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Two new multinary thioantimonates(III) with d10 transition metals (TMs) Rb2HgSb4S8 and CdSb2S4 have been prepared by environmental-friendly ionothermal method. Rb2HgSb4S8 has [HgS4]6− tetrahedrons, [SbS3]3− triangular pyramids, free Rb+ cations, and exhibits a unique two-dimensional (2D) cluster double-layer architecture. CdSb2S4 is the first Cd2+-containing multinary thioantimonate(III). It has two kinds of metal centers [SbS3]3− and [SbS4]5−, and exhibits a novel 2D ∞[Sb2S4]2− cluster layer, which is constructed by disulfide bonds linking with ∞[Sb4S8]4− chains. Remarkably, free Cd2+ cations as well as disulfide bonds are first found in thioantimonates. The band gaps of Rb2HgSb4S8 and CdSb2S4 are 1.80 and 1.57 eV, respectively, which indicates that these compounds are potential semiconductor materials. The birefringences of them are calculated to be 0.128 and 0.143 at 1064 nm, respectively. Theoretical studies using density functional theory have been implemented to further understand the relationship between their band gaps and crystal structures.

Under the regulation of transition metal Ag+, two new metal chalcogenides Rb2Sb4S7 and RbAgSb4S7·H2O have been prepared by ionothermal method under mild temperature. The crystal structure of Rb2Sb4S7 possesses two kind of metal centers [SbS3]3− triangular pyramid and [SbS4]5− twisted tetrahedron, and form a one-dimensional (1-D) cluster chain with free alkali metal cations. RbAgSb4S7·H2O possesses [SbS3]3− triangular pyramid, [SbS4]5− and [AgS4]7− twisted tetrahedrons, and exhibits a unique three-dimensional (3-D) framework with six kinds of member rings (MR), free alkali metal cations and free H2O molecules. Especially, 20-MR is first found in thioantimonates. The band gaps of Rb2Sb4S7 and RbAgSb4S7·H2O are 1.73 and 1.85 eV, respectively, which indicates that these two compounds can act as semiconductor materials. And the birefringences of Rb2Sb4S7 and RbAgSb4S7·H2O are calculated to be 0.182 and 0.065 at 1064 nm, respectively. Under the same synthesis condition, the addition of transition metal Ag+ has a great influence on their crystal structures and band gaps, which provides the possibility for designing and synthesizing diversified chalcogenides under ionothermal conditions.

Multidentate organic ligand with bridged and chelated functions is firstly developed to build cluster-based metal–organic framework. N-donating multidentate ligand 4-phenyl-2,6-bis(2′-pyrazinyl)pyridine (PBPP) is deliberately selected to construct a unique metal–organic framework {[WS4Cu4I4[Ni(PBPP)2]]2·DMF]}n (1) (DMF = N,N′-dimethylformamide). X-ray structure analysis reveals that 1 exhibits a 2D (6,3) graphene-like network, fabricated by rare pentanuclear [WS4Cu4]2+ building clusters, Ni2+ building metals, bridged and chelated PBPP and terminal I−. 1 has good water stability and luminescence. More importantly, the detection performance of 1 is explored through luminescence quenching effect, which reveals that 1 can detect 2,4,6-trinitrophenol (TNP) with high sensitivity and selectivity. The sensing mechanism has also been studied.

Immunotherapies that target programmed cell death protein 1 (PD-1) and its ligand PD-L1 as well as cytotoxic T-lymphocyte-associated protein 4 (CTLA4) have shown impressive clinical outcomes for multiple tumours. However, only a subset of patients achieves durable responses, suggesting that the mechanisms of the immune checkpoint pathways are not completely understood. Here, we report that PD-L1 translocates from the plasma membrane into the nucleus through interactions with components of the endocytosis and nucleocytoplasmic transport pathways, regulated by p300-mediated acetylation and HDAC2-dependent deacetylation of PD-L1. Moreover, PD-L1 deficiency leads to compromised expression of multiple immune-response-related genes. Genetically or pharmacologically modulating PD-L1 acetylation blocks its nuclear translocation, reprograms the expression of immune-response-related genes and, as a consequence, enhances the anti-tumour response to PD-1 blockade. Thus, our results reveal an acetylation-dependent regulation of PD-L1 nuclear localization that governs immune-response gene expression, and thereby advocate targeting PD-L1 translocation to enhance the efficacy of PD-1/PD-L1 blockade.

Whether glucose is predominantly metabolized via oxidative phosphorylation or glycolysis differs between quiescent versus proliferating cells, including tumor cells. However, how glucose metabolism is coordinated with cell cycle in mammalian cells remains elusive. Here, we report that mammalian cells predominantly utilize the tricarboxylic acid (TCA) cycle in G1 phase, but prefer glycolysis in S phase. Mechanistically, coupling cell cycle with metabolism is largely achieved by timely destruction of IDH1/2, key TCA cycle enzymes, in a Skp2-dependent manner. As such, depleting SKP2 abolishes cell cycle-dependent fluctuation of IDH1 protein abundance, leading to reduced glycolysis in S phase. Furthermore, elevated Skp2 abundance in prostate cancer cells destabilizes IDH1 to favor glycolysis and subsequent tumorigenesis. Therefore, our study reveals a mechanistic link between two cancer hallmarks, aberrant cell cycle and addiction to glycolysis, and provides the underlying mechanism for the coupling of metabolic fluctuation with periodic cell cycle in mammalian cells.

A new Mo/S/Cu cluster-based metal–organic framework, namely {[(MoS4Cu4)(CN)2(DPMF)2]·2MeCN}n (1), had been firstly synthesized by using a functional angular ligand 4,4′-((9H-fluoren-9-ylidene)methylene)dipyridine (DPMF). X-ray structural analysis reveals that 1 is constructed by saddle-shaped [MoS4Cu4]2+ clusters, DPMF and CN− bridges to exhibit an unusual 2D 8-connected network structure with a rare (312·414·52) topology. Interestingly, a cavity with diameter of 5.6 A is formed between two cross-arranged angular DPMF bridges. Luminescence measurements exhibit that 1 can detect 2,4,6-trinitrophenol (TNP) with high sensitivity, selectivity and good recyclability. These results demonstrate that 1 can serve as an excellent sensor for TNP through luminescent quenching effect.

Anti-PD-1/PD-L1 immunotherapy has achieved impressive therapeutic outcomes in patients with multiple cancer types. However, the underlined molecular mechanism(s) for moderate response rate (15–25%) or resistance to PD-1/PD-L1 blockade remains not completely understood. Here, we report that inhibiting the deubiquitinase, USP8, significantly enhances the efficacy of anti-PD-1/PD-L1 immunotherapy through reshaping an inflamed tumor microenvironment (TME). Mechanistically, USP8 inhibition increases PD-L1 protein abundance through elevating the TRAF6-mediated K63-linked ubiquitination of PD-L1 to antagonize K48-linked ubiquitination and degradation of PD-L1. In addition, USP8 inhibition also triggers innate immune response and MHC-I expression largely through activating the NF-κB signaling. Based on these mechanisms, USP8 inhibitor combination with PD-1/PD-L1 blockade significantly activates the infiltrated CD8+ T cells to suppress tumor growth and improves the survival benefit in several murine tumor models. Thus, our study reveals a potential combined therapeutic strategy to utilize a USP8 inhibitor and PD-1/PD-L1 blockade for enhancing anti-tumor efficacy.

MYC drives the tumorigenesis of human cancers, including prostate cancer (PrCa), thus deubiquitinase (DUB) that maintains high level of c-Myc oncoprotein is a rational therapeutic target. Several ubiquitin-specific protease (USP) family members of DUB have been reported to deubiquitinate c-Myc, but none of them is the physiological DUB for c-Myc in PrCa. By screening all the DUBs, here we reveal that OTUD6A is exclusively amplified and overexpressed in PrCa but not in other cancers, eliciting a prostatic-specific oncogenic role through deubiquitinating and stabilizing c-Myc oncoprotein. Moreover, genetic ablation of OTUD6A efficiently represses prostatic tumorigenesis of both human PrCa cells and the Hi-Myc transgenic PrCa mice, via reversing the metabolic remodeling caused by c-Myc overexpression in PrCa. These results indicate that OTUD6A is a physiological DUB for c-Myc in PrCa setting and specifically promotes prostatic tumorigenesis through stabilizing c-Myc oncoprotein, suggesting that OTUD6A could be a unique therapeutic target for Myc-driven PrCa.

A new water-stable W/S/Cu heterothiometallic cluster, namely {[WS4Cu3I(2-abpt)2]·2-abpt} (1, 2-abpt = 4-amino-3,5-bis(2-pyridyl)-1,2,4-triazole) has been synthesized and structurally characterized by single crystal and powder X-ray diffractions, elemental analysis, FT-IR and TGA. X-ray structural analysis reveals that 1 is constructed by the T-shaped heterothiometallic building cluster [WS4Cu3]+, chelated 2-abpt ligand and terminal I− ligand. 1 shows good water stability and strong luminescence, and is firstly explored to sense nitroaromatic compounds (NACs) as a discrete heterothiometallic cluster. Luminescence measurements exhibit that 1 can detect 2, 4, 6-trinitrophenol (TNP) with high sensitivity and selectivity in aqueous medium. The emission quenching mechanism of the sensing property of 1 towards TNP was studied as well. These results demonstrate that 1 can serve as an excellent sensor for TNP through luminescence quenching process.

As a regulator of osteogenesis, microRNA-218 (miR-218) is reported to promote osteogenesis of mesenchymal stem cells (MSCs). However, the in vivo osteogenic effect of miR-218 remains elusive. In this study, miR-218 was confirmed to promote osteogenic differentiation of MSCs by stimulating the alkaline phosphatase activity, calcium nodule formation, and osteogenic marker gene expression. For in vivo study, the miR-218-overexpressing BMSCs were locally administrated into the fracture sites in a femur fracture mouse model. Based on the X-rays, micro-computed tomography, mechanical testing, histology, and immunohistochemistry examinations, miR-218 overexpression improved new bone formation and accelerated fracture healing. These findings suggest that miR-218 may be a promising therapeutic target for bone repair in future clinical applications.

A potassium-crownether host–guest cation-templated synthetic method was used to build a heterothiometallic Mo/S/Cu cluster {[(K ⊂ dibenzo-18-crown-6)(NMP)2]2[(K ⊂ dibenzo-18-crown-6)(NMP)]2[Mo8S32Cu12]·H2O} (1). 1 was structurally determined by X-ray single crystal and powder diffractions. The anionic Mo/S/Cu cluster [Mo8S32Cu12]4− exhibits a unique octameric eicosanuclear supra-cubane-like architecture. Potassium-crownether cations show “satellite-receiver”-shaped and hexagonal-pyramidal configurations. Moreover, the third-order nonlinear optical (NLO) property was studied through Z-scan method (532 nm, 4 ns pulses), which reveals that 1 possesses effective NLO absorptive and refractive properties.

Distraction osteogenesis (DO) is a widely applied technique in orthopedics surgery, which involves rapid stem cell migration, homing, and differentiation. Interactions between the chemokine receptor Cxcr4 and its ligand, stromal derived factor-1 (SDF-1), regulate hematopoietic stem cell trafficking to the ischemic area and induce their subsequent differentiation. Here, we examined SDF-1 expression and further investigated the role of SDF-1/Cxcr4 signaling antagonist AMD3100 during bone regeneration in rat DO model. The results showed that expression levels of SDF-1 and osteogenic genes were higher in DO zones than in the fracture zones, and SDF-1 expression level was the highest at the termination of the distraction phase. Radiological, mechanical, and histological analyses demonstrated that the local administration of AMD3100 (400 μM) to DO rats significantly inhibited new bone formation. In the rat bone marrow mesenchymal stem cells culture, comparing to the group treated with osteogenic induction medium, AMD3100 supplement led to a considerable decrease in the expression of alkaline phosphatase and early osteogenic marker genes. However, the amount of calcium deposits in rat MSCs did not differ between the groups. Therefore, our study demonstrated that the DO process induced higher expression of SDF-1, which collated to rapid induction of callus formation. Local application of SDF-1/Cxcr4 signaling antagonist AMD3100 significantly inhibited bone mineralization and osteogenesis in DO, which may represent a potential therapeutic approach to the enhancement of bone consolidation in patients undergoing DO.

Acute myeloid leukemia (AML) is a genetically heterogeneous malignant disorder of the hematopoietic system, characterized by the accumulation of DNA-damaged immature myeloid precursors. Here, we find that hCINAP is involved in the repair of double-stranded DNA breaks (DSB) and that its expression correlates with AML prognosis. Following DSB, hCINAP is recruited to damage sites where it promotes SENP3-dependent deSUMOylation of NPM1. This in turn results in the dissociation of RAP80 from the damage site and CTIP-dependent DNA resection and homologous recombination. NPM1 SUMOylation is required for recruitment of DNA repair proteins at the early stage of DNA-damage response (DDR), and SUMOylated NPM1 impacts the assembly of the BRCA1 complex. Knockdown of hCINAP also sensitizes a patient-derived xenograft (PDX) mouse model to chemotherapy. In clinical AML samples, low hCINAP expression is associated with a higher overall survival rate in patients. These results provide mechanistic insight into the function of hCINAP during the DNA-damage response and its role in AML resistance to therapy., Acute myeloid leukemia cells are often resistant to radiotherapy and chemotherapy. Here, the authors suggest that hCINAP contributes to the resistance of acute myeloid leukemia cells by regulating SUMOylation of Nucleophosmin during the DNA-damage response.

Background Tendons are a crucial component of the musculoskeletal system and responsible for transmission forces derived from muscle to bone. Patients with tendon injuries are often observed with decreased collagen production and matrix degeneration, and healing of tendon injuries remains a challenge as a result of limited understanding of tendon biology. Recent studies highlight the contribution of miR-378a on the regulation gene expression during tendon differentiation. Methods We examined the tendon microstructure and tendon repair with using miR-378a knock-in transgenic mice, and the tendon-derived stem cells were also isolated from transgenic mice to study their tenogenic differentiation ability. Meanwhile, the expression levels of tenogenic markers were also examined in mouse tendon-derived stem cells transfected with miR-378a mimics during tenogenic differentiation. With using online prediction software and luciferase reporter assay, the binding target of miR-378a was also studied. Results Our results indicated miR-378a impairs tenogenic differentiation and tendon repair by inhibition collagen and extracellular matrix production both in vitro and in vivo. We also demonstrated that miR-378a exert its inhibitory role during tenogenic differentiation through binding at TGFβ2 by luciferase reporter assay and western blot. Conclusions Our investigation suggests that miR-378a could be considered as a new potential biomarker for tendon injury diagnosis or drug target for a possible therapeutic approach in future clinical practice. Electronic supplementary material The online version of this article (10.1186/s13287-019-1216-y) contains supplementary material, which is available to authorized users.

A unique mixed-valence CuII/CuI organic–inorganic hybrid supramolecular cluster {[Cu(DMSO)5][Cu4I6(DMSO)]}n (1) has been achieved in the presence of CuI under the acid condition, and characterized by X-ray single and powder crystal diffractions, elemental analysis, IR, UV–vis, thermogravimetric analysis. 1 has an unusual five DMSO coordinated bivalent copper cation [Cu(DMSO)5]2+; while the anionic architecture of 1 exhibits a 1-D wavelike CuI iodide hybrid cluster chain, constructed by [Cu4I6(DMSO)]2− repeated cluster units linking each other through shared μ2-I and μ3-I atoms. The solvent-coordinated cations interact with the 1-D anionic cluster chains to form a 3-D supramolecular framework through hydrogen bonds. Moreover, the luminescence and 2,4,6-trinitrophenol (TNP) sensing properties of 1 were explored in 2-propanol suspension, which revealed that 1 exhibits highly sensitive for TNP detection through energy transfer process.

SrAl2O4:Eu2+, Dy3+ powder has been successfully prepared via a combustion method and then introduced into the titanium dioxide (TiO2) film photoanode of the dye-sensitized solar cell (DSSC). The influence of the amount of doping on the light-to-electric energy conversion efficiency was discussed. At the concentration 7 wt% of SrAl2O4:Eu2+, Dy3+ (weight ratio of phosphor powder to TiO2), an overall 20 % improvement was achieved compared to that of the DSSC without SrAl2O4:Eu2+, Dy3+ phosphor doping. The enhancement is mainly due to the presence of the long persistent phosphor doping. It can convert ultraviolet to visible luminescence via down-conversion luminescence. Owing to the emission of long persistent light, the DSSC with SrAl2O4:Eu2+, Dy3+ showed an efficiency of 0.0076 % in the dark after illuminated under a simulated solar light for 1 min. This method represents a novel approach to increase the efficiency of DSSC.

Two heterothiometallic W/S/Cu dimeric clusters, {[WS4Cu4Cl2(phen)2]2·MeCN} (1) and {[CuCl(phen)2]2[WOS3Cu3Cl2(phen)]2} (2), were synthesized by the reactions of 1,10-phenanthroline (phen), CuCl and (NH4)2WS4 or (NH4)2WOS3, in DMF. 1 and 2 were characterized by elemental analyses, IR, UV–Vis, X-ray powder and single crystal diffractions. 1 exhibits a rare dimeric architecture, constructed by two parallel pentanuclear planar ‘open’ [WS4Cu4Cl2(phen)2] clusters linked together via a pair of μ 2-Cl bridges. While 2 consists of the five-coordinated cation [CuCl(phen)2]+ and the dimeric anionic cluster {[WOS3Cu3Cl2(phen)]2}2−, which is fabricated by a pair of tetranuclear nest-shaped clusters, connected by two μ 2-Cl bridges. Moreover, the photocatalytic activities of heterothiometallic clusters were firstly explored by monitoring the photodegradation of methylene blue (MB), which reveals that 1 and 2 both exhibit effective photocatalytic properties under Xe-illuminator irradiation.

Reactions of (NH4)WS4, CuCN and pyridine (Py) in different reaction solvents, namely DMF, DMSO and aniline, generated three isomeric heterothiometallic W/S/Cu cluster-based coordination polymers [WS4Cu4(CN)2(Py)4]n (1 and 2) and {[WS4Cu4(CN)2(Py)4]2·4CH3CN}n 3. All three complexes are constructed from planar ‘open’ [W(µ3-S)4Cu4]2+ clusters, CN− bridges and terminal Py ligands, but exhibit distinct architectures, consisting of a unique 1-D serrated chain for 1, a 2-D (4,4) network for 2 and a 1-D linear chain for 3. The photocatalytic activities of complex 1 were explored by monitoring the photodegradation of methylene blue, revealing that this complex exhibits effective photocatalytic properties under visible light irradiation.

A unique eicosanuclear heterothiometallic W/S/Cu octameric cluster [K(dibenzo-18-crown-6)(DMF)(CH3CN)]4[W8S32Cu12] (1), induced by potassium-crownether host–guest cation, was synthesized by the reaction of (NH4)2WS4, CuI, KI, dibenzo-18-crown-6 in DMF. 1 was characterized by elemental analyses, IR, UV–Vis, thermogravimetric analyses (TGA), X-ray powder and single crystal diffractions. The cation of 1 has the host–guest configuration, where K+ is embeded in the center of dibenzo-18-crown-6. The anionic architecture of 1 exhibits a supra-cubic cage, constructed by four nest-shaped clusters [W(µ1-S)(µ3-S)3Cu3]+ and four flywheel-shaped clusters [W(µ2-S)3(µ4-S)Cu3]+ linking each other through shared Cu atoms.

Gamboge is a traditional Chinese medicine and our previous study showed that gambogic acid and gambogenic acid suppress the proliferation of HCC cells. In the present study, another active component, 1,3,6,7-tetrahydroxyxanthone (TTA), was identified to effectively suppress HCC cell growth. In addition, our Hoechst-PI staining and flow cytometry analyses indicated that TTA induced apoptosis in HCC cells. In order to identify the targets of TTA in HCC cells, a two-dimensional gel electrophoresis was performed, and proteins in different expressions were identified by MALDA-TOF MS and MS/MS analyses. In summary, eighteen proteins with different expressions were identified in which twelve were up-regulated and six were down-regulated. Among them, the four most distinctively expressed proteins were further studied and validated by western blotting. The β-tubulin and translationally controlled tumor protein were decreased while the 14-3-3σ and P16 protein expressions were up-regulated. In addition, TTA suppressed tumorigenesis partially through P16-pRb signaling. 14-3-3σ silence reversed the suppressive effect of cell growth and apoptosis induced by introducing TTA. In conclusion, TTA effectively suppressed cell growth through, at least partially, up-regulation of P16 and 14-3-3σ.

For preparation of polystyrene (PS) composites, a polymeric dispersant, pyrene-capped polystyrene (PyPS), was applied for noncovalent functionalization of single-walled carbon nanotubes (SWNTs) to improve both dispersion quality and PS–SWNT interfacial interactions. To demonstrate the critical role of PyPS, the composites with the absence of PyPS (PS/SWNT) were also prepared for comparison. Rheological studies suggest that addition of SWNTs, particularly of PyPS-functionalized SWNTs, suppresses significantly large-scale relaxation of PS chains but has little effect on their short-range dynamics. Relative to PS, moderately improved thermal and mechanical properties took place on the composites with either pristine or PyPS-functionalized SWNTs. The PS/PyPS/SWNT composite usually presents better performance than the PS/SWNT one at a fixed SWNT content.

High-dose arabinoside (HiDAC) and daunorubicin (DNR)-based chemotherapy are the primary consolidation treatment options for older adults (50–60 years old) with acute myeloid leukemia in China. We analyzed the event-free survival (EFS) and hospital treatment charges of older adult patients with different cytogenetic risk profiles. In patients with a better/intermediate risk profile, the average total treatment cost of HiDAC was similar to that of DNR (P = 0.11). A 5-year follow-up of patients with better/intermediate cytogenetic risk profiles revealed that the median EFS of patients who received HiDAC was significantly longer than for patients who received the DNR-based regimen (27 vs. 20 months, P = 0.03). Average cost per year of life saved was 18,746.84 USD for HiDAC, compared to 32,733.37 USD for DNR. In contrast, for patients with a poor cytogenetic risk profile, the average total treatment cost for HiDAC was higher than for DNR (P < 0.005). In addition, the median EFS in the HiDAC protocol group was significantly lower than in the DNR group (11 vs. 20 months, P = 0.003). Meanwhile, in this risk group, the average cost per year of life saved was 103,237.70 USD compared to 32,277.93 USD, respectively, in the HiDAC and DNR regimens. We conclude that HiDAC is a more efficacious and cost-effective consolidation treatment regimen in the better/intermediate risk group, while the DNR-based regimen is more cost-effective in the poor risk group.

hCINAP is a highly conserved and ubiquitously expressed protein in eukaryotic organisms and its overexpression decreases the average number of Cajal bodies (CBs) with diverse nuclear functions. Here, we report that hCINAP is associated with important components of CBs. Depletion of hCINAP by RNA interference causes defects in CB formation and disrupts subcellular localizations of its components including coilin, survival motor neurons protein, spliceosomal small nuclear ribonucleoproteins, and nuclear protein ataxia-telangiectasia. Moreover, knockdown of hCINAP expression results in marked reduction of histone transcription, lower levels of U small nuclear RNAs (U1, U2, U4, and U5), and a loss of cell viability. Detection of increased caspase-3 activities in hCINAP-depleted cells indicate that apoptosis is one of the reasons for the loss of viability. Altogether, these data suggest that hCINAP is essential for the formation of canonical CBs, histone transcription, and cell viability.

Bone homeostasis is tightly orchestrated and maintained by the balance between osteoblasts and osteoclasts. Recent studies have greatly expanded our understanding of the molecular mechanisms of cellular differentiation. However, the functional roles of non-coding RNAs particularly lncRNAs in remodeling bone architecture remain elusive. In our study, lncRNA H19 was found to be upregulated during osteogenesis in hMSCs. Stable expression of H19 significantly accelerated in vivo and in vitro osteoblast differentiation. Meanwhile, by using bioinformatic investigations and RIP assays combined with luciferase reporter assays, we demonstrated that H19 functioned as an miRNA sponge for miR-141 and miR-22, both of which were negative regulators of osteogenesis and Wnt/β-catenin pathway. Further investigations revealed that H19 antagonized the functions of these two miRNAs and led to de-repression of their shared target gene β-catenin, which eventually activated Wnt/β-catenin pathway and hence potentiated osteogenesis. In addition, we also identified a novel regulatory feedback loop between H19 and its encoded miR-675-5p. And miR-675-5p was found to directly target H19 and counteracted osteoblast differentiation. To sum up, these observations indicate that the lncRNA H19 modulates Wnt/β-catenin pathway by acting as a competing endogenous RNA, which may shed light on the functional role of lncRNAs in coordinating osteogenesis.

Anaphase-promoting complex/cyclosome/Cdh1 is a multi-subunit ubiquitin E3 ligase that drives M to G1 cell cycle progression through primarily earmarking various substrates for ubiquitination and subsequent degradation by the 26S proteasome. Notably, emerging evidence suggested that Cdh1 could also function in various cellular processes independent of anaphase-promoting complex/cyclosome. To this end, we recently identified an anaphase-promoting complex/cyclosome-independent function of Cdh1 in modulating osteoblast differentiation through activating Smurf1, one of the NEDD4 family of HECT domain-containing E3 ligases. However, it remains largely unknown whether Cdh1 could exert its tumor suppressor role through similarly modulating the E3 ligase activities of other NEDD4 family members, most of which have characterized important roles in tumorigenesis. Here we report that in various tumor cells, Cdh1, conversely, suppresses the E3 ligase activity of WWP2, another NEDD4 family protein, in an anaphase-promoting complex/cyclosome-independent manner. As such, loss of Cdh1 activates WWP2, leading to reduced abundance of WWP2 substrates including PTEN, which subsequently activates PI3K/Akt oncogenic signaling to facilitate tumorigenesis. This study expands the non-anaphase-promoting complex/cyclosome function of Cdh1 in regulating the NEDD4 family E3 ligases, and further suggested that enhancing Cdh1 to inhibit the E3 ligase activity of WWP2 could be a promising strategy for treating human cancers.

A method utilizing polymer-bound 4-(bromomethyl)-3-nitrobenzoic acid as a key precursor leading to 1,4-benzodiazepin-2,3-dione scaffold is described. It involves a four-step sequence including nucleophilic displacement, acylation, simultaneous reduction-cyclization and alkylation, providing rapid access to the title compounds in excellent yield and purity.

An efficient method for solid-phase constructionof tetrahydro-1,4-benzodiazepin-2-one scaffold is described.Polymer-bound 4-(bromomethyl)-3-nitrobenzoic acid was reactedwith α-amino acid methyl esters, followed by nitro groupreduction and hydrolysis. Subsequent intramolecular cyclizationand alkylation at N(4) afforded the structurally diverse productsin high yields and excellent purities.

Basin-fill sequences of Mesozoic typical basins in the Yanshan area, North China may be divided into four phases, reflecting lithosphere tectonic evolution from flexure (T3), flexure with weak rifting (J1+2), tectonic transition (J3), and rifting (K). Except the first phase, the other three phases all start with lava and volcaniclastic rocks, and end with thick coarse clastic rocks and/or conglomerates, showing cyclic basin development rather than simple cyclic rift mechanism and disciplinary basin-stress change from extension to compression in each phase. Prototype basin analysis, based on basin-fill sequences, paleocurrent distribution and depositional systems, shows that single basin-strike and structural-line direction controlling basin development had evidently changed from east-west to northeast in Late Jurassic in the Yanshan area, although basin group still occurred in east-west zonal distribution. Till Early Cretaceous, main structural-line strike controlling basins just turned to northeast by north in the studied area.