Some, but not all, glycine substitution mutations in COL7A1 result in intracellular accumulation of collagen VII, loss of anchoring fibrils, and skin blistering

COL7A1 gene mutations cause dystrophic epidermolysis bullosa, a skin blistering disorder. The phenotypes result from defects of collagen VII, the major component of the anchoring fibrils at the dermo-epidermal junction; however, the molecular mechanisms underlying the phenotypes remain elusive. We investigated naturally occurring COL7A1 mutations and showed that some, but not all, glycine substitutions in collagen VII interfered with biosynthesis of the protein in a dominant-negative manner. Three point mutations in exon 73 caused glycine substitutions G2006D, G2034R, and G2015E in the triple helical domain of collagen VII and interfered with its folding and secretion. Confocal laser scanning studies and semiquantitative immunoblotting determined that dystrophic epidermolysis bullosa keratinocytes retained up to 2.5-fold more procollagen VII within the rough endoplasmic reticulum than controls. Limited proteolytic digestions of mutant procollagen VII produced aberrant fragments and revealed reduced stability of the triple helix. In contrast, the glycine substitution G1519D in another segment of the triple helix affected neither procollagen VII secretion nor anchoring fibril function and remained phenotypically silent. These data demonstrate that collagen VII presents a remarkable exception among collagens in that not all glycine substitutions within the triple helix exert dominant-negative interference and that the biological consequences of the substitutions probably depend on their position within the triple helix.     

Implementation of the WEEE-directive — economic effects and improvement potentials for reuse and recycling in Germany

Reducing the quantity of waste for disposal and saving natural resources were main drivers for the introduction of the European Directive on waste electrical and electronic equipment (WEEE-directive). This policy focused on an extension of the producer responsibility (EPR) to the end-of-life-phase of their products. Because of the EPR concept, the national transposition of the WEEE-directive, especially the German transposition in the law ElektroG, caused changes in the organisation and material flows that are sometimes not in line with the aim of the directive, which is to enforce the waste management premise “avoidance prior recycling prior disposal”. Thus, the objective of this contribution is to analyse and compare the situation before and after implementation of the ElektroG in Germany, and deduce improvement potentials. Therefore, a co-operation of a municipality and a nearby disassembly company in Germany is analysed and evaluated, taking into account material flows and costs before/after implementation of the ElektroG, as well as degrees of freedom. Based on this analysis, recommendations are deduced for political decision makers and actors of the WEEE treatment system.     

Crystal structure of the nucleosome core particle at 2.8 A resolution

The X-ray crystal structure of the nucleosome core particle of chromatin shows in atomic detail how the histone protein octamer is assembled and how 146 base pairs of DNA are organized into a superhelix around it. Both histone/histone and histone/DNA interactions depend on the histone fold domains and additional, well ordered structure elements extending from this motif. Histone amino-terminal tails pass over and between the gyres of the DNA superhelix to contact neighbouring particles. The lack of uniformity between multiple histone/DNA-binding sites causes the DNA to deviate from ideal superhelix geometry.     

Phase II study of mitoguazone, cyclophosphamide, doxorubicin, vincristine and prednisone for patients with diffuse histologic subtypes of non-Hodgkin's lymphoma: an Eastern Cooperative Oncology Group Study (PE481)

Mitoguazone, an investigational agent with significant activity in advanced lymphoma, was added to a modified CHOP regimen (COPA) in an effort to improve the activity of standard therapy in 66 previously untreated patients with stages II-IV lymphoma and diffuse histology of intermediate or high grade other than lymphoblastic in this phase II pilot study. The regimen was well tolerated and the complete response rate in diffuse large cell lymphoma was 55%. Sixty-five percent of all complete responders were in complete response for at least one year. Despite these excellent results. it is unlikely that the addition of mitoguazone improved results compared with those obtained with standard therapy alone, since similar results have been frequently reported with the latter.     

From Alan Turing to modern AI: practical solutions and an implicit epistemic stance

It has been just over 100 years since the birth of Alan Turing and more than 65 years since he published in Mind his seminal paper, Computing Machinery and Intelligence (Turing in Computing machinery and intelligence. Oxford University Press, Oxford, 1950). In the Mind paper, Turing asked a number of questions, including whether computers could ever be said to have the power of “thinking” (“I propose to consider the question, Can computers think?” ...Alan Turing, Computing Machinery and Intelligence, Mind, 1950). Turing also set up a number of criteria—including his imitation game—under which a human could judge whether a computer could be said to be “intelligent”. Turing’s paper, as well as his important mathematical and computational insights of the 1930s and 1940s led to his popular acclaim as the “Father of Artificial Intelligence”. In the years since his paper was published, however, no computational system has fully satisfied Turing’s challenge. In this paper we focus on a different question, ignored in, but inspired by Turing’s work: How might the Artificial Intelligence practitioner implement “intelligence” on a computational device? Over the past 60 years, although the AI community has not produced a general-purpose computational intelligence, it has constructed a large number of important artifacts, as well as taken several philosophical stances able to shed light on the nature and implementation of intelligence. This paper contends that the construction of any human artifact includes an implicit epistemic stance. In AI this stance is found in commitments to particular knowledge representations and search strategies that lead to a product’s successes as well as its limitations. Finally, we suggest that computational and human intelligence are two different natural kinds, in the philosophical sense, and elaborate on this point in the conclusion.     

Mechanical property characterization of LPCVD silicon nitride thin films at cryogenic temperatures

T-shape, LPCVD silicon nitride cantilevers are fabricated to determine Young's modulus and fracture strength of silicon nitride thin films at room and cryogenic temperatures. A helium-cooled measurement setup is developed and installed inside a focused-ion-beam (FIB) system. A lead-zirconate-titanate (PZT) translator powered by a function generator and a dc voltage is utilized as an actuator, and a silicon diode is used as a temperature sensor in this setup. Resonant frequencies of identical cantilevers with different "milling masses" are measured to obtain thickness and Young's modulus of the silicon nitride thin films, while a bending test is performed to obtain fracture strength. From the experiment, the average Young's modulus of low-pressure chemical-vapor deposition (LPCVD) silicon nitride thin films varies from 260.5 GPa at room temperature (298 K) to 266.6 GPa at 30 K, and the average fracture strength ranges from 6.9 GPa at room temperature to 7.9 GPa at 30 K. The measurement setup and technique presented here can be used to characterize the mechanical properties of different MEMS materials at cryogenic temperatures.     

Neuropeptides in the skin: interactions between the neuroendocrine and the skin immune systems

The interaction between components of the nervous system and multiple target cells in the cutaneous immune system has been receiving increasing attention. It has been observed that certain skin diseases such as psoriasis and atopic dermatitis have a neurogenic component. Neuropeptides released by sensory nerves that innervate the skin and often contact epidermal and dermal cells can directly modulate functions of keratinocytes, Langerhans cells (LC), mast cells, dermal microvascular endothelial cells and infiltrating immune cells. Among these neuropeptides the tachykinins substance P (SP) and neurokinin A (NKA), calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP) and somatostatin (SOM) have been reported to effectively modulate skin and immune cell functions such as cell proliferation, cytokine production or antigen presentation under physiological or pathophysiological conditions. Expression and regulation of their corresponding receptors that are expressed on a variety of skin cells as well as the presence of neuropeptide-specific peptidases such as neutral endopeptidase (NEP) or angiotensin-converting enzyme (ACE) determine the final biological response mediated by these peptides on the target cell or tissue. Likewise, skin cells like keratinocytes or fibroblasts are a source for neurotrophins such as nerve growth factor that are required not only for survival and regeneration of sensory neurons but also to control responsiveness of these neurons to external stimuli. Therefore, neuropeptides, neuropeptide receptors, neuropeptide-degrading enzymes and neurotrophins participate in a complex, interdependent network of mediators that modulate skin inflammation, wound healing and the skin immune system. This review will focus on recent studies demonstrating the role of tachykinins, CGRP, SOM and VIP and their receptors and neuropeptide-degrading enzymes in mediating neurogenic inflammation in the skin.     

Model studies on the detectability of genetically modified feeds in milk

Detecting the use of genetically modified feeds in milk has become important, because the voluntary labeling of milk and dairy products as "GMO free" or as "organically grown" prohibits the employment of genetically modified organisms (GMOs). The aim of this work was to investigate whether a DNA transfer from foodstuffs like soya and maize was analytically detectable in cow's milk after digestion and transportation via the bloodstream of dairy cows and, thus, whether milk could report for the employment of transgene feeds. Blood, milk, urine, and feces of dairy cows were examined, and foreign DNA was detected by polymerase chain reaction by specifically amplifying a 226-bp fragment of the maize invertase gene and a 118-bp fragment of the soya lectin gene. An intravenous application of purified plant DNA showed a fast elimination of marker DNA in blood or its reduction below the detection limit. With feeding experiments, it could be demonstrated that a specific DNA transfer from feeds into milk was not detectable. Therefore, foreign DNA in milk cannot serve as an indicator for the employment of transgene feeds unless milk is directly contaminated with feed components or airborne feed particles.     

Depoteffect of benzathine-penicillin (author's transl)

15 test persons received an injection of 2,400,000 units of benzathine penicillin. Serum levels were subsequently assayed, as well as the excretion of the antibiotic in the urine. The samples were stored in liquid-nitrogen between collection and examination. Each of the speciemens was tested 5 to 10 times and the results were ascertained by empirical evaluation of every single analysis. This assay showed the existence of mean levels above 0.036 I.U./ml in the serum and above 19.75 I.U./ml in the urine for the duration of 26 days. The evaluation of serum levels after the administration of antibiotics is difficult due to several sources of error. Reliable results can, therefore, be obtained only by examination at special institutes which possess experienced technical personnel. The establishment of reference laboratories for this purpose is suggested. The results of the study confirm the efficacy of one-shot treatment of the syphilis by administration of 2,400,000 to units of benzathine penicillin.