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Lithium metal batteries (LMBs) possess outstanding theoretical energy density and have attracted widespread attention as the next generation of energy storage devices for various crucial applications. However, the commercialization of LMBs has to simultaneously overcome numerous challenges, such as inferior Coulombic efficiency and cycling performance, high self-discharge, and complicated interfacial reactions. It has traditionally been an enormous challenge about the uniform deposition of lithium on the surface of current collector to relieve the formation of lithium dendrites. In this study, a novel efficient strategy of plating uniform lithiophilic polythiophene derivatives substrates on Cu foils was developed and the nucleation mechanism of Li ions on polythiophene derivatives substrates was further explored. We first explored the interaction between polythiophene derivatives substrates and Li ions by first-principles calculations, and found shorter side chains of polythiophene derivatives can enhance the adsorption energy and promote the diffusion rate of Li ions. Polythiophene derivatives substrates have a large number of dispersive lipophilic sites and Li ions diffusion channels in the main chain, which can effectively regulate the nucleation and growth stages of Li ions deposition. We further found polythiophene derivatives with different side chains can induce the electrodeposition of Li ions with different morphology, while the polythiophene derivatives with the shortest side chains can contribute to the most excellent cycle efficiency, resulting in a uniform lithium deposition with less lithium dendritic growth experimentally.

Ketones are widely applied moieties in designing functional materials and are commonly obtained by oxidation of alcohols. However, when alcohols are protected/functionalized, the direct oxidation strategies are substantially curbed. Here we show a highly efficient copper bromide promoted one-step direct oxidation of benzylic ethers to ketones with the aid of a fullerene pendant. Mechanistic studies unveil that fullerene can serve as an electron pool proceeding the one-step oxidation of alkoxy group to ketone. In the absence of the fullerene pendant, the unreachable activation energy threshold hampers the direct oxidation of the alkoxy group. In the presence of the fullerene pendant, generated fullerene radical cation can activate the neighbour C–H bond of the alkoxy moiety, allowing a favourable energy barrier for initiating the direct oxidation. The produced fullerene-fused ketone possesses high thermal stability, affording the pin-hole free and amorphous electron-transport layer with a high electron-transport mobility. Fullerenes are intrinsically electron deficient species which can facilitate challenging transformations in organic chemistry. Here fullerene-fused alkoxy ethers are shown to undergo copper-promoted oxidation by single electron transfer to the corresponding ketones via a fullerene radical cation intermediate.

Rationale: Differential activation of macrophages correlates closely with tumor progression, and the epigenetic factor lysine demethylase 6B (KDM6B, previously named JMJD3) mediates the regulation of macrophage polarization through an unknown mechanism. Methods: We developed a suspension coculture system comprising breast cancer cells and macrophages and used RT-qPCR and western blotting to measure KDM6B expression. Bioinformatics and luciferase reporter assays were used to identify candidate microRNAs of cancer cells responsible for the downregulation of KDM6B. To determine if exosomes mediated the transfer of miR-138-5p between cancer cells to macrophages, we treated macrophages with exosomes collected from the conditioned medium of cancer cells. The effects of exosomal miR-138-5p on macrophage polarization were measured using RT-qPCR, flow cytometry, and chromatin immunoprecipitation assays. We employed a mouse model of breast cancer, metastatic to the lung, to evaluate the effects on tumor metastasis of macrophages treated with miR-138-5p-enriched exosomes. To develop a diagnostic evaluation index, the levels of exosomal miR-138-5p in samples from patients with breast cancer were compared to those of controls. Results: Coculture of breast cancer cells led to downregulation of KDM6B expression in macrophages. Cancer cell-derived exosomal miR-138-5p inhibited M1 polarization and promoted M2 polarization through inhibition of KDM6B expression in macrophages. Macrophages treated with exosomal miR-138-5p promoted lung metastasis, and the level of circulating exosomal miR-138-5p positively correlated with the progression of breast cancer. Conclusion: Our data suggest that miR-138-5p was delivered from breast cancer cells to tumor-associated macrophages via exosomes to downregulate KDM6B expression, inhibit M1 polarization, and stimulate M2 polarization. Therefore, exosomal miR-138-5p represents a promising prognostic marker and target for the treatment of breast cancer.

Hexameric structure formation through packing of three C-terminal helices and an N-terminal trimeric coiled-coil core has been proposed as a general mechanism of class I enveloped virus entry. In this process, the C-terminal helical repeat (HR2) region of viral membrane fusion proteins becomes transiently exposed and accessible to N-terminal helical repeat (HR1) trimer-based fusion inhibitors. Herein, we describe a mimetic of the HIV-1 gp41 HR1 trimer, N3G, as a promising therapeutic against HIV-1 infection. Surprisingly, we found that in addition to protection against HIV-1 infection, N3G was also highly effective in inhibiting infection of human β-coronaviruses, including MERS-CoV, HCoV-OC43, and SARS-CoV-2, possibly by binding the HR2 region in the spike protein of β-coronaviruses to block their hexameric structure formation. These studies demonstrate the potential utility of anti-HIV-1 HR1 peptides in inhibiting human β-coronavirus infection. Moreover, this strategy could be extended to the design of broad-spectrum antivirals based on the supercoiling structure of peptides.

The n%-SnO2/SiO2 (n = 2, 4, 6) supported catalyst was prepared by the sol–gel and calcination method. Compared with the traditional impregnation method, the catalyst prepared by sol–gel method has higher oxidative desulfurization activity.

ZIF-8 MOFs, with their large specific surface area and void volume, unique biodegradability and pH sensitivity, and significant loading capacity, have been widely used as carrier materials for bioactive molecules such as drugs, vaccines and genes. In these applications, ZIF-8 MOFs are usually delivered intravenously. Therefore, it is necessary to know the interaction between ZIF-8 MOFs and blood components, which from this sense is a key factor affecting their delivery effectiveness and biosafety. However, until now there has been no report on the evaluation of hemocompatibility of ZIF-8 MOFs. The lack of biosafety information of ZIF-8 MOFs seriously impedes their clinical applications. In this work, we studied the biosafety of two different sizes of ZIF-8 MOFs, mainly focusing on their in vivo and in vitro effects on the key components of blood (red blood cells (RBCs), platelets, etc.) and the coagulation function. It was found that, in vitro, a high concentration of ZIF-8 MOFs could induce RBC aggregation and hemolysis, and prolong the coagulation time. In vivo, intravenous administration of 45 mg kg−1 ZIF-8 MOFs significantly disturbed the RBC and platelet-related blood routine indexes, as well as coagulation function indexes, but it did not cause significant abnormalities in blood coagulation and tissue structures (heart, liver, spleen, lung, and kidney).

Insulin resistance (IR) is the primary pathological mechanism underlying Type 2 diabetes mellitus (T2DM). Many researches have reported the relationship between chronic inflammation and IR, while the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway is rapidly activated in inflammatory conditions. However, the functional role of ERK1/2 in IR remains to be identified. We here reported that C-Jun activation domain-binding protein-1 (JAB1) was upregulated in IR. In addition, we showed that depletion of JAB1 led to recovery of insulin sensitivity. Given the fact that JAB1 played as an activator of ERK1/2, we assumed JAB1 was involved in IR through ERK pathway. So we assessed the effects of JAB1 knockdown in palmitate acid (PA) treated HepG2 cells. Importantly, JAB1 siRNA blocked the effect of PA-induced activation of ERK1/2. Furthermore, silencing of JAB1 could reduce the release of inflammatory factors, facilitate hepatic glucose uptake and improve lipid metabolism. All these data implicated that JAB1 knockdown might alleviate PA-induced IR through ERK pathway in hepatocytes.

Oxide catalysts have been developed in polymer electrolyte fuel cell cathodes to replace platinum-group-metal catalysts while retaining moderate oxygen reduction reaction (ORR) activity. Recently, ...

Objective: Angiogenesis plays a vital role in tumor growth and metastasis. Here, we aimed to find novel efficient antiangiogenic molecules targeting vascular endothelial growth factor A (VEGFA ) at the transcriptional level to treat triple-negative breast cancer (TNBC). Methods: We used a cell-based seryl tRNA synthetase (SerRS) promoter-driven dual-luciferase reporter system to screen an in-house library of 384 naturally occurring small molecules and their derivatives to find candidate molecules that could upregulate the expression of SerRS, a potent transcriptional repressor of VEGFA. The levels of SerRS and VEGFA were examined by quantitative RT-PCR (qRT-PCR), western blotting, and/or ELISAs in TNBC cells after candidate molecule administration. Zebrafish, the Matrigel plug angiogenesis assay in mice, the TNBC allograft, and xenograft mouse models were used to evaluate the in vivo anti-angiogenic and anti-cancer activities. Furthermore, the potential direct targets of the candidates were identified by proteomics and biochemical studies. Results: We found the most active compound was 3-(4-methoxyphenyl) quinolin-4(1H)-one (MEQ), an isoflavone derivative. In TNBC cells, MEQ treatment resulted in increased SerRS mRNA (P < 0.001) and protein levels and downregulated VEGFA production. Both the vascular development of zebrafish and Matrigel plug angiogenesis in mice were inhibited by MEQ. MEQ also suppressed the angiogenesis in TNBC allografts and xenografts in mice, resulting in inhibited tumor growth and prolonged overall survival (P < 0.05). Finally, we found that MEQ regulated SerRS transcription by interacting with MTA2 (Metastasis Associated 1 Family Member 2). Conclusions: Our findings suggested that the MTA2/SerRS/VEGFA axis is a drug-treatable anti-angiogenic target, and MEQ is a promising anti-tumor molecule that merits further investigation for clinical applications.

Vertically aligned carbon nanotube forests on solid substrates that can be drawn into fibers, like pulling silk from a cocoon, have inspired many exciting potential applications. Single-walled carb...

Anti-angiogenesis is an important and promising strategy in cancer therapy. However, the current methods using anti-vascular endothelial growth factor A (VEGFA) antibodies or inhibitors targeting VEGFA receptors are not as efficient as expected partly due to their low efficiencies in blocking VEGFA signaling in vivo. Until now, there is still no method to effectively block VEGFA production in cancer cells from the very beginning, i.e., from the transcriptional level. Here, we aimed to find bioactive small molecules to block VEGFA transcription. Methods: We screened our natural compound pool containing 330 small molecules derived from Chinese traditional herbs for small molecules activating the expression of seryl-tRNA synthetase (SerRS), which is a newly identified potent transcriptional repressor of VEGFA, by a cell-based screening system in MDA-MB-231 cell line. The activities of the candidate molecules on regulating SerRS and VEGFA expression were first tested in breast cancer cells. We next investigated the antiangiogenic activity in vivo by testing the effects of candidate drugs on the vascular development in zebrafish and by matrigel plug angiogenesis assay in mice. We further examined the antitumor activities of candidate drugs in two triple-negative breast cancer (TNBC)-bearing mouse models. Furthermore, streptavidin-biotin affinity pull-down assay, coimmunoprecipitation assays, docking analysis and chromatin immunoprecipitation were performed to identify the direct targets of candidate drugs. Results: We identified emodin that could greatly increase SerRS expression in TNBC cells, consequently reducing VEGFA transcription. Emodin potently inhibited vascular development of zebrafish and blocked tumor angiogenesis in TNBC-bearing mice, greatly improving the survival. We also identified nuclear receptor corepressor 2 (NCOR2) to be the direct target of emodin. Once bound by emodin, NCOR2 got released from SerRS promoter, resulting in the activation of SerRS expression and eventually the suppression of VEGFA transcription. Conclusion: We discovered a herb-sourced small molecule emodin with the potential for the therapy of TNBC by targeting transcriptional regulators NCOR2 and SerRS to suppress VEGFA transcription and tumor angiogenesis.

Heterostructures built from 2D, atomically thin crystals are bound by the van der Waals force and exhibit unique optoelectronic properties. Here, we report the structure, composition and optoelectronic properties of 1D van der Waals heterostructures comprising carbon nanotubes wrapped by atomically thin nanotubes of boron nitride and molybdenum disulfide (MoS2). The high quality of the composite was directly made evident on the atomic scale by transmission electron microscopy, and on the macroscopic scale by a study of the heterostructure’s equilibrium and ultrafast optoelectronics. Ultrafast pump−probe spectroscopy across the visible and terahertz frequency ranges identified that, in the MoS 2 nanotubes, excitons coexisted with a prominent population of free charges. The electron mobility was comparable to that found in high-quality atomically thin crystals. The high mobility of the MoS2 nanotubes highlights the potential of 1D van der Waals heterostructures for nanoscale optoelectronic devices.

Carbon nanotubes (CNTs) and boron nitride nanotubes (BNNTs) are one-dimensional materials with high thermal conductivity and similar crystal structures. Additionally, BNNTs feature higher thermal stability in air than CNTs. In this work, a single-walled carbon nanotube (SWCNT) film was used as a template to synthesize a BNNT coating by the chemical vapor deposition (CVD) method to form a coaxial heterostructure. Then, a contact-free steady-state infrared (IR) method was adopted to measure the in-plane sheet thermal conductance of the as-synthesized film. The heterostructured SWCNT-BNNT film demonstrates an enhanced sheet thermal conductance compared with the bare SWCNT film. The increase in sheet thermal conductance shows a reverse relationship with SWCNT film transparency. An enhancement of over 80% (from ∼3.6 to ∼6.4 μW·K

A novel series of cyclin-dependent kinases (CDKs) inhibitors, which play critical roles in the cell cycle control and regulation of cell transcription, were synthesised. A systematic study of enzymatic and cellular assays led to the identification of compound X22 with a nanomolar potency against CDK4 and CDK9 and potent antiproliferative activities against a panel of tumour cell lines. X22 could induce cell cycle arrest and cell apoptosis in cancer cell lines. X22 dose-dependently inhibits signalling pathways downstream of CDKs in cancer cells. In vivo antitumor activity assays, oral administration of X22 led to significant tumour regression in mouse model without obvious toxicity. Superior anti-cancer efficacy in vitro and in vivo of X22 demonstrated combined depletion of cell cycle and transcriptional CDK all contributed to antitumor activity. Taken together, concomitant inhibition of cell cycle and transcriptional CDK activities provided valuable guide for further structural optimisation.

Small extracellular vesicles (sEVs) play a key role in intercellular communication. Cargo molecules carried by sEVs may affect the phenotype and function of recipient cells. Epithelial cancer cell‐derived sEVs, particularly those enriched in CD151 or tetraspanin8 (TSPAN8) and associated integrins, promote tumour progression. The mechanism of binding and modulation of sEVs to recipient cells remains elusive. Here, we used genetically engineered breast cancer cells to derive TSPAN8‐enriched sEVs and evaluated the impact of TSPAN8 on target cell membrane's diffusion and transport properties. The single‐particle tracking technique showed that TSPAN8 significantly promoted sEV binding via confined diffusion. Functional assays indicated that the transgenic TSPAN8‐sEV cargo increased cancer cell motility and epithelial‐mesenchymal transition (EMT). In vivo, transgenic TSPAN8‐sEV promoted uptake of sEVs in the liver, lung, and spleen. We concluded that TSPAN8 encourages the sEV‐target cell interaction via forced confined diffusion and significantly increases cell motility. Therefore, TSPAN8‐sEV may serve as an important direct or indirect therapeutic target.

Significance We recently synthesized coaxially nested one-dimensional van der Waals heterostructures in which boron nitride nanotubes or molybdenum disulfide nanotubes grew seamlessly on a single-walled carbon nanotube template. In this work, edge structures, nucleation sites, and crystal epitaxial relationships in heteronanotubes are unambiguously revealed by a nondestructive transmission electron microscopic technique. These understandings, together with the characterization technique developed here, can help to optimize the synthesis process. Structure-controlled heteronanotubes may, ultimately, be used to build nanoscale devices such as gate-all-around nanotube transistors., We recently synthesized one-dimensional (1D) van der Waals heterostructures in which different atomic layers (e.g., boron nitride or molybdenum disulfide) seamlessly wrap around a single-walled carbon nanotube (SWCNT) and form a coaxial, crystalized heteronanotube. The growth process of 1D heterostructure is unconventional—different crystals need to nucleate on a highly curved surface and extend nanotubes shell by shell—so understanding the formation mechanism is of fundamental research interest. In this work, we perform a follow-up and comprehensive study on the structural details and formation mechanism of chemical vapor deposition (CVD)–synthesized 1D heterostructures. Edge structures, nucleation sites, and crystal epitaxial relationships are clearly revealed using transmission electron microscopy (TEM). This is achieved by the direct synthesis of heteronanotubes on a CVD-compatible Si/SiO2 TEM grid, which enabled a transfer-free and nondestructive access to many intrinsic structural details. In particular, we have distinguished different-shaped boron nitride nanotube (BNNT) edges, which are confirmed by electron diffraction at the same location to be strictly associated with its own chiral angle and polarity. We also demonstrate the importance of surface cleanness and isolation for the formation of perfect 1D heterostructures. Furthermore, we elucidate the handedness correlation between the SWCNT template and BNNT crystals. This work not only provides an in-depth understanding of this 1D heterostructure material group but also, in a more general perspective, serves as an interesting investigation on crystal growth on highly curved (radius of a couple of nanometers) atomic substrates.

As the power density and integration level of electronic devices increase, there are growing demands to improve the thermal conductivity of polymers for addressing the thermal management issues. On the basis of the ultrahigh intrinsic thermal conductivity, graphene has exhibited great potential as reinforcing fillers to develop polymer composites, but the resultant thermal conductivity of reported graphene-based composites is still limited. Here, an interconnected and highly ordered graphene framework (HOGF) composed of high-quality and horizontally aligned graphene sheets was developed by a porous film-templated assembly strategy, followed by a stress-induced orientation process and graphitization post-treatment. After embedding into the epoxy (EP), the HOGF/EP composite (24.7 vol %) exhibits a record-high in-plane thermal conductivity of 117 W m-1 K-1, equivalent to ≈616 times higher than that of neat epoxy. This thermal conductivity enhancement is mainly because the HOGF as a filler concurrently has high intrinsic thermal conductivity, relatively high density, and a highly ordered structure, constructing superefficient phonon transport paths in the epoxy matrix. Additionally, the use of our HOGF/EP as a heat dissipation plate was demonstrated, and it achieved 75% enhancement in practical thermal management performance compared to that of conventional alumina for cooling the high-power LED.

Deregulated telomere length is a causative factor in many physiological and pathological processes, including aging and cancer. Many studies focusing on telomeres have revealed important roles for cooperation between the Shelterin protein complex and telomerase in maintaining telomere length. However, it remains largely unknown whether and how aging-related stresses, such as deregulated protein homeostasis, impact telomere length. Here, we explored the possible roles of aminoacyl tRNA synthetases (AARSs), key enzymes catalyzing the first reactions in protein synthesis, in regulating telomere length and aging. We selected seryl tRNA synthetase (SerRS) since our previous studies discovered expanded functions of SerRS in the nucleus in addition to its canonical cytoplasmic role in protein synthesis. In this study, we revealed that overexpression of SerRS promoted cellular senescence and inhibited the growth of cervical tumor xenografts in mice by triggering the senescence of tumor cells. In the nucleus, SerRS directly bound to telomeric DNA repeats and tethered more POT1 proteins to telomeres through a direct interaction between the UNE-S domain of SerRS and the OB1 domain of POT1. We further demonstrated that SerRS-induced enrichment of POT1 prevented the recruitment of telomerase to telomeres, resulting in progressive telomere shortening. Our data suggested a possible molecular link between protein synthesis and telomere length control, the deregulation of which may be associated with aging and cancer.

Zona occludens-1 (ZO-1) is a key component of tight junctions that govern the function of the endothelial barrier against tumor metastasis. Factors secreted by tumor cells contribute to the maintenance of tumor vascular networks. How tumor cell-derived protein signals regulate ZO-1 expression is unclear. Here, we explored the effect of tumor cell-secreted asparaginyl endopeptidase (AEP) on the permeability of endothelial cells in the tumor microenvironment. First, we confirmed the existence of AEP in conditioned medium (CM) from AEP-overexpressing MDA-MB-231 and 4T1 cells. Treatment with CM from AEP-overexpressing tumor cells increased the permeability and tumor cell transversal of an endothelial monolayer. Furthermore, CM from AEP-overexpressing tumor cells suppressed endothelial ZO-1 expression, as well as ZO-1-associated nucleic acid binding protein ZONAB. In addition, the level of phosphorylated STAT3 was increased by treatment with AEP-containing CM. A mutation of RGD or blocking integrin αvβ3 with antibody recovered the ZO-1 downregulation induced by AEP. In vivo, a lung metastatic mouse model showed increased endothelial permeability in the AEP-overexpressing group compared with the control group. An orthotopic tumor transplantation model was established using AEP-overexpression and compared with mice receiving control 4T1 cells. Compared with controls, overexpression of AEP increased lung metastatic foci and area, as well as vascular instability in primary tumors or lung metastatic sites. Moreover, endothelial ZO-1 was decreased in the AEP-overexpressing group. Taken together, our data show that tumor cell-derived AEP increases the permeability of endothelial barriers. Interactions between RGD and endothelial integrin αvβ3 mediate this effect by downregulating ZO-1.

Ceftolozane is MSD's 5th generation cephalosporin antibiotic with broad-spectrum gram-negative activity. While refining the synthetic route to the drug substance, a dimeric impurity was observed in the final active pharmaceutical ingredient (API) of ceftolozane. Through impurity enrichment and preparative isolation, the structure of the impurity was subsequently established through LC/HRMS, HRMSMS, H/D exchange and 2D-NMR studies. A kinetic study of the impurity formation was conducted to determine the best conditions to control it in the final chemical process.

Summary The structure-specific endonuclease ERCC1/XPF plays an important role in nucleotide excision repair and interstrand cross-link repair. In this study, we identified new functions of ERCC1/XPF in DNA double-strand break (DSB) repair. We found that the conserved function of ERCC1/XPF to remove non-homologous sequences at DSBs is a rate-limiting step for homologous recombination in mammalian cells, and more importantly, we uncovered an indispensable role of ERCC1/XPF in repair of DSBs containing DNA secondary structures, including the structure-prone AT-rich DNA sequences derived from common fragile sites and G-quadruplexes (G4s). We also demonstrated a synthetic lethal interaction of XPF with DNA translocase FANCM that is involved in removing DNA secondary structures. Furthermore, inactivation of XPF sensitizes FANCM-deficient cells to G4-interacting compounds. These results suggest an important function of ERCC1/XPF in protecting DNA secondary structures and provide a rationale for targeted treatment of FANCM-deficient tumors through inhibition of XPF., Graphical Abstract, Highlights • ERCC1/XPF has a conserved role in removing non-homologous tails at DSBs during HR • ERCC1/XPF is required for repairing DSBs containing DNA secondary structures by HR • XPF is synthetic lethal with FANCM • XPF deficiency causes sensitivity to G4-interacting compounds, Biological Sciences; Molecular Biology; Cell Biology

Photoactivated therapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is a spatiotemporally precise, controllable, and noninvasive method for tumor therapy and has therefore attracted increasing attention in recent years. However, it is still a challenge to obtain highly efficient therapeutic photoactive agents (PAAs) and deliver them into tumor, especially the core of solid tumors. Here, we have developed a newly engineered monocyte (MNC)-based PAA system that realizes precise and highly efficient tumor diagnosis and therapy. First, a near-infrared emissive PAA molecule with both strong singlet oxygen (1O2) production and high photothermal conversion efficiency was precisely designed for realizing simultaneous PDT and PTT of tumor and was further fabricated to form PAA nanoparticles (NPs). After loading the PAA NPs into MNCs, the MNCs were then decorated with cyclic Arg-Gly-Asp (cRGD) groups through a metabolic labeling method to further improve their ability of targeting and homin...

Tumor cells need to attain anoikis resistance to survive prior to metastasis making it a vital trait of malignancy. The molecular mechanism by which hepatocellular carcinoma (HCC) cells resist anoikis remains not fully understood. Here, we report that ZNF32 expression is markedly upregulated in HCC cells upon detachment. Enforced ZNF32 expression significantly promotes the anchorage-independent growth capability of HepG2 and Huh7 cells, whereas knockdown of ZNF32 results in increased apoptosis of HCC cells after detachment. Mechanistically, we demonstrate that ZNF32 overexpression suppresses the reactive oxygen species (ROS) accumulation and maintains mitochondrial membrane potential, leading to ATP, GSH and NADPH elevation and promoting HCC cell survival in response to suspension. Moreover, ZNF32 enhances the phosphorylation and activation of Src/FAK signaling. Src and FAK inhibitors effectively reverse ZNF32-induced anoikis resistance in HCC cells. Collectively, our findings not only reveal a novel and important mechanism by which ZNF32 contributes to anoikis resistance through maintaining redox homeostasis and activating Src/FAK signaling, but also suggest the potential therapeutic value of ZNF32 in HCC patients.

As a result of terrestrial input and local circulation, an area containing continuously deposited mud with abundant organic matter (OM) has formed in the Yellow Sea (YS) off the Shandong Peninsula, China, during the Holocene. The understanding of temporal variations in sedimentary organic matter (SOM) from this mud area helps to evaluate the influences of Yellow River discharge and marine productivity on the burial of organic matter in the YS. In this study, multiple organic geochemical proxies were used to reconstruct Holocene changes in SOM in a sediment core (A02C) recovered from the mud area of the YS. Higher total organic carbon (TOC) and biomarker contents during the early Holocene relative to the middle and late Holocene are attributed to sea-level fluctuations. The δ13C values of TOC (δ13CTOC) range from −21.8‰ to −23.5‰, becoming more positive from the bottom to the top of the core. TMBR' (terrestrial and marine biomarker ratio) values vary from 0.43 to 0.80, with a decreasing trend during the Holocene. The decrease in TOM contribution was related to elevated sea-level, shifting of the mouth of the Yellow River, and weakening of the East Asian Winter Monsoon (EAWM) during the Holocene. A mixing model with three end-members, based on δ13CTOC and TMBR', reveals that the contribution of soil OM (average 42%) is higher than that of plant OM (average 17%). Simultaneous decreases in the plant OM fraction and the marine OM fraction occurred around 10.3, 8.2, 5.9, 4.2, and 2.8 kyr BP, corresponding to drift-ice events in the North Atlantic. Spectral analyses also reveal that all three OM fractions exhibit 1015-year periodicity and that the soil and plant OM fractions display 1420-year periodicity, consistent with the 1000-year cycle of solar activity and the 1500-year cycle of the Kuroshio Current (KC), respectively.

Planktic foraminifera-bound organic nitrogen isotopes (FB-δ 15 N) archived in sediments provide an opportunity to reveal past changes in marine nitrogen cycling in the upper water column. However, detailed knowledge about living foraminifera FB-δ 15 N is still critically lacking. This study presents the FB-δ 15 N analysis of planktic foraminifera collected from plankton tows and sediment traps in the South China Sea and the Bay of Bengal. Tests of Globigerinoides sacculifer with- and without-sac like chamber from plankton tows showed almost identical FB-δ 15 N values, suggesting that high thermocline δ 15 N is not incorporated into the carbonate tests during gametogenic calcification. Sediment trap samples revealed that species dwelling in the upper euphotic zone, such as Globigerinoides sacculifer , contained slightly depleted FB-δ 15 N relative to the deeper-dwelling species, such as Orbulina universa and Globigerinella siphonifera . The three species also contained FB-δ 15 N similar to δ 15 N of the suspended particulate organic matter at corresponding dwelling depths. Our results confirm the increase in FB-δ 15 N from shallower-dwelling species to deeper-dwelling species and these FB-δ 15 N differences (Δ 15 N vertical ) between shallower- and deeper-dwelling species may shed light on the nitrogen dynamics of the euphotic zone in the South China Sea, which is under the influence of the East Asian winter monsoon.

The rapid development of integrated circuits and electronic devices creates a strong demand for highly thermally conductive yet electrically insulating composites to efficiently solve "hot spot" problems during device operation. On the basis of these considerations, hexagonal boron nitride nanosheets (BNNS) have been regarded as promising fillers to fabricate polymer matrix composites. However, so far an efficient approach to prepare ultrahigh-aspect-ratio BNNS with large lateral size while maintaining an atomically thin nature is still lacking, seriously restricting further improvement of the thermal conductivity for BNNS/polymer composites. Here, a rapid and high-yield method based on a microfluidization technique is developed to obtain exfoliated BNNS with a record high aspect ratio of ≈1500 and a low degree of defects. A foldable and electrically insulating film made of such a BNNS and poly(vinyl alcohol) (PVA) matrix through filtration exhibits an in-plane thermal conductivity of 67.6 W m

Histone lysine demethylase 4D (KDM4D), also known as JMJD2D, plays an important role in cell proliferation and survival and has been associated with several tumor types. KDM4D has emerged as a potential target for the treatment of human cancer. Here, we reported crystal complex structures for two KDM4D inhibitors, OWS [2-(1H-pyrazol-3-yl)isonicotinic acid] and 10r (5-hydroxy-2-methylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-3-carbonitrile), which were both determined to 2.0 A. OWS is a newly discovered KDM4D inhibitor (IC50 = 4.28 μM) and the critical pharmacophores of this compound are confirmed by the complex structure. Compound 10r is a KDM4D inhibitor reported by us previously. To clarify the binding mode in more detail, the crystal structure was determined and the comparison analysis revealed unique interactions that had never been observed before. Overall, our data provide new structural insights for rational design and offer an opportunity for optimization of KDM4D inhibitors.

Silicon is important as a nutrient for phytoplankton (diatom, radiolarian, silicoflagellates and sponges) and for the phytolith production by terrestrial vegetation. Silicon also contributes in removing carbon dioxide from the atmosphere through silicate weathering. Hence it is important to understand the behavior of the silicon cycle throughout earth history. Silica is the second most abundant element in the earth's crust and the concentration of silicic acid in the marine environment has not changed since the past 10,000 years. Phytolith plays an important role in the silicon cycle. While the phytoplankton in marine environment bioengineers silica within the water column, phytolith transports terrestrial biogenic silica into the marine environment and act as a silicon sink. Though astonishingly, very few researches have been carried out in the field of marine phytolith sink and also on the phytoliths in the marine environment.For this study, we have chosen the world highest terrestrial sediment receiving submarine fan, the Bengal fan. The core sample was extracted at a water depth of 3520m at 85.960985 N, 9.99351 E. 24 phytolith types were identified and all the morphotypes were counted dividing into three size classes. These size classes were specific to considering morphotypes. Most related simple geometries were used to calculate the volume of phytolith cells and these volume data were used in calculating the total volume of phytolith in one gram of sediment by combining with an absolute abundance of phytolith data for each size class, which were later used to calculate the total weight of phytolith in one gram of marine sediment. According to the results in deep oceanic sediment at the core, the location contains ⁓0.15mg/g phytolith during the low phytolith flux periods (ex. Late Holocene) and ⁓2.678mg/g of phytolith during the high phytolith flux periods such as 25ka to 30ka B.P. and around the beginning of deglaciation. After removing 10% from the total weight as phytolith occluded carbon (PhytOC), phytolith derived biogenic silica content in sediment varies from ⁓0.135mg/g - ⁓2.41mg/g. Thus, phytolith in marine sediment contributes as a permanent silicon and carbon sink. By considering average marine sediment density as 1.7g/cm3, in a 1cm thick, one square km sediment layer contains ⁓2 to 40 metric tons of biogenic silica derived from phytolith, during low and high phytolith flux periods. This study serves as the pioneer of this field of study and further it is important to investigate the release of biogenic silica in to marine environment by phytolith and PhytOC content in different morphotypes and in different geological regions, for better understanding the contribution of phytolith to the biogenic silicon cycle in the marine environment.Keywords: Marine phytolith, Deep oceanic sediment, Silicon cycle, Phytolith Flux, Silicon sink.AcknowledgementsThis work was funded by the National Natural Science Foundation of China (NSFC 41876062) and Key Special Project for Introduced Talents Team of Southern Marine Science and EngineeringGuangdong Laboratory (Guangzhou) (GML2019ZD0206).

The synthesis of one-dimensional van der Waals heterostructures was realized recently, which opens up new possibilities for prospective applications in electronics and optoelectronics. The even reduced dimension will enable novel properties and further miniaturization beyond the capabilities of its two-dimensional counterparts have revealed. The natural doping results in p-type electrical characteristics for semiconducting single-walled carbon nanotubes, while n-type for molybdenum disulfide with conventional noble metal contacts. Therefore, we demonstrate here a one-dimensional heterostructure nanotube of 11-nm-wide, with the coaxial assembly of semiconducting single-walled carbon nanotube, insulating boron nitride nanotube, and semiconducting molybdenum disulfide nanotube which induces a radial semiconductor-insulator-semiconductor heterojunction. When opposite potential polarity was applied on semiconducting single-walled carbon nanotube and molybdenum disulfide nanotube, respectively, the rectifying effect was materialized., Comment: 29 pages, 6 figures

At the electron linac for beams with high brilliance and low emittance (ELBE) center for high-power radiation sources, the second version of a superconducting radio-frequency (SRF) photoinjector has been put into operation and has been routinely applied for user operation at the ELBE electron accelerator. SRF guns are suitable for generating a continuous wave electron beam with high average currents and high beam brightness. The SRF gun at ELBE has the goal to generate short electron pulses with bunch charges of 200–300 pC at typical repetition rates of 100 kHz for the production of superradiant, coherent terahertz radiation. The SRF gun includes a 3.5-cell, 1.3-GHz niobium cavity and a superconducting solenoid. A support system with liquid nitrogen (LN_{2}) cooling allows the operation of normal-conducting, high quantum efficiency photocathodes. We present the design and performance of the SRF gun as well as beam measurement results of the operation with Mg photocathodes at an acceleration gradient of 8 MV/m (4 MeV kinetic energy). In the last section, we discuss the SRF gun application for production of coherent terahertz radiation at the ELBE facility.

The thermal properties of individual single-walled carbon nanotubes (SWCNTs) have been well documented in the literature following decades of intensive study. However, when SWCNTs form a macroscale assembly, the thermal transport in these complex structures usually not only depends on the properties of the individual tubes, but also is affected and sometimes dominated by inner structural details, e.g. bundles and junctions. In this work, we first performed an experimental measurement of the thermal conductivities of individual SWCNT bundles of different sizes using a suspended micro-thermometer. The results, together with the data that we obtained from a previous work, give a complete experimental understanding of the effect of bundling on the thermal conductivity of SWCNTs. With these quantitative understandings, we propose a phenomenological model to describe the thermal transport in two-dimensional (2D) SWCNT films. The term ‘line density’ is defined to describe the effective thermal transport channels in this complex 2D network. Along with experimentally obtained geometric statistics and film transparency, the thermal conductance of SWCNTs is estimated, and the effects of bundle length, diameter, and contact conductance are systematically discussed. Finally, we extend this model to explain thermal transport in 2D networks of one-dimensional van der Waals heterostructures, which are coaxial hetero-nanotubes we recently synthesized using SWCNTs as the template. This extended model suggests that the contribution of boron nitride nanotubes (BNNTs) to the overall performance of a SWCNT–BNNT heterostructured film depends on the transparency of the original SWCNT film. The increase in the thermal conductance of a highly transparent film is estimated to be larger than that of a less transparent film, which shows a good agreement with our experimental observations and proves the validity of the proposed phenomenological model.

Ketones, one of widely applied moieties in designing electrical and medical materials, commonly converted from the alcohols through the oxidation reactions. However, when alcohols are protected/functionalized, the direct oxidation strategies are substantially curbed. Here we show a highly efficient copper bromide promoted one-step direct oxidation of alkoxy to ketone with the aid of a fullerene pendant. Mechanistic studies unveil that fullerene can serve as an electron poor proceeding the one-step oxidation of alkoxy group to ketone. In the absence of fullerene pendant, the unreachable activation energy threshold hampers the direct oxidation of alkoxy group. In the presence of fullerene pendant, copper bromide oxidized fullerene radical cation can activate neighboring C–H bond of alkoxy moieties, allowing a favorable energy barrier for initiating the direct oxidation of alkoxy group. Produced fullerene-fused ketone indicates high thermal stability, affording the pin-hole free and amorphous electron-transport layer with high electron-transport mobility.

Graphene is usually embedded into polymer matrices for the development of thermally conductive composites, preferably forming an interconnected and anisotropic framework. Currently, the directional self‐assembly of exfoliated graphene sheets is demonstrated to be the most effective way to synthesize anisotropic graphene frameworks. However, achieving a thermal conductivity enhancement (TCE) over 1500% with per 1 vol% graphene content in polymer matrices remains challenging, due to the high junction thermal resistance between the adjacent graphene sheets within the self‐assembled graphene framework. Here, a multiscale structural modulation strategy for obtaining highly ordered structure of graphene framework and simultaneously reducing the junction thermal resistance is demonstrated. The resultant anisotropic framework contributes to the polymer composites with a record‐high thermal conductivity of 56.8–62.4 W m−1 K−1 at the graphene loading of ≈13.3 vol%, giving an ultrahigh TCE per 1 vol% graphene over 2400%. Furthermore, thermal energy management applications of the composites as phase change materials for solar‐thermal energy conversion and as thermal interface materials for electronic device cooling are demonstrated. The finding provides valuable guidance for designing high‐performance thermally conductive composites and raises their possibility for practical use in thermal energy storage and thermal management of electronics., The dual‐assembled graphene framework (DAGF), which combines a highly oriented graphene structure along the vertical direction and a low junction thermal resistance between the graphene building blocks, exhibits excellent performance in improving the thermal conductivity of polymers. The resultant composites have a record‐high thermal conductivity of 56.8–62.4 W m−1 K−1(≈13.3 vol%), significantly outperforming previously reported results.

Rationale: Considerable evidence suggests that breast cancer metastasis and recurrence occur due to emergence of cancer stem cells (CSCs). In our previous study, we designed a high-throughput siRNA screening platform that identifies inflammation genes involved in the regulation of cancer cell stemness. We reported that CCL16 protein decreases OCT4 expression and reduces the ALDH+ subpopulation. However, the mechanism by which CCL16 maintains stem cell-like properties remains unclear. Methods: Tissue microarrays were used to evaluate CCL16 expression. Cancer stemness assays were performed in CCL16 knockdown and overexpressing cells in vitro and in a xenograft model in vivo. Human phosphokinase array, immunofluorescence and chromatin immunoprecipitation assays were performed to explore the underlying mechanism. Results: We report that CCL16 was overexpressed in breast tumors and significantly correlated with clinical progression. We found that silencing CCL16 in MDA-MB-231 and BT549 cells diminished CSC properties including ALDH+ subpopulation, side population, chemo-resistance, and sphere formation. Furthermore, mice bearing CCL16-silenced MDA-MB-231 xenografts had lower tumorigenic frequency and developed smaller tumors. Exploration of the underlying mechanism found that CCL16 selects CCR2 to activate p-AKT/GSK3β signaling and facilitate β-catenin nuclear translocation. Further, CCL16 binds to the OCT4 promoter and promotes OCT4 expression. In addition, shRNAs targeting CCR2 and XAV939 targeting β-catenin abolished CCL16-mediated cancer stemness. Upstream, IL10 mediates STAT3 activation, which binds to the CCL16 promoter and enhances its expression. The STAT3-targeted inhibitor Stattic suppressed CCL16 expression in vitro and restrained tumor progression in vivo. Conclusions: We identified a potential CSC regulator and suggest a novel mechanism for how CCL16 governs cancer cell stemness. We propose that CCL16 could be an effective target for breast cancer therapy.

Arteriosclerotic cardiovascular disease (ASCVD) is one of the major causes of death worldwide and most commonly develops as a result of atherosclerosis (AS). As we all know, dyslipidemia is a leading pathogenic risk factor for ASCVD, which leads to cardiac ischemic injury and myocardial infarction. Dyslipidemias include hypercholesterolemia, hypertriglyceridemia, increased low-density lipoprotein cholesterol (LDL-c) and decreased high density lipoproteins cholesterol (HDL-c). Mutations of dyslipidemia related genes have been proved to be the crucial contributor to the development of AS and ASCVD. In this study, a Han-Chinese family with ASCVD was enrolled and the lipid testing discovered an obvious reduced levels of HDL-c in the affected members. We then performed whole exome sequencing to detect the candidate genes of the family. After data filtering, a novel heterozygous nonsense mutation (NM_007168: c.3460C>T; p.R1154X) of ABCA8 was detected and validated to be co-separated in the family members by Sanger sequencing. Previous studies have proved that deleterious heterozygous ABCA8 variants may disrupt cholesterol efflux and reduce HDL-c levels in humans and mice. This study may be the second report related to ABCA8 mutations in patients with reduced levels of HDL-c. Our study not only contributed to the genetic counseling and prenatal genetic diagnosis of patients with ASCVD caused by reduced HDL-c levels, but also provided a new sight among ABCA8, cholesterol efflux and HDL-c levels.

Influenza continues to be a significant public health challenge. Two glycoproteins on the surface of influenza virus, hemagglutinin and neuraminidase, play a prominent role in the process of influenza virus infection and release. Monoclonal antibodies targeting glycoproteins can effectively prevent the spread of the virus. In this review, we summarized currently reported human monoclonal antibodies targeting glycoproteins of influenza A and B viruses.

We report a series of palladium(II)-catalyzed, intramolecular alkene hydrofunctionalization reactions with carbon, nitrogen, and oxygen nucleophiles to form five- and six-membered carbo- and heterocycles. In these reactions, the presence of a proximal bidentate directing group controls the cyclization pathway, dictating the ring size that is generated, even in cases that are disfavored based on Baldwin’s rules and in cases where there is an inherent preference for an alternative pathway. DFT studies shed light on the origins of pathway selectivity in these processes.

Serine/threonine protein kinases Aurora A, B, and C play essential roles in cell mitosis and cytokinesis, and a number of Aurora kinase inhibitors have been evaluated in the clinic. Herein we report the synthesis and their antiproliferation of 3,5-disubstituted-2-aminopyrazines as kinases inhibitors. Amongst, 4-((3-amino-6- (3,5-dimethylisoxazol-4-yl)pyrazin-2-yl)oxy)-N-(3-chlorophenyl) benzamide (12Aj) exhibited the strongest antiproliferative activities against U38, HeLa, HepG2 and LoVo cells with IC50 values were 11.5 ± 3.2, 1.34 ± 0.23, 7.30 ± 1.56 and 1.64 ± 0.48 μM, as well as inhibited Aurora A and B with the IC50 values were 90 and 152 nM, respectively. Molecular docking studies indicated that 12Aj appeared to form stable hydrogen bonds with either Aurora A or Aurora B. Furthermore, 12Aj arrested HeLa cell cycle in G2/M phase by regulating protein levels of cyclinB1 and cdc2. In addition, the bioinformatics prediction further revealed that 12Aj possessed good drug likeness using SwissADME. These results suggested that 12Aj was worthy of future development of potent anticancer agents as pan-Aurora kinases.

Background: Tetraspanins constitute a family of transmembrane spanning proteins that function mainly by organizing the plasma membrane into micro-domains. CD82, a member of tetraspanins, is a potent inhibitor of cancer metastasis in numerous malignancies. CD82 is a highly glycosylated protein, however, it is still unknown whether and how this post-translational modification affects CD82 function and cancer metastasis. Methods: The glycosylation of CD82 profiles are checked in the paired human ovarian primary and metastatic cancer tissues. The functional studies on the various glycosylation sites of CD82 are performed in vitro and in vivo. Results: We demonstrate that CD82 glycosylation at Asn157 is necessary for CD82-mediated inhibition of ovarian cancer cells migration and metastasis in vitro and in vivo. Mechanistically, we discover that CD82 glycosylation is pivotal to disrupt integrin α5β1-mediated cellular adhesion to the abundant extracellular matrix protein fibronectin. Thereby the glycosylated CD82 inhibits the integrin signaling pathway responsible for the induction of the cytoskeleton rearrangements required for cellular migration. Furthermore, we reveal that the glycosyltransferase MGAT3 is responsible for CD82 glycosylation in ovarian cancer cells. Metastatic ovarian cancers express reduced levels of MGAT3 which in turn may result in impaired CD82 glycosylation. Conclusions: Our work implicates a pathway for ovarian cancers metastasis regulation via MGAT3 mediated glycosylation of tetraspanin CD82 at asparagine 157.

Single- and multi-walled molybdenum disulfide (MoS$_2$) nanotubes have been coaxially grown on small diameter boron nitride nanotubes (BNNTs) which were synthesized from heteronanotubes by removing single-walled carbon nanotubes (SWCNTs), and systematically investigated by optical spectroscopy. The strong photoluminescence (PL) from single-walled MoS$_2$ nanotubes supported by core BNNTs is observed in this work, which evidences a direct band gap structure for single-walled MoS$_2$ nanotubes with around 6 - 7 nm in diameter. The observation is consistent with our DFT results that the single-walled MoS$_2$ nanotube changes from an indirect-gap to a direct-gap semiconductor when the diameter of a nanotube is more than around 5 nm. On the other hand, when there are SWCNTs inside the heteronanotubes of BNNTs and MoS$_2$ nanotubes, the PL signal is considerably quenched. The charge transfer and energy transfer between SWCNTs and single-walled MoS$_2$ nanotubes were examined through characterizations by PL, XPS, and Raman spectroscopy. Unlike the single-walled MoS$_2$ nanotubes, multi-walled MoS$_2$ nanotubes do not emit light. Single- and multi-walled MoS$_2$ nanotubes exhibit different Raman features in both resonant and non-resonant Raman spectra. The method of assembling heteronanotubes using BNNTs as templates provides an efficient approach for exploring the electronic and optical properties of other transition metal dichalcogenide nanotubes.

Transition metal catalysts in pharmaceutical processes is widely used, but health care agencies such as the Food and Drug Administration and the European Medicines Agency highly regulate the residual level of elemental impurities in the final drug substance and drug product to avoid any adverse effect on patients. Controlling these elemental impurities requires a thorough understanding of the catalytic mechanism and the fate of each elemental impurity. Only with this knowledge in hand can a process be developed to sufficiently remove residual elemental impurities to acceptable levels. Recently, there has been tremendous progress in metal speciation directly assisted by HPLC-ICP-MS. To investigate the removal of elemental impurities from reaction process, we have utilized metal speciation data to provide critical information on the fate of each elemental impurity and a deeper understanding of the catalytic mechanism. Herein we present our recent analytical showcases on (i) how we successfully implemented a...

Impacts of hot water extraction (HWE), pressurized water extraction (PWE), high-speed shearing homogenization extraction, microwave assisted extraction (MAE), ultrasound assisted extraction (UAE), ultrasound assisted enzymatic extraction, and ultrasound-microwave assisted extraction (UMAE) on physicochemical characteristics and bioactivities of polysaccharides from loquat (Eriobotrya japonica) leaves (LLPs) were investigated. Results showed that the degrees of esterification, contents of phenolics and uronic acids, constituent monosaccharides, apparent viscosities, and molecular weights of LLPs varied by different extraction methods. Bioactivities of LLPs were also significantly affected by different extraction methods. The high molecular weight and high degree of esterification of LLP-W and LLP-P extracted by HWE and PWE, respectively, might contribute to their strong binding capacities. The strong antioxidant activities and inhibitory effects on α-amylase and α-glucosidase were found in LLP-M and LLP-U extracted by MAE and UAE, respectively, which might be attributed to their contents of uronic acids, contents of total phenolics, and molecular weights. The low molecular weights and viscosities of LLP-U and LLP-UM extracted by UMAE might contribute to their strong prebiotic effects. These findings could provide scientific foundations for selecting appropriate extraction methods to obtain LLPs with desired bioactivities for applications in the pharmaceutical and functional food industries.

Two distinct macrophage phenotypes contribute to kidney injury and repair during the progression of renal interstitial fibrosis; proinflammatory (M1) and antiinflammatory (M2) macrophages. Legumain, an asparaginyl endopeptidase of the cysteine protease family, is overexpressed in macrophages in some pathological conditions. However, the macrophage subtype and function of macrophage-derived legumain remains unclear. To resolve this we tested whether M2 macrophages contribute to the accumulation of legumain in the unilateral ureteral obstruction model. Legumain-null mice exhibited more severe fibrotic lesions after obstruction compared with wild-type control. In vitro, IL4-stimulated M2 polarization led to the overexpression and secretion of legumain. The levels of fibronectin and collagen I/III, major components of the extracellular matrix, were reduced in the conditioned medium of TGF-β1-stimulated tubular epithelial cells or fibroblasts after treatment with legumain or conditioned medium from IL4-stimulated macrophages. Administration of the legumain inhibitor RR-11a exacerbated fibrotic lesions following obstruction. Therapeutically, adoptive transfer of legumain-overexpressing macrophages or IL4-stimulated macrophages ameliorated the deposition of collagen and fibronectin induced by ureteral obstruction, either in the wild-type mice or in lgmn–/– mice. Thus, M2 macrophages overexpress and secret legumain and legumain mediates the anti-fibrotic effect of M2 macrophages in obstructive nephropathy.

Two new pyrazinoquinazoline alkaloids, epi-fiscalin D (1) and epi-fiscalin E (2), as well as three known analogues, norquinadoline A (3), quinadoline A (4), and fiscalin C (5), were isolated from ethyl acetate extract of the fermentation broth of Stentrophomonas maltophilia QB-77. The structures of new compounds were elucidated on the basis of extensive spectroscopic data analysis including UV, HRESIMS, and 1D and 2D NMR experiments. All the isolated compounds were tested for their in vitro cytotoxicity against five human cancer cell lines (SMMC-7721, MCF-7, HL-60, SW480, and A-549) and antibacterial activities against Bacillus subtilis, Escherichia coli, and Staphylococcus aureus.

A series of novel LEE011 derivatives containing pyridine N-oxide were designed, synthesized and evaluated. Systematic study of the structure-activity relationship (SAR) improves the selectivity for CDK4 and led to the identification of compound 9a. The compound showed comparable CDK4 kinase activity with ribociclib and greater selectivity over the closely related CDK6 kinase. The selective CDK4 inhibitor 9a has been demonstrated the antitumor activity via G1 phase cell cycle arrest, as well as dual CDK4/CDK6 inhibitor ribociclib and significantly down-regulated the activity of CDK4-cyclinD-Rb pathway of tumor cells. Taken together, this compound may act as promising lead compound for further development of new CDK4 inhibitors.

Marginal seas are important transitional zones for the delivery of terrestrial organic matter (TOM) from land to the open sea, and they play an important role in the carbon cycle. Tracing the source of sedimentary organic matter (SOM) deposited in marginal seas is fundamental to our understanding of the dispersal, degradation, migration, and conversion of organic matter. This paper presents high-resolution records of bulk organic matter and biomarker proxies from Core T08 that was recovered from the inner shelf of the East China Sea (ECS), and aims to identify the contributions of marine and terrestrial organic matter over the past 3725 yrs. Total organic carbon (TOC) values were low (0.50%) and showed no significant change between 3725 and 1800 yr BP (Period I), and increased continuously from 0.40% to 0.86% after 1800 yr BP (Period II: 1800–750 yr BP; Period III: 750 yr BP–present). The TMBR′ (ratio of terrestrial to marine biomarkers) and δ13CTOC (δ13C of TOC) values showed steady TOM contribution during Period I and higher TOM contribution driven by the increased Changjiang River (CR)-derived TOM under strong East Asian Summer Monsoon (EASM) and El Nino during Period II. During Period III, the increase in marine organic matter (MOM) contribution was indicated by the TMBR′, and this was caused by enhanced marine productivity related to intensified vertical mixture that was driven by the strengthened East Asian Winter Monsoon (EAWM). δ13CTOC shows a contrary trend to the TMBR′ during Period III, probably influenced by variations in the C3 vegetation type during this period. Spectral analysis of the TMBR′ series for the last 1200 yrs shows cycles with periods of 119, 75–85, and 54 yrs, confirming that climate-related events influenced the variation in SOM under the modulation of solar activity and solar irradiance at the centennial scale.