The development of straightforward synthesis of regio- and stereodefined alkenes with multiple aliphatic substituents under mild conditions is an unmet challenge owing to competitive β-hydride ...elimination and selectivity issues. Herein, we report the nickel-catalyzed intermolecular cross-dialkylation of alkynes devoid of directing or activating groups to afford multiple aliphatic substituted alkenes in a syn-selective fashion at room temperature. The combination of two-electron oxidative cyclometallation and single-electron cross-electrophile coupling of nickel enables the syn-cross-dialkylation of alkynes at room temperature. This reductive protocol enables the sequential installation of two different alkyl substituents onto alkynes in a regio- and stereo-selective manner, circumventing the tedious preformation of sensitive organometallic reagents. The synthetic utility of this protocol is demonstrated by efficient synthesis of multi-substituted unfunctionalized alkenes and diverse transformations of the product.
Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases expressed on the cell membrane that play crucial roles in both developmental and adult cells. Dysregulation of ...FGFRs has been implicated in a wide variety of cancers, such as urothelial carcinoma, hepatocellular carcinoma, ovarian cancer and lung adenocarcinoma. Due to their functional importance, FGFRs have been considered as promising drug targets for the therapy of various cancers. Multiple small molecule inhibitors targeting this family of kinases have been developed, and some of them are in clinical trials. Furthermore, the pan-FGFR inhibitor erdafitinib (JNJ-42756493) has recently been approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic or unresectable urothelial carcinoma (mUC). This review summarizes the structure of FGFR, especially its kinase domain, and the development of small molecule FGFR inhibitors.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Apartial discrete Dirichlet boundary value problem involving mean curvature operator is concerned in this paper. Under proper assumptions on the nonlinear term, we obtain some feasible conditions on ...the existence of multiple solutions by the method of critical point theory. We further separately determine open intervals of the parameter to attain at least two positive solutions and an unbounded sequence of positive solutions with the help of the maximum principle.
Transition metal dichalcogenide (TMD) nanomaterials, specially MoS2, are proven to be appealing nanoagents for photothermal cancer therapies. However, the impact of the crystal phase of TMDs on their ...performance in photoacoustic imaging (PAI) and photothermal therapy (PTT) remains unclear. Herein, the preparation of ultrasmall single‐layer MoS2 nanodots with different phases (1T and 2H phase) is reported to explore their phase‐dependent performances as nanoagents for PAI guided PTT in the second near‐infrared (NIR‐II) window. Significantly, the 1T‐MoS2 nanodots give a much higher extinction coefficient (25.6 L g−1 cm−1) at 1064 nm and subsequent photothermal power conversion efficiency (PCE: 43.3%) than that of the 2H‐MoS2 nanodots (extinction coefficient: 5.3 L g−1 cm−1, PCE: 21.3%). Moreover, the 1T‐MoS2 nanodots also give strong PAI signals as compared to negligible signals of 2H‐MoS2 nanodots in the NIR‐II window. After modification with polyvinylpyrrolidone, the 1T‐MoS2 nanodots can be used as a highly efficient agent for PAI guided PTT to effectively ablate cancer cells in vitro and tumors in vivo under 1064 nm laser irradiation. This work proves that the crystal phase plays a key role in determining the performance of nanoagents based on TMD nanomaterials for PAI guided PTT.
Ultrasmall single‐layer 1T‐ and 2H‐phase MoS2 nanodots are prepared to explore their phase‐dependent photoacoustic imaging (PAI) and photothermal therapy (PTT) properties. The polyvinylpyrrolidone‐modified 1T‐MoS2 nanodots can be used as a highly efficient agent for PAI guided PTT to effectively ablate cancer cells in vitro and tumors in vivo under 1064 nm laser irradiation.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The interindividual genetic variations in drug metabolizing enzymes and transporters influence the efficacy and toxicity of numerous drugs. As a fundamental element in precision medicine, ...pharmacogenomics, the study of responses of individuals to medication based on their genomic information, enables the evaluation of some specific genetic variants responsible for an individual’s particular drug response. In this article, we review the contributions of genetic polymorphisms to major individual variations in drug pharmacotherapy, focusing specifically on the pharmacogenomics of phase-I drug metabolizing enzymes and transporters. Substantial frequency differences in key variants of drug metabolizing enzymes and transporters, as well as their possible functional consequences, have also been discussed across geographic regions. The current effort illustrates the common presence of variability in drug responses among individuals and across all geographic regions. This information will aid health-care professionals in prescribing the most appropriate treatment aimed at achieving the best possible beneficial outcomes while avoiding unwanted effects for a particular patient.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Layered metal oxides including MoO3 and WO3 have been widely explored for biological applications owing to their excellent biocompatibility, low toxicity, and easy preparation. However, they normally ...exhibit weak or negligible near‐infrared (NIR) absorption and thus are inefficient for photo‐induced biomedical applications. Herein, the structural engineering of layered MoO3 and WO3 nanostructures is first reported to activate their NIR‐II absorption for efficient photothermal cancer therapy in the NIR‐II window. White‐colored micrometre‐long MoO3 nanobelts are transformed into blue‐colored short, thin, defective, interlayer gap‐expanded MoO3−x nanobelts with a strong NIR‐II absorption via the simple lithium treatment. The blue MoO3−x nanobelts exhibit a large extinction coefficient of 18.2 L g−1 cm−1 and high photothermal conversion efficiency of 46.9% at 1064 nm. After surface modification, the MoO3−x nanobelts can be used as a robust nanoagent for photoacoustic imaging‐guided photothermal therapy to achieve efficient cancer cell ablation and tumor eradication under irradiation by a 1064 nm laser. Importantly, the biodegradable MoO3−x nanobelts can be rapidly degraded and excreted from body. The study highlights that the structural engineering of layered metal oxides is a powerful strategy to tune their properties and thus boost their performances in given applications.
The structural engineering of layered MoO3 and WO3 nanostructures is reported here to activate their NIR‐II absorption for efficient photothermal cancer therapy. The MoO3−x nanobelts can be used as a robust nanoagent for photoacoustic imaging‐guided photothermal therapy to achieve efficient cancer cell ablation and tumor eradication in the NIR‐II window.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Cushing's disease, also known as adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (PAs) that cause excess cortisol production, accounts for up to 85% of corticotrophin-dependent ...Cushing's syndrome cases. However, the genetic alterations in this disease are unclear. Here, we performed whole-exome sequencing of DNA derived from 12 ACTH-secreting PAs and matched blood samples, which revealed three types of somatic mutations in a candidate gene, USP8 (encoding ubiquitin-specific protease 8), exclusively in exon 14 in 8 of 12 ACTH-secreting PAs. We further evaluated somatic USP8 mutations in additional 258 PAs by Sanger sequencing. Targeted sequencing further identified a total of 17 types of USP8 variants in 67 of 108 ACTH-secreting PAs (62.04%). However, none of these mutations was detected in other types of PAs (n = 150). These mutations aggregate within the 14-3-3 binding motif of USP8 and disrupt the interaction between USP8 and 14-3-3 protein, resulting in an elevated capacity to protect EGFR from lysosomal degradation. Accordingly, PAs with mutated USP8 display a higher incidence of EGFR expression, elevated EGFR protein abundance and mRNA expression levels of POMC, which encodes the precursor of ACTH. PAs with mutated USP8 are significantly smaller in size and have higher ACTH production than wild-type PAs. In surgically resected primary USP8-mutated tumor cells, USP8 knockdown or blocking EGFR effectively attenuates ACTH secretion. Taken together, somatic gain-of-function USP8 mutations are common and contribute to ACTH overproduction in Cushing's disease. Inhibition of USP8 or EGFR is promising for treating USP8-mutated corticotrophin adenoma. Our study highlights the potentially functional mutated gene in Cushing's disease and provides insights into the therapeutics of this disease.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
•A novel ternary lanthanide system was assembled.•Electrospinning technique was employed to control microstructure.•Emission evolution was observed in the presence of HCl.
The generation of novel ...optical sensing structures through the lanthanide coordination has been a key scientific endeavor. The design of molecular indicator for chemical response is derived from the assembly of a polymeric-based ternary europium (III) complex system (Eu(NTA)3L/PVA (NTA = 4,4,4-trifluoro-1-(naphthalen-2-yl)butane-1,3-dione, L = 2-(4-(4-(allyloxy)phenyl)-6-(pyridin-2-yl)pyridin-2-yl)pyridine, PVA = poly(vinyl acetate)). The electrospinning technique has been employed to create a nanometer scale membrane and this functional film with ultrafine fibers (diameter of about 110 nm) exhibits intense red light at 618 nm under ultra-violet excitation of 340 nm. The luminescent signal transduction involves the interaction of hydrogen chloride (HCl) with the organic ligand. The strong acidity of the analyte induces dissociation of complex network and the evolution of emission from red to blue has been observed. The fabricated nanosensor demonstrates rapid response time (<2 s) and the detection limit has been calculated to be 3.0 ppm. This effective strategy for achieving lanthanide complex-encapsulated polymer fibers will contribute to the development of new intelligent photonic devices.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
By employing critical point theory, we investigate the existence of solutions to a boundary value problem for a
p
-Laplacian partial difference equation depending on a real parameter. To be specific, ...we give precise estimates of the parameter to guarantee that the considered problem possesses at least three solutions. Furthermore, based on a strong maximum principle, we show that two of the obtained solutions are positive under some suitable assumptions of the nonlinearity.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
DIVERGE is a software system for phylogeny-based analyses of protein family evolution and functional divergence. It provides a suite of statistical tools for selection and prioritization of the amino ...acid sites that are responsible for the functional divergence of a gene family. The synergistic efforts of DIVERGE and other methods have convincingly demonstrated that the pattern of rate change at a particular amino acid site may contain insightful information about the underlying functional divergence following gene duplication. These predicted sites may be used as candidates for further experiments. We are now releasing an updated version of DIVERGE with the following improvements: 1) a feasible approach to examining functional divergence in nearly complete sequences by including deletions and insertions (indels); 2) the calculation of the false discovery rate of functionally diverging sites; 3) estimation of the effective number of functional divergence-related sites that is reliable and insensitive to cutoffs; 4) a statistical test for asymmetric functional divergence; and 5) a new method to infer functional divergence specific to a given duplicate cluster. In addition, we have made efforts to improve software design and produce a well-written software manual for the general user.
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