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Ethylene is an important feedstock in the chemical industry, but currently requires production from fossil resources. The electrocatalytic oxidative decarboxylation of succinic acid offers in principle an environmentally friendly route to generate ethylene. Here, a detailed investigation of the role of different carbon electrode materials and characteristics revealed that a flat electrode surface and high ordering of the carbon material are conducive for the reaction. A range of electrochemical and spectroscopic approaches such as Koutecky-Levich analysis, rotating ring-disk electrode (RRDE) studies, and Tafel analysis as well as quantum chemical calculations, electron paramagnetic resonance (EPR), and in situ infrared (IR) spectroscopy generated further insights into the mechanism of the overall process. A distinct reaction intermediate was detected, and the decarboxylation onset potential was determined to be 2.2-2.3 V versus the reversible hydrogen electrode (RHE). Following the mechanistic studies and electrode optimization, a two-step bio-electrochemical process was established for ethylene production using succinic acid sourced from food waste. The initial step of this integrated process involves microbial hydrolysis/fermentation of food waste into aqueous solutions containing succinic acid (0.3 M; 3.75 mmol per g bakery waste). The second step is the electro-oxidation of the obtained intermediate succinic acid to ethylene using a flow setup at room temperature, with a productivity of 0.4-1 μmol ethylene cmelectrode -2 h-1. This approach provides an alternative strategy to produce ethylene from food waste under ambient conditions using renewable energy.

Many photoactivated processes involve a change in oxidation state during the reaction pathway and formation of highly reactive photoactivated species. Isolating these reactive species and studying their early-stage femtosecond to nanosecond (fs–ns) photodynamics can be challenging. Here we introduce a combined ultrafast transient absorption-spectroelectrochemistry (TA-SEC) approach using freestanding boron doped diamond (BDD) mesh electrodes, which also extends the time domain of conventional spectrochemical measurements. The BDD electrodes offer a wide solvent window, low background currents, and a tuneable mesh size which minimises light scattering from the electrode itself. Importantly, reactive intermediates are generated electrochemically, via oxidation/reduction of the starting stable species, enabling their dynamic interrogation using ultrafast TA-SEC, through which the early stages of the photoinduced relaxation mechanisms are elucidated. As a model system, we investigate the ultrafast spectroscopy of both anthraquinone-2-sulfonate (AQS) and its less stable counterpart, anthrahydroquinone-2-sulfonate (AH2QS). This is achieved by generating AH2QS in situ from AQS via electrochemical means, whilst simultaneously probing the associated early-stage photoinduced dynamical processes. Using this approach we unravel the relaxation mechanisms occurring in the first 2.5 ns, following absorption of ultraviolet radiation; for AQS as an extension to previous studies, and for the first time for AH2QS. AQS relaxation occurs via formation of triplet states, with some of these states interacting with the buffered solution to form a transient species within approximately 600 ps. In contrast, all AH2QS undergoes excited-state single proton transfer with the buffered solution, resulting in formation of ground state AHQS− within approximately 150 ps., A spectroelectrochemical set-up using a boron doped diamond mesh electrode is presented; from ultrafast photodynamics to steady-state, the photochemistry and photophysics of redox active species and their reactive intermediates can be investigated.

The transcriptome from lupulin glands and associated bracts from cone tissue of hop (Humulus lupulus) c.v. ‘Cascade’, during three stages of development: early, mid, and late or near-harvest, was s...

The organocatalytic transformation of resorcinols is extremely rare. In this article, we report a highly enantioselective, organocatalytic intramolecular cyclization of these systems by a Friedel-Crafts-type 1,4-addition using a Jorgensen-Hayashi-like organocatalyst with a large silyl protecting group, and show that heat improves reaction yield with virtually no detriment to enantioselectivity. A variety of bicyclic resorcinols were obtained with excellent enantioselectivities (up to 94%). To show the utility of these constructs, and as part of a wider project involving the synthesis of cannabinoid-like compounds, the resorcinol formed was used to generate both 'normal' and 'abnormal' cannabidiol (CBD) derivatives which were shown to have anticonvulsant activity.

Introduction Current guidelines advocate reviewing peri-procedural anticoagulation on individual case basis for transvenous lead extraction (TLE). We investigated the safety of TLE on uninterrupted warfarin with therapeutic INR. Methods Retrospective registry of consecutive patients undergoing TLE on uninterrupted warfarin (Warfarin Group) across two centres. Age and sex matched controls not on anticoagulation (No-Warfarin Group) and undergoing TLE over the same time-period were included. Both groups were compared over one-year. Results 121 TLEs over 18-months. 22 patients on uninterrupted anticoagulation were compared to 22 controls. Groups were well matched for baseline demographics other than INR. Warfarin group had mean INR of 2.2 ± 0.6 (range 2–3.5). Primary end point was procedural safety and efficacy. Amongst cases, 43/45 (96%) leads were removed in their entirety compared to 37/40 (93%) in controls (p = 0.66). In the cases, these included 44% defibrillator, 47% pace-sense and 9% CS leads of average duration 7yrs. There was no reported tamponade, haemothorax or procedural mortality in either group. One patient amongst cases required inotropic support while two patients amongst controls had device-site haematomas. No significant difference reported in Hb drop post-procedure or overall complication rate between the groups (p = 0.11,0.32). Cox regression showed a significant association between procedural success and device infection, number of leads extracted, serum creatinine (p = 0.03, 0.04, 0.02). Over a 1-year follow-up, there was lead displacement in one case and one control had infection of the re-implanted device. Conclusion TLE can be carried out safely in anticoagulated patients with therapeutic INRs. Larger multicentre studies are required to confirm these findings.

Summary Background PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. Methods KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov , number NCT02853305 . Findings Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5–8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4–7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65–0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5–19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3–16·7) in the chemotherapy group (0·86, 0·72–1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1–17·9] with pembrolizumab vs 14·3 months [12·3–16·7] with chemotherapy; HR 0·92, 95% CI 0·77–1·11) and the population with CPS of at least 10 (16·1 months [13·6–19·9] with pembrolizumab vs 15·2 months [11·6–23·3] with chemotherapy; 1·01, 0·77–1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. Interpretation The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. Funding Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.

Gamma-butyrolactone (GBL), a commonly used industrial solvent, is used recreationally as a central nervous system (CNS) depressant and, therefore, is a United States Drug Enforcement Agency List 1 chemical of the Controlled Substances Act. GBL was identified presumptively in the liquid from JUUL Virginia Tobacco flavored pods during routine untargeted screening analysis of e-cigarette products by gas chromatography–mass spectrometry (GC–MS). Methods for the analysis of GBL were developed for GC–MS and liquid chromatography–tandem mass spectrometry (LC–MS-MS) in the liquids and the aerosol generated from the liquid. Three flavors of JUUL pods available at the time of analysis were obtained by direct purchase from the manufacturer, purchase from a local vape shop and submission from a third party. The only liquid flavor to contain GBL was Virginia Tobacco, with an average of 0.37 mg/mL of GBL, and it was detected in the aerosol. Studies evaluating the pharmacological effects of inhaling GBL do not exist; however, a case report of chronic oral GBL ingestion indicates acute lung injury. The identification of GBL in an e-cigarette product purportedly compliant with federal regulation continues to demonstrate public health and public safety concerns.

Fengycins are cyclic lipo-depsipeptides produced by Bacillus spp. that display potent antifungal properties but are chemically unstable. This instability has meant that no total synthesis of any fengycin has been published. Here we report the synthesis of fengycin A analogues that display enhanced antifungal properties and chemical stability under both basic and acidic conditions. The analogues prepared also demonstrate that the fengycin core structure can be modified and simplified without the loss of antifungal activity.

An SU-8 probe with an array of nine, individually addressable gold microband electrodes (100 μm long, 4 μm wide, separated by 4-μm gaps) was photolithographically fabricated and characterized for detection of low concentrations of chemicals in confined spaces and in vivo studies of biological tissues. The probe’s shank (6 mm long, 100 μm wide, 100 μm thick) is flexible, but exhibits sufficient sharpness and rigidity to be inserted into soft tissue. Laser micromachining was used to define probe geometry by spatially revealing the underlying sacrificial aluminum layer, which was then etched to free the probes from a silicon wafer. Perfusion with fluorescent nanobeads showed that, like a carbon fiber electrode, the probe produced no noticeable damage when inserted into rat brain, in contrast to damage from an inserted microdialysis probe. The individual addressability of the electrodes allows single and multiple electrode activation. Redox cycling is possible, where adjacent electrodes serve as generators (that oxidize or reduce molecules) and collectors (that do the opposite) to amplify signals of small concentrations without background subtraction. Information about electrochemical mechanisms and kinetics may also be obtained. Detection limits for potassium ferricyanide in potassium chloride electrolyte of 2.19, 1.25, and 2.08 μM and for dopamine in artificial cerebral spinal fluid of 1.94, 1.08, and 5.66 μM for generators alone and for generators and collectors during redox cycling, respectively, were obtained.

This paper evaluates the aggregation behavior of a potential drug and gene delivery system that combines branched polyethyleneimine (PEI), a positively-charged polyelectrolyte, and elastin-like polypeptide (ELP), a recombinant polymer that exhibits lower critical solution temperature (LCST). The LCST behavior of ELP has been extensively studied, but there are no quantitative ways to control the size of aggregates formed after the phase transition. The aggregate size cannot be maintained when the temperature is lowered below the LCST, unless the system exhibits hysteresis and forms irreversible aggregates. This study shows that conjugation of ELP with PEI preserves the aggregation behavior that occurs above the LCST and achieves precise aggregate radii when the solution conditions of pH (3, 7, 10), polymer concentration (0.1, 0.15, 0.3 mg/mL), and salt concentration (none, 0.2, 1 M) are carefully controlled. K-means cluster analyses showed that salt concentration was the most critical factor controlling the hydrodynamic radius and LCST. Conjugating ELP to PEI allowed crosslinking the aggregates and achieved stable particles that maintained their size below LCST, even after removal of the harsh (high salt or pH) conditions used to create them. Taken together, the ability to control aggregate sizes and use of crosslinking to maintain stability holds excellent potential for use in biological delivery systems.

We previously reviewed the use of 19F NMR in the broad field of chemical biology [Cobb, S. L.; Murphy, C. D. J. Fluorine Chem. 2009, 130, 132–140] and present here a summary of the literature from the last decade that has the technique as the central method of analysis. The topics covered include the synthesis of new fluorinated probes and their incorporation into macromolecules, the application of 19F NMR to monitor protein–protein interactions, protein–ligand interactions, physiologically relevant ions and in the structural analysis of proteins and nucleic acids. The continued relevance of the technique to investigate biosynthesis and biodegradation of fluorinated organic compounds is also described.

We report the one-step syntheses, X-ray structures, and spectroscopic characterization of synthetic iron clusters bearing inorganic sulfides or thiolate with interstitial carbide motifs. Treatment of historical iron-carbide-carbonyl clusters [Fe n ( μ n -C)(CO) m ] x ( n = 5,6; m = 15,16; x = 0,-2) with electrophilic sulfur sources (S 2 Cl 2 , S 8 ) results in the formation of several μ 4 -S 'dimers of clusters' ( 1 and 2 ), and moreover the iron-sulfide-(sulfocarbide) clusters 3 and 4 . The core 'carbide' motif in 3 and 4 is the sulfocarbide unit {C-S} 4- , which serves as a structural model for the proposed intermediate in the radical-SAM biogenesis of the M-cluster. Furthermore, the 'electrophilic sulfur' strategy has been extended to provide the first ever thiolato-iron-carbide complex: An analogous reaction with toluylsulfenyl-chloride (tolS-Cl) affords the cluster [Fe 5 ( μ 5 -C)(SC 7 H 7 )(CO) 13 ] - ( 5 ). The 'electrophilic sulfur donor' strategy described herein provides a breakthrough towards developing logical syntheses of biomimetic iron-sulfur-carbide clusters like FeMoco.

A series of Ni complexes [Ni(Cl)2(PR3)2] with R = Me (1-Me), nPr (1-nPr), and nBu (1-nBu) and nickelocenes [Ni(η5-C5H4R′)2] with R′ = H (2-H), Me (2-Me), and SiMe3 (2-SiMe3) were synthesized and ch...

Chirality is ubiquitous within biological systems where many of the roles and functions are still undetermined. Given this, there is a clear need to design and develop sensitive chiral optical probes that can function within a biological setting. Here we report the design and synthesis of magnetically responsive Circularly Polarized Luminescence (CPL) complexes displaying exceptional photophysical properties (quantum yield up to 31 % and |glum| up to 0.240) by introducing chiral substituents onto the macrocyclic scaffolds. Magnetic CPL responses are observed in these chiral EuIII complexes, promoting an exciting development to the field of magneto‐optics. The |glum| of the 5D0 → 7F1 transition increases by 20 % from 0.222 (0 T) to 0.266 (1.4 T) displaying a linear relationship between the Δglum and the magnetic field strength. These EuIII complexes with magnetic CPL responses, provides potential development to be used in CPL imaging applications due to improved sensitivity and resolution., A series of chiral, water‐soluble, DO3A‐based EuIII complexes was designed and synthesized. The chiral substituents introduced onto the macrocyclic scaffolds enhanced the photophysical properties with quantum yields up to 31 % and |glum| up to 0.240. The |glum| value increased by 20 % from 0.222 to 0.267 under external magnetic field showing a linear response.

Glutamate (Glu) is a key molecule in cellular metabolism, the most abundant excitatory neurotransmitter in the brain, and the principal neurotransmitter of cortical efferents. Glutamate dysfunction, on the other hand, is common in neurodegenerative disorders, and likely contributes to age-related declines in behavioral and cognitive functioning. Nonetheless, the extant literature measuring age-related changes in brain glutamate in vivo has yet to be comprehensively and quantitatively summarized. This meta-analysis examines proton spectroscopy (1HMRS) measures of Glu-related brain metabolites across 589 healthy young and older adults. Glu (Cohen's d = −0.82) and Glu+glutamine (Cohen's d = −0.51) concentrations were significantly lower in older compared with younger adults, whereas the concentration of glutamine (d = 0.43) was significantly higher in older individuals. Notably, 1HMRS methodological choices impacted effect sizes for age-related Glu differences. Glu metabolite change appears to be a robust marker of aging-related neurological change; however, additional studies are needed to elucidate age-related trajectories of glutamatergic alterations and their relationship to cognitive phenotypes.

The presence of sp2 bonded carbon on a diamond or doped diamond surface, as a result of growth or processing, can affect material properties negatively, hence removal processes must be developed. Using boron doped diamond (BDD) we investigate the effectiveness of different removal methods via electrochemistry and transmission electron microscopy. We focus on two BDD surfaces, one processed by ns laser micromachining and the second which contains sp2 bonded carbon as a result of chemical vapour deposition (CVD) growth. After micromachining a layer of ordered graphite sits on the BDD surface, topped by fissured amorphous carbon (total thickness ∼ μm). Oxidative acid treatment at elevated temperature cannot remove all the sp2 bonded carbon and much smaller clusters of perpendicularly-orientated graphite (tens of nm in diameter), capped with a thinner layer of amorphous carbon – that we term “denatured graphite” – remain. In contrast, thermal oxidation in air at 600 °C is capable of all cluster removal, and can also be used to remove sp2 bonded carbon from as-grown CVD BDD. Such understanding is important to any application where sp2 bonded surface carbon resulting from CVD growth or laser processing is detrimental for the intended application, e.g. in diamond quantum technology, photonics and electrochemistry.

With antibiotic-resistant bacteria becoming increasingly prevalent, biomaterials capable of targeted, in situ drug delivery are urgently needed. The synthetic polymer Poloxamer 407 (P407) is of particular interest due to its thermoreversible gelation. Clinical use of P407 typically involves sterilization via autoclaving, but the effects of these extreme environmental conditions on hydrogel water content, rheological properties and efficacy as a drug delivery vehicle remain unknown. The aim of this study was to investigate the effects of autoclaving on the properties of P407 hydrogel. Autoclaving reduced hydrogel water content due to evaporation, thus increasing the polymer weight fraction of the hydrogels. In contrast, except for a reduction in gelation temperature following autoclaving, autoclaved hydrogels had similar rheological properties as nonautoclaved hydrogels. In vitro, autoclaving did not hinder the hydrogel’s efficacy as a carrier for vancomycin antibiotic, and P407 (with and without vancomycin) had a bactericidal effect on planktonic Staphylococcus aureus. An in vivo pilot study using P407 to deliver bacteriophage highlighted the need for additional understanding of the functionality of the hydrogel for surgical applications. In conclusion, P407 hydrogel water content and gelation temperature were reduced by autoclave sterilization, while other rheological properties and the efficacy of the biomaterial as a delivery vehicle for vancomycin in vitro were unaffected.

Nanoscale mineralized collagen fibrils may be important determinants of whole-bone mechanical properties and contribute to the risk of age-related fractures. In a cross-sectional study nano- and tissue-level mechanics were compared across trabecular sections from the proximal femora of three groups (n = 10 each): ageing non-fractured donors (Controls); untreated fracture patients (Fx-Untreated); bisphosphonate-treated fracture patients (Fx-BisTreated). Collagen fibril, mineral and tissue mechanics were measured using synchrotron X-Ray diffraction of bone sections under load. Mechanical data were compared across groups, and tissue-level data were regressed against nano. Compared to controls fracture patients exhibited significantly lower critical tissue strain, max strain and normalized strength, with lower peak fibril and mineral strain. Bisphosphonate-treated exhibited the lowest properties. In all three groups, peak mineral strain coincided with maximum tissue strength (i.e. ultimate stress), whilst peak fibril strain occurred afterwards (i.e. higher tissue strain). Tissue strain and strength were positively and strongly correlated with peak fibril and mineral strains. Age-related fractures were associated with lower peak fibril and mineral strain irrespective of treatment. Indicating earlier mineral disengagement and the subsequent onset of fibril sliding is one of the key mechanisms leading to fracture. Treatments for fragility should target collagen-mineral interactions to restore nano-scale strain to that of healthy bone.

Exposure to polychlorinated biphenyls (PCBs), an endocrine-disrupting compound, is ubiquitous despite decades-old bans on the manufacture and use of PCBs. Increased exposure to PCBs is associated with adverse health consequences throughout life, including type 2 diabetes and cancer. PCB exposure is also associated with alterations in epigenetic marks and gene transcription, which could lead to adverse health outcomes, but many of these are population-specific. To further investigate the association between PCB and epigenetic marks, DNA methylation was measured at 787,684 CpG sites in 641 peripheral blood samples from the Michigan Polybrominated Biphenyl (PBB) Registry. 1345 CpGs were associated with increased total PCB level after controlling for age, sex, and 24 surrogate variables (FDR < 0.05). These CpGs were enriched in active promoter and transcription associated regions (p

Objective Hispanic immigrants exhibit more positive outcomes than U.S.-born Hispanics across educational, psychological, and physical health indices, a phenomenon called the immigrant paradox. We examined the immigrant paradox in relation to alcohol use severity among Hispanic young adults while considering both positive (optimism) and negative (depressive symptoms) processes. Method Among 200 immigrant and U.S.-born Hispanic young adults (Mage = 21.30; 49% male) in Arizona and Florida, we tested whether optimism and depressive symptoms statistically mediated the relationship between nativity and alcohol use severity. Specifically, we examined whether Hispanic immigrants reported greater optimism than their U.S.-born counterparts, and whether such optimism was, in turn, associated with less depressive symptoms and thus lower alcohol use severity. Results Indirect effects were significant in hypothesized directions (nativity → optimism → depressive symptoms → alcohol use severity). Conclusions Both positive and negative psychological processes are important to consider when accounting for the immigrant paradox vis-a-vis alcohol use severity among Hispanic young adults.

Being able to utilise a protecting group to influence remote regiocontrol offers a simple alternative approach to direct late-stage functionalisation of complex organic molecules. However, protecting groups that have the ability to influence reaction regioselectivity remote to their local chemical environment are not widely reported in the literature. Herein, we report the development of remote regioselective electrophilic aromatic substitution (SEAr) reactions that are enabled via the application of the tetrafluoropyridyl (TFP) phenol protecting group. We demonstrate that through sequential reactions and protection/deprotection of the TFP group, substitution patterns which do not conform to classical SEAr regioselectivity rules can be readily accessed.

Locomotion and mobility have been studied extensively in Drosophila melanogaster but less is known about the locomotor capacity of other Drosophila species, while the response to chronic exercise in other species has yet to be examined. We have shown that adult male D. melanogaster adapt to exercise training with improved running endurance, climbing speed, and flight ability compared to unexercised flies. Here, we examine baseline mobility of D. sechellia, D. simulans, and D. virilis, and their response to chronic exercise training. We found significant interspecific differences in mobility and in the response to exercise. Although there is a significant sex difference in exercise adaptations in D. melanogaster, intraspecific analysis reveals few sex differences in other Drosophila species. As octopamine has been shown to be important for exercise adaptations in D. melanogaster, we also asked if any observed differences could be attributed to baseline octopamine levels. We find that octopamine and tyramine levels have the same rank order as baseline climbing speed and endurance in males, but do not predict the response to chronic exercise in males or females. Future research should focus on determining the mechanisms responsible for the inter- and intraspecific differences in mobility and the response to exercise.

Not a big deal after all Do volcanic eruptions affect El Niño–Southern Oscillation (ENSO) variability? Models indicate that sulfate aerosols resulting from large eruptions can initiate an El Niño–like response in the tropical Pacific, but observations have not shown evidence of such behavior. Dee et al . present an oxygen-isotope time series of fossil corals from the central tropical Pacific to investigate ENSO's response to large volcanic eruptions during the past millennium. They found a weak tendency for an El Niño–like response in the year after an eruption, but not one that was statistically significant. These results suggest that large volcanic events have not triggered a detectable response in ENSO over the past thousand years and that their impact is small relative to the degree of natural variability. Science , this issue p. 1477

The troponin complex regulates the Ca(2+) activation of myofilaments during striated muscle contraction and relaxation. Troponin genes emerged 500–700 million years ago during early animal evolution. Troponin T (TnT) is the thin-filament–anchoring subunit of troponin. Vertebrate and invertebrate TnTs have conserved core structures, reflecting conserved functions in regulating muscle contraction, and they also contain significantly diverged structures, reflecting muscle type- and species-specific adaptations. TnT in insects contains a highly-diverged structure consisting of a long glutamic acid–rich C-terminal extension of ∼70 residues with unknown function. We found here that C-terminally truncated Drosophila TnT (TpnT–CD70) retains binding of tropomyosin, troponin I, and troponin C, indicating a preserved core structure of TnT. However, the mutant TpnT(CD70) gene residing on the X chromosome resulted in lethality in male flies. We demonstrate that this X-linked mutation produces dominant-negative phenotypes, including decreased flying and climbing abilities, in heterozygous female flies. Immunoblot quantification with a TpnT-specific mAb indicated expression of TpnT–CD70 in vivo and normal stoichiometry of total TnT in myofilaments of heterozygous female flies. Light and EM examinations revealed primarily normal sarcomere structures in female heterozygous animals, whereas Z-band streaming could be observed in the jump muscle of these flies. Although TpnT–CD70-expressing flies exhibited lower resistance to cardiac stress, their hearts were significantly more tolerant to Ca(2+) overloading induced by high-frequency electrical pacing. Our findings suggest that the Glu-rich long C-terminal extension of insect TnT functions as a myofilament Ca(2+) buffer/reservoir and is potentially critical to the high-frequency asynchronous contraction of flight muscles.

Significance Enzyme bioelectrochemistry concerns the integration of oxidoreductase enzymes into electrodes to enable and study the transfer of electrons between the solid-state material surface and the biological catalyst. To achieve higher enzyme loading, and hence greater current densities, high-surface-area strategies have been employed to immobilize enzymes, but these porous electrode architectures amplify the formation of local chemical gradients. Enzyme selectivity and activity is highly dependent on such changes in local environment, such as substrate concentration, pH, and electrolyte species concentration. Here, electrochemistry and computational techniques are applied to explore, and hence optimize, the local environment of the fuel-producing oxidoreductases, hydrogenase and formate dehydrogenase, within porous electrodes., Bioelectrochemistry employs an array of high-surface-area meso- and macroporous electrode architectures to increase protein loading and the electrochemical current response. While the local chemical environment has been studied in small-molecule and heterogenous electrocatalysis, conditions in enzyme electrochemistry are still commonly established based on bulk solution assays, without appropriate consideration of the nonequilibrium conditions of the confined electrode space. Here, we apply electrochemical and computational techniques to explore the local environment of fuel-producing oxidoreductases within porous electrode architectures. This improved understanding of the local environment enabled simple manipulation of the electrolyte solution by adjusting the bulk pH and buffer pKa to achieve an optimum local pH for maximal activity of the immobilized enzyme. When applied to macroporous inverse opal electrodes, the benefits of higher loading and increased mass transport were employed, and, consequently, the electrolyte adjusted to reach −8.0 mA ⋅ cm−2 for the H2 evolution reaction and −3.6 mA ⋅ cm−2 for the CO2 reduction reaction (CO2RR), demonstrating an 18-fold improvement on previously reported enzymatic CO2RR systems. This research emphasizes the critical importance of understanding the confined enzymatic chemical environment, thus expanding the known capabilities of enzyme bioelectrocatalysis. These considerations and insights can be directly applied to both bio(photo)electrochemical fuel and chemical synthesis, as well as enzymatic fuel cells, to significantly improve the fundamental understanding of the enzyme–electrode interface as well as device performance.

Summary Background Electronic nicotine delivery systems (ENDSs) are used by some smokers to reduce cigarette consumption, but their effectiveness is uncertain. We aimed to examine the extent to which ENDSs or a non-nicotine cigarette substitute influence tobacco-related toxicant exposure and cigarette consumption in smokers interested in smoking reduction. Methods We did a four-arm, parallel-group, randomised controlled trial at two sites in the USA (Penn State University, Hershey, PA, and Virginia Commonwealth University, Richmond, VA). We enrolled adults aged 21–65 years who smoked more than nine cigarettes per day (for at least the past year), with exhaled CO of more than 9 parts per million at screening, who were not currently using an ENDS, and who were interested in reducing smoking but not quitting. Participants were randomised (site-specific with allocation concealment; 1:1:1:1) to receive either a cartomiser-based, pen-style ENDS (eGo-style) paired with 0, 8, or 36 mg/mL liquid nicotine (participants and researchers masked to concentration) or a non-ENDS cigarette-shaped plastic tube that delivered no nicotine or aerosol (cigarette substitute; unmasked) for 24 weeks. Conditions were chosen to reflect a range of nicotine delivery including none (cigarette substitute and 0 mg/mL ENDS), low (8 mg/mL), and cigarette-like (36 mg/mL), and all conditions were paired with smoking reduction instructions. The primary outcome was concentration of the tobacco-specific carcinogen metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL; urinary total) collected at randomisation and at 4, 12, and 24 weeks. Multiple imputation with and without covariate adjustment was used in addition to sensitivity analyses. This trial is registered with ClinicalTrials.gov, NCT02342795. Findings Between July 22, 2015, and Nov 16, 2017, 684 individuals were screened and 520 (76%) were enrolled and randomised. 188 (36%) of 520 participants were lost to follow-up by week 24; attrition did not differ by study group (39 [30%] of 130 in the cigarette substitute group, 56 [43%] of 130 in the ENDS with 0 mg/mL nicotine group, 49 [38%] of 130 in the ENDS 8 mg/mL group, and 44 [34%] of 130 in the ENDS 36 mg/mL group). Urinary total NNAL at 24 weeks in the ENDS with 36 mg/mL nicotine group was 210·80 pg/mg creatinine (95% CI 163·03–274·42) compared with 346·09 pg/mg creatinine (265·00–455·32) in the cigarette substitute group (p=0·0061). No other significant differences between groups were observed for any time point for urinary total NNAL. Serious adverse event frequency was similar across groups (12 events in 12 participants [9%] in the ENDS with 36 mg/mL nicotine group, seven events in six participants [5%] in the 8 mg/mL group, 11 events in ten participants [8%] in the 0 mg/mL group, and 13 events in 13 participants [10%] in the cigarette substitute group), and all of these were deemed unrelated or unlikely to be related to study product use. There was one death between randomisation and 24 weeks (suicide; in the ENDS with 0 mg/mL nicotine group). Interpretation Use of an ENDS with cigarette-like nicotine delivery can reduce exposure to a major pulmonary carcinogen, NNAL, even with concurrent smoking. Future ENDS trials should involve products with well characterised nicotine delivery, including those with nicotine delivery approaching that of a cigarette. Funding National Institutes of Health, US Food and Drug Administration.

Sub-micrometre single crystal diamond membranes are of huge importance for next generation optical, quantum and electronic device applications. Electrochemical etching has proven a critical step in the production of such membranes. Etching is used to selectively remove a very thin layer of sub-surface sp2 carbon, prepared by ion implantation in bulk diamond, releasing the diamond membrane. Due to the nanosized dimensions, etching is typically carried out using non-contact electrochemistry in low conductivity solutions (bipolar arrangement) which whilst effective, results in extremely slow etch rates. In this work, a new method of non-contact electrochemical etching is presented which uses high conductivity, high concentration, fully dissociated aqueous electrolytes. Careful choice of the electrolyte anion results in significant improvements in the sp2 carbon etch rate. In particular, we show both chloride and sulfate electrolytes increase etch rates significantly (up to × 40 for sulfate) compared to our measurements using the current state-of-the-art solutions and methodologies. Electron paramagnetic resonance experiments, recorded after the electrode potential has been switched off, reveal sizeable hydroxyl radical concentrations at timescales > 107 longer than their lifetime (≤μs). These measurements highlight the importance of electrochemically initiated, solution chemistry radical generation and regeneration pathways in high concentration sulfate and chloride solutions for nano-etching applications.

Although targeted MAPK pathway inhibition has achieved remarkable patient responses in many cancers, the development of resistance has remained a critical challenge. Adaptive tumor response underlies the drug resistance. Furthermore, such bypass mechanisms often lead to the activation of many pro-survival kinases, which complicates the rational design of combination therapies. Here we performed global tyrosine phosphoproteomic (pTyr) analyses and demonstrated that targeted MAPK signaling inhibition in melanoma leads to a profound remodeling of the pTyr proteome. Intriguingly, altered cholesterol metabolism might drive, in a coordinated fashion, the activation of these kinases. Indeed, we found an accumulation of intracellular cholesterol in melanoma cells (with BRAF(V600E) mutations) and non-small cell lung cancer cells (with KRAS(G12C) mutations) treated with MAPK and KRAS(G12C) inhibitors, respectively. Importantly, depletion of cholesterol not only prevents the feedback activation of pTyr signaling but also enhances the cytotoxic effects of MAPK pathway inhibitors, both in vitro and in vivo. Together, our findings suggest that cholesterol contributes to the tumor adaptive response upon targeted MAPK pathway inhibitors. These results also suggest that MAPK pathway inhibitors could be combined with cholesterol-lowering agents to achieve a more complete and durable response in tumors with hyperactive MAPK signaling. PRIDE identifier: PXD021877.

Age‐related macular degeneration (AMD) is a leading cause of blindness worldwide. Drusen are key contributors to the etiology of AMD and the ability to modulate drusen biogenesis could lead to therapeutic strategies to slow or halt AMD progression. The mechanisms underlying drusen biogenesis, however, remain mostly unknown. Here we demonstrate that under homeostatic conditions extracellular vesicles (EVs) secreted by retinal pigment epithelium (RPE) cells are enriched in proteins associated with mechanisms involved in AMD pathophysiology, including oxidative stress, immune response, inflammation, complement system and drusen composition. Furthermore, we provide first evidence that drusen‐associated proteins are released as cargo of extracellular vesicles secreted by RPE cells in a polarised apical:basal mode. Notably, drusen‐associated proteins exhibited distinctive directional secretion modes in homeostatic conditions and, differential modulation of this directional secretion in response to AMD stressors. These observations underpin the existence of a finely‐tuned mechanism regulating directional apical:basal sorting and secretion of drusen‐associated proteins via EVs, and its modulation in response to mechanisms involved in AMD pathophysiology. Collectively, our results strongly support an active role of RPE‐derived EVs as a key source of drusen proteins and important contributors to drusen development and growth.

We conducted an experimental evaluation of treatments to limit Heterobasidion occidentale infection of white fir (Abies concolor) stumps and wounds in California mixed conifer forests. We tested the efficacy of urea, borate, and a mixture of two locally collected Phlebiopsis gigantea strains in preventing pathogen colonization of fir stumps and separately, urea and borate as infection controls on experimental stem wounds. These were paired with a laboratory test on ~100 g wood blocks with and without a one-week delay between inoculation and treatment. Urea, borates, and Phlebiopsis treatments all significantly reduced the stump surface area that was colonized by H. occidentale at 84%, 91%, and 68%, respectively, relative to the controls. However, only the borate treatments significantly lowered the number of stumps that were infected by the pathogen. The laboratory study matched the patterns that were found in the stump experiment with a reduced area of colonization for urea, borates, or P. gigantea treatments relative to the controls; delaying the treatment did not affect efficacy. The field wound experiment did not result in any Heterobasidion colonization, even in positive control treatments, rendering the experiment uninformative. Our study suggests treatments that are known to limit Heterobasidion establishment on pine or spruce stumps elsewhere in the world may also be effective on true firs in California.

RATIONALE AND OBJECTIVE: The safety of intensive blood pressure (BP) targets is controversial for persons with chronic kidney disease (CKD). We studied the effects of hypertension treatment on cerebral perfusion and structure in those with and without CKD. STUDY DESIGN: Neuroimaging substudy of a randomized trial. SETTING & PARTICIPANTS: A subset of participants in the Systolic Blood Pressure Intervention Trial who underwent brain MRI studies. Presence of baseline CKD was assessed by estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (UACR). INTERVENTION: Participants were randomly assigned to intensive (systolic BP 30 mg/g (N=151), the effects of intensive versus standard BP treatment on change in global cerebral blood flow, WMLs and total brain volume were 1.91 ml/100g/min (95% CI −3.01, 6.82), 0.003 cm(3) (asinh transformed, 95% CI −0.13, 0.13), and −7.0 cm(3) (95% CI −13.3, −0.3), respectively. The overall treatment effects on cerebral blood flow and total brain volume were not modified by baseline eGFR or UACR; however the effect on WMLs was attenuated in participants with albuminuria (interaction p-value 0.04). LIMITATIONS: Measurement variability due to multi-site design. CONCLUSIONS: Among hypertensive adults with primarily early kidney disease, intensive versus standard blood pressure treatment did not appear to have a detrimental effect on brain perfusion or structure. The findings support the safety of intensive blood pressure treatment targets on brain health in persons with early kidney disease. FUNDING: The Systolic Blood Pressure Intervention Trial was funded by the National Institutes of Health (including the National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Institute of Neurological Disorders and Stroke), and this substudy was funded by the National Institutes of Diabetes and Digestive and Kidney Diseases. TRIAL REGISTRATION: SPRINT was registered at ClinicalTrials.gov with the study number NCT01206062.

Widespread use of reduced-sodium salts can potentially lower excessive population-level dietary sodium intake. This study aimed to identify key barriers and facilitators to implementing reduced-sodium salt as a population level intervention. Semi-structured interviews were conducted with key informants from academia, the salt manufacturing industry, and government. We used the reach, effectiveness, adoption, implementation, and maintenance (RE-AIM) framework to inform our interview guides and data analysis. Eighteen key informants from nine countries across five World Health Organization regions participated in the study from January 2020 to July 2020. Participants were concerned about the lack of robust evidence on safety for specific populations such as those with renal impairment. Taste and price compared to regular salt and an understanding of the potential health benefits of reduced-sodium salt were identified as critical factors influencing the adoption of reduced-sodium salts. Higher production costs, low profit return, and reduced market demand for reduced-sodium salts were key barriers for industry in implementation. Participants provided recommendations as potential strategies to enhance the uptake. There are presently substantial barriers to the widespread use of reduced-sodium salt but there are also clear opportunities to take actions that would increase uptake.

Made available in DSpace on 2022-04-28T19:44:08Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-09-02 The amount of carbon stored in deadwood is equivalent to about 8 per cent of the global forest carbon stocks1. The decomposition of deadwood is largely governed by climate2–5 with decomposer groups—such as microorganisms and insects—contributing to variations in the decomposition rates2,6,7. At the global scale, the contribution of insects to the decomposition of deadwood and carbon release remains poorly understood7. Here we present a field experiment of wood decomposition across 55 forest sites and 6 continents. We find that the deadwood decomposition rates increase with temperature, and the strongest temperature effect is found at high precipitation levels. Precipitation affects the decomposition rates negatively at low temperatures and positively at high temperatures. As a net effect—including the direct consumption by insects and indirect effects through interactions with microorganisms—insects accelerate the decomposition in tropical forests (3.9% median mass loss per year). In temperate and boreal forests, we find weak positive and negative effects with a median mass loss of 0.9 per cent and −0.1 per cent per year, respectively. Furthermore, we apply the experimentally derived decomposition function to a global map of deadwood carbon synthesized from empirical and remote-sensing data, obtaining an estimate of 10.9 ± 3.2 petagram of carbon per year released from deadwood globally, with 93 per cent originating from tropical forests. Globally, the net effect of insects may account for 29 per cent of the carbon flux from deadwood, which suggests a functional importance of insects in the decomposition of deadwood and the carbon cycle. Ecosystem Dynamics and Forest Management Group School of Life Sciences Technical University of Munich Berchtesgaden National Park Epidemiology Biostatistics and Prevention Institute University of Zurich Southern Research Station USDA Forest Service Field Station Fabrikschleichach University of Würzburg Biological Sciences University of Toronto Scarborough Fenner School of Environment and Society The Australian National University Department of Biogeography University of Bayreuth Department of Disturbance Ecology University of Bayreuth Instituto de Ecología Regional CONICET-Universidad Nacional de Tucumán Department of Animal Ecology and Tropical Biology University of Würzburg Laboratory of Environmental Microbiology Institute of Microbiology The Czech Academy of Sciences Agricultural and Natural Resources Research Centre of Mazandaran Lancaster Environment Centre Lancaster University Universidade Federal de Lavras Department of Biodiversity Conservation Goethe-University Frankfurt Bavarian Forest National Park CIRAD UMR Ecologie des Forêts de Guyane (EcoFoG) AgroParisTech CNRS INRA Universite des Antilles Universite de Guyane Environmental Change Institute University of Oxford Grassland Vegetation Lab Federal University of Rio Grande do Sul Faculty of Environmental Sciences and Natural Resource Management Norwegian University of Life Sciences Institute of Ecology and Botany Centre for Ecological Research Institute for Wildlife Management and Nature Conservation Hungarian University of Agriculture and Life Sciences Animal Ecology University of Marburg École d’Ingénieurs de Purpan Université de Toulouse UMR 1201 Dynafor Ecosystem Science and Management Program University of Northern British Columbia Laboratory of Applied Ecology University of Abomey-Calavi Department of Ecology University of Granada Réserves Naturelles de France Royal Alberta Museum Conservation Ecology University of Marburg Science and Engineering Faculty Queensland University of Technology Centre for the Environment Institute for Future Environments Forest Research Institute Malaysia International Institute of Tropical Forestry USDA Forest Service Forest Entomology Swiss Federal Research Institute WSL Evolutionary Zoology University of Salzburg Natural Resources Canada Canadian Forest Service Eurofins Ahma Oy Department of Plant Systematics University of Bayreuth Department of Wildlife Fish and Environmental Studies Swedish University of Agricultural Sciences Applied Landscape Ecology Chuo University School of Forest Sciences University of Eastern Finland School of Agricultural Forest and Food Sciences Bern University of Applied Sciences CAS Key Laboratory for Plant Diversity and Biogeography of East Asia Kunming Institute of Botany Chinese Academy of Sciences ECNU-Alberta Joint Lab for Biodiversity Study Tiantong National Station for Forest Ecosystem Research East China Normal University Institute of Biological Sciences University of the Philippines Los Banos Department of Thermodynamics Universidad Nacional del Nordeste Tropical Forests and People Research Centre University of the Sunshine Coast Forest Ecosystem Monitoring Laboratory National University of Mongolia School of Environment and Science Griffith University School of Biological Earth and Environmental Sciences University College Cork Edge Hill University Institute of Forestry Tribhuvan University Institute of Evolution University of Haifa Scion (New Zealand Forest Research Institute) School of Forestry University of Canterbury Institute of Zoology University of Hamburg Faculté des Sciences Université d’Antananarivo Tropical Biodiversity and Social Enterprise Departamento de Ecologia Universidade Estadual Paulista Ecology Group University Erlangen-Nuremberg H. J. Andrews Experimental Forest Environmental and Conservation Sciences Murdoch University Environmental Futures Research Institute Griffith University Ashoka Trust for Research in Ecology and the Environment ARC Centre for Forest Value University of Tasmania Terrestrial Ecology Research Group School of Life Sciences Technical University of Munich EcoBank Team National Institute of Ecology College of Forestry Beijing Forestry University Departamento de Ecologia Universidade Estadual Paulista

Excess sodium consumption and insufficient potassium intake contribute to high blood pressure and thus increase the risk of heart disease and stroke. In low-sodium salt, a portion of the sodium in salt (the amount varies, typically ranging from 10 to 50%) is replaced with minerals such as potassium chloride. Low-sodium salt may be an effective, scalable, and sustainable approach to reduce sodium and therefore reduce blood pressure and cardiovascular disease at the population level. Low-sodium salt programs have not been widely scaled up, although they have the potential to both reduce dietary sodium intake and increase dietary potassium intake. This article proposes a framework for a successful scale-up of low-sodium salt use in the home through four core strategies: availability, awareness and promotion, affordability, and advocacy. This framework identifies challenges and potential solutions within the core strategies to begin to understand the pathway to successful program implementation and evaluation of low-sodium salt use.

Introduction: Hormonal agents remain the most effective therapies for estrogen receptor positive (ER+) HER2- breast cancer. The androgen receptor (AR) is the most highly expressed steroid receptor found in up to 95% of ER+ breast cancer patients. Androgen agonists have antiproliferative activity in ER+ breast cancer and have been used in treatment, however their lack of availability and virilizing side effects have limited their use. Enobosarm is a non-steroidal tissue-selective AR modulator that that is being developed for AR targeted treatment of ER+/AR+ breast cancer. Methods: An international, Phase 2, open label, parallel design, randomized study was conducted in 136 patients (pts) to investigate the efficacy and safety of enobosarm in postmenopausal women with metastatic ER+/AR+ breast cancer that progressed on previous endocrine therapy. Pts were randomized to receive 9 mg (n=72) or 18 mg (n=64) of oral daily enobosarm. The primary endpoint was clinical benefit rate (CBR) at 24 weeks (defined as CR, PR or SD) by RECIST 1.1. Secondary endpoints included objective response rate, best overall response rate (BOR), progression free survival (PFS), duration of clinical benefit. Results: The study population consisted of heavily pre-treated pts with a mean of 4 (range 1-6) prior hormone therapies and >90% receiving one prior course of chemotherapy. Median age was 60.8 years (35-83) for 9 mg and 62.1 (42-81) for the 18 mg cohort. AR positivity was centrally confirmed in 73.6% and 81.2% in the 9 and 18 mg cohorts, respectively. Efficacy: In the evaluable pts, 50 in the 9 mg arm and 52 in the 18 mg arm (AR confirmed), 32% of the 9mg cohort met the primary endpoint of CBR at 24 weeks (95% CI, 19.5%; 46.7%) and 29% (95% CI, 17.1%; 43.1%) in the 18 mg cohort. The BOR was 2 CRs, 10 PRs in the 9 mg and 3 CRs,7 PRs in the 18 mg group by central review. Median PFS was 5.6 (2.9 to 27.5) and 4.2 (2.8 to 11) months (mo) in the 9 mg and 18 mg groups. The median duration of treatment was 4.0 months (0.23-30.3 months) in the 9 mg group and 3.8 months (0.5-16.7 months) in the 18 mg group. At the time the study was terminated, the median duration of clinical benefit was not reached (NR) in the 9 mg group (range 8.2 mo to NR) and 14.1 mo (range 11.0 to 16.5) in the 18 mg group. QOL: Using a standardized instrument of generic health status (EQ-5D), a significant percentage of pts reported improvement in measurements including mobility (40%, 50%), anxiety/depression (50%, 29%) and pain discomfort (50%, 31%) for the 9 and 18 mg groups, respectively. Drug related severe adverse events (SAEs) (Grades 3-4) were observed in 6 (8.0%) at the 9 mg and 10 (16.4%) at the 18 mg dose. The SAEs (Grade 3-4) attributed to the study drug by the site investigator were for the 9 mg group: fatigue (1), elevated transaminases (2), headache (1), hypercalcemia (2) and anemia (1). For the 18 mg group the drug attributable SAEs (Grade 3-4) were: dry mouth (1), increased aminotransferase (2), decreased white blood cell count (1), fatigue (2), hypercalcemia (1), decreased appetite (1), headache (1), tumor flare (2), agitation (1), lymphadenopathy (1) and acute kidney injury (1). Conclusions: In this Phase 2 parallel design study, enobosarm (9 mg and 18 mg) has significant clinical activity and was well tolerated in heavily pretreated patients with ER+/AR+ metastatic breast cancer. Given the limited options of hormonal therapy for metastatic ER+ breast cancer, enobosarm merits further clinical development in a Phase 3 clinical program as an AR targeted treatment for metastatic ER+AR+ breast cancer. Citation Format: Carlo Palmieri, Hannah Linden, Stephen Birrell, Elgene Lim, Lee S Schwartzberg, Hope S Rugo, Patrick Cobb, Kirti Jain, Charles Vogel, Joyce A O’Shaughnessy, Robert H Getzenberg, Mitchell S Steiner, Adam Brufsky, Beth Overmoyer. Efficacy and safety of enobosarm, a selective androgen receptor modulator, to target AR in women with advanced ER+/AR+ breast cancer - final results from an international Phase 2 randomized study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD8-10.

This research aims to reduce solid waste, resource depletion, and material toxicity in the footwear industry. Mycelium, the root structure of mushrooms, binds together substrate materials as it grows, offering opportunities for composite development. Mycelium composites were developed using edible mushroom species alongside other natural materials. The 4 × 2 experiment tested four mushroom species (reishi, oyster, king oyster, and yellow oyster) and two fabric levels (with or without a natural fabric mat). Scanning electron microscopy images confirmed mycelium growth within the composite and around the substrates. Two-way analysis of variance tests found that both species and fabric significantly affected the density, and the species significantly affected the compressive strength. A positive and significant linear relationship was found between density and compressive strength, with higher density leading to higher compressive strength. The compressive strength of the mycelium composites, especially those made from king oyster mycelium, provides opportunities for renewable and biodegradable footwear inputs.

Purpose Polymeric mesh implantation has become the golden standard in hernia repair, which nowadays is one of the most frequently performed surgeries in the world. However, many biocompatibility issues remain to be a concern for hernioplasty, with chronic pain being the most notable post-operative complication. Oxidative stress appears to be a major factor in the development of those complications. Lack of material inertness in vivo and oxidative environment formed by inflammatory cells result in both mesh deterioration and slowed healing process. In a pilot in vivo study, we prepared and characterized polypropylene hernia meshes with vitamin E (α-tocopherol)-a potent antioxidant. The results of that study supported the use of vitamin E as potential coating to alleviate post-surgical inflammation, but the pilot nature of the study yielded limited statistical data. The purpose of this study was to verify the observed trend of the pilot study statistically. Methods In this work, we conducted a 5-animal experiment where we have implanted vitamin E-coated and uncoated control meshes into the abdominal walls of rabbits. Histology of the mesh-adjacent tissues and electron microscopy of the explanted mesh surface were conducted to characterize host tissue response to the implanted meshes. Results As expected, modified meshes exhibited reduced foreign body reaction, as evidenced by histological scores for fatty infiltrates, macrophages, neovascularization, and collagen organization, as well as by the surface deterioration of the meshes. Conclusion In conclusion, results indicate that vitamin E coating reduces inflammatory response following hernioplasty and protects mesh material from oxidative deterioration.

Use of salt substitutes containing potassium chloride is a potential strategy to reduce sodium intake, increase potassium intake, and thereby lower blood pressure and prevent the adverse consequences of high blood pressure. In this review, we describe the rationale for using potassium-enriched salt substitutes, summarize current evidence on the benefits and risks of potassium-enriched salt substitutes and discuss the implications of using potassium-enriched salt substitutes as a strategy to lower blood pressure. A benefit of salt substitutes that contain potassium chloride is the expected reduction in dietary sodium intake at the population level because of reformulation of manufactured foods or replacement of sodium chloride added to food during home cooking or at the dining table. There is empirical evidence that replacement of sodium chloride with potassium-enriched salt substitutes lowers systolic and diastolic blood pressure (average net Δ [95% CI] in mm Hg: –5.58 [–7.08 to –4.09] and –2.88 [–3.93 to –1.83], respectively). The risks of potassium-enriched salt substitutes include a possible increased risk of hyperkalemia and its principal adverse consequences: arrhythmias and sudden cardiac death, especially in people with conditions that impair potassium excretion such as chronic kidney disease. There is insufficient evidence regarding the effects of potassium-enriched salt substitutes on the occurrence of hyperkalemia. There is a need for additional empirical research on the effect of increasing dietary potassium and potassium-enriched salt substitutes on serum potassium levels and the risk of hyperkalemia, as well as for robust estimation of the population-wide impact of replacing sodium chloride with potassium-enriched salt substitutes.

The serine/threonine protein kinase casein kinase 1α (CK1α) functions as a negative regulator of Wnt signaling, phosphorylating β-catenin at serine 45 (P–S45) to initiate its eventual ubiquitin-mediated degradation. We previously showed that the repurposed, FDA-approved anthelminthic drug pyrvinium potently inhibits Wnt signaling in vitro and in vivo. Moreover, we proposed that pyrvinium’s Wnt inhibitory activity was the result of its function as an activator of CK1α. An understanding of the mechanism by which pyrvinium activates CK1α is important because pyrvinium was given an orphan drug designation by the FDA to treat familial adenomatous polyposis, a precancerous condition driven by constitutive Wnt signaling. In the current study, we show that pyrvinium stimulates the phosphorylation of S45 β-catenin, a known CK1α substrate, in a cell-based assay, and does so in a dose- and time-dependent manner. Alternative splicing of CK1α results in four forms of the protein with distinct biological properties. We evaluated these splice products and identified the CK1α splice variant, CK1αS, as the form that exhibits the most robust response to pyrvinium in cells. Kinetic studies indicate that pyrvinium also stimulates the kinase activity of purified, recombinant CK1αS in vitro, increasing its catalytic efficiency (k(cat)/K(m)) toward substrates. These studies provide strong and clear mechanistic evidence that pyrvinium enhances CK1α kinase activity.

Circulatory protein glycosylation is a biomarker of multiple disease and inflammatory states and has been applied in the clinic for liver dysfunction, heart disease and diabetes. With the notable exception of antibodies, the liver produces most of the circulatory glycoproteins, including the acute phase proteins released as a function of the inflammatory response. Among these proteins is β-galactoside α2,6-sialyltransferase (ST6Gal1), an enzyme required for α2,6-linked sialylation of glycoproteins. Here, we describe a hepatocyte-specific conditional knockout of ST6Gal1 (H-cKO) using albumin promoter-driven Cre-lox recombination. We confirm the loss of circulatory glycoprotein α2,6 sialylation and note no obvious dysfunction or pathology in young H-cKO mice, yet these mice show robust changes in plasma glycoprotein fucosylation, branching and the abundance of bisecting GlcNAc and marked changes in a number of metabolic pathways. As H-cKO mice aged, they spontaneously developed fatty liver disease characterized by the buildup of fat droplets in the liver, inflammatory cytokine production and a shift in liver leukocyte phenotype away from anti-inflammatory Kupffer cells and towards proinflammatory M1 macrophages. These findings connect hepatocyte and circulatory glycoprotein sialylation to the regulation of metabolism and inflammation, potentially identifying the glycome as a new target for liver-driven disease.

The combination of 19 F NMR spectroscopy tagging and paramagnetic relaxation enhancement (PRE) NMR spectroscopy experiments was evaluated as a versatile method to probe protein-protein interactions and conformational changes of intrinsically disordered proteins upon complex formation. The feasibility of the approach is illustrated with an application to the Myc-Max protein complex; this is an oncogenic transcription factor that binds enhancer box DNA fragments. The single cysteine residue of Myc was tagged with highly fluorinated [19 F]3,5-bis(trifluoromethyl)benzyl bromide. Structural dynamics of the protein complex were monitored through intermolecular PREs between 19 F-Myc and paramagnetic (1-oxyl-2,2,5,5-tetramethyl-Δ3-pyrroline-3-methyl)methanethiosulfonate (MTSL)-tagged) Max. The 19 F R2 relaxation rates obtained with three differently MTSL-tagged Max mutants revealed novel insights into the differential structural dynamics of Myc-Max bound to DNA and the tumour suppressor breast cancer antigen 1. Given its ease of implementation, fruitful applications of this strategy to structural biology and inhibitor screening can be envisaged.

The oscillating open-circuit voltage generated by the digestion of aluminum rods, catalyzed by copper(II) chloride in 3 M nitric acid at 90 °C, is presented as a demonstration appropriate for a general chemistry or advanced laboratory. This demonstration encourages discussion of the possible kinetic mechanism as well as the general electrochemical half-reactions involved and the limited conditions under which oscillations occur. The objective is to provide general chemistry students with an interesting reaction beyond typical kinetics or electrochemistry. Apart from 1100-alloy aluminum rods and a recording voltmeter, the demonstration uses standard lab equipment, and the materials for the solutions are those typically found in a general lab setting.

Dust samples were collected from four indoor environments, including childcare facilities, houses, hair salons, and a research facility from the USA and were analyzed for brominated compounds using full scan liquid chromatography high-resolution mass spectrometry. A total of 240 brominated compounds were detected in these dust samples, and elemental formulas were predicted for 120 more abundant ions. In addition to commonly detected brominated flame retardants (BFRs), nitrogen-containing brominated azo dyes (BADs) were among the most frequently detected and abundant. Specifically, greater abundances of BADs were detected in indoor dusts from daycares and salons compared to houses and the research facility. Using authentic standards, a quantitative method was established for two BADs (DB373: Disperse Blue 373 and DV93: Disperse Violet 93) and 2-bromo-4,6-dinitroaniline, a commonly used precursor in azo dye production, in indoor dust. Generally, greater concentrations of DB373 (≤3850 ng/g) and DV93 (≤1190 ng/g) were observed in indoor dust from daycares highlighting children as a susceptible population to potential health risk from exposure to BADs. These data are important because, to date, targeted analysis of brominated compounds in indoor environments has focused mainly on BFRs and appears to underestimate the total amount of brominated compounds.

Background Michigan residents were directly exposed to endocrine-disrupting compounds, polybrominated biphenyl (PBB) and polychlorinated biphenyl (PCB). A growing body of evidence suggests that exposure to certain endocrine-disrupting compounds may affect thyroid function, especially in people exposed as children, but there are conflicting observations. In this study, we extend previous work by examining age of exposure’s effect on the relationship between PBB exposure and thyroid function in a large group of individuals exposed to PBB. Methods Linear regression models were used to test the association between serum measures of thyroid function (total thyroxine (T4), total triiodothyronine (T3), free T4, free T3, thyroid stimulating hormone (TSH), and free T3: free T4 ratio) and serum PBB and PCB levels in a cross-sectional analysis of 715 participants in the Michigan PBB Registry. Results Higher PBB levels were associated with many thyroid hormones measures, including higher free T3 (p = 0.002), lower free T4 (p = 0.01), and higher free T3: free T4 ratio (p = 0.0001). Higher PCB levels were associated with higher free T4 (p = 0.0002), and higher free T3: free T4 ratio (p = 0.002). Importantly, the association between PBB and thyroid hormones was dependent on age at exposure. Among people exposed before age 16 (N = 446), higher PBB exposure was associated with higher total T3 (p = 0.01) and free T3 (p = 0.0003), lower free T4 (p = 0.04), and higher free T3: free T4 ratio (p = 0.0001). No significant associations were found among participants who were exposed after age 16. No significant associations were found between TSH and PBB or PCB in any of the analyses conducted. Conclusions This suggests that both PBB and PCB are associated with thyroid function, particularly among those who were exposed as children or prenatally. Electronic supplementary material The online version of this article (10.1186/s12940-019-0509-z) contains supplementary material, which is available to authorized users.