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1.
J Cell Mol Med ; 28(11): e18447, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38837574

ABSTRACT

The purpose of this study was to identify the mechanisms underlying the involvement of glycolytic genes in pulmonary arterial hypertension (PAH). This study involved downloading 3 datasets from the GEO database at the National Center for Biotechnology Information. The datasets were processed to obtain expression matrices for analysis. Genes involved in glycolysis-related pathways were obtained, and genes related to glycolysis were selected based on significant differences in expression. Gene Ontology functional annotation analysis, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis, and GSEA enrichment analysis were performed on the DEGs. Combining LASSO regression with SVM-RFE machine learning technology, a PAH risk prediction model based on glycolysis related gene expression was constructed, and CIBERSORTx technology was used to analyse the immune cell composition of PAH patients. Gene enrichment analysis revealed that the DEGs work synergistically across multiple biological pathways. A total of 6 key glycolysis-related genes were selected using LASSO regression and SVM. A bar plot was constructed to evaluate the weights of the key genes and predict the risk of PAH. The clinical application value and predictive accuracy of the model were assessed. Immunological feature analysis revealed significant correlations between key glycolysis-related genes and the abundances of different immune cell types. The glycolysis genes (ACSS2, ALAS2, ALDH3A1, ADOC3, NT5E, and TALDO1) identified in this study play important roles in the development of pulmonary arterial hypertension, providing new evidence for the involvement of glycolysis in PAH.


Subject(s)
Computational Biology , Glycolysis , Pulmonary Arterial Hypertension , Humans , Glycolysis/genetics , Computational Biology/methods , Pulmonary Arterial Hypertension/genetics , Pulmonary Arterial Hypertension/metabolism , Gene Expression Profiling , Gene Regulatory Networks , Gene Ontology , Gene Expression Regulation , Databases, Genetic
2.
J Am Chem Soc ; 146(5): 3136-3146, 2024 Feb 07.
Article in English | MEDLINE | ID: mdl-38276886

ABSTRACT

Aqueous Zn batteries have recently emerged as promising candidates for large-scale energy storage, driven by the need for a safe and cost-effective technology with sufficient energy density and readily accessible electrode materials. However, the energy density and cycle life of Zn batteries have been limited by inherent chemical, morphological, and mechanical instabilities at the electrode-electrolyte interface where uncontrolled reactions occur. To suppress the uncontrolled reactions, we designed a crystalline polymer interphase for both electrodes, which simultaneously promotes electrode reversibility via fast and selective Zn transport through the adaptive formation of ion channels. The interphase comprises an ultrathin layer of crystalline poly(1H,1H,2H,2H-perfluorodecyl acrylate), synthesized and applied as a conformal coating in a single step using initiated chemical vapor deposition (iCVD). Crystallinity is optimized to improve interphase stability and Zn-ion transport. The optimized interphase enables a cycle life of 9500 for Zn symmetric cells and over 11,000 for Zn-MnO2 full-cell batteries. We further demonstrate the generalizability of this interphase design using Cu and Li as examples, improving their stability and achieving reversible cycling in both. The iCVD method and molecular design unlock the potential of highly reversible and cost-effective aqueous batteries using earth-abundant Zn anode materials, pointing to grid-scale energy storage.

3.
J Am Chem Soc ; 146(26): 17600-17605, 2024 Jul 03.
Article in English | MEDLINE | ID: mdl-38869355

ABSTRACT

Coupling two magnetic anisotropic lanthanide ions via a direct covalent bond is an effective way to realize high magnetization blocking temperature of single-molecule magnets (SMMs) by suppressing quantum tunneling of magnetization (QTM), whereas so far only single-electron lanthanide-lanthanide bonds with relatively large bond distances are stabilized in which coupling between lanthanide and the single electron dominates over weak direct 4f-4f coupling. Herein, we report for the first time synthesis of short Dy(II)-Dy(II) single bond (3.61 Å) confined inside a carbon cage in the form of an endohedral metallofullerene Dy2@C82. Such a direct Dy(II)-Dy(II) covalent bond renders a strong Dy-Dy antiferromagnetic coupling that effectively quenches QTM at zero magnetic field, thus opening up magnetic hysteresis up to 25 K using a field sweep rate of 25 Oe/s, concomitant with a high 100 s magnetization blocking temperature (TB,100s) of 27.2 K.

4.
Biochem Biophys Res Commun ; 727: 150270, 2024 Jun 20.
Article in English | MEDLINE | ID: mdl-38917617

ABSTRACT

Neuroinflammation has been implicated in cognitive deficits of neurological and neurodegenerative diseases. There is abundant evidence that the application of ghrelin, an orexigenic hormone regulating appetite and energy balance, abrogates neuroinflammation and rescues associated memory impairment. However, the underlying mechanism is uncertain. In this study, we find that both intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) administration of lipopolysaccharide (LPS) impairs spatial memory in mice. LPS treatment causes neuroinflammation and microglial activation in the hippocampus. Ghsr1a deletion suppresses LPS-induced microglial activation and neuroinflammation, and rescued LPS-induced memory impairment. Our findings thus suggest that GHS-R1a signaling may promote microglial immunoactivation and contribute to LPS-induced neuroinflammation. GHS-R1a may be a new therapeutic target for cognitive dysfunction associated with inflammatory conditions.

5.
Small ; 20(16): e2307948, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38016077

ABSTRACT

Heat-set supramolecular gels exhibited totally opposite phase behaviors of dissolution upon cooling and gelation on heating. They are commonly discovered by chance and their rational design remains a great challenge. Herein, a rational design strategy is proposed to realize heat-set supramolecular hydrogelation through regulation of the hydrophilic-lipophilic balance of the system. A newly synthesized amphiphile hydrogelator with pyrene embedded in its lipophilic terminal can self-assemble into a hydrogel through a heating and cooling cycle. However, the host-guest complex of the gelator and hydrophilic γ-cyclodextrin (γ-CyD) results in a sol at room temperature. Thus, heat-set hydrogelation is realized from the sol state in a controllable manner. Heat-set gelation mechanism is revealed by exploring critical heat-set supramolecular gelation and the related findings provide a general strategy for developing new functional molecular gels with tunable hydrophilic-lipophilic balance.

6.
Eur J Clin Invest ; : e14198, 2024 Mar 19.
Article in English | MEDLINE | ID: mdl-38501711

ABSTRACT

PURPOSE: The purpose of this research is to demonstrate echinacoside promotes osteogenesis and angiogenesis and inhibits osteoclast formation. METHODS: We conducted a cell experiment in vitro to study how echinacoside affects angiogenesis, osteogenesis and osteoclast formation. We used polymerase chain reaction and Western blotting to detect the expression levels of proteins and genes related to angiogenesis, osteogenesis and osteoclast formation. We established a bone fracture model with rats to test angiogenesis, osteogenesis and osteoclast formation of echinacoside. We labelled osteogenic markers, blood vessels and osteoclastic markers in fracture sections of rats. RESULTS: The in vitro cell experiments showed echinacoside improved the osteogenic activity of mouse embryo osteoblast precursor cells and promoted the migration and tube formation of human umbilical vein endothelial cells. In addition, it inhibited differentiation of mouse leukaemia cells of monocyte macrophage. Echinacoside increased the expression of related proteins and genes and improved angiogenesis and osteogenesis while inhibiting osteoclast formation by repressing the expression of related proteins and genes. From in vivo experiments, the results of IHC and HE experiments demonstrated echinacoside significantly decreased the content of MMP-9 and improved the content of VEGF and OCN. The fluorescence immunoassay showed echinacoside promoted the activities of RUNX2 and VEGF and inhibited CTSK. Echinacoside reduced the content of TNF-α, IL-1ß and IL-6, thus demonstrating its anti-inflammatory activity. CONCLUSION: Echinacoside improved angiogenesis and osteogenesis and inhibited osteoclast formation to promote fracture healing.

7.
Exp Dermatol ; 33(1): e14812, 2024 Jan.
Article in English | MEDLINE | ID: mdl-37086043

ABSTRACT

Rosacea is a complex chronic inflammatory skin disorder with high morbidity. Pyroptosis is known as a regulated inflammatory cell death. While its association with immune response to various inflammatory disorders is well established, little is known about its functional relevance of rosacea. So, we aimed to explore and enrich the pathogenesis involved in pyroptosis-related rosacea aggravations. In this study, we evaluated the pyroptosis-related patterns of rosacea by consensus clustering analysis of 45 ferroptosis-related genes (FRGs), with multiple immune cell infiltration analysis to identify the pyroptosis-mediated immune response in rosacea using GSE65914 dataset. The co-co-work between PRGs and WGCNA-revealed hub genes has established using PPI network. FRG signature was highlighted in rosacea using multi-transcriptomic and experiment analysis. Based on this, three distinct pyroptosis-related rosacea patterns (non/moderate/high) were identified, and the notably enriched pathways have revealed through GO, KEGG and GSEA analysis, especially immune-related pathways. Also, the XCell/MCPcount/ssGSEA/Cibersort underlined the immune-related signalling (NK cells, Monocyte, Neutrophil, Th2 cells, Macrophage), whose hub genes were identified through WGCNA (NOD2, MYD88, STAT1, HSPA4, CXCL8). Finally, we established a pyroptosis-immune co-work during the rosacea aggravations. FRGs may affect the progression of rosacea by regulating the immune cell infiltrations. In all, pyroptosis with its mediated immune cell infiltration is a critical factor during the development of rosacea.


Subject(s)
Pyroptosis , Rosacea , Humans , Pyroptosis/genetics , Rosacea/genetics , Skin , Adaptor Proteins, Signal Transducing , Gene Expression Profiling
8.
Cell Mol Biol (Noisy-le-grand) ; 70(5): 155-160, 2024 May 27.
Article in English | MEDLINE | ID: mdl-38814221

ABSTRACT

In order to explore a new mode for the diagnosis of angioimmunoblastic T-cell lymphoma (AITL), 31 cases of AITL and 28 cases of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) were used as the study subjects. Identifying T follicular helper (TFH) cells with CD4, CD10, Bcl-6, and PD-1, identifying proliferative B cells with CD20 and EZH2, identifying proliferative follicular dendritic cells (FDCs) with CD21 and CD23, and analyzing the value of TFH/B/FDC proliferation and immunolocalization in the diagnosis of AITL. (1) Outside the inherent lymphoid follicles, simultaneous proliferation of TFH/B/FDC (a new diagnostic mode) were observed in AITL [83.87%; 26/31], with their immunolocalizations in the same site [83.87%; 26/31], while this phenomenon was not observed in 28 cases of PTCL-NOS (P<0.05). (2) The sensitivity and specificity of using this new mode to diagnose AITL were both high (83.87%, 100%), which was superior to CD2 (100%, 0%), CD3 (100%, 0%), CD4 (100%, 32.14%), CD5 (100%, 25%), CD10 (61.9%, 100%), Bcl-6 (42.86%, 100%), PD-1 (83.87%, 96.43%), and its Youden Index (0.84) was the highest. The areas under the curve (AUC) of CD10, Bcl-6, PD-1, and new mode to diagnosis AITL were 0.81, 0.71, 0.90, and 0.92, respectively, while the new mode had the highest AUC. The simultaneous proliferation of TFH/B/FDC cells outside the inherent lymphoid follicles can be used to assist in the diagnosis of AITL, and the simultaneous spatiotemporal proliferation of TFH/B/FDC cells is a specific immunomorphology of AITL.


Subject(s)
Proto-Oncogene Proteins c-bcl-6 , Humans , Female , Male , Middle Aged , Aged , Proto-Oncogene Proteins c-bcl-6/metabolism , Neprilysin/metabolism , Immunoblastic Lymphadenopathy/diagnosis , Immunoblastic Lymphadenopathy/pathology , Dendritic Cells, Follicular/pathology , Dendritic Cells, Follicular/metabolism , Programmed Cell Death 1 Receptor/metabolism , Adult , Lymphoma, T-Cell/diagnosis , Lymphoma, T-Cell/pathology , Lymphoma, T-Cell/metabolism , Enhancer of Zeste Homolog 2 Protein/metabolism , Cell Proliferation , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , T Follicular Helper Cells/immunology , T Follicular Helper Cells/metabolism , Receptors, Complement 3d/metabolism , Receptors, Complement 3d/analysis , Antigens, CD20/metabolism , Antigens, CD20/analysis , Lymphoma, T-Cell, Peripheral/diagnosis , Lymphoma, T-Cell, Peripheral/pathology , CD4 Antigens/metabolism , Sensitivity and Specificity , Aged, 80 and over , Immunohistochemistry/methods , ROC Curve
9.
Support Care Cancer ; 32(5): 286, 2024 Apr 13.
Article in English | MEDLINE | ID: mdl-38613655

ABSTRACT

AIM: This study aimed to explore the characteristics of stigma in postoperative oral cancer patients to provide a reference for the formulation of targeted intervention measures. METHODS: A qualitative study was conducted on 25 postoperative oral cancer patients in a tertiary A hospital in Hunan, China, from March to July 2021. Semi-structured face-to-face interviews focused on experiences of stigma were performed. The interview data was analyzed using the NVivo V.12 software based on the reflexive intuitive thematic analysis method. The paper complies with the COREQ. RESULTS: The stigma experience of postoperative oral cancer patients can be divided into 3 themes: (1) triggers (impaired appearance and oral function and psycho-social pressure); (2) forms (overall isolation, unpleasant feeling of inferiority, and unpleasant social discrimination); (3) coping strategies (positive psychological adjustment, seeking social support and coming out of the unpleasant shadows). CONCLUSION: Postoperative oral cancer patients clearly articulated that stigma was present in their lives and they experienced multiple forms of stigma. Further work is needed to increase education and awareness about oral cancer to guide them to take positive coping and reduce stigma.


Subject(s)
Mouth Neoplasms , Humans , Mouth Neoplasms/surgery , Social Stigma , Qualitative Research , China , Coping Skills
10.
J Chem Phys ; 160(14)2024 Apr 14.
Article in English | MEDLINE | ID: mdl-38597315

ABSTRACT

As initiated Chemical Vapor Deposition (iCVD) finds increasing application in precision industries like electronics and optics, defect prevention will become critical. While studies of non-ideal morphology exist in the iCVD literature, no studies investigate the role of defects. To address this knowledge gap, we show that the buildup of short-chain polymers or oligomers during normal operation of an iCVD reactor can lead to defects that compromise film integrity. We used atomic force microscopy to show that oligomer aggregates selectively prevented film growth, causing these hole-like defects. X-ray diffraction and optical microscopy demonstrated the crystallinity of the aggregates, pointing to a flat-on lamellar or mono-lamellar structure. To understand the origin of the aggregates, spectroscopic ellipsometry showed that samples exposed to the reactor consistently accrued low-volatility contaminants. X-ray photoelectron spectroscopy revealed material derived from polymerization in the contamination, while scanning electron microscopy showed the presence of defect-causing aggregates. We directly linked oligomeric/polymeric contamination with defect formation by showing an increased defect rate when a contaminant polymer was heated alongside the sample. Most importantly, we showed that starting a deposition at a high sample temperature (e.g., 50 °C) before reducing it to the desired setpoint (e.g., 9 °C) unilaterally prevented defects, providing a simple method to prevent defects with minimal impact on operations.

11.
AIDS Res Ther ; 21(1): 8, 2024 01 31.
Article in English | MEDLINE | ID: mdl-38297382

ABSTRACT

BACKGROUND: Studies on antiretroviral therapy (ART) in children living with HIV (CLHIV) are limited due to the small population and low accession rate of ART. METHODS: All 0-14-year-old CLHIV admitted to the Ganzhou Center for Disease Control and Prevention from January 2006 to June 2023 were included retrospectively. The information of treatment regimens, disease progression, and laboratory tests of the patients under ART were used to explore the outcomes and impacts of long-term ART. The normality of all the data was tested by the Shapiro-Wilk test. RESULTS: From 2006 to 2023, 18 CLHIV were reported in Ganzhou. Among them, 11 received ART and were followed up for 60.0 ± 48.4 months. After receiving ART, the median viral load of them decreased from 89,600 copies/ml to 22 copies/ml (P = 0.007), the median CD4+ T cell count increased from 380.7 cells/µL to 661.9 cells/µL (P = 0.028), and the median CD8+ T cell count decreased from 1065.8 cells/µL to 983.3 cells/µL (P = 0.584). The laboratory test results regarding liver function, renal function, blood cell count, and glucolipid metabolism tended to be within normal reference ranges, and the mean height-for-age z-score and weight-for-age z-score increased. However, all the three CLHIV who received cotrimoxazole developed pneumocystis carinii pneumonia, upper respiratory infection, skin lesions, bacterial pneumonia and/or thrush; the mean body-mass-index-for-age z-score decreased from 0.52 to -0.63. CONCLUSION: For CLHIV, ART could effectively inhibit the replication of HIV and improve the immune function of patients. More studies that focus on ART in CLHIV are urgently needed.


Subject(s)
Anti-HIV Agents , HIV Infections , Child , Humans , Infant, Newborn , Infant , Child, Preschool , Adolescent , HIV Infections/epidemiology , Retrospective Studies , Anti-Retroviral Agents/therapeutic use , Disease Progression , CD4 Lymphocyte Count , China/epidemiology , Viral Load , Anti-HIV Agents/therapeutic use
12.
Pediatr Dermatol ; 41(1): 166-168, 2024.
Article in English | MEDLINE | ID: mdl-38111302

ABSTRACT

Proteasome-associated autoinflammatory syndrome-2 (PRAAS2) is characterized by early onset combined immunodeficiency, inflammatory neutrophilic dermatosis, and autoimmunity. We report the case of a premature baby (GA 35+5 weeks) born with disseminated and confluent red papules, diagnosed with PRAAS2. A novel de novo frameshift proteasome maturation protein (POMP) mutation (c.333delT (p.t111fs)) was detected, confirming the diagnosis.


Subject(s)
Proteasome Endopeptidase Complex , Infant, Newborn , Humans , Proteasome Endopeptidase Complex/genetics , Proteasome Endopeptidase Complex/metabolism , Syndrome , Mutation
13.
J Formos Med Assoc ; 2024 Mar 23.
Article in English | MEDLINE | ID: mdl-38521760

ABSTRACT

BACKGROUND: In patients with advanced soft tissue sarcoma (STS), surgery had been reported to be associated with superior overall survival (OS). Chemotherapy details for such patients were less reported, and whether multimodal treatment with surgery and chemotherapy provides extra survival benefit remains unclear. METHODS: We retrospectively reviewed patients with newly diagnosed advanced STS treated at National Taiwan University Hospital from January 1, 2011, to December 31, 2017. OS was calculated from the day of diagnosis of advanced STS to the day of death or last follow-up. Baseline patient characteristics and details regarding surgery and chemotherapy were recorded. RESULTS: A total of 545 patients were diagnosed with STS from 2011 to 2017, of which 226 patients had advanced STS. The median age was 54.7 years, and 54% of patients were women. Approximately 38% of patients with advanced STS underwent surgery and exhibited a trend of longer OS compared with who did not (median = 18.6 vs. 11.9 months, p = 0.083). In the chemotherapy subgroup, the benefit of surgery was more prominent (median = 21.9 vs. 16.5 months, p = 0.037). Patients who received chemotherapy prior to surgery exhibited numerically longer OS than those who underwent surgery first (median = 33.9 vs. 18.3 months, p = 0.155). After adjusting other clinical factors, chemotherapy remained an independent factor associated with favourable OS. CONCLUSION: Surgery may be more beneficial for the patients who receive chemotherapy. Our results support evaluation of sequential multimodal treatments strategy including surgery and chemotherapy in patients with advanced STS.

14.
Nano Lett ; 23(7): 2764-2770, 2023 Apr 12.
Article in English | MEDLINE | ID: mdl-37010357

ABSTRACT

Two-dimensional (2D) semiconductors such as monolayer molybdenum disulfide (MoS2) are promising building blocks for ultrascaled field effect transistors (FETs), benefiting from their atomic thickness, dangling-bond-free flat surface, and excellent gate controllability. However, despite great prospects, the fabrication of 2D ultrashort channel FETs with high performance and uniformity remains a challenge. Here, we report a self-encapsulated heterostructure undercut technique for the fabrication of sub-10 nm channel length MoS2 FETs. The fabricated 9 nm channel MoS2 FETs exhibit superior performances compared with sub-15 nm channel length including the competitive on-state current density of 734/433 µA/µm at VDS = 2/1 V, record-low DIBL of ∼50 mV/V, and superior on/off ratio of 3 × 107 and low subthreshold swing of ∼100 mV/dec. Furthermore, the ultrashort channel MoS2 FETs fabricated by this new technique show excellent homogeneity. Thanks to this, we scale the monolayer inverter down to sub-10 nm channel length.

15.
Angew Chem Int Ed Engl ; 63(14): e202317167, 2024 Apr 02.
Article in English | MEDLINE | ID: mdl-38323917

ABSTRACT

Hydroxylamine (NH2OH) is an important feedstock in fuels, pharmaceuticals, and agrochemicals. Nanostructured electrocatalysts drive green electrosynthesis of hydroxylamine from nitrogen oxide species in water. However, current electrocatalysts still suffer from low selectivity and manpower-consuming trial-and-error modes, leaving unclear selectivity/activity origins and a lack of catalyst design principles. Herein, we theoretically analyze key determinants of selectivity/activity and propose the adsorption energy of NHO (Gad(*NHO)) as a performance descriptor. A weak *NH2OH binding affinity and a favorable reaction pathway (*NHO pathway) jointly enable single-atom catalysts (SACs) with superior NH2OH selectivity. Then, an activity volcano plot of Gad(*NHO) is established to predict a series of SACs and discover Mn SACs as optimal electrocatalysts that exhibit pH-dependent activity. These theoretical prediction results are also confirmed by experimental results, rationalizing our Gad(*NHO) descriptor. Furthermore, Mn-Co geminal-atom catalysts (GACs) are predicted to optimize Gad(*NHO) and are experimentally proved to enhance NH2OH formation.

16.
Angew Chem Int Ed Engl ; 63(9): e202314859, 2024 Feb 26.
Article in English | MEDLINE | ID: mdl-38224179

ABSTRACT

Liquid crystal actuators conventionally undergo shape changes across an order-disorder phase transition between liquid crystal (LC) and isotropic phases. In this study, we introduce an innovative Liquid Crystal Polymer (LCP) actuator harnessing an order-order LC phase transition mechanism. The LCP film is easily stretchable within the LC phase, facilitated by the π-π stacking of phenyl groups serving as robust physical crosslinking points, and thereby transforms to a stable monodomain structure. The resultant monodomain LCP actuator shows a distinctive reversible dynamic shape change, exhibiting extension followed by contraction along the LC director on cooling. The extension is propelled by the reversible smectic C to smectic A phase transition, and the contraction is attributed to the re-entry to the smectic C phase from smectic A phase. Thermal annealing temperature determines this peculiar dynamic shape change, which occurs during both heating and cooling processes. This pivotal attribute finds manifestation in gripper and flower-shaped actuators, adeptly executing grabbing and releasing as well as blooming and closure motions within a single thermal stimulation. In essence, our study introduces an innovative approach to the realm of LCP actuators, ushering in a new avenue for the design and fabrication of versatile and dynamically responsive LCP actuators.

17.
Angew Chem Int Ed Engl ; : e202404819, 2024 May 10.
Article in English | MEDLINE | ID: mdl-38728151

ABSTRACT

Interfacial engineering of synergistic catalysts is one of the keys to achieving multiple proton-coupled electron transfer processes in nitrate-to-ammonia conversion. Herein, by joining ultrathin nickel-based metal-organic framework (denoted Ni-MOF) nanosheets with few-layered hydrogen-substituted graphdiyne-supported copper single atoms and clusters (denoted HsGDY@Cu), a tandem catalyst of Ni-MOFs@HsGDY@Cu with dual-active interfaces was developed for the concerted catalysis of nitrate-to-ammonia. In such a system, the sandwiched HsGDY layer could serve as a bridge to connect the coordinated unsaturated Ni2+ sites with Cu single atoms/clusters in a limited range of 0 to 3.6 nm. From Ni2+ to Cu, via the hydrogen spillover process, the hydrogen radicals (H⋅) generated at the unsaturated Ni2+ sites could migrate across HsGDY to the Cu sites to participate in the transformation of *HNO3 to NH3. From Cu to Ni2+, bypassing the higher reaction energy for *HNO3 formation on the Ni2+ sites, the NO2 - detached from the Cu sites could diffuse onto the unsaturated Ni2+ sites to form NH3 as well. The combined results make this hybrid a tandem catalyst with dual active sites for the catalysis of nitrate-to-ammonia conversion with improved Faradaic efficiency at lower overpotentials.

18.
Angew Chem Int Ed Engl ; 63(9): e202317613, 2024 Feb 26.
Article in English | MEDLINE | ID: mdl-38195970

ABSTRACT

Most of the anticancer compounds synthesized by chemists are primarily evaluated for their direct cytotoxic effects at the cellular level, often overlooking the critical role of the immune system. In this study, we developed a patient-derived, T-cell-retaining tumor organoid model that allows us to evaluate the anticancer efficacy of chemical drugs under the synergistic paradigm of antigen-specific T-cell-dependent killing, which may reveal the missed drug hits in the simple cytotoxic assay. We evaluated clinically approved platinum (Pt) drugs and a custom library of twenty-eight PtIV compounds. We observed low direct cytotoxicity of Pt drugs, but variable synergistic effects in combination with immune checkpoint inhibitors (ICIs). In contrast, the majority of PtIV compounds exhibited potent tumor-killing capabilities. Interestingly, several PtIV compounds went beyond direct tumor killing and showed significant immunosynergistic effects with ICIs, outstanding at sub-micromolar concentrations. Among these, Pt-19, PtIV compounds with cinnamate axial ligands, emerged as the most therapeutically potent, demonstrating pronounced immunosynergistic effects by promoting the release of cytotoxic cytokines, activating immune-related pathways and enhancing T cell receptor (TCR) clonal expansion. Overall, this initiative marks the first use of patient-derived immunocompetent tumor organoids to explore and study chemotherapy, advancing their path toward more effective small molecule drug discovery.


Subject(s)
Antineoplastic Agents , Humans , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Platinum/chemistry , T-Lymphocytes , Organoids
19.
Angew Chem Int Ed Engl ; 63(13): e202316133, 2024 Mar 22.
Article in English | MEDLINE | ID: mdl-38279624

ABSTRACT

Biocatalytic oxidations are an emerging technology for selective C-H bond activation. While promising for a range of selective oxidations, practical use of enzymes catalyzing aerobic hydroxylation is presently limited by their substrate scope and stability under industrially relevant conditions. Here, we report the engineering and practical application of a non-heme iron and α-ketoglutarate-dependent dioxygenase for the direct stereo- and regio-selective hydroxylation of a non-native fluoroindanone en route to the oncology treatment belzutifan, replacing a five-step chemical synthesis with a direct enantioselective hydroxylation. Mechanistic studies indicated that formation of the desired product was limited by enzyme stability and product overoxidation, with these properties subsequently improved by directed evolution, yielding a biocatalyst capable of >15,000 total turnovers. Highlighting the industrial utility of this biocatalyst, the high-yielding, green, and efficient oxidation was demonstrated at kilogram scale for the synthesis of belzutifan.


Subject(s)
Indenes , Mixed Function Oxygenases , Oxidation-Reduction , Hydroxylation , Biocatalysis
20.
J Am Chem Soc ; 145(23): 12701-12716, 2023 06 14.
Article in English | MEDLINE | ID: mdl-37276352

ABSTRACT

Despite the rich information about the physiological state of a cell encoded in the dynamic changes of cell-surface glycans, chemical methods to capture specific glycan epitopes at the single-cell level are quite limited. Here, we report a chemoenzymatic method for the single-cell detection of N-acetyllactosamine (LacNAc) by labeling LacNAc with a specific DNA barcode. The chemoenzymatic labeling does not alter the transcriptional status of immune cells and is compatible with multiple scRNA-seq platforms. Integrated analysis of LacNAc and the transcriptome of T cells at the single-cell level reveals that the amount of cell-surface LacNAc is significantly upregulated in activated CD8+ T cells but maintained at basal levels in resting CD8+ T cells (i.e., naive and central memory T cells). Further analysis confirms that LacNAc levels are positively correlated with the glycolytic activity of CD8+ T cells during differentiation. Taken together, our study demonstrates the feasibility of the chemoenzymatic detection of cell-surface glycan in single-cell RNA sequencing-based multiomics with TCR sequence and cell-surface epitope information (i.e., scTCR and CITE-seq), and provides a new way to characterize the biological role of glycan in diverse physiological states.


Subject(s)
CD8-Positive T-Lymphocytes , Multiomics , Polysaccharides/chemistry , Transcriptome , Epitopes
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