The specific patterns and functional properties of electrical synapses of a nervous system are defined by the neuron-specific complement of electrical synapse constituents. We systematically examined ...the molecular composition of the electrical connectome of the nematode C. elegans through a genome- and nervous-system-wide analysis of the expression patterns of the invertebrate electrical synapse constituents, the innexins. We observe highly complex combinatorial expression patterns throughout the nervous system and found that these patterns change in a strikingly neuron-type-specific manner throughout the nervous system when animals enter an insulin-controlled diapause arrest stage under harsh environmental conditions, the dauer stage. By analyzing several individual synapses, we demonstrate that dauer-specific electrical synapse remodeling is responsible for specific aspects of the altered locomotory and chemosensory behavior of dauers. We describe an intersectional gene regulatory mechanism involving terminal selector and FoxO transcription factors mediating dynamic innexin expression plasticity in a neuron-type- and environment-specific manner.
Display omitted
•Mapped complex, neuron-type-specific combinatorial patterns of innexin expression•The neuron-specific innexin expression code shows remarkable plasticity under stress•Altered innexin expression leads to circuit modification and behavioral plasticity•A FoxO-dependent combinatorial mechanism controls spatiotemporal innexin plasticity
Mapping the electrical connectome of C. elegans reveals the combinatorial patterns of synaptic protein expression that dictate behaviors associated with the physiological state of the animal.
Several lines of evidence suggest that long non-coding RNA (lncRNA)-dependent mechanisms regulate transcription and CpG DNA methylation. Whereas CpG island methylation has been studied in detail, the ...significance of enhancer DNA methylation and its relationship with lncRNAs is relatively unexplored. Previous experiments proposed that the ultraconserved lncRNA Evf2 represses transcription through Dlx6 antisense (Dlx6as) transcription and methyl-CpG binding protein (MECP2) recruitment to the Dlx5/6 ultraconserved DNA regulatory enhancer (Dlx5/6ei) in embryonic day 13.5 medial ganglionic eminence (E13.5 MGE). Here, genetic epistasis experiments show that MECP2 transcriptional repression of Evf2 and Dlx5, but not Dlx6, occurs through antagonism of DLX1/2 in E13.5 MGE. Analysis of E13.5 MGE from mice lacking Evf2 and of partially rescued Evf2 transgenic mice shows that Evf2 prevents site-specific CpG DNA methylation of Dlx5/6ei in trans, without altering Dlx5/6 expression. Dlx1/2 loss increases CpG DNA methylation, whereas Mecp2 loss does not affect Dlx5/6ei methylation. Based on these studies, we propose a model in which Evf2 inhibits enhancer DNA methylation, effectively modulating competition between the DLX1/2 activator and MECP2 repressor. Evf2 antisense transcription and Evf2-dependent balanced recruitment of activator and repressor proteins enables differential transcriptional control of adjacent genes with shared DNA regulatory elements.
Many neuronal identity regulators are expressed in distinct populations of cells in the nervous system, but their function is often analyzed only in specific isolated cellular contexts, thereby ...potentially leaving overarching themes in gene function undiscovered. We show here that the
Prop1-like homeobox gene
is expressed in 15 distinct sensory, inter- and motor neuron classes throughout the entire
nervous system. Strikingly, all 15 neuron classes expressing
are synaptically interconnected, prompting us to investigate whether
controls the functional properties of this circuit and perhaps also the assembly of these neurons into functional circuitry. We found that
defines the routes of communication between these interconnected neurons by controlling the expression of neurotransmitter pathway genes, neurotransmitter receptors, neuropeptides, and neuropeptide receptors. Anatomical analysis of
mutant animals reveals defects in axon pathfinding and synaptic connectivity, paralleled by expression defects of molecules involved in axon pathfinding, cell-cell recognition, and synaptic connectivity. We conclude that
establishes functional circuitry by acting as a terminal selector of functionally connected neuron types. We identify a number of additional transcription factors that are also expressed in synaptically connected neurons and propose that terminal selectors may also function as 'circuit organizer transcription factors' to control the assembly of functional circuitry throughout the nervous system. We hypothesize that such organizational properties of transcription factors may be reflective of not only ontogenetic, but perhaps also phylogenetic trajectories of neuronal circuit establishment.
Abstract Increasing evidence suggests that GABA neuropathies play a major role in a variety of neuronal disorders. In addition, the role of non-coding RNAs in regulating a wide range of cellular ...processes is an intense area of investigation. This commentary discusses the intersection of these two fields, a corollary to the finding that adult hippocampal GABAergic interneuron development is controlled by an embryonic non-coding RNA during development.
This paper presents the design and characterization of simple and low-cost zero-bias Schottky diodes used as power detectors operating under pulsed-radio-frequency (pulsed-RF) or complex modulated ...signals in six-port-reflectometer network analyzers. Measurement results obtained at 1.8 GHz for quadrature-phase-shift-keying (QPSK) modulated signals and pulsed-RF signals for pulse durations of down to 300 ns are reported.
The safety of tacrine (Cognex), a centrally active, reversible acetylcholinesterase inhibitor approved in 1993 for the treatment of mild to moderate dementia of the Alzheimer type, was evaluated in ...2,706 patients with Alzheimer disease (AD) in clinical trials and in 9861 patients with AD in a treatment investigational new drug (TIND) program. More than 190,000 patients in the United States received tacrine during the first 2 years following marketing approval. The most common tacrine-associated adverse events were elevated liver transaminase levels alanine aminotransferase (ALT) and, to a lesser degree, aspartate aminotransferase and peripheral cholinergic events involving primarily the digestive system (nausea, vomiting, diarrhea, dyspepsia, anorexia, and weight loss). Based on clinical trial experience, potentially clinically significant (>3 x upper limit of normal) ALT elevations occurred in 25% of patients, requiring routine monitoring early in treatment. The elevations were almost always asymptomatic, rarely accompanied by significant increases in bilirubin, and related to time on drug rather than to dose (90% occurred within the first 12 weeks of treatment). Gastrointestinal events were related to dose and generally of mild to moderate intensity. Tacrine-associated events, including ALT elevations, were reversible. Cholinergic events were manageable with dosage adjustment. Tacrine was not associated with permanent liver injury in clinical trials or a TIND setting.
An original measurement system for nonlinear microwave power-transistor characterization using six-port reflectometers is presented. It allows independent active tuning of the output impedances at ...f/sub 0/ and 2f/sub 0/ (multiharmonic load-pull) and variation of the source impedance at the input port at f/sub 0/ (source-pull). An appropriate search algorithm enables automatic optimization of the output impedances and leads to fast user-friendly operation of the system. Experimental results are shown for a commercial GaAs MESFET power transistor at f/sub 0/=2 GHz.
The complete calibration of a double six-port network analyzer includes constants for the measurement of wave ratios (S-parameters) as well as constants for absolute power level measurements for ...nonlinear device characterization. This paper describes how a complete set of constants can be obtained for on-wafer measurements from a complete calibration in a coaxial measurement plane and a subsequent on-wafer calibration with the minimum number of elements.
One of the most suitable protocols for traffic engineering is multi-protocol label switching (MPLS). On the one hand, a look-up in a switching table is certainly less complex and time-consuming than ...a corresponding routing table lookup in an IP router as long as no specialized hardware such as a Content Addressable Memory is deployed. On the other hand, MPLS introduces an additional shim header that increases packet transmission delay. The question this paper intends to answer is thus if the common statement that MPLS generally allows for faster packet forwarding than IP is true. Therefore, an extensive performance evaluation based on an implementation on standard network processors is performed. It is shown that packet forwarding is only faster with MPLS when the packet size remains below certain bound, i.e. it is demonstrated that the common statement that MPLS always allows for faster packet forwarding does not even hold on standard hardware.
PDF
