Modular Design of Biodegradable Ionizable Lipids for Improved mRNA Delivery and Precise Cancer Metastasis Delineation In Vivo.

Lipid nanoparticles (LNPs) represent the most clinically advanced nonviral mRNA delivery vehicles; however, the full potential of the LNP platform is greatly hampered by inadequate endosomal escape capability. Herein, we rationally introduce a disulfide bond-bridged ester linker to modularly synthesize a library of 96 linker-degradable ionizable lipids (LDILs) for improved mRNA delivery in vivo. The top-performing LDILs are composed of one 4A3 amino headgroup, four disulfide bond-bridged linkers, and four 10-carbon tail chains, whose unique GSH-responsive cone-shaped architectures endow optimized 4A3-SCC-10 and 4A3-SCC-PH lipids with superior endosomal escape and rapid mRNA release abilities, outperforming their parent lipids 4A3-SC-10/PH without a disulfide bond and control lipids 4A3-SSC-10/PH with a disulfide bond in the tail. Notably, compared to DLin-MC3-DMA via systematic administration, 4A3-SCC-10- and 4A3-SCC-PH-formulated LNPs significantly improved mRNA delivery in livers by 87-fold and 176-fold, respectively. Moreover, 4A3-SCC-PH LNPs enabled the highly efficient gene editing of 99% hepatocytes at a low Cre mRNA dose in tdTomato mice following intravenous administration. Meanwhile, 4A3-SCC-PH LNPs were able to selectively deliver firefly luciferase mRNA and facilitate luciferase expression in tumor cells after intraperitoneal injection, further improving cancer metastasis delineation and surgery via bioluminescence imaging. We envision that the chemistry adopted here can be further extended to develop new biodegradable ionizable lipids for broad applications such as gene editing and cancer immunotherapy.

"Dual-Key-and-Lock" NIR-II NSCyanines Enable High-Contrast Activatable Phototheranostics in Extrahepatic Diseases.

Conventional cyanine dyes with a symmetric structure are "always-on", which can easily accumulate in the liver and display high liver background fluorescence, inevitably interfering the accurate diagnosis and therapy in extrahepatic diseases. We herein report a platform of NIR-II non-symmetric cyanine (NSCyanine) dyes by harnessing a non-symmetric strategy, which are extremely sensitive to pH/viscosity and can be activated via a "dual-key-and-lock" strategy. These NSCyanine dyes with a low pKa (<4.0) only show weak fluorescence at lysosome pH (key1), however, the fluorescence can be completely switched on and significantly enhanced by intracellular viscosity (key2) in disease tissues, exhibiting high target-to-liver ratios up to 19.5/1. Notably, high-contrast phototheranostics in extrahepatic diseases are achieved, including intestinal metastasis-imaging, acute gastritis-imaging, bacteria infected wound healing, and tumor ablation via targeted combined photothermal therapy and chemotherapy.

Androgen receptor, a possible anti-infective therapy target and a potent immune respondent in SARS-CoV-2 spike binding: a computational approach.

BACKGROUND: Although androgen in gender disparity of COVID-19 has been implied, no direct link has been provided. RESEARCH DESIGN AND METHODS: Here, we applied AlphaFold multimer, network and single cells database analyses to highlight specificity of Androgen receptor (AR) against spike receptor binding protein (RBD) of SARS-CoV-2. RESULTS: LXXL motifs in spike RBD are essential for AR binding. RBD LXXA mutation complex with the AR depicting slightly reduced binding energy, as LXXLL motif usually mediates nuclear receptor binding to coregulators. Moreover, AR preferred to bind a LYRL motif in specificity and interaction interface, and showed reduced affinity against Omicron compared to other variants (alpha, beta, gamma, and delta). Importantly, RBD LYRL motif is a conserved antigenic epitope (9 residues) for T-cell response. Network analysis of AR-related genes against COVID-19 database showed T-cell signaling regulation, and CD8+ T-cell spatial location in AR+ single cells, which is consistent with the AR binding motif LYRL in epitope function. CONCLUSIONS: We provided the potent mechanisms of AR binding to RBD linking to immune response and vaccination shift. AR could be an anti-infective therapy target for anti-Omicron new lineages.

Factors Associated with Medication Adherence among Community-Dwelling Older People with Frailty and Pre-Frailty in China.

BACKGROUND: Frail and pre-frail older people often need to take medications. However, factors related to medication adherence among this population remain unclear, warranting further research. This study aims to identify correlates of medication adherence among frail and pre-frail older adults. METHODS: From November 2020 to December 2020; a total of 4218 community-dwelling residents aged ≥ 60 years were interviewed by a cross-sectional survey in China. Data on subjects' general information; medication adherence; and frailty status was obtained via the face-to-face structured questionnaire. Logistic regression models were fitted; separately; to examine these factors linked to medication adherence. RESULTS: We found that 36.2% (n = 1527) and 18.8% (n = 792) of respondents were classified as pre-frail and frail. According to the Morisky scale scores, 66.74% (n = 2815) were found to have adequate medication adherence, and 33.26% (n = 1403) were found to have inadequate medication adherence. Among the pre-frail respondents, age (adjusted odds ratio (AOR) = 1.64; 95% confidence interval (CI): 1.18-2.29, P = 0.003), marital status (AOR = 1.52; 95% CI: 1.04-2.21, P = 0.030), smoking status (AOR = 0.61; 95% CI: 0.37-0.99, P = 0.044), and functional ability (AOR = 0.72; 95% CI: 0.58-0.91, P = 0.006) were significantly related to medication adherence. Among them, advanced age and single were risk factors, which were positively related to the medication adherence of subjects in pre-frailty, while quitting smoking and limited functional ability contributed to improving their medication adherence. In contrast, only age (AOR = 1.77; 95% CI: 1.16-2.69, P = 0.008) was significantly associated with medication adherence among frail subjects. CONCLUSION: Influencing factors to medication adherence of old people in pre-frailty and frailty have been enriched, which provides a certain reference for promoting medication adherence in this population. Future adherence intervention methods should be designed based on these factors.

Three Birds with One Stone: Acceptor Engineering of Hemicyanine Dye with NIR-II Emission for Synergistic Photodynamic and Photothermal Anticancer Therapy.

It is challenging to develop a near-infrared (NIR) small molecular photosensitizer for synergistic phototherapy in deep tissues. Herein, first, a heavy-atom-free NIR hemicyanine photosensitizer (BHcy) for 808 nm light-mediated synergistic photodynamic therapy/photothermal therapy (PDT/PTT) anticancer therapy by leveraging the acceptor engineering strategy is reported. This strategy endows BHcy with a more planar and larger π-conjugated structure, resulting in long NIR absorption/emission at 770/915-1200 nm as well as enhanced singlet oxygen (1 O2 ) generation ability and photothermal effect, which is ascribed to the reduced energy levels of excited singlet/triplet states and the promoted intersystem crossing process. Notably, BHcy-based nanoparticles (BHcy-NPs) exhibit efficient 1 O2 yield (12.9%) and high photothermal conversion efficiency (55.1%). More importantly, BHcy-NPs are able to significantly kill cancer cells by destroying main organelles and inhibit tumor growth in vivo after a single irradiation. Overall, this study provides a strategy to design new heavy-atom-free PDT/PTT agents for potential clinical applications.

Bichromatic Imaging with Hemicyanine Fluorophores Enables Simultaneous Visualization of Non-alcoholic Fatty Liver Disease and Metastatic Intestinal Cancer.

Simultaneous detection of different diseases via a single fluorophore is challenging. We herein report a bichromatic fluorophore named Cy-914 for the simultaneous diagnosis of non-alcoholic fatty liver disease (NAFLD) and metastatic intestinal cancer by leveraging its NIR-I/NIR-II dual-color imaging capability. Cy-914 with a pKa of 6.98 exhibits high sensitivity to pH and viscosity, showing turn-on NIR-I fluorescence at 795 nm in an acidic tumor microenvironment, meanwhile displaying intense NIR-II fluorescence at 914/1030 nm under neutral to slightly basic viscous conditions. Notably, Cy-914 could sensitively and noninvasively monitor viscosity variations in the progression of NAFLD. More importantly, it was able to simultaneously visualize NAFLD (ex/em = 808/1000-1700 nm) and intestinal metastases (ex/em = 570/810-875 nm) in two independent channels without spectral cross interference after topical spraying, further improving fluorescence-guided surgery of tiny metastases less than 3 mm. This strategy may provide an understanding for developing multi-color fluorophores for multi-disease diagnosis.

The expression, clinical relevance, and prognostic significance of HJURP in cholangiocarcinoma.

Background: Cholangiocarcinoma (CCA) is the malignancy originating from the biliary epithelium, including intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA) CCA. The prognosis of CCA is very poor, and the biomarkers of different CCA subsets should be investigated separately. Holliday junction recognition protein (HJURP) is a key component of the pre-nucleosomal complex, which is responsible for normal mitosis. The ectopic expression of HJURP has been reported in several cancers, but not CCA. Materials and methods: In our study, we investigated the expression of HJURP in 127 CCA patients which were composed of 32 iCCAs, 71 pCCAs, and 24 dCCAs with immunohistochemistry and divided these patients into subgroups with a low or high expression of HJURP. With chi-square test and univariate and multivariate analyses, we evaluated the clinical relevance and prognostic significance of HJURP in iCCAs, pCCAs, and dCCAs. Results: HJURP was ectopically upregulated in CCAs compared with the para-tumor tissues based on TCGA and other mRNA-seq databases. A high expression of HJURP was correlated with low overall survival rates of iCCA and pCCA, but not in dCCA. Moreover, HJURP was an independent prognostic biomarker in both iCCA and pCCA. Patients with high HJURP were more likely to suffer CCA-related death after operation. Conclusions: HJURP was an independent prognostic biomarker in both iCCA and pCCA, but not in dCCA. Our results provide more evidence of the molecular features of different CCA subsets and suggest that patients with high HJURP are more high-risk, which can guide more precision follow-up and treatment of CCA.

The morphological mapping of lateral compression type 1 pelvic fracture and pelvic ring stability classification: a finite element analysis.

PURPOSE: This finite element analysis assessed lateral compression (LC-1) fracture stability using machine learning for morphological mapping and classification of pelvic ring stability. METHODS: Computed tomography (CT) files of LC-1 pelvic fractures were collected. After morphological mapping and producing matrix data, we used K-means clustering in unsupervised machine learning to classify the fractures. Based on these subtypes, we manually added fracture lines in ANSYS software. Finally, we performed a finite element analysis of a normal pelvis and eight fracture subtypes based on von Mises stress and total deformation changes. RESULTS: A total of 218 consecutive cases were analyzed. According to the three main factors-zone of sacral injury and completion, pubic ramus injury side, and the sagittal rotation of the injured hemipelvis-the LC-1 injuries were classified into eight subtypes (I-VIII). No significant differences in stress or deformation were observed between unilateral and bilateral public ramus fractures. Subtypes VI and VIII showed the maximum stress while subtypes V-VIII showed the maximum deformation in the total pelvis and sacrum. The subtypes did not differ in superior public ramus deformation. CONCLUSIONS: Complete fracture of sacrum zones 2/3 may be a feature of unstable LC-1 fractures. Surgeons should give surgical strategies for subtypes V-VIII.

Development of pH-activatable fluorescent probes for rapid visualization of metastatic tumours and fluorescence-guided surgery via topical spraying.

A series of pH-activatable aza-BODIPY-based fluorescent probes were developed for rapid cancer visualization and real-time fluorescence-guided surgery by harnessing topical spraying. These probes exhibited good water-solubility, a tunable pKa from 5.0 to 7.9, and stable intense NIR emission at ∼725 nm under acidic conditions. AzaB5 with a pKa value of 6.7 was able to rapidly and clearly visualize pulmonary and abdominal metastatic tumours including tiny metastases less than 2 mm via topical spraying, further improving intraoperative fluorescence-guided resection. We believe that AzaB5 is promising as a powerful tool to rapidly delineate a broad range of malignancies and assist surgical tumour resection.

Meroterpenoid enantiomers from Ganoderma sinensis.

Zizhines A-F (1-6), six pairs of new meroterpenoid enantiomers and a known meroterpenoid (7) were isolated from the fruiting bodies of Ganoderma sinensis. The structures and absolute configurations of the new substances were assigned by spectroscopic and computational methods. All the compounds apart from 7 were evaluated for their inhibition on extracellular matrix component (fibronectin) generation by using TGF-ß1-induced rat kidney tubular epithelial cells. Although none of them was found to be active in these cells, the present findings add new facets for the chemistry of Ganoderma.