High Versatility of IPP and DMAPP Methyltransferases Enables Synthesis of C6, C7 and C8 Terpenoid Building Blocks

The natural substance class of terpenoids covers an extremely wide range of different structures, although their building block repertoire is limited to the C₅ compounds DMAPP and IPP. This study aims at the characterization of methyltransferases (MTases) that modify these terpene precursors and the demonstration of their suitability for biotechnological purposes. All seven enzymes tested accepted IPP as substrate and altogether five C₆ compounds and six C₇ compounds were formed within the reactions. A high selectivity for the deprotonation site as well as high stereoselectivity could be observed for most of the biocatalysts. Only the enzyme from Micromonospora humi also accepted DMAPP as substrate, converting it into (2R)-2-methyl-IPP in vitro. In vivo studies demonstrated the production of a C₈ compound and a hydride shift step within the MTase-catalyzed reaction. Our study presents IPP/DMAPP MTases with very different catalytic properties, which provide biosynthetic access to many novel terpene-derived structures.     

Combinatorial Strategies by Marine Cyanobacteria: Symplostatin 4, an Antimitotic Natural Dolastatin 10/15 Hybrid that Synergizes with the Coproduced HDAC Inhibitor Largazole

Combinatorial biosynthesis meets combinatorial pharmacology, cyanobacterial style : A new antimitotic natural product with features of both dolastatins 10 and 15 was isolated from the same Floridian Symploca sp. sample that produced the histone deacetylase inhibitor largazole. Both agents in combination are more effective in inhibiting cancer cell proliferation than either agent alone.

     

Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset

About 50% of patients with arrhythmogenic cardiomyopathy (ACM) carry a pathogenic or likely pathogenic mutation in the desmosomal genes. However, there is a significant number of patients without positive familial anamnesis. Therefore, the molecular reasons for ACM in these patients are frequently unknown and a genetic contribution might be underestimated. Here, we used a next-generation sequencing (NGS) approach and in addition single nucleotide polymor-phism (SNP) arrays for the genetic analysis of two independent index patients without familial medical history. Of note, this genetic strategy revealed a homozygous splice site mutation (DSG2–c.378+1G>T) in the first patient and a nonsense mutation (DSG2–p.L772X) in combination with a large deletion in DSG2 in the second one. In conclusion, a recessive inheritance pattern is likely for both cases, which might contribute to the hidden medical history in both families. This is the first report about these novel loss-of-function mutations in DSG2 that have not been previously identi-fied. Therefore, we suggest performing deep genetic analyses using NGS in combination with SNP arrays also for ACM index patients without obvious familial medical history. In the future, this finding might has relevance for the genetic counseling of similar cases.     

De Novo Missense Mutations in TNNC1 and TNNI3 Causing Severe Infantile Cardiomyopathy Affect Myofilament Structure and Function and Are Modulated by Troponin Targeting Agents

Rare pediatric non-compaction and restrictive cardiomyopathy are usually associated with a rapid and severe disease progression. While the non-compaction phenotype is characterized by structural defects and is correlated with systolic dysfunction, the restrictive phenotype exhibits diastolic dysfunction. The molecular mechanisms are poorly understood. Target genes encode among others, the cardiac troponin subunits forming the main regulatory protein complex of the thin filament for muscle contraction. Here, we compare the molecular effects of two infantile de novo point mutations in TNNC1 (p.cTnC-G34S) and TNNI3 (p.cTnI-D127Y) leading to severe non-compaction and restrictive phenotypes, respectively. We used skinned cardiomyocytes, skinned fibers, and reconstituted thin filaments to measure the impact of the mutations on contractile function. We investigated the interaction of these troponin variants with actin and their inter-subunit interactions, as well as the structural integrity of reconstituted thin filaments. Both mutations exhibited similar functional and structural impairments, though the patients developed different phenotypes. Furthermore, the protein quality control system was affected, as shown for TnC-G34S using patient’s myocardial tissue samples. The two troponin targeting agents levosimendan and green tea extract (-)-epigallocatechin-3-gallate (EGCg) stabilized the structural integrity of reconstituted thin filaments and ameliorated contractile function in vitro in some, but not all, aspects to a similar degree for both mutations.     

Bio‐inspired Highly Scattering Networks via Polymer Phase Separation

A common strategy to optimize whiteness in living organisms consists in using 3D random networks with dense and polydisperse scattering elements constituted by relatively low refractive index materials. Inspired by these natural architectures, a fast and scalable method to produce highly scattering porous polymer films via phase separation is developed. By varying the molecular weight of the polymer, the morphology of the porous films is modified, and therefore their scattering properties are tuned. The achieved transport mean free paths are in the micrometer range, improving the scattering strength of analogous low refractive index systems, e.g., standard white paper, by an order of magnitude. The produced porous films show a broadband reflectivity of ≈75% while only 4 µm thick. In addition, the films are flexible and can be readily index‐matched with water (i.e., they become transparent when wet), allowing for various applications such as coatings with tunable transmittance and responsive paints.     

澳门1999-2009——回归后第一个十年之建筑与城市

本期专辑描绘了澳门从1999年-2009年主权从葡萄牙管辖下回归祖国之后10年间的建筑与城市化进程。在这期间,澳门作为一个特别行政区经历了非凡的10年,在这10年间,澳门的发展是意义深远的,这次的主题也同样跟随澳门的发展方向转变,是从1990年代的＂文化之城＂到＂亚洲的拉斯维加斯＂和将来有可能的＂知识之城＂这样的顺序展开的。     

Probing the dynamics of nanoparticle growth in a flame using synchrotron radiation

Flame synthesis is one of the most versatile and promising technologies for large-scale production of nanoscale materials. Pyrolysis has recently been shown to be a useful route for the production of single-walled nanotubes, quantum dots and a wide variety of nanostructured ceramic oxides for catalysis and electrochemical applications. An understanding of the mechanisms of nanostructural growth in flames has been hampered by a lack of direct observations of particle growth, owing to high temperatures (2,000 K), rapid kinetics (submillisecond scale), dilute growth conditions (10(-6) volume fraction) and optical emission of synthetic flames. Here we report the first successful in situ study of nanoparticle growth in a flame using synchrotron X-ray scattering. The results indicate that simple growth models, first derived for colloidal synthesis, can be used to facilitate our understanding of flame synthesis. Further, the results indicate the feasibility of studies of nanometre-scale aerosols of toxicological and environmental concern.     

Signals in science - On the importance of signaling in gaining attention in science

Which signals are important in gaining attention in science? For a group of 1,371 scientific articles published in 17 demography journals in the years 1990-1992 we track their influence and discern which signals are important in receiving citations. Three types of signals are examined: the author's reputation (as producer of the idea), the journal (as the broker of the idea), and the state of uncitedness (as an indication of the assessment by the scientific community of an idea). The empirical analysis points out that, first, the reputation of journals plays an overriding role in gaining attention in science. Second, in contrast to common wisdom, the state of uncitedness does not affect the future probability of being cited. And third, the reputation of a journal may help to get late recognition (so-called sleeping beauties) as well as generate 'flash-in-the-pans': immediately noted articles but apparently not very influential in the long run.     

From salad to bowl: The role of sensory analysis in product experience research

Methods originally developed for the sensory evaluation of foods are increasingly being applied to other product categories, ranging from personal care products to car interiors and air conditioning units. Furthermore, because an increasing number of food products tend to be available in packages from which they can be consumed directly, the sensory properties of packages have become an integral part of consumers’ food experiences and require thorough investigation. In addition, food consumption in everyday life takes place within a physical, social, and cultural context. This asks for a reconsideration of the role of sensory analysis in the product development process. To seduce consumers in highly saturated markets, products should not only provide good quality and be appealing, but they should offer interesting and engaging experiences. Therefore, research on sensory evaluation needs to be linked to research on product aesthetics, product meaning, and product emotions. Capturing the entire consumer experience requires an integral approach, in which research approaches from various academic fields are combined and integrated. For this approach to succeed in industrial companies, many different departments will need to work together in close cooperation.