Polymer Photoelectrodes for Solar Fuel Production: Progress and Challenges.

Converting solar energy to fuels has attracted substantial interest over the past decades because it has the potential to sustainably meet the increasing global energy demand. However, achieving this potential requires significant technological advances. Polymer photoelectrodes are composed of earth-abundant elements, e.g. carbon, nitrogen, oxygen, hydrogen, which promise to be more economically sustainable than their inorganic counterparts. Furthermore, the electronic structure of polymer photoelectrodes can be more easily tuned to fit the solar spectrum than inorganic counterparts, promising a feasible practical application. As a fast-moving area, in particular, over the past ten years, we have witnessed an explosion of reports on polymer materials, including photoelectrodes, cocatalysts, device architectures, and fundamental understanding experimentally and theoretically, all of which have been detailed in this review. Furthermore, the prospects of this field are discussed to highlight the future development of polymer photoelectrodes.

Linking in situ charge accumulation to electronic structure in doped SrTiO3 reveals design principles for hydrogen-evolving photocatalysts.

Recently, high solar-to-hydrogen efficiencies were demonstrated using La and Rh co-doped SrTiO3 (La,Rh:SrTiO3) incorporated into a low-cost and scalable Z-scheme device, known as a photocatalyst sheet. However, the unique properties that enable La,Rh:SrTiO3 to support this impressive performance are not fully understood. Combining in situ spectroelectrochemical measurements with density functional theory and photoelectron spectroscopy produces a depletion model of Rh:SrTiO3 and La,Rh:SrTiO3 photocatalyst sheets. This reveals remarkable properties, such as deep flatband potentials (+2 V versus the reversible hydrogen electrode) and a Rh oxidation state dependent reorganization of the electronic structure, involving the loss of a vacant Rh 4d mid-gap state. This reorganization enables Rh:SrTiO3 to be reduced by co-doping without compromising the p-type character. In situ time-resolved spectroscopies show that the electronic structure reorganization induced by Rh reduction controls the electron lifetime in photocatalyst sheets. In Rh:SrTiO3, enhanced lifetimes can only be obtained at negative applied potentials, where the complete Z-scheme operates inefficiently. La co-doping fixes Rh in the 3+ state, which results in long-lived photogenerated electrons even at very positive potentials (+1 V versus the reversible hydrogen electrode), in which both components of the complete device operate effectively. This understanding of the role of co-dopants provides a new insight into the design principles for water-splitting devices based on bandgap-engineered metal oxides.

Dynamics of photoconversion processes: the energetic cost of lifetime gain in photosynthetic and photovoltaic systems.

The continued development of solar energy conversion technologies relies on an improved understanding of their limitations. In this review, we focus on a comparison of the charge carrier dynamics underlying the function of photovoltaic devices with those of both natural and artificial photosynthetic systems. The solar energy conversion efficiency is determined by the product of the rate of generation of high energy species (charges for solar cells, chemical fuels for photosynthesis) and the energy contained in these species. It is known that the underlying kinetics of the photophysical and charge transfer processes affect the production yield of high energy species. Comparatively little attention has been paid to how these kinetics are linked to the energy contained in the high energy species or the energy lost in driving the forward reactions. Here we review the operational parameters of both photovoltaic and photosynthetic systems to highlight the energy cost of extending the lifetime of charge carriers to levels that enable function. We show a strong correlation between the energy lost within the device and the necessary lifetime gain, even when considering natural photosynthesis alongside artificial systems. From consideration of experimental data across all these systems, the emprical energetic cost of each 10-fold increase in lifetime is 87 meV. This energetic cost of lifetime gain is approx. 50% greater than the 59 meV predicted from a simple kinetic model. Broadly speaking, photovoltaic devices show smaller energy losses compared to photosynthetic devices due to the smaller lifetime gains needed. This is because of faster charge extraction processes in photovoltaic devices compared to the complex multi-electron, multi-proton redox reactions that produce fuels in photosynthetic devices. The result is that in photosynthetic systems, larger energetic costs are paid to overcome unfavorable kinetic competition between the excited state lifetime and the rate of interfacial reactions. We apply this framework to leading examples of photovoltaic and photosynthetic devices to identify kinetic sources of energy loss and identify possible strategies to reduce this energy loss. The kinetic and energetic analyses undertaken are applicable to both photovoltaic and photosynthetic systems allowing for a holistic comparison of both types of solar energy conversion approaches.

Efficient Hole Trapping in Carbon Dot/Oxygen-Modified Carbon Nitride Heterojunction Photocatalysts for Enhanced Methanol Production from CO2 under Neutral Conditions.

Artificial photosynthesis of alcohols from CO2 is still unsatisfactory owing to the rapid charge relaxation compared to the sluggish photoreactions and the oxidation of alcohol products. Here, we demonstrate that CO2 is reduced to methanol with 100 % selectivity using water as the only electron donor on a carbon nitride-like polymer (FAT) decorated with carbon dots. The quantum efficiency of 5.9 % (λ=420 nm) is 300 % higher than the previously reported carbon nitride junction. Using transient absorption spectroscopy, we observed that holes in FAT could be extracted by the carbon dots with nearly 75 % efficiency before they become unreactive by trapping. Extraction of holes resulted in a greater density of photoelectrons, indicative of reduced recombination of shorter-lived reactive electrons. This work offers a strategy to promote photocatalysis by increasing the amount of reactive photogenerated charges via structure engineering and extraction before energy losses by deep trapping.

Tracking Charge Transfer to Residual Metal Clusters in Conjugated Polymers for Photocatalytic Hydrogen Evolution.

Semiconducting polymers are versatile materials for solar energy conversion and have gained popularity as photocatalysts for sunlight-driven hydrogen production. Organic polymers often contain residual metal impurities such as palladium (Pd) clusters that are formed during the polymerization reaction, and there is increasing evidence for a catalytic role of such metal clusters in polymer photocatalysts. Using transient and operando optical spectroscopy on nanoparticles of F8BT, P3HT, and the dibenzo[b,d]thiophene sulfone homopolymer P10, we demonstrate how differences in the time scale of electron transfer to Pd clusters translate into hydrogen evolution activity optima at different residual Pd concentrations. For F8BT nanoparticles with common Pd concentrations of >1000 ppm (>0.1 wt %), we find that residual Pd clusters quench photogenerated excitons via energy and electron transfer on the femto-nanosecond time scale, thus outcompeting reductive quenching. We spectroscopically identify reduced Pd clusters in our F8BT nanoparticles from the microsecond time scale onward and show that the predominant location of long-lived electrons gradually shifts to the F8BT polymer when the Pd content is lowered. While a low yield of long-lived electrons limits the hydrogen evolution activity of F8BT, P10 exhibits a substantially higher hydrogen evolution activity, which we demonstrate results from higher yields of long-lived electrons due to more efficient reductive quenching. Surprisingly, and despite the higher performance of P10, long-lived electrons reside on the P10 polymer rather than on the Pd clusters in P10 particles, even at very high Pd concentrations of 27000 ppm (2.7 wt %). In contrast, long-lived electrons in F8BT already reside on Pd clusters before the typical time scale of hydrogen evolution. This comparison shows that P10 exhibits efficient reductive quenching but slow electron transfer to residual Pd clusters, whereas the opposite is the case for F8BT. These findings suggest that the development of even more efficient polymer photocatalysts must target materials that combine both rapid reductive quenching and rapid charge transfer to a metal-based cocatalyst.

Biomarker-driven phase 2 umbrella trial study for patients with recurrent small cell lung cancer failing platinum-based chemotherapy.

BACKGROUND: A high percentage of small cell lung cancer (SCLC) cases harbor cell cycle-related gene mutations and RICTOR amplification. Based on underlying somatic mutations, the authors have conducted a phase 2 biomarker-driven, multiarm umbrella study. METHODS: The SCLC Umbrella Korea StudiES (SUKSES) is an adaptive platform trial that undergoes continual modification according to the observed outcomes. This study included 286 patients with SCLC who failed platinum therapy and who had known genomic profiles based on a predesigned screening trial. Patients with MYC amplification or CDKN2A and TP53 co-alterations were allocated to adavosertib (SUKSES protocol C [SUKSES-C]; 7 patients) and those with RICTOR amplification were allocated to vistusertib (SUKSES-D; 4 patients). Alternatively, patients who were without any predefined biomarkers were assigned to a non-biomarker-selected arm: adavosertib (SUKSES-N1; 21 patients) or AZD2811NP (SUKSES-N3; 15 patients). RESULTS: Patients in the SUKSES-C and SUKSES-N1 arms demonstrated no objective response. Three patients presented with stable disease (SD) in SUKSES-C and 6 patients in SUKSES-N1. The median progression-free survival (PFS) was 1.3 months (95% confidence interval, 0.9 months to not available) for SUKSES-C and 1.2 months (95% CI, 1.1-1.4 months) for SUKSES-N1. Patients in the SUKSES-D arm demonstrated no objective response and no SD, with a PFS of 1.2 months (95% CI, 1.0 months to not available). The SUKSES-N3 arm had 5 patients with SD and a PFS of 1.6 months (95% CI, 0.9-1.7 months), without an objective response. Grade≥3 adverse events (graded according to National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.03]) were observed as follows: 3.2% in the SUKSES-C and SUKSES-N1 arms and 50.0% in the SUKSES-D arm. Target-related neutropenia (grade≥3) was observed in approximately 60.0% of patients in the AZD2811NP arm using the current dosing schedule. CONCLUSIONS: To the best of the authors' knowledge, the current study is the first biomarker-driven umbrella study conducted in patients with recurrent SCLC. Although the current study demonstrated the limited clinical efficacy of monotherapy, novel biomarker approaches using other cell cycle inhibitor(s) or combinations warrant further investigation.

Heteroarylamide smoothened inhibitors: Discovery of N-[2,4-dimethyl-5-(1-methylimidazol-4-yl)phenyl]-4-(2-pyridylmethoxy)benzamide (AZD8542) and N-[5-(1H-imidazol-2-yl)-2,4-dimethyl-phenyl]-4-(2- pyridylmethoxy)benzamide (AZD7254).

Aberrant hedgehog (Hh) pathway signaling is implicated in multiple cancer types and targeting the Smoothened (SMO) receptor, a key protein of the Hh pathway, has proven effective in treating metastasized basal cell carcinoma. Our lead optimization effort focused on a series of heteroarylamides. We observed that a methyl substitution ortho to the heteroaryl groups on an aniline core significantly improved the potency of this series of compounds. These findings predated the availability of SMO crystal structure in 2013. Here we retrospectively applied quantum mechanics calculations to demonstrate the o-Me substitution favors the bioactive conformation by inducing a dihedral twist between the heteroaryl rings and the core aniline. The o-Me also makes favorable hydrophobic interactions with key residue side chains in the binding pocket. From this effort, two compounds (AZD8542 and AZD7254) showed excellent pharmacokinetics across multiple preclinical species and demonstrated in vivo activity in abrogating the Hh paracrine pathway as well as anti- tumor effects.

Quantifying Heme-Protein Maturation from Ratiometric Fluorescence Lifetime Measurements on the Single Fluorophore in Its GFP Fusion.

Protein maturation by heme insertion is a common post-translation modification of key biological importance. Nonetheless, where and when this maturation occurs in eukaryotic cells remain unknown for most heme proteins. Here, we demonstrate for the first time that the maturation of a chromosomally expressed, endogenous heme protein fused to a green fluorescent protein (GFP) can be tracked in live cells. Selecting yeast cytochrome c peroxidase (Ccp1) as our model heme-binding protein, we first characterized the emission in vitro of recombinant Ccp1-GFP with GFP fused C-terminally to Ccp1 by the linker GRRIPGLIN. Time-correlated single-photon counting reveals a single fluorescence lifetime for heme-free apoCcp1-GFP, τ0 = 2.84 ± 0.01 ns. Heme bound to Ccp1 only partially quenches GFP fluorescence since holoCcp1-GFP exhibits two lifetimes, τ1 = 0.95 ± 0.02 and τ2 = 2.46 ± 0.03 ns with fractional amplitudes a1 = 38 ± 1.5% and a2 = 62 ± 1.5%. Also, τ and a are independent of Ccp1-GFP concentration and solution pH between 5.5 and 8.0, and a standard plot of a1 vs % holoCcp1-GFP in mixtures with apoCcp1-GFP is linear, establishing that the fraction of Ccp1-GFP with heme bound can be determined from a1. Fluorescence lifetime imaging microscopy (FLIM) of live yeast cells chromosomally expressing the same Ccp1-GFP fusion revealed 30% holoCcp1-GFP (i.e., mature Ccp1) and 70% apoCcp1-GFP in agreement with biochemical measurements on cell lysates. Thus, ratiometric fluorescence lifetime measurements offer promise for probing heme-protein maturation in live cells, and we can dispense with the reference fluorophore required for ratiometric intensity-based measurements.

Electron Accumulation Induces Efficiency Bottleneck for Hydrogen Production in Carbon Nitride Photocatalysts.

This study addresses the light intensity dependence of charge accumulation in a photocatalyst suspension, and its impact on both charge recombination kinetics and steady-state H2 evolution efficiency. Cyanamide surface functionalized melon-type carbon nitride (NCNCNx) has been selected as an example of emerging carbon nitrides photocatalysts because of its excellent charge storage ability. Transient spectroscopic studies (from ps to s) show that the bimolecular recombination of photogenerated electrons and holes in NCNCNx can be well described by a random walk model. Remarkably, the addition of hole scavengers such as 4-methylbenzyl alcohol can lead to ∼400-fold faster recombination kinetics (lifetime shortening to ∼10 ps). We show that this acceleration is not the direct result of ultrafast hole extraction by the scavenger, but is rather caused by long-lived electron accumulation in NCNCNx after hole extraction. The dispersive pseudo-first order recombination kinetics become controlled by the density of accumulated electrons. H2 production and steady-state spectroscopic measurements indicate that the accelerated recombination caused by electron accumulation limits the H2 generation efficiency. The addition of a reversible electron acceptor and mediator, methyl viologen (MV2+), accelerates the extraction of electrons from the NCNCNx and increases the H2 production efficiency under one sun irradiation by more than 30%. These results demonstrate quantitatively that while long-lived electrons are essential to drive photoinduced H2 generation in many photocatalysts, excessive electron accumulation may result in accelerated recombination losses and lower performance, and thus highlight the importance of efficient electron and hole extraction in enabling efficient water splitting photocatalysts.

Phase I studies of AZD1208, a proviral integration Moloney virus kinase inhibitor in solid and haematological cancers.

BACKGROUND: Proviral integration Moloney virus (PIM) kinases (PIM1, 2 and 3) are overexpressed in several tumour types and contribute to oncogenesis. AZD1208 is a potent ATP-competitive PIM kinase inhibitor investigated in patients with recurrent or refractory acute myeloid leukaemia (AML) or advanced solid tumours. METHODS: Two dose-escalation studies were performed to evaluate the safety and tolerability, and to define the maximum tolerated dose (MTD), of AZD1208 in AML and solid tumours. Secondary objectives were to evaluate the pharmacokinetics, pharmacodynamics (PD) and preliminary efficacy of AZD1208. RESULTS: Sixty-seven patients received treatment: 32 in the AML study over a 120-900 mg dose range, and 25 in the solid tumour study over a 120-800 mg dose range. Nearly all patients (98.5%) in both studies experienced adverse events, mostly gastrointestinal (92.5%). Dose-limiting toxicities included rash, fatigue and vomiting. AZD1208 was not tolerated at 900 mg, and the protocol-defined MTD was not confirmed. AZD1208 increased CYP3A4 activity after multiple dosing, resulting in increased drug clearance. There were no clinical responses; PD analysis showed biological activity of AZD1208. CONCLUSIONS: Despite the lack of single-agent clinical efficacy with AZD1208, PIM kinase inhibition may hold potential as an anticancer treatment, perhaps in combination with other agents.

Time-Resolved Spectroscopic Investigation of Charge Trapping in Carbon Nitrides Photocatalysts for Hydrogen Generation.

Carbon nitride (g-C3N4) as a benchmark polymer photocatalyst is attracting significant research interest because of its visible light photocatalytic performance combined with good stability and facile synthesis. However, little is known about the fundamental photophysical processes of g-C3N4, which are key to explain and promote photoactivity. Using time-resolved absorption and photoluminescence spectroscopies, we have investigated the photophysics of a series of carbon nitrides on time scales ranging from femtoseconds to seconds. Free charge carriers form within a 200 fs excitation pulse, trap on the picosecond time scale with trap states in a range of energies, and then recombine with power law decays that are indicative of charge trapping-detrapping processes. Delayed photoluminescence is assigned to thermal excitation of trapped carriers back up to the conduction/valence bands. We develop a simple, quantitative model for the charge carrier dynamics in these photocatalysts, which includes carrier relaxation into an exponential tail of trap states extending up to 1.5 eV into the bandgap. This trapping reduces the efficiency of surface photocatalytic reactions. Deep trapped electrons observed on micro- to millisecond time scales are unable to reduce electron acceptors on the surface or in solution. Within a series of g-C3N4, the yield of these unreactive trapped electrons correlates inversely with H2 evolution rates. We conclude by arguing that the photophysics of these carbon nitride materials show closer parallels with inorganic semiconductors than conjugated polymers, and that the key challenge to optimize photocatalytic activity of these materials is to prevent electron trapping into deep, and photocatalytically inactive, electron trap states.

Stoichiometry and Dispersity of DNA Nanostructures Using Photobleaching Pair-Correlation Analysis.

A wide variety of approaches have become available for the fabrication of nanomaterials with increasing degrees of complexity, precision, and speed while minimizing cost. Their quantitative characterization, however, remains a challenge. Analytical methods to better inspect and validate the structure and composition of large nanoscale objects are required to optimize their applications in diverse technologies. Here, we describe single-molecule fluorescence-based strategies relying on photobleaching and multiple-color co-localization features toward the characterization of supramolecular structures. By optimizing imaging conditions, including surface passivation, excitation power, frame capture rate, fluorophore choice, buffer media, and antifading agents, we have built a robust method by which to dissect the structure of synthetic nanoscale systems. We showcase the use of our methods by retrieving key structural parameters of four DNA nanotube systems differing in their preparation strategy. Our method rapidly and accurately assesses the outcome of synthetic work building nano- and mesoscale architectures, providing a key tool for product studies in nanomaterial synthesis.

Enhancing Light Absorption and Charge Transfer Efficiency in Carbon Dots through Graphitization and Core Nitrogen Doping.

Single-source precursor syntheses have been devised for the preparation of structurally similar graphitic carbon dots (CDs), with (g-N-CD) and without (g-CD) core nitrogen doping for artificial photosynthesis. An order of magnitude improvement has been realized in the rate of solar (AM1.5G) H2 evolution using g-N-CD (7950 µmolH2 (gCD )-1 h-1 ) compared to undoped CDs. All graphitized CDs show significantly enhanced light absorption compared to amorphous CDs (a-CD) yet undoped g-CD display limited photosensitizer ability due to low extraction of photogenerated charges. Transient absorption spectroscopy showed that nitrogen doping in g-N-CD increases the efficiency of hole scavenging by the electron donor and thereby significantly extends the lifetime of the photogenerated electrons. Thus, nitrogen doping allows the high absorption coefficient of graphitic CDs to be translated into high charge extraction for efficient photocatalysis.

Monitoring Chemical and Biological Electron Transfer Reactions with a Fluorogenic Vitamin K Analogue Probe.

We report herein the design, synthesis, and characterization of a two-segment fluorogenic analogue of vitamin K, B-VKQ, prepared by coupling vitamin K3, also known as menadione (a quinone redox center), to a boron-dipyrromethene (BODIPY) fluorophore (a lipophilic reporter segment). Oxidation-reduction reactions, spectroelectrochemical studies, and enzymatic assays conducted in the presence of DT-diaphorase illustrate that the new probe shows reversible redox behavior on par with that of vitamin K, provides a high-sensitivity fluorescence signal, and is compatible with biological conditions, opening the door to monitor remotely (i.e., via imaging) redox processes in real time. In its oxidized form, B-VKQ is non-emissive, while upon reduction to the hydroquinone form, B-VKQH2, BODIPY fluorescence is restored, with emission quantum yield values of ca. 0.54 in toluene. Density functional theory studies validate a photoinduced electron transfer intramolecular switching mechanism, active in the non-emissive quinone form and deactivated upon reduction to the emissive dihydroquinone form. Our results highlight the potential of B-VKQ as a fluorogenic probe to study electron transfer and transport in model systems and biological structures with optimal sensitivity and desirable chemical specificity. Use of such a probe may enable a better understanding of the role that vitamin K plays in biological redox reactions ubiquitous in key cellular processes, and help elucidate the mechanism and pathological significance of these reactions in biological systems.

Fluorogenic Ubiquinone Analogue for Monitoring Chemical and Biological Redox Processes.

We report herein the synthesis and characterization of a fluorogenic analogue of ubiquinone designed to reversibly report on redox reactions in biological systems. The analogue, H2B-Q, consists of the redox-active quinone segment found in ubiquinone, 2,3-dimethoxy-1,4-benzoquinone, coupled to a boron-dipyrromethene (BODIPY) fluorophore segment that both imparts lipophilicity in lieu of the isoprenyl tail of ubiquinone, and reports on redox changes at the quinone/quinol segment. Redox sensing is mediated by a photoinduced electron transfer intramolecular switch. In its reduced dihydroquinone form, H2B-QH2 is highly emissive in nonpolar media (quantum yields 55-66%), while once oxidized, the resulting quinone H2B-Q emission is suppressed. Cyclic voltammetry of H2B-Q shows two reversible, 1-electron reduction peaks at -1.05 V and -1.37 V (vs ferrocene) on par with those of ubiquinone. Chemical reduction of H2B-Q by NaBH4 resulted in >200 fold emission enhancement. H2B-QH2 is shown to react with peroxyl radicals, a form of reactive oxygen species (ROS) as well as to cooperatively interact with chromanol (the active segment of α-tocopherol). Kinetic analysis further shows the antioxidant reactivity of the nonfluorescent intermediate semiquinone. We anticipate that the H2B-Q/H2B-QH2 off/on reversible couple may serve as a tool to monitor chemical redox processes in real-time and in a noninvasive manner.

Solar-Driven Reduction of Aqueous Protons Coupled to Selective Alcohol Oxidation with a Carbon Nitride-Molecular Ni Catalyst System.

Solar water-splitting represents an important strategy toward production of the storable and renewable fuel hydrogen. The water oxidation half-reaction typically proceeds with poor efficiency and produces the unprofitable and often damaging product, O2. Herein, we demonstrate an alternative approach and couple solar H2 generation with value-added organic substrate oxidation. Solar irradiation of a cyanamide surface-functionalized melon-type carbon nitride ((NCN)CNx) and a molecular nickel(II) bis(diphosphine) H2-evolution catalyst (NiP) enabled the production of H2 with concomitant selective oxidation of benzylic alcohols to aldehydes in high yield under purely aqueous conditions, at room temperature and ambient pressure. This one-pot system maintained its activity over 24 h, generating products in 1:1 stoichiometry, separated in the gas and solution phases. The (NCN)CNx-NiP system showed an activity of 763 µmol (g CNx)(-1) h(-1) toward H2 and aldehyde production, a Ni-based turnover frequency of 76 h(-1), and an external quantum efficiency of 15% (λ = 360 ± 10 nm). This precious metal-free and nontoxic photocatalytic system displays better performance than an analogous system containing platinum instead of NiP. Transient absorption spectroscopy revealed that the photoactivity of (NCN)CNx is due to efficient substrate oxidation of the material, which outweighs possible charge recombination compared to the nonfunctionalized melon-type carbon nitride. Photoexcited (NCN)CNx in the presence of an organic substrate can accumulate ultralong-lived "trapped electrons", which allow for fuel generation in the dark. The artificial photosynthetic system thereby catalyzes a closed redox cycle showing 100% atom economy and generates two value-added products, a solar chemical, and solar fuel.

Dye lipophilicity and retention in lipid membranes: implications for single-molecule spectroscopy.

Fluorescence studies of individual lipid vesicles rely on the proper positioning of probes in the lipid milieu. This is true for both positional tags and chemoselective fluorogenic probes that undergo chemical modification following reaction with an analyte of interest within the lipid environment. The present report describes lipophilicity and localization estimations for a series of BODIPY dyes bearing substituents of varying hydrophobicity. We also studied fluorogenic trap-reporter probes that undergo fluorescence emission enhancement upon trapping of reactive oxygen species (ROS), including lipid peroxyl radicals. We show that caution has to be taken to extrapolate ensemble partition measurements of dyes to the single-molecule regime as a result of the dramatically different lipid concentration prevailing in ensemble versus single-molecule experiments. We show that the mole fraction of dyes that remains embedded in liposomes during a typical single-molecule experiment may be accurately determined from a ratiometric single-particle imaging analysis. We further demonstrate that fluorescence correlation spectroscopy (FCS) provides a very rapid and reliable estimate of the lipophilic nature of a given dye under highly dilute single-molecule-like conditions. Our combined single-particle spectroscopy and FCS experiments suggest that the minimal mole fraction of membrane-associated dyes (x(m)) as determined from FCS experiments is about 0.5 for adequate dye retention during single-molecule imaging in lipid membranes. Our work further highlights the dramatic effect that chemical modifications can have on chemoselective fluorogenic probe localization.

Phase I/II Study of the WEE1 Inhibitor Adavosertib (AZD1775) in Combination with Carboplatin in Children with Advanced Malignancies: Arm C of the AcSé-ESMART Trial.

PURPOSE: AcSé-ESMART Arm C aimed to define the recommended dose and activity of the WEE1 inhibitor adavosertib in combination with carboplatin in children and young adults with molecularly enriched recurrent/refractory malignancies. PATIENTS AND METHODS: Adavosertib was administered orally, twice every day on Days 1 to 3 and carboplatin intravenously on Day 1 of a 21-day cycle, starting at 100 mg/m2/dose and AUC 5, respectively. Patients were enriched for molecular alterations in cell cycle and/or homologous recombination (HR). RESULTS: Twenty patients (median age: 14.0 years; range: 3.4-23.5) were included; 18 received 69 treatment cycles. Dose-limiting toxicities were prolonged grade 4 neutropenia and grade 3/4 thrombocytopenia requiring transfusions, leading to two de-escalations to adavosertib 75 mg/m2/dose and carboplatin AUC 4; no recommended phase II dose was defined. Main treatment-related toxicities were hematologic and gastrointestinal. Adavosertib exposure in children was equivalent to that in adults; both doses achieved the cell kill target. Overall response rate was 11% (95% confidence interval, 0.0-25.6) with partial responses in 2 patients with neuroblastoma. One patient with medulloblastoma experienced unconfirmed partial response and 5 patients had stable disease beyond four cycles. Seven of these eight patients with clinical benefit had alterations in HR, replication stress, and/or RAS pathway genes with or without TP53 alterations, whereas TP53 pathway alterations alone (8/10) or no relevant alterations (2/10) were present in the 10 patients without benefit. CONCLUSIONS: Adavosertib-carboplatin combination exhibited significant hematologic toxicity. Activity signals and identified potential biomarkers suggest further studies with less hematotoxic DNA-damaging therapy in molecularly enriched pediatric cancers.

Aminosilanized Interface Promotes Electrochemically Stable Carbon Nitride Films with Fewer Trap States on FTO for (Photo)electrochemical Systems.

We have demonstrated the direct growth of a CNx layer on a plasma-cleaned and aminosilanized F-doped SnO2 (FTO) electrode to study the CNx|FTO interface that is critical for (photo)electrocatalytic systems. The (3-aminopropyl)triethoxysilane (APTES) was chosen as a bifunctional organosilane, with the amino end incorporating into CNx and the silane end connecting to the hydroxylated FTO surface. Plasma cleaning and aminosilanization resulted in a highly hydrophilic surface, which leads to better contact of melted thiourea to the aminosilanized FTO (p-FTONH2) during CNx polymer condensation, thus generating a thinner and more compact CNx layer. The modification at the interface was shown to influence the CNx growth on length scales of tens of micrometers. We grew CNx thin films on p-FTONH2 (CNx/p-FTONH2) and nonaminosilanized p-FTO (CNx/p-FTO). CNx/p-FTONH2 had a smaller density of trap states and passed 2.4 times the charges before failure compared to CNx/p-FTO. Additionally, a 40% decrease in interfacial charge transfer resistance at the CNx|electrolyte interface was measured for CNx/p-FTONH2 compared to CNx/p-FTO under -0.5 V vs RHE in 0.1 M Na2SO4. Furthermore, with the CNx surface coated with a Pt cocatalyst, Pt/CNx/p-FTONH2 exhibited faster hydrogen evolution rates and larger current densities than Pt/CNx/p-FTO. The highest Faraday efficiency toward electrochemical hydrogen evolution (FEH2) in 0.1 M Na2SO4 (pH = 7) was 46.1%, 37.3%, 57.7%, and 70.5% for Pt/CNx/p-FTONH2, Pt/CNx/p-FTO, CNx/p-FTONH2, and CNx/p-FTO, respectively. The increase in hydrogen evolution rate did not follow the magnitude of the current density change, indicating electrochemical processes other than proton reduction. Overall, we have carefully investigated the CNx|FTO interface and suggested potential solutions to make CNx films better (photo)electrodes for (photo)electrochemical systems.