ctDNA guiding adjuvant immunotherapy in urothelial carcinoma.

Minimally invasive approaches to detect residual disease after surgery are needed to identify patients with cancer who are at risk for metastatic relapse. Circulating tumour DNA (ctDNA) holds promise as a biomarker for molecular residual disease and relapse1. We evaluated outcomes in 581 patients who had undergone surgery and were evaluable for ctDNA from a randomized phase III trial of adjuvant atezolizumab versus observation in operable urothelial cancer. This trial did not reach its efficacy end point in the intention-to-treat population. Here we show that ctDNA testing at the start of therapy (cycle 1 day 1) identified 214 (37%) patients who were positive for ctDNA and who had poor prognosis (observation arm hazard ratio = 6.3 (95% confidence interval: 4.45-8.92); P < 0.0001). Notably, patients who were positive for ctDNA had improved disease-free survival and overall survival in the atezolizumab arm versus the observation arm (disease-free survival hazard ratio = 0.58 (95% confidence interval: 0.43-0.79); P = 0.0024, overall survival hazard ratio = 0.59 (95% confidence interval: 0.41-0.86)). No difference in disease-free survival or overall survival between treatment arms was noted for patients who were negative for ctDNA. The rate of ctDNA clearance at week 6 was higher in the atezolizumab arm (18%) than in the observation arm (4%) (P = 0.0204). Transcriptomic analysis of tumours from patients who were positive for ctDNA revealed higher expression levels of cell-cycle and keratin genes. For patients who were positive for ctDNA and who were treated with atezolizumab, non-relapse was associated with immune response signatures and basal-squamous gene features, whereas relapse was associated with angiogenesis and fibroblast TGFß signatures. These data suggest that adjuvant atezolizumab may be associated with improved outcomes compared with observation in patients who are positive for ctDNA and who are at a high risk of relapse. These findings, if validated in other settings, would shift approaches to postoperative cancer care.

6-Hydroxy Picolinohydrazides Promoted Cu(I)-Catalyzed Hydroxylation Reaction in Water: Machine-Learning Accelerated Ligands Design and Reaction Optimization.

Hydroxylated (hetero)arenes are privileged motifs in natural products, materials, small-molecule pharmaceuticals and serve as versatile intermediates in synthetic organic chemistry. Herein, we report an efficient Cu(I)/6-hydroxy picolinohydrazide-catalyzed hydroxylation reaction of (hetero)aryl halides (Br, Cl) in water. By establishing machine learning (ML) models, the design of ligands and optimization of reaction conditions were effectively accelerated. The N-(1,3-dimethyl-9H- carbazol-9-yl)-6-hydroxypicolinamide (L32, 6-HPA-DMCA) demonstrated high efficiency for (hetero)aryl bromides, promoting hydroxylation reactions with a minimal catalyst loading of 0.01 mol % (100 ppm) at 80 °C to reach 10000 TON; for substrates containing sensitive functional groups, the catalyst loading needs to be increased to 3.0 mol % under near-room temperature conditions. N-(2,7-Di-tert-butyl-9H-carbazol-9-yl)-6-hydroxypicolinamide (L42, 6-HPA-DTBCA) displayed superior reaction activity for chloride substrates, enabling hydroxylation reactions at 100 °C with 2-3 mol % catalyst loading. These represent the state of art for both lowest catalyst loading and temperature in the copper-catalyzed hydroxylation reactions. Furthermore, this method features a sustainable and environmentally friendly solvent system, accommodates a wide range of substrates, and shows potential for developing robust and scalable synthesis processes for key pharmaceutical intermediates.

Modulating Electronic Structure and Atomic Insights into the Novel Hierarchically Porous PdCuFe Trimetallic Alloy Aerogel for Efficient Oxygen Reduction.

The high cost of noble Pd/Pt required for the oxygen reduction reaction (ORR) in the cathode restricts the wide applications of fuel cells. In this study, the synthesis of a novel Pd3 CuFe0.5 aerogel electrocatalyst is successfully demonstrated using self-assembly and lyophilization techniques, employing a mild reducing agent. The resulting aerogel electrocatalyst exhibits a distinctive 3D network structure, possessing a substantial BET-specific surface area of 75.19 m2  g-1 . It is worth noting that the optimized Pd3 CuFe0.5 aerogel demonstrates exceptional ORR performance with a high half-wave potential of 0.92 V versus RHE, a significant limiting current density of 7.6 mA cm-2 , and the excellent electrocatalytic stability, superior to the reported noble metal electrocatalysts, with the ORR activity decays only 4.9% after 16 000 s. In addition, the Pd3 CuFe0.5 aerogel electrocatalyst shows superior cycling stability for ≈120 h at a charge/discharge current density of 10 mA cm-2 , indicating its promising application in fuel cells. Furthermore, the resulting composite aerogel possesses excellent hydrogen evolution reaction and ethanol oxidation reaction activity. The density functional theory calculations show that the partial oxidation of Pd3 CuFe0.5 aerogel leads to a negative shift of the d-band center, which energetically optimizes the binding strength of *O intermediates, therefore accelerating the ORR activity.

Dynamic Electronic and Ionic Transport Actuated by Cobalt-Doped MoSe2 /rGO for Superior Potassium-Ion Batteries.

Molybdenum selenium (MoSe2 ) has tremendous potential in potassium-ion batteries (PIBs) due to its large interlayer distance, favorable bandgap, and high theoretical specific capacity. However, the poor conductivity and large K+ insertion/extraction in MoSe2 inevitably leads to sluggish reaction kinetics and poor structural stability. Herein, Coinduced engineering is employed to illuminate high-conductivity electron pathway and mobile ion diffusion of MoSe2 nanosheets anchored on reduced graphene oxide substrate (Co-MoSe2 /rGO). Benefiting from the activated electronic conductivity and ion diffusion kinetics, and an expanded interlayer spacing resulting from Co doping, combined with the interface coupling with highly conductive reduced graphene oxide (rGO) substrate through Mo-C bonding, the Co-MoSe2 /rGO anode demonstrates remarkable reversible capacity, superior rate capability, and stable long-term cyclability for potassium storage, as well as superior energy density and high power density for potassium-ion capacitors. Systematic performance measurement, dynamic analysis, in-situ/ex-situ measurements, and density functional theory (DFT) calculations elucidate the performance-enhancing mechanism of Co-MoSe2 /rGO in view of the electronic and ionic transport kinetics. This work offers deep atomic insights into the fundamental factors of electrodes for potassium-ion batteries/capacitors with superior electrochemical performance.

Development of Regular Hydrophobic Silica Aerogel Microspheres for Efficient Oil Adsorption.

The objective of this research was to develop new hydrophobic silica aerogel microspheres (HSAMs) with water glass and hexmethyldisilazane for oil adsorption. The effects of the hexmethyldisilazane concentration and drying method on the structure and organic liquid adsorption capacity were investigated. The hexmethyldisilazane concentration of the modification solution did not influence the microstructure and pore structure in a noteworthy manner, which depended more on the drying method. Vacuum drying led to more volume shrinkage of the silica gel microsphere (SGM) than supercritical CO2 drying, thus resulting in a larger apparent density, lower pore volume, narrower pore size distribution, and more compact network. Owing to the large pore volume and pore size, the HSAMs synthesized via supercritical CO2 drying had a larger organic liquid adsorption capacity. The adsorption capacities of the HSAMs with pore volumes of 4.04-6.44 cm3/g for colza oil, vacuum pump oil, and hexane are up to 18.3, 18.9, and 11.8 g/g, respectively, higher than for their state-of-the-art counterparts. The new sorbent preparation method is facile, cost-effective, safe, and ecofriendly, and the resulting HSAMs are exceptional in capacity, stability, and regenerability.

Discontinuous Dissolution Mechanism of Olivine Deduced from a Topography Observation Method.

Olivine dissolution plays an important role in environmental science and technology, from controlling global element circulation to carbon capture for climate change mitigation. Most studies have been focused on investigating its dissolution rates by monitoring chemical effluent changes under various conditions. However, only by observation of surface reactivity can we unravel the actual mechanism (s) of dissolution. Here, we studied the dissolution of an olivine (010) plane in a flow-through reaction cell with an acidic solution, a surface-controlled regime, and far-from-equilibrium conditions. Direct mineral surface topography measurements using vertical scanning interferometry and atomic force microscopy allowed for quantitative analyses of the spatial and temporal changes in the dissolution rate. The (010) plane dissolved discontinuously in time for different surface sites, resulting in a heterogeneously distributed rate map. Pits with different depths showed opposite dissolution rate distributions from the dislocation center to further out from the etch pit. Based on the step-wave model, we propose a mechanism of dissolution that is governed by the competition between Gibbs free energy of the dissolution process, ΔG, and the critical free energy of the opening of etch pits, i.e., ΔGcrit. The migration of step waves, the distribution of surface defects, the strain field of etch pits, and other dynamic elements, resulting in the instantaneous change of ΔGcrit on the surface, are important factors leading to the discontinuous dissolution of crystal materials. This discontinuous dissolution provides new insight into the guidance of crystalline mineral applications and the prediction of material properties regarding mineral dissolution variation.

Diagnosis and treatment of biliary mucinous cystic neoplasms: A single-center experience.

BACKGROUND: Biliary mucinous cystic neoplasms (BMCNs) are rare hepatobiliary cystic tumors, which can be divided into noninvasive and invasive types. This study aimed to investigate the diagnosis, treatment, and prognosis of BMCNs in a large single center. METHODS: We analyzed 49 patients with BMCNs confirmed by postoperative pathology at the First Affiliated Hospital, Zhejiang University School of Medicine between January 2007 and December 2021. RESULTS: Among the 49 patients, 37 were female (75.5%), and the average age was 57.04 years. Common symptoms included abdominal discomfort, jaundice and fever, while 22 patients (44.9%) had no symptoms. Serum carbohydrate antigen (CA) 19-9 and CA125 concentrations were elevated in 34.8% and 19.6% of patients, respectively. Forty-eight patients had tumors in the intrahepatic bile ducts and only one had a tumor in the extrahepatic bile duct. Forty-eight patients with noninvasive intrahepatic BMCNs were further analyzed in terms of pathological features: 34 (70.8%) had low-grade intraepithelial neoplasms (LGINs), and 14 (29.2%) had high-grade intraepithelial neoplasms (HGINs). The potential immunohistochemical markers of BMCNs were cytokeratin (CK) 19, CK7, estrogen receptor and progesterone receptor. Follow-up data for 37 patients with intrahepatic BMCNs were obtained. The median overall survival (OS) of BMCNs was not reached. The longest survival time was 137 months.The 5- and 10-year OS rates were 100% and 85.4%, respectively. The 5- and 10-year recurrence-free survival (RFS) rates were 93.9% and 80.2%, respectively. CONCLUSIONS: BMCNs are rare cystic neoplasms that commonly occur in middle-aged females. BMCNs can only be diagnosed and classified by postoperative pathology, as there are no specific clinical presentations, serological indicators or imaging modalities for preoperative diagnosis. Complete surgical resection is necessary for BMCNs, and the postoperative prognosis is favorable.

Ethoxy-erianin phosphate and afatinib synergistically inhibit liver tumor growth and angiogenesis via regulating VEGF and EGFR signaling pathways.

The therapeutic efficacy of tyrosine kinase inhibitors (TKIs) on solid tumors is limited by drug resistance and side effects. Currently, the combination therapy comprises of TKIs and angiogenesis inhibitors have been corroborated as an effective approach in cancer therapy. Ethoxy-erianin phosphate (EBTP) is an anti-angiogenic compound with low toxicity obtained by structural modification of the natural product erianin. Here, we aimed to evaluate whether EBTP can cooperate with TKIs to inhibit the proliferation and angiogenesis of tumor cells and reduce toxic effects. First, CCK-8 results showed that EBTP can effectively inhibit the proliferation of liver cancer cell line HepG2. We combined EBTP with four TKIs (Bosutinib, Apatinib, Afatinib and Erlotinib) to treat HepG2 cells and CompuSyn software analysis suggested that EBTP/Afatinib(Afa)shows the best synergistic inhibitory effect. Meanwhile, EBTP/Afa can significantly suppress the proliferation, invasion, migration and angiogenesis of HepG2 and HUVECs. ELISA results revealed that EBTP/Afa inhibits the secretion of VEGF in HepG2. EBTP/Afa down-regulates the expression of VEGF, p-VEGFR1, p-VEGFR2 and p-EGFR in both HepG2 and HUVECs. Further, the supernatant of HepG2 cells treated with EBTP/Afa blocks the intracellular downstream signal transduction shared by VEGF and EGFR in HUVECs. Finally, EBTP/Afa significantly inhibits tumor growth and angiogenesis in vivo. To conclude, EBTP/Afa targets VEGF and EGFR signaling pathways in liver cancer cells and tumor vasculature, thereby inhibiting the proliferation, motion and angiogenesis of liver cancer cells. Overall, this study provides a new combined strategy for the clinical treatment of hepatocellular carcinoma.

Remarkable enhancement in the electrochemical properties of cosmetic brush-like Co3O4 nanowires via in situ surface modification with Ni2.

Cosmetic brush-like Co3O4 nanowires grown on carbon cloth were prepared by regulating the addition of trisodium citrate by hydrothermal synthesis. Then a simple liquid-phase ion exchange was carried out to improve the electrochemical performance of Co3O4 by surface modification with Ni2+. After surface modification, at a current density of 4 A g-1, the specific capacity significantly increased from 276.1 C g-1 (720.5 F g-1) to 655.9 C g-1 (1525.4 F g-1). Meanwhile, the electrocatalytic oxidation performances of methanol and urea were also improved significantly. The enhanced electrochemical properties were attributed to the modification of the surface of Co3O4 with Ni2+.

Asymmetric photoredox transition-metal catalysis activated by visible light.

Asymmetric catalysis is seen as one of the most economical strategies to satisfy the growing demand for enantiomerically pure small molecules in the fine chemical and pharmaceutical industries. And visible light has been recognized as an environmentally friendly and sustainable form of energy for triggering chemical transformations and catalytic chemical processes. For these reasons, visible-light-driven catalytic asymmetric chemistry is a subject of enormous current interest. Photoredox catalysis provides the opportunity to generate highly reactive radical ion intermediates with often unusual or unconventional reactivities under surprisingly mild reaction conditions. In such systems, photoactivated sensitizers initiate a single electron transfer from (or to) a closed-shell organic molecule to produce radical cations or radical anions whose reactivities are then exploited for interesting or unusual chemical transformations. However, the high reactivity of photoexcited substrates, intermediate radical ions or radicals, and the low activation barriers for follow-up reactions provide significant hurdles for the development of efficient catalytic photochemical processes that work under stereochemical control and provide chiral molecules in an asymmetric fashion. Here we report a highly efficient asymmetric catalyst that uses visible light for the necessary molecular activation, thereby combining asymmetric catalysis and photocatalysis. We show that a chiral iridium complex can serve as a sensitizer for photoredox catalysis and at the same time provide very effective asymmetric induction for the enantioselective alkylation of 2-acyl imidazoles. This new asymmetric photoredox catalyst, in which the metal centre simultaneously serves as the exclusive source of chirality, the catalytically active Lewis acid centre, and the photoredox centre, offers new opportunities for the 'green' synthesis of non-racemic chiral molecules.

MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer.

There have been no major advances for the treatment of metastatic urothelial bladder cancer (UBC) in the last 30 years. Chemotherapy is still the standard of care. Patient outcomes, especially for those in whom chemotherapy is not effective or is poorly tolerated, remain poor. One hallmark of UBC is the presence of high rates of somatic mutations. These alterations may enhance the ability of the host immune system to recognize tumour cells as foreign owing to an increased number of antigens. However, these cancers may also elude immune surveillance and eradication through the expression of programmed death-ligand 1 (PD-L1; also called CD274 or B7-H1) in the tumour microenvironment. Therefore, we examined the anti-PD-L1 antibody MPDL3280A, a systemic cancer immunotherapy, for the treatment of metastatic UBC. MPDL3280A is a high-affinity engineered human anti-PD-L1 monoclonal immunoglobulin-G1 antibody that inhibits the interaction of PD-L1 with PD-1 (PDCD1) and B7.1 (CD80). Because PD-L1 is expressed on activated T cells, MPDL3280A was engineered with a modification in the Fc domain that eliminates antibody-dependent cellular cytotoxicity at clinically relevant doses to prevent the depletion of T cells expressing PD-L1. Here we show that MPDL3280A has noteworthy activity in metastatic UBC. Responses were often rapid, with many occurring at the time of the first response assessment (6 weeks) and nearly all were ongoing at the data cutoff. This phase I expansion study, with an adaptive design that allowed for biomarker-positive enriched cohorts, demonstrated that tumours expressing PD-L1-positive tumour-infiltrating immune cells had particularly high response rates. Moreover, owing to the favourable toxicity profile, including a lack of renal toxicity, patients with UBC, who are often older and have a higher incidence of renal impairment, may be better able to tolerate MPDL3280A versus chemotherapy. These results suggest that MPDL3280A may have an important role in treating UBC-the drug received breakthrough designation status by the US Food and Drug Administration (FDA) in June 2014.

Halide-Based Materials and Chemistry for Rechargeable Batteries.

Rechargeable batteries are considered one of the most effective energy storage technologies to bridge the production and consumption of renewable energy. The further development of rechargeable batteries with characteristics such as high energy density, low cost, safety, and a long cycle life is required to meet the ever-increasing energy-storage demands. This Review highlights the progress achieved with halide-based materials in rechargeable batteries, including the use of halide electrodes, bulk and/or surface halogen-doping of electrodes, electrolyte design, and additives that enable fast ion shuttling and stable electrode/electrolyte interfaces, as well as realization of new battery chemistry. Battery chemistry based on monovalent cation, multivalent cation, anion, and dual-ion transfer is covered. This Review aims to promote the understanding of halide-based materials to stimulate further research and development in the area of high-performance rechargeable batteries. It also offers a perspective on the exploration of new materials and systems for electrochemical energy storage.

Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial.

BACKGROUND: Few options exist for patients with locally advanced or metastatic urothelial carcinoma after progression with platinum-based chemotherapy. We aimed to assess the safety and efficacy of atezolizumab (anti-programmed death-ligand 1 [PD-L1]) versus chemotherapy in this patient population. METHODS: We conducted this multicentre, open-label, phase 3 randomised controlled trial (IMvigor211) at 217 academic medical centres and community oncology practices mainly in Europe, North America, and the Asia-Pacific region. Patients (aged ≥18 years) with metastatic urothelial carcinoma who had progressed after platinum-based chemotherapy were randomly assigned (1:1), via an interactive voice and web response system with a permuted block design (block size of four), to receive atezolizumab 1200 mg or chemotherapy (physician's choice: vinflunine 320 mg/m2, paclitaxel 175 mg/m2, or 75 mg/m2 docetaxel) intravenously every 3 weeks. Randomisation was stratified by PD-L1 expression (expression on <1% [IC0] or 1% to <5% [IC1] of tumour-infiltrating immune cells vs ≥5% of tumour-infiltrating immune cells [IC2/3]), chemotherapy type (vinflunine vs taxanes), liver metastases (yes vs no), and number of prognostic factors (none vs one, two, or three). Patients and investigators were aware of group allocation. Patients, investigators, and the sponsor were masked to PD-L1 expression status. The primary endpoint of overall survival was tested hierarchically in prespecified populations: IC2/3, followed by IC1/2/3, followed by the intention-to-treat population. This study, which is ongoing but not recruiting participants, is registered with ClinicalTrials.gov, number NCT02302807. FINDINGS: Between Jan 13, 2015, and Feb 15, 2016, we randomly assigned 931 patients from 198 sites to receive atezolizumab (n=467) or chemotherapy (n=464). In the IC2/3 population (n=234), overall survival did not differ significantly between patients in the atezolizumab group and those in the chemotherapy group (median 11·1 months [95% CI 8·6-15·5; n=116] vs 10·6 months [8·4-12·2; n=118]; stratified hazard ratio [HR] 0·87, 95% CI 0·63-1·21; p=0·41), thus precluding further formal statistical analysis. Confirmed objective response rates were similar between treatment groups in the IC2/3 population: 26 (23%) of 113 evaluable patients had an objective response in the atezolizumab group compared with 25 (22%) of 116 patients in the chemotherapy group. Duration of response was numerically longer in the atezolizumab group than in the chemotherapy group (median 15·9 months [95% CI 10·4 to not estimable] vs 8·3 months [5·6-13·2]; HR 0·57, 95% CI 0·26-1·26). In the intention-to-treat population, patients receiving atezolizumab had fewer grade 3-4 treatment-related adverse events than did those receiving chemotherapy (91 [20%] of 459 vs 189 [43%] of 443 patients), and fewer adverse events leading to treatment discontinuation (34 [7%] vs 78 [18%] patients). INTERPRETATION: Atezolizumab was not associated with significantly longer overall survival than chemotherapy in patients with platinum-refractory metastatic urothelial carcinoma overexpressing PD-L1 (IC2/3). However, the safety profile for atezolizumab was favourable compared with chemotherapy, Exploratory analysis of the intention-to-treat population showed well-tolerated, durable responses in line with previous phase 2 data for atezolizumab in this setting. FUNDING: F Hoffmann-La Roche, Genentech.

Association between the T6459C point mutation of the mitochondrial MT-CO1 gene and susceptibility to sepsis among Chinese Han people.

To search for an association between sepsis and mitochondrial genetic basis, we began our study. In this study, a proband harbouring mitochondrial T6459C mutation with sepsis and his Chinese Han pedigree including 7 members of 3 generations were enrolled. General information, blood parameters and mitochondrial full sequence scanning of all members were performed, and cellular functions, including cellular reactive oxygen species (ROS) levels, mitochondrial membrane potential (MMP), degrees of cell apoptosis and adenosine triphosphate (ATP) concentrations, were measured in members with and without the T6459C mutation. Through mitochondrial full sequence scanning and analysis of all members we found, the maternal members (I-1, II-1, II-2 and II-4) in this Chinese Han pedigree all had the mitochondrial T6459C mutation and were used as the mutation group. The non-maternal members (II-3, III-1 and III-2) did not have this mutation and were used as the non-mutation group. The differences in all indicators, including the blood routine, blood biochemistry and coagulation function tests, between members in these two groups were not significant. Under the non-stimulation condition, the mutation group had higher ROS levels (4210.42 ± 1043.35 vs 3387.78 ± 489.66, P = .028) and apoptosis ratios (P = .004) and lower ATP concentrations (P = .049) and MMP levels (P = .047) than the non-mutation group. After 6 hours of simulated LPS stimulation, the mutation group had significantly increased ROS levels (5759.25 ± 2297.90 vs 3862.00 ± 1519.77, P = .045) compared with the non-mutation group, whereas the mutation group continued to demonstrate higher ROS levels (P = .045) and apoptosis ratios (P = .003) and lower MMP levels (P = .005) and ATP concentrations (P = .010). We speculated that the mtDNA T6459C mutation might be the basis for the genetic susceptibility to sepsis.

Preparation and Characterization of Polyimide Aerogels with a Uniform Nanoporous Framework.

Polyimide (PI) aerogels were successfully synthesized via a straightforward sol-gel process under room temperature along with the supercritical CO2 drying method using 4-amino- N-methylbenzamide and 3,3',4,4'-biphenyltetracarboxylic dianhydride. 1,3,5-Triaminophenoxybenzene was used as the cross-linker. The chemical structure, pore structure, morphology, thermal performance, CO2 adsorption, and mechanical performance of PI aerogels were investigated. The as-prepared PI aerogels had low bulk densities (0.091-0.167 g/cm3), low shrinkages (9.73-17.36%), low thermal conductivities (0.0307-0.0341 W/m·K), high specific surface areas (449.76-538.19 m2/g), small pore diameter (10.37-22.41 nm), high thermal stability (onset of decomposition above 560 °C), and excellent mechanical property. The CO2 adsorption capacities of PI aerogels were substantially higher than the values of the previous porous materials reported under the similar conditions, and the CO2 uptake capacity was as high as 31.19 cm3/g at 25 °C and 1.0 bar. The resulting PI aerogels could be potentially used as thermal insulators and CO2 adsorbents.

The chromosomal SezAT toxin-antitoxin system promotes the maintenance of the SsPI-1 pathogenicity island in epidemic Streptococcus suis.

Streptococcus suis has emerged as a causative agent of human meningitis and streptococcal toxic shock syndrome over the last years. The high pathogenicity of S. suis may be due in part to a laterally acquired pathogenicity island (renamed SsPI-1), which can spontaneously excise and transfer to recipients. Cells harboring excised SsPI-1 can potentially lose this island if cell division occurs prior to its reintegration; however, attempts to cure SsPI-1 from the host cells have been unsuccessful. Here, we report that an SsPI-1-borne Epsilon/Zeta toxin-antitoxin system (designated SezAT) promotes SsPI-1 stability in bacterial populations. The sezAT locus consists of two closely linked sezT and sezA genes encoding a toxin and its cognate antitoxin, respectively. Overproduction of SezT induces a bactericidal effect that can be neutralized by co-expression of SezA, but not by its later action. When devoid of a functional SezAT system, large-scale deletion of SsPI-1 is straightforward. Thus, SezAT serves to ensure inheritance of SsPI-1 during cell division, which may explain the persistence of epidemic S. suis. This report presents the first functional characterization of TA loci in S. suis, and the first biochemical evidence for the adaptive significance of the Epsilon/Zeta system in the evolution of pathogen virulence.

A Rhodium Catalyst Superior to Iridium Congeners for Enantioselective Radical Amination Activated by Visible Light.

A bis-cyclometalated rhodium(III) complex catalyzes a visible-light-activated enantioselective α-amination of 2-acyl imidazoles with up to 99 % yield and 98 % ee. The rhodium catalyst is ascribed a dual function as a chiral Lewis acid and, simultaneously, as a light-activated smart initiator of a radical-chain process through intermediate aminyl radicals. Notably, related iridium-based photoredox catalysts reported before were unsuccessful in this enantioselective radical C-N bond formation. The surprising preference for rhodium over iridium is attributed to much faster ligand-exchange kinetics of the rhodium complexes involved in the catalytic cycle, which is crucial to keep pace with the highly reactive and thus short-lived nitrogen-centered radical intermediate.

Discovery of EBI-907: A highly potent and orally active B-Raf(V600E) inhibitor for the treatment of melanoma and associated cancers.

A novel series of pyrazolo[3,4-c]isoquinoline derivatives was discovered as B-Raf(V600E) inhibitors through scaffold hopping based on a literature lead PLX4720. Further SAR exploration and optimization led to the discovery of potent B-Raf(V600E) inhibitors with good oral bioavailability in rats and dogs. One of the compounds EBI-907 (13g) demonstrated excellent in vivo efficacy in B-Raf(V600E) dependent Colo-205 tumor xenograft models in mouse and is under preclinical studies for the treatment of melanoma and B-Raf(V600E) associated cancers.

Thickness dependence of surface energy and contact angle of water droplets on ultrathin MoS2 films.

We have performed a systematic density functional study of surface energy of MoS2 films as a function of thickness from one to twelve layers with the consideration of van der Waals (vdW) interactions using the vdW-DF and DFT-D2 methods. Both vdW schemes show that the surface energy will increase with the increase of the number of atomic layers and converge to a constant value at about six layers. Based on the calculated surface energies, we further analyze the surface contact angle of water droplets on the MoS2 film surface using Young's equation as a function of thickness in comparison with experiments, from which the water-MoS2 interfacial energy is derived to be independent of MoS2 thickness. Our calculations indicate that the vdW interactions between the MoS2 layers play an important role in determining surface energy, and results in the thickness dependence of the contact angle of water droplets on the MoS2 film surface. Our results explain well the recent wetting experiment [Nano Lett., 2014, 14(8), 4314], and will be useful for future studies of physical and chemical properties of ultrathin MoS2 films.