AbstactThe growing prevalence of synthetically modified proteins in pharmaceuticals and materials has exposed the need for efficient strategies to enable chemical modifications with high ...site-selectivity. While genetic engineering can incorporate non-natural amino acids into recombinant proteins, regioselective chemical modification of wild-type proteins remains a challenge. Herein, we use photoredox catalysis to develop a site-selective tyrosine bioconjugation pathway that incorporates bioorthogonal formyl groups, which subsequently allows for the synthesis of structurally defined fluorescent conjugates from native proteins. A water-soluble photocatalyst, lumiflavin, has been shown to induce oxidative coupling between a previously unreported phenoxazine dialdehyde tag and a single tyrosine site, even in the presence of multiple tyrosyl side chains, through the formation of a covalent C–N bond. A variety of native proteins, including those with multiple tyrosines, can successfully undergo both tyrosine-specific and single-site-selective labelling. This technology directly introduces aldehyde moieties onto native proteins, enabling rapid product diversification using an array of well-established bioorthogonal functionalization protocols including the alkyne–azide click reaction.Regioselective chemical modification of wild-type proteins remains challenging. Now, by harnessing the varied SOMOphilicity of native tyrosine residues through photoredox catalysis, a site-selective bioconjugation method has been developed. This technology directly incorporates bioorthogonal formyl groups in one step, forming structurally defined fluorescent conjugates that can be rapidly diversified to biorelevant products.
Bioconjugation technologies have revolutionized the practice of biology and medicine by allowing access to novel biomolecular scaffolds. New methods for residue-selective bioconjugation are highly ...sought to expand the toolbox for a variety of bioconjugation applications. Herein we report a site-selective methionine bioconjugation protocol that uses photoexcited lumiflavin to generate open-shell intermediates. This reduction-potential-gated strategy enables access to residues unavailable with traditional nucleophilicity-based conjugation methods. To demonstrate the versatility and robustness of this new protocol, we have modified various proteins and further utilized this functional handle to append diverse biological payloads.
The performance of semiconductor devices is fundamentally governed by charge-carrier dynamics within the active materials1–6. Although advances have been made towards understanding these dynamics ...under steady-state conditions, the importance of non-equilibrium phenomena and their effect on device performances remains elusive7,8. In fact, the ballistic propagation of carriers is generally considered to not contribute to the mechanism of photovoltaics (PVs) and light-emitting diodes, as scattering rapidly disrupts such processes after carrier generation via photon absorption or electric injection9. Here we characterize the spatiotemporal dynamics of carriers immediately after photon absorption in methylammonium lead iodide perovskite films using femtosecond transient absorption microscopy (fs-TAM) with a 10 fs temporal resolution and 10 nm spatial precision. We found that non-equilibrium carriers propagate ballistically over 150 nm within 20 fs of photon absorption. Our results suggest that in a typical perovskite PV device operating under standard conditions, a large fraction of carriers can reach the charge collection layers ballistically. The ballistic transport distance appears to be limited by energetic disorder within the materials, probably due to disorder-induced scattering. This provides a direct route towards optimization of the ballistic transport distance via improvements in materials and by minimizing the energetic disorder. Our observations reveal an unexplored regime of carrier transport in perovskites, which could have important consequences for device performance.Charge-carrier dynamics are fundamental to the operation and performance of semiconductor devices. In methylammonium lead iodide perovskites, carriers in the non-equilibrium regime after excitation propagate ballistically over 150 nm within 20 fs.
This paper presents a new energy-based failure criterion that is based on the simplified viscoelastic continuum damage model. This study found that the average reduction in pseudo stiffness up to ...failure, referred to here as D
R
, is a material constant that is independent of mode of loading, temperature, and stress/strain amplitude. Twenty different asphalt mixtures were used to validate the proposed method. This paper presents typical values of D
R
and shows that the D
R
changes with the mixture characteristics. The advantages of the D
R
failure criterion over a previous failure criterion (known as the G
R
criterion) are that it: (1) allows the prediction of fatigue failure in arithmetic scale, which reduces possible errors due to extrapolation of the accelerated laboratory fatigue test data to realistic traffic volumes encountered in the field and (2) reduces the number of tests required to characterise the failure criterion. Statistical analysis was performed in this study and the results show confidence levels that can be obtained from two or three fatigue tests.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Chronic obstructive pulmonary disease (COPD) is the third commonest cause of death globally, and manifests as a progressive inflammatory lung disease with no curative treatment. The lung microbiome ...contributes to COPD progression, but the function of the gut microbiome remains unclear. Here we examine the faecal microbiome and metabolome of COPD patients and healthy controls, finding 146 bacterial species differing between the two groups. Several species, including Streptococcus sp000187445, Streptococcus vestibularis and multiple members of the family Lachnospiraceae, also correlate with reduced lung function. Untargeted metabolomics identifies a COPD signature comprising 46% lipid, 20% xenobiotic and 20% amino acid related metabolites. Furthermore, we describe a disease-associated network connecting Streptococcus parasanguinis_B with COPD-associated metabolites, including N-acetylglutamate and its analogue N-carbamoylglutamate. While correlative, our results suggest that the faecal microbiome and metabolome of COPD patients are distinct from those of healthy individuals, and may thus aid in the search for biomarkers for COPD.
Kim and Oliver discuss the study by Salih et al which present data that begin to shed light on the complex innate immune reprogramming of macrophages in chronic obstructive pulmonary disease (COPD). ...They first transcriptionally profile bone marrow--derived macrophages (BMDMs) in an in vivo model of COPD. They demonstrate that several genes were alternatively spliced following in vivo cigarette smoke exposure. The study provides new clues to the old question of why and how macrophage function is dysregulated in COPD.
Over recent years, significant research has been conducted to investigate ways to predict fatigue cracking and permanent deformation (rutting), which are two common distresses found in asphalt ...pavements. These distresses are affected by material properties, environmental conditions, and the pavement’s structure. This paper investigates common pavement design parameters, including surface mixture type, base layer thickness, base layer type, sub-base layer thickness, and an anti-frost layer, with regard to the asphalt pavement performance of the Korea Expressway Corporation (KEC) test road. Test roads are often regarded as the most realistic tools for evaluating the effects of various parameters because they are subjected to real traffic and environmental factors. The KEC test road is 7.7 km long and was constructed with the aim of developing a Korean mechanistic-empirical pavement design guide. According to the findings, the surface layer type, base layer thickness, and base layer material type were found to affect the fatigue cracking and rutting performance, whereas the sub-base thickness and anti-frost layer were found not to affect the amount of distress significantly. The newly developed ‘layered viscoelastic pavement analysis for critical distresses’ (LVECD) program was able to capture the effects of the changes in the aforementioned parameters on the amount of cracking and rut depths. Reasonable agreement was found between the LVECD predictions and the field distress measurements. However, it remains necessary to develop a laboratory-to-field transfer function in order to obtain more accurate field performance predictions.
Background Cigarette smoke–induced chronic obstructive pulmonary disease (COPD) is a life-threatening inflammatory disorder of the lung. The development of effective therapies for COPD has been ...hampered by the lack of an animal model that mimics the human disease in a short timeframe. Objectives We sought to create an early-onset mouse model of cigarette smoke–induced COPD that develops the hallmark features of the human condition in a short time-frame. We also sought to use this model to better understand pathogenesis and the roles of macrophages and mast cells (MCs) in patients with COPD. Methods Tightly controlled amounts of cigarette smoke were delivered to the airways of mice, and the development of the pathologic features of COPD was assessed. The roles of macrophages and MC tryptase in pathogenesis were evaluated by using depletion and in vitro studies and MC protease 6–deficient mice. Results After just 8 weeks of smoke exposure, wild-type mice had chronic inflammation, mucus hypersecretion, airway remodeling, emphysema, and reduced lung function. These characteristic features of COPD were glucocorticoid resistant and did not spontaneously resolve. Systemic effects on skeletal muscle and the heart and increased susceptibility to respiratory tract infections also were observed. Macrophages and tryptase-expressing MCs were required for the development of COPD. Recombinant MC tryptase induced proinflammatory responses from cultured macrophages. Conclusion A short-term mouse model of cigarette smoke–induced COPD was developed in which the characteristic features of the disease were induced more rapidly than in existing models. The model can be used to better understand COPD pathogenesis, and we show a requirement for macrophages and tryptase-expressing MCs.
We explore potential dysregulation of macrophage phenotypes in COPD pathogenesis through integrated study of human small airway tissue, bronchoalveolar lavage (BAL) and an experimental murine model ...of COPD. We evaluated human airway tissue and BAL from healthy controls, normal lung function smokers (NLFS), and COPD subjects. Both small airways and BAL cells were immunohistochemically stained with anti-CD68 for total macrophages and with anti-CD163 for M2, and anti-iNOS for M1 macrophages. Multiplex ELISA measured BAL cytokines. Comparable cigarette smoke-induced experimental COPD mouse model was assessed for relevant mRNA profiles. We found an increase in pro-inflammatory M1s in the small airways of NLFS and COPD compared to controls with a reciprocal decrease in M2 macrophages, which remained unchanged among pathological groups. However, luminal macrophages showed a dominant M2 phenotype in both NLFS and COPD subjects. BAL cytokine skewed towards an M2 profile with increase in CCL22, IL-4, IL-13, and IL-10 in both NLFS and COPDs. The mouse-model of COPD showed similar increase in mRNA for M2 markers. Our finding suggests abnormal macrophage switching in both mucosal and luminal areas of COPD patients, that strongly associated with cytokine balance. There may be potential for beneficial therapeutic cytokine manipulation of macrophage phenotypes in COPD.
Over the last several decades, significant research has been conducted to predict the fatigue cracking performance of asphalt pavements. Recently, the simplified viscoelastic continuum damage ...(S-VECD) model was developed as an efficient method of characterising the fatigue performance of asphalt mixtures under a wide range of loading conditions. Two important material properties that can be determined from the S-VECD model are the damage characteristic curve that defines how damage evolves in a specimen and the energy-based failure criterion that defines when the specimen fails. These two material functions are unique for a given mixture regardless of temperature, mode of loading, stress/strain amplitude and loading history. This study presents the application of the Layered Viscoelastic Crirtical Distresses (LVECD) programme to predict the fatigue performance of 18 pavement sections from different locations in the United States and Canada. The capability of the LVECD programme to capture crack initiation, crack propagation and damage in the pavement sections is investigated by comparing the simulation results with field observations. This study found reasonable agreement in trends between the damage growth throughout the pavement cross sections as predicted by the LVECD programme and the surface crack growth as evidenced by field observations.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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