Net-1,2-Hydrogen Atom Transfer of Amidyl Radicals: Toward the Synthesis of 1,2-Diamine Derivatives.

Hydrogen atom transfer (HAT) processes are among the most useful approaches for the selective construction of C(sp3)-C(sp3) bonds. 1,5-HAT with heteroatom-centered radicals (O•, N•) have been well established and are favored relative to other 1,n-HAT processes. In comparison, net 1,2-HAT processes have been observed infrequently. Herein, the first amidyl radicalls are reported that preferentially undergo a net 1,2-HAT over 1,5-HAT. Beginning with single electron transfer from 2-azaallyl anions to N-alkyl N-aryloxy amides, the latter generate amidyl radicals. The amidyl radical undergoes a net-1,2-HAT to generate a C-centered radical that participates in an intermolecular radical-radical coupling with the 2-azaallyl radical to generate 1,2-diamine derivatives. Mechanistic and EPR experiments point to radical intermediates. Density functional theory calculations provide support for a base-assisted, stepwise-1,2-HAT process. It is proposed that the generation of amidyl radicals under basic conditions can be greatly expanded to access α-amino C-centered radicals that will serve as valuable synthetic intermediates.

LINC00955 suppresses colorectal cancer growth by acting as a molecular scaffold of TRIM25 and Sp1 to Inhibit DNMT3B-mediated methylation of the PHIP promoter.

BACKGROUND: Long non-coding RNAs play an important role in the development of colorectal cancer (CRC), while many CRC-related lncRNAs have not yet been identified. METHODS: The relationship between the expression of LINC00955 (Long Intergenic Non-protein Coding RNA 955) and the prognosis of colorectal cancer patients was analyzed using the sequencing results of the TCGA database. LINC00955 expression levels were measured using qRT-PCR. The anti-proliferative activity of LINC00955 was evaluated using CRC cell lines in vitro and xenograft models in nude mice in vivo. The interaction of TRIM25-Sp1-DNMT3B-PHIP-CDK2 was analyzed by western blotting, protein degradation experiment, luciferase, RNA-IP, RNA pull-down assays and immunohistochemically analysis. The biological roles of LINC00955, tripartite motif containing 25 (TRIM25), Sp1 transcription factor (Sp1), DNA methyltransferase 3 beta (DNMT3B), pleckstrin homology domain interacting protein (PHIP), cyclin dependent kinase 2 (CDK2) in colorectal cancer cells were analyzed using ATP assays, Soft agar experiments and EdU assays. RESULTS: The present study showed that LINC00955 is downregulated in CRC tissues, and such downregulation is associated with poor prognosis of CRC patients. We found that LINC00955 can inhibit CRC cell growth both in vitro and in vivo. Evaluation of its mechanism of action showed that LINC00955 acts as a scaffold molecule that directly promotes the binding of TRIM25 to Sp1, and promotes ubiquitination and degradation of Sp1, thereby attenuating transcription and expression of DNMT3B. DNMT3B inhibition results in hypomethylation of the PHIP promoter, in turn increasing PHIP transcription and promoting ubiquitination and degradation of CDK2, ultimately leading to G0/G1 growth arrest and inhibition of CRC cell growth. CONCLUSIONS: These findings indicate that downregulation of LINC00955 in CRC cells promotes tumor growth through the TRIM25/Sp1/DNMT3B/PHIP/CDK2 regulatory axis, suggesting that LINC00955 may be a potential target for the therapy of CRC.

Structural basis for allosteric, substrate-dependent stimulation of SIRT1 activity by resveratrol.

Sirtuins with an extended N-terminal domain (NTD), represented by yeast Sir2 and human SIRT1, harbor intrinsic mechanisms for regulation of their NAD-dependent deacetylase activities. Elucidation of the regulatory mechanisms is crucial for understanding the biological functions of sirtuins and development of potential therapeutics. In particular, SIRT1 has emerged as an attractive therapeutic target, and the search for SIRT1-activating compounds (STACs) has been actively pursued. However, the effectiveness of a class of reported STACs (represented by resveratrol) as direct SIRT1 activators is under debate due to the complication involving the use of fluorogenic substrates in in vitro assays. Future efforts of SIRT1-based therapeutics necessitate the dissection of the molecular mechanism of SIRT1 stimulation. We solved the structure of SIRT1 in complex with resveratrol and a 7-amino-4-methylcoumarin (AMC)-containing peptide. The structure reveals the presence of three resveratrol molecules, two of which mediate the interaction between the AMC peptide and the NTD of SIRT1. The two NTD-bound resveratrol molecules are principally responsible for promoting tighter binding between SIRT1 and the peptide and the stimulation of SIRT1 activity. The structural information provides valuable insights into regulation of SIRT1 activity and should benefit the development of authentic SIRT1 activators.

Spatial distribution and source apportionment of surface soil's polycyclic aromatic hydrocarbons in the Yangtze River Delta.

Soil acts as a crucial reservoir of polycyclic aromatic hydrocarbons (PAHs) in the environment, and its PAH content serves as a significant indicator of regional PAH pollution. Monitoring PAH levels in soil is important for assessing the potential risks to human and environmental health. In this study, 53 surface soil samples were collected from the Yangtze River Delta. These samples were monitored for 16 priority PAHs. Pollution levels, compositional profiles, and source differences of soil PAHs were analyzed among different regions, urban and rural areas, and functional zones. The total PAH content (Σ16PAHs) in the surface soil of the Yangtze River Delta was 2326.01 ± 2901.53 ng/g. High-ring PAHs (4-6 rings) accounted for the predominant portion (85.50%) of total PAHs. The average pollution level of soil PAHs in Jiangsu Province (2651.92 ± 3242.87 ng/g) was significantly higher than that of Zhejiang Province (2001.44 ± 2621.71 ng/g) and Shanghai (1669.13 ± 1758.34 ng/g), and high-ring PAHs constituted a predominant portion in these three regions. There was no significant difference in the PAH content between urban and rural areas. In different functional areas, automobile stations exhibited the highest PAH levels among the functional zones analyzed, with traffic emissions identified as a major source of soil PAH in this area. The primary factors influencing the distribution of soil PAHs in the study area were the duration of urbanization exposure (r = 0.753, p < 0.01) and soil organic carbon content (r = 0.452, p < 0.01). This provides novel evidence for the cumulative build-up of PAHs during urbanization. The positive matrix factorization model was used to analyze the sources of PAHs in the surface soil of the Yangtze River Delta, revealing that biomass and coal combustion (60.19%) and traffic emissions and coal combustion (31.82%) were the primary sources of PAHs in the region.

A Novel Mechanism for SIRT1 Activators That Does Not Rely on the Chemical Moiety Immediately C-Terminal to the Acetyl-Lysine of the Substrate.

SIRT1, an NAD+-dependent deacetylase, catalyzes the deacetylation of proteins coupled with the breakdown of NAD+ into nicotinamide and 2'-O-acetyl-ADP-ribose (OAADPr). Selective SIRT1 activators have potential clinical applications in atherosclerosis, acute renal injury, and Alzheimer's disease. Here, we found that the activity of the potent SIRT1 activator CWR is independent of the acetylated substrate. It adopts a novel mechanism to promote SIRT1 activity by covalently bonding to the anomeric C1' carbon of the ribose ring in OAADPr. In addition, CWR is highly selective for SIRT1, with no effect on SIRT2, SIRT3, SIRT5, or SIRT6. The longer distance between the anomeric C1' carbon of the ribose ring in OAADPr and Arg274 of SIRT1 (a conserved residue among sirtuins) than that between the anomeric C1' carbon in OAADPr and the Arg of SIRT2, SIRT3, SIRT5, and SIRT6, should be responsible for the high selectivity of CWR for SIRT1. This was confirmed by site-directed mutagenesis of SIRT3. Consistent with the in vitro assays, the activator also reduced the acetylation levels of p53 in a concentration-dependent manner via SIRT1 in cells. Our study provides a new perspective for designing SIRT1 activators that does not rely on the chemical moiety immediately C-terminal to the acetyl-lysine of the substrate.

Cycloastragenol upregulates SIRT1 expression, attenuates apoptosis and suppresses neuroinflammation after brain ischemia.

Cycloastragenol (CAG) is the active form of astragaloside IV isolated from Astragalus Radix, which displays multiple pharmacological effects. Silent information regulator 1 (SIRT1), a class III histone deacetylase, has been shown to play an important role in neuroprotection against cerebral ischemia. In this study, we investigated whether CAG protected against ischemic brain injury and, if so, whether the beneficial effects were associated with the regulation of SIRT1 in the ischemic brain. Mice were subjected to 45 min of middle cerebral artery occlusion (MCAO) followed by reperfusion. CAG (5, 10, 20 mg/kg) was injected intraperitoneally at the onset of reperfusion, 12 h later and then twice daily for up to three days. CAG dose-dependently reduced brain infarct volume, significantly ameliorated functional deficits, and prevented neuronal cell loss in MCAO mice. Meanwhile, CAG significantly reduced matrix metalloproteinase-9 activity, prevented tight junction degradation and subsequently ameliorated blood-brain barrier disruption. Moreover, CAG significantly upregulated SIRT1 expression in the ischemic brain but did not directly activate its enzymatic activity. Concomitant with SIRT1 upregulation, CAG reduced p53 acetylation and the ratio of Bax to Bcl-2 in the ischemic brain. CAG also inhibited NF-κB p65 nuclear translocation. As a result, CAG suppressed the mRNA expression of pro-inflammatory cytokines, including TNF-α and IL-1ß, and inhibited the activation of microglia and astrocytes in the ischemic brain. Our findings suggest that CAG is neuroprotective against ischemic brain injury in mice and that its beneficial effect may involve SIRT1 upregulation and the inhibition of apoptosis and neuroinflammation in the ischemic brain.

Design, Synthesis, and Biological Evaluation of 8-Mercapto-3,7-Dihydro-1H-Purine-2,6-Diones as Potent Inhibitors of SIRT1, SIRT2, SIRT3, and SIRT5.

Sirtuins (SIRT1-7) are a family of NAD+-dependent deacetylases. They regulate many physiological processes and play important roles in inflammation, diabetes, cancers, and neurodegeneration diseases. Sirtuin inhibitors have potential applications in the treatment of neurodegenerative diseases and various cancers. Herein, we identified new sirtuin inhibitors based on the scaffold of 8-mercapto-3,7-dihydro-1H-purine-2,6-dione. To elucidate the inhibitory mechanism, the binding modes of the inhibitors in SIRT3 were established by molecular docking, showing that the inhibitors occupy the acetyl lysine binding site and interact with SIRT3, mainly through hydrophobic interactions. The interactions were validated by site-directed mutagenesis of SIRT3 and structure-activity relationship analysis of the inhibitors. Consistently, enzyme kinetic assays and microscale thermophoresis showed that these compounds are competitive inhibitors to the acetyl substrate, and mix-type inhibitors to NAD+. Furthermore, we demonstrated that the compounds are potent SIRT1/2/3/5 pan-inhibitors. This study provides novel hits for developing more potent sirtuin inhibitors.

Structural basis for the interaction of diapause hormone with its receptor in the silkworm, Bombyx mori.

Diapause hormone (DH) is a 24-aa amidated neuropeptide that elicits the embryonic diapause of the silkworm, Bombyx mori ( Bommo), via sensitive and selective interaction with its receptor, Bommo DH receptor ( Bommo-DHR). Previous studies of the structure-activity relationship of Bommo-DH were all based on an in vivo diapause-induction bioassay, which has provided little information on the structure of Bommo-DHR or its iteration with DH. Here, to unveil the interaction of Bommo-DH with its receptor, N-terminally truncated analogs and alanine-scanning mutants of Bommo-DH were chemically synthesized and functionally evaluated by using a Cy5.5-labeled Bommo-DH competitive binding assay and Bommo-DHR-based functional assays, including cAMP assay and Ca2+ mobilization assay. Our study demonstrates that the C-terminal residues of Arg23 and Leu24 of Bommo-DH are essential for the binding and activation of Bommo-DHR, and that Trp19 and Phe20 also contribute to the functional activity of Bommo-DH. In contrast, when Gly21 or Pro22 were replaced with alanine, both mutants exhibited binding and signaling activities that were indistinguishable from the wild-type peptide. Furthermore, our homology modeling and molecular dynamics simulations, together with experimental validations, have identified the residues of Glu89, Phe172, Phe194, and Tyr299 in Bommo-DHR that are critically involved in the interaction with Bommo-DH. These results may deepen our understanding of the interactions of class-A GPCRs with their peptidic ligands, particularly those between pheromone biosynthesis-activating neuropeptide/DH family neuropeptides and their cognate receptors.-Shen, Z., Jiang, X., Yan, L., Chen, Y., Wang, W., Shi, Y., Shi, L., Liu, D., Zhou, N. Structural basis for the interaction of diapause hormone with its receptor in the silkworm, Bombyx mori.

Humanin decreases mitochondrial membrane permeability by inhibiting the membrane association and oligomerization of Bax and Bid proteins.

Humanin (HN) is a 24-residue peptide identified from the brain of a patient with Alzheimer's disease (AD). HN has been found to protect against neuronal insult caused by Aß peptides or transfection of familial AD mutant genes. In order to elucidate the molecular mechanisms of HN neuroprotection, we explored the effects of HN on the association of Bax or Bid with lipid bilayers and their oligomerization in the membrane. By using single-molecule fluorescence and Förster resonance energy transfer techniques, we showed that Bax was mainly present as monomers, dimers and tetramers in lipid bilayers, while truncated Bid (tBid) enhanced the membrane association and tetramerization of Bax. HN (100 nmol/L) inhibited the self-association and tBid-activated association of Bax with the bilayers, and significantly decreased the proportion of Bax in tetramers. Furthermore, HN inhibited Bid translocation to lipid bilayers. HN could bind with Bax and Bid either in solution or in the membrane. However, HN could not pull the proteins out of the membrane. Based on these results, we propose that HN binds to Bax and cBid in solution and inhibits their translocation to the membrane. Meanwhile, HN interacts with the membrane-bound Bax and tBid, preventing the recruitment of cytosolic Bax and its oligomerization in the membrane. In this way, HN inhibits Bax pore formation in mitochondrial outer membrane and suppresses cytochrome c release and mitochondria-dependent apoptosis.

Human Neuropeptide S Receptor Is Activated via a Gαq Protein-biased Signaling Cascade by a Human Neuropeptide S Analog Lacking the C-terminal 10 Residues.

Human neuropeptide S (NPS) and its cognate receptor regulate important biological functions in the brain and have emerged as a future therapeutic target for treatment of a variety of neurological and psychiatric diseases. The human NPS (hNPS) receptor has been shown to dually couple to Gαs- and Gαq-dependent signaling pathways. The human NPS analog hNPS-(1-10), lacking 10 residues from the C terminus, has been shown to stimulate Ca(2+)mobilization in a manner comparable with full-length hNPSin vitrobut seems to fail to induce biological activityin vivo Here, results derived from a number of cell-based functional assays, including intracellular cAMP-response element (CRE)-driven luciferase activity, Ca(2+)mobilization, and ERK1/2 phosphorylation, show that hNPS-(1-10) preferentially activates Gαq-dependent Ca(2+)mobilization while exhibiting less activity in triggering Gαs-dependent CRE-driven luciferase activity. We further demonstrate that both Gαq- and Gαs-coupled signaling pathways contribute to full-length hNPS-mediated activation of ERK1/2, whereas hNPS-(1-10)-promoted ERK1/2 activation is completely inhibited by the Gαqinhibitor UBO-QIC but not by the PKA inhibitor H89. Moreover, the results of Ala-scanning mutagenesis of hNPS-(1-13) indicated that residues Lys(11)and Lys(12)are structurally crucial for the hNPS receptor to couple to Gαs-dependent signaling. In conclusion, our findings demonstrate that hNPS-(1-10) is a biased agonist favoring Gαq-dependent signaling. It may represent a valuable chemical probe for further investigation of the therapeutic potential of human NPS receptor-directed signalingin vivo.

Integration and oligomerization of Bax protein in lipid bilayers characterized by single molecule fluorescence study.

Bax is a pro-apoptotic Bcl-2 family protein. The activated Bax translocates to mitochondria, where it forms pore and permeabilizes the mitochondrial outer membrane. This process requires the BH3-only activator protein (i.e. tBid) and can be inhibited by anti-apoptotic Bcl-2 family proteins such as Bcl-xL. Here by using single molecule fluorescence techniques, we studied the integration and oligomerization of Bax in lipid bilayers. Our study revealed that Bax can bind to lipid membrane spontaneously in the absence of tBid. The Bax pore formation undergoes at least two steps: pre-pore formation and membrane insertion. The activated Bax triggered by tBid or BH3 domain peptide integrates on bilayers and tends to form tetramers, which are termed as pre-pore. Subsequent insertion of the pre-pore into membrane is highly dependent on the composition of cardiolipin in lipid bilayers. Bcl-xL can translocate Bax from membrane to solution and inhibit the pore formation. The study of Bax integration and oligomerization at the single molecule level provides new evidences that may help elucidate the pore formation of Bax and its regulatory mechanism in apoptosis.

Structure-activity relationship and interaction studies of new SIRT1 inhibitors with the scaffold of 3-(furan-2-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole.

SIRT1 is a NAD(+)-dependent deacetylase. It deacetylates a broad range of substrates and is involved in multiple diseases such as type 2 diabetes and cancer. Here we discovered a new class of SIRT1 inhibitors with the scaffold of 3-(furan-2-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole. The inhibitors up-regulate acetyl p53 level in human breast cells MCF-7. The docking simulations indicated that the scaffold and the R-substituents of the inhibitors bind in the C and D pocket of SIRT1, respectively, which was supported by the structure-activity relationship and SIRT1 mutagenesis studies. We propose that binding of the inhibitors repels the entering of the nicotinamide moiety of NAD(+) to the C pocket, prevents its transformation to the productive conformation and therefore inhibits the deacetylation catalyzed by SIRT1.

Efficient construction of functionalized pyrroloindolines through cascade radical cyclization/intermolecular coupling.

Pyrroloindolines are important structural units in nature and the pharmaceutical industry, however, most approaches to such structures involve transition-metal or photoredox catalysts. Herein, we describe the first tandem SET/radical cyclization/intermolecular coupling between 2-azaallyl anions and indole acetamides. This method enables the transition-metal-free synthesis of C3a-substituted pyrroloindolines under mild and convenient conditions. The synthetic utility of this transformation is demonstrated by the construction of an array of C3a-methylamine pyrroloindolines with good functional group tolerance and yields. Gram-scale sequential one-pot synthesis and hydrolysis reactions demonstrate the potential synthetic utility and scalability of this approach.

Air pollutant prediction model based on transfer learning two-stage attention mechanism.

Atmospheric pollution significantly impacts the regional economy and human health, and its prediction has been increasingly emphasized. The performance of traditional prediction methods is limited due to the lack of historical data support in new atmospheric monitoring sites. Therefore, this paper proposes a two-stage attention mechanism model based on transfer learning (TL-AdaBiGRU). First, the first stage of the model utilizes a temporal distribution characterization algorithm to segment the air pollutant sequences into periods. It introduces a temporal attention mechanism to assign self-learning weights to the period segments in order to filter out essential period features. Then, in the second stage of the model, a multi-head external attention mechanism is introduced to mine the network's hidden layer key features. Finally, the adequate knowledge learned by the model at the source domain site is migrated to the new site to improve the prediction capability of the new site. The results show that (1) the model is modeled from the data distribution perspective, and the critical information within the sequence of periodic segments is mined in depth. (2) The model employs a unique two-stage attention mechanism to capture complex nonlinear relationships in air pollutant data. (3) Compared with the existing models, the mean absolute error (MAE), root mean square error (RMSE), and mean absolute percentage error (MAPE) of the model decreased by 14%, 13%, and 4%, respectively, and the prediction accuracy was greatly improved.

Spatial and temporal characteristics analysis and prediction model of PM2.5 concentration based on SpatioTemporal-Informer model.

The primary cause of hazy weather is PM2.5, and forecasting PM2.5 concentrations can aid in managing and preventing hazy weather. This paper proposes a novel spatiotemporal prediction model called SpatioTemporal-Informer (ST-Informer) in response to the shortcomings of spatiotemporal prediction models commonly used in studies for long-input series prediction. The ST-Informer model implements parallel computation of long correlations and adds an independent spatiotemporal embedding layer to the original Informer model. The spatiotemporal embedding layer captures the complex dynamic spatiotemporal correlations among the input information. In addition, the ProbSpare Self-Attention mechanism in this model can focus on extracting important contextual information of spatiotemporal data. The ST-Informer model uses weather and air pollutant concentration data from numerous stations as its input data. The outcomes of the trials indicate that (1) The ST-Informer model can sharply capture the peaks and sudden changes in PM2.5 concentrations. (2) Compared to the current models, the ST-Informer model shows better prediction performance while maintaining high-efficiency prediction [Formula: see text]. (3) The ST-Informer model has universal applicability, and the model was applied to the concentration of other pollutants prediction with good results.

Critical role in CXCR4 signaling and internalization of the polypeptide main chain in the amino terminus of SDF-1α probed by novel N-methylated synthetically and modularly modified chemokine analogues.

The replication of human immunodeficiency virus type 1 (HIV-1) can be profoundly inhibited by the natural ligands of two major HIV-1 coreceptors, CXCR4 and CCR5. Stromal cell-derived factor-1α (SDF-1α) is a natural ligand of CXCR4. We have recently developed a synthetic biology approach of using synthetically and modularly modified (SMM)-chemokines to dissect various aspects of the structure-function relationship of chemokines and their receptors. Here, we used this approach to design novel SMM-SDF-1α analogues containing unnatural N-methylated residues in the amino terminus to investigate whether the polypeptide main chain amide bonds in the N-terminus of SDF-1α play a role in SDF-1α signaling via CXCR4 and/or receptor internalization. The results show that SDF-1α analogues with a modified N-methylated main chain at position 2, 3, or 5 retain significant CXCR4 binding and yet completely lose signaling activities. Furthermore, a representative N-methylated analogue has been shown to be incapable of causing CXCR4 internalization. These results suggest that the ability of SDF-1α to activate CXCR4 signaling and internalization is dependent upon the main chain amide bonds in the N-terminus of SDF-1α. This study demonstrates the feasibility and value of applying a synthetic biology approach to chemically engineer natural proteins and peptide ligands as probes of important biological functions that are not addressed by other biological techniques.

A novel synthetic bivalent ligand to probe chemokine receptor CXCR4 dimerization and inhibit HIV-1 entry.

Chemokine receptor CXCR4 is one of two principal coreceptors for the entry of HIV-1 into target cells. CXCR4 is known to form homodimers. We previously demonstrated that the amino terminus of viral macrophage protein II (vMIP-II) is the major determinant for CXCR4 recognition, and that V1 peptide derived from the N-terminus of vMIP-II (1-21 residues) showed significant CXCR4 binding. Interestingly, an all-d-amino acid analogue of V1 peptide, DV1 peptide, displayed an even higher binding affinity and strong antiviral activity in inhibiting the replication of CXCR4-dependent HIV-1 strains. In this study, we synthetically linked two DV1 peptides with the formation of a disulfide bond between the two cysteine residues present in the peptide sequence to generate a dimeric molecule potentially capable of interacting with two CXCR4 receptors. DV1 dimer exhibited enhanced binding affinity and antiviral activity compared with those of DV1 monomer. Ligand binding site mapping experiments showed that DV1 dimer overlaps with HIV-1 gp120 on CXCR4 binding sites, including several transmembrane (TM) residues located close to the extracellular side and the N-terminus of CXCR4. This finding was supported by the molecular modeling of CXCR4 dimer-DV1 dimer interaction based on the crystal structure of CXCR4, which showed that DV1 dimer is capable of interacting with the CXCR4 dimeric structure by allowing the N-terminus of each DV1 monomer to reach into the binding pocket of CXCR4 monomer. The development of this bivalent ligand provides a tool for further probing the functions of CXCR4 dimerization and studying CXCR4 heterodimerization with other receptors.

Loading of microplastics by two related macroalgae in a sea area where gold and green tides occur simultaneously.

Macroalgae are important components of offshore ecosystems and can also cause algal blooms. Microplastics (MPs) have been found in macroalgae and exhibit interactions during algal blooms. Ulva prolifera and Sargassum horneri are common algae in the Yellow Sea in China and are also the major macroalgae that cause green and gold tides. However, the loading of MPs by S. horneri along the coast of China has not been investigated, and the loading characteristics of MPs by two related macroalgae in a sea area where gold and green tides occur simultaneously have not been reported. Because U. prolifera and S. horneri occur simultaneously in the Yellow Sea, we investigated the characteristics of MPs in U. prolifera and S. horneri at 9 stations in the Yellow Sea located along the migration paths of green and gold tides. It was found that U. prolifera exhibited a higher abundance of MPs (0.065 ± 0.047 items/g-1 fresh weight) and ratio of the MP abundance in macroalgae to that in seawater (Rm/Rs = 97.33) than S. horneri (0.016 ± 0.016 items/g-1 fresh weight, Rm/Rs = 24.56). Moreover, the MPs in U. prolifera showed increased diversity in shape, color and material than those in S. horneri, and the particle sizes in the former were also smaller. Fast-growing biomass, slender branches, hollow air sacs and soft epidermis may allow U. prolifera to load more MPs. However, these mechanisms have not been fully established and merit further study. The relationship between severe algal blooms and MP pollution should be considered.

Aryl acrylonitriles synthesis enabled by palladium-catalyzed α-alkenylation of arylacetonitriles with vinyl halides/triflates.

Aryl acrylonitriles are an important subclass of acrylonitriles in the medicinal chemistry and pharmaceutical industry. Herein, an efficient synthesis of aryl acrylonitrile derivatives using a Palladium/NIXANTPHOS-based catalyst system was developed. This approach furnishes a variety of substituted and functionalized aryl acrylonitriles (up to 95% yield). The scalability of the transformation and the synthetic versatility of aryl acrylonitrile were demonstrated.

Computational screening for active compounds targeting protein sequences: methodology and experimental validation.

The three-dimensional (3D) structures of most protein targets have not been determined so far, with many of them not even having a known ligand, a truly general method to predict ligand-protein interactions in the absence of three-dimensional information would be of great potential value in drug discovery. Using the support vector machine (SVM) approach, we constructed a model for predicting ligand-protein interaction based only on the primary sequence of proteins and the structural features of small molecules. The model, trained by using 15,000 ligand-protein interactions between 626 proteins and over 10,000 active compounds, was successfully used in discovering nine novel active compounds for four pharmacologically important targets (i.e., GPR40, SIRT1, p38, and GSK-3ß). To our knowledge, this is the first example of a successful sequence-based virtual screening campaign, demonstrating that our approach has the potential to discover, with a single model, active ligands for any protein.