Wave aberration corrections in PSF ellipticity measurements of astronomical telescopes using a multi-objective optimization.

The weak gravitational lensing (WGL) produces a shear effect on the observed galactic ellipticity that is much smaller than the endogenous ellipticity of the galaxy itself. Achieving such a high-level astronomical observation requires the superior performance of telescopes. To ensure the optical properties of telescopes to be competent in WGL detections, it is very necessary to measure point spread function (PSF) ellipticity of telescopes in labs. In this paper, a 2 m off-axis telescope that would be used to detect WGL in space is analyzed and studied. A collimator whose aperture is 2 m has been built to measure PSF ellipticity of the telescope. The wave aberrations of the collimator are roughly equal to those of the telescope, so they are important systematical errors and must be removed. However, it is difficult to precisely measure the wave aberrations of optical systems that have large apertures and long focal lengths. In addition, a 2 m flat mirror, which is indispensable to measure wave aberrations of optical systems, has significant surface errors. In this paper, a multi-objective optimization method is proposed to eliminate the effects of wave aberrations on PSF ellipticity measurements of the telescope. By constructing an equivalent model, the wave aberrations from collimators and flat mirrors can be corrected so that PSF ellipticity measurement error is reduced to within 0.01. Measurement accuracy of PSF ellipticity of the telescopes can be improved significantly.

Design of low polarization off-axis three-mirror reflective optical systems.

Off-axis optical systems have several important advantages over on-axis ones. However, high polarization aberrations, which play important roles in many applications, become critical disadvantages of off-axis systems. Thanks to the seven free design parameters, three-mirror reflective systems have a good potential to achieve low polarization. A general method to design low polarization off-axis three-mirror reflective optical systems is proposed in this paper. Based on genetic algorithms, several off-axis three-mirror systems with both low polarization aberrations and good wave aberrations are designed. The method proposed in this paper is versatile and can be used to design other types of optical systems that demand low polarization aberrations.

Systemic administration of STING agonist promotes myeloid cells maturation and antitumor immunity through regulating hematopoietic stem and progenitor cell fate.

STING is a pivotal mediator of effective innate and adaptive anti-tumor immunity; however, intratumoral administration of STING agonists have shown limited therapeutic benefit in clinical trials. The systemic effect of the intravenous delivery of STING agonists in cancer is not well-defined. Here, we demonstrated that systemic administration of STING agonist inhibited melanoma growth, improved inflammatory effector cell infiltration, and induced bone marrow mobilization and extramedullary hematopoiesis, causing widespread changes in immune components in the peripheral blood. The systemically administered STING agonist promoted HSC expansion and influenced lineage fate commitment, which was manifested as the differentiation of HSPCs was skewed toward myeloid cells at the expense of B-cell lymphopoiesis and erythropoiesis. Transcriptome analysis revealed upregulation of myeloid lineage differentiation-related and type I interferon-related genes. This myeloid-biased differentiation promoted the production and maturation of myeloid cells toward an activated phenotype. Furthermore, depletion of Gr-1+ myeloid cells attenuated the anti-tumor immunity of STING agonist. Our findings reveal the anti-tumor mechanism of systemic administration of STING agonist that involves modulating HSPC differentiation and promoting myeloid cells maturation. Our study may help explain the limited clinical activity of STING agonists administered intratumorally.

A Novel PD-L1 Antibody Promotes Antitumor Function of Peripheral Cytotoxic Lymphocytes after Radical Nephrectomy in Patients with Renal Cell Carcinoma.

The intrinsic and acquired resistance to PD-1/PD-L1 immune checkpoint blockade is an important challenge for patients and clinicians because no reliable tool has been developed to predict individualized response to immunotherapy. In this study, we demonstrate the translational relevance of an ex vivo functional assay that measures the tumor cell killing ability of patient-derived CD8 T and NK cells (referred to as "cytotoxic lymphocytes," or CLs) isolated from the peripheral blood of patients with renal cell carcinoma. Patient-derived PBMCs were isolated before and after nephrectomy from patients with renal cell carcinoma. We compared the efficacy of U.S. Food and Drug Administration (FDA)-approved PD-1/PD-L1 inhibitors (pembrolizumab, nivolumab, atezolizumab) and a newly developed PD-L1 inhibitor (H1A Ab) in eliciting cytotoxic function. CL activity was improved at 3 mo after radical nephrectomy compared with baseline, and it was associated with higher circulating levels of tumor-reactive effector CD8 T cells (CD11ahighCX3CR1+GZMB+). Treatment of PBMCs with FDA-approved PD-1/PD-L1 inhibitors enhanced tumor cell killing activity of CLs, but a differential response was observed at the individual-patient level. H1A demonstrated superior efficacy in promoting CL activity compared with FDA-approved PD-1/PD-L1 inhibitors. PBMC immunophenotyping by mass cytometry revealed enrichment of effector CD8 T and NK cells in H1A-treated PBMCs and immunosuppressive regulatory T cells in atezolizumab-treated samples. Our study lays the ground for future investigation of the therapeutic value of H1A as a next-generation immune checkpoint inhibitor and the potential of measuring CTL activity in PBMCs as a tool to predict individual response to immune checkpoint inhibitors in patients with advanced renal cell carcinoma.

Photoredox catalytic radical fluorosulfonylation of olefins enabled by a bench-stable redox-active fluorosulfonyl radical precursor.

Sulfonyl fluorides have attracted considerable and growing research interests from various disciplines, which raises a high demand for novel and effective methods to access this class of compounds. Radical flurosulfonylation is recently emerging as a promising approach for the synthesis of sulfonyl fluorides. However, the scope of applicable substrate and reaction types are severely restricted by limited known radical reagents. Here, we introduce a solid state, redox-active type of fluorosulfonyl radical reagents, 1-fluorosulfonyl 2-aryl benzoimidazolium triflate (FABI) salts, which enable the radical fluorosulfonylation of olefins under photoredox conditions. In comparison with the known radical precursor, gaseous FSO2Cl, FABI salts are bench-stable, easy to handle, affording high yields in the radical fluorosulfonylation of olefins with before challenging substrates. The advantage of FABIs is further demonstrated in the development of an alkoxyl-fluorosulfonyl difunctionalization reaction of olefins, which forges a facile access to useful ß-alkoxyl sulfonyl fluorides and related compounds, and would thus benefit the related study in the context of chemical biology and drug discovery in the future.

Erratum: MicroRNA-23a-3p Inhibits Mucosal Melanoma Growth and Progression through Targeting Adenylate Cyclase 1 and Attenuating cAMP and MAPK Pathways: Erratum.

[This corrects the article DOI: 10.7150/thno.30516.].

Alignment algorithm of nonsymmetric off-axis reflective astronomical telescopes based on the modified third-order nodal aberration theory.

For pupil-offset off-axis reflective astronomical telescopes with designed tilts and decenters, owing to the absence of symmetry, axial and lateral misalignments exhibit strong coupling. The astigmatic and coma aberration fields of the misaligned optical systems are not only effected by lateral misalignments but also closely related to axial misalignments. However, the traditional misalignment algorithm based on nodal aberration theory (NAT) usually ignore the effect of axial misalignments on the aberration fields of optical systems when constructing calculation models. As a result, the presence of axial misalignments in pupil-offset off-axis telescopes with designed tilts and decenters will invalidate the traditional NAT-based lateral misalignment algorithm, which makes it difficult to be applied to actual computer-aided alignment experiments. In order to solve this issue, on the framework of modified NAT, third-order astigmatic, third-order coma, and third-order spherical net aberration fields of pupil-offset off-axis systems with designed tilts and decenters induced by axial and lateral misalignments are separated from the total aberration fields, and their inherent relations are analytically expressed. On this basis, in order to construct a solution model that can simultaneously and quantitatively calculate the axial and lateral misalignments, a method is proposed to fit the partial derivative coefficient matrix of misalignments according to field dependence of the net aberrations induced by misalignments. The simulation and actual alignment experiments were performed on a real wide-field off-axis three-mirror telescope using the constructed solution model, which proved the feasibility of the proposed method. Simulation experiments show that for different misalignment conditions generated randomly, both axial and lateral misalignments have achieved convergent solution results. In the actual alignment experiment, the average RMS wavefront errors of the nine field of views is corrected from 1.9 λ to 0.12 λ (λ = 632.8nm) through 3-5 iterations.

EZH2 Inhibitor Enhances the STING Agonist‒Induced Antitumor Immunity in Melanoma.

STING agonists are a new class of drugs for cancer immunotherapy that activate both innate and adaptive antitumor immunity. Recently, multiple clinical trials of STING agonists have been conducted in hematological malignancies and solid tumors. However, STING is commonly suppressed in melanoma through mechanisms that remain unclear. We found that STING expression was epigenetically suppressed by H3K27me3 in melanoma, and EZH2 inhibitor could induce an H3K27 shift from trimethylation to acetylation, resulting in increased expression of STING. Furthermore, a combination of STING agonist and EZH2 inhibitor upregulated major histocompatibility complex class I expression and chemokine production. Whole-transcriptome analysis showed that IFN-1‒related genes were significantly upregulated in the combination treatment group. In addition, the combination treatment synergistically reduced tumor growth and increased CD8+ T-cell infiltration in a poorly immunogenic melanoma mouse model B16-F10. These results showed, to our knowledge, a previously unreported mechanism underlying the epigenetic regulation of STING expression in melanoma; a combination of STING agonists and EZH2 inhibitors can boost the antitumor immune response and would be a promising treatment option for patients with melanoma who are refractory to current immunotherapies.

Optical Coherence Tomography-Derived Changes in Plaque Structural Stress Over the Cardiac Cycle: A New Method for Plaque Biomechanical Assessment.

Introduction: Cyclic plaque structural stress has been hypothesized as a mechanism for plaque fatigue and eventually plaque rupture. A novel approach to derive cyclic plaque stress in vivo from optical coherence tomography (OCT) is hereby developed. Materials and Methods: All intermediate lesions from a previous OCT study were enrolled. OCT cross-sections at representative positions within each lesion were selected for plaque stress analysis. Detailed plaque morphology, including plaque composition, lumen and internal elastic lamina contours, were automatically delineated. OCT-derived vessel and plaque morphology were included in a 2-dimensional finite element analysis, loaded with patient-specific intracoronary pressure tracing data, to calculate the changes in plaque structural stress (ΔPSS) on vessel wall over the cardiac cycle. Results: A total of 50 lesions from 41 vessels were analyzed. A significant ΔPSS gradient was observed across the plaque, being maximal at the proximal shoulder (45.7 [32.3, 78.6] kPa), intermediate at minimal lumen area (MLA) (39.0 [30.8, 69.1] kPa) and minimal at the distal shoulder (35.1 [28.2, 72.3] kPa; p = 0.046). The presence of lipidic plaques were observed in 82% of the diseased segments. Larger relative lumen deformation and ΔPSS were observed in diseased segments, compared with normal segments (percent diameter change: 8.2 ± 4.2% vs. 6.3 ± 2.3%, p = 0.04; ΔPSS: 59.3 ± 48.2 kPa vs. 27.5 ± 8.2 kPa, p < 0.001). ΔPSS was positively correlated with plaque burden (r = 0.37, p < 0.001) and negatively correlated with fibrous cap thickness (r = -0.25, p = 0.004). Conclusions: ΔPSS provides a feasible method for assessing plaque biomechanics in vivo from OCT images, consistent with previous biomechanical and clinical studies based on different methodologies. Larger ΔPSS at proximal shoulder and MLA indicates the critical sites for future biomechanical assessment.

Introducing A New Class of Sulfonyl Fluoride Hubs via Radical Chloro-Fluorosulfonylation of Alkynes.

Sulfonyl fluorides have widespread applications in many important fields, including ligation chemistry, chemical biology, and drug discovery. Therefore, new methods to increase the synthetic efficiency and expand the available structures of sulfonyl fluorides are highly in demand. Here, we introduce a new and powerful class of sulfonyl fluoride hubs, ß-chloro alkenylsulfonyl fluorides (BCASF), which can be constructed via radical chloro-fluorosulfonyl difunctionalization of alkynes under photoredox conditions. BCASF molecules exhibit versatile reactivities and well undergo a series of transformations at the chloride site while keeping the sulfonyl fluoride group intact, including reduction, Suzuki coupling, Sonogashira coupling, as well as nucleophilic substitution with various nitrogen, oxygen, and sulfur nucleophiles. By using BCASF as a synthetic hub, a wide range of sulfonyl fluorides becomes readily accessible, such as cis alkenylsulfonyl fluorides, dienylsulfonyl fluorides, and ynenylsulfonyl fluorides, which are challenging or even not possible to synthesize before with the known methods. Moreover, further application of BCASF to the late-stage modification of peptides and drugs is also demonstrated.

Radical Fluorosulfonylation: Accessing Alkenyl Sulfonyl Fluorides from Alkenes.

Sulfonyl fluorides have widespread applications in many fields. In particular, their unique biological activity has drawn considerable research interest in the context of chemical biology and drug discovery in the past years. Therefore, new and efficient methods for the synthesis of sulfonyl fluorides are highly in demand. In contrast to extensive studies on FSO2+ -type reagents, a radical fluorosulfonylation reaction with a fluorosulfonyl radical (FSO2. ) remains elusive so far, probably owing to its instability and difficulty in generation. Herein, the development of the first radical fluorosulfonylation of alkenes based on FSO2 radicals generated under photoredox conditions is reported. This radical approach provides a new and general access to alkenyl sulfonyl fluorides, including structures that would otherwise be challenging to synthesize with previously established cross-coupling methods. Moreover, extension to the late-stage fluorosulfonylation of natural products is also demonstrated.

Decarboxylative thiolation of redox-active esters to free thiols and further diversification.

Thiols are important precursors for the synthesis of a variety of pharmaceutically important sulfur-containing compounds. In view of the versatile reactivity of free thiols, here we report the development of a visible light-mediated direct decarboxylative thiolation reaction of alkyl redox-active esters to free thiols based on the abundant carboxylic acid feedstock. This transformation is applicable to various carboxylic acids, including primary, secondary, and tertiary acids as well as natural products and drugs, forging a general and facile access to free thiols with diverse structures. Moreover, the direct access to free thiols affords an advantage of rapid in situ diversification with high efficiency to other important thiol derivatives such as sulfide, disulfide, thiocyanide, thioselenide, etc.

Decarboxylative Thiolation of Redox-Active Esters to Thioesters by Merging Photoredox and Copper Catalysis.

Thioesters and related thiols are critically important to biological systems and also widely employed in the synthesis of pharmaceutically important molecules and polymeric materials. However, known synthetic methods often suffer from the disadvantage of being specific only to certain substrates. Herein, we describe a facile decarboxylative thioesterification of alkyl acid derived redox-active esters by merging photoredox catalysis and copper catalysis. This reaction is applicable to a wide range of carboxylic acids, as well as natural products and drugs, allowing for the synthesis of various thioesters with diverse structures, including tertiary ones that are not accessible via traditional nucleophilic substitution from tertiary halides. Moreover, product utilization is demonstrated with a direct transformation of thioesters to sulfonyl fluorides.

Metal-free dehydrosulfurization of thioamides to nitriles under visible light.

A visible light-mediated, metal-free dehydrosulfurization reaction of thioamides to nitriles is described. This reaction features high yields, mild reaction conditions, and the use of a cheap organic dye as the photoredox catalyst and air as the oxidant.

A Functional Synonymous Variant in PDGFRA Is Associated with Better Survival in Acral Melanoma.

Purpose: Polymorphisms of genes in the platelet-derived growth factor (PDGF) signaling pathway have been found to predict cutaneous melanoma (CM) survival, but their clinical effects in acral melanoma (AM) patients have not been explored. The aim of this study was to characterize the functional effect of the tag single-nucleotide polymorphism (SNP) rs2228230:C>T and assess its association with clinical outcomes in AM patients. Methods: The effect of rs2228230:C>T on mRNA structures and codon usage values were evaluated using in silico analyses. PDGF receptor alpha (PDGFRA) expression vectors with the rs2228230:C or rs2228230:T allele were constructed to evaluate the expression and signaling activity of PDGFRA. The expression of PDGFRA in AM samples was measured using in situ RNAscope hybridization and immunohistochemical staining. The association of the rs2228230 genotype with survival was analyzed in two independent AM cohorts. Results: In silico analyses indicated that the rs2228230:T allele increases the minimum free energy and reduces synonymous codon usage. The rs2228230:T allele decreased the expression of PDGFRA by reducing the stability of its mRNA and protein as well as the signaling activity of the MAPK and PI3K/AKT pathways. PDGFRA mRNA and protein expression was significantly reduced in AM tissues with the rs2228230:T allele. The progression-free survival and overall survival of AM patients with the rs2228230:T allele were significantly longer than those of patients with the CC genotype. Conclusion: Our study indicated that rs2228230:T can reduce the expression of PDGFRA and downstream signaling activity and is associated with better survival in AM patients.

Visible-Light-Induced Deaminative Thioesterification of Amino Acid Derived Katritzky Salts via Electron Donor-Acceptor Complex Formation.

A visible-light-mediated deaminative thioesterification of amino acid derived Katritzky salts with thiobenzoic acid has been developed, which provides a novel synthetic method for the synthesis of α-mercapto acid derivatives under mild conditions. This photoredox catalyst-free generation of alkyl radicals via C-N bond cleavage is enabled by the formation of an electron-donor-acceptor (EDA) complex between the Katritzky salt and thiobenzoic acid anion, which represents a new entry for EDA complex chemistry.

A rapid access to aliphatic sulfonyl fluorides.

The past few years have witnessed a fast-growing research interest on the study of sulfonyl fluorides as reactive probes in chemical biology and molecular pharmacology, which raises an urgent need for the development of effective synthetic methods to expand the toolkit. Herein, we present the invention of a facile and general approach for the synthesis of aliphatic sulfonyl fluorides via visible-light-mediated decarboxylative fluorosulfonylethylation. The method is based on abundant carboxylic acid feed stock, applicable to various alkyl carboxylic acids including primary, secondary, and tertiary acids, and is also suitable for the modification of natural products like amino acids, peptides, as well as drugs, forging a rapid, metal-free approach to build sulfonyl fluoride compound libraries of considerable structural diversity. Further diversification of the SO2F-containing products is also demonstrated, which allows for access to a range of pharmaceutically important motifs such as sultam, sulfonate, and sulfonamide.

Identification of a functional polymorphism within the 3'-untranslated region of denticleless E3 ubiquitin protein ligase homolog associated with survival in acral melanoma.

BACKGROUND: High expression of denticleless E3 ubiquitin protein ligase homologue (DTL) correlates with poor disease-free survival and overall survival in cutaneous melanoma, but the molecular features and clinical significance of this gene in acral melanoma (AM) remain unclear. METHODS: The expression levels of DTL were compared between AM and benign melanocytic nevi using existing Gene Expression Omnibus data and validated in fresh frozen tissues. Two candidate tag single-nucleotide polymorphisms (SNPs) in the 3'-untranslated region (3'UTR) of DTL in patients with AM were sequenced and analysed for their association with survival in a discovery cohort (n = 570), and the significant SNP was subjected to a replication cohort (n = 201). The expression of DTL was evaluated by immunohistochemistry. The microRNA interacting with rs11275300:C > G was predicted using in silico target prediction tools and validated by in vitro analysis. RESULTS: DTL was overexpressed in AM compared with benign melanocytic nevi. rs11275300:C > G was found to be significantly associated with progression-free survival and overall survival of patients with AM in both cohorts and the combined cohort. Furthermore, the DTL expression level in the patients with the rs11275300:G allele was higher than that in patients with the CC genotype. In vitro analysis demonstrated that DTL was a direct target of hsa-miR-4672, and the rs11275300:G allele interfered with the binding affinity of hsa-miR-4672 with the 3'UTR of DTL and thereby increased DTL expression. CONCLUSION: The rs11275300:G allele in the 3'UTR of DTL may lead to a poor prognosis and allele-specific increase in the expression of DTL by post-transcriptional regulation in AM.

miR-let-7b and miR-let-7c suppress tumourigenesis of human mucosal melanoma and enhance the sensitivity to chemotherapy.

BACKGROUND: Mucosal melanoma with poor prognosis is a common histopathologic subtype of melanoma among Chinese and other Asian peoples. Regulated microRNAs (miRNAs) have been reported as oncogenes or tumour suppressors in melanoma. However, the roles of specific miRNAs in mucosal melanoma remain largely unknown. Here, we aimed to assess the biological functions, molecular mechanisms and clinical potential of miR-let-7b and miR-let-7c in mucosal melanoma. METHODS: The expression of miR-let-7b and miR-let-7c in mucosal melanoma was determined by quantitative polymerase chain reaction (qPCR). Cutoff scores for miR-let-7b and miR-let-7c expressions were calculated through receiver operating characteristic (ROC) curve analysis in 106 mucosal melanoma patients according to recurrence. Correlations of miR-let-7b and miR-let-7c expression with clinicopathological characteristics, disease-free survival (DFS) and clinical benefits after treatment were then statistically analysed. The biological functions and molecular mechanisms of miR-let-7b and miR-let-7c were studied in vitro and in vivo. RESULTS: The expression of miR-let-7b and miR-let-7c was decreased in 94 cases (88.7%) and 89 cases (84.0%) of 106 mucosal melanoma patients compared with mucosal nevi. A correlation was observed between the expression of miR-let-7b, miR-let-7c and DFS after surgery. In addition, overexpression of miR-let-7b or miR-let-7c inhibited mucosal melanoma cell growth, migration, invasion and metastasis and induced cell apoptosis and cell cycle arrest in vitro and in vivo. Mechanistically, miR-let-7b and miR-let-7c directly targeted metadherin (MTDH) and calumenin (CALU) and suppressed phospho-ERK in mucosal melanoma cells. MTDH and CALU reversed the partial function of miR-let-7b and miR-let-7c in vitro. Furthermore, progression-free survival (PFS) of mucosal melanoma patients upon temozolomide-based and paclitaxel-based chemotherapy was related to miR-let-7b and miR-let-7c expression. Overexpression of miR-let-7b or miR-let-7c in patient-derived xenograft (PDX) models and certain mucosal melanoma cells had better growth inhibition after temozolomide and paclitaxel treatment. MTDH reversed the sensitivity of miR-let-7b and miR-let-7c to paclitaxel in vitro. CONCLUSIONS: Our results suggested that miR-let-7b and miR-let-7c inhibited the recurrence of mucosal melanoma through inhibiting cell growth, migration, invasion and metastasis, inducing cell apoptosis and cell cycle arrest by targeting MTDH and CALU. In addition, miR-let-7b and miR-let-7c increased sensitivity to chemotherapeutic agents by targeting MTDH.

MicroRNA-23a-3p Inhibits Mucosal Melanoma Growth and Progression through Targeting Adenylate Cyclase 1 and Attenuating cAMP and MAPK Pathways.

Mucosal melanoma (MM) is the second most common melanoma subtype in Asian populations. Deregulation of microRNAs (miRNAs) has been extensively investigated in various cancers, including cutaneous melanoma. However, the roles of miRNAs in MM are unclear. In this study, we carried out miRNA profiling in MM, and we investigated the clinical and biological roles of miR-23a-3p in MM. Methods: miRNA expression in MM was profiled by miRNA microarray analysis. The expression of miR-23a-3p was quantitated by qRT-PCR in a cohort of 117 patients with MM, and its prognostic significance was evaluated. The biological effect of miR-23a-3p was demonstrated by both in vitro and in vivo studies through ectopic expression of miR-23a-3p. The target gene of miR-23a-3p and molecular pathway influenced by it was characterized using in silico target prediction tools, dual luciferase reporter assays, knockdown, and rescue experiments. Results: Microarray and qRT-PCR results showed that the miR-23a-3p level was substantially lower in MM, and low miR-23a-3p expression was significantly associated with poor outcomes. Ectopic expression of miR-23a-3p suppressed MM cell proliferation, migration, invasion, and tumorigenicity, indicating that miR-23a-3p has a tumor-suppressive role in MM. Mechanistic investigations identified adenylate cyclase 1 (ADCY1) as a direct target of miR-23a-3p in MM, and knockdown of ADCY1 recapitulated all the phenotypic characteristics of miR-23a-3p overexpression. Targeting of ADCY1 by miR-23a-3p resulted in the suppression of cyclic adenosine monophosphate (cAMP) and mitogen-activated protein kinase (MAPK) signaling pathways. Conclusions: Our data highlight the molecular etiology and clinical significance of miR-23a-3p in MM and reveal its major target and biological function. miR-23a-3p may represent a new prognostic biomarker or therapeutic target in MM.