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Bosentan, clazosentan, and tezosentan are three small-molecule endothelin receptor antagonists (ERAs), displacing endothelin-1 (ET-1) from its binding site. A target-mediated drug disposition (TMDD) pharmacokinetic (PK) model described the non-linearity in the PK of bosentan caused by its high receptor binding affinity with time-dependent varying receptor expression or reappearance. The aim of this analysis was to investigate the presence of TMDD for clazosentan and tezosentan and to corroborate the hypothesis of a diurnal receptor synthesis. PK data from healthy subjects after intravenous (i.v.) administration of single ascending doses of bosentan, clazosentan, and tezosentan were analyzed. Frequent blood samples for PK measurements were collected. Population analyses, simulations, and evaluations were performed using a non-linear mixed-effects modeling approach. Two-compartment TMDD models were successfully developed describing the PK of all three ERAs with different receptor-complex internalization properties. The observed multiple peaks in the concentration-time profiles were captured with cosine functions on the receptor synthesis rate mimicking a diurnal receptor expression or reappearance. The results strongly suggest that TMDD is a class effect of ERAs. The developed TMDD PK models are a next step towards understanding the complex PK of ERAs and further support the hypothesis that TMDD is a class effect of ERAs.

All solid-state batteries offer the possibility of increased safety at potentially higher energy densities compared to conventional lithium-ion batteries. In an all-ceramic oxide battery, the composite cathode consists of at least one ion-conducting solid electrolyte and an active material, which are typically densified by sintering. In this study, the reaction of the solid electrolyte Li1.3Al0.3Ti1.7(PO4)3 (LATP) and the active material LiNi0.6Co0.2Mn0.2O2 (NCM622) is investigated by cosintering at temperatures between 550 and 650 °C. The characterization of the composites and the reaction layer is performed by optical dilatometry, X-ray diffractometry, field emission scanning electron microscopy with energy dispersive X-ray spectroscopy, time-of-flight secondary ion mass spectrometry, as well as scanning transmission electron microscopy (STEM). Even at low sintering temperatures, elemental diffusion occurs between the two phases, which leads to the formation of secondary phases and decomposition reactions of the active material and the solid electrolyte. As a result, the densification of the composite is prevented and ion-conducting paths between individual particles cannot be formed. Based on the experimental results, a mechanism of the reactions in cosintered LATP and NCM622 oxide composite cathodes is suggested.

Tertiarybutylarsine (TBAs) and tertiarybutylphosphine (TBP) are getting more and more established as group V precursors for the growth of V/III semiconductors by metal organic vapor phase epitaxy (MOVPE). Due to this development, the thermal decomposition of these precursors was studied during the growth of GaAs and GaP utilizing the Ga precursors, trimethylgallium (TMGa), triethylgallium (TEGa), and tritertiarybutylgallium (TTBGa), in a horizontal AIXTRON AIX 200 GFR MOVPE system. The decomposition and reaction products were measured in line with a real-time Fourier transform quadrupole ion trap mass spectrometer from Carl Zeiss SMT GmbH. The decomposition temperatures and the related activation energies were determined for all the mentioned precursors under comparable reactor conditions. The decomposition curves suggest, on the one hand, a catalytic effect of the GaAs surface on the decomposition of TBAs. On the other hand, the decomposition products indicate alkyl exchange as a relevant step during the bimolecular decomposition of TBAs and TBP with the Ga precursors TMGa, TEGa, and TTBGa. The catalytic reaction reduces the decomposition temperature of TBAs and TBP by up to 200 °C. In addition, for the growth of GaAs with TBAs and TEGa and for the growth of GaP with TBP and TEGa, a significant decrease of the decomposition temperature with an increasing V/III ratio is observed. This behavior, which is related to an alkyl exchange reaction, gives insights into the low-temperature growth of GaAs and GaP and is converted into an effective V/III ratio. Finally, the growth of GaAs with TTBGa and TBAs is realized at 300 °C below the unimolecular decomposition temperature of TBAs, underlining the catalytic effect of the GaAs surface. Altering the growth surface with trimethylbismuth led to the prevention of the catalytic effect.

Understanding the thermal transport in nanostructures has important applications in fields such as thermoelectric energy conversion, novel computing and heat dissipation. Using non-homogeneous equilibrium molecular dynamic simulations, we studied the thermal transport in pristine and resonant Si membranes bounded with {110} facets. The break of symmetry by surfaces led to the anisotropic thermal transport with the thermal conductivity along the [110]-direction to be 1.78 times larger than that along the [100]-direction in the pristine structure. In the pristine membranes, the mean free path of phonons along both the [100]- and [110]-directions could reach up to ∼100 µm. Such modes with ultra-long MFP could be effectively hindered by surface resonant pillars. As a result, the thermal conductivity was significantly reduced in resonant structures, with 87.0% and 80.8% reductions along the [110]- and [100]-directions, respectively. The thermal transport anisotropy was also reduced, with the ratio κ110/κ100 decreasing to 1.23. For both the pristine and resonant membranes, the thermal transport was mainly conducted by the in-plane modes. The current work could provide further insights in understanding the thermal transport in thin membranes and resonant structures.

Molecular compounds of the general formula [(RT)4E6] (R=organic or organometallic substituent; T=C, Si, Ge, Sn; E=CH2, S, Se), hence adamantane derivatives and inorganic-organic hybrid compounds based on a heteroadamantane structure exhibit a non-linear optical response upon radiation with a continuous-wave near-infrared laser. The effect depends on the compounds’ habitus, which itself depends on the elemental composition of the cluster core, and on the nature of the organic substituents. A combination of these parameters that cause the material to be intrinsically amorphous leads to supercontinuum generation and thus to the emission of a broad spectrum, potentially appearing as white light. Notably, the emission essentially retains the driving laser's directionality. For crystalline samples, second harmonic generation is observed instead, which points to a close relationship of the optical properties and the intermolecular order. Variation of R, T, and E allows further fine-tuning of the emitted spectra. We present all studies made in regards to these effects and our overarching conclusions derived from them.

This study investigated the ability of Staphylococcus aureus isolates from milk to form biofilm, through detection of adhesion genes, investigating exopolysaccharide (EPS) production and biofilm formation on polystyrene (PS) and stainless steel (SS) surfaces, and by quantifying the expression of ebpS and cna genes under different temperatures and culture media. Among the 31 isolates, the adhesion genes ebpS and cna were found in 81% and 61% of the isolates, respectively. The screening tests for phenotype revealed that 58% of the isolates were EPS producers, and 45% showed the ability to produce biofilm on PS. Nine of the 31 isolates were selected to verify their ability to form biofilm on SS, of which 3 were non-biofilm producers, 3 were poor biofilm producers, and 3 were moderate biofilm producers. However, all nine isolates produced biofilm on SS, regardless of their phenotypic profile on PS. Reverse-transcriptase quantitative PCR (RT–qPCR) revealed no variation in the expression levels of ebpS and cna genes at different temperatures, except for isolate S24 at 10 °C, for both genes tested. Moreover, RT–qPCR assays revealed that the expression levels of the adhesion genes ebpS and cna are isolate- and temperature-dependent; however, they are independent of the phenotypic biofilm-formation profile.

The application of nickel-rich LiNixCoyAlzO2 (NCA) cathode materials in solid-state lithium-ion batteries (SSBs) promises significant improvements in energy density, stability, and safety over trad...

The preparation of carbons for technical applications is typically based on a treatment of a precursor, which is transformed into the carbon phase with the desired structural properties. During such treatment the material passes through several different structural stages, for example, starting from precursor molecules via an amorphous phase into crystalline-like phases. While the structure of non-graphitic and graphitic carbon has been well studied, the transformation stages from molecular to amorphous and non-graphitic carbon are still not fully understood. Disordered carbon often contains a mixture of sp3-, sp2-and sp1-hybridized bonds, whose analysis is difficult to interpret. We systematically address this issue by studying the transformation of purely sp3-hybridized carbons, that is, nanodiamond and adamantane, into sp2-hybridized non-graphitic and graphitic carbon. The precursor materials are thermally treated at different temperatures and the transformation stages are monitored. We employ Raman spectroscopy, WAXS and TEM to characterize the structural changes. We correlate the intensities and positions of the Raman bands with the lateral crystallite size La estimated by WAXS analysis. The behavior of the D and G Raman bands characteristic for sp2-type material formed by transforming the sp3-hybridized precursors into non-graphitic and graphitic carbon agrees well with that observed using sp2-structured precursors.

The thermal stability of cathode active materials (CAMs) is of major importance for the safety of lithium-ion batteries (LIBs). A thorough understanding of how commercially viable layered oxide CAMs behave at the atomic length scale upon heating is indispensable for the further development of LIBs. Here, structural changes of Li(Ni0.85Co0.15Mn0.05)O2 (NCM851005) at elevated temperatures are studied by in situ aberration-corrected scanning transmission electron microscopy (AC-STEM). Heating NCM851005 inside the microscope under vacuum conditions enables us to observe phase transitions and other structural changes at high spatial resolutions. This has been primarily possible by establishing low-dose electron beam conditions in STEM. Specific focus is put on the evolution of inherent nanopore defects found in the primary grains, which are believed to play an important role in LIB degradation. The onset temperature of structural changes is found to be ∼175 °C, resulting in phase transformation from a layered to a rock-salt-like structure, especially at the internal interfaces, and increasing intragrain inhomogeneity. The reducing environment and heat application lead to the formation and subsequent densification of {003}- and {014}-type facets. In the light of these results, postsynthesis electrode drying processes applied under reducing environment and heat, for example, in the preparation of solid-state batteries, should be re-examined carefully.

Store-operated Ca(2+) entry (SOCE) is the major route of Ca(2+) influx in platelets. The Ca(2+) sensor stromal interaction molecule 1 (STIM1) triggers SOCE by forming punctate structures with the Ca(2+) channel Orai1 and the inositol trisphosphate receptor (IP(3)R), thereby linking the endo-/sarcoplasmic reticulum to the plasma membrane. Here, we identified the BAR domain superfamily member bridging integrator 2 (BIN2) as an interaction partner of STIM1 and IP(3)R in platelets. Deletion of platelet BIN2 (Bin2(fl/fl,Pf4-Cre) mice) resulted in reduced Ca(2+) store release and Ca(2+) influx in response to all tested platelet agonists. These defects were a consequence of impaired IP(3)R function in combination with defective STIM1-mediated SOC channel activation, while Ca(2+) store content and agonist-induced IP(3) production were unaltered. This severely defective Ca(2+) signaling translated into impaired thrombus formation under flow and a protection of Bin2(fl/fl,Pf4-Cre) mice in models of arterial thrombosis and stroke. Our results establish BIN2 as a central regulator of platelet activation in thrombosis and thrombo-inflammatory disease settings.

The extracellular matrix (ECM) naturally surrounds cells in humans, and therefore represents the ideal biomaterial for tissue engineering. ECM from different tissues exhibit different composition and physical characteristics. Thus, ECM provides not only physical support but also contains crucial biochemical signals that influence cell adhesion, morphology, proliferation and differentiation. Next to native ECM from mature tissue, ECM can also be obtained from the in vitro culture of cells. In this study, we aimed to highlight the supporting effect of cell-derived- ECM (cdECM) on adipogenic differentiation. ASCs were seeded on top of cdECM from ASCs (scdECM) or pre-adipocytes (acdECM). The impact of ECM on cellular activity was determined by LDH assay, WST I assay and BrdU assay. A supporting effect of cdECM substrates on adipogenic differentiation was determined by oil red O staining and subsequent quantification. Results revealed no effect of cdECM substrates on cellular activity. Regarding adipogenic differentiation a supporting effect of cdECM substrates was obtained compared to control. With these results, we confirm cdECM as a promising biomaterial for adipose tissue engineering.

Tissue constructs of physiologically relevant scale require a vascular system to maintain cell viability. However, in vitro vascularization of engineered tissues is still a major challenge. Successful approaches are based on a feeder layer (FL) to support vascularization. Here, we investigated whether the supporting effect on the self-assembled formation of prevascular-like structures by microvascular endothelial cells (mvECs) originates from the FL itself or from its extracellular matrix (ECM). Therefore, we compared the influence of ECM, either derived from adipose-derived stem cells (ASCs) or adipogenically differentiated ASCs, with the classical cell-based FL. All cell-derived ECM (cdECM) substrates enabled mvEC growth with high viability. Prevascular-like structures were visualized by immunofluorescence staining of endothelial surface protein CD31 and could be observed on all cdECM and FL substrates but not on control substrate collagen I. On adipogenically differentiated ECM, longer and higher branched structures could be found compared with stem cell cdECM. An increased concentration of proangiogenic factors was found in cdECM substrates and FL approaches compared with controls. Finally, the expression of proteins associated with tube formation (E-selectin and thrombomodulin) was confirmed. These results highlight cdECM as promising biomaterial for adipose tissue engineering by inducing the spontaneous formation of prevascular-like structures by mvECs.

Purpose:To determine if the degree of estrogen suppression with aromatase inhibitors (AI: anastrozole, exemestane, letrozole) is associated with efficacy in early-stage breast cancer, and to examine for differences in the mechanism of action between the three AIs.Experimental Design:Matched case–control studies [247 matched sets from MA.27 (anastrozole vs. exemestane) and PreFace (letrozole) trials] were undertaken to assess whether estrone (E1) or estradiol (E2) concentrations after 6 months of adjuvant therapy were associated with risk of an early breast cancer event (EBCE). Preclinical laboratory studies included luciferase activity, cell proliferation, radio-labeled ligand estrogen receptor binding, surface plasmon resonance ligand receptor binding, and nuclear magnetic resonance assays.Results:Women with E1 ≥1.3 pg/mL and E2 ≥0.5 pg/mL after 6 months of AI treatment had a 2.2-fold increase in risk (P = 0.0005) of an EBCE, and in the anastrozole subgroup, the increase in risk of an EBCE was 3.0-fold (P = 0.001). Preclinical laboratory studies examined mechanisms of action in addition to aromatase inhibition and showed that only anastrozole could directly bind to estrogen receptor α (ERα), activate estrogen response element-dependent transcription, and stimulate growth of an aromatase-deficient CYP19A1−/− T47D breast cancer cell line.Conclusions:This matched case–control clinical study revealed that levels of estrone and estradiol above identified thresholds after 6 months of adjuvant anastrozole treatment were associated with increased risk of an EBCE. Preclinical laboratory studies revealed that anastrozole, but not exemestane or letrozole, is a ligand for ERα. These findings represent potential steps towards individualized anastrozole therapy.

III/V semiconductors containing small amounts of nitrogen (dilute nitrides) are promising for applications such as lasers and solar cells. Metal–organic vapor-phase epitaxy (MOVPE) is a widely used...

In pancreatic beta cells, the entry of glucose and downstream signaling for insulin release is regulated by the glucose transporter 2 (Glut2) in rodents. Dysfunction of the insulin-signaling cascade may lead to diabetes mellitus. Gangliosides, sialic acid-containing glycosphingolipids (GSLs), have been reported to modulate the function of several membrane proteins.Murine islets express predominantly sialylated GSLs, particularly the simple gangliosides GM3 and GD3 having a potential modulatory role in Glut2 activity. Conditional, tamoxifen-inducible gene targeting in pancreatic islets has now shown that mice lacking the glucosylceramide synthase (Ugcg), which represents the rate-limiting enzyme in GSL biosynthesis, displayed impaired glucose uptake and showed reduced insulin secretion. Consequently, mice with pancreatic GSL deficiency had higher blood glucose levels than respective controls after intraperitoneal glucose application. High-fat diet feeding enhanced this effect. GSL-deficient islets did not show apoptosis or ER stress and displayed a normal ultrastructure. Their insulin content, size and number were similar as in control islets. Isolated beta cells from GM3 synthase null mice unable to synthesize GM3 and GD3 also showed lower glucose uptake than respective control cells, corroborating the results obtained from the cell-specific model. We conclude that in particular the negatively charged gangliosides GM3 and GD3 of beta cells positively influence Glut2 function to adequately respond to high glucose loads.

Fluorescence microscopy is widely used for high content screening in 2D cell cultures and 3D models. In particular, 3D tissue models are gaining major relevance in modern drug development. Enabling direct multiparametric evaluation of complex samples, fluorescence lifetime imaging (FLIM) adds a further level to intensity imaging by the sensitivity of the fluorescence lifetime to the microenvironment. However, the use of FLIM is limited amongst others by the acquisition of sufficient photon numbers without phototoxic effects in live cells. Herein, we developed a new cluster-based analysis method to enhance insight, and significantly speed up analysis and measurement time for the accurate translation of fluorescence lifetime information into pharmacological pathways. Methods: We applied a fluorescently-labeled dendritic core-multishell nanocarrier and its cargo Bodipy as molecules of interest (MOI) to human cells and reconstructed human tissue. Following the sensitivity and specificity assessment of the fitting-free Cluster-FLIM analysis of data in silico and in vitro, we evaluated the dynamics of cellular molecule uptake and intracellular interactions. For 3D live tissue investigations, we applied multiphoton (mp) FLIM. Owing to Cluster-FLIM's statistics-based fitting-free analysis, we utilized this approach for automatization. Results: To discriminate the fluorescence lifetime signatures of 5 different fluorescence species in a single color channel, the Cluster-FLIM method requires only 170, respectively, 90 counts per pixel to obtain 95% sensitivity (hit rate) and 95% specificity (correct rejection rate). Cluster-FLIM revealed cellular interactions of MOIs, representing their spatiotemporal intracellular fate. In a setting of an automated workflow, the assessment of lysosomal trapping of the MOI revealed relevant differences between normal and tumor cells, as well as between 2D and 3D models. Conclusion: The automated Cluster-FLIM tool is fitting-free, providing images with enhanced information, contrast, and spatial resolution at short exposure times and low fluorophore concentrations. Thereby, Cluster-FLIM increases the applicability of FLIM in high content analysis of target molecules in drug development and beyond.

Introdução: O morango (Fragaria x ananassa Duch) destaca-se no Brasil pela ótima aceitação no mercado consumidor e pelo elevado valor comercial. Espécie oriunda das Américas pertencente à família das rosáceas, além de ser consumido in natura pode ser utilizado em processos industriais. Objetivo: O presente trabalho teve como objetivo estudar a desinfestação e aspectos relacionados à germinação in vitro de morangueiro. Materiais e Métodos: Esse estudo foi dividido em duas etapas sendo a primeira voltada para desinfestação de aquênios analisando a concentração adequada de hipoclorito de sódio (NaClO – 2%, 4%, 6%) em diferentes tempos de imersão (5, 10, 15 e 30 minutos). Os morangos foram colhidos e os aquênios foram retirados. Após, os mesmos foram submetidos aos tratamentos de desinfestação e inoculados em Ágar bacteriológico, sendo mantidos em BOD para o seu desenvolvimento, com temperatura de 25 ± 2ºC e fotoperíodo de 16 horas. Para a segunda etapa, testes de viabilidade de aquênios foram avaliados através das porcentagens de germinação de aquênios armazenados com polpa e sem polpa nos períodos de 5, 15, 25 e 35 dias de armazenamento em ± 10ºC. Resultados: Os morangos foram colhidos, retirados 150 aquênios, onde 50 foram inoculados aos zero dias de armazenamento para testemunha e, o restante armazenados pelos períodos propostos juntamente com os aquênios com polpa. No decorrer dos períodos de armazenamento, foram inoculados em Ágar bacteriológico 25 aquênios do tratamento sem polpa e 25 aquênios do tratamento com polpa. Notou-se, no primeiro estudo o desenvolvimento de contaminações desde a primeira avaliação aos sete dias. Após o período de 42 dias, pode-se concluir que o tratamento com 4% de NaClO demonstrou 100% do lote sem contaminação. Conclusões: No experimento de viabilidade de aquênios, o tratamento com polpa demonstrou maior porcentagem de germinações (16% aos 35 dias de armazenamento).

Colorectal cancer (CRC) is one of the most frequently diagnosed cancers in humans. At early stages CRC is treated by surgery and at advanced stages combined with chemotherapy. We examined here the potential effect of glucosylceramide synthase (GCS)-inhibition on CRC biology. GCS is the rate-limiting enzyme in the glycosphingolipid (GSL)-biosynthesis pathway and overexpressed in many human tumors. We suppressed GSL-biosynthesis using the GCS inhibitor Genz-123346 (Genz), NB-DNJ (Miglustat) or by genetic targeting of the GCS-encoding gene UDP-glucose-ceramide-glucosyltransferase- (UGCG). GCS-inhibition or GSL-depletion led to a marked arrest of the cell cycle in Lovo cells. UGCG silencing strongly also inhibited tumor spheroid growth in Lovo cells and moderately in HCT116 cells. MS/MS analysis demonstrated markedly elevated levels of sphingomyelin (SM) and phosphatidylcholine (PC) that occurred in a Genz-concentration dependent manner. Ultrastructural analysis of Genz-treated cells indicated multi-lamellar lipid storage in vesicular compartments. In mice, Genz lowered the incidence of experimentally induced colorectal tumors and in particular the growth of colorectal adenomas. These results highlight the potential for GCS-based inhibition in the treatment of CRC.

In vitro models of human adipose tissue may serve as beneficial alternatives to animal models to study basic biological processes, identify new drug targets, and as soft tissue implants. With this approach, we aimed to evaluate adipose-derived stem cells (ASC) and mature adipocytes (MA) comparatively for the application in the in vitro setup of adipose tissue constructs to imitate native adipose tissue physiology. We used human primary MAs and human ASCs, differentiated for 14 days, and encapsulated them in collagen type I hydrogels to build up a three-dimensional (3D) adipose tissue model. The maintenance of the models was analyzed after seven days based on a viability staining. Further, the expression of the adipocyte specific protein perilipin A and the release of leptin and glycerol were evaluated. Gene transcription profiles of models based on dASCs and MAs were analyzed with regard to native adipose tissue. Compared to MAs, dASCs showed an immature differentiation state. Further, gene transcription of MAs suggests a behavior closer to native tissue in terms of angiogenesis, which supports MAs as preferred cell type. In contrast to native adipose tissue, genes of de novo lipogenesis and tissue remodeling were upregulated in the in vitro attempts.

Ichthyosis with confetti (IWC) is a genodermatosis associated with dominant‐negative variants in keratin 10 (KRT10) or keratin 1 (KRT1). These frameshift variants result in extended aberrant proteins, localized to the nucleus rather than the cytoplasm. This mislocalization is thought to occur as a result of the altered carboxy (C)‐terminus, from poly‐glycine to either a poly‐arginine or ‐alanine tail. Previous studies on the type of C‐terminus and subcellular localization of the respective mutant protein are divergent. In order to fully elucidate the pathomechanism of IWC, a greater understanding is critical. This study aimed to establish the consequences for localization and intermediate filament formation of altered keratin 10 (K10) C‐termini. To achieve this, plasmids expressing distinct KRT10 variants were generated. Sequences encoded all possible reading frames of the K10 C‐terminus as well as a nonsense variant. A keratinocyte line was transfected with these plasmids. Additionally, gene editing was utilized to introduce frameshift variants in exon 6 and exon 7 at the endogenous KRT10 locus. Cellular localization of aberrant K10 was observed via immunofluorescence using various antibodies. In each setting, immunofluorescence analysis demonstrated aberrant nuclear localization of K10 featuring an arginine‐rich C‐terminus. However, this was not observed with K10 featuring an alanine‐rich C‐terminus. Instead, the protein displayed cytoplasmic localization, consistent with wild‐type and truncated forms of K10. This study demonstrates that, of the various 3′ frameshift variants of KRT10, exclusively arginine‐rich C‐termini lead to nuclear localization of K10.

Objectives The aim of this study was to investigate associations between baseline characteristics and CD4 cell count response on first-line antiretroviral therapy and risk of virological failure (VF) with or without drug resistance. Methods We conducted an analysis of UK Collaborative HIV Cohort data linked to the UK HIV Drug Resistance Database. Inclusion criteria were viral sequence showing no resistance prior to initiation of first-line efavirenz + tenofovir disoproxil fumarate + emtricitabine and virological suppression within 6 months. Outcomes of VF (≥200 copies/mL) with or without drug resistance were assessed using a competing risks approach fitted jointly with a model for CD4 cell count recovery. Hazard ratios for each VF outcome were estimated for baseline CD4 cell count and viral load and characteristics of CD4 cell count response using latent variables on a standard normal scale. Results A total of 3640 people were included with 338 VF events; corresponding viral sequences were available in 134 with ≥1 resistance mutation in 36. VF with resistance was associated with lower baseline CD4 (0.30, 0.09–0.62), lower CD4 recovery (0.04, 0.00–0.17) and higher CD4 variability (4.40, 1.22–12.68). A different pattern of associations was observed for VF without resistance, but the strength of these results was less consistent across sensitivity analyses. Cumulative incidence of VF with resistance was estimated to be >2% at 3 years for baseline CD4 ≥350 cells/μL. Conclusion Lower baseline CD4 cell count and suboptimal CD4 recovery are associated with VF with drug resistance. People with low CD4 cell count before ART or with suboptimal CD4 recovery on treatment should be a priority for regimens with high genetic barrier to resistance.

Ni-rich layered LiNi1-x-yCoxMnyO2 (NCM, x + y ≤ 0.2) is an intensively studied class of cathode active materials for lithium-ion batteries, offering the advantage of high specific capacities. However, their reactivity is also one of the major issues limiting the lifetime of the batteries. NCM degradation, in literature, is mostly explained both by disintegration of secondary particles (large anisotropic volume changes during lithiation/delithiation) and by formation of rock-salt like phases at the grain surfaces at high potential with related oxygen loss. Here, we report the presence of intragranular nanopores in Li1+x(Ni0.85Co0.1Mn0.05)1-xO2 (NCM851005) and track their morphological evolution from pristine to cycled material (200 and 500 cycles) using aberration-corrected scanning transmission electron microscopy (STEM), electron energy loss spectroscopy, energy dispersive X-ray spectroscopy, and time-of-flight secondary ion mass spectrometry. Pores are already found in the primary particles of pristine material. Any potential effect of TEM sample preparation on the formation of nanopores is ruled out by performing thickness series measurements on the lamellae produced by focused ion beam milling. The presence of nanopores in pristine NCM851005 is in sharp contrast to previously observed pore formation during electrochemical cycling or heating. The intragranular pores have a diameter in the range between 10 and 50 nm with a distinct morphology that changes during cycling operation. A rock-salt like region is observed at the pore boundaries even in pristine material, and these regions grow with prolonged cycling. It is suggested that the presence of nanopores strongly affects the degradation of high-Ni NCM, as the pore surfaces apparently increase (i) oxygen loss, (ii) formation of rock-salt regions, and (iii) strain-induced effects within the primary grains. High-resolution STEM demonstrates that nanopores are a source of intragranular cracking during cycling.

III–V semiconductors containing small amounts of nitrogen (“dilute nitrides”) are very promising material systems for optoelectronic applications. Devices based on dilute nitrides currently suffer ...

Tris(1,3-dichloro-2-propyl)phosphate (TDCIPP) is a high-production-volume organophosphate flame retardant (OPFR) that induces epiboly defects during zebrafish embryogenesis, leading to the disruption of dorsoventral patterning. Therefore, the objectives of this study were to (1) identify the potential mechanisms involved in TDCIPP-induced epiboly defects and (2) determine whether coexposure to triphenyl phosphate (TPHP)-an OPFR commonly detected with TDCIPP-enhances or mitigates epiboly defects. Although TDCIPP-induced epiboly defects were not associated with adverse impacts on cytoskeletal protein abundance in situ, the coexposure of embryos to TPHP partially blocked TDCIPP-induced epiboly defects. As nuclear receptors are targets for both TPHP and TDCIPP, we exposed the embryos to TDCIPP in the presence or absence of 69 nuclear receptor ligands and, similar to TPHP, found that ciglitazone (a peroxisome proliferator-activated receptor γ agonist) and 17β-estradiol (E2; an estrogen receptor α agonist) nearly abolished TDCIPP-induced epiboly defects. Moreover, E2 and ciglitazone mitigated TDCIPP-induced effects on CpG hypomethylation within the target loci prior to epiboly, and ciglitazone altered TDCIPP-induced effects on the abundance of two polar metabolites (acetylcarnitine and cytidine-5-diphosphocholine) during epiboly. Overall, our results point to a complex interplay among nuclear receptor ligands, cytosine methylation, and the metabolome in both the induction and mitigation of epiboly defects induced by TDCIPP.

Biological membrane fluidity and thus the local viscosity in lipid membranes are of vital importance for many life processes and implicated in various diseases. Here, we introduce a novel viscosity sensor design for lipid membranes based on a reporting nanoparticle, a sulfated dendritic polyglycerol (dPGS), conjugated to a fluorescent molecular rotor, indocarbocyanine (ICC). We show that dPGS-ICC provides high affinity to lipid bilayers, enabling viscosity sensing in the lipid tail region. The systematic characterization of viscosity- and temperature-dependent photoisomerization properties of ICC and dPGS-ICC allowed us to determine membrane viscosities in different model systems and in living cells using fluorescence lifetime imaging (FLIM). dPGS-ICC distinguishes between ordered lipids and the onset of membrane defects in small unilamellar single lipid vesicles and is highly sensitive in the fluid phase to small changes in viscosity introduced by cholesterol. In microscopy-based viscosity measurements of large multilamellar vesicles, we observed an order of magnitude more viscous environments by dPGS-ICC, lending support to the hypothesis of heterogeneous nanoviscosity environments even in single lipid bilayers. The existence of such complex viscosity structures could explain the large variation in the apparent membrane viscosity values found in the literature, depending on technique and probe, both for model membranes and live cells. In HeLa cells, a tumor-derived cell line, our nanoparticle-based viscosity sensor detects a membrane viscosity of ∼190 cP and is able to discriminate between cell membrane and intracellular vesicle localization. Thus, our results show the versatility of the dPGS-ICC nano-conjugate in physicochemical and biomedical applications by adding a new analytical functionality to its medical properties.

A strategy is presented to deposit defined layers of TiO2 onto the pore surface within ordered mesoporous, crystalline CeO2-ZrO2 thin films using atomic layer deposition (ALD). As structure-directing agent, a special diblock copolymer, poly(isobutylene)-block-poly(ethylene oxide), was used, resulting in a three-dimensional arrangement of spherical pores with diameter around 13 nm. High resolution transmission electron microscopy investigations evidence the presence of anatase TiO2 coatings within the mesopores, while ellipsometric porosimetry studies together with time-of-flight secondary-ion mass spectrometry depth profiles indicate the deposition inside the mesopores up to 50 ALD cycles. Afterward, the interconnecting channels between the mesopores are filled completely prohibiting further transport of the gaseous TiO2 precursor into the ordered structure of mesopores and hence, limit the layer growth on the surfaces of the pores. Therefore, the size of the mesopores and their connections are decisive w...

Background Studies leading to the approval of trastuzumab emtansine (T-DM1) have been conducted without pertuzumab as previous therapy. Therefore data about patient characteristics and the efficacy of T-DM1 after a treatment with pertuzumab is scarce. Aim of this study was to analyze a real world patient cohort of advanced breast cancer (aBC) patients, who were treated with T-DM1 after a treatment containing pertuzumab in the metastatic setting with regard to patient characteristics and progression free survival (PFS). Methods The PRAEGNANT metastatic breast cancer registry (NCT02338167) is a prospective registry for metastatic breast cancer patients with focus on molecular biomarkers. Patients of all therapy lines with any kind of treatment are eligible for this registry. Collected data comprises all relevant patient and tumor characteristics, therapies, adverse events, quality of life, patient reported outcomes, response and survival (PFS/OS). Here we report on the patient characteristics and PFS data for HER2 positive patients treated with T-DM1 after a treatment with pertuzumab. Patients had to be included before or at the beginning of the T-DM1 therapy. Results A total of 58 patients could be identified, who were suitable for the analysis. Of those 34 were treated in the second line, 14 in the third line and 10 in the fourth line or higher. Most of the pertuzumab therapies before T-DM1 were conducted in first line (n=46; 79.3%). Median PFS for all patients was 4.8 months (95% CI: 3.0-7.8 months). Median PFS for patients treated in the 3rdline and 4thline or higher was 4.2 months(95%CI: 2.3 - NA) and 4.0 months (95%CI: 1.8-N.A.), respectively. In patients treated 2ndline with T-DM1 PFS was 7.7 months (95%CI: 2.8 – 12.2). Conclusion T-DM1 is effective as 2ndand further line therapy following pretreatment with pertuzumab. Overall PFS was about 5 months with 7.7 months as 2nd-line therapy. The PFS in higher therapy lines might be shorter. As the sample size of this real world cohort was rather low and analyses have to be considered exploratory, this data need to be confirmed in studies with a larger sample size. Citation Format: Schneeweiss A, Lux MP, Hartkopf AD, Volz B, Kolberg H-C, Hadji P, Tesch H, Haeberle L, Ettl J, Lüftner DI, Wallwiener M, Müller V, Beckmann MW, Belleville E, Wimberger P, Hielscher C, Geberth M, Lermann J, Abenhardt W, Kurbacher C, Wuerstlein R, Thomssen C, Untch M, Overkamp F, Huober J, Taran F-A, Janni W, Wallwiener D, Brucker SY, Fasching PA, Fehm TN. Progression free survival (PFS) and overall survival (OS) of patients treated with trastuzumab emtansine (T-DM1) after previous treatment with pertuzumab in patients with advanced breast cancer (NCT02338167) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-22.

Purpose: This analysis describes comprehensive real-world data concerning the use of anti-HER2 therapies in HER2 positive metastatic breast cancer (MBC). Specifically, it describes the therapy patterns of treatments with trastuzumab (TZM), pertuzumab+trastuzumab (PTZ/TZM), lapatinib (LAP) and trastuzumab emtansine (T-DM1). Methods: The PRAEGNANT study is a real-time, real-world registry for patients with MBC. Patients can be registered for PRAEGNANT at any time during the course of their metastatic disease and are followed up until death. All therapy lines are documented. This analysis presents the utilization of anti-HER2 therapies as well as therapy sequences. Results: Of 1936 patients within PRAEGNANT at the time of database closure 451 were HER2 positive (23.3%). Within the analysis set (417 patients after an unilateral breast cancer diagnosis), of which 53% were included in PRAEGNANT in the 1stline setting, 241 were treated with TZM (58%), 237 with PTZ (57%), 85 with LAP (20%) and 125 with T-DM1 (30%) during the course of their therapies. The sequence PTZ/TZMàT-DM1 was given to 51 patients (12%). Worse ECOG, negative hormone receptor status, and visceral or brain metastases were associated with a more frequent use of this therapy sequence. Most patients received T-DM1 after a therapy with pertuzumab. Conclusions: Both novel therapies (PTZ/TZM and T-DM1) are utilized in a high proportion of HER2 positive breast cancer patients. As most patients receive T-DM1 after pertuzumab real world data might help to understand whether this sequence has similar efficacy like in the approval study. Citation Format: Lux MP, Hartkopf AD, Huober J, Volz B, Taran F-A, Overkamp F, Hadji P, Tesch H, Haeberle L, Ettl J, Lueftner DI, Wallwiener M, Müller V, Beckmann MW, Belleville E, Wimberger P, Hielscher C, Geberth M, Lermann J, Abenhardt W, Kurbacher C, Wuerstlein R, Thomssen C, Untch M, Fasching PA, Janni W, Fehm TN, Wallwiener D, Brucker SY, Schneeweiss A, Kolberg H-C. Therapy landscape of patients with metastatic, HER2 positive breast cancer - Data from the real world breast cancer registry PRAEGNANT (NCT02338167) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-37.

We investigate the material properties of GaAsP graded buffers on both GaP and Si substrates in order to determine limitations to dislocation glide in GaAsP. Phase separation is not observed in these GaAsP buffers, but CuPtB atomic ordering is present, and has an impact on the Burgers vector distribution of gliding dislocations. Tellurium surfactant eliminates ordering in GaAsP, allowing control over the glide plane distribution while highlighting the importance of the growth surface and choice of dopant. The impact of single-variant CuPtB ordering of GaAsP buffers grown on GaP substrates is investigated by monitoring the threading dislocation density throughout the buffer in sequential steps. The dislocation density rises steadily throughout the graded buffer, implying that factors other than ordering-induced glide plane switches play a dominant role in the final dislocation density. We observe an increase in surface roughness throughout the buffer and speculate that a dislocation nucleation source on the surface has a low activation energy and may lead to increased threading dislocation density. On Si substrates, the GaAsP buffer displays dual-variant CuPtB ordering rather than single-variant ordering due to the surface step geometry. We discuss how dual-variant ordering leads to a variable glide force, and thus has a different impact on dislocation dynamics than single-variant ordering. Because the III-V on Si nucleation procedure determines the step geometry, it also influences the dislocation dynamics.

Ozone application has been suggested as an additional measure to the slaughter animals under hygiene programs. In this study, we determined the efficacy of gaseous ozone applied to pig carcasses during chilling (16 h at 2–5°C). Forty carcasses were allocated to each treatment: control, without ozone application (T1) and 5 ppm gaseous ozone application (T2), divided in two 4-h periods. The carcasses were sampled before and after chilling. The average counts of total aerobic mesophilic (TAM) bacteria before chilling were not different (p = 0.55) between T1 and T2. In turn, after chilling, the ozone-treated carcasses had significantly reduced about 0.4 colony-forming units (CFU)/cm2 of TAM counts (p

The Argentina Continental Margin represents a unique geologic setting to study interactions between bottom currents and sediment deposition as well as their impact on (bio)geochemical processes, particularly the cycling of iron (Fe). Our aim was to determine (1) how different depositional conditions control post-depositional (bio)geochemical processes and (2) how stable Fe isotopes (δ56Fe) of pore water and solid phases are affected accordingly. Furthermore, we (3) evaluated the applicability of δ56Fe of solid Fe pools as a proxy to trace past diagenetic alteration of Fe, which might be decoupled from current redox conditions. Sediments from two different depositional environments were sampled during RV SONNE expedition SO260: a site dominated by contouritic deposition on a terrace (Contourite Site) and the lower continental slope (Slope Site) dominated by hemipelagic sedimentation. Sequentially extracted sedimentary Fe [1] and δ56Fe analyses of extracts and pore water [2,3] were combined with sedimentological, radioisotope, geochemical and magnetic data. Our study presents the first sedimentary δ56Fe dataset at the Argentina Continental Margin.The depositional conditions differed between and within both sites as evidenced by variable grain sizes, organic carbon contents and sedimentation rates. At the Contourite Site, non-steady state pore-water conditions and diagenetic overprint occurs in the post-oxic zone and the sulfate-methane transition (SMT). In contrast, pore-water profiles at the Slope Site suggest that currently steady-state conditions prevail, leading to a strong diagenetic overprint of Fe oxides at the SMT. Pore-water δ56Fe values at the Slope Site are mostly negative, which is typical for on-going microbial Fe reduction. At the Contourite Site the pore-water δ56Fe values are mostly positive and range between -0.35‰ to 1.82‰. Positive δ56Fe values are related to high sulfate reduction rates that dominate over Fe reduction in the post-oxic zone. The HS- liberated during organoclastic sulfate reduction or sulfate-mediated anaerobic oxidation of methane (AOM) reacts with Fe2+ to form Fe sulfides. Hereby, light Fe isotopes are preferentially removed from the dissolved pool. The isotopically light Fe sulfides drive the acetate-leached Fe pool towards negative values. Isotopic trends were absent in other extracted Fe pools, partly due to unintended dissolution of silicate Fe masking the composition of targeted Fe oxides. Significant amounts of reactive Fe phases are preserved below the SMT and are possibly available for reduction processes, such as Fe-mediated AOM [4]. Fe2+ in the methanic zone is isotopically light at both sites, which is indicative for a microbial Fe reduction process.Our results demonstrate that depositional conditions exert a significant control on geochemical conditions and dominant (bio)geochemical processes in the sediments of both contrasting sites. We conclude that the applicability of sedimentary δ56Fe signatures as a proxy to trace diagenetic Fe overprint is limited to distinct Fe pools. The development into a useful tool depends on the refining of extraction methods or other means to analyse δ56Fe in specific sedimentary Fe phases. References:[1]Poulton and Canfield, 2005. Chemical Geology 214: 209-221.[2]Henkel et al., 2016. Chemical Geology 421: 93-102.[3]Homoky et al., 2013. Nature Communications 4: 1-10.[4]Riedinger et al., 2014. Geobiology 12: 172-181.

Chemicals are listed on California's Proposition 65 (Prop 65) for their potential to cause cancer, birth defects or other reproductive harm, and certain chemicals from this list are often detected within interior vehicle dust and air. Therefore, this study examined the potential risk associated with five Prop 65-listed chemicals detected within vehicle interiors: benzene, formaldehyde, di (2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP), and tris(1,3-dichloro-2-propyl)phosphate (TDCIPP). Exposure estimates based on time spent within a vehicle were derived from a meta-analysis of estimated concentrations from the literature. Regulatory levels established by the California Office of Environmental Health Hazard Assessment (OEHHA) were then used to generate percent reference doses (%RfDs) for chemical-specific daily doses as well as determine the probability of risk (exceedance probability) as a function of %RfD for each chemical-specific daily dose. Based on our meta-analysis, benzene and formaldehyde were detected in vehicle interior air whereas DEHP, DBP and TDCIPP were detected in vehicle interior dust. Benzene and formaldehyde were the only two chemicals with an estimated %RfD>100 across any of the commute times. For commute times of 20min or longer, the %RfD was>100 for maximum exposures based on the "maximum allowable daily level" for benzene, and for 95th-percentile exposures based on the "no significant risk level" for benzene and formaldehyde. Furthermore, the probability of exceeding 100% RfD was highest for cancer risks associated with benzene, followed by cancer risks associated with formaldehyde and the risk of reproductive and developmental toxicity associated with benzene. Lastly, within the entire state of California, the percent of commuters with a 10% probability of exceeding cancer risk associated with benzene or formaldehyde exposure was 78% and 63%, respectively. Overall, our study raises concerns about the potential risk associated with inhalation of benzene and formaldehyde for people who spend a significant amount of time in their vehicles, an issue that is especially pertinent to traffic-congested areas where people have longer commutes.

The severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) has emerged as the infectious agent causing the pandemic coronavirus disease 2019 (COVID-19) with dramatic consequences for global human health and economics. Previously, we reached clinical evaluation with our vector vaccine based on vaccinia virus MVA against the Middle East respiratory syndrome coronavirus (MERS-CoV), which causes an infection in humans similar to SARS and COVID-19. Here, we describe the construction and preclinical characterization of a recombinant MVA expressing full-length SARS-CoV-2 spike (S) protein (MVA-SARS-2-S). Genetic stability and growth characteristics of MVA-SARS-2-S, plus its robust synthesis of S antigen, make it a suitable candidate vaccine for industrial scale production. Vaccinated mice produced S antigen-specific CD8+ T cells and serum antibodies binding to S glycoprotein that neutralized SARS-CoV-2. Prime-boost vaccination with MVA-SARS-2-S protected mice sensitized with a human ACE2-expressing adenovirus from SARS-CoV-2 infection. MVA-SARS-2-S is currently being investigated in a phase I clinical trial as aspirant for developing a safe and efficacious vaccine against COVID-19.Significance StatementThe highly attenuated vaccinia virus MVA is licensed as smallpox vaccine, and as vector it is a component of the approved Adenovirus-MVA-based prime-boost vaccine against Ebola virus disease. Here we provide results from testing the COVID-19 candidate vaccine MVA-SARS-2-S, a poxvirus-based vector vaccine that proceeded to clinical evaluation. When administered by intramuscular inoculation, MVA-SARS-2-S expresses and safely delivers the full-length SARS-CoV-2 spike (S) protein, inducing balanced SARS-CoV-2-specific cellular and humoral immunity, and protective efficacy in vaccinated mice. Substantial clinical experience has already been gained with MVA vectors using homologous and heterologous prime-boost applications, including the immunization of children and immunocompromised individuals. Thus, MVA-SARS-2-S represents an important resource for developing further optimized COVID-19 vaccines.

Radiation therapy using protons and heavier ions is a fast-growing therapeutic option for cancer patients. A clinical system for particle imaging in particle therapy would enable online patient position verification, estimation of the dose deposition through range monitoring and a reduction of uncertainties in the calculation of the relative stopping power of the patient. Several prototype imaging modalities offer radiography and computed tomography using protons and heavy ions. A Digital Tracking Calorimeter (DTC), currently under development, has been proposed as one such detector. In the DTC 43 longitudinal layers of laterally stacked ALPIDE CMOS monolithic active pixel sensor chips are able to reconstruct a large number of simultaneously recorded proton tracks. In this study, we explored the capability of the DTC for helium imaging which offers favorable spatial resolution over proton imaging. Helium ions exhibit a larger cross section for inelastic nuclear interactions, increasing the number of produced secondaries in the imaged object and in the detector itself. To that end, a filtering process able to remove a large fraction of the secondaries was identified, and the track reconstruction process was adapted for helium ions. By filtering on the energy loss along the tracks, on the incoming angle and on the particle ranges, 97.5% of the secondaries were removed. After passing through 16 cm water, 50.0% of the primary helium ions survived; after the proposed filtering 42.4% of the primaries remained; finally after subsequent image reconstruction 31% of the primaries remained. Helium track reconstruction leads to more track matching errors compared to protons due to the increased available focus strength of the helium beam. In a head phantom radiograph, the Water Equivalent Path Length error envelope was 1.0 mm for helium and 1.1 mm for protons. This accuracy is expected to be sufficient for helium imaging for pre-treatment verification purposes.

To develop new and flexible CuI containing luminescent substances, we extend our previous investigations on two metal‐centered species to four metal‐centered complexes. These complexes could be a basis for designing new organic light‐emitting diode (OLED) relevant species. Both the synthesis and in‐depth spectroscopic analysis, combined with high‐level theoretical calculations are presented on a series of tetranuclear CuI complexes with a halide containing Cu4X4 core (X=iodide, bromide or chloride) and two 2‐(diphenylphosphino)pyridine bridging ligands with a methyl group in para (4‐Me) or ortho (6‐Me) position of the pyridine ring. The structure of the electronic ground state is characterized by X‐ray diffraction, NMR, and IR spectroscopy with the support of theoretical calculations. In contrast to the para system, the complexes with ortho‐substituted bridging ligands show a remarkable and reversible temperature‐dependent dual phosphorescence. Here, we combine for the first time the luminescence thermochromism with time‐resolved FTIR spectroscopy. Thus, we receive experimental data on the structures of the two triplet states involved in the luminescence thermochromism. The transient IR spectra of the underlying triplet metal/halide‐to‐ligand charge transfer (3 m/XLCT) and cluster‐centered (3CC) states were obtained and interpreted by comparison with calculated vibrational spectra. The systematic and significant dependence of the bridging halides was analyzed., Highly luminescent! The synthesis and an in‐depth photophysical characterization of highly luminescent tetranuclear CuI complexes are presented. For these promising candidates for organic light‐emitting diodes, a pronounced luminescence thermochromism with clearly separated emission bands is observed. The corresponding excited state structures are determined by applying temperature‐dependent time‐resolved step‐scan FTIR spectroscopy in combination with DFT calculations.

Graphical abstract, Highlights • Human (HepG2) cells were exposed to PPARγ ligands to induce systems-level effects. • Ciglitazone decreases HepG2 cell viability while GW 9662 had no effect. • Ciglitazone and GW 9662 increase neutral lipids as a function of concentration. • Cholesterol biosynthesis transcripts are affected by ciglitazone and GW 9662. • Ciglitazone alters lipid profiles but GW 9662 was similar to vehicle-exposed cells., Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor that, upon activation by ligands, heterodimerizes with retinoid X receptor (RXR), binds to PPAR response elements (PPREs), and activates transcription of downstream genes. As PPARγ plays a central role in adipogenesis, fatty acid storage, and glucose metabolism, PPARγ-specific pharmaceuticals (e.g., thiazolidinediones) have been developed to treat Type II diabetes and obesity within human populations. However, to our knowledge, no prior studies have concurrently assessed the effects of PPARγ ligand exposure on genome-wide PPARγ binding as well as effects on the transcriptome and lipidome within human cells at biologically active, non-cytotoxic concentrations. In addition to quantifying concentration-dependent effects of ciglitazone (a reference PPARγ agonist) and GW 9662 (a reference PPARγ antagonist) on human hepatocarcinoma (HepG2) cell viability, PPARγ abundance in situ, and neutral lipids, HepG2 cells were exposed to either vehicle (0.1% DMSO), ciglitazone, or GW 9662 for up to 24 h, and then harvested for 1) chromatin immunoprecipitation-sequencing (ChIP-seq) to identify PPARγ-bound regions across the entire genome, 2) mRNA-sequencing (mRNA-seq) to identify potential impacts on the transcriptome, and 3) lipidomics to identify potential alterations in lipid profiles. Following exposure to ciglitazone and GW 9662, we found that PPARγ levels were not significantly different after 2–8 h of exposure. While ciglitazone and GW 9662 resulted in a concentration-dependent increase in neutral lipids, the magnitude and localization of PPARγ-bound regions across the genome (as identified by ChIP-seq) did not vary by treatment. However, mRNA-seq and lipidomics revealed that exposure of HepG2 cells to ciglitazone and GW 9662 resulted in significant, treatment-specific effects on the transcriptome and lipidome. Overall, our findings suggest that exposure of human cells to PPARγ ligands at biologically active, non-cytotoxic concentrations results in toxicity that may be driven by a combination of both PPARγ-dependent and PPARγ-independent mechanisms.

Journal of materials research : JMR (2021). doi:10.1557/s43578-021-00221-6, Published by Springer, Berlin

Bitopertin is a small molecule selective inhibitor of glycine transporter 1 (GlyT1), initially developed to increase brain extracellular levels of glycine in the vicinity of neuronal N-methyl-D-aspartate receptors for the treatment of schizophrenia. GlyT1, the pharmacological target of bitopertin, is also present as a transmembrane transporter in erythroid cells1 and accounts for 50–55% of glycine uptake in human red blood cells (RBCs).2, 3 Erythroid GlyT1 inhibition by bitopertin leads to reduced intracellular glycine availability, interfering with the first step of haem synthesis, in which 5-aminolevulinate synthase catalyses the condensation reaction between glycine and succinyl-coenzyme A, forming 5-aminolevulinic acid.1

Heat conduction in silicon can be effectively engineered by means of sub-micrometre porous thin free-standing membranes. Tunable thermal properties make these structures good candidates for integrated heat management units such as waste heat recovery, rectification or efficient heat dissipation. However, possible applications require detailed thermal characterisation at high temperatures which, up to now, has been an experimental challenge. In this work we use the contactless two-laser Raman thermometry to study heat dissipation in periodic porous membranes at high temperatures via lattice conduction and air-mediated losses. We find the reduction of the thermal conductivity and its temperature dependence closely correlated with the structure feature size. On the basis of two-phonon Raman spectra, we attribute this behaviour to diffuse (incoherent) phonon-boundary scattering. Furthermore, we investigate and quantify the heat dissipation via natural air-mediated cooling, which can be tuned by engineering the porosity., Nanostructuring of silicon allows acoustic phonon engineering, but the mechanism of related thermal transport in these structures is not fully understood. Here, the authors study the heat dissipation in silicon membranes with periodic nanoholes and show the importance of incoherent scattering.

Plants exude secondary metabolites from the roots to shape the composition and function of their microbiome. Many of these compounds are known for their anti-microbial activity and are part of the plant immunity, such as the indole-derived phytoalexin camalexin. Here we studied the dynamics of camalexin synthesis and exudation upon induction of Arabidopsis thaliana with a plant growth promotion bacteria Pseudomonas sp. CH267 or a bacterial pathogen Burkholderia glumae PG1. We show that while the camalexin accumulation and exudation is more rapidly but transiently induced upon interaction with the growth promoting strain, the pathogen induces a higher and more stable camalexin levels. The concentration of camalexin in shoots, roots and exudates is well correlated, triggering a question on the origin of the exuded camalexin. By combination of experiments with cut shoots and roots and grafting of wild type plant with mutants in camalexin synthesis we showed that while camalexin can be produced and released by both organs, in intact plant the exuded camalexin originates in the shoots. We show that camalexin synthesis in response to B. glumae PG1 is dependent on cooperation of four CYP71 genes and a loss of function of any of them reduces camalexin synthesis. In conclusion, camalexin synthesis seems to be controlled on a whole plant level and coordinated between shoots and roots.

Polycyclic aromatic hydrocarbons (PAHs) are pervasive pollutants in aquatic ecosystems, and developing fish embryos are especially sensitive to PAH exposure. Exposure to crude oil or phenanthrene (a reference PAH found in oil) produces an array of gross morphological abnormalities in developing fish embryos, including cardiotoxicity. Recently, studies utilizing transcriptomic analyses in several oil-exposed fish embryos found significant changes in the abundance of transcripts involved in cholesterol biosynthesis. Given the vital role of cholesterol availability in embryonic heart development, we hypothesized that cholesterol dysregulation in early development contributes to phenanthrene-induced cardiotoxicity. We exposed zebrafish embryos to 12 or 15 µM phenanthrene from 6 to 72 h post fertilization (hpf) and demonstrated that, in conjunction with pericardial edema and bradycardia, several genes (fdft1 and hmgcra) in the cholesterol biosynthetic pathway were significantly altered. When embryos were pretreated with a cholesterol solution from 6 to 24 hpf followed by exposure to phenanthrene from 24 to 48 hpf, the effects of phenanthrene on heart rate were partially mitigated. Despite changes in gene expression, whole-mount in situ staining of cholesterol was not significantly affected in embryos exposed to phenanthrene ranging in stage from 24 to 72 hpf. However, the 2-dimensional yolk area was significantly increased with phenanthrene exposure at 72 hpf, suggesting that lipid transport from the yolk to the developing embryo was impaired. Environ Toxicol Chem 2021;40:1586-1595. © 2021 SETAC.

Hydrodynamic phonon transport in solids exhibits unique thermal transport behaviors, such as second sound, the Poiseuille flow, and ultrahigh thermal conductivity. However, those have been limited up to the cryogenic temperature ($\ensuremath{\sim}1$ K) for a few materials. In this work, by employing the phonon Boltzmann transport equation, we demonstrate hydrodynamic phonon transport in organic systems such as bulk crystalline polymers. Remarkable hydrodynamic phonon transport up to 50 K is demonstrated for both polyacene ${(\ensuremath{-}{\mathrm{C}}_{4}{\mathrm{H}}_{2}\ensuremath{-})}_{n}$ and polyacetylene ${(\ensuremath{-}{\mathrm{C}}_{2}{\mathrm{H}}_{2}\ensuremath{-})}_{n}$ crystals. More interestingly, a weak phonon hydrodynamic behavior takes place in crystalline polyethylene ${(\ensuremath{-}{\mathrm{C}}_{2}{\mathrm{H}}_{4}\ensuremath{-})}_{n}$ in the intermediate-temperature range around 120 K, different from the observed hydrodynamics in most systems. The spectral phonon analysis reveals that the torsional motion of the ${A}_{2}$ mode causes this unique hydrodynamic behavior. A modified criterion for the emergence of hydrodynamic phonon transport is proposed which agrees quantitatively with the results from thermal conductivity and phonon drifting component calculations. This study provides physical insights into the understanding of phonon hydrodynamics in organic materials and also a reliable criterion to probe the hydrodynamic phonon transport in complex systems.

SUMMARYMenthol is widely used in tobacco products. This study compared the effects of menthol on human bronchial epithelium using submerged cultures, a VITROCELL® cloud chamber that provides air liquid interface (ALI) exposure without solvents or heating, and a Cultex ALI system that delivers aerosol equivalent to that inhaled during vaping. In submerged culture, menthol significantly increased calcium influx and mitochondrial reactive oxygen species (ROS) via the TRPM8 receptor, responses that were inhibited by a TRPM8 antagonist. VITROCELL® cloud chamber exposure of BEAS-2B monolayers increased mitochondrial protein oxidation, expression of the antioxidant enzyme SOD2, activation of NF-κB, and secretion of inflammatory cytokines (IL-6 and IL-8). Proteomics data collected following ALI exposure of 3D EpiAirway tissue in the Cultex showed upregulation of NRF-2-mediated oxidative stress, oxidative phosphorylation, and IL-8 signaling. Across the three platforms, menthol adversely effected human bronchial epithelium in a manner that could lead to respiratory disease. Graphical Abstract. Mechanism of action of menthol on human bronchial epithelium.Three in vitro platforms were used to study the effect of menthol on bronchial epithelium. In submerged culture (using BEAS-2B cells), menthol produced rapid calcium influx followed by an increase in oxidative stress and inflammatory cytokines. ALI exposure of BEAS-2B cells to unheated menthol in a cloud chamber caused activation of an inflammatory transcription factor (NF-κB) and oxidative stress. Proteomics analysis of human EpiAirway tissues exposed at the ALI to heated menthol EC aerosols identified changes in the expression of proteins involved in oxidative stress and in an inflammatory response.

In this report, we present bulk solid-phase major and minor element contents and Fe and S species in sediments from Site M0060 in the Anholt Basin recovered during Integrated Ocean Drilling Program Expedition 347 to the Baltic Sea. Site M0060 is characterized by alternating sand- and clay-/silt-dominated sediment sequences that indicate deposition under brackish-marine and limnic conditions, respectively. We use Al-normalized elemental ratios and transition metal data to characterize the different sediment sequences and to study the impact of early diagenetic processes on the abundance and reactivity of Fe oxide and Fe sulfide mineral phases across lithologic boundaries. Ratios of Fe/Al and Mn/Al exceed the continental crustal average in the clay-/silt-dominated sequences, whereas low ratios are associated with the sandy units. About 10%–20% of the total bulk Fe content is associated with Fe oxides and Fe sulfides, whereas the major Fe fraction is bound in clay minerals. The transition metals (V, Ni, Cr, and Co) correlate with the depth profile of Fe/Al, which indicates that they are adsorbed onto Fe oxides and concomitantly deposited. Sequential leaching reveals that magnetite is the most abundant Fe oxide phase. Leached contents approach 1 wt% followed by crystalline and easily reducible Fe oxides. Pyrite is the dominant Fe sulfide phase and is enriched at several lithologic boundaries that can likely be associated with the formation of pyrite. Pyrite is formed through the reaction of Fe monosulfides with (1) polysulfides and/or S0 in zones dominated by organoclastic sulfate and Fe oxide reduction and (2) sulfide released during the anaerobic oxidation of methane.

Highly-mismatched III-V semiconductor alloys containing dilute concentrations of bismuth (Bi) have attracted significant attention in recent years since their unique electronic properties open up a range of possibilities for practical applications in semiconductor lasers, photovoltaics, spintronics, photodiodes, and thermoelectrics. Research on dilute bismide alloys has primarily focused to date on $\text{GaAs}_{1-x}\text{Bi}_{x}$ , where incorporation of Bi brings about a strong reduction of the direct $\Gamma$ -point band gap ( $E_{g}{}^{\Gamma}$ ) –by up to 90 meV per % Bi at low Bi compositions $x$ –characterised by strong, composition-dependent bowing. This unusual behaviour derives from the large differences in size (covalent radius) and chemical properties (electronegativity) between As and Bi.Bi, being significantly larger and more electropositive than As, acts as an isovalent impurity which primarily impacts and strongly perturbs the valence band (VB) structure. This is in contrast to dilute nitride alloys, in which small electronegative nitrogen (N) atoms strongly perturb the conduction band (CB) structure in $\text{GaN}_{x}\text{As}_{1-x}$ and related alloys. Additionally, Bi, being the largest stable group-V element, has strong relativistic (spin-orbit coupling) effects. As such, the reduction of $E_{g}{}^{\Gamma}$ in $(\text{In})\text{GaAs}_{1-x}\text{Bi}_{x}$ is accompanied by a strong increase in the VB spin-orbit splitting energy ( $\Delta_{\text{SO}}$ ).

Epitaxial III-V on silicon multi-junction solar cells allow to increase the conversion efficiency of single-junction silicon devices. We report progress on the development of high-efficiency GaInP/GaAs/Si triple-junction devices over the last two years. The AM1.5g conversion efficiency has been increased from 19.7% to 22.3%, 24.3%, and finally a value of 25.9% could be achieved. The improvement was enabled by a reduction of nucleation-related crystal defects in the silicon to gallium phosphide transition and a reduction of parasitic absorption within the metamorphic GaAsP buffer structure which was limiting the current in the silicon subcell. By increasing the bandgaps in the graded buffer structure, a ∼2x reduction of the threading dislocation density was observed and the short-circuit current density increased by 22% relative. A majority barrier was identified and could be suppressed to obtain a new record conversion efficiency of 25.9% with an open-circuit voltage of 2.647 V, a short-circuit current density of 12.2 mA/cm2 and a fill factor of 80.2%.