Design, Synthesis, and Biological Evaluation of Chroman Derivatives as PD-1/PD-L1 Antagonists.

Programmed death-ligand 1 (PD-L1) has emerged as a promising therapeutic target for various cancers due to its crucial role in promoting tumor immune evasion. Here, we report a novel class of chroman-like small-molecule PD-L1 inhibitors exhibiting significant activity in inhibiting the PD-1/PD-L1 interaction. Employing a "ring-close" strategy for conformational restriction, we have achieved compound C27, which demonstrates superior PD-1/PD-L1 inhibitory activity compared to the positive control. Molecular dynamics simulation and binding free energy calculation predict that (R)-C27 with inhibitory activity surpassed (S)-C27. The experimental results from bioassay and X-ray structural analysis corroborate these findings. All these results collectively indicate that (R)-C27 is a promising lead compound deserving further exploration.

Advances in Vaccine Adjuvants: Nanomaterials and Small Molecules.

Adjuvants have been extensively and essentially formulated in subunits and certain inactivated vaccines for enhancing and prolonging protective immunity against infections and diseases. According to the types of infectious diseases and the required immunity, adjuvants with various acting mechanisms have been designed and applied in human vaccines. In this chapter, we introduce the advances in vaccine adjuvants based on nanomaterials and small molecules. By reviewing the immune mechanisms induced by adjuvants with different characteristics, we aim to establish structure-activity relationships between the physicochemical properties of adjuvants and their immunostimulating capability for the development of adjuvants for more effective preventative and therapeutic vaccines.

Biomolecular phase separation in stress granule assembly and virus infection.

Liquid-liquid phase separation (LLPS) has emerged as a crucial mechanism for cellular compartmentalization. One prominent example of this is the stress granule. Found in various types of cells, stress granule is a biomolecular condensate formed through phase separation. It comprises numerous RNA and RNA-binding proteins. Over the past decades, substantial knowledge has been gained about the composition and dynamics of stress granules. SGs can regulate various signaling pathways and have been associated with numerous human diseases, such as neurodegenerative diseases, cancer, and infectious diseases. The threat of viral infections continues to loom over society. Both DNA and RNA viruses depend on host cells for replication. Intriguingly, many stages of the viral life cycle are closely tied to RNA metabolism in human cells. The field of biomolecular condensates has rapidly advanced in recent times. In this context, we aim to summarize research on stress granules and their link to viral infections. Notably, stress granules triggered by viral infections behave differently from the canonical stress granules triggered by sodium arsenite (SA) and heat shock. Studying stress granules in the context of viral infections could offer a valuable platform to link viral replication processes and host anti-viral responses. A deeper understanding of these biological processes could pave the way for innovative interventions and treatments for viral infectious diseases. They could potentially bridge the gap between basic biological processes and interactions between viruses and their hosts.

The Relationship Between the Atmospheric Environment and Road Traffic Fatalities - Shandong Province, China, 2012-2021.

Introduction: This study aims to analyze the potential impact of the meteorological environment and air pollutants on road traffic fatalities. Methods: Road traffic fatality data in Shandong Province from 2012 to 2021 were obtained from the Population Death Information Registration Management System. Meteorological and air pollutant data for the same period were collected from the U.S. National Oceanic and Atmospheric Administration and the Ecological Environment Monitoring Center of Shandong Province, China. Pearson's correlation and ridge regression were used to analyze the impact of the meteorological environment and air pollutants on road traffic fatalities. Results: From 2012 to 2021, there were 163,863 road traffic fatality cases. The results of the ridge regression analysis showed that the daily average temperature was negatively correlated with total fatalities and passengers and positively correlated with pedestrians, nonmotorized drivers, and motorized drivers. The daily minimum temperature was negatively correlated with total fatalities and positively correlated with motorized drivers. The daily maximum temperature was positively correlated with both pedestrian and nonmotorized drivers. The daily accumulated precipitation was negatively correlated with pedestrians. Sunshine duration was positively correlated with both nonmotorized and motorized drivers. Inhalable particulate matter (PM10) and nitrogen dioxide (NO2) were positively correlated with total fatalities, pedestrians, and nonmotorized drivers. Sulfur dioxide (SO2) was positively correlated with total fatalities but negatively correlated with nonmotorized drivers, passengers, and motorized drivers. Conclusions: Atmospheric factors associated with the occurrence of road traffic fatalities include air temperature, daily accumulated precipitation, sunshine duration, and air pollutants such as PM10, NO2, and SO2.

Aluminum oxyhydroxide-Poly(I:C) combination adjuvant with balanced immunostimulatory potentials for prophylactic vaccines.

The development of high-purity antigens promotes the urgent need of novel adjuvant with the capability to trigger high levels of immune response. Polyinosinic-polycytidylic (Poly(I:C)) is a synthetic double-stranded RNA (dsRNA) that can engage Toll-like receptor 3 (TLR3) to initiate immune responses. However, the Poly(I:C)-induced toxicity and inefficient delivery prevent its applications. In our study, combination adjuvants are formulated by aluminum oxyhydroxide nanorods (AlOOH NRs) and Poly(I:C), named Al-Poly(I:C), and the covalent interaction between the two components is further demonstrated. Al-Poly(I:C) mediates enhanced humoral and cellular immune responses in three antigen models, i.e., HBsAg virus-like particles (VLPs), human papilloma virus (HPV) VLPs and varicella-zoster virus (VZV) glycoprotein E (gE). Further mechanistic studies demonstrate that the dose and molecular weight (MW) of Poly(I:C) determine the physicochemical properties and adjuvanticity of the Al-Poly(I:C) combination adjuvants. Al-Poly(I:C) with higher Poly(I:C) dose promotes antigen-bearing dendritic cells (DCs) recruitment and B cells proliferation in lymph nodes. Al-Poly(I:C) formulated with higher MW Poly(I:C) induces higher activation of helper T cells, B cells, and CTLs. This study demonstrates that Al-Poly(I:C) potentiates the humoral and cellular responses in vaccine formulations. It offers insights for adjuvant design to meet the formulation requirements in both prophylactic and therapeutic vaccines.

The orientation of CpG conjugation on aluminum oxyhydroxide nanoparticles determines the immunostimulatory effects of combination adjuvants.

In subunit vaccines, aluminum salts (Alum) are commonly used as adjuvants, but with limited cellular immune responses. To overcome this limitation, CpG oligodeoxynucleotides (ODNs) have been used in combination with Alum. However, current combined usage of Alum and CpG is limited to linear mixtures, and the underlying interaction mechanism between CpG and Alum is not well understood. Thus, we propose to chemically conjugate Alum nanoparticles and CpG (with 5' or 3' end exposed) to design combination adjuvants. Our study demonstrates that compared to the 3'-end exposure, the 5'-end exposure of CpG in combination adjuvants (Al-CpG-5') enhances the activation of bone-marrow derived dendritic cells (BMDCs) and promotes Th1 and Th2 cytokine secretion. We used the SARS-CoV-2 receptor binding domain (RBD) and hepatitis B surface antigen (HBsAg) as model antigens to demonstrate that Al-CpG-5' enhanced antigen-specific antibody production and upregulated cytotoxic T lymphocyte markers. Additionally, Al-CpG-5' allows for coordinated adaptive immune responses even at lower doses of both CpG ODNs and HBsAg antigens, and enhances lymph node transport of antigens and activation of dendritic cells, promoting Tfh cell differentiation and B cell activation. Our novel Alum-CPG strategy points the way towards broadening the use of nanoadjuvants for both prophylactic and therapeutic vaccines.

Silicon or Calcium Doping Coordinates the Immunostimulatory Effects of Aluminum Oxyhydroxide Nanoadjuvants in Prophylactic Vaccines.

Aluminum salts still remain as the most popular adjuvants in marketed human prophylactic vaccines due to their capability to trigger humoral immune responses with a good safety record. However, insufficient induction of cellular immune responses limits their further applications. In this study, we prepare a library of silicon (Si)- or calcium (Ca)-doped aluminum oxyhydroxide (AlOOH) nanoadjuvants. They exhibit well-controlled physicochemical properties, and the dopants are homogeneously distributed in nanoadjuvants. By using Hepatitis B surface antigen (HBsAg) as the model antigen, doped AlOOH nanoadjuvants mediate higher antigen uptake and promote lysosome escape of HBsAg through lysosomal rupture induced by the dissolution of the dopant in the lysosomes in bone marrow-derived dendritic cells (BMDCs). Additionally, doped nanoadjuvants trigger higher antigen accumulation and immune cell activation in draining lymph nodes. In HBsAg and varicella-zoster virus glycoprotein E (gE) vaccination models, doped nanoadjuvants induce high IgG titer, activations of CD4+ and CD8+ T cells, cytotoxic T lymphocytes, and generations of effector memory T cells. Doping of aluminum salt-based adjuvants with biological safety profiles and immunostimulating capability is a potential strategy to mediate robust humoral and cellular immunity. It potentiates the applications of engineered adjuvants in the development of vaccines with coordinated immune responses.

Discovery of Novel PD-L1 Small-Molecular Inhibitors with Potent In Vivo Anti-tumor Immune Activity.

Programmed death-ligand 1 (PD-L1) has surfaced as a promising therapeutic target for various cancers due to its pivotal role in facilitating tumor immune evasion. Herein, we report a series of novel small-molecule PD-L1 inhibitors exhibiting remarkable inhibitory activity against the PD-1/PD-L1 interaction (X18: IC50 = 1.3 nM) and reinstating the suppressive effect of PD-L1 on T cells (X18: EC50 = 152.8 nM). Crystallographic studies revealed the binding mode of X18 and PD-L1. Through a rational prodrug design approach, we have successfully optimized the oral pharmacokinetic properties of X22, effectively addressing the poor oral pharmacokinetic profile of PD-L1 small-molecule inhibitors. Notably, X22 demonstrated significant antitumor efficacy in murine models of MC38 and CT26 colon cancer through the upregulation of tumor infiltration and cytotoxicity of CD8+ T cells partially. These findings offer promising prospects for the advancement of PD-L1 inhibitors as innovative agents in cancer immunotherapy.

Temporal and spatial trends in road traffic fatalities from 2001 to 2019 in Shandong Province, China.

OBJECTIVE: This study explored the temporal and spatial trends in road traffic fatalities in Shandong Province from 2001 to 2019 and discusses the possible influencing factors. METHODS: We collected data from the statistical yearbooks of the China National Bureau of Statistics and the Shandong Provincial Bureau of Statistics. Join-point Regression Program 4.9.0.0 and ArcGIS 10.8 software were used to analyze the temporal and spatial trends. RESULTS: The mortality rate of road traffic injuries in Shandong Province decreased from 2001 to 2019, with an average annual decrease of 5.8% (Z = -20.7, P < 0.1). The three key time points analyzed in the Join-point regression model roughly corresponded to the implementation times of traffic laws and regulations in China. The temporal trend in case fatality rate in Shandong Province from 2001 to 2019 was not statistically significant (Z = 2.8, P < 0.1). The mortality rate showed spatial autocorrelation (global Moran's I = 0.3889, Z = 2.2043, P = 0.028) and spatial clustering. No spatial autocorrelation was observed in the case fatality rate (global Moran's I = -0.0183, Z = 0.2308, P = 0.817). CONCLUSIONS: The mortality rate in Shandong Province decreased significantly over the studied period, but the case fatality rate did not decline significantly and remains relatively high. Many factors influence road traffic fatalities, among which laws and regulations are the most important.

Cropformer: A new generalized deep learning classification approach for multi-scenario crop classification.

Accurate and efficient crop classification using remotely sensed data can provide fundamental and important information for crop yield estimation. Existing crop classification approaches are usually designed to be strong in some specific scenarios but not for multi-scenario crop classification. In this study, we proposed a new deep learning approach for multi-scenario crop classification, named Cropformer. Cropformer can extract global features and local features, to solve the problem that current crop classification methods extract a single feature. Specifically, Cropformer is a two-step classification approach, where the first step is self-supervised pre-training to accumulate knowledge of crop growth, and the second step is a fine-tuned supervised classification based on the weights from the first step. The unlabeled time series and the labeled time series are used as input for the first and second steps respectively. Multi-scenario crop classification experiments including full-season crop classification, in-season crop classification, few-sample crop classification, and transfer of classification models were conducted in five study areas with complex crop types and compared with several existing competitive approaches. Experimental results showed that Cropformer can not only obtain a very significant accuracy advantage in crop classification, but also can obtain higher accuracy with fewer samples. Compared to other approaches, the classification performance of Cropformer during model transfer and the efficiency of the classification were outstanding. The results showed that Cropformer could build up a priori knowledge using unlabeled data and learn generalized features using labeled data, making it applicable to crop classification in multiple scenarios.

The Mediating Effect of Stress between Extracurricular Activities and Suicidal Ideation in Chinese College Students.

OBJECTIVE: The objective of this study was to explore the relationship between extracurricular activities, stress, and suicidal ideation and to examine the mediating effect of stress between extracurricular activities and suicidal ideation in Chinese college students. METHOD: A total of 6446 college students were surveyed with a web-based online data collection system using the self-made demographic questionnaire, Suicidal Behaviors Questionnaire-Revised (SBQ-R), and the 21-Item Depression Anxiety Stress Scales (DASS-21). SPSS 24.0 was used for descriptive statistics and correlation analysis, and the bootstrap method in the process procedure for SPSS Version 3.4.1 was used to construct the mediating effect model. RESULTS: Gender, school grades, living area, and family income status were influencing factors for suicidal ideation, stress, and extracurricular activities. Extracurricular activities were negatively correlated with stress (r = -0.083, p < 0.001) and suicidal ideation (r = -0.039, p < 0.01). Extracurricular activities had no direct predictive effect on college students' suicidal ideation (c = -0.198, CI: -0.418, 0.023), while stress had a mediating effect between extracurricular activities and suicidal ideation; the indirect mediating effect was 0.159. CONCLUSIONS: Extracurricular activities indirectly predict college students' suicidal ideation through stress. A variety of extracurricular activities can decrease the stress and suicidal ideation of college students and benefit their mental health.

Mental health literacy and suicidal ideation among Chinese college students: The mediating role of depressive symptoms and anxiety symptoms.

BACKGROUND: Mental health literacy (MHL) is essential to mental health. Symptoms of depression and anxiety are significant antecedents and closely related to suicide among college students. Few studies have explored the mediating role of depressive and anxiety symptoms between MHL and suicidal ideation. METHODS: 5578 college students were included in the analysis. The online Wenjuanxing platform was used to collect data from November 2020 to March 2021. The bootstrapping method was used to test the mediating role of depressive and anxiety symptoms in the links between MHL and suicidal ideation. RESULTS: Approximately 18.8 % of Chinese college students in our study reported having suicidal ideation. MHL exhibited a significant and negative correlation with depressive symptoms, anxiety symptoms, and suicidal ideation, whereas depressive and anxiety symptoms correlated significantly and positively with suicidal ideation. Compared with the lowest MHL quartile, the 3rd and 4th quartiles of MHL were associated with a significantly lower risk of suicidal ideation after adjusting for various confounding factors. Depressive and anxiety symptoms partially mediated the relationship between MHL and suicidal ideation, and the mediating effect of depressive symptoms was significantly greater than that of anxiety symptoms. LIMITATIONS: This study was a cross-sectional survey. Future longitudinal studies on this relation are needed. CONCLUSIONS: Depressive and anxiety symptoms mediate the relationship between MHL and suicidal ideation. Comprehensive school-based specific psychological education programs are needed to improve college students' MHL and change their attitudes toward mental health services.

Virus-Like Particle-Templated Silica-Adjuvanted Nanovaccines with Enhanced Humoral and Cellular Immunity.

Virus-like particles (VLPs) are self-assembled viral proteins that represent a superior form of antigens in vaccine formulations. To enhance immunogenicity, adjuvants, especially the aluminum salts (Alum), are essentially formulated in VLP vaccines. However, Alum only induce biased humoral immune responses that limits further applications of VLP-based vaccines. To stimulate more balanced immunity, we, herein, develop a one-step strategy of using VLPs as the biotemplates to synthesize raspberry-like silica-adjuvanted VLP@Silica nanovaccines. Hepatitis B surface antigen (HBsAg) VLPs and human papillomavirus type 18 (HPV 18) VLPs are selected as model templates. Circular dichroism (CD) and affinity analyses demonstrate that HBsAg VLPs in the nanovaccines maintain their secondary structure and immunogenicity, respectively. VLP@Silica promote silica dissolution-induced lysosomal escape and cytosolic delivery of antigens, and enhance the secretion of both Th1 and Th2 type cytokines in murine bone marrow-derived dendritic cells (BMDCs). Additionally, they could improve antigen trafficking and mediate DC activation in draining lymph nodes (DLNs). Vaccination study demonstrate that both HBsAg VLP@Silica and HPV 18 VLP@Silica nanovaccines induce enhanced antigen-specific antibody productions and T-cell mediated adaptive immune responses. This design strategy can utilize VLPs derived from a diversity of viruses or their variants as templates to construct both prophylactic and therapeutic vaccines with improved immunogenicity.

Depressive Symptoms as a Mediator between Excessive Daytime Sleepiness and Suicidal Ideation among Chinese College Students.

The purpose of this study was to verify the mediating role of depressive symptoms between excessive daytime sleepiness and suicidal ideation in college students. Of the 6944 participants, 2609 (37.6%) were male and 4335 (62.4%) were female. College students with excessive daytime sleepiness (p < 0.001) and those with depressive symptoms (p < 0.001) were more likely to have suicidal ideation. Moreover, both excessive daytime sleepiness (ß = 0.14, 95% CI: 1.01−1.32) and depressive symptoms (ß = 1.47, 95% CI: 3.80−5.00) were associated with suicidal ideation. The effect size of the mediating role of depressive symptoms in excessive daytime sleepiness to suicidal ideation was 50.41% for the entire sample, 58.33% for males, and 42.98% for females. Depressive symptoms partially mediated the relationship between excessive daytime sleepiness and suicidal ideation. The timely assessment of depressive symptoms in college students with excessive daytime sleepiness, and intervention, may reduce their risk of suicidal ideation.

The Prevalence and Determinant of PTSD Symptoms among Home-Quarantined Chinese University Students during the COVID-19 Pandemic.

BACKGROUND: When COVID-19 emerged in China in late 2019, most Chinese university students were home-quarantined to prevent the spread of the virus, considering the great impact of the lockdown on young people habits and their psychological well-being. This study explored the prevalence of post-traumatic stress disorder (PTSD) and its associated factors among Chinese university students who are isolated at home during the COVID-19 pandemic. METHOD: 4520 participants from five universities in China were surveyed by online questionnaire and the PTSD Checklist-Civilian Version (PCL-C) was adopted as a screening instrument. RESULTS: Exposure to virus was significantly related to PTSD outcomes. The most important predictors for PTSD outcomes were parents' relationship and the way parents educated, and university-provided psychological counseling was a protective factor against developing PTSD. CONCLUSIONS: The COVID-19 pandemic had adverse psychological consequences on Chinese university students who were isolated at home due to the relatively high prevalence rate of PTSD which was reported. Adverse parental relationships and the extreme way parents educate their children could be the major risk factors for PTSD outcomes. Psychological interventions need to be made available to home-quarantined university students, and those in the worst-hit and exposed areas to virus should be given priority focus.

Syntheses, Biological Evaluations, and Mechanistic Studies of Benzo[c][1,2,5]oxadiazole Derivatives as Potent PD-L1 Inhibitors with In Vivo Antitumor Activity.

A series of novel benzo[c][1,2,5]oxadiazole derivatives were designed, synthesized, and biologically evaluated as inhibitors of PD-L1. Among them, compound L7 exhibited 1.8 nM IC50 value in a homogeneous time-resolved fluorescence (HTRF) assay, which was 20-fold more potent than the lead compound BMS-1016. In the surface plasmon resonance (SPR) assay, L7 bound to human PD-L1 (hPD-L1) with a KD value of 3.34 nM, without showing any binding to hPD-1. In the cell-based coculture assay, L7 blocked PD-1/PD-L1 interaction with an EC50 value of 375 nM, while BMS-1016 had an EC50 value of 2075 nM. Moreover, compound L24, an ester prodrug of L7, was orally bioavailable and displayed significant antitumor effects in tumor models of syngeneic and PD-L1 humanized mice. Mechanistically, L24 exhibited significant in vivo antitumor effects probably through promoting antitumor immunity. Together, this series of benzoxadiazole PD-L1 inhibitors holds promise for tumor immunotherapy. Preclinical trials with selected compounds are ongoing in our laboratory.

Association between Mental Health Knowledge Level and Depressive Symptoms among Chinese College Students.

This study aimed to explore the association between mental health knowledge level and the prevalence of depressive symptoms among Chinese college students. A cross-sectional study was conducted in six universities in Jinan, Shandong Province, China, and a total of 600 college students were recruited to self-complete a series of questionnaires. The Mental Health Knowledge Questionnaire (MHKQ) was used to investigate the level of mental health knowledge. Depressive symptoms were investigated with the depression subscale of the Depression Anxiety Stress Scale (DASS-21). The prevalence rate of depressive symptoms among college students was 31.2%. Compared with MHKQ scoring in the 1st quartile, college students with MHKQ scoring in the 3rd quartile and in the 4th quartile reported lower levels of depressive symptoms after adjusting for potential confounding factors. Since mental health knowledge level was related to depressive symptoms among college students, increased efforts to promote the level of mental health knowledge in Chinese college students are critical.

Psychometric properties of the psychological strain scales (PSS) in suicide attempters and community controls of rural China.

BACKGROUND: Psychological Strain Scales (PSS) were developed to measure four types of strain comprising value strain, deprivation strain, aspiration strain, and coping strain. This study aimed to evaluate the psychometric properties of the Chinese version of 40-item PSS in suicide attempters and community controls of rural China. METHODS: Data of this study came from the investigation of 132 suicide attempters and their paired community controls matched with the same sex, age (±3 years) and residence in five counties in rural Shandong, China. The Chinese version of PSS, the Center for Epidemiologic Studies Depression Scale (CES-D), the Trait Anxiety Inventory (TAI) and the Self-esteem Scale (SES) were administered and reliability test and validity test of the PSS were conducted. RESULTS: Cronbach's α and Guttman Spilt-Half coefficient of PSS was 0.942 and 0.842 for suicide attempters, and 0.950 and 0.874 for community controls. For both suicide attempters and community controls, the Exploratory Factor Analysis indicated a one-factor structure of each strain scale, which accorded with the original factor structure proposed by the authors. The scores of the total PSS and four subscales were positively correlated with the scores of CES-D and TAI; and negatively correlated with the score of SES, which indicated a good performance in convergent validity. LIMITATIONS: This study was limited to its generalizability to the Chinese urban population. CONCLUSIONS: The Chinese version of the 40-item PSS has satisfactory psychometric properties in terms of reliability and validity in Chinese rural suicide attempters and community controls.