Self-assembly provides an attractive route to functional organic materials, with properties and hence performance depending sensitively on the organization of the molecular building blocks. Molecular ...organization is a direct consequence of the pathways involved in the supramolecular assembly process, which is more amenable to detailed study when using one-dimensional systems. In the case of protein fibrils, formation and growth have been attributed to complex aggregation pathways that go beyond traditional concepts of homogeneous and secondary nucleation events. The self-assembly of synthetic supramolecular polymers has also been studied and even modulated, but our quantitative understanding of the processes involved remains limited. Here we report time-resolved observations of the formation of supramolecular polymers from π-conjugated oligomers. Our kinetic experiments show the presence of a kinetically favoured metastable assembly that forms quickly but then transforms into the thermodynamically favoured form. Quantitative insight into the kinetic experiments was obtained from kinetic model calculations, which revealed two parallel and competing pathways leading to assemblies with opposite helicity. These insights prompt us to use a chiral tartaric acid as an auxiliary to change the thermodynamic preference of the assembly process. We find that we can force aggregation completely down the kinetically favoured pathway so that, on removal of the auxiliary, we obtain only metastable assemblies.
Chronic liver inflammation drives hepatic fibrosis,and current immunosuppressive,anti-inflammatory,and anti-viral therapies can weaken this driver.Hepatic fibrosis is reversed,stabilized,or prevented ...in 57%-79%of patients by conventional treatment regimens,mainly by their anti-inflammatory actions.Responses,however,are commonly incomplete and inconsistently achieved.The fibrotic mechanisms associated with liver inflammation have been clarified,and anti-fibrotic agents promise to improve outcomes as adjunctive therapies.Hepatitis C virus and immune-mediated responses can activate hepatic stellate cells by increasing oxidative stress within hepatocytes.Angiotensin can be synthesized by activated hepatic stellate cells and promote the production of reactive oxygen species.Anti-oxidants(Nacetylcysteine,S-adenosyl-L-methionine,and vitamin E)and angiotensin inhibitors(losartin)have had antifibrotic actions in preliminary human studies,and they may emerge as supplemental therapies.Anti-fibrotic agents presage a new era of supplemental treatment for chronic liver disease.
Proteomics beyond trypsin Tsiatsiani, Liana; Heck, Albert J. R
The FEBS journal,
July 2015, Letnik:
282, Številka:
14
Journal Article
Recenzirano
Odprti dostop
Peptide‐centered shotgun analysis of proteins has been the core technology in mass spectrometry based proteomics and has enabled numerous biological discoveries, such as the large‐scale charting of ...protein–protein interaction networks, the quantitative analysis of protein post‐translational modifications and even the first drafts of the human proteome. The conversion of proteins into peptides in these so‐called bottom‐up approaches is nearly uniquely done by using trypsin as a proteolytic reagent. Here, we argue that our view of the proteome still remains incomplete and this is partially due to the nearly exclusive use of trypsin. Newly emerging alternative proteases and/or multi‐protease protein digestion aim to increase proteome sequence coverage and improve the identification of post‐translational modifications, through the analysis of complementary and often longer peptides, introducing an approach termed middle‐down proteomics. Of pivotal importance for this purpose is the identification of proteases beneficial for use in proteomics. Here, we describe some of the shortcomings of the nearly exclusive use of trypsin in proteomics and review the properties of other proteomics‐appropriate proteases. We describe favorable protease traits with an emphasis on middle‐down proteomics and suggest potential sources for the discovery of new proteases. We also highlight a few examples wherein the use of other proteases than trypsin enabled the generation of more comprehensive data sets leading to previously unexplored knowledge of the proteome.
High-Resolution Native Mass Spectrometry Tamara, Sem; den Boer, Maurits A; Heck, Albert J. R
Chemical reviews,
04/2022, Letnik:
122, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Native mass spectrometry (MS) involves the analysis and characterization of macromolecules, predominantly intact proteins and protein complexes, whereby as much as possible the native structural ...features of the analytes are retained. As such, native MS enables the study of secondary, tertiary, and even quaternary structure of proteins and other biomolecules. Native MS represents a relatively recent addition to the analytical toolbox of mass spectrometry and has over the past decade experienced immense growth, especially in enhancing sensitivity and resolving power but also in ease of use. With the advent of dedicated mass analyzers, sample preparation and separation approaches, targeted fragmentation techniques, and software solutions, the number of practitioners and novel applications has risen in both academia and industry. This review focuses on recent developments, particularly in high-resolution native MS, describing applications in the structural analysis of protein assemblies, proteoform profiling ofamong othersbiopharmaceuticals and plasma proteins, and quantitative and qualitative analysis of protein–ligand interactions, with the latter covering lipid, drug, and carbohydrate molecules, to name a few.
ASPM (known as Asp in fly and ASPM-1 in worm) is a microcephaly-associated protein family that regulates spindle architecture, but the underlying mechanism is poorly understood. Here, we show that ...ASPM forms a complex with another protein linked to microcephaly, the microtubule-severing ATPase katanin. ASPM and katanin localize to spindle poles in a mutually dependent manner and regulate spindle flux. X-ray crystallography revealed that the heterodimer formed by the N- and C-terminal domains of the katanin subunits p60 and p80, respectively, binds conserved motifs in ASPM. Reconstitution experiments demonstrated that ASPM autonomously tracks growing microtubule minus ends and inhibits their growth, while katanin decorates and bends both ends of dynamic microtubules and potentiates the minus-end blocking activity of ASPM. ASPM also binds along microtubules, recruits katanin and promotes katanin-mediated severing of dynamic microtubules. We propose that the ASPM-katanin complex controls microtubule disassembly at spindle poles and that misregulation of this process can lead to microcephaly.
I review the recent high-frequency trader (HFT) literature to single out the economic channels by which HFTs affect market quality. I first group the various theoretical studies according to common ...denominators and discuss the economic costs and benefits they identify. For each group, I then review the empirical literature that speaks to either the models' assumptions or their predictions. This enables me to come to a data-weighted judgement on the economic value of HFTs.
This paper characterizes the trading strategy of a large high frequency trader (HFT). The HFT incurs a loss on its inventory but earns a profit on the bid–ask spread. Sharpe ratio calculations show ...that performance is very sensitive to cost of capital assumptions. The HFT employs a cross-market strategy as half of its trades materialize on the incumbent market and the other half on a small, high-growth entrant market. Its trade participation rate in these markets is 8.1% and 64.4%, respectively. In both markets, four out of five of its trades are passive i.e., its price quote was consumed by others.
Native Mass Spectrometry: What is in the Name? Leney, Aneika C.; Heck, Albert J. R.
Journal of the American Society for Mass Spectrometry,
01/2017, Letnik:
28, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Electrospray ionization mass spectrometry (ESI-MS) is nowadays one of the cornerstones of biomolecular mass spectrometry and proteomics. Advances in sample preparation and mass analyzers have enabled ...researchers to extract much more information from biological samples than just the molecular weight. In particular, relevant for structural biology, noncovalent protein–protein and protein–ligand complexes can now also be analyzed by MS. For these types of analyses, assemblies need to be retained in their native quaternary state in the gas phase. This initial small niche of biomolecular mass spectrometry, nowadays often referred to as “native MS,” has come to maturation over the last two decades, with dozens of laboratories using it to study mostly protein assemblies, but also DNA and RNA-protein assemblies, with the goal to define structure–function relationships. In this perspective, we describe the origins of and (re)define the term native MS, portraying in detail what we meant by “native MS,” when the term was coined and also describing what it does (according to us) not entail. Additionally, we describe a few examples highlighting what native MS is, showing its successes to date while illustrating the wide scope this technology has in solving complex biological questions.
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Blended learning combines online digital resources with traditional classroom activities and enables students to attain higher learning performance through well-defined interactive strategies ...involving online and traditional learning activities. Learning analytics is a conceptual framework and as a part of our Precision education used to analyze and predict students' performance and provide timely interventions based on student learning profiles. This study applied learning analytics and educational big data approaches for the early prediction of students' final academic performance in a blended Calculus course. Real data with 21 variables were collected from the proposed course, consisting of video-viewing behaviors, out-of-class practice behaviors, homework and quiz scores, and after-school tutoring. This study applied principal component regression to predict students' final academic performance. The experimental results show that students' final academic performance could be predicted when only one-third of the semester had elapsed. In addition, we identified seven critical factors that affect students' academic performance, consisting of four online factors and three traditional factors. The results showed that the blended data set combining online and traditional critical factors had the highest predictive performance.
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