Cationic lipid-assisted nanoparticles for simultaneous delivery of CD47 siRNA and R848 to promote antitumor immune responses

Introduction: Triple-negative breast cancer (TNBC) usually has a poor prognosis. Although the immunotherapy of TNBC has achieved great progress, only a few patients can benefit from the current treatment. CD47 is widely expressed on the surface of TNBC cells and may become an immune checkpoint for TNBC treatment. Nevertheless, increasingly more attention has been paid to systemic side effects since the ubiquitous expression of CD47 on normal cells. The toll-like receptor (TLR) agonist resiquimod (R848) can activate dendritic cells (DCs) and promote the maturation of immune cells in the tumor microenvironment, which further enhances the tumor inhibition ability of the immune system and synergizes with CD47 small interfering RNA (siRNA) for TNBC therapy. However, ideal delivery platforms such as nanocarriers are still needed because its weakness of hydrophobicity.Methods: In order to improve efficacy and reduce toxicity, R848 and siCD47 were entrapped in amphiphilic PEG-PLGA nanoparticles by double emulsification and stable nanoparticles NP/R848/siCD47 were generated to investigate their anti-tumor effects in a TNBC tumor-bearing mouse model.Results: Here, we show that PEG-PLGA nanoparticles are effective nanocarriers that can safely and effectively deliver siCD47 and R848 to tumor tissue, as demonstrated by retarded tumor growth. Mechanistically, downregulation of CD47 expression and activation of DCs took part in promoting the immune response of cytotoxic T cells (CTLs). Meanwhile, a decrease of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) indicated the modulating of the tumor immune microenvironment.Discussion: To our best knowledge, our study pioneered co-delivery system for hydrophilic siCD47 and hydrophobic R848. It can maximize break tumor immune escape caused by CD47 and simultaneously enhance antigen presentation by activating DCs for effector T cell killing while regulating the tumor microenvironment as expected. Not only does it conform to the reports of previous basic research, but also it can break the bottleneck of their clinical application hopefully. Collectively, our findings could lay the foundation for future therapeutic strategies of TNBC

Identification of intraneuronal amyloid beta oligomers in locus coeruleus neurons of Alzheimer's patients and their potential impact on inhibitory neurotransmitter receptors and neuronal excitability

The author's final peer reviewed version can be found by following the URI link. The Publisher's final version can be found by following the DOI link.Aims Amyloid β oligomers (AβO) are potent modulators of Alzheimer’s pathology, yet their impact on one of the earliest brain regions to exhibit signs of the condition, the locus coeruleus (LC), remains to be determined. Of particular importance is whether AβO impact the spontaneous excitability of LC neurons. This parameter determines brain‐wide noradrenaline (NA) release, and thus NA‐mediated brain functions, including cognition, emotion and immune function, which are all compromised in Alzheimer’s. Therefore, the aim of the study was to determine the expression profile of AβO in the LC of Alzheimer’s patients and to probe their potential impact on the molecular and functional correlates of LC excitability, using a mouse model of increased Aβ production (APP‐PSEN1). Methods and Results Immunohistochemistry and confocal microscopy, using AβO‐specific antibodies, confirmed LC AβO expression both intraneuronally and extracellularly in both Alzheimer’s and APP‐PSEN1 samples. Patch clamp electrophysiology recordings revealed that APP‐PSEN1 LC neuronal hyperexcitability accompanied this AβO expression profile, arising from a diminished inhibitory effect of GABA, due to impaired expression and function of the GABA‐A receptor (GABAAR) α3 subunit. This altered LC α3‐GABAAR expression profile overlapped with AβO expression in samples from both APP‐PSEN1 mice and Alzheimer’s patients. Finally, strychnine‐sensitive glycine receptors (GlyRs) remained resilient to Aβ‐induced changes and their activation reversed LC hyperexcitability. Conclusions The data suggest a close association between AβO and α3‐GABAARs in the LC of Alzheimer’s patients, and their potential to dysregulate LC activity, thereby contributing to the spectrum of pathology of the LC‐NA system in this condition

Associations of 10 dietary habits with breast cancer: a Mendelian randomization study

IntroductionEpidemiological studies have revealed a link between dietary habits and the breast cancer risk. The causality of the association between food consumption and breast cancer requires further investigation.MethodsUsing Mendelian randomization, we assessed the causal effects of 10 dietary habits on the risks of breast cancer and its subtypes (estrogen receptor [ER]  +  and ER- breast cancer). We obtained dietary pattern data in 2018 (number of single-nucleotide polymorphisms [SNPs]  =  9,851,867) and breast cancer data in 2017 (number of SNPs  =  10,680,257) from IEU OpenGWAS. Rigorous sensitivity analyses were conducted to ensure that the study results were credible and robust.ResultsWe identified that genetic predisposition to higher dried fruit intake was linked to a reduced risk of overall breast cancer (inverse variance-weighted [IVW] odds ratio [OR] = 0.55; 95% confidence interval [CI]: 0.43–0.70; p = 1.75 × 10−6), ER+ breast cancer (IVW OR = 0.62; 95% CI: 0.47–0.82; p = 8.96 × 10−4) and ER− breast cancer (IVW OR = 0.48; 95% CI: 0.34–0.68; p = 3.18 × 10−5), whereas genetic predisposition to more oily fish intake was linked to a lower risk of ER+ breast cancer (IVW OR = 0.73; 95% CI: 0.53–0.99; p = 0.04).DiscussionOur findings suggest that a genetic predisposition for dried fruit and oily fish consumption may be protective against breast cancer; however, further investigation is required

Characterization and Comparison of the Tissue-Related Modules in Human and Mouse

BACKGROUND: Due to the advances of high throughput technology and data-collection approaches, we are now in an unprecedented position to understand the evolution of organisms. Great efforts have characterized many individual genes responsible for the interspecies divergence, yet little is known about the genome-wide divergence at a higher level. Modules, serving as the building blocks and operational units of biological systems, provide more information than individual genes. Hence, the comparative analysis between species at the module level would shed more light on the mechanisms underlying the evolution of organisms than the traditional comparative genomics approaches. RESULTS: We systematically identified the tissue-related modules using the iterative signature algorithm (ISA), and we detected 52 and 65 modules in the human and mouse genomes, respectively. The gene expression patterns indicate that all of these predicted modules have a high possibility of serving as real biological modules. In addition, we defined a novel quantity, "total constraint intensity," a proxy of multiple constraints (of co-regulated genes and tissues where the co-regulation occurs) on the evolution of genes in module context. We demonstrate that the evolutionary rate of a gene is negatively correlated with its total constraint intensity. Furthermore, there are modules coding the same essential biological processes, while their gene contents have diverged extensively between human and mouse. CONCLUSIONS: Our results suggest that unlike the composition of module, which exhibits a great difference between human and mouse, the functional organization of the corresponding modules may evolve in a more conservative manner. Most importantly, our findings imply that similar biological processes can be carried out by different sets of genes from human and mouse, therefore, the functional data of individual genes from mouse may not apply to human in certain occasions

What Promotes Natural Forest Protection and Restoration? Insights from the Perspective of Multiple Parties

The natural forest protection and restoration (NFPR) system is imperfect due to contradictions between the objectives of natural forest protection and the reality of situations, outdated cultivation concepts, conflicting interests among participating parties, and the lack of regulation guarantees and assessment criteria. These problems are not only common in China but also in international forest protection. As the NFPR system is more focused on the protection of natural forests, the level of natural forest restoration in China has been poor, with low natural forest quality and forest productivity. At the same time, the value of natural forest ecosystem services does not match the demand of farmers, forest management, and other multiple participating parties. As a result, except for the government, other multiple parties lack the intrinsic motivation to participate in NFPR, ultimately forming a sustainable management dilemma. Under the institutional analysis and development (IAD) framework, the objective of this research was to explore the influencing factors and outcomes of the participation of multiple parties in NFPR and to construct a multiple parties’ participation mechanism for solving this dilemma. This research found that among external variables, multiple parties’ characteristics, biophysical conditions, attributes of community, and rules-in-use jointly influence and constitute the driving mechanism of multiple parties’ participation in NFPR. The rules-in-use directly impact the participation action scenario and regulate the other three external variables. Various factors and mechanisms in NFPR interact in the action space and produce outcomes that create positive incentives for each external variable, thus promoting the whole mechanism to achieve a virtuous cycle of sustainable management. This study provides a theoretical contribution to understanding the behavior of multiple parties participating in NFPR

Genetic Code Expansion System for Tight Control of Gene Expression in Bombyx mori Cell Lines

Inducible gene expression systems are important tools for studying gene function and to control protein synthesis. With the completion of the detailed map of the silkworm (Bombyx mori) genome, the study of Bombyx mori has entered the post-genome era. While the functions of many genes have been described in detail, many coding genes remain unidentified. Except for the available tetracycline induction system, there is currently a dearth of other effective induction systems for B. mori. A genetic code expansion system can be used for protein labeling and to regulate gene expression. Here, we have established a genetic code expansion system for B. mori based on the well-researched tRNAPyl/PylRS pair from Methanosarcina mazei. We used H-Lys(Boc)-OH, which is a lysine derivative to efficiently and tightly control the expression of the reporter gene DsRed[TAG]EGFP (D[TAG]G), which encoded a H-Lys(Boc)-OH-bearing protein fused with DsRed and EGFP (here regarded as D[Boc]G) in B. mori cell lines BmE and BmNs. In D[TAG]G, the amber stop codon is recognized as the orthogonal tRNAPyl. Successful application of genetic code expansion system in silkworm cell lines will support the research into the function of silkworm genes and paves the way for the identification of new genes and protein markers in silkworm