2D Differential Metallic Immunopotentiators Drive High Diversity and Capability of Antigen-specific Immunity Against Tumor.

The therapeutic efficacy of vaccines for treating cancers in clinics remains limited. Here, a rationally designed cancer vaccine by placing immunogenically differential and clinically approved aluminum (Al) or manganese (Mn) in a 2D nanosheet (NS) architecture together with antigens is reported. Structurally optimal NS with a high molar ratio of Mn to Al (MANS-H) features distinctive immune modulation, markedly promoting the influx of heterogeneous innate immune cells at the injection site. Stimulation of multiple subsets of dendritic cells (DCs) significantly increases the levels, subtypes, and functionalities of antigen-specific T cells. MANS-H demonstrates even greater effectiveness in the production of antigen-specific antibodies than the commercial adjuvant (Alhydrogel) by priming T helper (Th)2 cells rather than T follicular helper (Tfh) cells. Beyond humoral immunity, MANS-H evokes high frequencies of antigen-specific Th1 and CD8+ cell immunity, which are comparable with Quil-A that is widely used in veterinary vaccines. Immunized mice with MANS-H adjuvanted vaccines exert strong potency in tumor regression by promoting effector T cells infiltrating at tumor and overcoming tumor resistance in multiple highly aggressive tumor models. The engineered immunogen with an intriguing NS architecture and safe immunopotentiators offers the next clinical advance in cancer immunotherapy.

Immuno-Nanocomplexes Target Heterogenous Network of Inflammation and Immunity in Myocardial Infarction.

Despite the proceeds in the management of acute myocardial infarction (AMI), the current therapeutic landscape still suffers from limited success in the clinic. Exaggerated inflammatory immune response and excessive oxidative stress are key pathological features aggravating myocardium damage. Herein, catalytic immunomodulatory nanocomplexes as anti-AMI therapeutics to resolve reactive oxygen species (ROS)-proinflammatory neutrophils-specific-inflammation is engineered. The nanocomplexes contain lyophilic S100A8/9 inhibitor ABR2575 in the core of nanoemulsions, which effectively disrupts the neutrophils-S100A8/A9-inflammation signaling pathway in the AMI microenvironment. Additionally, ROS scavenger ultrasmall CuxO nanoparticles are incorporated into the nanoemulsions via coordinating with SH groups of poly(ethylene glycol) (PEG)-conjugated lipids, which mimic multiple enzymes, dramatically alleviating the oxidative stress damage to myocardial tissue. This combination strategy significantly suppresses the infiltration of pro-inflammatory monocytes, macrophages, and neutrophils, as well as the secretion of inflammatory cytokines. Additionally, it potentially triggers cardiac Tert activation, which promotes myocardial function and decreases infarction size in preclinical murine AMI models. This approach offers a new nanomedicine for treating AMI, resulting in a dramatically enhanced therapeutic outcome.

Immunogenic Material Vaccine for Cancer Immunotherapy by Structure-Dependent Immune Cell Trafficking and Modulation.

Inherently immunogenic materials offer enormous prospects in enhancing vaccine efficacy. However, the understanding and improving material adjuvanticity remain elusive. Herein how the structural presentation of immunopotentiators in a material governs the dynamic dialogue between innate and adaptive immunity for enhanced cancer vaccination is reported. The immunopotentiator manganese into six differing structures that resemble the architectures of two types of pathogens (spherical viruses or rod-like bacteria) is precisely manipulated. The results reveal that innate immune cells accurately sense and respond to the architectures, of which two outperformed material candidates (151 nm hollow spheres and hollow microrods with an aspect ratio of 4.5) show higher competence in creating local proinflammatory environment with promoted innate immune cell influx and stimulation on dendritic cells (DCs). In combination with viral peptides, model proteins, or cell lysate antigens, the outperformed microrod material remarkably primes antigen-specific CD8 cytolytic T cells. In prophylactic and therapeutic regimens, the microrod adjuvanted vaccines display optimal aptitude in tumor suppression in four aggressive murine tumor models, by promoting the infiltration of heterogeneous cytolytic effector cells while decreasing suppressive immunoregulatory populations in tumors. This study demonstrates that a rationally selected architecture of immunogenic materials potentially advances the clinical reality of cancer vaccination.

Formyl phloroglucinol meroterpenoids from the leaves of Eucalyptus globulus subsp. maidenii and their ATP-citrate lyase inhibitory activities.

Three new formyl phloroglucinol meroterpenoids, eumaidials A-C (1-3), were isolated from the leaves of Eucalyptus globulus subsp. maidenii, along with ten known analogues (4-13). Their chemical structures were determined by various spectral data and electronic circular dichroism calculations. Eumaidial A (1) is the first ß-caryophyllene-based formyl phloroglucinol meroterpenoids from the genus Eucalyptus. Compounds 1-4 and 10 exhibited ATP-citrate lyase inhibitory activities, and compounds 2 and 3 suppressed the hepatocyte lipogenesis.

Associations between estimation of salt intake and salt-restriction spoons and hypertension status in patients with poorly controlled hypertension: a community-based study from Huzhou City, Eastern China.

BACKGROUND: As the prevalence of hypertension increases in China, it is advised to use salt-restriction spoons (SRS) as a lifestyle modification. This study aimed to examine the associations between estimated salt consumption, SRS usage, and the hypertension status in individuals with poorly controlled hypertension. METHODS: Data was collected in Huzhou City, Zhejiang Province, in 2021 using convenience sampling. The analysis involved ordinal logistic regression and restricted cubic splines to assess the relevant factors. RESULTS: The study found that 73.34% of the 1215 patients had uncontrolled blood pressure (BP). Urinary excretion was assessed through the utilization of the Kawasaki, INTERSALT, and Tanaka formulas. The outcomes of these three methodologies revealed average daily sodium excretion values of 208.70 (65.65), 154.78 (33.91), and 162.61 (40.87) mmol, respectively. The prevalence of utilizing SRS was found to be 37.78% in this study. Despite the acknowledgment among SRS users of the potential hazards associated with excessive salt consumption, there exists a contradictory pattern of attitudes and behaviors concerning salt reduction. Among individuals with different levels of salt intake (quartiles 1-4, Q1 vs Q4), there was a positive association between limiting salt and hypertension status when controlling for other variables (Kawasaki adjusted OR = 0.58, 95% CI = 0.43-0.79; INTERSALT adjusted OR = 0.62, 95% CI = 0.41-0.92; Tanaka adjusted OR = 0.61, 95% CI = 0.45-0.92, p < 0.05). Our research also revealed that using or used SRS was a protective factor for blood BP control (adjusted OR = 0.79, 95% CI = 0.64-0.99, P < 0.05). The restricted cubic spline plots illustrated a monotonic upward relationship between estimated 24-h urinary Na and BP (P-overall association < 0.05; P-non-linear association > 0.05). CONCLUSIONS: The use of dietary SRS could result in decrease in daily salt intake for BP control in patients with poorly controlled hypertension. To reduce the impact of high BP in China, additional studies are required to create interventions that can enhance the results for patients.

Cardiac glycosides from Streblus asper with potential antiviral activity.

Ten undescribed cardiac glycosides, strasperosides A-J, together with twelve known analogues, were isolated from Streblus asper Lour. Their structures were elucidated on the basis of spectroscopic analysis, electronic circular dichroism data, and chemical methods. These cardiac glycosides showed diversity in steroid skeleton and sugar moiety. Strasperosides A and B are a pair of unusual stereoisomers featuring different orientation of the lactone motif. Ten cardiac glycosides demonstrated potent antiviral effects on HSV-1 in vitro with the IC50 values from 0.19 ± 0.08 to 1.03 ± 0.25 µM and the therapeutic indices from 66.61 ± 5.08 to 326.75 ± 11.75.

Adjuvant physiochemistry and advanced nanotechnology for vaccine development.

Vaccines comprising innovative adjuvants are rapidly reaching advanced translational stages, such as the authorized nanotechnology adjuvants in mRNA vaccines against COVID-19 worldwide, offering new strategies to effectively combat diseases threatening human health. Adjuvants are vital ingredients in vaccines, which can augment the degree, extensiveness, and longevity of antigen specific immune response. The advances in the modulation of physicochemical properties of nanoplatforms elevate the capability of adjuvants in initiating the innate immune system and adaptive immunity, offering immense potential for developing vaccines against hard-to-target infectious diseases and cancer. In this review, we provide an essential introduction of the basic principles of prophylactic and therapeutic vaccination, key roles of adjuvants in augmenting and shaping immunity to achieve desired outcomes and effectiveness, and the physiochemical properties and action mechanisms of clinically approved adjuvants for humans. We particularly focus on the preclinical and clinical progress of highly immunogenic emerging nanotechnology adjuvants formulated in vaccines for cancer treatment or infectious disease prevention. We deliberate on how the immune system can sense and respond to the physicochemical cues (e.g., chirality, deformability, solubility, topology, and chemical structures) of nanotechnology adjuvants incorporated in the vaccines. Finally, we propose possible strategies to accelerate the clinical implementation of nanotechnology adjuvanted vaccines, such as in-depth elucidation of nano-immuno interactions, antigen identification and optimization by the deployment of high-dimensional multiomics analysis approaches, encouraging close collaborations among scientists from different scientific disciplines and aggressive exploration of novel nanotechnologies.

Regulating the Electronic Structure of Bismuth Nanosheets by Titanium Doping to Boost CO2 Electroreduction and Zn-CO2 Batteries.

The electrochemical carbon dioxide reduction reaction (E-CO2 RR) to formate is a promising strategy for mitigating greenhouse gas emissions and addressing the global energy crisis. Developing low-cost and environmentally friendly electrocatalysts with high selectivity and industrial current densities for formate production is an ideal but challenging goal in the field of electrocatalysis. Herein, novel titanium-doped bismuth nanosheets (TiBi NSs) with enhanced E-CO2 RR performance are synthesized through one-step electrochemical reduction of bismuth titanate (Bi4 Ti3 O12 ). We comprehensively evaluated TiBi NSs using in situ Raman spectra, finite element method, and density functional theory. The results indicate that the ultrathin nanosheet structure of TiBi NSs can accelerate mass transfer, while the electron-rich properties can accelerate the production of *CO2 - and enhance the adsorption strength of *OCHO intermediate. The TiBi NSs deliver a high formate Faradaic efficiency (FEformate ) of 96.3% and a formate production rate of 4032 µmol h-1  cm-2 at -1.01 V versus RHE. An ultra-high current density of -338.3 mA cm-2 is achieved at -1.25 versus RHE, and simultaneously FEformate still reaches more than 90%. Furthermore, the rechargeable Zn-CO2 battery using TiBi NSs as a cathode catalyst achieves a maximum power density of 1.05 mW cm-2 and excellent charging/discharging stability of 27 h.

Impact of free hypertension pharmacy program and social distancing policy on stroke: A longitudinal study.

Background: The estimated lifetime risk of stroke was the highest in East Asia worldwide, especially in China. Antihypertensive therapy can significantly reduce stroke mortality. However, blood pressure control is poor. Medication adherence is a barrier as patients' out-of-pocket costs have risen. We aimed to take advantage of a free hypertension pharmacy intervention and quantified the impact on stroke mortality. Methods: A free pharmaceutical intervention program was implemented in Deqing, Zhejiang province in April 2018. Another non-pharmaceutical intervention, social distancing due to the pandemic of Coronavirus disease 2019 (COVID-19), was also key to affecting stroke mortality. We retrospectively collected the routine surveillance data of stroke deaths from Huzhou Municipal Center for Disease Prevention and Control in 2013-2020 and obtained within-city mobility data from Baidu Migration in 2019-2020, then we quantified the effects of both pharmaceutical intervention and social distancing using Serfling regression model. Results: Compared to the predicted number, the actual number of stroke deaths was significantly lower by 10% (95% CI, 6-15%; p < 0.001) from April 2018 to December 2020 in Deqing. Specifically, there was a reduction of 19% (95% CI, 10-28%; p < 0.001) in 2018. Moreover, we observed a 5% (95% CI, -4 - 14%; p = 0.28) increase in stroke mortality due to the adverse effect of COVID-19 but it wasn't statistically significant. Conclusion: Free hypertension pharmacy program has great potential to prevent considerable stroke deaths. In the future, the free supply of low-cost, essential medications that target patients with hypertension at increased risk of stroke could be taken into account in formulating public health policies and guiding allocations of health care resources.

Nanoformulations targeting immune cells for cancer therapy: mRNA therapeutics.

The approved worldwide use of two messenger RNA (mRNA) vaccines (BNT162b2 and mRNA-1273) in late 2020 has proven the remarkable success of mRNA therapeutics together with lipid nanoformulation technology in protecting people against coronaviruses during COVID-19 pandemic. This unprecedented and exciting dual strategy with nanoformulations and mRNA therapeutics in play is believed to be a promising paradigm in targeted cancer immunotherapy in future. Recent advances in nanoformulation technologies play a prominent role in adapting mRNA platform in cancer treatment. In this review, we introduce the biologic principles and advancements of mRNA technology, and chemistry fundamentals of intriguing mRNA delivery nanoformulations. We discuss the latest promising nano-mRNA therapeutics for enhanced cancer immunotherapy by modulation of targeted specific subtypes of immune cells, such as dendritic cells (DCs) at peripheral lymphoid organs for initiating mRNA cancer vaccine-mediated antigen specific immunotherapy, and DCs, natural killer (NK) cells, cytotoxic T cells, or multiple immunosuppressive immune cells at tumor microenvironment (TME) for reversing immune evasion. We highlight the clinical progress of advanced nano-mRNA therapeutics in targeted cancer therapy and provide our perspectives on future directions of this transformative integrated technology toward clinical implementation.

Targeted Cancer Immunotherapy: Nanoformulation Engineering and Clinical Translation.

With the rapid growth of advanced nanoengineering strategies, there are great implications for therapeutic immunostimulators formulated in nanomaterials to combat cancer. It is crucial to direct immunostimulators to the right tissue and specific immune cells at the right time, thereby orchestrating the desired, potent, and durable immune response against cancer. The flexibility of nanoformulations in size, topology, softness, and multifunctionality allows precise regulation of nano-immunological activities for enhanced therapeutic effect. To grasp the modulation of immune response, research efforts are needed to understand the interactions of immune cells at lymph organs and tumor tissues, where the nanoformulations guide the immunostimulators to function on tissue specific subsets of immune cells. In this review, recent advanced nanoformulations targeting specific subset of immune cells, such as dendritic cells (DCs), T cells, monocytes, macrophages, and natural killer (NK) cells are summarized and discussed, and clinical development of nano-paradigms for targeted cancer immunotherapy is highlighted. Here the focus is on the targeting nanoformulations that can passively or actively target certain immune cells by overcoming the physiobiological barriers, instead of directly injecting into tissues. The opportunities and remaining obstacles for the clinical translation of immune cell targeting nanoformulations in cancer therapy are also discussed.

The CC-NB-LRR protein BSR1 from Brachypodium confers resistance to Barley stripe mosaic virus in gramineous plants by recognising TGB1 movement protein.

Although some nucleotide binding, leucine-rich repeat immune receptor (NLR) proteins conferring resistance to specific viruses have been identified in dicot plants, NLR proteins involved in viral resistance have not been described in monocots. We have used map-based cloning to isolate the CC-NB-LRR (CNL) Barley stripe mosaic virus (BSMV) resistance gene barley stripe resistance 1 (BSR1) from Brachypodium distachyon Bd3-1 inbred line. Stable BSR1 transgenic Brachypodium line Bd21-3, barley (Golden Promise) and wheat (Kenong 199) plants developed resistance against BSMV ND18 strain. Allelic variation analyses indicated that BSR1 is present in several Brachypodium accessions collected from countries in the Middle East. Protein domain swaps revealed that the intact LRR domain and the C-terminus of BSR1 are required for resistance. BSR1 interacts with the BSMV ND18 TGB1 protein in planta and shows temperature-sensitive antiviral resistance. The R390 and T392 residues of TGB1ND (ND18 strain) and the G196 and K197 residues within the BSR1 P-loop motif are key amino acids required for immune activation. BSR1 is the first cloned virus resistance gene encoding a typical CNL protein in monocots, highlighting the utility of the Brachypodium model for isolation and analysis of agronomically important genes for crop improvement.

Metabolomics reveals that phenolamides are the main chemical components contributing to the anti-tyrosinase activity of bee pollen.

Bee pollen, which is known as a "full-nutrient food", has outstanding anti-tyrosinase activity. However, the chemical components contributing to this activity remain unknown. To comprehensively elucidate the chemical components of bee pollen inhibiting tyrosinase, we performed the anti-tyrosinase activity evaluation of bee pollen extract (BPE) of eight species, metabolomic analysis of chemical composition, multivariate statistical analysis and correlation analysis. The results revealed that the anti-tyrosinase activity of eight BPEs was significantly different (p < 0.05), with IC50 value ranging from 10.08 to 408.81 µg/mL. A total of 725 metabolites were detected from these BPEs, and 40 differential metabolites were identified, all of which were phenolamides. All these phenolamides were positively correlated with the anti-tyrosinase activity, among which 26 phenolamides (21 spermidine derivatives and five spermine derivatives) showed particularly high correlations (r > 0.7). This is the first report to reveal the main contributor to the anti-tyrosinase activity of bee pollen.

Childhood Maltreatment, Automatic Negative Thoughts, and Resilience: The Protective Roles of Culture and Genes.

Resilience, a psychological trait conceptualized as the ability to recover from setbacks, can be weakened by childhood maltreatment, which comprises childhood abuse and childhood neglect. The current study aimed to investigate whether childhood maltreatment could increase automatic negative thoughts (ANT), thus weakening resilience. Furthermore, as psychological characteristics are commonly subject to the moderating effects of cultural context and biology, the study also explored whether and how cultural and genetic factors separately interact with childhood maltreatment to predict resilience. In study 1, the participants comprised 237 American and 347 Chinese individuals; study 2 included 428 genotyped Chinese individuals. We combined regression, mediation, moderation, and machine learning methods to test the mediating effect of ANT on the link between childhood maltreatment and resilience as well as the moderating roles of culture and genetics. Study 1 found that both childhood abuse and childhood neglect increased ANT and thus weakened resilience. In addition, the ANT-mediating effects of childhood neglect were stronger in American than Chinese participants. In Study 2, using the leave-one-out approach, we constructed two separate prediction models based on 22 and 16 important single nucleotide polymorphisms (SNPs), and we found that the interaction between childhood abuse/neglect and polygenic scores based on important SNPs could predict ANT. The mediating effects of ANT on the relationship between childhood abuse/neglect and resilience were significant for participants with low polygenic scores but not for those with high polygenic scores. In conclusion, both the cultural environment and individual genetic makeup moderated the mediating effects of ANT on the association between childhood maltreatment and resilience. These findings indicated the roles of culture and genetics in protecting against the adverse effects of childhood maltreatment on resilience.

Acquisition of murine splenic myeloid cells for protein and gene expression profiling by advanced flow cytometry and CITE-seq.

Here, we outline detailed protocols to isolate and profile murine splenic dendritic cells (DCs) through advanced flow cytometry of the myeloid compartment and single-cell transcriptomic profiling with integrated cell surface protein expression through CITE-seq. This protocol provides a general transferrable road map for different tissues and species. For complete details on the use and execution of this protocol, please refer to Lukowski et al. (2021).

Effect of uncertainty-dependent residential mobility on loss aversion.

The current research aimed to examine the relationship between residential mobility and loss aversion, a ubiquitous decision-making bias conceptualized in prospect theory. Combining correlational, experimental, and electroencephalography approaches, we tested the hypothesis that residential mobility may increase loss aversion. The results revealed a positive correlation between residential mobility and loss aversion (Study 1). These effects were moderated by individuals' residential mobility/stability mindsets. Behaviorally, we observed a positive association between residential mobility history and loss aversion among individuals with a high (vs. low) subjective uncertainty after manipulating their residential mobility mindset by priming them with a mobile or stable lifestyle (Study 2). On the neural level, we found that the mindset of residential mobility (vs. stability) enhanced the differential feedback-related negativity (FRN) modulations between the large-win and large-loss conditions among Chinese participants with a high subjective uncertainty (Study 3). In conclusion, residential mobility elevated loss aversion by enhancing feelings of subjective uncertainty. Our findings provide novel insights into how changes in the socioecological environment shape individuals' decision-making bias.

Absence of Batf3 reveals a new dimension of cell state heterogeneity within conventional dendritic cells.

Conventional dendritic cells (cDCs) are traditionally subdivided into cDC1 and cDC2 lineages. Batf3 is a cDC1-required transcription factor, and we observed that Batf3-/- mice harbor a population of cDC1-like cells co-expressing cDC2-associated surface molecules. Using single-cell RNA sequencing with integrated cell surface protein expression (CITE-seq), we found that Batf3-/- mitotic immature cDC1-like cells showed reduced expression of cDC1 features and increased levels of cDC2 features. In wild type, we also observed a proportion of mature cDC1 cells expressing surface features characteristic to cDC2 and found that overall cDC cell state heterogeneity was mainly driven by developmental stage, proliferation, and maturity. We detected population diversity within Sirpa+ cDC2 cells, including a Cd33+ cell state expressing high levels of Sox4 and lineage-mixed features characteristic to cDC1, cDC2, pDCs, and monocytes. In conclusion, these data suggest that multiple cDC cell states can co-express lineage-overlapping features, revealing a level of previously unappreciated cDC plasticity.

Dimeric clerodane diterpenoids and antiviral constituents of Dodonaea viscosa.

Three unprecedented dimeric clerodane diterpenoids, dodovisdimers A-C (1-3), along with six known clerodane monomers (4-9), were isolated from Dodonaea viscosa. Compounds 1-3 may be biosynthetically formed via an intermolecular Diels-Alder [4+2] cycloaddition between the coexisting monomers 4-7. The structures of these clerodanes were characterized by spectroscopic techniques, X-ray crystallographic study, and ECD calculations. Some isolates exerted antiviral effects on human influenza A virus (H3N2) in vitro.