Activating Metal-Organic Cages by Incorporating Functional M(ImPhen)3 Metalloligands: From Structural Design to Applications.

ConspectusThe emulation of ingenious biofunctions has been a research focus for several decades. Metal-organic cages (MOCs), as a type of discrete supramolecular assembly with well-defined shapes and cavities, have aroused great interest in chemists to imitate natural protein cages or enzymes. However, to genuinely achieve tailored functionalities or reactivities of enzymes, the design of cage structures combining both the confined microenvironment and the active site is a prerequisite. Therefore, the integration of functionalized motifs into MOCs is expected to provide a feasible approach to construct biofunctional confined nanospaces, which not only allows the modulation of cage properties for applications such as molecular recognition, transport, and catalysis but also creates unique microenvironments that promote enzymatic effects for special reactivities and selectivities, thereby providing a versatile platform to achieve exceptional biomimetic functions and beyond.In this Account, we specifically focus on our research toward engineering active confined-nanospaces in MOCs via incorporation of M(ImPhen)3 metalloligands, a typical tris-chelate coordination moiety comprising imidazophenanthroline ligands and variable metal ions, as the principle functional units for stepwise assembly of active-MOCs. Starting from their structure design and merits, we describe the versatility of M(ImPhen)3 centers for multifunctionalization of the confined cage-nanospaces. By integrating different metal ions like Ru, Os, Fe, Co, Ni, Zn, the metal ion inherent properties, e.g., redox activity of Fe/Co-centers, chirality, and photoactivity of Ru-centers, and dynamics of Co/Zn-centers, could be integrated and tailored on the cages as isostructural nanosized containers or reactors. Changing the Pd or Pt cage vertices to organic clips could remarkably enhance acid-base stability and endow cages with flexibility and allostery. Utilization of ImPhen organic ligands containing imidazole groups introduces proton transfer capability, which can couple with the high-positive charges on the cage to create amphoteric microenvironments in the porous open-cage solution. Moreover, the nonplanar stereoconfiguration of M(ImPhen)3 confers multiple peripheral pockets on the cage, which render multisite, high-order, and dynamics guest binding for the benefit of applications such as drug delivery, molecular separation, and catalytic turnover.The construction of active-MOCs from tailorable M(ImPhen)3 metalloligands provides us with a new perspective on their structural design and functionalities. Merging the cage confinement with distinct physicochemical properties on a supramolecular level makes it practical to realize synergistic and cooperative effects for functionality enhancement beyond molecular components or the reactivity different from the bulky solution, which could largely expand the potential of MOCs as a multirole platform to wide application scenarios such as artificial photosynthesis, unconventional catalysis, and theranostic nanomedicine.

Promoting WLED-Excited High Temperature Long Afterglow by Orthogonally Anchoring Chromophores into 0D Metal-Organic Cages.

Afterglow materials have garnered significant interest due to distinct photophysical characteristics. However, it is still difficult to achieve long afterglow phosphorescence from organic molecules due to aggregation-caused quenching (ACQ) and energy dissipation. In addition, most materials reported so far have long afterglow emission only at room or even low temperatures, and mainly use UV light as an excitation source. In this work, we report a strategy to achieve high temperature long afterglow emission through the assembly of isolated 0D metal-organic cages (MOCs). In which, both ACQ and phosphorescence quenching effects are effectively mitigated by altering the stacking mode of organic chromophores through orthogonally anchoring into the edges of cubic MOCs. Furthermore, improvement in molecular rigidity, promotion of spin-orbit coupling and broadening of the absorption range are achieved through the MOC- engineering strategy. As a result, we successfully synthesized MOCs that can produce afterglow emission even after excitation by WLEDs at high temperatures (380 K). Moreover, the MOCs are capable of generating afterglow emissions when excited by mobile phone flashlight at room temperature. Given these features, the potential applications of MOCs in the visual identification of explosives, information encryption and multicolor display are explored.

4D-printed shape-programmable [H+]-responsive needles for determination of urea.

Four-dimensional printing (4DP) technologies are revolutionizing the fabrication, functionality, and applicability of stimuli-responsive analytical devices. More practically, 4DP technologies are effective in fabricating devices with complex geometric designs and functions, and the degree of shape programming of 4D-printed stimuli-responsive devices can be optimized to become a reliable analytical strategy. Although shape-programming modes play a critical role in determining the analytical characteristics of 4D-printed stimuli-responsive sensing devices, the effect of shape-programming modes on the analytical performance of 4D-printed stimuli-responsive devices remains an unexplored subject. We employed digital light processing three-dimensional printing (3DP) with acrylate-based photocurable resins and 2-carboxyethyl acrylate (CEA)-incorporated photocurable resins for 4DP of the bending, helixing, and twisting needles. Upon immersion in samples with pH values above the pKa of CEA, the electrostatic repulsion among the dissociated carboxyl groups of polyCEA caused swelling of the CEA-incorporated part and [H+]-dependent shape programming. When coupling with the derivatization reaction of the urease-mediated hydrolysis of urea, the decline in [H+] induced shape programming of the needles, offering reliable determination of urea based on the shape-programming angles. After optimizing the experimental conditions, the helixing needles provided the best analytical performance, with the method's detection limit of 0.9 µM. The reliability of this analytical method was validated by determining urea in samples of human urine and sweat, fetal bovine serum, and rat plasma with spike analyses and comparing these results with those obtained from a commercial assay kit. Our demonstration and analytical results suggest the importance of optimizing the shape-programming modes to improve the analytical performance of 4D-printed stimuli-responsive shape-programming sensing devices and emphasize the benefits and applicability of 4DP technologies in advancing the development and fabrication of stimuli-responsive sensing devices for chemical sensing and quantitative chemical analyses.

Pegvaliase treatment normalizes blood neurotransmitter metabolites in adults with phenylketonuria.

Phenylketonuria (PKU) is caused by deficient activity of phenylalanine hydroxylase (PAH), the enzyme that converts phenylalanine (Phe) to tyrosine (Tyr), leading to a toxic accumulation of Phe and reduced Tyr in the blood and brain. Abnormal Phe and Tyr levels in the brain disrupt normal neurotransmitter biosynthesis and may contribute to the cognitive and psychiatric deficits observed in individuals with PKU. Blood neurotransmitter metabolites (NTMs) may serve as biomarkers that reflect neurotransmitter levels in the brain. In this study, blood NTMs correlated with brain NTMs and neurotransmitters in wild-type and PAH-deficient mice treated with PAH gene therapy. Pegvaliase is an enzyme substitution therapy that lowers blood Phe levels and is approved for individuals with PKU and uncontrolled blood Phe concentrations (>600 µmol/L) despite prior management. The current work evaluated the relationship between blood NTMs and blood Phe in pegvaliase-treated, Phase 3, PRISM-1 (NCT01819727) and PRISM-2 (NCT01889862) study participants (Pegvaliase Group; N = 109). At baseline, individuals in the Pegvaliase Group had lower levels of the NTMs homovanillic acid (HVA), 3-methoxy-4-hydroxyphenyl glycol (MOPEG), and 5-hydroxyindoleacetic acid (5HIAA), and higher levels of the NTM phenylacetylglutamine (PAG) than age- and sex-matched healthy controls. PAG levels correlated positively with Phe levels (r = 0.833; p < 0.001), while HVA, MOPEG, and 5HIAA levels correlated negatively with Phe levels (r = -0.588, -0.561, and -0.857, respectively; all p < 0.001) across all timepoints. In participants with longitudinal NTM measurements available at baseline, 12 months, and 24 months (Pegvaliase Subgroup; n = 91), blood NTM levels improved from baseline with pegvaliase treatment at 12 months and 24 months, and median levels were normalized with blood Phe level reductions below 360 µmol/L after 24 months of treatment with pegvaliase, including in participants with blood Phe <30 µmol/L. In conclusion, blood NTM levels correlated with blood Phe levels, and pegvaliase improved blood NTM levels in a large cohort of individuals with PKU.

3D-printed thermally expanded monolithic foam for solid-phase extraction of multiple trace metals.

Digital light processing (DLP) 3DP, commercial acrylate-based photocurable resins, and thermally expandable microspheres-incorporated flexible photocurable resins were employed to fabricate an SPE column with a thermally expanded monolithic foam for extracting Mn, Co, Ni, Cu, Zn, Cd, and Pb ions prior to the determination using inductively coupled plasma mass spectrometry. After optimization of the thermally activated foaming, the design and fabrication of the SPE column, and the automatic analytical system, the DLP 3D-printed SPE column with the thermally expanded monolithic foam extracted the metal ions with up to 14.8-fold enhancement (relative to that without incorporating the microspheres), with absolute extraction efficiencies all higher than 95.6%, and method detection limits in the range from 0.5 to 5.2 ng L-1. We validated the reliability and applicability of this method by determination of the metal ions in several reference materials (CASS-4, SLRS-5, 1643f, and Seronorm Trace Elements Urine L-2) and spiked seawater, river water, ground water, and human urine samples. The results illustrated that to incorporate the thermally expandable microspheres into the photocurable resins with a post-printing heating treatment enabled the DLP 3D-printed thermally expanded monolithic foam to substantially improve the extraction of the metal ions, thereby extending the applicability of SPE devices fabricated by vat photopolymerization 3DP techniques.

Chromosome-level genome assembly of Oriental chestnut gall wasp (Dryocosmus kuriphilus).

Dryocosmus kuriphilus, commonly known as the chestnut gall wasp, belongs to the family Cynipidae and is native to China. It is a highly invasive insect species causing serious damage to chestnut trees and has rapidly spread to various continents, including Europe, North America, and Oceania. The D. kuriphilus has become one of the important pests of chestnut plants in the world and is listed as a quarantine object by the European and Mediterranean Plant Protection Organization (EPPO). In this study, we used PacBio long reads, Illumina short reads, and Hi-C sequencing data to construct a chromosome-level assembly of the D. kuriphilus genome. The assembled genome includes 14,729 contigs with a total length of 2.28 Gb and a contig N50 of 0.8 Mb. With Hi-C technology, 2.17 Gb (95.02%) of contigs were anchored and oriented into the 10 pseudochromosomes with the scaffold N50 of 198.8 Mb and the scaffold N90 of 158.8 Mb. In total, 24,086 protein-coding genes were predicted in the assembled D. kuriphilus genome as the reference gene set. A total of 1.82 Gb repeats (occupying 79.7% of the genome), including 1.42 Gb of transposable elements and 0.40 Gb of tandem repeats, were identified in D. kuriphilus genome. In the evaluation of completeness, the BUSCO analysis determined a level of 98.1% completeness for the assembled genome sequences based on the Insecta database (OrthoDB version 10). The high-quality genome assembly of D. kuriphilus will not only provide a valuable reference for the study of its evolutionary history and genetic structure but also facilitate the research of host-pest interactions and invasiveness. Moreover, this genome assembly will promote in the development of effective management strategies to mitigate the economic and ecological impacts of this invasive pest on chestnut trees and ecosystems.

Decoding 11-oxygenated androgen synthesis: insights from enzyme gene expression and LC-MS/MS quantification.

BACKGROUND: Adrenal-origin and peripheral tissue-transformed 11-oxygenated androgens are recognized as significant androgens. However, our current understanding of the synthesis of 11-oxygenated androgens, including the organs and cell types involved, remains limited. METHODS: We performed comprehensive analyses on an extensive dataset of normal human tissues, which included bulk RNA data from 30 tissues, single-cell RNA sequencing (scRNA) data from 16 tissues and proteomics data from 29 tissues, to characterize the expression profiles of enzyme-encoding genes. To validate the findings, immunohistochemical and liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques were employed. RESULTS: Our investigation revealed that the gene expression levels of the enzymes HSD11B2 and AKR1C3 were notably elevated in the kidney and intestines. Intriguingly, within these organs, we observed an increasing trend in enzyme expression with age in women, while a decreasing trend was apparent in men. scRNA analysis revealed that HSD11B2 was predominantly expressed in collecting duct principal cells in the kidney, while AKR1C3 was primarily expressed in the proximal tubules. Intriguingly, nearly all epithelial cells in the intestine expressed these key enzymes. Further analysis using LC-MS/MS revealed that the kidney exhibited the highest levels of 11-ketoandrostenedione (11KA4) and 11-ketotestosterone (11KT) among the seven tissues examined, and substantial synthesis of 11KA4 and 11KT was also observed in the intestine. Finally, we developed the TransMap website (http://gxmujyzmolab.cn:16245/TransMap/) to provide comprehensive visualization of all currently available transcriptome data. CONCLUSION: This study offers an overarching perspective on tracing the synthesis of 11-oxygenated androgens in peripheral tissues, thereby providing valuable insights into the potential role of these androgens in humans.

Bismuth-based electrocatalytic scheme enabling efficient and selective electrosynthesis of 4-aminophenol in acidic media.

A highly efficient electrocatalytic platform based on in situ formed metallic bismuth submicron crystals (microBi) was developed for 4-aminophenol electrosynthesis via the electrochemical reduction of 4-nitrophenol at acidic pH. The facile formation and high reactivity of microBi enable efficient electrosynthesis of 4-aminophenol with high selectivity (∼100%) at the expense of an ultra-low overpotential.

Ultra-Microporous Fe-MOF with Prolonged NO Delivery in Biological Media for Therapeutic Application.

Nitric oxide (NO), a key element in the regulation of essential biological mechanisms, presents huge potential as therapeutic agent in the treatment and prevention of chronic diseases. Metal-organic frameworks (MOFs) with open metal sites are promising carriers for NO therapies but delivering it over an extended period in biological media remains a great challenge due to i) a fast degradation of the material in body fluids and/or ii) a rapid replacement of NO by water molecules onto the Lewis acid sites. Here, a new ultra-narrow pores Fe bisphosphonate MOF, denoted MIP-210(Fe) or Fe(H2O)(Hmbpa) (H4mbpa = p-xylenediphosphonic acid) is described that adsorbs NO due to an unprecedented sorption mechanism: coordination of NO through the Fe(III) sites is unusually preferred, replacing bound water, and creating a stable interaction with the free H2O and P-OH groups delimiting the ultra-narrow pores. This, associated with the high chemical stability of the MOF in body fluids, enables an unprecedented slow replacement of NO by water molecules in biological media, achieving an extraordinarily extended NO delivery time over at least 70 h, exceeding by far the NO kinetics release reported with others porous materials, paving the way for the development of safe and successful gas therapies.

Shirt-color recognition for the color-blindness.

Color-blind is a generic disability whereby the affected individuals are not given the opportunity to benefit from the various functions provided by color that would impact humans physically and psychologically. Although this disability is not fatal, it brought plenty of turbulence in the affected individuals' daily activities. This paper aims to develop a system for recognizing and detecting colors of clothes in images, improve accuracy by using advanced algorithms to handle lighting variations, and provide color matching recommendations to assist color-blind individuals in making informed choices when purchasing shirts. The proposed methodology for color recognition involves:•retrieving the RGB values of a given point from the input image and converting them into HSV values.•creating web application integrated with a machine learning model to classify and predict the corresponding color based on the HSV values.•predicting the color name with suggestions of matching colors will be displayed on the interface.

Decoding Human Somatosensory Sensitivity Through Resting EEG and Behavioral Analysis: A Multimodal Fusion Approach.

In precision medicine and clinical pain management, the creation of quantitative, objective indicators to assess somatosensory sensitivity was essential. This study proposed a fusion approach for decoding human somatosensory sensitivity, which combined multimodal (quantitative sensory test and neurophysiology) features to classify the dataset on individual somatosensory sensitivity and reveal distinct types of brain activation patterns. Sixty healthy participants took part in the experiment on somatosensory sensitivity that implemented cold, heat, mechanical punctate, and pressure stimuli, and the resting-state electroencephalography (EEG) was collected using BrainVision. The quantitative sensory testing (QST) scores of the participants were clustered using the unsupervised k-means algorithm into four subgroups: generally hypersensitive (HS), generally non-sensitive (NS), predominantly thermally sensitive (TS), and predominantly mechanically sensitive (MS). Furthermore, two types of power spectral density (PSD), band-based PSD (BB-PSD) and frequency-based PSD (FB-PSD), and two types of inter-electrode connectivity (IEC), band-based connectivity (BBC) and frequency-based connectivity (FBC), derived from resting-state EEG were subjected to feature selection with a proposed prior-compared minimum-redundancy maximum-relevance (PCMRMR) protocol. Their effectiveness was then tested by the supervised classification tasks using support vector machine (SVM), k-nearest neighbor (kNN), random forest (RF), and Gaussian classifier (GC). Brain networks of four somatosensory types were revealed by decoding fused multimodal data, namely type-averaged connectivity. The data from sixty healthy individuals were divided into training (n =59) and validation (n =1) datasets according to leave-one-subject-out (LOSO) criteria. The FBC was identified, which can serve as better brain signatures than BB-PSD, FB-PSD, and BBC to classify subjects as HS, NS, TS, or MS groups. Using the SVM, kNN, RF, and GC models, the best accuracy of 87% was obtained when classifying participants into HS, NS, TS, or MS groups. Moreover, the brain networks were decoded from HS, NS, TS, and MS groups by decoding the type-averaged connectivity fused from somatosensory phenotypes and selected FBC. It indicated that quantified multi-parameter somatosensory sensitivity could be achieved with acceptable accuracy, leading to considerable possibilities for using objective pain perception evaluation in clinical practice.

Multipocket Cage Enables the Binding of High-Order Bulky and Drug Guests Uncovered by MS Methodology.

Achieving high guest loading and multiguest-binding capacity holds crucial significance for advancement in separation, catalysis, and drug delivery with synthetic receptors; however, it remains a challenging bottleneck in characterization of high-stoichiometry guest-binding events. Herein, we describe a large-sized coordination cage (MOC-70-Zn8Pd6) possessing 12 peripheral pockets capable of accommodating multiple guests and a high-resolution electrospray ionization mass spectrometry (HR-ESI-MS)-based method to understand the solution host-guest chemistry. A diverse range of bulky guests, varying from drug molecules to rigid fullerenes as well as flexible host molecules of crown ethers and calixarenes, could be loaded into open pockets with high capacities. Notably, these hollow cage pockets provide multisites to capture different guests, showing heteroguest coloading behavior to capture binary, ternary, or even quaternary guests. Moreover, a pair of commercially applied drugs for the combination therapy of chronic lymphocytic leukemia (CLL) has been tested, highlighting its potential in multidrug delivery for combined treatment.

Molecular engineering of a theranostic molecule that detects Aß plaques, inhibits Iowa and Dutch mutation Aß self-aggregation and promotes lysosomal biogenesis for Alzheimer's disease.

Extracellular clustering of amyloid-ß (Aß) and an impaired autophagy lysosomal pathway (ALP) are the hallmark features in the early stages of incurable Alzheimer's disease (AD). There is a pressing need to find or develop new small molecules for diagnostics and therapeutics for the early stages of AD. Herein, we report a small molecule, namely F-SLCOOH, which can bind and detect Aß1-42, Iowa mutation Aß, Dutch mutation Aß fibrils and oligomers exhibiting enhanced emission with high affinity. Importantly, F-SLCOOH can readily pass through the blood-brain barrier and shows highly selective binding toward the extracellular Aß aggregates in real-time in live animal imaging of a 5XFAD mice model. In addition, a high concentration of F-SLCOOH in both brain and plasma of wildtype mice after intraperitoneal administration was found. The ex vivo confocal imaging of hippocampal brain slices indicated excellent colocalization of F-SLCOOH with Aß positive NU1, 4G8, 6E10 A11 antibodies and THS staining dye, affirming its excellent Aß specificity and targetability. The molecular docking studies have provided insight into the unique and specific binding of F-SLCOOH with various Aß species. Importantly, F-SLCOOH exhibits remarkable anti-fibrillation properties against toxic Aß aggregate formation of Aß1-42, Iowa mutation Aß, and Dutch mutation Aß. F-SLCOOH treatment also exerts high neuroprotective functions and promotes autophagy lysosomal biogenesis in neuronal AD cell models. In summary, the present results suggest that F-SLCOOH is a highly promising theranostic agent for diagnosis and therapeutics of AD.

Stereochemical Control of Redox CoII/CoIII-Cages with Switchable Cotton Effects Based on Labile-Static States.

The structural dynamics of artificial assemblies, in aspects such as molecular recognition and structural transformation, provide us with a blueprint to achieve bioinspired applications. Here, we describe the assembly of redox-switchable chiral metal-organic cages Λ8/Δ8-[Pd6(CoIIL3)8]28+ and Λ8/Δ8-[Pd6(CoIIIL3)8]36+. These isomeric cages demonstrate an on-off chirality logic gate controlled by their chemical and stereostructural dynamics tunable through redox transitions between the labile CoII-state and static CoIII-state with a distinct Cotton effect. The transition between different states is enabled by a reversible redox process and chiral recognition originating in the tris-chelate Co-centers. All cages in two states are thoroughly characterized by NMR, ESI-MS, CV, CD, and X-ray crystallographic analysis, which clarify their redox-switching behaviors upon chemical reduction/oxidation. The stereochemical lability of the CoII-center endows the Λ8/Δ8-CoII-cages with efficient chiral-induction by enantiomeric guests, leading to enantiomeric isomerization to switch between Λ8/Δ8-CoII-cages, which can be stabilized by oxidation to their chemically inert forms of Λ8/Δ8-CoIII-cages. Kinetic studies reveal that the isomerization rate of the Δ8-CoIII-cage is at least an order of magnitude slower than that of the Δ8-CoII-cage even at an elevated temperature, while its activation energy is 16 kcal mol-1 higher than that of the CoII-cage.

Hsa-miR-134-5p predicts cardiovascular risk in circulating mononuclear cells and improves angiogenic action of senescent endothelial progenitor cells.

This research explores the role of microRNA in senescence of human endothelial progenitor cells (EPCs) induced by replication. Hsa-miR-134-5p was found up-regulated in senescent EPCs where overexpression improved angiogenic activity. Hsa-miR-134-5p, which targeted transforming growth factor ß-activated kinase 1-binding protein 1 (TAB1) gene, down-regulated TAB1 protein, and inhibited phosphorylation of p38 mitogen-activated protein kinase (p38) in hsa-miR-134-5p-overexpressed senescent EPCs. Treatment with siRNA specific to TAB1 (TAB1si) down-regulated TAB1 protein and subsequently inhibited p38 activation in senescent EPCs. Treatment with TAB1si and p38 inhibitor, respectively, showed angiogenic improvement. In parallel, transforming growth factor Beta 1 (TGF-ß1) was down-regulated in hsa-miR-134-5p-overexpressed senescent EPCs and addition of TGF-ß1 suppressed the angiogenic improvement. Analysis of peripheral blood mononuclear cells (PBMCs) disclosed expression levels of hsa-miR-134-5p altered in adult life, reaching a peak before 65 years, and then falling in advanced age. Calculation of the Framingham risk score showed the score inversely correlates with the hsa-miR-134-5p expression level. In summary, hsa-miR-134-5p is involved in the regulation of senescence-related change of angiogenic activity via TAB1-p38 signalling and via TGF-ß1 reduction. Hsa-miR-134-5p has a potential cellular rejuvenation effect in human senescent EPCs. Detection of human PBMC-derived hsa-miR-134-5p predicts cardiovascular risk.

Galactokinase 1 is the source of elevated galactose-1-phosphate and cerebrosides are modestly reduced in a mouse model of classic galactosemia.

Classic galactosemia (CG) arises from loss-of-function mutations in the Galt gene, which codes for the enzyme galactose-1-phosphate uridylyltransferase (GALT), a central component in galactose metabolism. The neonatal fatality associated with CG can be prevented by galactose dietary restriction, but for decades it has been known that limiting galactose intake is not a cure and patients often have lasting complications. Even on a low-galactose diet, GALT's substrate galactose-1-phosphate (Gal1P) is elevated and one hypothesis is that elevated Gal1P is a driver of pathology. Here we show that Gal1P levels were elevated above wildtype (WT) in Galt mutant mice, while mice doubly mutant for Galt and the gene encoding galactokinase 1 (Galk1) had normal Gal1P levels. This indicates that GALK1 is necessary for the elevated Gal1P in CG. Another hypothesis to explain the pathology is that an inability to metabolize galactose leads to diminished or disrupted galactosylation of proteins or lipids. Our studies reveal that levels of a subset of cerebrosides-galactosylceramide 24:1, sulfatide 24:1, and glucosylceramide 24:1-were modestly decreased compared to WT. In contrast, gangliosides were unaltered. The observed reduction in these 24:1 cerebrosides may be relevant to the clinical pathology of CG, since the cerebroside galactosylceramide is an important structural component of myelin, the 24:1 species is the most abundant in myelin, and irregularities in white matter, of which myelin is a constituent, have been observed in patients with CG. Therefore, impaired cerebroside production may be a contributing factor to the brain damage that is a common clinical feature of the human disease.

Unfolding the mysteries of heterogeneity from a high-resolution perspective: integration analysis of single-cell multi-omics and spatial omics revealed functionally heterogeneous cancer cells in ccRCC.

The genomic landscape of clear cell renal cell carcinoma (ccRCC) has a considerable intra-tumor heterogeneity, which is a significant obstacle in the field of precision oncology and plays a pivotal role in metastasis, recurrence, and therapeutic resistance of cancer. The mechanisms of intra-tumor heterogeneity in ccRCC have yet to be fully established. We integrated single-cell RNA sequencing (scRNA-seq) and transposase-accessible chromatin sequencing (scATAC-seq) data from a single-cell multi-omics perspective. Based on consensus non-negative matrix factorization (cNMF) algorithm, functionally heterogeneous cancer cells were classified into metabolism, inflammatory, and EMT meta programs, with spatial transcriptomics sequencing (stRNA-seq) providing spatial information of such disparate meta programs of cancer cells. The bulk RNA sequencing (RNA-seq) data revealed high clinical prognostic values of functionally heterogeneous cancer cells of three meta programs, with transcription factor regulatory network and motif activities revealing the key transcription factors that regulate functionally heterogeneous ccRCC cells. The interactions between varying meta programs and other cell subpopulations in the microenvironment were investigated. Finally, we assessed the sensitivity of cancer cells of disparate meta programs to different anti-cancer agents. Our findings inform on the intra-tumor heterogeneity of ccRCC and its regulatory networks and offers new perspectives to facilitate the designs of rational therapeutic strategies.

Senescence induces miR-409 to down-regulate CCL5 and impairs angiogenesis in endothelial progenitor cells.

This study explores the impact of senescence on autocrine C-C motif chemokine ligand 5 (CCL5) in human endothelial progenitor cell (EPCs), addressing the poorly understood decline in number and function of EPCs during ageing. We examined the effects of replication-induced senescence on CCL5/CCL5 receptor (CCR5) signalling and angiogenic activity of EPCs in vitro and in vivo. We also explored microRNAs controlling CCL5 secretion in senescent EPCs, its impact on EPC angiogenic activity, and validated our findings in humans. CCL5 secretion and CCR5 levels in senescent EPCs were reduced, leading to attenuated angiogenic activity. CCL5 enhanced EPC proliferation via the CCR5/AKT/P70S6K axis and increased vascular endothelial growth factor (VEGF) secretion. Up-regulation of miR-409 in senescent EPCs resulted in decreased CCL5 secretion, inhibiting the angiogenic activity, though these negative effects were counteracted by the addition of CCL5 and VEGF. In a mouse hind limb ischemia model, CCL5 improved the angiogenic activity of senescent EPCs. Analysis involving 62 healthy donors revealed a negative association between CCL5 levels, age and Framingham Risk Score. These findings propose CCL5 as a potential biomarker for detection of EPC senescence and cardiovascular risk assessment, suggesting its therapeutic potential for age-related cardiovascular disorders.

Thermal control over phosphorescence or thermally activated delayed fluorescence in a metal-organic framework.

By integrating a tailor-made donor-acceptor (D-A) ligand in a metal-organic framework (MOF), a material with unprecedented features emerges. The ligand combines a pair of cyano groups as acceptors with four sulfanylphenyls as donors, which expose each a carboxylic acid as coordination sites. Upon treatment with zinc nitrate in a solvothermal synthesis, the MOF is obtained. The new material combines temperature-assisted reverse intersystem crossing (RISC) and intersystem crossing (ISC). As these two mechanisms are active in different temperature windows, thermal switching between their characteristic emission wavelengths is observed for this material. The two mechanisms can be activated by both, one-photon absorption (OPA) and two-photon absorption (TPA) resulting in a large excitement window ranging from ultraviolet (UV) over visible light (VL) to near infrared (NIR). Furthermore, the emission features of the material are pH sensitive, such that its application potential is demonstrated in a first ammonia sensor.

Anion Modulation of Ag-Imidazole Cuboctahedral Cage Microenvironments for Efficient Electrocatalytic CO2 Reduction.

How to achieve CO2 electroreduction in high efficiency is a current challenge with the mechanism not well understood yet. The metal-organic cages with multiple metal sites, tunable active centers, and well-defined microenvironments may provide a promising catalyst model. Here, we report self-assembly of Ag4L4 type cuboctahedral cages from coordination dynamic Ag+ ion and triangular imidazolyl ligand 1,3,5-tris(1-benzylbenzimidazol-2-yl) benzene (Ag-MOC-X, X=NO3, ClO4, BF4) via anion template effect. Notably, Ag-MOC-NO3 achieves the highest CO faradaic efficiency in pH-universal electrolytes of 86.1 % (acidic), 94.1 % (neutral) and 95.3 % (alkaline), much higher than those of Ag-MOC-ClO4 and Ag-MOC-BF4 with just different counter anions. In situ attenuated total reflection Fourier transform infrared spectroscopy observes formation of vital intermediate *COOH for CO2-to-CO conversion. The density functional theory calculations suggest that the adsorption of CO2 on unsaturated Ag-site is stabilized by C-H⋅⋅⋅O hydrogen-bonding of CO2 in a microenvironment surrounded by three benzimidazole rings, and the activation of CO2 is dependent on the coordination dynamics of Ag-centers modulated by the hosted anions through Ag⋅⋅⋅X interactions. This work offers a supramolecular electrocatalytic strategy based on Ag-coordination geometry and host-guest interaction regulation of MOCs as high-efficient electrocatalysts for CO2 reduction to CO which is a key intermediate in chemical industry process.