Femtosecond time-delay X-ray holography

Extremely intense and ultrafast X-ray pulses from free-electron lasers offer unique opportunities to study fundamental aspects of complex transient phenomena in materials. Ultrafast time-resolved methods usually require highly synchronized pulses to initiate a transition and then probe it after a precisely defined time delay. In the X-ray regime, these methods are challenging because they require complex optical systems and diagnostics. Here we propose and apply a simple holographic measurement scheme, inspired by Newton's 'dusty mirror' experiment, to monitor the X-ray-induced explosion of microscopic objects. The sample is placed near an X-ray mirror; after the pulse traverses the sample, triggering the reaction, it is reflected back onto the sample by the mirror to probe this reaction. The delay is encoded in the resulting diffraction pattern to an accuracy of one femtosecond, and the structural change is holographically recorded with high resolution. We apply the technique to monitor the dynamics of polystyrene spheres in intense free-electron-laser pulses, and observe an explosion occurring well after the initial pulse. Our results support the notion that X-ray flash imaging can be used to achieve high resolution, beyond radiation damage limits for biological samples. With upcoming ultrafast X-ray sources we will be able to explore the three-dimensional dynamics of materials at the timescale of atomic motion.     

Improved 2 D Stability Margin Test for 2 D Discrete Systems

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Poly(ADP-ribosyl)ation regulates CTCF-dependent chromatin insulation

Chromatin insulators demarcate expression domains by blocking the cis effects of enhancers or silencers in a position-dependent manner. We show that the chromatin insulator protein CTCF carries a post-translational modification: poly(ADP-ribosyl)ation. Chromatin immunoprecipitation analysis showed that a poly(ADP-ribosyl)ation mark, which exclusively segregates with the maternal allele of the insulator domain in the H19 imprinting control region, requires the bases that are essential for interaction with CTCF. Chromatin immunoprecipitation-on-chip analysis documented that the link between CTCF and poly(ADP-ribosyl)ation extended to more than 140 mouse CTCF target sites. An insulator trap assay showed that the insulator function of most of these CTCF target sites is sensitive to 3-aminobenzamide, an inhibitor of poly(ADP-ribose) polymerase activity. We suggest that poly(ADP-ribosyl)ation imparts chromatin insulator properties to CTCF at both imprinted and nonimprinted loci, which has implications for the regulation of expression domains and their demise in pathological lesions.     

The substrate degradome of meprin metalloproteases reveals an unexpected proteolytic link between meprin β and ADAM10

The in vivo roles of meprin metalloproteases in pathophysiological conditions remain elusive. Substrates define protease roles. Therefore, to identify natural substrates for human meprin α and β we employed TAILS (terminal amine isotopic labeling of substrates), a proteomics approach that enriches for N-terminal peptides of proteins and cleavage fragments. Of the 151 new extracellular substrates we identified, it was notable that ADAM10 (a disintegrin and metalloprotease domain-containing protein 10)—the constitutive α-secretase—is activated by meprin β through cleavage of the propeptide. To validate this cleavage event, we expressed recombinant proADAM10 and after preincubation with meprin β, this resulted in significantly elevated ADAM10 activity. Cellular expression in murine primary fibroblasts confirmed activation. Other novel substrates including extracellular matrix proteins, growth factors and inhibitors were validated by western analyses and enzyme activity assays with Edman sequencing confirming the exact cleavage sites identified by TAILS. Cleavages in vivo were confirmed by comparing wild-type and meprin^?/? mice. Our finding of cystatin C, elafin and fetuin-A as substrates and natural inhibitors for meprins reveal new mechanisms in the regulation of protease activity important for understanding pathophysiological processes.     

Immunological memory ≠ protective immunity

So-called ‘immunological memory’ is, in my view, a typical example where a field of enquiry, i.e. to understand long-term protection to survive reexposure to infection, has been overtaken by ‘l’art pour l’art’ of ‘basic immunology’. The aim of this critical review is to point out some key differences between academic text book-defined immunological memory and protective immunity as viewed from a co-evolutionary point of view, both from the host and the infectious agents. A key conclusion is that ‘immunological memory’ of course exists, but only in particular experimental laboratory models measuring ‘quicker and better’ responses after an earlier immunization. These often do correlate with, but are not the key mechanisms of, protection. Protection depends on pre-existing neutralizing antibodies or pre-activated T cells at the time of infection—as documented by the importance of maternal antibodies around birth for survival of the offspring. Importantly, both high levels of antibodies and of activated T cells are antigen driven. This conclusion has serious implications for our thinking about vaccines and maintaining a level of protection in the population to deal with old and new infectious diseases.     

Zur Kinematik der Planetenbewegung in Copernicus' Commentariolus

Zusammenfassung Copernicus versucht, die Ptolemäischen Konstruktionen auf konzentrische Kreise und Epizykel zu reduzieren und aus ihnen ein wirklich einheitliches System zu schaffen. Bei der Umordnung, die er dazu vornimmt, bemüht er sich aber, so viel wie möglich vom Ptolemäischen System zu erhalten. Das punctum aequans ersetzt er bei den äußeren Planeten durch eine Näherungskonstruktion mit Hilfe eines Epizykels. Im Fall des Ptolemäischen Deferenten der Venus, der nach seinen Vorstellungen die Erdbahn wiedergibt, muß er einen dem punctum aequans annähernd gleichwertigen Epizykelmechanismus auf die Venusbahn verpflanzen. Vorgelegt von B. L. van der Waerden     

Recruitment and retention: factors that affect pericyte migration

Pericytes are critical for vascular morphogenesis and contribute to several pathologies, including cancer development and progression. The mechanisms governing pericyte migration and differentiation are complex and have not been fully established. Current literature suggests that platelet-derived growth factor/platelet-derived growth factor receptor-β, sphingosine 1-phosphate/endothelial differentiation gene-1, angiopoietin-1/tyrosine kinase with immunoglobulin-like and EGF-like domains 2, angiopoietin-2/tyrosine kinase with immunoglobulin-like and EGF-like domains 2, transforming growth factor β/activin receptor-like kinase 1, transforming growth factor β/activin receptor-like kinase 5, Semaphorin-3A/Neuropilin, and matrix metalloproteinase activity regulate the recruitment of pericytes to nascent vessels. Interestingly, many of these pathways are directly affected by secreted protein acidic and rich in cysteine (SPARC). Here, we summarize the function of these factors in pericyte migration and discuss if and how SPARC might influence these activities and thus provide an additional layer of control for the recruitment of vascular support cells. Additionally, the consequences of targeted inhibition of pericytes in tumors and the current understanding of pericyte recruitment in pathological environments are discussed.     

Serotonin metabolism in chronic alcoholism (author's transl)

Serotonin was determined in platelets of 47 patients with alcoholism during the state of withdrawal as well as in a group of healthy persons. The results show that serotonin values were significantly lower in the group of patients with alcoholism as compared with the control group of healthy persons.