A conserved chronobiological complex times C. elegans development.

The mammalian PAS-domain protein PERIOD (PER) and its C. elegans orthologue LIN-42 have been proposed to constitute an evolutionary link between two distinct, circadian and developmental, timing systems. However, while the function of PER in animal circadian rhythms is well understood molecularly and mechanistically, this is not true for the function of LIN-42 in timing rhythmic development. Here, using targeted deletions, we find that the LIN-42 PAS domains are dispensable for the protein's function in timing molts. Instead, we observe arrhythmic molts upon deletion of a distinct sequence element, conserved with PER. We show that this element mediates stable binding to KIN-20, the C. elegans CK1δ/ε orthologue. We demonstrate that CK1δ phosphorylates LIN-42 and define two conserved helical motifs, CK1δ-binding domain A (CK1BD-A) and CK1BD-B, that have distinct roles in controlling CK1δ-binding and kinase activity in vitro . KIN-20 and the LIN-42 CK1BD are required for proper molting timing in vivo . These interactions mirror the central role of a stable circadian PER-CK1 complex in setting a robust ∼24-hour period. Hence, our results establish LIN-42/PER - KIN-20/CK1δ/ε as a functionally conserved signaling module of two distinct chronobiological systems.

C. elegans molting requires rhythmic accumulation of the Grainyhead/LSF transcription factor GRH-1.

C. elegans develops through four larval stages that are rhythmically terminated by molts, that is, the synthesis and shedding of a cuticular exoskeleton. Each larval cycle involves rhythmic accumulation of thousands of transcripts, which we show here relies on rhythmic transcription. To uncover the responsible gene regulatory networks (GRNs), we screened for transcription factors that promote progression through the larval stages and identified GRH-1, BLMP-1, NHR-23, NHR-25, MYRF-1, and BED-3. We further characterize GRH-1, a Grainyhead/LSF transcription factor, whose orthologues in other animals are key epithelial cell-fate regulators. We find that GRH-1 depletion extends molt durations, impairs cuticle integrity and shedding, and causes larval death. GRH-1 is required for, and accumulates prior to, each molt, and preferentially binds to the promoters of genes expressed during this time window. Binding to the promoters of additional genes identified in our screen furthermore suggests that we have identified components of a core molting-clock GRN. Since the mammalian orthologues of GRH-1, BLMP-1 and NHR-23, have been implicated in rhythmic homeostatic skin regeneration in mouse, the mechanisms underlying rhythmic C. elegans molting may apply beyond nematodes.

Protease-mediated processing of Argonaute proteins controls small RNA association.

Small RNA pathways defend the germlines of animals against selfish genetic elements, yet pathway activities need to be contained to prevent silencing of self genes. Here, we reveal a proteolytic mechanism that controls endogenous small interfering (22G) RNA activity in the Caenorhabditis elegans germline to protect genome integrity and maintain fertility. We find that DPF-3, a P-granule-localized N-terminal dipeptidase orthologous to mammalian dipeptidyl peptidase (DPP) 8/9, processes the unusually proline-rich N termini of WAGO-1 and WAGO-3 Argonaute (Ago) proteins. Without DPF-3 activity, these WAGO proteins lose their proper complement of 22G RNAs. Desilencing of repeat-containing and transposon-derived transcripts, DNA damage, and acute sterility ensue. These phenotypes are recapitulated when WAGO-1 and WAGO-3 are rendered resistant to DPF-3-mediated processing, identifying them as critical substrates of DPF-3. We conclude that N-terminal processing of Ago proteins regulates their activity and promotes silencing of selfish genetic elements by ensuring Ago association with appropriate small RNAs.

From experiments to ecosystems? Reviewing public participation, scientific governance and the systemic turn.

The article discusses a recent systemic turn in public participation in science studies. It reviews the main lines of criticism brought forward in science, technology and society towards public participation in science discourse and argues that much of it refers to the field's preoccupation with isolated, stage-managed minipublics. It then discusses a series of efforts in science, technology and society, and other fields to study public participation in a more systemic or holistic perspective. The article advances the argument that there are different ways of conceptualizing such a perspective, not all of which are well equipped to account for contestation, conflict and power. We distinguish between an aggregative approach, deliberative systems theory, an eco-systemic and a decentred governance approach and argue that the latter allows us to study the complexities of public participation without relying on a normative concept of system and account for power relations that may structure the field of public participation.

From Ethical Exceptionalism to Ethical Exceptions: The Rule and exception Model and the Changing Meaning of Ethics In German Bioregulation.

Germany is an interesting case with respect to the governance of reprogenetics. It has a strong profile in the technosciences and high aims regarding the global bioeconomy, yet her regulation of human genetics, reproductive medicine and embryo research has for a long time been rather restrictive. German biopolitical exceptionalism has often been explained by reference to Catholicism and the legacy of the Nazi past. The Germans, so goes the common story, have learnt the lessons of history and translated them into unconditional respect for human dignity, which in turn translates into unconditional protection of human life, including the human embryo, and the firm repudiation of any eugenic distinction between 'life worth to live' and 'life not worth to live'. This, however, is not the whole story. Alongside deontological strictness we find another strand of governing body politics and reprogenetics in Germany, the rule-and-exception model, running from the mid-1970s abortion law via the 2002 Stem Cell Act to the 2011 regulation of pre-implantation genetic diagnosis. In contrast to the former, that strongly draws on Kant and his concept of human dignity, the latter bears resemblances to Carl Schmitt's concept of state of exception. The article will show that the rule-and-exception model builds the exception into the rule and transforms the meaning and mandate of ethics, namely from safeguarding ethical standards to deciding about the exception. Given that the exception has now tended to become the rule, the question is whether the lessons of history will govern German reprogenetics for much longer.

"... a certain amount of engineering involved": constructing the public in participatory governance arrangements.

This paper argues that it is time for public understanding of science to develop a critical inventory of the forms, formats and methods of public participation and their respective implications and ambiguities. It highlights the need for analysing not only the limitations and deficiencies of participatory arrangements but also their constructive dimension, in particular the construction of the subject of participation. Looking into participatory governance arrangements in the issue area of genetic testing in Germany and the UK the paper presents a typology of formats according to the way the respective public is constructed and identifies four major constructions of publics: the general public, the pure public, the affected public and the partisan public. Each of these enables certain speaking positions while foreclosing others. The study shows that the main purposes of participatory arrangements in this issue area are knowledge production and education rather than political deliberation and decision-making.

Not just for experts: the public debate about reprogenetics in Germany.

When reproductive and genetic technologies spurred an extended German policy debate, the issues at stake went beyond the technologies to include the very meaning of "ethics" and the respective roles of ethicists and of the public in thinking about ethical questions.