Synthetic biology: ethical ramifications 2009

During 2007 and 2008 synthetic biology moved from the manifesto stage to research programs. As of 2009, synthetic biology is ramifying; to ramify means to produce differentiated trajectories from previous determinations. From its inception, most of the players in synthetic biology agreed on the need for (a) rationalized design and construction of new biological parts, devices, and systems as well as (b) the re-design of natural biological systems for specified purposes, and that (c) the versatility of designed biological systems makes them suitable to address such challenges as renewable energy, the production of inexpensive drugs, and environmental remediation, as well as providing a catalyst for further growth of biotechnology. What is understood by these goals, however, is diverse. Those assorted understandings are currently contributing to different ramifications of synthetic biology. The Berkeley Human Practices Lab, led by Paul Rabinow, is currently devoting its efforts to documenting and analyzing these ramifications as they emerge

A Forward-Genetic Screen and Dynamic Analysis of Lambda Phage Host-Dependencies Reveals an Extensive Interaction Network and a New Anti-Viral Strategy

Latently infecting viruses are an important class of virus that plays a key role in viral evolution and human health. Here we report a genome-scale forward-genetics screen for host-dependencies of the latently-infecting bacteriophage lambda. This screen identified 57 Escherichia coli (E. coli) genes—over half of which have not been previously associated with infection—that when knocked out inhibited lambda phage's ability to replicate. Our results demonstrate a highly integrated network between lambda and its host, in striking contrast to the results from a similar screen using the lytic-only infecting T7 virus. We then measured the growth of E. coli under normal and infected conditions, using wild-type and knockout strains deficient in one of the identified host genes, and found that genes from the same pathway often exhibited similar growth dynamics. This observation, combined with further computational and experimental analysis, led us to identify a previously unannotated gene, yneJ, as a novel regulator of lamB gene expression. A surprising result of this work was the identification of two highly conserved pathways involved in tRNA thiolation—one pathway is required for efficient lambda replication, while the other has anti-viral properties inhibiting lambda replication. Based on our data, it appears that 2-thiouridine modification of tRNAGlu, tRNAGln, and tRNALys is particularly important for the efficient production of infectious lambda phage particles

Biochemical and Structural Insights into the Mechanisms of SARS Coronavirus RNA Ribose 2′-O-Methylation by nsp16/nsp10 Protein Complex

The 5′-cap structure is a distinct feature of eukaryotic mRNAs, and eukaryotic viruses generally modify the 5′-end of viral RNAs to mimic cellular mRNA structure, which is important for RNA stability, protein translation and viral immune escape. SARS coronavirus (SARS-CoV) encodes two S-adenosyl-L-methionine (SAM)-dependent methyltransferases (MTase) which sequentially methylate the RNA cap at guanosine-N7 and ribose 2′-O positions, catalyzed by nsp14 N7-MTase and nsp16 2′-O-MTase, respectively. A unique feature for SARS-CoV is that nsp16 requires non-structural protein nsp10 as a stimulatory factor to execute its MTase activity. Here we report the biochemical characterization of SARS-CoV 2′-O-MTase and the crystal structure of nsp16/nsp10 complex bound with methyl donor SAM. We found that SARS-CoV nsp16 MTase methylated m7GpppA-RNA but not m7GpppG-RNA, which is in contrast with nsp14 MTase that functions in a sequence-independent manner. We demonstrated that nsp10 is required for nsp16 to bind both m7GpppA-RNA substrate and SAM cofactor. Structural analysis revealed that nsp16 possesses the canonical scaffold of MTase and associates with nsp10 at 1∶1 ratio. The structure of the nsp16/nsp10 interaction interface shows that nsp10 may stabilize the SAM-binding pocket and extend the substrate RNA-binding groove of nsp16, consistent with the findings in biochemical assays. These results suggest that nsp16/nsp10 interface may represent a better drug target than the viral MTase active site for developing highly specific anti-coronavirus drugs

Do stress coping strategies influence chronotype-related differences in sleep quality?

Zschoche M, Bugl P, Schlarb A. Do stress coping strategies influence chronotype-related differences in sleep quality? Somnologie. 2017;21(S1):37-43.Background Chronotype manifestation often has a broad influence on sleep quality. One possible explanation for daytime impairments in evening types is the concept of “social jetlag”. Social jetlag is caused by an incompatibility between circadian preference and the socially accepted rhythm. This can be declared as a social stressor. Objective The association between chronotype, stress coping, and sleep quality was assessed in a pilot study. Materials and methods A total of 75 female adults aged 20–41 years participated in the study and completely answered all questions. Various questionnaires including sociodemographic data, information about sleep quality (Pittsburgh Sleep Quality Index, PSQI), chronotype (morningness–eveningness questionnaire, MEQ), and stress coping (Stress Coping Style Questionnaire, SVF78) were applied. Results Heightened use of maladaptive coping strategies is associated with a reduction in sleep quality. Chronotypes did not differ in terms of sleep quality and the coping strategies used. Conclusion Maladaptive coping strategy use seems to have a negative influence on sleep quality. Preventive education in adaptive stress coping strategies and avoidance of maladaptive stress coping thus seems useful to reduce these adverse influences on sleep quality.Hintergrund Die Ausprägung des Chronotyps hat oft einen Einfluss auf die Schlafqualität. Das Konzept des „social jetlag“, welches auf die Unvereinbarkeit von Chronotyp und sozialem Rhythmus zurückgeführt wird, dient als ein Erklärungsansatz für die Alltagsbeeinträchtigungen von Abendtypen. „Social jetlag“ kann als in diesem Zusammenhang als Stressor interpretiert werden. Fragestellung In einer Pilotstudie wurde der Zusammenhang zwischen Chronotyp, Stressverarbeitung und Schlafqualität untersucht. Material und Methoden Die Studienteilnehmer, 75 Frauen im Alter von 20 bis 41 Jahren, füllten Fragebögen zu soziodemographischen Variablen, zur Schlafqualität (Pittsburgh Sleep Quality Index, PSQI), zum Chronotyp (Morningness–Eveningness Questionnaire, MEQ) und zu Stressverarbeitungsstrategien (Stress Coping Style Questionnaire, SVF78) aus. Ergebnisse Erhöhte Werte bei der Nutzung maladaptiver Stressverarbeitungsstrategien hingen mit einer reduzierten Schlafqualität zusammen. Die einzelnen Chronotypen unterschieden sich jedoch nicht signifikant hinsichtlich ihrer Schlafqualität und der genutzten Stressverarbeitungsstrategien. Schlussfolgerung Eine vermehrte Anwendung von maladaptiven Stressverarbeitungsstrategien schien einen Einfluss auf die Schlafqualität zu haben. Daraus lässt sich ableiten, dass eine präventive Aufklärung über wirkungsvolle Stressverarbeitungsstrategien angebracht erscheint, um die ungünstigen Auswirkungen von Stress auf die Schlafqualität zu reduzieren

New Venture Value Creation in Syndicates Between Independent and Corporate Investors

Consistent with the resource-based view research on investment syndicates indicates relative performance advantages of syndicate-backed ventures. However, in line with agency theory, the literature shows that heterogeneous syndicates between independent venture capital (IVC) and corporate venture capital (CVC) produce portfolio firms that exert only marginal growth and are less likely to exit successfully. These contrasting views motivate this study, which aims to shed light on the determinants of value creation for new venture firms in IVC–CVC co-investing. Our qualitative research builds on a cross-industry sample of 35 interviewees identifying a distinctive set of value drivers comprising shareholder relationships, corporate setup, venture life cycle, and deal terms. </jats:p

Bone Marrow Derived Mesenchymal Cells Secrete Granulopoietic Cytokines upon Danger Signaling

Abstract Granulopoietic homeostasis is regulated at steady-state to supply sufficient numbers of pooled and circulating neutrophils to maintain barrier function against commensal flora. In addition, upon pathogenic microbial challenge, an increased formation of neutrophils is induced, termed ‘emergency granulopoiesis’. Antibody-mediated reduction of neutrophil numbers in steady-state induces a feedback loop leading to an increase of bone marrow granulopoiesis with expansion of hematopoetic stem and progenitor cells. This feedback loop was demonstrated to depend on TLR4 and TRIF, but not MyD88 signaling (Bugl et al. Blood 2013). In contrast, emergency granulopoiesis was shown to be dependent on MyD88 signaling in endothelial cells (Boettcher et al. Blood 2014). Bone marrow mesenchymal stromal cells (MSC) are niche-forming cells, harboring and regulating hematopoiesis. Upon steady-state neutropenia an increase of niche size was observed. Here we investigated, whether niche-forming MSC act as sensors of pathogen-associated molecular patterns (PAMPs) and induce granulopoietic cytokines to stimulate expansion of adjacent hematopoietic stem and progenitor cells. MSC of C57BL/6 and TLR4-KO mice were cultured in vitro and treated with LPS for 24 hours. Cells were harvested and qRT-PCR for G-CSF, TLR4, MyD88, TRIF, GM-CSF, IL-1β, IL-18 and Casp-1 was performed After treatment with LPS, RNA of granulopoietic cytokines G-CSF and GM-CSF were massively up regulated in MSC of WT mice. Upstream regulating, inflammasome components IL-1ß and caspase-1 RNA levels increased as well, with little changes in IL-18, TLR4, MyD88 and TRIF. Unexpectedly, TLR4-KO MSC up regulated transcription of IL-1β and G-CSF upon LPS stimulation as well, and caspase-1 was found to be strongly up-regulated in unstimulated TLR4-KO compared to WT MSC. In summary, bone marrow stromal cells are found to be PAMP-sensing and secrete cytokines that regulate granulopoiesis. TLR4-independent sensing of LPS by MSC might correspond to the alternative noncanonical inflammasome pathway recently described (Kayagaki et al. Science 2013). Disclosures No relevant conflicts of interest to declare. </jats:sec