Neurohormonal signaling via a sulfotransferase antagonizes insulin-like signaling to regulate a Caenorhabditis elegans stress response

Insulin and insulin-like signaling regulates a broad spectrum of growth and metabolic responses to a variety of internal and environmental stimuli. For example, the inhibition of insulin-like signaling in C. elegans mediates its response to both osmotic stress and starvation. We report that in response to osmotic stress the cytosolic sulfotransferase SSU-1 antagonizes insulin-like signaling and promotes developmental arrest. Both SSU-1 and the DAF-16 FOXO transcription factor, which is activated when insulin signaling is low, are needed to drive specific responses to reduced insulin-like signaling. We demonstrate that SSU-1 functions in a single pair of sensory neurons to control intercellular signaling via the nuclear hormone receptor NHR-1 and promote both the specific transcriptional response to osmotic stress and altered lysophosphatidylcholine metabolism. Our results show the requirement of a sulfotransferase–nuclear hormone receptor neurohormonal signaling pathway for some but not all consequences of reduced insulin-like signaling.National Center for Research Resources (U.S.)National Institutes of Health (U.S.) (grant GM024663)National Science Foundation (U.S.) (grant 1122374)University of Cambridge. Centre for Trophoblast Research (Next Generation Fellowship)National Institutes of Health (U.S.) (grant GM117408

Neurohormonal signaling via a sulfotransferase antagonizes insulin-like signaling to regulate a Caenorhabditis elegans stress response.

Insulin and insulin-like signaling regulates a broad spectrum of growth and metabolic responses to a variety of internal and environmental stimuli. For example, the inhibition of insulin-like signaling in C. elegans mediates its response to both osmotic stress and starvation. We report that in response to osmotic stress the cytosolic sulfotransferase SSU-1 antagonizes insulin-like signaling and promotes developmental arrest. Both SSU-1 and the DAF-16 FOXO transcription factor, which is activated when insulin signaling is low, are needed to drive specific responses to reduced insulin-like signaling. We demonstrate that SSU-1 functions in a single pair of sensory neurons to control intercellular signaling via the nuclear hormone receptor NHR-1 and promote both the specific transcriptional response to osmotic stress and altered lysophosphatidylcholine metabolism. Our results show the requirement of a sulfotransferase-nuclear hormone receptor neurohormonal signaling pathway for some but not all consequences of reduced insulin-like signaling

The short coiled-coil domain-containing protein UNC-69 cooperates with UNC-76 to regulate axonal outgrowth and normal presynaptic organization in Caenorhabditis elegans

BACKGROUND: The nematode Caenorhabditis elegans has been used extensively to identify the genetic requirements for proper nervous system development and function. Key to this process is the direction of vesicles to the growing axons and dendrites, which is required for growth-cone extension and synapse formation in the developing neurons. The contribution and mechanism of membrane traffic in neuronal development are not fully understood, however. RESULTS: We show that the C. elegans gene unc-69 is required for axon outgrowth, guidance, fasciculation and normal presynaptic organization. We identify UNC-69 as an evolutionarily conserved 108-amino-acid protein with a short coiled-coil domain. UNC-69 interacts physically with UNC-76, mutations in which produce similar defects to loss of unc-69 function. In addition, a weak reduction-of-function allele, unc-69(ju69), preferentially causes mislocalization of the synaptic vesicle marker synaptobrevin. UNC-69 and UNC-76 colocalize as puncta in neuronal processes and cooperate to regulate axon extension and synapse formation. The chicken UNC-69 homolog is highly expressed in the developing central nervous system, and its inactivation by RNA interference leads to axon guidance defects. CONCLUSION: We have identified a novel protein complex, composed of UNC-69 and UNC-76, which promotes axonal growth and normal presynaptic organization in C. elegans. As both proteins are conserved through evolution, we suggest that the mammalian homologs of UNC-69 and UNC-76 (SCOCO and FEZ, respectively) may function similarly

Organizational factors and depression management in community-based primary care settings

Abstract Background Evidence-based quality improvement models for depression have not been fully implemented in routine primary care settings. To date, few studies have examined the organizational factors associated with depression management in real-world primary care practice. To successfully implement quality improvement models for depression, there must be a better understanding of the relevant organizational structure and processes of the primary care setting. The objective of this study is to describe these organizational features of routine primary care practice, and the organization of depression care, using survey questions derived from an evidence-based framework. Methods We used this framework to implement a survey of 27 practices comprised of 49 unique offices within a large primary care practice network in western Pennsylvania. Survey questions addressed practice structure (e.g., human resources, leadership, information technology (IT) infrastructure, and external incentives) and process features (e.g., staff performance, degree of integrated depression care, and IT performance). Results The results of our survey demonstrated substantial variation across the practice network of organizational factors pertinent to implementation of evidence-based depression management. Notably, quality improvement capability and IT infrastructure were widespread, but specific application to depression care differed between practices, as did coordination and communication tasks surrounding depression treatment. Conclusions The primary care practices in the network that we surveyed are at differing stages in their organization and implementation of evidence-based depression management. Practical surveys such as this may serve to better direct implementation of these quality improvement strategies for depression by improving understanding of the organizational barriers and facilitators that exist within both practices and practice networks. In addition, survey information can inform efforts of individual primary care practices in customizing intervention strategies to improve depression management.http://deepblue.lib.umich.edu/bitstream/2027.42/78269/1/1748-5908-4-84.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78269/2/1748-5908-4-84-S1.PDFhttp://deepblue.lib.umich.edu/bitstream/2027.42/78269/3/1748-5908-4-84.pdfPeer Reviewe

Adaptive Oblivious Transfer and Generalization

International audienceOblivious Transfer (OT) protocols were introduced in the seminal paper of Rabin, and allow a user to retrieve a given number of lines (usually one) in a database, without revealing which ones to the server. The server is ensured that only this given number of lines can be accessed per interaction, and so the others are protected; while the user is ensured that the server does not learn the numbers of the lines required. This primitive has a huge interest in practice, for example in secure multi-party computation, and directly echoes to Symmetrically Private Information Retrieval (SPIR). Recent Oblivious Transfer instantiations secure in the UC framework suf- fer from a drastic fallback. After the first query, there is no improvement on the global scheme complexity and so subsequent queries each have a global complexity of O(|DB|) meaning that there is no gain compared to running completely independent queries. In this paper, we propose a new protocol solving this issue, and allowing to have subsequent queries with a complexity of O(log(|DB|)), and prove the protocol security in the UC framework with adaptive corruptions and reliable erasures. As a second contribution, we show that the techniques we use for Obliv- ious Transfer can be generalized to a new framework we call Oblivi- ous Language-Based Envelope (OLBE). It is of practical interest since it seems more and more unrealistic to consider a database with uncontrolled access in access control scenarii. Our approach generalizes Oblivious Signature-Based Envelope, to handle more expressive credentials and requests from the user. Naturally, OLBE encompasses both OT and OSBE, but it also allows to achieve Oblivious Transfer with fine grain access over each line. For example, a user can access a line if and only if he possesses a certificate granting him access to such line. We show how to generically and efficiently instantiate such primitive, and prove them secure in the Universal Composability framework, with adaptive corruptions assuming reliable erasures. We provide the new UC ideal functionalities when needed, or we show that the existing ones fit in our new framework. The security of such designs allows to preserve both the secrecy of the database values and the user credentials. This symmetry allows to view our new approach as a generalization of the notion of Symmetrically PIR

Structure-Preserving Smooth Projective Hashing

International audienceSmooth projective hashing has proven to be an extremely useful primitive, in particular when used in conjunction with commitments to provide implicit decommitment. This has lead to applications proven secure in the UC framework, even in presence of an adversary which can do adaptive corruptions, like for example Password Authenticated Key Exchange (PAKE), and 1-out-of-m Oblivious Transfer (OT). However such solutions still lack in efficiency, since they heavily scale on the underlying message length. Structure-preserving cryptography aims at providing elegant and efficient schemes based on classical assumptions and standard group operations on group elements. Recent trend focuses on constructions of structure- preserving signatures, which require message, signature and verification keys to lie in the base group, while the verification equations only consist of pairing-product equations. Classical constructions of Smooth Projective Hash Function suffer from the same limitation as classical signatures: at least one part of the computation (messages for signature, witnesses for SPHF) is a scalar. In this work, we introduce and instantiate the concept of Structure- Preserving Smooth Projective Hash Function, and give as applications more efficient instantiations for one-round PAKE and three-round OT, and information retrieval thanks to Anonymous Credentials, all UC- secure against adaptive adversaries

Symbolic Encryption with Pseudorandom Keys

We give an efficient decision procedure that, on input two (acyclic) cryptographic expressions making arbitrary use of an encryption scheme and a (length doubling) pseudorandom generator, determines (in polynomial time) if the two expressions produce computationally indistinguishable distributions for any pseudorandom generator and encryption scheme satisfying the standard security notions of pseudorandomness and indistinguishability under chosen plaintext attack. The procedure works by mapping each expression to a symbolic pattern that captures, in a fully abstract way, the information revealed by the expression to a computationally bounded observer. We then prove that if any two (possibly cyclic) expressions are mapped to the same pattern, then the associated distributions are indistinguishable. At the same time, if the expressions are mapped to different symbolic patterns and do not contain encryption cycles, there are secure pseudorandom generators and encryption schemes for which the two distributions can be distinguished with overwhelming advantage

Insulin-like signalling to the maternal germline controls progeny response to osmotic stress

In 1893 August Weismann proposed that information about the environment could not pass from somatic cells to germ cells, a hypothesis now known as the Weismann barrier. However, recent studies have indicated that parental exposure to environmental stress can modify progeny physiology and that parental stress can contribute to progeny disorders. The mechanisms regulating these phenomena are poorly understood. We report that the nematode Caenorhabditis elegans can protect itself from osmotic stress by entering a state of arrested development and can protect its progeny from osmotic stress by increasing the expression of the glycerol biosynthetic enzyme GPDH-2 in progeny. Both of these protective mechanisms are regulated by insulin-like signalling: insulin-like signalling to the intestine regulates developmental arrest, while insulin-like signalling to the maternal germline regulates glycerol metabolism in progeny. Thus, there is a heritable link between insulin-like signalling to the maternal germline and progeny metabolism and gene expression. We speculate that analogous modulation of insulin-like signalling to the germline is responsible for effects of the maternal environment on human diseases that involve insulin signalling, such as obesity and type-2 diabetes

Bilobalide modulates serotonin-controlled behaviors in the nematode Caenorhabditis elegans

<p>Abstract</p> <p>Background</p> <p>Dysfunctions in the serotonergic system have been implicated in several neurological disorders such as depression. Elderly individuals who have been diagnosed with clinical depression show elevated cases of neurodegenerative diseases. This has led to suggestions that modulating the serotonin (5-HT) system could provide an alternative method to current therapies for alleviating these pathologies. The neuroprotective effects of bilobalide <it>in vitro </it>have been documented. We aim to determine whether bilobalide affects the 5-HT system in the nematode <it>C. elegans</it>. The wild type worms, as well as well-characterized 5-HT mutants, were fed with bilobalide in a range of concentrations, and several 5-HT controlled behaviors were tested.</p> <p>Results</p> <p>We observed that bilobalide significantly inhibited 5-HT-controlled egg-laying behavior in a dose-dependent manner, which was blocked in the 5-HT receptor mutants (<it>ser-4, mod-1</it>), but not in the 5-HT transporter (<it>mod-5</it>) or synthesis (<it>tph-1</it>) mutants. Bilobalide also potentiated a 5-HT-controlled, experience-dependent locomotory behavior, termed the enhanced slowing response in the wild type animals. However, this effect was fully blocked in 5-HT receptor <it>mod-1 </it>and dopamine defective <it>cat-2 </it>mutants, but only partially blocked in <it>ser-4 </it>mutants. We also demonstrated that acetylcholine transmission was inhibited in a transgenic <it>C. elegans </it>strain that constitutively expresses Aβ, and bilobalide did not significantly affect this inhibition.</p> <p>Conclusion</p> <p>These results suggest that bilobalide may modulate specific 5-HT receptor subtypes, which involves interplay with dopamine transmission. Additional studies for the function of bilobalide in neurotransmitter systems could aid in our understanding of its neuroprotective properties.</p

Variability in gene expression underlies incomplete penetrance

The phenotypic differences between individual organisms can often be ascribed to underlying genetic and environmental variation. However, even genetically identical organisms in homogeneous environments vary, indicating that randomness in developmental processes such as gene expression may also generate diversity. To examine the consequences of gene expression variability in multicellular organisms, we studied intestinal specification in the nematode Caenorhabditis elegans in which wild-type cell fate is invariant and controlled by a small transcriptional network. Mutations in elements of this network can have indeterminate effects: some mutant embryos fail to develop intestinal cells, whereas others produce intestinal precursors. By counting transcripts of the genes in this network in individual embryos, we show that the expression of an otherwise redundant gene becomes highly variable in the mutants and that this variation is subjected to a threshold, producing an ON/OFF expression pattern of the master regulatory gene of intestinal differentiation. Our results demonstrate that mutations in developmental networks can expose otherwise buffered stochastic variability in gene expression, leading to pronounced phenotypic variation.National Institutes of Health (U.S.). Pioneer AwardMathematical Sciences Postdoctoral Research Fellowships (DMS-0603392)National Institutes of Health (U.S.). Ruth L. Kirschstein National Research Service Award (5F32GM080966