moral support from the family is also very important.

Rejection Sensitivity and Reactive Aggression in Early Adults: The Mediating Role of Loneliness and Maladaptive Coping.

Reactive aggression is an aggressive response to a perceived threat or provocation. It has detrimental effects on individuals and society. Rejection sensitivity, a disposition that one tends to anxiously expect, readily perceive, and intensely react to social rejection, has been associated with reactive aggression. Considering that the mechanism underlying this link remains unclear, this study explores the mediating role of loneliness and maladaptive coping. Participants included 1104 early adults between the ages of 17-23 (Mage = 20.35, SD = 1.11, 33.6% men) in China who completed the Chinese version of the Tendency to Expect Rejection Scale, Loneliness Scale, Ways of Coping Questionnaire, and Reactive-Active Aggression Questionnaire. The serial mediation model revealed that loneliness and maladaptive coping independently mediated the association of rejection sensitivity with reactive aggression. More importantly, the chain mediating effect of "loneliness-maladaptive coping" also accounted for this link. The above findings contribute to a deeper understanding of the relationships among these factors and suggested that rejection sensitivity could positively be related to reactive aggression through loneliness and maladaptive coping.

The first clinical validation of whole-genome screening on standard trophectoderm biopsies of preimplantation embryos.

Objective: To validate the performance of our laboratory-developed whole-genome screening assay within clinical preimplantation genetic testing environments. Design: Perform a laboratory-developed whole-genome assay on both cell lines and trophectoderm biopsies, subsequently employing the next-generation sequencing procedure to reach a sequencing depth of 30X. Adhere to the Genome Analysis Toolkit best practices for accuracy, sensitivity, specificity, and precision calculations by comparing samples with references. Our assay was then applied to cell lines and biopsies harboring known pathogenic variants, aiming to ascertain these changes solely from the next-generation sequencing data, independent of parental genome information. Settings: Clinical laboratory. Patients: Coriell cell lines and research embryos with known chromosomal or genetic variants. Research trophectoderm biopsies from a couple that are heterozygous carriers for distinct variants in the same autosomal recessive gene (HOGA1). Intervention: Not applicable. Main Outcome Measures: Accuracy, sensitivity, specificity, and precision were assessed by comparing the samples to their references. For samples with known variants, we calculated our sensitivity to detecting established variants. For the research embryos, noncarrier, carrier, and compound heterozygous states of inherited HOGA1 variants were distinguished independently of parental samples. Results: Amplification of DNA from cell lines and embryos yielded success rates exceeding 99.9% and 98.2%, respectively, although maintaining an accuracy of >99.9% for aneuploidy assessment. The accuracy (99.99%), specificity (99.99%), sensitivity (98.0%), and precision (98.1%) of amplified genome in the bottle (reference NA12878) and embryo biopsies were comparable to results on genomic DNA, including mitochondrial heteroplasmy. Using our assay, we achieved >99.99% sensitivity when examining samples with known chromosomal and genetic variants. This encompassed pathogenic CFTR, BRCA1, and other variants, along with uniparental isodisomies and microdeletions such as DiGeorge syndrome. Our research study identified noncarrier, carrier, and compound heterozygous states within trophectoderm biopsies while simultaneously screening for 1,300 other severe monogenic diseases. Conclusion: To our knowledge, this is the first clinical validation of whole-genome embryo screening. In this study, we demonstrated high accuracy for aneuploidy calls (>99.9%) and genetic variants (99.99%), even in the absence of parental genomes. This assay demonstrates advancements in genomic screening and an extended scope for testing capabilities in the realm of preimplantation genetic testing.

A preliminary study on plasma concentration, short-term efficacy, and safety profile of dolutegravir in Chinese people with HIV.

BACKGROUND: This study examined the plasma concentration, clinical efficacy, and safety of dolutegravir (DTG) in Chinese people with HIV (PWH). METHODS: In this observational study, HIV-positive individuals on DTG-based regimens for at least 6 months were included. Plasma DTG concentrations were measured 1 month after initiating treatment. Viral loads (VL) and CD4+ T cell counts were evaluated at baseline and after 1 and 6 months of therapy. High-performance liquid chromatography was used for measuring DTG concentrations, polymerase chain reaction for VL, and flow cytometry for CD4+ T cell counts. Safety assessments included monitoring liver enzymes, serum creatinine estimated glomerular filtration rate, and adverse reactions. RESULTS: Eighty-two Chinese PWH were enrolled. Average VL decreased significantly from baseline by 3.1 log at 1 month and 3.5 log at 6 months. CD4+ T cell counts increased from 273 cells/mm3 at baseline to 378 cells/mm3 and 446 cells/mm3 after 1 and 6 months, respectively. Seventy-five percent achieved undetectable VLs (<20 copies/mL) by 6 months. Cmax and Cτ were 4.63 and 1.98 µg/mL, respectively. The safety profile was favorable with only 4.88% experiencing transient dizziness. CONCLUSION: Preliminary findings suggest higher DTG plasma concentrations in Chinese PWH compared to Western populations, with promising short-term efficacy and safety.

Binding capacity and co-migration potential of Pb(II), Cu(II), and Cd(II) on colloids in road runoff.

To evaluate the co-migration potential between heavy metal ions and road runoff colloids, the influence of contact time, temperature, initial concentration of metal ions, pH, humic acid (HA), and polymetallic coexistence on the binding capacity of heavy metals onto runoff colloids were investigated. The adsorption of heavy metals by runoff colloids was extremely rapid, approximately 80% of the equilibrium adsorption capacity was achieved in the first 30 min. The binding capacity exhibited an increasing trend with the initial concentration of metal ions increasing, and the maximum adsorption capacities of Pb(II), Cu(II), and Cd(II) achieved 159.13, 56.06, and 78.35 mg/g at 298 K, respectively. The adsorption capacity of Cu(II) and Cd(II) by runoff colloids increased with temperature increasing, while it displayed a converse trend for Pb(II). Neutral pH facilitated the combination of metal ions and runoff colloids. The presence of humic acid increased the binding capacity of Pb(II), Cu(II), and Cd(II) onto runoff colloids by 72.19, 63.31, and 13.83mg/g, respectively. Compared to the monometallic systems, the binding capacity of Pb(II), Cu(II), and Cd(II) by runoff colloids decreased by 18.44%, 22.35%, and 56.06% in polymetallic systems, respectively. Pb(II) bounded with colloids in the road runoff should be controlled preferentially to avoid their migrations to aquatic environments.

Study on the effects and mechanisms of Wenzhong Bushen Formula in improving ovarian reserve decline in mice based on network pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: The Wenzhong Bushen Formula (WZBSF) is a traditional Chinese medicine empirical formula known for its effects in tonifying qi, strengthening the spleen, warming the kidneys, promoting yang, regulating blood circulation, and balancing menstruation. Clinical evidence has demonstrated its significant efficacy in treating Diminished Ovarian Reserve (DOR) by improving ovarian reserves. However, the specific pharmacological mechanisms of WZBSF remain unclear. AIM OF THE STUDY: This study aims to investigate the mechanisms by which WZBSF improves ovarian reserve decline through network pharmacology and animal experiments. METHODS AND MATERIALS: WZBSF was analyzed using a dual UPLC-MS/MS and GC-MS platform. Effective components and targets of WZBSF were obtained from the TCMSP database and standardized using UniProt. Disease targets were collected from GeneCard, OMIM, PHARMGKB, and DisGeNET databases, with cross-referencing between the two sets of targets. A PPI protein interaction network was constructed using Cytoscape3.9.1 and STRING database, followed by KEGG and GO enrichment analysis using the Metascape database. Finally, an ovarian reserve decline model was established in mice, different doses of WZBSF were administered, and experimental validation was conducted through serum hormone detection, H&E staining, immunofluorescence (IF), immunohistochemistry (IHC), and Western blot analysis (WB). RESULTS: WZBSF shares 145 common targets with ovarian reserve decline. GO enrichment analysis revealed involvement in biological processes such as response to hormone stimulation and phosphatase binding, while KEGG analysis implicated pathways including the PI3K-AKT signaling pathway and FoxO signaling pathway. In mice with ovarian reserve decline, WZBSF restored weight gain rate, increased ovarian index, normalized estrous cycles, reversed serum hormone imbalances, restored various follicle counts, and improved ovarian morphology. Additionally, WZBSF reduced p-AKT and p-FOXO3a levels, preventing excessive activation of primordial follicles and maintaining ovarian reserve. CONCLUSION: WZBSF can ameliorate cyclophosphamide and busulfan-induced ovarian reserve decline, and its mechanism may be associated with the inhibition of the PI3K/AKT/FOXO3a signaling pathway.

Danlou Recipe promotes cholesterol efflux in macrophages RAW264.7 and reverses cholesterol transport in mice with hyperlipidemia induced by P407.

INTRODUCTION: Liver X Receptor (LXR) agonists could attenuate the development of atherosclerosis but bring excess lipid accumulation in the liver. Danlou Recipe was believed to be a benefit for improving the lipid profile. Thus, it is unclear whether Danlou Recipe could attenuate hyperlipidemia without excess lipid accumulated in the liver of mice. This study aimed to clarify if Danlou Recipe could alleviate the progression of hyperlipidemia in mice without extra lipids accumulated in the liver. METHODS: Male murine macrophage RAW264.7 cells and murine peritoneal macrophages were used for the in vitro experiments. Cellular cholesterol efflux was determined using the fluorescent cholesterol labeling method. Those genes involved in lipid metabolism were evaluated by qRT-PCR and western blotting respectively. In vivo, a mouse model of hyperlipidemia induced by P407 was used to figure out the effect of Danlou Recipe on reverse cholesterol transport (RCT) and hyperlipidemia. Ethanol extract of Danlou tablet (EEDL) was prepared by extracting the whole powder of Danlou Prescription from ethanol, and the chemical composition was analyzed by ultra-performance liquid chromatography (UPLC). RESULTS: EEDL inhibits the formation of RAW264.7 macrophage-derived foam cells, and promotes ABCA1/apoA1 conducted cholesterol efflux in RAW264.7 macrophages and mouse peritoneal macrophages. In the P407-induced hyperlipidemia mouse model, oral administration of EEDL can promote RCT in vivo and improve fatty liver induced by a high-fat diet. Consistent with the findings in vitro, EEDL promotes RCT by upregulating the LXR activities. CONCLUSION: Our results demonstrate that EEDL has the potential for targeting RCT/LXR in the treatment of lipid metabolism disorders to be developed as a safe and effective therapy.

Association Between Negative Affect and Perceived Mortality Threat During the COVID-19 Pandemic: The Role of Brain Activity and Connectivity.

The prevalence of the novel coronavirus (COVID-19) has been considered a major threat to physical and mental health around the world, causing great pressure and mortality threat to most people. The current study aimed to investigate the neurological markers underlying the relationship between perceived mortality threat (PMT) and negative affect (NA). We examined whether the regional amplitude of low-frequency fluctuations (ALFF) and resting-state functional connectivity (RSFC) before the COVID-19 outbreak (October 2019 to December 2019, wave 1) were predictive for NA and PMT during the mid-term of the COVID-19 pandemic (February 22 to 28, 2020, wave 2) among 603 young adults (age range 17-22, 70.8% females). Results indicated that PMT was associated with spontaneous activity in several regions (e.g., inferior temporal gyrus, medial occipital gyrus, medial frontal gyrus, angular gyrus, and cerebellum) and their RSFC with the distributed regions of the default mode network and cognitive control network. Furthermore, longitudinal mediation models showed that ALFF in the cerebellum, medial occipital gyrus, medial frontal gyrus, and angular gyrus (wave 1) predicted PMT (wave 2) through NA (wave 2). These findings revealed functional neural markers of PMT and suggest candidate mechanisms for explaining the complex relationship between NA and mental/neural processing related to PMT in the circumstance of a major crisis.

Scarcity mindset impairs distractor suppression but not target enhancement in selective attention: Evidence from ERPs.

A scarcity mindset, induced by a perception of material scarcity, profoundly influences how individuals allocate their attention. Selective attention, a crucial cognitive control process enabling individuals to focus on relevant information while ignoring distractions, holds significant importance in both professional and personal domains. However, the specific impact of a scarcity mindset on selective attention and its underlying mechanisms remains uncertain. The objective of this study is to examine the specific impact of a scarcity mindset on selective attention using an experimental approach. Participants were subjected to either scarcity or neutral conditions, and their brain activity was measured using Electroencephalography (EEG) while performing a visual search task. The task involved identifying the direction of a target while disregarding a distractor, which was presented either laterally or in conjunction with the target along the vertical midline. The findings of our study indicate that individuals with a scarcity mindset displayed compromised selective attention, as evidenced by longer response times and weaker N2pc amplitudes in EEG recordings. Notably, distractor suppression was compromised, as evidenced by diminished Pd amplitudes, whereas the enhancement of targets remained relatively unaltered, as indicated by similar Nt amplitudes. These findings highlight a reduced ability to filter out irrelevant information in individuals with a scarcity mindset, thereby holding significant implications for social policies and practices.

Phosphorylation of USP27X by GSK3ß maintains the stability and oncogenic functions of CBX2.

Chromobox protein homolog 2 (CBX2) exerts a multifaceted impact on the progression of aggressive cancers. The proteasome-dependent pathway is crucial for modulating CBX2 regulation, while the specific regulatory roles and mechanisms of deubiquitinating enzymes targeting CBX2 remain poorly understood. Mass spectrometry analysis identified ubiquitin-specific peptidase 27X (USP27X) as a deubiquitinating enzyme that targets CBX2. Overexpression of USP27X significantly enhances CBX2 levels by promoting deubiquitination, while deficiency of USP27X leads to CBX2 degradation, thereby inhibiting tumorigenesis. Furthermore, it has been revealed that glycogen synthase kinase 3 beta (GSK3ß) can directly bind to and phosphorylate USP27X, thereby enhancing the interaction between USP27X and CBX2 and leading to further stabilization of the CBX2 protein. Clinically, the co-expression of high levels of USP27X and CBX2 in breast cancer tissues is indicative of a poor prognosis for patients with this disease. These findings collectively underscore the critical regulatory role played by USP27X in modulating CBX2, thereby establishing the GSK3ß-USP27X-CBX2 axis as a pivotal driver of malignant progression in breast cancer.

Non-canonical C-terminal variant of MeCP2 R344W exhibits enhanced degradation rate.

Rett Syndrome (RTT) is a neurodevelopmental disorder caused by pathogenic variants in the MECP2 gene. While the majority of RTT-causing variants are clustered in the methyl-CpG binding domain and NCoR/SMRT interaction domain, we report a female patient with a functionally uncharacterized MECP2 variant in the C-terminal domain, c.1030C>T (R344W). We functionally characterized MECP2-R344W in terms of protein stability, NCoR/SMRT complex interaction, and protein nuclear localization in vitro. MECP2-R344W cells showed an increased protein degradation rate without significant change in NCoR/SMRT complex interaction and nuclear localization pattern, suggesting that enhanced MECP2 degradation is sufficient to cause a Rett Syndrome-like phenotype. This study highlights the pathogenicity of the C-terminal domain in Rett Syndrome, and demonstrates the potential of targeting MECP2 protein stability as a therapeutic approach.

[Qirong Tablets inhibits apoptosis of ovarian granulosa cells via PI3K/Akt/ HIF-1 signaling pathway].

This study aims to observe the effect and explore the mechanism of Qirong Tablets in the treatment of premature ovarian insufficiency(POI) in mice via the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt)/hypoxia inducible factor 1(HIF-1) signaling pathway. Sixty SPF female BALB/c mice were randomly divided into normal group, model group, positive control group, Qirong Tablets low-, medium-and high-dose group. The normal group was intraperitoneally injected with the same amount of normal saline, and the other groups were intraperitoneally injected with cyclophosphamide 120 mg·kg~(-1)·d~(-1) once to establish a POI animal model. After the model was successfully established, the low-, medium-and high-dose groups of Qirong Tablets were administered orally with 0.6, 1.2, 2.4 mg·kg~(-1)·d~(-1) respectively. The positive control group was given 0.22 mg·kg~(-1)·d~(-1) Clementine Tablets by intragastric administration, and the normal group and model group were given intragastric administration with the same amount of normal saline, and the treatment was 28 d as a course of treatment. After drug intervention, enzyme-linked immunosorbent assay(ELISA) was employed to measure the levels of estradiol(E_2), follicle-stimulating hormone(FSH), luteinizing hormone(LH), and anti-mullerian hormone(AMH) in peripheral blood, and hematoxylin-eosin(HE) staining to observe the ovarian tissue. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling(TUNEL) assay was used to detect the apoptosis of granulosa cells, and Western blot to determine the expression levels of B-cell lymphoma-2(Bcl-2), Bcl-2-associated X protein(Bax), caspase-3, PI3K, Akt, and HIF-1. Compared with the normal group, the modeling of POI caused loose or destroyed ovarian tissue with vacuolar structures, edema and fibrosis in the ovarian interstitium, disordered or loose arrangement of granulosa cells, and reduced normal follicles. Compared with the model group, drug interventions restored the ovarian tissue and follicles at all the development stages and reduced atretic follicles. Compared with the normal group, the modeling of POI lowered the serum level of E_2 and AMH(P<0.01), and elevated the level of FSH and LH(P<0.01). Compared with the model group, high-dose Qirong Tablets elevated the levels of E_2 and AMH(P<0.05), and lowered the levels of FSH and LH(P<0.05). Compared with the normal group, the modeling of POI up-regulated the protein levels of PI3K, Akt, HIF-1, Bax, and caspase-3 and down-regulated the protein level of Bcl-2 in the ovarian tissue(P<0.01). Compared with the model group, low-, medium-, and high-dose Qirong Tablets down-regulated the protein levels of PI3K, Akt, HIF-1, Bax, and caspase-3 proteins and up-regulated the protein level of Bcl-2 in the ovarian tissue(P<0.05). In conclusion, Qirong Tablets can up-regulate the expression Bcl-2, down-regulate the expression of Bax and caspase-3 in POI mice. Qirong Tablets may inhibit the apoptosis of follicular granulosa cells in mice, thereby delaying ovarian aging, improving reproductive axis function, and strengthening ovarian reserve capacity, which may be associated with the inhibition of PI3K/Akt/HIF-1 pathway.

Large-scale genomic survey and characterization of mcr genes carried by foodborne Cronobacter isolates.

IMPORTANCE: Cronobacter is an emerging foodborne opportunistic pathogen, which can cause neonatal meningitis, bacteremia, and NEC by contaminating food. However, the entire picture of foodborne Cronobacter carriage of the mcr genes is not known. Here, we investigated the mcr genes of Cronobacter isolates by whole-genome sequencing and found 133 previously undescribed Cronobacter isolates carrying mcr genes. Further genomic analysis revealed that these mcr genes mainly belonged to the mcr-9 and mcr-10. Genomic analysis of the flanking structures of mcr genes revealed that two core flanking structures were prevalent in foodborne Cronobacter isolates, and the flanking structure carrying IS1R was found for the first time in this study.

Development and validation of an HPLC method for quantification of dolutegravir in human plasma.

Dolutegravir (DTG) has been the first-line drug in many human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) guidelines for the treatment of naïve and experienced HIV-infected individuals, which calls for cost-effective and convenient methods for quantitative detection of DTG in human plasma for pharmacokinetic studies and patient adherence evaluation. Here, an HPLC-ultraviolet method in combination with liquid-liquid extraction with isocratic elution was developed for the first time. The analysis was performed on a CLC-ODS column (6 mm internal diameter × 15 cm, 5 µm) using a mixture of acetonitrile and phosphate buffer (40:60, v/v) as the mobile phase at the flow rate of 1 mL/min. Using triamcinolone as the internal standard, 100 µL of plasma sample was extracted by methyl tert-butyl ether, followed by evaporating under nitrogen stream, re-dissolving with 100 µL mobile phase, and injection of 20-40 µL of supernatant into the chromatographic system. The linearity of DTG was good in the range of 0.05-10 µg/mL (r = 0.9995), and the inter- and intra-day variabilities were 0.4%-4.3% (n = 10) and 1.2%-6.2% (n = 10) for the lower limit of quantification, low-, medium-, and high-concentration quality control samples (0.05, 0.1, 0.8, and 8 µg/mL), respectively, while the methodological and extraction recoveries were 98.0%-103.0% (n = 20) and 65.2%-75.7% (n = 3), respectively. This method was successfully applied to analyze DTG plasma concentration in 84 Chinese patients with HIV.

The relationship between loneliness and problematic smartphone use among adolescents during the COVID-19 pandemic: The mediating role of negative emotions and maladaptive coping.

INTRODUCTION: Given the observed increased feelings of loneliness and problematic smartphone use among adolescents during the COVID-19 pandemic, further research was needed to determine whether and how the increased loneliness of adolescents during such major public health crisis events affects the risk of problematic smartphone use among adolescents. This study aimed to examine the relationship between loneliness and problematic smartphone use among Chinese adolescents (aged 10-16 years) during the COVID-19 pandemic and to investigate the possible mediating role of negative emotions and maladaptive coping. METHODS: A total of 672 Chinese adolescents (Mage = 13.05, SD = 1.51, 50.4% boys, 93.8% from rural areas, 22.5% of whom were only children) took part in this cross-sectional study in April 2022 by completing the Chinese adolescent version of the Loneliness Scale, the Positive and Negative Affect Scale (subscale), the Ways of Coping Questionnaire, and the Mobile Phone Addiction Index Scale. RESULTS: The serial mediation model revealed that negative emotions and maladaptive coping independently mediated the relationship between adolescents' loneliness and problematic smartphone use. In addition, the mediation effects of "negative emotions-maladaptive coping" could also mediate the relationship between loneliness and problematic smartphone use. CONCLUSIONS: Loneliness may be positively related to problematic smartphone use through negative emotions and maladaptive coping among adolescents during major public health crisis events, such as the COVID-19 pandemic.

Immunogenicity and protective effects of recombinant bivalent COVID-19 vaccine in mice and rhesus macaques.

Coronavirus disease (COVID-19) is still spreading rapidly worldwide, and a safe, effective, and cheap vaccine is still required to combat the COVID-19 pandemic. Here, we report a recombinant bivalent COVID-19 vaccine containing the RBD proteins of the prototype strain and beta variant. Immunization studies in mice demonstrated that this bivalent vaccine had far greater immunogenicity than the ZF2001, a marketed monovalent recombinant protein COVID-19 vaccine, and exhibited good immunization effects against the original COVID-19 strain and various variants. Rhesus macaque challenge experiments showed that this bivalent vaccine drastically decreased the lung viral load and reduced lung lesions in SARS-CoV-2 (the causative virus of COVID-19)-infected rhesus macaques. In summary, this bivalent vaccine showed immunogenicity and protective efficacy that was far superior to the monovalent recombinant protein vaccine against the prototype strain and provided an important basis for developing broad-spectrum COVID-19 vaccines.

Personal relative deprivation impairs the ability to inhibit impulsive responses: an exploratory ERP study.

Evidence indicates that personal relative deprivation (PRD) can lead to various impulsive behaviors. Given that impulsive behaviors are usually caused by a failure to exert cognitive control, the purpose of this study was to explore whether PRD affects the ability to exert cognitive control on behavior. Forty-six healthy participants were randomly assigned to PRD or non-PRD group. Participants of the PRD group were told their income would lie below the Chinese average. While their electrophysiological responses were recorded, they underwent a Go/No-Go task simultaneously assessing the ability to detect response conflict and inhibit the predominant response. We found that the individuals with induced PRD show diminished ability to inhibit predominant response. We suggest this is because PRD-related concerns consume cognitive resources, leaving less for other tasks. However, we also found that individuals with induced PRD show enhanced ability to detect conflict. This might be because that individuals with induced PRD were sensitive to potentially threatening information (high-conflict No-Go trials) and they can detect conflict with less cognitive resources. These findings may facilitate future attempts to design interventions for relatively deprived individuals to manage their impulsive behavior.

Based on network pharmacology to explore the effect and mechanism of Yipibushen decoction in improving obese type 2 diabetes mellitus with oligoasthenotspermia.

ETHNOPHARMACOLOGICAL RELEVANCE: A traditional Chinese medicine experience compound known as Yipibushen (YPBS) decoction stimulates qi and nourishes yin, stimulates the kidney and solid essence, dissolves phlegm and eliminates stasis. YPBS decoction has proven to be successful in treating obese type 2 diabetes mellitus with oligoasthenotspermia in clinical settings. Nevertheless, the pharmacological mechanism is not understood. AIM OF THE STUDY: Investigating the mechanism of action of YPBS decoction in enhancing the obese type 2 diabetes mellitus with oligoasthenotspermia involved network pharmacology and animal validation techniques. METHODS AND MATERIALS: The YPBS Decoction' active components were found in the TCMSP database and their targets were identified using UniProtKB. Additionally, targets for the obese type 2 diabetes mellitus with oligoasthenotspermia were found in the GeneCard, DisGeNet, TTD and OMIM databases. The intersection of active ingredients, the obese type 2 diabetes mellitus with oligoasthenotspermia was chosen as the intersection target. The protein-protein interaction (PPI) network of the intersection target was built with the aid of Cytoscape 3.9.1, the core target of PPI was obtained through software analysis in R-project, GO enrichment and KEGG enrichment analysis was carried out on the core target. Finally, animal experiments were used to verify the intersection target. RESULTS: The research revealed 74 intersection targets of YPBS decoction active ingredients in the obese type 2 diabetes mellitus with oligoasthenotspermia. There were also 18 PPI core targets, GO enrichment analysis of PPI core targets involving response to oxidative stress, membrane raft, DNA-binding transcription regulator complex and other biological processes; KEGG involving endocrine resistance, PI3K/AKT signaling pathway, apoptosis and other signal pathways. In the obese type 2 diabetes mellitus with oligoasthenotspermia mice, animal studies have shown that YPBS decoction group could decrease blood glucose levels and improve insulin resistance; improve testicular function, enhance sperm count, sperm motility, sperm viability, and decrease the malformation rate. It could increase the levels of T-SOD and GSH-Px, and decrease the MDA level. In addition to this, it could improve the amount of testosterone hormone, and enhance the expression of PI3K, p-AKT and Bcl-2. CONCLUSION: By controlling the degree of oxidative stress and the PI3K/AKT/Bcl-2 pathway, YPBS decoction may enhance the obese type 2 diabetes mellitus with Oligoasthenotspermia, provide a scientific basis for clinical diagnosis and therapy.