AL008 Enhances Myeloid Antitumor Function by Inhibiting SIRPα Signaling and Activating Fc Receptors.

Antagonizing the CD47-signal regulatory protein (SIRP)α pathway, a critical myeloid checkpoint, promotes antitumor immunity. In this study, we describe the development of AL008, a pan-allelic, SIRPα-specific Ab that triggers the degradation of SIRPα and, concurrently, stimulates FcγR activation of myeloid cells through an engineered Fc domain. AL008 showed superior enhancement of phagocytosis of tumor cells opsonized with antitumor Ag Abs compared with another SIRPα Ab tested. Unlike ligand-blocking SIRPα Abs, AL008 demonstrated single-agent activity by increasing tumor cell engulfment by human monocyte-derived macrophages even in the absence of opsonizing agents. This effect was due to enhanced Fc function, as blocking FcγR2A abrogated AL008-mediated phagocytic activity. AL008 also promoted human monocyte-derived dendritic cell-mediated T cell proliferation. In humanized mouse models, AL008 induced internalization of SIRPα and increased expression of CD86 and HLA-DR on human tumor-associated macrophages, confirming that the mechanism of action is retained in vivo. Monotherapy treatment with AL008 significantly reduced tumor growth in humanized mice implanted with human MDA-MB-231 tumor cells. AL008 also significantly potentiated the effects of T cell checkpoint blockade with anti-programmed death ligand-1 in syngeneic tumor models. This dual and specific mechanism of AL008, to our knowledge, provides a novel therapeutic strategy for targeting myeloid cells for immune activation.

INHBA promotes tumor growth and induces resistance to PD-L1 blockade by suppressing IFN-γ signaling.

Inhibin beta A (INHBA) and its homodimer activin A have pleiotropic effects on modulation of immune responses and tumor progression, but it remains uncertain whether tumors may release activin A to regulate anti-tumor immunity. In this study we investigated the effects and mechanisms of tumor intrinsic INHBA on carcinogenesis, tumor immunity and PD-L1 blockade. Bioinformatic analysis on the TCGA database revealed that INHBA expression levels were elevated in 33 cancer types, including breast cancer (BRCA) and colon adenocarcinoma (COAD). In addition, survival analysis also corroborated that INHBA expression was negatively correlated with the prognosis of many types of cancer patients. We demonstrated that gain or loss function of Inhba did not alter in vitro growth of colorectal cancer CT26 cells, but had striking impact on mouse tumor models including CT26, MC38, B16 and 4T1 models. By using the TIMER 2.0 tool, we figured out that in most cancer types, Inhba expression in tumors was inversely associated with the infiltration of CD4+ T and CD8+ T cells. In CT26 tumor-bearing mice, overexpression of tumor INHBA eliminated the anti-tumor effect of the PD-L1 antibody atezolizumab, whereas INHBA deficiency enhanced the efficacy of atezolizumab. We revealed that tumor INHBA significantly downregulated the interferon-γ (IFN-γ) signaling pathway. Tumor INHBA overexpression led to lower expression of PD-L1 induced by IFN-γ, resulting in poor responsiveness to anti-PD-L1 treatment. On the other hand, decreased secretion of IFN-γ-stimulated chemokines, including C-X-C motif chemokine 9 (CXCL9) and 10 (CXCL10), impaired the infiltration of effector T cells into the tumor microenvironment (TME). Furthermore, the activin A-specific antibody garetosmab improved anti-tumor immunity and its combination with the anti-PD-L1 antibody atezolizumab showed a superior therapeutic effect to monotherapy with garetosmab or atezolizumab. We demonstrate that INHBA and activin A are involved in anti-tumor immunity by inhibiting the IFN-γ signaling pathway, which can be considered as potential targets to improve the responsive rate of PD-1/PD-L1 blockade.

Latozinemab, a novel progranulin-elevating therapy for frontotemporal dementia.

BACKGROUND: Heterozygous loss-of-function mutations in the progranulin (PGRN) gene (GRN) cause a reduction in PGRN and lead to the development of frontotemporal dementia (FTD-GRN). PGRN is a secreted lysosomal chaperone, immune regulator, and neuronal survival factor that is shuttled to the lysosome through multiple receptors, including sortilin. Here, we report the characterization of latozinemab, a human monoclonal antibody that decreases the levels of sortilin, which is expressed on myeloid and neuronal cells and shuttles PGRN to the lysosome for degradation, and blocks its interaction with PGRN. METHODS: In vitro characterization studies were first performed to assess the mechanism of action of latozinemab. After the in vitro studies, a series of in vivo studies were performed to assess the efficacy of a mouse-cross reactive anti-sortilin antibody and the pharmacokinetics, pharmacodynamics, and safety of latozinemab in nonhuman primates and humans. RESULTS: In a mouse model of FTD-GRN, the rodent cross-reactive anti-sortilin antibody, S15JG, decreased total sortilin levels in white blood cell (WBC) lysates, restored PGRN to normal levels in plasma, and rescued a behavioral deficit. In cynomolgus monkeys, latozinemab decreased sortilin levels in WBCs and concomitantly increased plasma and cerebrospinal fluid (CSF) PGRN by 2- to threefold. Finally, in a first-in-human phase 1 clinical trial, a single infusion of latozinemab caused a reduction in WBC sortilin, tripled plasma PGRN and doubled CSF PGRN in healthy volunteers, and restored PGRN to physiological levels in asymptomatic GRN mutation carriers. CONCLUSIONS: These findings support the development of latozinemab for the treatment of FTD-GRN and other neurodegenerative diseases where elevation of PGRN may be beneficial. Trial registration ClinicalTrials.gov, NCT03636204. Registered on 17 August 2018, https://clinicaltrials.gov/ct2/show/NCT03636204 .

Contribution of trehalose to ethanol stress tolerance of Wickerhamomyces anomalus.

BACKGROUND: The ascomycetous heterothallic yeast Wickerhamomyces anomalus (WA) has received considerable attention and has been widely reported in the winemaking industry for its distinctive physiological traits and metabolic attributes. An increased concentration of ethanol during ethanol fermentation, however, causes ethanol stress (ES) on the yeast cells. Trehalose has been implicated in improving survival under various stress conditions in microorganisms. Herein, we determined the effects of trehalose supplementation on the survival, differentially expressed genes (DEGs), cellular morphology, and oxidative stress tolerance of WA in response to ES. RESULTS: The results indicated that trehalose improved the survival and anomalous surface and ultrastructural morphology of WA. Additionally, trehalose improved redox homeostasis by reducing the levels of reactive oxygen species (ROS) and inducing the activities of antioxidant enzymes. In addition, DEGs affected by the application of trehalose were enriched in these categories including in gene expression, protein synthesis, energy metabolism, and cell cycle pathways. Additionally, trehalose increased the content of intracellular malondialdehyde (MDA) and adenosine triphosphate. CONCLUSIONS: These results reveal the protective role of trehalose in ES mitigation and strengthen the possible uses of WA in the wine fermentation sector.

Enhanced efficiency of launching hyperbolic phonon polaritons in stacked α-MoO3 flakes.

In this work, we reported a systemic study on the enhanced efficiency of launching hyperbolic phonon polaritons (PhPs) in stacked α-phase molybdenum trioxide (α-MoO3) flakes. By using the infrared photo-induced force microscopy (PiFM), real-space near-field images (PiFM images) of mechanically exfoliated α-MoO3 thin flakes were recorded within three different Reststrahlen bands (RBs). As referred with PiFM fringes of the single flake, PiFM fringes of the stacked α-MoO3 sample within the RB 2 and RB 3 are greatly improved with the enhancement factor (EF) up to 170%. By performing numerical simulations, it reveals that the general improvement in near-field PiFM fringes arises from the existence of a nanoscale thin dielectric spacer in the middle part between two stacked α-MoO3 flakes. The nanogap acts as a nanoresonator for prompting the near-field coupling of hyperbolic PhPs supported by each flake in the stacked sample, contributing to the increase of polaritonic fields, and verifying the experimental observations Our findings could offer fundamental physical investigations into the effective excitation of PhPs and will be helpful for developing functional nanophotonic devices and circuits.

Analysis of the ethanol stress response mechanism in Wickerhamomyces anomalus based on transcriptomics and metabolomics approaches.

BACKGROUND: Wickerhamomyces anomalus (W. anomalus) is a kind of non-Saccharomyces yeast that has a variety of unique physiological characteristics and metabolic features and is widely used in many fields, such as food preservation, biomass energy, and aquaculture feed protein production. However, the mechanism of W. anomalus response to ethanol stress is still unclear, which greatly limits its application in the production of ethanol beverages and ethanol fuels. Therefore, we checked the effects of ethanol stress on the morphology, the growth, and differentially expressed genes (DEGs) and metabolites (DEMs) of W. anomalus. RESULTS: High concentrations of ethanol (9% ethanol and 12% ethanol) remarkably inhibited the growth of W. anomalus. Energy metabolism, amino acid metabolism, fatty acids metabolism, and nucleic acid metabolism were significantly influenced when exposing to 9% ethanol and 12% ethanolstress, which maybe universal for W. anomalus to response to different concentrations of ethanol stressl Furthermore, extracellular addition of aspartate, glutamate, and arginine significantly abated ethanol damage and improved the survival rate of W. anomalus. CONCLUSIONS: The results obtained in this study provide insights into the mechanisms involved in W. anomalus response to ethanol stress. Therefore, new strategies can be realized to improve the ethanol tolerance of W. anomalus through metabolic engineering.

Two-photon-pumped amplified spontaneous emission from Ruddlesden-Popper perovskite flakes.

Herein, we report the two-photon pumped amplified spontaneous emission (ASE) in the 2D RPPs flakes at room temperature. We prepared high-quality (BA)2(MA)n-1PbnI3n+1 (n = 1, 2, 3, 4, 5) flakes by mechanical exfoliating from the fabricated crystals. We show that the (BA)2(MA)n-1PbnI3n+1 flakes display a tunable two-photon pumped emission from 527 nm to 680 nm, as n increases from 1 to 5. Furthermore, we demonstrated two-photon pumped ASE from the (BA)2(MA)n-1PbnI3n+1 (n = 3, 4, 5) flakes. The two-photon pumped ASE thresholds of the RPPs are lower than lots of the other semiconductor nanostructures, indicating an excellent performance of the RPPs for two-photon pumped emission. In addition, we investigated the pump-wavelength-dependent two-photon pumped ASE behaviors of the RPPs flakes, which suggest that the near-infrared laser in a wide wavelength range can be converted into visible light by the frequency upconversion process in RPPs. This work has opened new avenues for realizing nonlinearly pumped ASE based on the RPPs, which shows great potential for the applications in wavelength-tunable frequency upconversion.

Giant optical anisotropy of WS2flakes in the visible region characterized by Au substrate assisted near-field optical microscopy.

Transition metal dichalcogenides (TMD) have attracted considerable attention in the field of photonic integrated circuits due to their giant optical anisotropy. However, on account of their inherent loss in the visible region and the difficulty of measuring high refractive index materials, near-field characterizations of the optical anisotropy of TMD in the visible region have inherent experimental difficulties. In this work, we present a systematical characterization of the optical anisotropy in tungsten disulfide (WS2) flakes by using scattering-type scanning near-field optical microscopy (s-SNOM) excited at 671 nm. Transverse-electric and transverse-magnetic (TM) waveguide modes can be excited in WS2flakes with suitable thickness, respectively. With the assistance of the Au substrate, the contrast of the near-field fringes is enhanced in comparison with the SiO2substrate. By combining waveguide mode near-field imaging and theoretical calculations, the in-plane and out-of-plane refractive indexes of WS2are determined to be 4.96 and 3.01, respectively, indicating a high birefringence value up to 1.95. This work offers experimental evidence for the potential application of WS2in optoelectronic integrated circuits in the visible region.

Discovery of cinnamamide-barbiturate hybrids as a novel class of Nrf2 activator against myocardial ischemia/reperfusion injury.

Myocardial ischemia/reperfusion (MI/R) has been a challenge for global public health. Activation of nuclear factor erythroid-2-related factor 2 (Nrf2) signaling could attenuate MI/R injury by maintaining cell redox balance and reducing oxidative damage. Cinnamamide derivatives have been proven to be a class of potential Nrf2 activators and cardioprotective agents. The development of novel cinnamamide derivatives to combat oxidative stress in cardiomyocytes is highly desirable. In this study, twenty-three cinnamamide-barbiturate hybrids were studied. Cell-based assays showed that most of the compounds exhibited excellent protective activity against H2O2-induced oxidative injury in H9c2 cells. Notably, compound 7w, which had the highest activity and low cytotoxicity, was demonstrated to remarkably reduce intracellular ROS accumulation by activating the mRNA expression of Nrf2 and its downstream antioxidant gene HO-1, indicating a novel promising antioxidant and Nrf2 activator. The probable binding mode between protein Keap1 and compound 7w was also studied via molecule docking. Furthermore, we found that the administration of compound 7w could significantly reduce the cardiac infarct size and improve the cardiac function against MI/R injury in rats, as well as decrease cardiac oxidative stress. Taken together, we report, for the first time, that cinnamamide-barbiturate hybrids are a novel class of potential cardioprotective agents. The excellent cardioprotective action of such compounds rely on enhancing the endogenous antioxidative system by upregulating the Nrf2 signaling pathway in vitro and in vivo against MI/R damage. These findings provide a new perspective for designing cinnamamide-barbiturate hybrids as a novel class of Nrf2 activator against cardiovascular diseases.

Mass spectrometry imaging: new eyes on natural products for drug research and development.

Natural products (NPs) and their structural analogs represent a major source of novel drug development for disease prevention and treatment. The development of new drugs from NPs includes two crucial aspects. One is the discovery of NPs from medicinal plants/microorganisms, and the other is the evaluation of the NPs in vivo at various physiological and pathological states. The heterogeneous spatial distribution of NPs in medicinal plants/microorganisms or in vivo can provide valuable information for drug development. However, few molecular imaging technologies can detect thousands of compounds simultaneously on a label-free basis. Over the last two decades, mass spectrometry imaging (MSI) methods have progressively improved and diversified, thereby allowing for the development of various applications of NPs in plants/microorganisms and in vivo NP research. Because MSI allows for the spatial mapping of the production and distribution of numerous molecules in situ without labeling, it provides a visualization tool for NP research. Therefore, we have focused this mini-review on summarizing the applications of MSI technology in discovering NPs from medicinal plants and evaluating NPs in preclinical studies from the perspective of new drug research and development (R&D). Additionally, we briefly reviewed the factors that should be carefully considered to obtain the desired MSI results. Finally, the future development of MSI in new drug R&D is proposed.

Highly Tunable Enhancement and Switching of Nonlinear Emission from All-Inorganic Lead Halide Perovskites via Electric Field.

Herein, we demonstrate a highly tunable enhancement and switching of nonlinear emission from all-inorganic metal halide perovskites based on an asymmetrically biased metal-insulator-semiconductor (MIS) structure. We achieve 2 orders of magnitude enhancement of the two-photon-pumped photoluminescence (TPL) from CsPbBr3 microplates with the MIS structure, due to comprehensive effects including localized field effect, trap-filling effect, and collection enhancement. In particular, taking advantage of electric-field-induced passivation/activation of Br vacancies, we realize highly tunable TPL enhancement, ranging from ∼61.2-fold to ∼370.3-fold. Moreover, we demonstrate an efficient modulation of the two-photon-pumped lasing from the MIS structure, which exhibits electric field induced switching with a high on/off ratio of 67:1. This work has opened new avenues for steering carrier transport and nonlinear emission in lead halide perovskites, which shows great promise for realizing high-efficiency and tunable nonlinear nanophotonic devices.

The fate of heavy metals in the co-processing of solid waste in converter steelmaking.

The improper disposal of large amounts of solid waste (SW) has led to serious ecological and environmental problems, especially heavy metal (HM) pollution. Converter steelmaking has the potential to co-process SW, but the distribution of heavy metals (HMs) during converter steelmaking is unclear. In this study, the effects of smelting temperature and slag alkalinity on the distribution of typical HMs in the SW of steel samples, steel slag, and the gas phase were investigated in a specially-made induction furnace. The results showed that upon increasing the smelting temperature, As (As2S3) was mainly distributed in the steel sample, and the HM-containing compounds Cr2O3, CrCl3, ZnCl2, ZnS, ZnO, PbCl2, PbS, and PbO were mainly distributed in the gas phase. Upon increasing the alkalinity within a certain range, the distribution of HMs in steel samples and steel slag increased gradually, while their distribution in the gas phase decreased. Thermodynamic calculations, Eh-pH diagrams, XRD patterns, and XPS spectra indicated that impurity elements in the hot metal and the CaO content affected the chemical reactions by which HM-containing compounds in the steel sample formed elemental HMs and those in steel slag existed as oxides; therefore, it is necessary to choose a suitable temperature and alkalinity for slag when disposing of different types of SW.

Heavy metal and metalloid emissions during co-processing of waste in a sintering kiln: Migration characteristics in the kiln and long-term leaching from bricks.

Heavy metals (HMs) in mixed hazardous waste can be volatilized in the kiln for preparing sintered bricks, which greatly increases the environmental risk. In this study, the volatilization, transformation, and leaching of HMs from bricks were evaluated. Field tests and laboratory leaching experiments were carried out. HM-contaminated soil was used to prepare sintered bricks at high-temperature in a tunnel kiln. Release of HMs from brick under rainfall conditions was investigated in laboratory simulation experiments. The field tests showed that the total amount of Pb, Zn, Cd distributed to the gas phase were all less than 2%, but the amount of Hg entering the gas phase 40.1%-60.5% in the particulate forms. The As leaching rate increased after sintering of bricks in the kiln, which was attributed to the increased formation of soluble arsenate and the reduced availability of sorption sites. The tank leaching test indicated that the release mechanism of trance elements (Cr, As, Zn, Cd, Pb and Ni) was mainly controlled by diffusion. This study provides useful knowledge for decreasing the volatilization and leaching of HMs from sintered bricks prepared using hazardous waste.

Electrochemical-induced hydroxylation of aryl halides in the presence of Et3N in water.

A thorough study of mild and environmentally friendly electrochemical-induced hydroxylation of aryl halides without a catalyst is presented. The best protocol consists of hydroxylation of different aryl iodides and aryl bromides by water solution in the presence of Et3N under air, affording the target phenols in good isolated yields. Moreover, aryl chlorides were successfully employed as substrates. This methodology also provides a direct pathway for the formation of deoxyphomalone, which displayed a significant anti-proliferation effect.

Effect of urea feeding on transforming and migrating soil fluorine in a tea garden of hilly region.

The hilly region of western Sichuan is famous for producing Mengding-mountain tea in China. However, it is very easy to enrich fluorine (F) in tea, which recently raised people's concern on fluorosis. In this study, we simulated the local special climate conditions, especially the natural precipitation through column leaching experiment to investigate the effect of fertilization on F desorption from soil. The results suggested different fertilizers could greatly affect desorption of F from soil, but only urea (CO(NH2)2) could significantly and continuously promote the dissolution of F from soil. Furthermore, to reveal the effect of CO(NH2)2 on migration of F from soil to tea, field plots experiment in a tea garden was carried out. The results showed that CO(NH2)2 promoted soil acidification continuously, resulting in the increase of dissolved F and Al content in soil, which were migrated to tea in the form of F-Al complex. Therefore, the key to reducing the F content in tea is to alleviate soil acidification and reduce F-Al complex content in soil. Most importantly, with CO(NH2)2 addition, the contents of F in tea increased significantly from first bud to fifth bud in comparison with those of without CO(NH2)2, especially in 2016, indicating the accelerating and prolonging enrichment of F in tea by adding CO(NH2)2. This study would have important guidance for controlling F mitigation from soil to tea by managing fertilizers application and anthropogenic activities.

Histone methyltransferase SETDB1 promotes colorectal cancer proliferation through the STAT1-CCND1/CDK6 axis.

Upregulation of histone methyltransferase SET domain bifurcated 1 (SETDB1) is associated with poor prognosis in cancer patients. However, the mechanism of oncogenicity of SETDB1 in cancer is hitherto unknown. Here, we show that SETDB1 is upregulated in human colorectal cancer (CRC) where its level correlates with poor clinical outcome. Ectopic SETDB1 promotes CRC cell proliferation, whereas SETDB1 attenuation inhibits this process. Flow cytometry reveals that SETDB1 promotes proliferation by driving the CRC cell cycle from G0/G1 phase to S phase. Mechanistically, SETDB1 binds directly to the STAT1 promoter region resulting in increased STAT1 expression. Functional characterization reveals that STAT1-CCND1/CDK6 axis is a downstream effector of SETDB1-mediated CRC cell proliferation. Furthermore, SETDB1 upregulation is sufficient to accelerate in vivo proliferation in xenograft animal model. Taken together, our results provide insight into the upregulation of SETDB1 within CRC and can lead to novel treatment strategies targeting this cell proliferation-promoting gene.

Generation of second harmonic Bessel beams through hybrid meta-axicons.

Bessel beams are of great potential applications in many fields due to their non-diffraction and self-reconstruction. Here we firstly present a type of nonlinear meta-axicon to generate second harmonic Bessel beams. The nonlinear meta-axicons are based on Au/WS2 hybrid nanostructures. Zero-order and first-order Bessel beams of second harmonic are generated under exciting of 810 nm femtosecond laser. In addition, the performances of the nonlinear meta-axicons, such as the second harmonic generation (SHG) efficiency, non-diffracting distance and full width at half maximum (FWHM) are analyzed theoretically and experimentally. The experimental results are consistent with the predicted, which can enable miniaturized nonlinear optical devices related to generate nonlinear Bessel beams, having potential application in nonlinear optical manipulation, imaging and tractor beams.

Improved photoemission and stability of 2D organic-inorganic lead iodide perovskite films by polymer passivation.

2D organic-inorganic lead iodide perovskites hold great promise for functional optoelectronic devices. However, their performances have been seriously limited by poor long-term stability in ambient environment. Here, we perform a systematic study for the stability improvement of a typical 2D organic-inorganic lead iodide perovskite (PEA)2PbI4. The degradation of the (PEA)2PbI4 films can be attributed to the interaction with the humidity in environment, which leads to decomposition of the perovskite components. Then, we demonstrate that polymer passivation provides an effective approach for improving the crystal quality and stability of the (PEA)2PbI4 films. Correspondingly, the photoemission of the polymer-passivated (PEA)2PbI4 films has been enhanced due to the decreased trap states. More importantly, a hydrophobic polymer (Poly(4-Vinylpyridine), PVP) will protect the (PEA)2PbI4 films from humidity in ambient environment, which can greatly improve the physical and chemical stability of the 2D perovskite films. As a result, the PVP-passivated (PEA)2PbI4 films can produce a bright emission even after long-term (>15 d) exposure to ambient environment (25 °C, 80% RH) and continuous UV illumination. This work provides a convenient and effective approach for improving the long-term stability of 2D organic-inorganic lead iodide perovskites, which shows great promise for fabricating large-area and versatile optoelectronic devices.

Cadmium Isotopic Fractionation in the Soil-Plant System during Repeated Phytoextraction with a Cadmium Hyperaccumulating Plant Species.

Analysis of stable metal isotopes can provide important information on biogeochemical processes in the soil-plant system. Here, we conducted a repeated phytoextraction experiment using the cadmium (Cd) hyperaccumulator Sedum plumbizincicola X. H. Guo et S. B. Zhou ex L. H. Wu (Crassulaceae) in four different Cd-contaminated agricultural soils over five consecutive crops. Isotope composition of Cd was determined in the four soils before and after the fifth crop, in the plant shoots harvested in all soils in the first crop, and in the NH4OAc extracts of two contrasting soils with large differences in soil pH (5.73 and 7.32) and clay content (20.4 and 31.3%) before and after repeated phytoextraction. Before phytoextraction NH4OAc-extractable Cd showed a slight but significant negative isotope fractionation or no fractionation compared with total Cd (Δ114/110Cdextract-soil = -0.15 ± 0.05 (mean ± standard error) and 0.01 ± 0.01‰), and the extent of fractionation varied with soil pH and clay content. S. plumbizincicola preferentially took up heavy Cd from soils (Δ114/110Cdshoot-soil = 0.02-0.14‰), and heavy isotopes were significantly depleted in two soils after repeated phytoextraction (Δ114/110Cdsoil:P5-soil:P0 = -0.15 ± 0.02 and -0.12 ± 0.01‰). This provides evidence for the existence of specific Cd transporters in S. plumbizincicola, leading to positive isotope fractionation during uptake. After phytoextraction by five sequential crops, the NH4OAc-extractable Cd pool was significantly enriched in heavy isotopes (Δ114/110Cdextract:P5-extract:P0 = 0.07 ± 0.02 and 0.18 ± 0.05‰) despite the preferential uptake of heavy isotopes, indicating the occurrence of root-induced Cd mobilization in soils, which is supposed to favor heavy Cd in the organo-complexes with root exudates. Our results demonstrate that Cd is taken up by S. plumbizincicola via specific transporters, partly after active mobilization from the more strongly bound soil pool such as iron/manganese (hydr)oxide-bound Cd during repeated phytoextraction. This renders S. plumbizincicola a suitable plant for large-scale field phytoremediation.

Synthesis of Disulfide Surrogate Peptides Incorporating Large-Span Surrogate Bridges Through a Native-Chemical-Ligation-Assisted Diaminodiacid Strategy.

The use of synthetic bridges as surrogates for disulfide bonds has emerged as a practical strategy to obviate the poor stability of some disulfide-containing peptides. However, peptides incorporating large-span synthetic bridges are still beyond the reach of existing methods. Herein, we report a native chemical ligation (NCL)-assisted diaminodiacid (DADA) strategy that enables the robust generation of disulfide surrogate peptides incorporating surrogate bridges up to 50 amino acids in length. This strategy provides access to some highly desirable but otherwise impossible-to-obtain disulfide surrogates of bioactive peptide. The bioactivities and structures of the synthetic disulfide surrogates were verified by voltage clamp assays, NMR, and X-ray crystallography; and stability studies established that the disulfide replacements effectively overcame the problems of disulfide reduction and scrambling that often plague these pharmacologically important peptides.