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The architecture of transparent contacts is of utmost importance for creation of efficient flexible light-emitting devices (LEDs) and other deformable electronic devices. We successfully combined the newly synthesized transparent and durable silicone rubbers and the semiconductor materials with original fabrication methods to design LEDs and demonstrate their significant flexibility. We developed electrodes based on a composite GaP nanowire-phenylethyl-functionalized silicone rubber membrane, improved with single-walled carbon nanotube films for a hybrid poly(ethylene oxide)-metal-halide perovskite (CsPbBr3) flexible green LED. The proposed approach provides a novel platform for fabrication of flexible hybrid optoelectronic devices.

In the U.S., Hepatocellular carcinoma (HCC) incidence rates have increased. We aimed to determine whether environmental exposure plays a role in the high incidence of HCC observed in New York City. We conducted a hospital-based case only study to examine the prevalence of aflatoxin B1 (AFB1)- and polycyclic aromatic hydrocarbon (PAH)-albumin adducts and the distribution of adducts by different characteristics of HCC patients. Blood samples were collected from 155 HCC patients for biomarker analyses. We observed that about 46% and 49% of cases had detectable AFB1- and PAH-albumin adducts, respectively. There were significant differences between AFB1-albumin adducts and selected factors such as HCV infection status (p = 0.04), diabetes (p = 0.03) and Barcelona Clinic Liver Cancer (BCLC) stage (p = 0.02). Cases with detectable PAH-albumin adducts had a smoking history compared with those with nondetectable levels (p = 0.04). The level of AFB1-albumin adducts was positively correlated with plasma bilirubin (rs=0.32, p s=0.28, p = 0.0005). The level of aflatoxin B1-albumin adducts was negatively associated with blood albumin concentration (rs=-0.28, p = 0.0009) and plasma DNA LINE-1 methylation (rs=-0.16, p = 0.04). Our study provides additional evidence that environmental exposures including to aflatoxin might partially explain the increase in the incidence of HCC in the US.

Electrocatalytic “green” production of hydrogen from water for sustainable energy provision schemes is currently inefficient due to the sluggish kinetics of the oxygen evolution reaction (OER) at the anodes of the electrolysers. In the case of acidic polymer electrolyte membrane electrolysers, iridium (Ir) oxide catalysts pose a promising compromise between good OER activity and stability. However, the structure–activity relations for these materials remain largely unknown because the surface of a “real” oxide catalyst under reaction conditions becomes amorphous. In order to contribute to the understanding of these systems, we use electrochemical scanning tunnelling microscopy under reaction conditions (‘noise’ or n-EC-STM). With this technique, active areas can be detected by an increased noise level of the STM signal compared to inactive sites. The n-EC-STM measurements are applied to an amorphous iridium oxide surface, which is formed during electrochemical cycling of Ir(1 1 1). By doing so, we can monitor OER activity in-situ while simultaneously assessing the surface morphology. In order to elucidate the active areas, step and terrace sites were quantitatively compared to each other. The measurements reveal that terraces, step sites and concavities lead to a similar noise level increase in the STM signal. We, thus, conclude that the OER on the amorphous extended iridium oxide surface shows little structure-sensitivity. Subsequently, we suggest that in contrast to, e.g., metallic Pt for the oxygen electro-reduction, the shape of amorphous IrOx nanoparticles in an acidic medium should not significantly influence the OER turnover frequency.

Chronic arsenic exposure is associated with a number of systemic diseases, including cardiovascular disease. Selenium has been shown to promote arsenic excretion from the body. We investigated if a high-selenium lentil diet has an effect on blood pressure and plasma lipid levels in an arsenic-exposed population by conducting a 6-month randomized controlled dietary intervention trial with 405 participants.

A family of the C,N-cyclometalated species [Pt(ppy)Cl(PPh3)], [Pt(ppy)Cl(CNCy)], [Pt(ppy)(CNCy)(PPh3)](OTf), and [Pt(ppy)(CNCy)2](BF4) (ppy = 2-phenylpyridinato-C2,N; Cy = cyclohexyl) was generated...

Tumor microenvironment responsive drug delivery systems are potential approaches to reduce the acute toxicity caused by high-dose cancer chemotherapy. Notwithstanding the conventional nano-drug delivery systems, the redox and pH stimuli drug delivery systems are currently gaining attention. Therefore, the current study was designed to compare three different covalent carbon dots (C-dots) systems based on doxorubicin (dox) release profiles and cancer cell viability efficacy under acidic and physiological conditions. The C-dots nanosystems that were examined in this study are directly conjugated (C-dots-dox), pH triggered (C-dots-HBA-dox), and the redox stimuli (C-dots-S-S-dox) conjugates. The drug loading content (DLC%) of the C-dots-S-S-dox, C-dots-HBA-dox, and C-dots-dox was 34.2 ± 0.4, 60.0 ± 0.3, and 70.0 ± 0.2%, respectively, that examined by UV-vis spectral analysis. The dox release paradigms were emphasized that all three conjugates were promisingly released the dox from C-dots faster in acidic pH than in physiological pH. The displayed highest dox released percentage in the acidic medium was 74.6 ± 0.8% obtained by the pH stimuli, C-dots-HBA-dox conjugate. When introducing the redox inducer, dithiothreitol (DTT), preferentially, the redox stimuli C-dot-S-S-dox conjugate demonstrated a faster dox release at acidic pH than in the pH 7.4. The SJGBM2 cell viability experiments revealed that the pH stimuli, C-dots-HBA-dox conjugate, displayed a significant cell viability drop in the artificially acidified pH 6.4 medium. However, in the physiological pH, the redox stimuli, C-dots-S-S-dox conjugate, was promising over the pH stimuli C-dots-HBA-dox, exhibiting cell viability of 60%, though its' efficacy dropped slightly in the artificially acidified pH 6.4 medium. Moreover, the current study illustrates the stimuli conjugates' remarkable efficacy on sustain drug release than direct amide linkage.

Made available in DSpace on 2021-06-25T10:45:32Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-01-25 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) Lactose (LAC) is a disaccharide - major sugar, present in milk and dairy products. LAC content is an important indicator of milk quality and abnormalities in food industries, as well as in human and animal health. The present study reports the development of an innovative imprinted voltammetric sensor for sensitive detection of LAC. The sensor was constructed using electropolymerized pyrrole (Py) molecularly imprinted polymer (MIP) on graphite paper electrode (PE). The MIP film was constructed through the electrosynthesis of polypyrrole (PPy) in the presence of LAC (template molecule) on PE (PPy/PE). To optimize the detection conditions, several factors affecting the PPy/PE sensor performance were assessed by multivariate methods (Plackett–Burman design and central composite design). Under optimized conditions, the proposed analytical method was applied for LAC detection in whole and LAC-free milks, where it demonstrated high sensitivity and selectivity, with two dynamic linear ranges of concentration (1.0–10 nmol L−1 and 25–125 nmol L−1) and a detection limit of 0.88 nmol L−1. The MIP sensor showed selective molecular recognition for LAC in the presence of structurally related molecules. The proposed PPy/PE sensor exhibited good stability, as well as excellent reproducibility and repeatability. Based on the results obtained, the PPy/PE is found to be highly promising for sensitive detection of LAC. Analytical Chemistry Department Institute of Chemistry São Paulo State University (UNESP), 55 Prof. Francisco Degni St., São Paulo State Institute of Exact and Natural Sciences of Pontal Federal University of Uberlandia, 1600 20 St., Ituiutaba, Minas Gerais State Bioenergy Research Institute (IPBEN) São Paulo State University (UNESP), 55 Prof. Francisco Degni St., São Paulo State Analytical Chemistry Department Institute of Chemistry São Paulo State University (UNESP), 55 Prof. Francisco Degni St., São Paulo State Bioenergy Research Institute (IPBEN) São Paulo State University (UNESP), 55 Prof. Francisco Degni St., São Paulo State FAPESP: 2017/25329–6 FAPESP: 2018/12131–6 FAPESP: 2019/13818–8 CNPq: 408783/2018–4 CNPq: 443315/2014–0 CNPq: 447668/2014–5 CAPES: 88887.368610/2019–00 FAPEMIG: APQ-02078-15 FAPEMIG: APQ-02905-15

Exposure to silver-containing compounds can result in reversible discoloration of the skin, presenting as an irregular brown or black macule, which can have a clinical appearance similar to melanoma. Both the clinical scenario and the histopathology are unique. Silver nitrate darkens with exposure to light, and the area can appear to change over time. On microscopic examination, there are coarse pigmented granules dispersed throughout the corneal layer, and largely absent from the remainder of the epidermis-although the precise location may depend on the duration of topical exposure. While argyria, its irreversible counterpart, has been well-characterized, only a single source has previously reported the histopathology of transient topical silver nitrate exposure. We present two cases, review the clinical and histopathologic differentials, and detail the distinctive histopathology that enables a diagnosis to be suggested in this clinical mimicker of melanoma.

Exposure to diacetyl (DA) has been linked to the respiratory condition bronchiolitis obliterans. Previous research has demonstrated that DA and other α-dicarbonyl compounds can be detected in both the e-liquids and aerosols of e-vapor products (EVPs). While some EVP manufacturers may add these compounds as flavor ingredients, the primary objective of this work was to determine the potential for the formation of α-dicarbonyl compounds during the generation of aerosols from EVPs where no DA or other α-dicarbonyl compounds are added to the e-liquid. A novel ultraperformance liquid chromatography-mass spectrometry-based analytical method for the determination of DA, acetyl propionyl, glyoxal, and methylglyoxal was developed and validated. Next, eight commercially available cig-a-like-type EVPs were evaluated for α-dicarbonyl formation. Increased levels of α-dicarbonyls were observed in the aerosols of all evaluated EVPs compared to their respective e-liquids. Mechanistic studies were conducted using a model microwave reaction system to identify key reaction precursors for DA generated from propylene glycol (PG) and carbon-13-labeled glycerin (GLY). These studies, along with the corresponding retrosynthetic analysis, resulted in the proposed formation pathway where hydroxyacetone is generated from PG and/or GLY. Hydroxyacetone then participates in an aldol condensation with formaldehyde where formaldehyde can also be generated from PG and/or GLY; the resultant product then dehydrates to form DA. This proposed pathway was further investigated through in situ synthetic organic experiments within the model microwave reaction system. This work establishes that DA is formed in the aerosol generation process of the EVPs tested though at levels below toxicological concern.

Total body radiation (TBI) can result in death associated with hematopoietic insufficiency. Although radiation causes apoptosis of white blood cells, red blood cells (RBC) undergo hemolysis due to hemoglobin denaturation. RBC lysis post-irradiation results in the release of iron into the plasma, producing a secondary toxic event. We investigated the impact of radiation-induced iron release on the spleen of mice following TBI and the effects of the radiation mitigator captopril. RBC and hematocrit were reduced ~7 days (nadir ~14 days) post-TBI. Prussian blue staining revealed ~20-60-fold increased Fe3+ in the spleen 7-14 days post-irradiation, also associated with altered expression of iron binding and transport proteins, determined by qPCR, western blotting, and immunohistochemistry. Captopril did not prevent iron deposition in the spleen, and did not significantly modulate most iron-binding proteins. Spleen volumes were markedly decreased 7-14 days, correlating with high Fe3+. At these time points, caspase-3 was activated and we identified four markers of ferroptosis, iron-dependent programmed cell death. Interestingly, p21/Waf1, a marker of accelerated senescence, was not upregulated in vivo. Macrophage inflammation is an important effect of TBI. We investigated the effects of radiation and Fe3+ on the cultured J774A.1 murine macrophage cell line. Radiation induced p21/Waf1 and ferritin, but not caspase-3, within 24 h. Radiation ± iron upregulated several markers of pro-inflammatory M1 polarization; radiation with iron also upregulated a marker of anti-inflammatory M2 polarization. Our data indicate that following TBI, iron accumulates in the spleen where it regulates iron binding proteins and triggers ferroptosis.

We report a mild, fast and convenient catalytic system for the coupling of aryl chlorides with primary, secondary, as well as previously challenging tertiary alkyl thiols using an air-stable nickel(II) precatayst in combination with the low-cost base potassium acetate at room temperature. This new catalytic system tolerates a variety of functional groups and enables the generation of thioethers for a wide range of substrates, including pharmaceutical compounds in excellent yields. Chemoselec-tive functionalization of disubstituted substrates was demonstrated. Kinetic and NMR-studies, as well as DFT computations support a Ni(0)/Ni(II) catalytic cycle and identify the oxidative addition product as the resting state. Acetate coordination and subsequent acetate facilitated formation of a thiolate complex via internal deprotonation play a key role in the catalytic cycle.

C,N-Chelate deprotonated diaminocarbene platinum(II) complexes were synthesized by coupling coordinated isocyanides and azinyl-substituted ureas. The complexes act as catalysts of α,ω-divinylpolydimethylsiloxane and poly(dimethylsiloxane-co-methylhydrosiloxane) hydrosilylation cross-linking. Silicone rubbers obtained with (aminoisoquinoline)-containing complex 3d exhibit temperature-responsive luminescence. Their emission changes irreversibly when heated from 80–100 °C (green radiation) to 120 °C or more (blue radiation).

Funding Information: V.N. thanks the Russian Foundation for Basic Research (RFBR project No. 19-32-60040) for PDMS/MW membrane fabrication and optical measurements. V.F. thanks the Russian Foundation for Basic Research (RFBR project No. 19-32-60037) for the support of the MBE growth. V.N. and F.K. thank the support from the Russian Foundation for Basic Research (grant 20-32-90182) for electrical measurements. V.N., F.K., R.I. and I.M. thank the Russian Scientific Foundation (RSF project No. 20-19-00256) for chemical treatment of PDMS. V.N., V.F., A.M., F.K. and K.S. thank the Ministry of Science and Higher Education of the Russian Federation (FSRM-2020-0005) for the general support. E.M. thanks the Basic Research Program at the National Research University Higher School of Economics (HSE University) in 2021 for optical measurements. N.A.-M. and M.T. thank ITN Marie Curie project INDEED (grant No. 722176) for GaPAs NW/PDMS membrane investigation. This work received financial support from Partenariats Hubert Curien Kolmogorov project No. 43784UJ and Indo French Centre for the Promotion of Advanced Research (CEFIPRA) Project No. 6008-1. A.G.N. acknowledges the Russian Scientific Foundation (RSF project No. 21-72-20050) for synthesis of SWCNTs. Funding Information: Funding: V.N. thanks the Russian Foundation for Basic Research (RFBR project No. 19-32-60040) for PDMS/MW membrane fabrication and optical measurements. V.F. thanks the Russian Foundation for Basic Research (RFBR project No. 19-32-60037) for the support of the MBE growth. V.N. and F.K. thank the support from the Russian Foundation for Basic Research (grant 20-32-90182) for electrical measurements. V.N., F.K., R.I. and I.M. thank the Russian Scientific Foundation (RSF project No. 20-19-00256) for chemical treatment of PDMS. V.N., V.F., A.M., F.K. and K.S. thank the Ministry of Science and Higher Education of the Russian Federation (FSRM-2020-0005) for the general support. E.M. thanks the Basic Research Program at the National Research University HigherSchool of Economics (HSE University) in 2021 for optical measurements. N.A.-M. and M.T. thank ITN Marie Curie project INDEED (grant No. 722176) for GaPAs NW/PDMS membrane investigation. This work received financial support from Partenariats Hubert Curien Kolmogorov project No. 43784UJ and Indo French Centre for the Promotion of Advanced Research (CEFIPRA) Project No. 6008-1. A.G.N. acknowledges the Russian Scientific Foundation (RSF project No. 21-72-20050) for synthesis of SWCNTs. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. We demonstrate flexible red light-emitting diodes based on axial GaPAs/GaP heterostruc-tured nanowires embedded in polydimethylsiloxane membranes with transparent electrodes involv-ing single-walled carbon nanotubes. The GaPAs/GaP axial nanowire arrays were grown by molecular beam epitaxy, encapsulated into a polydimethylsiloxane film, and then released from the growth substrate. The fabricated free-standing membrane of light-emitting diodes with contacts of single-walled carbon nanotube films has the main electroluminescence line at 670 nm. Membrane-based light-emitting diodes (LEDs) were compared with GaPAs/GaP NW array LED devices processed directly on Si growth substrate revealing similar electroluminescence properties. Demonstrated membrane-based red LEDs are opening an avenue for flexible full color inorganic devices.

Background Both drug and natural reward-seeking have been shown to increase following an extended period of abstinence, a phenomenon termed ‘incubation of craving’. Although this phenomenon involves many brain regions, the projections from the prelimbic cortex (PrL) to the nucleus accumbens (NAc) core have been strongly implicated in incubation of cocaine-seeking. However, this circuit has not been investigated in the context of incubation of craving for natural rewards. Methods Male Long Evans rats were trained to self-administer cocaine or water/saline 6 h/d for 14 days and subsequently entered 1 month of experimenter-imposed abstinence. Rats then underwent an optogenetic stimulation protocol used to induce long term depression in the PrL terminals to the NAc core immediately before beginning an extinction test used to assess incubation of craving. Results Control cocaine rats showed heightened drug-seeking on day 30 when compared to day 1 of abstinence, demonstrating incubation of craving. Notably, optogenetic stimulation of the PrL to NAc core pathway blocked this behavior in cocaine rats. In contrast, optogenetic stimulation of the PrL to NAc core pathway induced incubation of craving in water/saline rats. Conclusions These findings suggest that neuroadaptations in the PrL to NAc core pathway play opposing roles in the incubation of craving for cocaine versus water.

Recent reports have suggested that (1) formaldehyde levels (measured as a hydrazone derivative using the DNPH derivatization method) in Electronic Nicotine Delivery Systems (ENDS) products were underreported because formaldehyde may react with propylene glycol (PG) and glycerin (Gly) in the aerosol to form hemiacetals; (2) the equilibrium would shift from the hemiacetals to the acetals in the acidic DNPH trapping solution. In both cases, neither the hemiacetal nor the acetal would react with DNPH to form the target formaldehyde hydrazone, due to the lack of the carbonyl functional group, thus underreporting formaldehyde. These reports were studied in our laboratory. Our results showed that the aerosol generated from formaldehyde-fortified e-liquids provided a near-quantitative recovery of formaldehyde in the aerosol, suggesting that if any hemiacetal was formed in the aerosol, it would readily hydrolyze to free formaldehyde and, consequently, form formaldehyde hydrazone in the acidic DNPH trapping solution. We demonstrated that custom-synthesized Gly and PG hemiacetal adducts added to the DNPH trapping solution would readily hydrolyze to form the formaldehyde hydrazone. We demonstrated that acetals of PG and Gly present in e-liquid are almost completely transferred to the aerosol during aerosolization. The study results demonstrate that the DNPH derivatization method allows for an accurate measurement of formaldehyde in vapor products.

Glioblastoma (GBM) remains one of the most lethal primary brain tumors in children and adults. Targeting tumor metabolism has emerged as a promising-targeted therapeutic strategy for GBM and characteristically resistant GBM stem-like cells (GSCs). Gene expression data was obtained from the online patient-histology database, GlioVis. GSC mitochondria morphology was examined by TEM. Cell viability and effect on GSC self-renewal was determined via MTS assay and neurosphere assay, respectively. Proteins were evaluated by Western Blot. Enzymes necessary for ketone catabolism (BDH1, OXCT1 and ACAT1) are significantly downregulated in adult and pediatric GBM. GSC mitochondrial ultrastructure suggested defects in oxidative phosphorylation. Treatment of both GBM and GSC cell lines resulted in dose-dependent decreases in viability in response to glycolytic inhibitor 2-deoxy-D-glucose (2-DG), and ketone body Acetoacetate (AA), but not β-hydroxybutyrate (βHB). AA induced apoptosis was confirmed by western blot analysis, indicating robust caspase activation and PARP cleavage. AA reduced neurosphere formation at concentrations as low as 1 mM. Combined treatment of low dose 2-DG (50 μM) with AA resulted in more cell death than either treatment alone. The effect was greater than additive at low concentrations of AA, reducing viability approximately 50% at 1 mM AA. AA was found to directly upregulate mitochondrial uncoupling protein 2 (UCP2), which may explain this potential drug synergism via multi-faceted inhibition of the glycolytic pathway. Targeting the metabolic pathway of GBM via glycolytic inhibition in conjunction with ketogenic diet or exogenous ketone body supplementation warrants further investigation as a promising adjunctive treatment to conventional therapy.

Rubber materials are the key components of flexible optoelectronic devices, especially for the light-emitting diodes based on arrays of inorganic nanowires (NWs). This paper reports on polydimethylsiloxane-graft-polystyrene (PDMS-St) as a new flexible substrate of GaP NW array structures. The NWs were encapsulated by the newly introduced G-coating method to substitute the inefficient mainstream spin-coating. To further exploit the flexibility and the stretchability of the NW/PDMS-St structures, the ferrocenyl-containing polymethylhydrosiloxane was synthesized and successfully used as an electrode for the NWs. In order to make an alternative highly efficient transparent electrode, a new application of conductive single-walled carbon nanotubes was demonstrated. The novel materials and methods demonstrated unsurpassed mechanical stability of the fabricated flexible electronic devices.

Nanoparticle tracking analysis (NTA) is an important technique for measuring hydrodynamic size of globular biological particles including liposomes and viruses. Less attention has been paid to NTA of rod-like particles, despite their considerable interest. For example, amyloid fibrils and protofibrils are protein aggregates with rod-like morphology, diameters of 2-15 nm, and lengths from 50 nm to 1 μm, and linked to diseases including Alzheimer's and Parkinson's. We used NTA to measure the concentration and hydrodynamic size of gold nanorods (10 nm diameter, 35-250 nm length) and myosin (2 nm diameter, 160 nm length), as models of rod-like particles. Measured hydrodynamic diameters of gold nanorods were consistent with theoretical calculations, as long as particle concentration and solution conditions were controlled. Myosin monomers were invisible by NTA, but a small population of aggregates was detected. We combined NTA results with other light scattering data to gain insight into number and size distribution of protein solutions containing both monomer and aggregates. Finally, we demonstrated the utility of NTA and its limitations by characterizing aggregates of alpha-synuclein. Of note is the use of NTA to detect a change in morphology from compact to elongated by analyzing the ratio of hydrodynamic size to intensity.

Infant maltreatment increases vulnerability to physical and mental disorders, yet specific mechanisms embedded within this complex infant experience that induce this vulnerability remain elusive. To define critical features of maltreatment-induced vulnerability, rat pups were reared from postnatal day 8 (PN8) with a maltreating mother, which produced amygdala and hippocampal deficits and decreased social behavior at PN13. Next, we deconstructed the maltreatment experience to reveal sufficient and necessary conditions to induce this phenotype. Social behavior and amygdala deficits (volume, neurogenesis, c-Fos, local field potential) required combined chronic high corticosterone and maternal presence (not maternal behavior). Hippocampal deficits were induced by chronic high corticosterone regardless of social context. Causation was shown by blocking corticosterone during maltreatment and suppressing amygdala activity during social behavior testing. These results highlight (1) that early life maltreatment initiates multiple pathways to pathology, each with distinct causal mechanisms and outcomes, and (2) the importance of social presence on brain development.

Diatoms perform an estimated 20% of global photosynthesis, form the base of the marine food web, and sequester carbon into the deep ocean through the biological pump. In some areas of the ocean, diatom growth is limited by the micronutrient cobalamin (vitamin B12), yet the biochemical ramifications of cobalamin limitation are not well understood. In a laboratory setting, we grew the diatom Thalassiosira pseudonana under replete and low cobalamin conditions to elucidate changes in metabolite pools. Using metabolomics, we show that the diatom experienced a metabolic cascade under cobalamin limitation that affected the central methionine cycle, transsulfuration pathway, and composition of osmolyte pools. In T. pseudonana, 5'-methylthioadenosine decreased under low cobalamin conditions, suggesting a disruption in the diatom's polyamine biosynthesis. Furthermore, two acylcarnitines accumulated under low cobalamin, suggesting the limited use of an adenosylcobalamin-dependent enzyme, methylmalonyl CoA mutase. Overall, these changes in metabolite pools yield insight into the metabolic consequences of cobalamin limitation in diatoms and suggest that cobalamin availability may have consequences for microbial interactions that are based on metabolite production by phytoplankton.

There are no FDA-approved drugs that can be administered prior to ionizing radiation exposure to prevent hematopoietic–acute radiation syndrome (H-ARS). A suspension of synthetic genistein nanoparticles was previously shown to be an effective radioprotectant against H-ARS when administered prior to exposure to a lethal dose of total body radiation. Here we aimed to determine the time to protection and the duration of protection when the genistein nanosuspension was administered by intramuscular injection, and we also investigated the drug’s mechanism of action. A single intramuscular injection of the genistein nanosuspension was an effective radioprotectant when given prophylactically 48 h to 12 h before irradiation, with maximum effectiveness occurring when administered 24 h before. No survival advantage was observed in animals administered only a single dose of drug after irradiation. The dose reduction factor of the genistein nanosuspension was determined by comparing the survival of treated and untreated animals following different doses of total body irradiation. As genistein is a selective estrogen receptor beta agonist, we also explored whether this was a central component of its radioprotective mechanism of action. Mice that received an intramuscular injection of an estrogen receptor antagonist (ICI 182,780) prior to administration of the genistein nanosuspension had significantly lower survival following total body irradiation compared with animals only receiving the nanosuspension (P < 0.01). These data define the time to and duration of radioprotection following a single intramuscular injection of the genistein nanosuspension and identify its likely mechanism of action.

4-Substituted O-benzyl benzamide oximes reacted with 2-iodobenzonitrile in the presence of 0.1 mol % of [Pd2(dba)3], 0.2 mol % of XantPhos, and 1.5 equiv of Cs2CO3 in dioxane under argon to give 2-arylquinazolin-4-amines. The described reaction is a new type of cascade processes, which affords 4-amino-quinazoline derivatives without using highly reactive chlorinating agents.

Acetylacetonate and 4-arylimino-2-pentanonate carbonyl complexes of rhodium(I) [Rh(RC(O)C(R')C(O)R“)(CO)2] (1: R = Me, R' = H, R'' = Me; 2: R = Me, R' = Cl, R'' = Me; 3: R = Me, R' = H, R'' = CO2Me; 4: R = Ph, R' = H, R'' = Me; 5: R = Ph, R' = H, R'' = Ph) and [Rh(MeC(NR''')CHC(O)Me)(CO)2] (6: R''' = Ph; 7: R''' = 2,6-Me2C6H3) were examined as hydrosilylation cross-linking catalysts at RT for the reaction of poly(dimethylsiloxane-co-ethylhydrosiloxane) copolymer with vinyl terminated poly(dimethylsiloxane) or vinyl terminated poly(dimethylsiloxane-co-styrene) copolymer. All complexes allow cross-linking of vinyl- and hydride-containing polysiloxanes and copolymers at RT without inhibitor addition. Complexes 1–7 possess catalytic activity comparable to the industrially used complex of Pt0 and divinyltetramethyldisiloxane (Karstedt’s catalyst). 1 is the most active among the studied rhodium complexes at 1.0 × 10−4 mol⋅L−1 and 1.0 × 10−5 mol⋅L−1. Silicone rubbers obtained with the rhodium catalysts compared to Karstedt’s catalyst possess no visible defects (bubbles or cracks), and differed by improved elastic properties (the elongation at break increased from 160 to 255%) The activity and improved silicone rubber properties using 1 renders it one of the suitable alternatives to Karstedt’s catalyst.

Chimeric antigen receptor (CAR) T cells have induced remarkable antitumor responses in B cell malignancies. Some patients do not respond because of T cell deficiencies that hamper the expansion, persistence, and effector function of these cells. We used longitudinal immune profiling to identify phenotypic and pharmacodynamic changes in CD19-directed CAR T cells in patients with chronic lymphocytic leukemia (CLL). CAR expression maintenance was also investigated because this can affect response durability. CAR T cell failure was accompanied by preexisting T cell-intrinsic defects or dysfunction acquired after infusion. In a small subset of patients, CAR silencing was observed coincident with leukemia relapse. Using a small molecule inhibitor, we demonstrated that the bromodomain and extra-terminal (BET) family of chromatin adapters plays a role in downregulating CAR expression. BET protein blockade also ameliorated CAR T cell exhaustion as manifested by inhibitory receptor reduction, enhanced metabolic fitness, increased proliferative capacity, and enriched transcriptomic signatures of T cell reinvigoration. BET inhibition decreased levels of the TET2 methylcytosine dioxygenase, and forced expression of the TET2 catalytic domain eliminated the potency-enhancing effects of BET protein targeting in CAR T cells, providing a mechanism linking BET proteins and T cell dysfunction. Thus, modulating BET epigenetic readers may improve the efficacy of cell-based immunotherapies.

Background: Phthalates and phenols from the environment have been inconsistently associated with breast cancer risk or mortality. Studies on the potential modifying role of leukocyte telomere length (LTL), a biomarker of biological aging, on these associations are lacking. Methods: We included 1,268 women from the Long Island Breast Cancer Study Project with available data on phthalate and phenol analytes and LTL measurements. Twenty-two phthalate and phenol analytes were measured in spot urines and LTL was measured in blood. The modifying effect of LTL on the associations of individual analyte with breast cancer risk as well as mortalities was estimated using interaction terms between LTL and urinary concentrations of analyte in logistic regression and Cox regression models, respectively. ORs, HRs, and corresponding 95% confidence intervals for a one-unit (ln μg/g creatinine) increase of urinary phthalate/phenol level were estimated at 10th, 50th, and 90th percentiles of LTL. Results: LTL significantly (P < 0.05) modified associations between 11 of 22 of urinary phthalate/phenols analytes and breast cancer risk. An inverse association between phthalate/phenols analytes and breast cancer risk at shorter LTL and a positive association at longer LTL was generally suggested. No modifying effect was found for LTL on the association between these phthalate/phenols analytes and breast cancer mortalities. Conclusions: LTL may modify the associations between phthalate and phenol exposures and breast cancer risk. Impact: This study is the first study that determined the modifying effect of biological aging in the association between environmental chemical exposure and breast cancer risk.

Objective: Efavirenz (EFV) use is associated with neuropsychiatric side effects, which may include poor neurocognitive performance. We evaluated single nucleotide polymorphisms in genes that contribute to EFV pharmacokinetics and examined them in association with EFV concentrations in plasma and hair, as well as neurocognitive performance. Design: Cross-sectional study in which adults with HIV receiving 600-mg EFV for at least 2 months were recruited and paired hair and dried blood spots (DBS) samples collected. Methods: Participants (N = 93, 70.3% female) were genotyped for seven single nucleotide polymorphisms in CYP2B6, NRII3 and ABCB1 using DBS. EFV was quantified in DBS and hair using validated liquid-chromatography–tandem-mass-spectrometry methods, with plasma EFV concentrations derived from DBS levels. Participants were also administered a neurocognitive battery of 10 tests (seven domains) that assessed total neurocognitive functioning. Results: Strong correlation (r = 0.66, P T, (P C (P = 0.001) were each associated with hair EFV concentrations. Similarly, 516G>T (P C (P = 0.009) were significantly associated with plasma EFV concentration. No other genetic associations were observed. Contrary to other studies, total neurocognitive performance was significantly associated with plasma EFV concentrations (r = 0.23, P = 0.043) and 983T>C genotype (r = 0.38, P

Temperament is an innate, stable predisposition towards particular emotional and behavioral responses. In humans, certain temperaments are associated with a heightened risk of developing anxiety later in life. Non-human animals, including rodents, also exhibit innate, stable dispositions; these are referred to as behavioral phenotypes. The interaction between behavioral phenotype and early life adverse events is critical for the development of maladaptive anxiety. Rodent studies of typically developing animals have identified a number of mechanisms that protect against aversive experiences in early life. One such mechanism is an early life quiescence of threat learning, which protects against the effects of stress and facilitates safety and attachment learning. However, little is known about the factors that alleviate the effects of early life aversive events on phenotypes vulnerable to pathological anxiety. Here, we examined threat learning and the stress response in selectively-bred infant rats that show an anxiety-like phenotype relative to typically developing animals. We investigated the potential roles of maternal presence and the anxiolytic neurotrophic factor fibroblast growth factor 2 (FGF2) in regulating threat learning and the stress response in infant anxiety-like phenotype animals. We observed that rats selectively-bred for anxiety-like behaviors could acquire conditioned freezing earlier in life than typically developing animals. FGF2 administration on postnatal day 1 (PND 1) and maternal presence during threat conditioning were both capable of suppressing this early emergence of conditioned freezing. However, neither FGF2 nor maternal presence during threat conditioning were associated with reduced corticosterone levels during threat conditioning. Our results suggest that although an anxiety-like phenotype may be associated with early threat learning, environmental factors (such as maternal presence) and pharmacological intervention (such as modulation of the FGF2 system) may be capable of counteracting that early aversive learning. Interventions in vulnerable infants may thus decrease the impact of aversive events.

Carbon is ubiquitous as an electrode material in electrochemical energy conversion devices. If used as support material, the evolution of H2 is undesired on carbon. However, recently carbon-based materials are of high interest as economic and eco-conscious alternative to noble metal catalysts. The targeted design of improved carbon electrode materials requires atomic scale insight into the structure of the sites that catalyse H2 evolution. This work demonstrates that electrochemical scanning tunnelling microscopy under reaction conditions (n-EC-STM) can monitor active sites of highly oriented pyrolytic graphite for the hydrogen evolution reaction. With down to atomic resolution, the most active sites in acidic medium are pinpointed near edge sites and defects, whereas the basal planes remain inactive. Density functional theory calculations support these findings and reveal that only specific defects on graphite are active. Motivated by these results, the extensive usage of n-EC-STM on doped carbon-based materials is encouraged to locate their active sites and guide the synthesis of enhanced electrocatalysts. The authors thank Prof. Plamen Atanassov (University of California, Irvine, USA) and Dr. Jun Maruyama (Osaka Research Institute of Industrial Science and Technology, Japan) for fruitful discussion regarding some experimental results. RMK, RWH and ASB acknowledge the financial support from the German Research Foundation (DFG), in the framework of the projects BA 5795/4-1 and BA 5795/3-1, and under Germany's Excellence Strategy–EXC 2089/1–390776260, cluster of excellence ‘e-conversion’. ASB acknowledges the funding from the European Union's Horizon 2020 research and innovation programme under grant agreement HERMES No. 952184. FCV acknowledges financial support from Spanish MICIUN through RTI2018-095460-B-I00 and María de Maeztu (MDM-2017-0767) grants and a Ramón y Cajal research contract (RYC-2015-18996), and also from Generalitat de Catalunya (grants 2017SGR13 and XRQTC). The use of supercomputing facilities at SURFsara was sponsored by NWO Physical Sciences, with financial support from NWO.