Plasma proteometabolome in lung cancer: exploring biomarkers through bidirectional Mendelian randomization and colocalization analysis.

Unlike other cancers with widespread screening (breast, colorectal, cervical, prostate, and skin), lung nodule biopsies for positive screenings have higher morbidity with clinical complications. Development of non-invasive diagnostic biomarkers could thereby significantly enhance lung cancer management for at-risk patients. Here, we leverage Mendelian Randomization (MR) to investigate the plasma proteome and metabolome for potential biomarkers relevant to lung cancer. Utilizing bidirectional MR and co-localization analyses, we identify novel associations, highlighting inverse relationships between plasma proteins SFTPB and KDELC2 in lung adenocarcinoma (LUAD) and positive associations of TCL1A with lung squamous cell carcinoma (LUSC) and CNTN1 with small cell lung cancer (SCLC). Additionally, our work reveals significant negative correlations between metabolites such as theobromine and paraxanthine, along with paraxanthine-related ratios, in both LUAD and LUSC. Conversely, positive correlations are found in caffeine/paraxanthine and arachidonate (20:4n6)/paraxanthine ratios with these cancer types. Through single-cell sequencing data of normal lung tissue, we further explore the role of lung tissue-specific protein SFTPB in carcinogenesis. These findings offer new insights into lung cancer etiology, potentially guiding the development of diagnostic biomarkers and therapeutic approaches.

Strain-Induced Heteromorphosis Multi-Cavity Cages: Tension-Driven Self-Expansion Strategy for Controllable Enhancement of Complexity in Supramolecular Assembly.

Coordinative supramolecular cages with adjustable cavities have found extensive applications in various fields, but the cavity modification strategies for multi-functional structures are still challenging. Here, we present a tension-driven self-expansion strategy for construction of multi-cavity cages with high structural complexity. Under the regulation of strain-induced capping ligands, unprecedented heteromorphosis triple-cavity cages S2 /S4 were obtained based on a metallo-organic ligand (MOL) scaffold. The heteromorphosis cages exhibited significant higher cavity diversity than the homomorphous double-cavity cages S1 /S3 ; all of the cages were thoroughly characterized through various analytical techniques including (1D and 2D) NMR, ESI-MS, TWIM-MS, AFM, and SAXS analyses. Furthermore, the encapsulation of porphyrin in the cavities of these multi-cavity cages were investigated. This research opens up new possibilities for the architecture of heteromorphosis supramolecular cages via precisely controlled "scaffold-capping" assembly with preorganized ligands, which could have potential applications in the development of multifunctional structures with higher complexity.

Integrated analysis of murine cornea identifies JAK/STAT signaling pathway upregulated specifically in female Vitamin A Deficient mice.

The Keratoconus (KC) is a corneal ectatic disease with unclear etiology. There are increasing studies that reported its association with a variety of inflammatory mechanisms. Vitamin A(VA) is an important nutrient related to inflammation regulation, and its deficiency may cause abnormalities of the ocular surface. However, the proportion of Vitamin A deficiency(VAD) was found surprisingly high among KC patients in our clinic practice. The aim of this study is to explore the effects of VAD on the transcriptome of corneas with the help of the VAD murine model and transcriptomics techniques. Blood samples of KC patients and non-KC controls (NC) were collected and the serum VA concentrations were measured and analyzed. A total of 52 NC and 39 KC were enrolled and the comparison of serum VA showed that the proportion of VAD in KC patients was 48.7% versus 1.9% in NC group. The further analysis of gender differences showed the proportion of VAD in female KC was 88.9% versus 36.7% in KC male patients. To explore the influence of VAD on cornea, the VAD mice fed with VAD diets were used. The RNA sequencing was employed to compare the corneal transcriptomic characteristics between the VAD female mice, NC female mice, VAD male mice and NC male mice. The transcriptome analysis revealed that the upregulated differential genes were mainly enriched in the immune response related pathways in VAD female mice versus NC female mice, especially the genes of JAK-STAT signaling pathway. The downstream molecules of JAK-STAT pathway were also significant after corneal mechanical scratching in female VAD mice. While, the differential genes between VAD male mice and NC male mice were estrogen signaling pathway instead of JAK-STAT pathway. This study indicates that VAD affects the transcriptomics of murine cornea with gender differences, which specifically affects the inflammatory status of the female murine cornea.

Multi-functionalized Metallo-Supramolecular Spoked Wheels: Their Emission-Tunable Hierarchically Assembled System with Dye Molecules.

Supramolecular architectures with multiple emissive units are especially appealing due to their desired properties, such as artificial light harvesting and white-light emission. But fully achieving multi-wavelength photoluminescence in a single supramolecular architecture remains a challenge. In this paper, functionalized supramolecular architectures containing twelve metal centers and six pyrene moieties were nearly quantitatively synthesized by multi-component self-assembly and fully characterized by 1D and 2D nuclear magnetic resonance, dynamic light scattering, electrospray ionization mass spectrometry, traveling-wave ion mobility mass spectrometry, and transmission electron microscopy. Moreover, the hierarchical nano-assemblies were prepared by introducing anionic dyes to the positively charged self-assembled framework, which contained three luminescence centers, namely, pyrene, tpy-Cd coordination parts, and Sulforhodamine B anions. Such a hierarchically assembled system displayed tunable emission by taking full advantage of aggregation-induced emission enhancement, aggregation-caused quenching, and fluorescence resonance energy transfer effects and showed the diverse emission colors. This research provides a new insight for constructing multiple emissive metallo-supramolecular assemblies.

The Marriage of Sierpinski Triangles and Platonic Polyhedra.

Fractal structures with self-similarity are of fundamental importance in the fields of aesthetic, chemistry and mathematics. Here, by taking advantage of constructs the rational geometry-directed precursor design, we report the construction of two fascinating Platonic solids, the Sierpinski tetrahedron ST-T and the Sierpinski octahedron ST-O, in which each possesses a fractal Sierpinski triangle on their independent faces. These two discrete complexes are formed in near-quantitative yield from the multi-component self-assembly of truncated Sierpinski triangular kernel L1 with tribenzotriquinacene-based hexatopic and anthracene-based tetratopic terpyridine ligands (L3 and L4 ) in the presence of metal ions, respectively. The enhanced stabilities of the 3D discrete structures were investigated by gradient tandem mass spectrometry (gMS2 ). This work provides new constructs for the imitation of complex virus assemblies and for the molecular encapsulation of giant guest molecules.

Russian-Doll-Like Molecular Cubes.

Nanosized cage-within-cage compounds represent a synergistic molecular self-assembling form of three-dimensional architecture that has received particular research focus. Building multilayered ultralarge cages to simulate complicated virus capsids is believed to be a tough synthetic challenge. Here, we synthesize two large double-shell supramolecular cages by facile self-assembly of presynthesized metal-organic hexatopic terpyridine ligands with metal ions. Differing from the mixture of prisms formed from the inner tritopic ligand, the redesigned metal-organic hexatopic ligands bearing high geometric constraints that led to the exclusive formation of discrete double-shell structures. These two unique nested cages are composed of inner cubes (5.1 nm) and outer huge truncated cubes (12.0 and 13.2 nm) with six large bowl-shape subcages distributed on six faces. The results with molecular weights of 75 232 and 77 667 Da were among the largest synthetic cage-in-cage supramolecules reported to date. The composition, size and shape were unambiguously characterized by a combination of 1H NMR, DOSY, ESI-MS, TWIM-MS, TEM, AFM, and SAXS. This work provides an interesting model for functional recognition, delivery, and detection of various guest molecules in the field of supramolecular materials.

Construction of Macromolecular Pinwheels Using Predesigned Metalloligands.

Developing a methodology to build target structures is one of the major themes of synthetic chemistry. However, it has proven to be immensely challenging to achieve multilevel elaborate molecular architectures in a predictable way. Herein, we describe the self-assembly of a series of pinwheel-shaped starlike supramolecules through three rationally preorganized metalloligands L1-L3. The key octa-uncomplexed terpyridine (tpy) metalloligand L3, synthesized with an 8-fold Suzuki coupling reaction to metal-containing complexes, has four different types of terpyridines connected with three ⟨tpy-Ru2+-tpy⟩ units, making this the most subunits known so far for a preorganized module. Based on the principle of geometric complementation and the high "density of coordination sites", these metalloligands were assembled with Zn2+ ions to form a pinwheel-shaped star trigon P1, pentagram P2, and hexagram P3 with precisely controlled shapes in nearly quantitative yields. With molecular weights ranging from 16756 to 56053 Da and diameters of 6.7-13.6 nm, the structural composition, shape, and rigidity of these pinwheel-shaped architectures have been fully characterized by 1D and 2D (NMR), electrospray ionization mass spectrometry, traveling-wave ion mobility mass spectrometry, and transmission electron microscopy.

Reinforced Topological Nanoassemblies: 2D Hexagon-Fused Wheel to 3D Prismatic Metallo-Lamellar Structure with Molecular Weight of 119 K Daltons.

By a precise metallo-ligand design, the advanced coordination-driven self-assembly could succeed in the preparation of giant molecular weight of the metallo-architectures. However, the synthesis of a single discrete high-molecular-weight (>100 K Da) structure has not been demonstrated due to the insurmountable synthetic challenge. Herein, we present a two-dimensional wheel structure (W1) and a gigantic three-dimensional dodecagonal prism-like architecture (P1), which were generated by multicomponent self-assembly of two similar metallo-organic ligands and a core ligand with metal ions, respectively. The giant 2D-suprastructure W1 with six hexagonal metallacycles that fused to the central spoke wheel was first achieved in nearly quantitative yield, and then, directed by introducing a meta-substituted coordination site into the key ligand, the supercharged (36 Ru2+ and 48 Cd2+ ions) double-decker prismatic structure P1 with two wheel structure W1s serve as the surfaces and 12 connectivities serve as the edges, where a molecular weight up to 119 498.18 Da was accomplished. The expected molecular composition and size morphology was unequivocally characterized by nuclear magnetic resonance, mass spectrometry, and transmission electron microscopy investigations. The introduction of a wheel structure is able to add considerable stability and complexity to the final architecture. These well-defined scaffolds are expected to play an important role in the functional materials field, such as molecular encapsulation and medicine sustained release.

Giant Truncated Metallo-Tetrahedron with Unexpected Supramolecular Aggregation Induced Emission Enhancement.

The artificial synthesis of giant, three-dimensional, and shell-like architectures with growing complexity and novel functionalities is an especially challenging task for chemists. Fullerenes and self-assembled cages are remarkable examples that are proven milestones in the field of functional materials. Herein, we present another unique system: a giant terpyridine-based truncated metallo-tetrahedral architecture that includes densely-packed ionic pairs with a significant internal cavity. This huge metallo-tetrahedron with a molecular weight up to 70 000 Da was self-assembled simultaneously with 64 components: 12 large antler-shaped ligands (5), 4 star-shaped ligands (6), and 48 Cd2+ ions. Surprisingly, the giant tetrahedron shows broad visible emission (400-640 nm) and aggregation induced emission enhancement (AIEE) via a hierarchical assembly into highly-ordered nanoaggregates. A tunable emission color and near white-light emission in mixed solvent systems were also achieved. The present work not only affords an effective approach to the creation of giant shell-like architectures that can be used to mimic biological viruses and chemical frameworks but also provides a new class of functional metallo-architectures.

Tetraphenylethylene(TPE)-Containing Metal-Organic Nanobelt and Its Turn-on Fluorescence for Sulfide (S2-).

A metal-organic supramolecular nanobelt was synthesized by quantitative self-assembling terpyridine-functionized tetraphenylethylene (TPE) and Cd2+, which only showed a weak emission both in solution or aggregated state. Nevertheless, nanobelt complex could be transferred to a fluorescence turn-on sensor to S2- by taking advantage of the structural transformation from nanobelt to its fluorescent ligand.

Trefoiled Propeller-Shaped Spiral Terpyridyl Metal-Organic Architectures.

Constructing exquisite and intricate molecular architectures is always the pursuit of chemists. In this report, the propeller-shaped trefoil structures S1 and S2 were successfully prepared by the stepwise self-assembly of predesigned tripodal metal-organic ligands, which consist of bis(terpyridine)s-Ru2+-tris(terpyridine)s connectivities for the following complexation with Fe2+. The complexes can be described as racemic spiral assemblies with three-fold spiralism. These unique discrete metal-organic architectures were fully characterized by 1H NMR, 2D NMR spectroscopy (COSY and NOESY), diffusion-ordered NMR spectroscopy (DOSY), ESI-MS, TWIM-MS, and TEM, and their photophysical and electrochemical properties were also investigated. Further, hybrid trefoiled structure [Fe3L1L2] was detected by taking advantage of the flexibility of metal-organic ligands.

Molecular Lemniscates from Organic-Metal Terpyridine-Based Self-Assembly and Host-Guest Recognition.

The intricate discrete supramolecular architectures via two or more noncovalent interactions are very attractive for chemists. In this paper, a series of homomeric metallo-supramolecular lemniscates were prepared in nearly quantitative yields by assembling either dialkylammonium salt- or benzo-21-crown-7 (B21C7)-containing terpyridyl metallo-organic ligands with Zn2+. Furthermore, the heteromeric analogue could be obtained through two ways: (1) the cooperative interaction of coordination-driven self-assembly and host-guest recognition and (2) the transformation from homodimers to heterodimers driven by host-guest interaction. These supramolecules were characterized by nuclear magnetic resonance (NMR), diffusion-ordered NMR spectroscopy, electrospray ionization mass spectrometry, and two-dimensional (2D) ion-mobility mass spectrometry.

ERα Gene Promoter Methylation in Cognitive Function and Quality of Life of Patients With Alzheimer Disease.

OBJECTIVE: Alzheimer disease (AD) has been recognized as a progressive neurodegenerative disorder. This study aims to investigate the effects of estrogen receptor α (ERα) gene promoter methylation on the cognitive function and quality of life (QOL) of patients with AD. METHODS: A total of 132 patients with AD and 135 healthy individuals were recruited for this study. The DNA in the peripheral blood was extracted and treated with bisulfite; then methylation-specific polymerase chain reaction and reverse transcription quantitative polymerase chain reaction were performed to determine the methylation status of ERα and ERα messenger RNA (mRNA) expression, respectively. Mini-Mental State Examination (MMSE), activities of daily living (ADL), and Quality of Life-Alzheimer Disease scale were employed to evaluate the cognitive functions, ADL, and QOL of the participants. RESULTS: The methylation group showed a decrease in ERα mRNA expression. The MMSE and ADL scores were indicative of a worse cognitive function in the methylation group. The ERα promoter methylated patients showed a higher rate of abnormal ADL score, while patients in the nonmethylation group enjoyed a better QOL. CONCLUSIONS: The ERα promoter methylation is related to impaired cognitive function and QOL of patients with AD by inhibiting ERα mRNA expression and transcription.

Synthesis, Characterization, Properties and DFT Calculations of 2-(Benzo[b]thiophen-2-yl)pyridine-based Iridium(III) Complexes with Different Ancillary Ligands.

A series of new cyclometalated btp-based iridium(III) complexes with three different ancillary ligands, Ir(btp)2(bozp) (3a), Ir(btp)2(btzp) (3b) and Ir(btp)2(izp) (3c) (btp = 2-(benzo[b]thiophen-2-yl)pyridine, bozp =2-(benzo[d]oxazol-2-yl)phenol, btzp =2-(benzo[d]thiazol-2-yl)phenol, izp = 2-(2 H-indazol-2-yl)phenol), have been synthesized and fully characterized. The crystal structure of 3b has been determined by single crystal X-ray diffraction analysis. A comparative study has been carried out for complexes 3a - 3c by UV-vis absorption spectroscopy, photoluminescence spectroscopy, cyclic voltammetry and DFT calculations. This observation illustrates that the substitution of N or S in ancillary ligand can lead to a marked bathochromic shift of absorption and emission wavelengths. The spectroscopic characterisation of these complexes has been complemented by DFT and TD-DFT calculations, supporting the assignment of (3)MLCT/(3)LC to the lowest energy excited state.

High-order layered self-assembled multicavity metal--organic capsules and anti-cooperative host-multi-guest chemistry.

The construction and application of metal-organic cages with accessible internal cavities have witnessed rapid development, however, the precise synthesis of complex metal-organic capsules with multiple cavities and achievement of multi-guest encapsulation, and further in-depth comprehension of host-multi-guest recognition remain a great challenge. Just like building LEGO blocks, herein, we have constructed a series of high-order layered metal-organic architectures of generation n (n = 1/2/3/4 is also the number of cavities) by multi-component coordination-driven self-assembly using porphyrin-containing tetrapodal ligands (like plates), multiple parallel-podal ligands (like clamps) and metal ions (like nodes). Importantly, these high-order assembled structures possessed different numbers of rigid and separate cavities formed by overlapped porphyrin planes with specific gaps. The host-guest experiments and convincing characterization proved that these capsules G2-G4 could serve as host structures to achieve multi-guest recognition and unprecedentedly encapsulate up to four C60 molecules. More interestingly, these capsules revealed negative cooperation behavior in the process of multi-guest recognition, which provides a new platform to further study complicated host-multi-guest interaction in the field of supramolecular chemistry.

Multidimensional Frailty Instruments Can Predict Acute Exacerbations Within One Year in Patients with Stable Chronic Obstructive Pulmonary Disease: A Retrospective Longitudinal Study.

Background: Chronic obstructive pulmonary disease (COPD) is closely associated with frailty, and prevention of acute exacerbations is important for disease management. Moreover, COPD patients with frailty experience a higher risk of acute exacerbations. However, the frailty instruments that can better predict acute exacerbations remain unclear. Purpose: (1) To explore the factors influencing frailty and acute exacerbations in stable COPD patients, and (2) quantify the ability of multidimensional frailty instruments to predict acute exacerbations within 1 year. Patients and methods: In this retrospective longitudinal study, stable COPD patients were recruited from the outpatient department of Sichuan Provincial People's Hospital from July 2022 to June 2023. COPD patients reviewed their frailty one year ago and their acute exacerbations within one year using face-to-face interviews with a self-developed frailty questionnaire. Frailty status was assessed using the Frailty Index (FI), frailty questionnaire (FRAIL), and Clinical Frailty Scale (CFS). One-way logistic regression was used to explore the factors influencing frailty and acute exacerbations. Multivariate logistic regression was used to establish a prediction model for acute exacerbations, and the accuracy of the three frailty instruments was compared by measuring the area under the receiver operating characteristic curve (AUC). Results: A total of 120 individuals were included. Frailty incidence estimates using FI, FRAIL, and CFS were 23.3%, 11.7%, and 15.8%, respectively. The three frailty instruments showed consistency in COPD assessments (P<0.05). After adjusting for covariates, frailty reflected by the FI and CFS score remained an independent risk factor for acute exacerbations. The CFS score was the best predictor of acute exacerbations (AUC, 0.764 (0.663-0.866); sensitivity, 57.9%; specificity, 80.0%). Moreover, the combination of CFS plus FRAIL scores was a better predictor of acute exacerbations (AUC, 0.792 (0.693-0.891); sensitivity, 86.3%; specificity, 60.0%). Conclusion: Multidimensional frailty assessments could improve the identification of COPD patients at high risk of acute exacerbations and facilitate targeted interventions to reduce acute exacerbations in these patients.

Multicellular ecotypes shape progression of lung adenocarcinoma from ground-glass opacity toward advanced stages.

Lung adenocarcinoma is a type of cancer that exhibits a wide range of clinical radiological manifestations, from ground-glass opacity (GGO) to pure solid nodules, which vary greatly in terms of their biological characteristics. Our current understanding of this heterogeneity is limited. To address this gap, we analyze 58 lung adenocarcinoma patients via machine learning, single-cell RNA sequencing (scRNA-seq), and whole-exome sequencing, and we identify six lung multicellular ecotypes (LMEs) correlating with distinct radiological patterns and cancer cell states. Notably, GGO-associated neoantigens in early-stage cancers are recognized by CD8+ T cells, indicating an immune-active environment, while solid nodules feature an immune-suppressive LME with exhausted CD8+ T cells, driven by specific stromal cells such as CTHCR1+ fibroblasts. This study also highlights EGFR(L858R) neoantigens in GGO samples, suggesting potential CD8+ T cell activation. Our findings offer valuable insights into lung adenocarcinoma heterogeneity, suggesting avenues for targeted therapies in early-stage disease.

Perinatal tissue-derived exosomes ameliorate colitis in mice by regulating the Foxp3 + Treg cells and gut microbiota.

BACKGROUND: The capacity of self-renewal and multipotent differentiation makes mesenchymal stem cells (MSC) one of the most widely investigated cell lines in preclinical studies as cell-based therapies. However, the low survival rate and poor homing efficiency of MSCs after transplantation hinder the therapeutic application. Exosomes derived from MSCs have shown promising therapeutic potential in many diseases. However, the heterogeneity of MSCs may lead to differences in the function of secreting exosomes. In this study, the therapeutic effects of hUC-Exos and hFP-Exos on the DSS-induced colitis mouse model were investigated. METHODS: The colitis mouse models were randomly divided into four groups: (1) DSS administered for 7 days and euthanasia (DSS7D), (2) DSS administered for 7 days and kept for another 7 days without any treatment (DSS14D), (3) DSS administered for 7 days and followed with hUC-EVs infusion for 7 days (hUC-EVs) and (4) DSS administered for 7 days and followed with hFP-EVs infusion for 7 days (hFP-EVs). We analyzed colon length, histopathology, Treg cells, cytokines and gut microbiota composition in each group. RESULTS: A large amount of IL-6, IL-17 and IFN-γ were produced along with the decrease in the number of CD4 + Foxp3 + and CD8 + Foxp3 + cells in DSS7D group, which indicated that Th17 cells were activated and Treg cells were suppressed. We found that the number of CD4 + Foxp3 + and CD8 + Foxp3 + cells increased in order to suppress inflammation, but the length of colon did not recover and the symotoms were worsened of the colonic tissue in DSS14D group. The subsequent infusion of either hUC-Exos or hFP-Exos mediated the transformation of Treg and Th17 cells in colitis mice to maintain immune balance. The infusion of hUC-Exos and hFP-Exos also both reduced the abundance of pro-inflammatory intestinal bacterial such as Verrucomicrobia and Akkermansia muciniphila to improve colitis. CONCLUSIONS: We found that Foxp3 + Treg cells can inhibit the inflammatory response, and the over-activated Treg cells can still further damage the intestinal mucosa. hUC-Exos and hFP-Exos can control inflammation by regulating the balance between Th17 cells and Treg cells. Decreased inflammatory response improved the structure of colon wall in mice and reduced the abundance of pro-inflammatory bacteria in the intestine. The improvement of intestinal wall structure provides conditions for the reproduction of beneficial bacteria, which further contributes to the reduction of colitis.

A 5.3 nm giant metal-organic cage and its supramolecular gel for the formation of dye molecular ionic pairs.

A terpyridine-based supramolecular cage was successfully synthesized by the self-assembly of a hexapodal metal-organic ligand with Zn2+. This metallo-cage exhibited two large parallel planes on the top and bottom with diameters close to 6 nm and a face-to-face distance close to 3.5 nm, thus possessing a large cavity. Electrospray ionization mass spectrometry (ESI-MS), nuclear magnetic resonance (NMR), two-dimensional nuclear Overhauser (2D-NOESY), and diffusion-ordered (DOSY) spectroscopies as well as transmission electron microscopy (TEM) and atomic force microscopy (AFM) measurements, unambiguously supported the formation of a supramolecular cage. Furthermore, the corresponding metal-organic gel was felicitously prepared in CH3CN/H2O and displayed good adsorption performance for dye molecules.

Spatial patterns of the cap-binding complex eIF4F in human melanoma cells.

As a central node of protein synthesis, the cap-binding complex, eukaryotic translation initiation factor 4 F (eIF4F), is involved in cell homeostasis, development and tumorigenesis. A large body of literature exists on the regulation and function of eIF4F in cancer cells, however the intracellular localization patterns of this complex are largely unknown. Since different subsets of mRNAs are translated in distinct subcellular compartments, understanding the distribution of translation initiation factors in the cell is of major interest. Here, we developed an in situ detection method for eIF4F at the single cell level. By using an image-based spot feature analysis pipeline as well as supervised machine learning, we identify five distinct spatial patterns of the eIF4F translation initiation complex in human melanoma cells. The quantity of eIF4F complex per cell correlated with the global mRNA translation activity, and its variation is dynamically regulated by cell state or extracellular stimuli. In contrast, the spatial patterns of eIF4F complexes at the single cell level could distinguish melanoma cells harboring different oncogenic driver mutations. This suggests that different tumorigenic contexts differentially regulate the subcellular localization of mRNA translation, with specific localization of eIF4F potentially associated with melanoma cell chemoresistance.