Atp13a5 Marker Reveals Pericyte Specification in The Mouse Central Nervous System.

Perivascular mural cells including vascular smooth cells (VSMCs) and pericytes are integral components of the vascular system. In the central nervous system (CNS), pericytes are also indispensable for the blood-brain barrier (BBB), blood-spinal cord barrier and blood-retinal barrier, and play key roles in maintaining cerebrovascular and neuronal functions. However, the functional specifications of pericytes between CNS and peripheral organs have not been resolved at the genetic and molecular levels. Hence, the generation of reliable CNS pericyte-specific models and genetic tools remains very challenging. Here, we report a new CNS pericyte marker in mice. This putative cation-transporting ATPase 13A5 (Atp13a5) marker was identified through single cell transcriptomics, based on its specificity to brain pericytes. We further generated a knock-in model with both tdTomato reporter and Cre recombinase. Using this model to trace the distribution of Atp13a5-positive pericytes in mice, we found that the tdTomato reporter reliably labels the CNS pericytes, including the ones in spinal cord and retina but not peripheral organs. Interestingly, brain pericytes are likely shaped by the developing neural environment, as Atp13a5-positive pericytes start to appear around murine embryonic day 15 (E15) and expand along the cerebrovasculature. Thus, Atp13a5 is a specific marker of CNS pericyte lineage, and this Atp13a5-based model is a reliable tool to explore the heterogeneity of pericytes and BBB functions in health and diseases.Significance Statement Pericyte is a key component of the blood-brain barrier (BBB) and highly implicated in neurological and neurodegenerative diseases. However, current genetic tools for brain pericytes often come with limitations, due to the lack of specificity to the pericytes in the brain or central nervous system (CNS), as well as the overlap with other cell types, particularly vascular smooth muscle cells. Here, we identified that Atp13a5 is a CNS-specific pericyte marker based on mouse single-cell transcriptomics, and further validate it using a knock-in model carrying Atp13a5-driven tdTomato reporter and Cre recombinase. The success of the Atp13a5-based model opens new possibility of genetic manipulations targeting only CNS pericytes in vivo and studying their biology and functions in health and diseases more specifically.

Efficacy of molnupiravir and interferon for the treatment of SARS-CoV-2 in golden Syrian hamster.

The mortality and hospitalization rate by COVID-19 dropped significantly currently, but its seasonal outbreaks make antiviral treatment still vital. The mortality and hospitazation rate by COVID-19 dropped significantly currently, but its seasonal ourbreaks make antiviral treatment still vital. In our study, syrian golden hamsters were treated with molnupiravir and interferons (IFNs) after SARS-CoV-2 infection. Their weight changes, pathological changes, virus replication and inflammation levels were evaluated. In the IFNs single treatment, only IFN-α group reduced viral load (p < 0.05) and virus titer in hamster lungs. The TNF-α expression decreased significantly in both IFNs treatment at 2dpi. Histological and immunofluorescence results showed lung damage in the IFNs groups were milder at 4dpi. In the molnupiravir/IFN-α combination treatment, weight loss and virus replication in lung were significantly decreased in the mono-molnupiravir group and combination group (p < 0.05), the expression of IL-6, TNF-α, IL-1ß and MIP-1α also decreased significantly (p < 0.05), but the combination treatment was not more effective than the mono-molnupiravir treatment. Histological and immunofluorescence results showed the lung damage and inflammation in mono-molnupiravir and combination groups were milder. In summary, IFNs treatment had anti-inflammatory effect against SARS-CoV-2, only IFN-α showed a weak antiviral effect. Molnupiravir/IFN-α combination treatment was effective against SARS-CoV-2 but was not superior to mono-molnupiravir treatment. IFN-α could be considered for immunocompromised patients to stimulate and activate early immune responses.

Predicting non-chemotherapy drug-induced agranulocytosis toxicity through ensemble machine learning approaches.

Agranulocytosis, induced by non-chemotherapy drugs, is a serious medical condition that presents a formidable challenge in predictive toxicology due to its idiosyncratic nature and complex mechanisms. In this study, we assembled a dataset of 759 compounds and applied a rigorous feature selection process prior to employing ensemble machine learning classifiers to forecast non-chemotherapy drug-induced agranulocytosis (NCDIA) toxicity. The balanced bagging classifier combined with a gradient boosting decision tree (BBC + GBDT), utilizing the combined descriptor set of DS and RDKit comprising 237 features, emerged as the top-performing model, with an external validation AUC of 0.9164, ACC of 83.55%, and MCC of 0.6095. The model's predictive reliability was further substantiated by an applicability domain analysis. Feature importance, assessed through permutation importance within the BBC + GBDT model, highlighted key molecular properties that significantly influence NCDIA toxicity. Additionally, 16 structural alerts identified by SARpy software further revealed potential molecular signatures associated with toxicity, enriching our understanding of the underlying mechanisms. We also applied the constructed models to assess the NCDIA toxicity of novel drugs approved by FDA. This study advances predictive toxicology by providing a framework to assess and mitigate agranulocytosis risks, ensuring the safety of pharmaceutical development and facilitating post-market surveillance of new drugs.

Gold Nanocluster: A Photoelectric Converter for X-Ray-Activated Chemotherapy.

Despite the promise of activatable chemotherapy, the development of a spatiotemporally controllable strategy for prodrug activation in deep tissues remains challenging. Herein, a proof-of-concept is proposed for a gold nanocluster-based strategy that utilizes X-ray irradiation to trigger the liberation of platinum (Pt)-based prodrug conjugates, thus enabling radiotherapy-directed chemotherapy. Mechanistically, the irradiated activation of prodrugs is achieved through direct photoelectron transfer from the excited-state gold nanoclusters to the Pt(IV) center, resulting in the release of cytotoxic Pt(II) agents. Compared to the traditional combination of chemotherapy and radiotherapy, this radiotherapy-directed chemotherapy strategy offers superior antitumor efficacy and safety benefits through spatiotemporal synergy at the tumor site. Additionally, this strategy elicits robust immunogenic cell death and yields profound outcomes for combined immunotherapy of breast cancer. This versatile strategy is ushering in a new era of radiation-mediated chemistry for controlled drug delivery and the precise regulation of biological processes.

Leveraging Senescent Cancer Cell Membrane to Potentiate Cancer Immunotherapy Through Biomimetic Nanovaccine.

Senescent cancer cells are endowed with high immunogenic potential that has been leveraged to elicit antitumor immunity and potentially complement anticancer therapies. However, the efficacy of live senescent cancer cell-based vaccination is limited by interference from immunosuppressive senescence-associated secretory phenotype and pro-tumorigenic capacity of senescent cells. Here, a senescent cancer cell-based nanovaccine with strong immunogenicity and favorable potential for immunotherapy is reported. The biomimetic nanovaccine integrating a senescent cancer cell membrane-coated nanoadjuvant outperforms living senescent cancer cells in enhancing dendritic cells (DCs) internalization, improving lymph node targeting, and enhancing immune responses. In contrast to nanovaccines generated from immunogenic cell death-induced tumor cells, senescent nanovaccines facilitate DC maturation, eliciting superior antitumor protection and improving therapeutic outcomes in melanoma-challenged mice with fewer side effects when combined with αPD-1. The study suggests a versatile biomanufacturing approach to maximize immunogenic potential and minimize adverse effects of senescent cancer cell-based vaccination and advances the design of biomimetic nanovaccines for cancer immunotherapy.

An Engineered Nanoplatform with Tropism Toward Irradiated Glioblastoma Augments Its Radioimmunotherapy Efficacy.

Combining radiotherapy with immune checkpoint blockade therapy offers a promising approach to treat glioblastoma multiforme (GBM), yet challenges such as limited effectiveness and immune-related adverse events (irAEs) persist. These issues are largely due to the failure in targeting immunomodulators directly to the tumor microenvironment. To address this, a biomimetic nanoplatform that combines a genetically modified mesenchymal stem cell (MSC) membrane with a bioactive nanoparticle core for chemokine-directed radioimmunotherapy of GBM is developed. The CC chemokine receptor 2 (CCR2)-overexpressing MSC membrane acts as a tactical tentacle to achieve radiation-induced tropism toward the abundant chemokine (CC motif) ligand 2 (CCL2) in irradiated gliomas. The nanoparticle core, comprising diselenide-bridged mesoporous silica nanoparticles (MSNs) and PD-L1 antibodies (αPD-L1), enables X-ray-responsive drug release and radiosensitization. In two murine models with orthotopic GBM tumors, this nanoplatform reinvigorated immunogenic cell death, and augmented the efficacy and specificity of GBM radioimmunotherapy, with reduced occurrence of irAEs. This study suggests a promising radiation-induced tropism strategy for targeted drug delivery, and presents a potent nanoplatform that enhances the efficacy and safety of radio-immunotherapy.

How COVID-19 Information Fear of Missing out Increases the Risk of Depression and Anxiety: Roles of Resilience and Personality Types.

During major health emergencies (e.g., the COVID-19 pandemic) people often fear missing relevant information. COVID-19 information fear of missing out (FOMO) is a phenomenon where people feel anxiety about losing control of COVID-19-related information. The present study aimed to examine how COVID-19 information FOMO relates to mental health (e.g., depression and anxiety), the mediating role of resilience, and the moderating role of personality types during the COVID-19 pandemic. We surveyed 1442 Chinese undergraduates (Mage = 21.68 ± 2.35 years) on the relevant variables. The results showed that COVID-19 information FOMO was positively associated with depression and anxiety, and resilience mediated these associations. Latent profile analysis (LPA) identified three personality types (undercontrolled, adaptive, and overcontrolled). Personality types moderated the mediation models, in which the indirect effects were only significant in the participants classified in the undercontrolled group rather than the participants classified in the other two groups. This study told us that undergraduates' mental health, particularly that of the undercontrollers, should be paid attention to when responding to a major public health emergency (e.g., the COVID-19 pandemic).

Adipose Triglyceride Lipase-Mediated Adipocyte Lipolysis Exacerbates Acute Pancreatitis Severity in Mouse Models and Patients.

Dyslipolysis of adipocytes plays a critical role in various diseases. Adipose triglyceride lipase (ATGL) is a rate-limiting enzyme in adipocyte autonomous lipolysis. However, the degree of adipocyte lipolysis related to the prognoses in acute pancreatitis (AP) and the role of ATGL-mediated lipolysis in the pathogenesis of AP remain elusive. Herein, the visceral adipose tissue consumption rate in the acute stage was measured in both patients with AP and mouse models. Lipolysis levels and ATGL expression were detected in cerulein-induced AP models. CL316,243, a lipolysis stimulator, and adipose tissue-specific ATGL knockout mice were used to further investigate the role of lipolysis in AP. The ATGL-specific inhibitor, atglistatin, was used in C57Bl/6N and ob/ob AP models. This study indicated that increased visceral adipose tissue consumption rate in the acute phase was independently associated with adverse prognoses in patients with AP, which was validated in mouse AP models. Lipolysis of adipocytes was elevated in AP mice. Stimulation of lipolysis aggravated AP. Genetic blockage of ATGL specifically in adipocytes alleviated the damage to AP. The application of atglistatin effectively protected against AP in both lean and obese mice. These findings demonstrated that ATGL-mediated adipocyte lipolysis exacerbates AP and highlighted the therapeutic potential of ATGL as a drug target for AP.

Interaction and antiviral treatment of coinfection between SARS-CoV-2 and influenza in vitro.

BACKGROUND: The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has lasted for three years. Coinfection with seasonal influenza may occur resulting in more severe diseases. The interaction between these two viruses for infection and the effect of antiviral treatment remains unclear. METHODS: A SARS-CoV-2 and influenza H1N1 coinfection model on Calu-3 cell line was established, upon which the simultaneous and sequential coinfection was evaluated by comparing the viral load. The efficacy of molnupiravir and baloxavir against individual virus and coinfection were also studied. RESULTS: The replication of SARS-CoV-2 was significantly interfered when the influenza virus was infected simultaneously or in advance (p < 0.05). On the contrary, the replication of the influenza virus was not affected by the SARS-CoV-2. Molnupiravir monotherapy had significant inhibitory effect on SARS-CoV-2 when the concentration reached to 6.25 µM but did not show any significant anti-influenza activity. Baloxavir was effective against influenza within the dosage range and showed significant effect of anti-SARS-CoV-2 at 16 µM. In the treatment of coinfection, molnupiravir had significant effect for SARS-CoV-2 from 6.25 µM to 100 µM and inhibited H1N1 at 100 µM (p < 0.05). The tested dosage range of baloxavir can inhibit H1N1 significantly (p < 0.05), while at the highest concentration of baloxavir did not further inhibit SARS-CoV-2, and the replication of SARS-CoV-2 significantly increased in lower concentrations. Combination treatment can effectively inhibit influenza H1N1 and SARS-CoV-2 replication during coinfection. Compared with molnupiravir or baloxavir monotherapy, combination therapy was more effective in less dosage to inhibit the replication of both viruses. CONCLUSIONS: In coinfection, the replication of SARS-CoV-2 would be interfered by influenza H1N1. Compared with molnupiravir or baloxavir monotherapy, treatment with a combination of molnupiravir and baloxavir should be considered for early treatment in patients with SARS-CoV-2 and influenza coinfection.

Leveraging Radiation-triggered Metal Prodrug Activation Through Nanosurface Energy Transfer for Directed Radio-chemo-immunotherapy.

Metal-based drugs currently dominate the field of chemotherapeutic agents; however, achieving the controlled activation of metal prodrugs remains a substantial challenge. Here, we propose a universal strategy for the radiation-triggered activation of metal prodrugs via nanosurface energy transfer (NSET). The core-shell nanoplatform (Ru-GNC) is composed of gold nanoclusters (GNC) and ruthenium (Ru)-containing organic-inorganic hybrid coatings. Upon X-ray irradiation, chemotherapeutic Ru (II) complexes were released in a controlled manner through a unique NSET process involving the transfer of photoelectron energy from the radiation-excited Ru-GNCs to the Ru-containing hybrid layer. In contrast to the traditional radiation-triggered activation of prodrugs, such an NSET-based system ensures that the reactive species in the tumor microenvironment are present in sufficient quantity and are not easily quenched. Additionally, ultrasmall Ru-GNCs preferably target mitochondria and profoundly disrupt the respiratory chain upon irradiation, leading to radiosensitization by generating abundant reactive oxygen species. Consequently, Ru-GNC-directed radiochemotherapy induces immunogenic cell death, resulting in significant therapeutic outcomes when combined with the programmed cell death-ligand 1 (PD-L1) checkpoint blockade. This NSET strategy represents a breakthrough in designing radiation-triggered nanoplatforms for metal-prodrug-mediated cancer treatment in an efficient and controllable manner.

X-ray-controllable release of carbon monoxide potentiates radiotherapy by ultrastable hybrid nanoreservoirs.

Carbon monoxide (CO) exhibits unique abilities in sensitizing cancer radiotherapy (RT). However, the development of a highly stable CO-delivery nanosystem with sustained CO release in tumor tissues and the prevention of CO leakage into normal tissues remains a challenge. Herein, an organic-inorganic hybrid strategy is proposed to create ultrastable CO nanoreservoirs by locking an unstable iron carbonyl (FeCO) prodrug in a stable mesoporous silica matrix. Different from traditional FeCO-loading nanoplatforms, FeCO-bridged nanoreservoirs not only tethered labile FeCO in the framework to prevent unwanted FeCO leakage, but also achieved sustained CO release in response to X-ray and endogenous H2O2. Importantly, FeCO-bridged nanoreservoirs exhibited the sequential release of CO and Fe2+, thereby performing highly efficient chemodynamic therapy. Such a powerful combination of RT, gas therapy, and chemodynamic therapy boosts robust immunogenic cell death, thus enabling the elimination of deeply metastatic colon tumors with minimal side effects. The proposed organic-inorganic hybrid strategy opens a new window for the development of stable nanoreservoirs for the on-demand delivery of unstable gases and provides a feasible approach for the sequential release of CO and metal ions from metal carbonyl complexes.

Thiol-Disulfide Exchange Coordinates the Release of Nitric Oxide and Dexamethasone for Synergistic Regulation of Intestinal Microenvironment in Colitis.

The cell-specific functions of nitric oxide (NO) in the intestinal microenvironment orchestrate its therapeutic effects in ulcerative colitis. While most biomaterials show promise by eliciting the characteristics of NO, the insufficient storage, burst release, and pro-inflammatory side effects of NO remain as challenges. Herein, we report the development of thiol-disulfide hybrid mesoporous organosilica nanoparticles (MONs) that improve the storage and sustained release of NO, broadening the therapeutic window of NO-based therapy against colitis. The tailored NO-storing nanomaterials coordinated the release of NO and the immunoregulator dexamethasone (Dex) in the intestinal microenvironment, specifically integrating the alleviation of oxidative stress in enterocytes and the reversal of NO-exacerbated macrophage activation. Mechanistically, such a synchronous operation was achieved by a self-motivated process wherein the thiyl radicals produced by NO release cleaved the disulfide bonds to degrade the matrix and release Dex via thiol-disulfide exchange. Specifically, the MON-mediated combination of NO and Dex greatly ameliorated intractable colitis compared with 5-aminosalicylic acid, even after delayed treatment. Together, our results reveal a key contribution of synergistic modulation of the intestinal microenvironment in NO-based colitis therapy and introduce thiol-disulfide hybrid nanotherapeutics for the management of inflammatory diseases and cancer.

Self-polymerized platinum (II)-Polydopamine nanomedicines for photo-chemotherapy of bladder Cancer favoring antitumor immune responses.

Systemic administration of platinum-based drugs has obvious limitations in the treatment of advanced bladder cancer (BC) owing to lower tumor accumulation and uncontrolled release of chemotherapeutics. There is an urgent need for advanced strategies to overcome the current limitations of platinum-based chemotherapy, to achieve maximal therapeutic outcomes with reduced side effects. In this study, self-polymerized platinum (II)-polydopamine nanocomplexes (PtPDs) were tailored for efficient chemo-photoimmunotherapy of BC. PtPDs with high Pt loading content (11.3%) were degradable under the combination of a reductive tumor microenvironment and near-infrared (NIR) light irradiation, thus controlling the release of Pt ions to achieve efficient chemotherapy. In addition, polydopamine promoted stronger photothermal effects to supplement platinum-based chemotherapy. Consequently, PtPDs provided effective chemo-photothermal therapy of MB49 BC in vitro and in vivo, strengthening the immunogenic cell death (ICD) effect and robust anti-tumoral immunity response. When combined with a PD-1 checkpoint blockade, PtPD-based photochemotherapy evoked systemic immune responses that completely suppressed primary and distant tumor growth without inducing systemic toxicities. Our work provides a highly versatile approach through metal-dopamine self-polymerization for the precise delivery of metal-based chemotherapeutic drugs, and may serve as a promising nanomedicine for efficient and safe platinum-based chemotherapy for BC.

Activation of innate immune cGAS-STING pathway contributes to Alzheimer's pathogenesis in 5×FAD mice.

cGAS senses microbial and host-derived double-stranded DNA in cytoplasm to trigger cellular innate immune response in a STING-dependent manner; however, it remains unknown whether the cGAS-STING pathway in innate immunity contributes to Alzheimer's disease (AD). Here we demonstrated the detectable binding of the cGAS double-stranded DNA in cytoplasm and the activation of the microglial cGAS-STING pathway in brains of human AD and aged mice. Cgas-/-;5×FAD mice were largely protected from cognitive impairment, amyloid-ß pathology, neuroinflammation and other sequelae associated with AD. Furthermore, Cgas deficiency in microglia inhibited a neurotoxic A1 astrocytic phenotype and thus alleviated oligomeric amyloid-ß peptide-induced neurotoxicity. Finally, administration of STING inhibitor H-151 potently suppressed the activation of the cGAS-STING pathway and ameliorated AD pathogenesis in 5×FAD mice. In conclusion, our present study has identified a critical molecular link between innate immunity and AD and suggests that therapeutic targeting of the cGAS-STING pathway activity might effectively interfere with the progression of AD.

Negative Life Events and Procrastination among Adolescents: The Roles of Negative Emotions and Rumination, as Well as the Potential Gender Differences.

Procrastination (the intentional delay of action despite knowing that one will be worse off due to the delay) is a widespread phenomenon with various negative consequences, especially among adolescents. Based on relevant evidence, this study examined the relation between negative life events and adolescents' procrastination, as well as the underlying mechanisms-specifically, the effects of negative emotions and rumination, as well as the potential gender differences. A total of 780 adolescents (Mage = 12.92 years old; 52.2% females) were recruited to complete a set of questionnaires assessing negative life events, procrastination, depression-anxiety-stress symptoms and rumination. Results showed that negative life events were positively associated with procrastination, and negative emotions significantly mediated the relation; rumination played a moderating role in this mediation model, specifically, both the direct and indirect effects in this mediation model were stronger for adolescents with higher rumination. Besides this, gender differences in this moderated mediation model were also found-the indirect effect of negative emotions was stronger for girls, and this mediating effect could be moderated by rumination only for boys. These results expanded our understanding of how negative life events influence procrastination and when (or for whom) negative life events influence procrastination the most. The findings also have significant implications for the prevention and intervention of adolescents' procrastination.

The Impact of Emotional Intelligence on Domain-Specific Creativity: The Mediating Role of Resilience and the Moderating Effects of Gratitude.

Creativity incorporates both domain-general and domain-specific ideas. While previous studies have explored the impact of emotional intelligence (EI) on creativity in both domains, a consensus has not been reached, and the mechanism is currently unclear. In the present study, we examined which aspect of creativity EI was most strongly associated with in a group of undergraduates. Moreover, we explored the moderated mediation effect between EI and domain-specific creativity. In Study 1, 532 undergraduates completed questionnaires measuring EI, convergent and divergent creative thinking, and creative achievement. The results revealed that the most reliable positive correlations were between EI and domain-specific creativity. In Study 2, 926 undergraduates completed measurements of EI, resilience, gratitude, and creative achievement. The results revealed that resilience mediates the relationship between EI and creative achievement. Furthermore, gratitude moderated the indirect effect of EI on creative achievement through resilience. The indirect effect of EI on creative achievement was stronger for high-gratitude individuals than for low-gratitude individuals. This orientation and other results are discussed. Overall, our findings add further nuance to the relationship between EI and creativity in different domains. This study serves as a basis for other contributions aligned with these concepts.

Boredom Proneness and Online Deviant Behaviors: The Mediating Role of Rumination and the Moderating Role of Gender.

Online deviant behaviors have received increasing attention. This study examined the association between boredom proneness and online deviant behaviors as well as the mediating role of rumination and the moderating role of gender in the relationship. A sample of 1001 college students (Mage = 20.20 ± 1.52 years, 50.25% female) was recruited to complete a set of questionnaires assessing the main variables. The results show that boredom proneness was positively associated with online deviant behaviors and that rumination played a mediating role in this relationship. Moreover, gender differences were found in the relationship, which was stronger for males than females. Despite several limitations, this study deepens our understanding of the influencing mechanism of boredom proneness on online deviant behaviors, which could provide practical implications for the prevention and intervention of online deviant behaviors.

Self-Assembled Ru(II)-Coumarin Complexes for Selective Cell Membrane Imaging.

The cell membrane, as the protecting frontier of cells, is closely related to crucial biological behaviors including cell growth, death, and division. Lots of fluorescent probes have been fabricated to monitor cell membranes due to their simplicity and intuitiveness. However, the efficiency of those traditional probes has been limited by their susceptibility to photobleaching and poor water solubility. In this study, we have reported Ru(II)-coumarin complexes consisting of ruthenium, 1,10-phenanthroline, and coumarin 6 to further form self-assembled nanoprobes, for cell membrane targeting and imaging. The fluorescent property could be switchable from red to green through the dynamic disassembly of nanoprobes. Compared with commercial Dil, biocompatible nanoprobes exhibited superior stability for long-term cell imaging, along with remarkedly reduced background interference. Therefore, our self-assembled nanoprobe provides a powerful solution for investigating lipid trafficking with optical imaging.