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The FGF receptors (FGFRs) belong to a family of receptor tyrosine kinases. Abundant evidence shows that FGFRs are closely related to tumor cell invasion and angiogenesis. Hence, targeted modulation of FGFRs has become an effective strategy for cancer treatment. Recently, the development of small-molecule inhibitors targeting FGFRs has been extensively studied, and three inhibitors have been approved for marketing. Based on the clinical problems with the current inhibitors, there is a need to develop novel inhibitors and technologies to address the pitfalls. This review summarizes recent advances in small-molecule inhibitors targeting FGFRs, focusing on structure–activity relationships. Moreover, recent progress of novel technologies are summarized to provide a reference for promoting the application of drugs targeting FGFRs in tumor therapy.

Neurodegenerative diseases (NDs) are currently incurable diseases that cause progressive degeneration of nerve cells. Many of the disease-causing proteins of NDs are "undruggable" for traditional small-molecule inhibitors (SMIs). None of the compounds that attenuated the amyloid-β (Aβ) accumulation process have entered clinical practice, and many phase III clinical trials of SMIs for Alzheimer's disease (AD) have failed. In recent years, emerging targeted protein degradation (TPD) technologies such as proteolysis-targeting chimeras (PROTACs), lysosome-targeting chimaeras (LYTACs), and autophagy-targeting chimeras (AUTACs) with TPD-assistive technologies such as click-formed proteolysis-targeting chimeras (CLIPTACs) and deubiquitinase-targeting chimera (DUBTAC) have developed rapidly.

Angiotensin-converting enzyme (ACE), a zinc metalloprotein, is a central component of the renin–angiotensin system (RAS). It degrades bradykinin and other vasoactive peptides. Angiotensin-converting-enzyme inhibitors (ACE inhibitors, ACEIs) decrease the formation of angiotensin II and increase the level of bradykinin, thus relaxing blood vessels as well as reducing blood volume, lowering blood pressure and reducing oxygen consumption by the heart, which can be used to prevent and treat cardiovascular diseases and kidney diseases. Nevertheless, ACEIs are associated with a range of adverse effects such as renal insufficiency, which limits their use. In recent years, researchers have attempted to reduce the adverse effects of ACEIs by improving the selectivity of ACEIs for structural domains based on conformational relationships, and have developed a series of novel ACEIs. In this review, we have summarized the research advances of ACE inhibitors, focusing on the development sources, design strategies and analysis of structure-activity relationships and the biological activities of ACE inhibitors.

The dissolution of Al2O3 particles in CaO-Al2O3-SiO2 slags was investigated by confocal scanning laser microscope at the temperature range from 1723 K to 1853 K. It was found that the rate-limiting step was the diffusion in the liquid slag. The dissolution of Al2O3 particles in CaO-Al2O3-SiO2 slags with various temperatures, CaO/Al2O3, and CaO/SiO2 in slag was in situ observed. Increasing the C/A and C/S of slag promoted the absorption of Al2O3 inclusions by the CaO-Al2O3-SiO2 slag, but only if the slag was pure liquid at the refining temperature. A model related to dissolution driving force and slag viscosity was shown to be v = 18.716 × ΔC/η to predict the dissolution rate of Al2O3. Effective binary diffusion coefficients for various CaO-Al2O3-rich slags were obtained using the developed model. The dissolution rate of Al2O3 in CaO-Al2O3-SiO2 slags with low SiO2 content at the steelmaking temperature was predicted.

CDK12 is a cyclin-dependent kinase that plays critical roles in DNA replication, transcription, mRNA splicing, and DNA damage repair. CDK12 genomic changes, including mutation, amplification, deletion, and fusion, lead to various cancers, such as colorectal cancer, gastric cancer, and ovarian cancer. An increasing number of CDK12 inhibitors have been reported since CDK12 was identified as a biomarker and cancer therapeutic target. A major challenge lies in that CDK12 and CDK13 share highly similar sequences, which leads to great difficulties in the development of highly selective CDK12 inhibitors. In recent years, great efforts were made in developing selective CDK12 blockers. Techniques including PROTAC and molecular glue degraders were also applied to facilitate their development. Also, the drug combination strategy of CDK12 small molecule inhibitors were studied. This review discusses the latest studies on CDK12 inhibitors and analyzes their structure-activity relationships, shedding light on their further development.

Hepatitis C virus (HCV) infection has become a global health problem with enormous risks. Nonstructural protein 5B (NS5B) RNA-dependent RNA polymerase (RdRp) is a component of HCV, which can promote the formation of the viral RNA replication complex and is also an essential part of the replication complex itself. It plays a vital role in the synthesis of the positive and negative strands of HCV RNA. Therefore, the development of small-molecule inhibitors targeting NS5B RdRp is of great value for treating HCV infection-related diseases. Compared with NS5B RdRp nucleoside inhibitors, non-nucleoside inhibitors have more flexible structures, simpler mechanisms of action, and more predictable efficacy and safety of drugs in humans. Technological advances over the past decade have led to remarkable achievements in developing NS5B RdRp inhibitors. This review will summarize the non-nucleoside inhibitors targeting NS5B RdRp developed in the past decade and describe their structure optimization process and structure-activity relationship.

We mainly study Pogorelov type $C^2$ estimates for solutions to the Dirichlet problem of Sum Hessian equations. We establish respectively Pogorelov type $C^2$ estimates for $k$-convex solutions and admissible solutions under some conditions. Furthermore, we apply such estimates to obtain a rigidity theorem for $k$-convex solutions of Sum Hessian equations in Euclidean space., 27 pages

EZH2, the catalytic subunit of PRC2, catalyzes histone H3 lysine 27 (H3K27) trimethylation to induce the agglutination of chromosomes and in turn represses the transcription of the target genes. Numerous reports indicate that EZH2 is overexpressed in a variety of malignant tumor tissues. Therefore, targeting EZH2 protein is a promising strategy for cancer treatment. So far, many small molecule EZH2 specific inhibitors have entered clinical trials, but many of them harbored limited clinical efficacy. New technologies and methods are imperative to enhance the anticancer activity of EZH2. In this review, the structure and biological functions of EZH2 protein will be reviewed. The internal relationship between EZH2 and various diseases will be expounded. The development status of specific inhibitors for EZH2, and the latest progress of new strategies such as drug combination, dual-target inhibitors, targeted protein degradation technology and protein-protein interactions (PPI) inhibitors will be emphatically summarized and analyzed.

Human dihydroorotate dehydrogenase (hDHODH) is a flavin-dependent enzyme catalyzing the fourth step of pyrimidine de novo biosynthesis. Since aberrant pyrimidine metabolism is closely related abnormal cell proliferation, hDHODH is believed to have an intimate linkage with cancers. For instance, hDHODH induces the abrogation of β-catenin degradation and cell proliferation in esophageal squamous cell carcinoma (ESCC). Thus, small molecular inhibitors targeting hDHODH has been considered as a promising strategy for cancer treatment. In recent years, in exploiting novel structural hDHODH inhibitors (hDHODHi), a candidate drug PTC299 has entered clinical trials for treating acute myelocytic leukemia (AML) and other tumors. This review discusses tumor-related research of hDHODH and highlights the structure-activity relationships of hDHODHi, providing insights into new drugs targeting hDHODH for antitumor clinical practice.

Depression is a common aspect of the modern lifestyle, and most patients are recalcitrant to the current antidepressants. Fingolimod (FTY720), a sphingosine analogue approved for the treatment of multiple sclerosis, has a significant neuroprotective effect on the central nervous system. The aim of this study was to determine the potential therapeutic effect of FTY720 on the behavior and cognitive function of rats exposed daily to chronic unpredictable mild stress (CUMS), and elucidate the underlying mechanisms. The 42-day CUMS modeling induced depression-like behavior as indicated by the scores of sugar water preference, forced swimming, open field and Morris water maze tests. Mechanistically, CUMS caused significant damage to the hippocampal neurons, increased inflammation and oxidative stress, activated the NF-κB/NLRP3 axis, and skewed microglial polarization to the M1 phenotype. FTY720 not only alleviated neuronal damage and oxidative stress, but also improved the depression-like behavior and cognitive function of the rats. It also inhibited NF-κB activation and blocked NLRP3 inflammasome assembly by down-regulating NLRP3, ACS and caspase-1. Furthermore, FTY720 inhibited the microglial M1 polarization markers iNOS and CD16, and promoted the M2 markers Arg-1 and CD206. This in turn reduced the levels of TNF-α, IL-6 and IL-1β, and increased that of IL-10 in the hippocampus. In conclusion, FTY720 protects hippocampal neurons from stress-induced damage and alleviates depressive symptoms by inhibiting neuroinflammation. Our study provides a theoretical basis for S1P receptor modulation in treating depression.

Dual-specificity tyrosine phosphorylation-regulated kinase 1 A (DYRK1A) is a conserved protein kinase that plays essential roles in various biological processes. It is located in the region q22.2 of chromosome 21, which is involved in the pathogenesis of Down syndrome (DS). Moreover, DYRK1A has been shown to promote the accumulation of amyloid beta (Aβ) peptides leading to gradual Tau hyperphosphorylation, which contributes to neurodegeneration. Additionally, alterations in the DRK1A expression are also associated with cancer and diabetes. Recent years have witnessed an explosive increase in the development of DYRK1A inhibitors. A variety of novel DYRK1A inhibitors have been reported as potential treatments for human diseases. In this review, the latest therapeutic potential of DYRK1A for different diseases and the novel DYRK1A inhibitors discoveries are summarized, guiding future inhibitor development and structural optimization.

Recycling Si from Si sawing waste is a good approach aiming at meeting the rapidly increasing demand for Si, and the separation of Si and SiC particles plays a key role in the production of high-quality Si. In this work, Si was successfully recovered from Si sawing waste by using a CaO–51mol%SiO2–15mol%MgO slag. This recovery included measurement of the contact angle between a CaO–SiO2–MgO slag and SiC using the sessile drop method. The results, θSiC/SiO2–CaO–MgO

In the research of fully nonlinear elliptic partial differential equations, the concavities of the nonlinear operators is always essential. The concavity is the key to establish the curvature estimates of these equations. However, very few concave operators are known. In the present paper, some new examples are provided, which are the sum Hessian operators and the linear combination of k Hessian operators. We obtain the concavities and the quotient concavities of these new operators. As an application of our concavities, we establish the curvature estimates of convex solutions for the equations with general right-hand side defined by these new operators.

We explore the firm quasi-dynamics (entry/exit and growth) in the Chinese manufacturing industries and investigate how these dynamics vary across regions. Our results show that relative to provinces with less developed economies, in provinces with more developed economies: (1) There are higher shares of new firms; (2) New firms are smaller and more labor-intensive; (3) Firms exit at a quicker rate and surviving firms grow faster. These results point toward cross-region differences in market efficiency in terms of how much it costs a firm to enter or exit the market. Our findings shed light on how firms should adapt their strategies across regions and how the government should create sound policies on industrial upgrading and relocation.

This paper deals with some parabolic Monge-Ampere equation raised from mathematical finance: VsVyy+ryVyVyy−θVy2= 0 (Vyy < 0). The existence and uniqueness of smooth solution to its initial-boundary value problem with some requirement is obtained.

We establish a C2 a priori estimate for convex hypersurfaces whose principal curvatures κ=(κ1,…, κn) satisfy σk(κ(X))=f(X,ν(X)), the Weingarten curvature equation. We also obtain such an estimate for admissible 2-convex hypersurfaces in the case k=2. Our estimates resolve a longstanding problem in geometric fully nonlinear elliptic equations.© 2015 Wiley Periodicals, Inc.

We report on the effect of the frequency of a non-biased sinusoidal alternating (AC) electric field on the optical non-linear response of 60 μm-thick homeotropic C60-doped nematic liquid crystals by using a two-beam coupling experiment. Experimental results indicate that the liquid crystal sample has two intrinsic frequencies of ∼0.05 Hz and ∼10 Hz. Below 0.05 Hz the energy transference is unstable, the first-order diffraction flashes in phase with the external AC electric field and its minimal intensity is almost zero. When the frequency is larger than ∼10 Hz, stable asymmetric energy transference, as that achieved under an external DC electric field, is obtained. In the regions between the above two frequencies, a stable asymmetric energy transference exists; at the same time, the transmitted intensities of the two writing beams are modulated by the external AC field and follow its variations.

For a class of elliptic Hessian operators raised by Caffarelli–Nirenberg–Spruck, the corresponding parabolic Monge–Ampere equation was studied, the existence and uniqueness of the admissible solution to the first initial-boundary value problem for the equation were established, which extended a result of Ivochkina–Ladyzhenskaya.

Photorefractive properties of congruent LiNbO3 crystals codoped with HfO2 and Fe2O3 have been investigated at 488 nm wavelength by holographic recording experiments. The results definitely show that when the HfO2 concentration is lower than its threshold concentration (4 mol.%), the photorefractive properties of Hf:Fe:LiNbO3 crystals are reduced with the increase of the HfO2 concentration. However, when the HfO2 concentration exceeds its threshold concentration, the photorefractive properties of the crystal return to enhance. This unusual behavior with various HfO2 concentrations is explained. Fe2+ ions are suggested to be the main contributor to the photoconductivity of the crystal and subsequently to induce the dissimilar photorefractive properties.

Optically active poly[triphenylmethyl methacrylate-co-phenyl[bis(2-pyridyl)]methyl methacrylate] (poly[TrMA-co-PB2PyMA], poly[diphenyl(2-pyridyl)methyl methacrylate-co-phenyl[bis(2-pyridyl)]methyl methacrylate] (poly[D2PyMA-co-PB2PyMA]), and poly[triphenylmethyl methacrylate-co-diphenyl(2-pyridyl)-methyl methacrylate] (poly[TrMA-co-D2PyMA]) were prepared by helix-sense-selective copolymerization with complexes of organolithium with (−)-sparteine [(−)Sp],(S, S)-(+)- and (R, R)-(−)-2,3-dimethoxy-1,4-bis(dimethylamino)butane [(+)- and (−)DDB], and (S)-(+)-2-(1-pyrrolidinylmethyl)pyridine [(+)PMP] as anionic initiators in toluene at low temperature. The copolymers obtained with (−)Sp and (+)DDB or (−)DDB complexes of organolithium showed low optical activity, but to [(+)PMP] complex with N,N′-diphenyleneamine monolithium amide [(+)PMP–DPEDA–Li)] was effective in synthesizing copolymers of high optical rotation ([α] about +320 to + 370°) which were comparable to those of corresponding homopolymers with one-handed helical structure. The optical rotations of poly[TrMA-co-PB2PyMA] and poly[TrMA-co-D2PyMA] were much more stable than that of poly(D2PyMA) or poly(PB2PyMA) in a solution of CHCl3–2,2,2-trifluoroethanol (10 : 1, v/v) at 25°C, but optical rotation of poly[D2PyMA-co-PB2PyMA] slowly decreased with time in the same conditions. © 1998 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 36: 2127–2133, 1998

Helix-sense-selective copolymerizations based on triphenylmethyl methacrylate (TrMA) with methyl methacrylate (MMA), benzyl methacrylate (BzMA) and diphenylmethyl methacrylate (DPMMA) in the presence of the chiral anionic complex initiator (−)-sparteine/9-fluorenyl-lithium (1) were investigated. The studies concentrated on the stereoregularity of the copolymers, the relative reactivity of the monomers, the specific rotation of the copolymers and the influence of the solvent on the copolymerization. The results show that the match of TrMA with MMA of smaller size would favour the form of the copolymer with isotactic one-handed helix having higher specific rotation as compared with BzMA ad DPMMA in toluene, but the TrMA/MMA copolymer obtained in tetrahydrofuran possessed a very low specific rotation because of the action of the polar tetrahydrofuran on the anion complex.

Hf:Fe:LiNbO3 crystals were grown in air by the Czochralski technique with various [Li]/[Nb] ratios ([Li]/[Nb]=0.94, 1.05, 1.20) in melt. The defect structure and location of doped ions were analyzed by the UV-visible absorption spectra. The optical damage resistance of Hf:Fe:LiNbO3 crystals was investigated by the photoinduced birefringence change and the transmitted light spot distortion method. The results show that the optical damage resistance ability of Hf:Fe:LiNbO3 crystals decreases with the increase of the [Li]/[Nb] ratio. The dependence of the optical damage resistance of Hf:Fe:LiNbO3 crystals on the defect structure is discussed in detail. (© 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

Phenyl[bis(2-pyridyl)]methyl methacrylate (PB2PyMA) was synthesized and anionically polymerized with the complexes of organolithiums with (-)-sparteine (Sp), (S,S)-(+)- and (R,R)-(-)-2,3-dimethoxy-1,4-bis(dimethylamino)butanes [(+)- and (-)-DDB], and (S)-(+)-1-(2-pyrrolidinylmethyl) pyrrolidine (PMP) in toluene at low temperature. The polymers obtained with Sp and DBB complexes showed low optical activity. PMP complexes were effective in synthesizing a polymer with high optical rotation ([α] 25 365 ∼ +1350°)