METTL3 protects METTL14 from STUB1-mediated degradation to maintain m6 A homeostasis.

N6 -Methyladenosine (m6 A) is an important RNA modification catalyzed by methyltransferase-like 3 (METTL3) and METTL14. m6 A homeostasis mediated by the methyltransferase (MTase) complex plays key roles in various biological processes. However, the mechanism underlying METTL14 protein stability and its role in m6 A homeostasis remain elusive. Here, we show that METTL14 stability is regulated by the competitive interaction of METTL3 with the E3 ligase STUB1. STUB1 directly interacts with METTL14 to mediate its ubiquitination at lysine residues K148, K156, and K162 for subsequent degradation, resulting in a significant decrease in total m6 A levels. The amino acid regions 450-454 and 464-480 of METTL3 are essential to promote METTL14 stabilization. Changes in STUB1 expression affect METTL14 protein levels, m6 A modification and tumorigenesis. Collectively, our findings uncover an ubiquitination mechanism controlling METTL14 protein levels to fine-tune m6 A homeostasis. Finally, we present evidence that modulating STUB1 expression to degrade METTL14 could represent a promising therapeutic strategy against cancer.

Microglial Pdcd4 deficiency mitigates neuroinflammation-associated depression via facilitating Daxx mediated PPARγ/IL-10 signaling.

The dysregulation of pro- and anti-inflammatory processes in the brain has been linked to the pathogenesis of major depressive disorder (MDD), although the precise mechanisms remain unclear. In this study, we discovered that microglial conditional knockout of Pdcd4 conferred protection against LPS-induced hyperactivation of microglia and depressive-like behavior in mice. Mechanically, microglial Pdcd4 plays a role in promoting neuroinflammatory responses triggered by LPS by inhibiting Daxx-mediated PPARγ nucleus translocation, leading to the suppression of anti-inflammatory cytokine IL-10 expression. Finally, the antidepressant effect of microglial Pdcd4 knockout under LPS-challenged conditions was abolished by intracerebroventricular injection of the IL-10 neutralizing antibody IL-10Rα. Our study elucidates the distinct involvement of microglial Pdcd4 in neuroinflammation, suggesting its potential as a therapeutic target for neuroinflammation-related depression.

MicroRNA169 integrates multiple factors to modulate plant growth and abiotic stress responses.

MicroRNA169 (miR169) has been implicated in multi-stress regulation in annual species such as Arabidopsis, maize and rice. However, there is a lack of experimental functional and mechanistic studies of miR169 in plants, especially in perennial species, and its impact on plant growth and development remains unexplored. Creeping bentgrass (Agrostis stolonifera L.) is a C3 cool-season perennial turfgrass of significant environmental and economic importance. In this study, we generated both miR169 overexpression and knockdown transgenic creeping bentgrass lines. We found that miR169 acts as a positive regulator in abiotic stress responses but is negatively associated with plant growth and development, playing multiple critical roles in the growth and environmental adaptation of creeping bentgrass. These roles include differentiated spatial hormone accumulation patterns associated with growth and stress accommodation, elevated antioxidant activity that alleviates oxidative damage induced by stress, ion-channelling membrane components for maintaining homeostasis under saline conditions, and potential cross-talks with stress-regulating transcription factors such as AsHsfA and AsWRKYs. Our results unravel the role of miR169 in modulating plant development and stress responses in perennial grass species. This underlines the potential of manipulating miR169 to generate crop cultivars with desirable traits to meet diverse agricultural demands.

Gene pyramiding for boosted plant growth and broad abiotic stress tolerance.

Abiotic stresses such as salinity, heat and drought seriously impair plant growth and development, causing a significant loss in crop yield and ornamental value. Biotechnology approaches manipulating specific genes prove to be effective strategies in crop trait modification. The Arabidopsis vacuolar pyrophosphatase gene AVP1, the rice SUMO E3 ligase gene OsSIZ1 and the cyanobacterium flavodoxin gene Fld have previously been implicated in regulating plant stress responses and conferring enhanced tolerance to different abiotic stresses when individually overexpressed in various plant species. We have explored the feasibility of combining multiple favourable traits brought by individual genes to acquire superior plant performance. To this end, we have simultaneously introduced AVP1, OsSIZ1 and Fld in creeping bentgrass. Transgenic (TG) plants overexpressing these three genes performed significantly better than wild type controls and the TGs expressing individual genes under both normal and various abiotic stress conditions, exhibited significantly enhanced plant growth and tolerance to drought, salinity and heat stresses as well as nitrogen and phosphate starvation, which were associated with altered physiological and biochemical characteristics and delicately fine-tuned expression of genes involved in plant stress responses. Our results suggest that AVP1, OsSIZ1 and Fld function synergistically to regulate plant development and plant stress response, leading to superior overall performance under both normal and adverse environments. The information obtained provides new insights into gene stacking as an effective approach for plant genetic engineering. A similar strategy can be extended for the use of other beneficial genes in various crop species for trait modifications, enhancing agricultural production.

A systematic two-sample and bidirectional MR process highlights a unidirectional genetic causal effect of allergic diseases on COVID-19 infection/severity.

BACKGROUND: Allergic diseases (ADs) such as asthma are presumed risk factors for COVID-19 infection. However, recent observational studies suggest that the assumed correlation contradicts each other. We therefore systematically investigated the genetic causal correlations between various ADs and COVID-19 infection/severity. METHODS: We performed a two-sample, bidirectional Mendelian randomization (MR) study for five types of ADs and the latest round of COVID-19 GWAS meta-analysis datasets (critically ill, hospitalized, and infection cases). We also further validated the significant causal correlations and elucidated the potential underlying molecular mechanisms. RESULTS: With the most suitable MR method, asthma consistently demonstrated causal protective effects on critically ill and hospitalized COVID-19 cases (OR < 0.93, p < 2.01 × 10-2), which were further confirmed by another validated GWAS dataset (OR < 0.92, p < 4.22 × 10-3). In addition, our MR analyses also observed significant causal correlations of food allergies such as shrimp allergy with the risk of COVID-19 infection/severity. However, we did not find any significant causal effect of COVID-19 phenotypes on the risk of ADs. Regarding the underlying molecular mechanisms, not only multiple immune-related cells such as CD4+ T, CD8+ T and the ratio of CD4+/CD8+ T cells showed significant causal effects on COVID-19 phenotypes and various ADs, the hematology traits including monocytes were also significantly correlated with them. Conversely, various ADs such as asthma and shrimp allergy may be causally correlated with COVID-19 infection/severity by affecting multiple hematological traits and immune-related cells. CONCLUSIONS: Our systematic and bidirectional MR analyses suggest a unidirectional causal effect of various ADs, particularly of asthma on COVID-19 infection/severity, but the reverse is not true. The potential underlying molecular mechanisms of the causal effects call for more attention to clinical monitoring of hematological cells/traits and may be beneficial in developing effective therapeutic strategies for allergic patients following infection with COVID-19.

Distinguishing the Geometric and Electronic Structures of Actinide Carbides AnxC8 (An = Th, U; x = 2, 3) through Exchange Interactions.

Global-minimum optimizations combined with relativistic quantum chemistry calculations have been performed to characterize the ground-state stable structures of four titled compounds and to analyze the bonding properties. Th2C8 was identified as being a ThC4-Th(C2)2 structure, U2C8 has been found to favor the U-U(C8) structure, and both Th3C8 and U3C8 adopt the (AnC3)2-(AnC2) structure. Then, the wave function analyses reveal that the interactions between the Th 7s-based orbital and the σg molecular orbital of the C2 unit compensate for the excitation energy of 7s16d1 → 6d2 and lead to the stabilization of two Th(IV)s in the ThC4-Th(C2)2 structure. It also reveals that the U species exhibit magnetic exchange coupling behavior in UxC8, for instance, as seen in the direct interaction of U2C8 and the superexchange pathway of U3C8, which effectively stabilizes their low-spin states. This interpretation indicates that the geometric and electronic structures of AnxC8 species are largely influenced by the local magnetic moment and spin correlation.

Mild hyperthermia enhanced synergistic uric acid degradation and multiple ROS elimination for an effective acute gout therapy.

BACKGROUND: Acute gouty is caused by the excessive accumulation of Monosodium Urate (MSU) crystals within various parts of the body, which leads to a deterioration of the local microenvironment. This degradation is marked by elevated levels of uric acid (UA), increased reactive oxygen species (ROS) production, hypoxic conditions, an upsurge in pro-inflammatory mediators, and mitochondrial dysfunction. RESULTS: In this study, we developed a multifunctional nanoparticle of polydopamine-platinum (PDA@Pt) to combat acute gout by leveraging mild hyperthermia to synergistically enhance UA degradation and anti-inflammatory effect. Herein, PDA acts as a foundational template that facilitates the growth of a Pt shell on the surface of its nanospheres, leading to the formation of the PDA@Pt nanomedicine. Within this therapeutic agent, the Pt nanoparticle catalyzes the decomposition of UA and actively breaks down endogenous hydrogen peroxide (H2O2) to produce O2, which helps to alleviate hypoxic conditions. Concurrently, the PDA component possesses exceptional capacity for ROS scavenging. Most significantly, Both PDA and Pt shell exhibit absorption in the Near-Infrared-II (NIR-II) region, which not only endow PDA@Pt with superior photothermal conversion efficiency for effective photothermal therapy (PTT) but also substantially enhances the nanomedicine's capacity for UA degradation, O2 production and ROS scavenging enzymatic activities. This photothermally-enhanced approach effectively facilitates the repair of mitochondrial damage and downregulates the NF-κB signaling pathway to inhibit the expression of pro-inflammatory cytokines. CONCLUSIONS: The multifunctional nanomedicine PDA@Pt exhibits exceptional efficacy in UA reduction and anti-inflammatory effects, presenting a promising potential therapeutic strategy for the management of acute gout.

Phosphine-Catalyzed γ'-Carbon 1,6-Conjugate Addition of α-Succinimide Substituted Allenoates with Para-Quinone Methides: Synthesis of 4-Diarylmethylated 3,4-Disubstituted Maleimides.

In this paper, an interesting γ'-carbon 1,6-conjugate addition for phosphine-catalyzed α-succinimide substituted allenoates has been disclosed. A wide array of substrates was found to participate in the reaction, resulting in the production of diverse 4-diarylmethylated 3,4-disubstituted maleimides with satisfactory to outstanding yields. Furthermore, a plausible mechanism for the reaction was proposed by the investigators.

Distinct mechanisms of dysfunctional antigen-presenting DCs and monocytes by single-cell sequencing in multiple myeloma.

Multiple myeloma (MM) is an incurable plasma cell malignancy with the hallmark of immunodeficiency, including dysfunction of T cells, NK cells, and APCs. Dysfunctional APCs have been reported to play a key role in promoting MM progression. However, the molecular mechanisms remain elusive. Here, single-cell transcriptome analysis of dendritic cells (DC) and monocytes from 10 MM patients and three healthy volunteers was performed. Both DCs and monocytes were divided into five distinct clusters, respectively. Among them, monocyte-derived DCs (mono-DC) were shown to develop from intermediate monocytes (IM) via trajectory analysis. Functional analysis showed that, compared with healthy controls, conventional DC2 (cDC2), mono-DC, and IM of MM patients exhibited impaired antigen processing and presentation capacity. Moreover, reduced regulon activity of interferon regulatory factor 1 (IRF1) was found in cDC2, mono-DC and IM of MM patients according to single-cell regulatory network inference and clustering (SCENIC) analysis, while the downstream mechanisms were distinct. Specifically in MM patients, cathepsin S (CTSS) was markedly downregulated in cDC2, major histocompatibility complex (MHC) class II transactivator (CIITA) was significantly decreased in IM, in addition both CTSS and CIITA were downregulated in mono-DC based on differentially expressed genes analysis. In vitro study validated that knockdown of Irf1 downregulated Ctss and Ciita respectively in mouse DC cell line DC2.4 and mouse monocyte/macrophage cell line RAW264.7, which ultimately inhibited proliferation of CD4+ T cells after being cocultured with DC2.4 or RAW264.7 cells. This current study unveils the distinct mechanisms of cDC2, IM, and mono-DC function impairment in MM, offering new insight into the pathogenesis of immunodeficiency.

Noncontact Manipulation of Intracellular Structure Based on Focused Surface Acoustic Waves.

Cell orientation is essential in many applications in biology, medicine, and chemistry, such as cellular injection, intracellular biopsy, and genetic screening. However, the manual cell orientation technique is a trial-and-error approach, which suffers from low efficiency and low accuracy. Although several techniques have improved these issues to a certain extent, they still face problems deforming or disrupting cell membranes, physical damage to the intracellular structure, and limited particle size. This study proposes a noncontact and noninvasive cell orientation method that rotates a cell using surface acoustic waves (SAWs). To realize the acoustic cell orientation process, we have fabricated a microdevice consisting of two pairs of focused interdigital transducers (FIDTs). Instead of rotating the entire cell, the proposed method rotates the intracellular structure, the cytoplasm, directly through the cell membrane by acoustic force. We have tested the rotational manipulation process on 30 zebrafish embryos. The system was able to orientate a cell to a target orientation with a one-time success rate of 93%. Furthermore, the postoperation survival rate was 100%. Our acoustic rotational manipulation technique is noninvasive and easy to use, which provides a starting point for cell-manipulation-essential tasks, such as single-cell analysis, organism studies, and drug discovery.

Manganese-Based Immunomodulatory Nanocomposite with Catalase-Like Activity and Microwave-Enhanced ROS Elimination Ability for Efficient Rheumatoid Arthritis Therapy.

Rheumatoid arthritis (RA) is a chronic autoimmune disease commonly associated with the accumulation of hyperactive immune cells (HICs), particularly macrophages of pro-inflammatory (M1) phenotype, accompanied by the elevated level of reactive oxygen species (ROS), decreased pH and O2 content in joint synovium. In this work, an immunomodulatory nanosystem (IMN) is developed for RA therapy by modulating and restoring the function of HICs in inflamed tissues. Manganese tetraoxide nanoparticles (Mn3 O4 ) nanoparticles anchored on UiO-66-NH2 are designed, and then the hybrid is coated with Mn-EGCG film, further wrapped with HA to obtain the final nanocomposite of UiO-66-NH2 @Mn3 O4 /Mn-EGCG@HA (termed as UMnEH). When UMnEH diffuses to the inflammatory site of RA synovium, the stimulation of microwave (MW) irradiation and low pH trigger the slow dissociation of Mn-EGCG film. Then the endogenously overexpressed hydrogen peroxide (H2 O2 ) disintegrates the exposed Mn3 O4 NPs to promote ROS scavenging and O2 generation. Assisted by MW irradiation, the elevated O2 content in the RA microenvironment down-regulates the expression of hypoxia-inducible factor-1α (HIF-1α). Coupled with the clearance of ROS, it promotes the re-polarization of M1 phenotype macrophages into anti-inflammatory (M2) phenotype macrophages. Therefore, the multifunctional UMnEH nanoplatform, as the IMN, exhibits a promising potential to modulate and restore the function of HICs and has an exciting prospect in the treatment of RA.

Epstein‒Barr virus and human herpesvirus 6 infection in patients with systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is a complex autoimmune disease, and the etiology is still unclear. Some studies have indicated that viral infection might contribute to the development of SLE. METHODS: A total of 105 individuals with SLE and 110 matched healthy controls were tested for EBV-specific DNA fragments in peripheral blood monocytes by PCR-Southern blotting. The expression of EBV-encoded genes was determined by RT-PCR and Southern blotting in EBV-positive patients. Serum EBV-specific IgM antibody was determined by ELISA. HHV-6 DNA in peripheral blood monocytes of those SLE patients and normal controls was tested by nested PCR. RESULTS: Statistical analysis showed that the EBV-positive rate of SLE patients was significantly higher than that of the control group (χ2 = 87.329, P = 0), while the difference in the HHV-6-positive rate between the two groups was not significant (P > 0.05). An association of EBV and HHV-6 positivity in SLE patients was found (P = 0, r = 0.38). The EBV IgM level was significantly higher in SLE patients than in healthy controls (χ2 = 25.184, P = 0). Forty-two of the 75 EBV DNA-positive specimens were positive for EBNA2 mRNA, and an association between EBV EBNA2 mRNA and anti-Sm antibody positivity was found (P = 0, r = 0.409). LMP1 mRNA was positive in 2 SLE patients with active phase, and no LMP2A mRNA expression was detected in EBV DNA-positive specimens. EBV early gene BARF1 mRNA was detected in 2 cases of EBV-positive SLE patients, and these 2 patients were also HHV-6 DNA positive. Thirty-eight patients were BcLF1 mRNA positive, and 33 of them were HHV-6 positive as well. These factors were associated (χ2 = 15.734, P = 0). The expression of the EBV immediate early gene BZLF1 was negative in all 75 EBV-positive SLE patients. CONCLUSIONS: The results suggest that EBV infection might be related to the occurrence of SLE. Although there is no direct evidence that HHV-6 infection is associated with the development of SLE, EBV and HHV-6 infection may have a coacceleration effect in SLE patients. This study provides a new theoretical and experimental basis for the study of viral etiology and the prevention and treatment of SLE.

Composition and Diversity of Gut Bacterial Community in Different Life Stages of a Leaf Beetle Gastrolina depressa.

Insect gut bacteria have a significant impact on host biology, which has a favorable or negative impact on insect fitness. The walnut leaf beetle (Gastrolina depressa) is a notorious pest in China, causing severe damage to Juglandaceae trees including Juglans regia and Pterocarya rhoifolia. To date, however, we know surprisingly little about the gut microbiota of G. depressa. This study used a high-throughput sequencing platform to investigate the gut bacterial community of G. depressa throughout its life cycle, including the 1st, 2nd, and 3rd instar larvae, as well as male, female, and pre-pregnant female adults. Our results showed that the diversity of the gut bacterial community in larvae was generally higher than that in adults, and young larvae (1st and 2nd larvae) possessed the most diversified and abundant community. Principal coordinate analysis results showed that the gut microbiota of adults cluster together, which is independent of the 1st and 2nd instar larvae. The main phyla were Proteobacteria and Firmicutes in the microbial community of G. depressa, while the dominant genera were Enterobacter, Rosenbergiella, Erwinia, Pseudomonas, and Lactococcus. The gut bacteria of G. depressa were mostly enriched in metabolic pathways (carbohydrate metabolism and amino acid metabolism) as revealed by functional prediction. This study contributes to a better knowledge of G. depressa's gut microbiota and its potential interactions with the host insect, facilitating the development of a microbial-based pest management strategy.

Incorporating Health Cobenefits into Province-Driven Climate Policy: A Case of Banning New Internal Combustion Engine Vehicle Sales in China.

Incorporating health cobenefits from coabated air pollution into carbon mitigation policy making is particularly important for developing countries to boost policy efficiency. For sectors that highly depend on electrification for decarbonization, it remains unclear how the increased electricity demand and consequent health impacts from sectoral mitigation policy in one province would change the scale and the regional and sectoral distributions of the overall health impacts in the whole country. This study chooses the banning of new sales of internal combustion engine vehicles in the private vehicle sector in China as a case. The results show that, without carbon neutrality and air pollution control goals in electricity generation, 53% of CO2 reduction and 65% of health benefits from the private vehicle sector would be offset by increased electricity demand. The regional distributions of CO2 reduction and health benefits due to a province-driven ban policy are greatly uneven, as the top five provinces take up over one-third of the total impact in China. Health benefits per ton of carbon reduction (H/C) may vary by up to 8 times across provinces. Finally, the provinces in southeast China and the Sichuan Basin, with their stably high H/C values, are suggested to enact the province-driven ban policy first.

Kinetically and thermodynamically controlled one-pot growth of gold nanoshells with NIR-II absorption for multimodal imaging-guided photothermal therapy.

Since the successful clinical trial of AuroShell for photothermal therapy, there is currently intense interest in developing gold-based core-shell structures with near-infrared (NIR) absorption ranging from NIR-I (650-900 nm) to NIR-II (900-1700 nm). Here, we propose a seed-mediated successive growth approach to produce gold nanoshells on the surface of the nanoscale metal-organic framework (NMOF) of UiO-66-NH2 (UiO = the University of Oslo) in one pot. The key to this strategy is to modulate the proportion of the formaldehyde (reductant) and its regulator / oxidative product of formic acid to harness the particle nucleation and growth rate within the same system. The gold nanoshells propagate through a well-oriented and controllable diffusion growth pattern (points → facets → octahedron), which has not been identified. Most strikingly, the gold nanoshells prepared hereby exhibit an exceedingly broad and strong absorption in NIR-II with a peak beyond 1300 nm and outstanding photothermal conversion efficiency of 74.0%. Owing to such superior performance, these gold nanoshells show promising outcomes in photoacoustic (PA), computed tomography (CT), and photothermal imaging-guided photothermal therapy (PTT) for breast cancer, as demonstrated both in vitro and in vivo.

Ablation of Death-Associated Protein Kinase 1 Changes the Transcriptomic Profile and Alters Neural-Related Pathways in the Brain.

Death-associated protein kinase 1 (DAPK1), a Ca2+/calmodulin-dependent serine/threonine kinase, mediates various neuronal functions, including cell death. Abnormal upregulation of DAPK1 is observed in human patients with neurological diseases, such as Alzheimer's disease (AD) and epilepsy. Ablation of DAPK1 expression and suppression of DAPK1 activity attenuates neuropathology and behavior impairments. However, whether DAPK1 regulates gene expression in the brain, and whether its gene profile is implicated in neuronal disorders, remains elusive. To reveal the function and pathogenic role of DAPK1 in neurological diseases in the brain, differential transcriptional profiling was performed in the brains of DAPK1 knockout (DAPK1-KO) mice compared with those of wild-type (WT) mice by RNA sequencing. We showed significantly altered genes in the cerebral cortex, hippocampus, brain stem, and cerebellum of both male and female DAPK1-KO mice compared to those in WT mice, respectively. The genes are implicated in multiple neural-related pathways, including: AD, Parkinson's disease (PD), Huntington's disease (HD), neurodegeneration, glutamatergic synapse, and GABAergic synapse pathways. Moreover, our findings imply that the potassium voltage-gated channel subfamily A member 1 (Kcna1) may be involved in the modulation of DAPK1 in epilepsy. Our study provides insight into the pathological role of DAPK1 in the regulatory networks in the brain and new therapeutic strategies for the treatment of neurological diseases.

Chloride intercellular channel 3 suppression-mediated macrophage polarization: a potential indicator of poor prognosis of hepatitis B virus-related acute-on-chronic liver failure.

Patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) are characterized by immune paralysis and susceptibility to infections. Macrophages are important mediators of immune responses can be subclassified into two main phenotypes: classically activated and alternatively activated. However, few studies have investigated changes to macrophage polarization in HBV-related liver diseases. Therefore, we investigated the functional status of monocyte-derived macrophages (MDMs) from patients with mild chronic hepatitis B (n = 226), HBV-related compensated cirrhosis (n = 36), HBV-related decompensated cirrhosis (n = 40), HBV-ACLF (n = 62) and healthy controls (n = 10), as well as Kupffer cells (KCs) from patients with HBV-ACLF (n = 3). We found that during the progression of HBV-related liver diseases, the percentage of CD163+ CD206+ macrophages increased, while the percentage of CD80+ human leukocyte antigen-DR+ macrophages decreased significantly. MDMs and KCs mainly exhibited high CD163+ CD206+ expression in patients with HBV-ACLF, which predicted poor clinical outcome and higher liver transplantation rate. Transcriptome sequencing analysis revealed that chloride intracellular channel-3 (CLIC3) was reduced in patients with HBV-ACLF, indicating a poor prognosis. To further study the effect of CLIC3 on macrophage polarization, human monocytic THP-1 cell-derived macrophages were used. We found that classical and alternative macrophage activation occurred through nuclear factor kappa B (NF-κB) and phosphoinositide 3-kinase/protein kinase B pathways, respectively. CLIC3 suppression inhibited NF-κB activation and promoted the alternative activation. In conclusion, macrophage polarization gradually changed from classically activated to alternatively activated as HBV-related liver diseases progressed. Both CLIC3 suppression and increased alternatively activated macrophage percentage were potential indicators of the poor prognosis of patients with HBV-ACLF.

12-Membered Ring Carbides with Stabilization of Actinide Atoms.

Actinide (Th and U) carbides as the potential nuclear fuels in nuclear reactors require basic research in order to understand the thermodynamic stability and performance of these substances. Here we report the structural characterization and bonding analyses of [C12], ThC12, and UC12 clusters via a global-minimum search combined with relativistic quantum chemistry calculations to elucidate the stability and bonding nature of An-C bonds. We predict that these [C12], ThC12, and UC12 compounds have a planar structure with C6h, D12h, and D12h symmetry, respectively. [C12] has a hyperconjugation structure containing alternating single and double bonds. The significant stabilization when forming AnC12 predominantly comes from the electrostatic interaction between An4+ and [C12]4- and also from a certain degree of orbital interaction between the An 5f6d7s valence shell and [C12] π orbitals. The covalent character of the An-C bonds exhibits a direct in-plane σ-type overlap of the C 2p-derived MOs of [C12] and the An 5fϕ AO, thus leading to an unprecedented electronic configuration of d1f1 for U in UC12. Our results present an example of the novel properties that can be expected for actinide compounds and would provide the knowledge required to obtain novel structures of AnC12 in future experiments.

Identification of Novel CD39 Inhibitors Based on Virtual Screening and Enzymatic Assays.

The accumulation of adenosine in the tumor microenvironment mediates immunosuppression and promotes tumor growth and proliferation. Intervention of the adenosine pathway is an important direction of antitumor immunity research. CD39 is an important ecto-nucleotidases for adenosine generation, therefore targeting the CD39-adenosine pathway is an emerging immune checkpoint for anticancer treatment. However, currently no CD39 inhibitor has been approved by the U.S. Food and Drug Administration. The development of CD39 drugs is urgent for clinical application. In this study, we combined homology modeling, virtual screening, and in vitro enzymatic activity to characterize the structural features of the CD39 protein and identify a triazinoindole-based compound as a CD39 inhibitor. The identified inhibitor and one of its analogues could effectively prevent the enzymatic activity of CD39 with IC50 values of 27.42 ± 5.52 and 79.24 ± 12.21 µM, respectively. At the same time, the inhibitor significantly inhibited the adenosine monophosphate production in colorectal cancer cell lines (HT29 and MC38) and thereafter prevented cell proliferation. Molecular docking studies, mutagenesis, and microscale thermophoresis indicated that residues such as R85 could be the main contributor in binding triazinoindole compounds. The binding mode can potentially be utilized for hit-to-lead optimization, and the identified inhibitor can be further tested for its anticancer activity in vivo or may serve as a chemical agent to study CD39-related functions.

Effectiveness of a mobile-based HIV prevention intervention for the rural and low-income population involving incentive policy to doctors in Liangshan, China: a randomized controlled trial protocol.

BACKGROUND: The HIV/AIDS epidemic is a concerning problem in many parts of the world, especially in rural and poor areas. Due to health service inequality and public stigma towards the disease, it is difficult to conduct face-to-face interventions. The widespread use of mobile phones and social media applications thus provide a feasible and acceptable approach for HIV prevention and education delivery in this population. The study aims to develop a generalizable, effective, acceptable, and convenient mobile-based information intervention model to improve HIV-related knowledge, attitudes, practices, and health outcomes in poverty-stricken areas in China and measure the impact of incentive policies on the work of village doctors in Liangshan, China. METHODS: A randomized controlled trial design is used to evaluate the effectiveness of an 18-month mobile-based HIV prevention intervention, collaborating with local village doctors and consisting of group-based knowledge dissemination and individualized communication on WeChat and the Chinese Version of TikTok in Liangshan, China. Each village is defined as a cluster managed by a village doctor with 20 adults possessing mobile phones randomly selected from different families as participants, totaling 200 villages. Clusters are randomized (1:1:1) to the Control without mobile-based knowledge dissemination, Intervention A with standardized compensation to the village doctors, or Intervention B with performance-based compensation to the village doctors. The intervention groups will receive biweekly messages containing HIV-related educational modules. Data will be collected at baseline and 6-, 12-, and 18-month periods for outcome measurements. The primary outcomes of the study are HIV-related knowledge improvement and the effectiveness of village doctor targeted incentive policies. The secondary outcomes include secondary knowledge transmission, behavioral changes, health outcomes, social factors, and study design's acceptability and reproducibility. These outcomes will be explored via various qualitative and quantitative means. DISCUSSION: The findings will provide insights into the effectiveness, generalizability, and challenges of the mobile-based HIV prevention intervention for the population living in rural communities with low education levels and will guide the development of similar models in other low-income and culturally isolated regions. TRIAL REGISTRATION: ClinicalTrial.gov: NCT05015062 ; Registered on June 6, 2022.