Combinatorial Code Research Articles

A Functionally Conserved Gene Regulatory Network Module Governing Olfactory Neuron Diversity.

Sensory neuron diversity is required for organisms to decipher complex environmental cues. In Drosophila, the olfactory environment is detected by 50 different olfactory receptor neuron (ORN) classes that are clustered in combinations within distinct sensilla subtypes. Each sensilla subtype houses stereotypically clustered 1–4 ORN identities that arise through asymmetric divisions from a single multipotent sensory organ precursor (SOP). How each class of SOPs acquires a unique differentiation potential that accounts for ORN diversity is unknown. Previously, we reported a critical component of SOP diversification program, Rotund (Rn), increases ORN diversity by generating novel developmental trajectories from existing precursors within each independent sensilla type lineages. Here, we show that Rn, along with BarH1/H2 (Bar), Bric-à-brac (Bab), Apterous (Ap) and Dachshund (Dac), constitutes a transcription factor (TF) network that patterns the developing olfactory tissue. This network was previously shown to pattern the segmentation of the leg, which suggests that this network is functionally conserved. In antennal imaginal discs, precursors with diverse ORN differentiation potentials are selected from concentric rings defined by unique combinations of these TFs along the proximodistal axis of the developing antennal disc. The combinatorial code that demarcates each precursor field is set up by cross-regulatory interactions among different factors within the network. Modifications of this network lead to predictable changes in the diversity of sensilla subtypes and ORN pools. In light of our data, we propose a molecular map that defines each unique SOP fate. Our results highlight the importance of the early prepatterning gene regulatory network as a modulator of SOP and terminally differentiated ORN diversity. Finally, our model illustrates how conserved developmental strategies are used to generate neuronal diversity.

Cloud Audit: A Data Integrity Verification Approach for Cloud Computing

Cloud computing is the fastest growing and promising field in the sector of service provision. It is a very trendy situation for security implementation in the Cloud. Thus, security restrictions are increasing on users and service providers as the growth of Cloud environment. The purpose of this paper is to suggest a better and efficient integrity verification technique for data (referred as “Cloud Audit”). The building blocks of our technique are a variant of the Paillier homomorphic cryptography system with homomorphic tag and combinatorial batch codes. A Paillier Homomorphic Cryptography (PHC) system used to obtain homomorphic encryption on data blocks. Homomorphic tags along with the Paillier cryptography system assigns a special verifiable value to each data block, which helps us in unleashing data operations on this block. Combinatorial batch codes are used to assign and store integral data into different distributed cloud sever. To demonstrate our approach, we have implemented an application based on Hadoop and MapReduce framework. We have tested this application based on various parameters. Effectiveness of the proposed method has been shown by the experimental results. Our method has shown large improvement over the other modern methods.

To Compose a Lead: Structures Related to Change Ringing

To Compose a Lead: Structures Related to Change Ringing

Connectomics, the Final Frontier.

How the synaptic connections in the nervous system are genetically encoded and formed during development remains an unsolved problem. The known connectivity of the nervous system of the nematode C. elegans provides an opportunity to search for the genes involved. The circuits for male mating behavior form a complex neural network that would seem to require a large family of molecular cell labels for pre- and postsynaptic cell recognition. It is suggested that a combinatorial code of neural cell adhesion proteins specifying the network of connections may be discovered by comparing the expression patterns of candidate genes with the pattern of connections.

Modeling of self-organization processes in crystal-forming systems: Symmetry and topology code for cluster self-assembly of crystal structures in MT-structures of polyvalent sulfates and phosphates

We consider the supramolecular chemistry of polyvalent metal sulfates and phosphates built of M(n+)(O, OH, H2O)6 polyhedral clusters with octahedral O-coordination (M-polyhedra) and SO4 and PO4 polyhedral clusters with tetrahedral O-coordination (T-polyhedra). These compounds form molecular (insular), chain, layered, or framework 3D MT structures by means of directed (bridging) hydrogen bonds O–H…O and/or bridging covalent O-bonds. Combinatorial–topological analysis algorithms are provided to restore, from structure data, the convergent matrix crystal structure self-assembly code. Cluster self-assembly modeling has been performed for the following sulfates: MgSO4 (Pnma and Cmcm), MgSO4 ∙ 1H2O (Kieserite), and CuSO4 ∙ 3H2O (Bonattite) having 3D MT strucutres; MgSO4 ∙ 2H2O (Sanderite), MgSO4 · 2.5H2O, MnSO4 · 3H2O, and MnSO4(OH) · 2H2O having 2D MT structures; MgSO4 · 4H2O (Cranswickite) and MgSO4 · 5H2O (Pentahydrite) having 1D MT structures; and MgSO4 · 4H2O (Starkeyite) having a 0D MT structure, for the following phosphates: (VO)(HPO4) (P-1), MgSO4 · H2O (Kieserite), and CuSO4 · 3H2O (Bonattite) having 3D MT structures; (VO)(HPO4)(H2O)0.5 (P121/c1 and Pmmn), (VO)(HPO4)(H2O)2 (P4/nmm and P121/c1), V(3+)(PO4)(H2O)2 (P121/n1), V(3+)(PO4)(H2O)4 (C12/c1), and Mg(HPO4)(H2O)3 (Newberyite, Pbca) having 2D MT structures; phosphite (VO(H2O)2)(HPO3)(H2O)3 (P41) and phosphate (VO)(HPO4)(H2O)4 (P-1) having 1D MT structures. For all compounds, the symmetry and combinatorial codes of cluster self-assembly code in the form of the following sequence: precursor nanocluster S30 → primary chain S31→ microlayer S32→ microframework S33. At the stage of primary chain S31 formation, in all of MT crystal structures considered, precursor clusters are four-polyhedral MTMT chains, transor cis, and their derivatives with additional O-bonds between polyhedra and ring cluster M2T2 (the result of coiling a cis-chain into a ring). Frequency analysis of topological and symmetry pathways in the formation and evolution of MT-clusters (from primary chain S31 through microlayer S32 to microframework S33) elucidates new crystal-formation trends in diverse chemical systems at the microscopic level.

Measuring and Specifying Combinatorial Coverage of Test Input Configurations.

A key issue in testing is how many tests are needed for a required level of coverage or fault detection. Estimates are often based on error rates in initial testing, or on code coverage. For example, tests may be run until a desired level of statement or branch coverage is achieved. Combinatorial methods present an opportunity for a different approach to estimating required test set size, using characteristics of the test set. This paper describes methods for estimating the coverage of, and ability to detect, t-way interaction faults of a test set based on a covering array. We also develop a connection between (static) combinatorial coverage and (dynamic) code coverage, such that if a specific condition is satisfied, 100% branch coverage is assured. Using these results, we propose practical recommendations for using combinatorial coverage in specifying test requirements.

Dynamic expression of transcription factor Brn3b during mouse cranial nerve development

During development, transcription factor combinatorial codes define a large variety of morphologically and physiologically distinct neurons. Such a combinatorial code has been proposed for the differentiation of projection neurons of the somatic and visceral components of cranial nerves. It is possible that individual neuronal cell types are not specified by unique transcription factors but rather emerge through the intersection of their expression domains. Brn3a, Brn3b, and Brn3c, in combination with each other and/or transcription factors of other families, can define subgroups of retinal ganglion cells (RGC), spiral and vestibular ganglia, inner ear and vestibular hair cell neurons in the vestibuloacoustic system, and groups of somatosensory neurons in the dorsal root ganglia. The present study investigates the expression and potential role of the Brn3b transcription factor in cranial nerves and associated nuclei of the brainstem. We report the dynamic expression of Brn3b in the somatosensory component of cranial nerves II, V, VII, and VIII and visceromotor nuclei of nerves VII, IX, and X as well as other brainstem nuclei during different stages of development into adult stage. We find that genetically identified Brn3b(KO) RGC axons show correct but delayed pathfinding during the early stages of embryonic development. However, loss of Brn3b does not affect the anatomy of the other cranial nerves normally expressing this transcription factor.

Circuit mechanisms encoding odors and driving aging-associated behavioral declines in Caenorhabditis elegans.

Chemosensory neurons extract information about chemical cues from the environment. How is the activity in these sensory neurons transformed into behavior? Using Caenorhabditis elegans, we map a novel sensory neuron circuit motif that encodes odor concentration. Primary neurons, AWC(ON) and AWA, directly detect the food odor benzaldehyde (BZ) and release insulin-like peptides and acetylcholine, respectively, which are required for odor-evoked responses in secondary neurons, ASEL and AWB. Consistently, both primary and secondary neurons are required for BZ attraction. Unexpectedly, this combinatorial code is altered in aged animals: odor-evoked activity in secondary, but not primary, olfactory neurons is reduced. Moreover, experimental manipulations increasing neurotransmission from primary neurons rescues aging-associated neuronal deficits. Finally, we correlate the odor responsiveness of aged animals with their lifespan. Together, these results show how odors are encoded by primary and secondary neurons and suggest reduced neurotransmission as a novel mechanism driving aging-associated sensory neural activity and behavioral declines.

Postmitotic diversification of olfactory neuron types is mediated by differential activities of the HMG‐box transcription factor SOX‐2

Diversification of neuron classes is essential for functions of the olfactory system, but the underlying mechanisms that generate individual olfactory neuron types are only beginning to be understood. Here we describe a role of the highly conserved HMG-box transcription factor SOX-2 in postmitotic specification and alternative differentiation of the Caenorhabditis elegans AWC and AWB olfactory neurons. We show that SOX-2 partners with different transcription factors to diversify postmitotic olfactory cell types. SOX-2 functions cooperatively with the OTX/OTD transcription factor CEH-36 to specify an AWC "ground state," and functions with the LIM homeodomain factor LIM-4 to suppress this ground state and drive an AWB identity instead. Our findings provide novel insights into combinatorial codes that drive terminal differentiation programs in the nervous system and reveal a biological function of the deeply conserved Sox2 protein that goes beyond its well-known role in stem cell biology.

Spatiotemporal Coding of Individual Chemicals by the Gustatory System.

Our results provide a new view of taste processing. Using a new, relatively simple model system and a new set of techniques to deliver taste stimuli and to examine gustatory receptor neurons and their immediate followers, we found no evidence for labeled line connectivity, or basic taste categories such as sweet, salty, bitter, and sour. Rather, individual tastant chemicals are represented as patterns of spiking activity distributed across populations of receptor neurons. These representations are transformed substantially as multiple types of receptor neurons converge upon follower neurons, leading to a combinatorial coding format that uniquely, rapidly, and efficiently represents individual taste chemicals. Finally, we found that the information content of these neurons can drive tastant-specific behavior.

Molecular profiling of activated olfactory neurons identifies odorant receptors for odors in vivo.

The mammalian olfactory system uses a large family of odorant receptors to detect and discriminate amongst a myriad of volatile odor molecules. Understanding odor coding requires comprehensive mapping between odorant receptors and corresponding odors. Here we present high–throughput in vivo identification of odorant receptor repertoires responding to odorants, using phosphorylated ribosome immunoprecipitation of mRNA from olfactory epithelium of odor–stimulated mice followed by RNA–Seq. This approach screens the endogenously expressed odorant receptors against an odor in one set of experiments, using awake and freely behaving mice. In combination with validations in a heterologous system, we identify sets of odorant receptors for two odorants, acetophenone and 2,5–dihydro–2,4,5–trimethylthiazoline (TMT), encompassing 69 odorant receptor–odorant pairs. We also identified shared amino acid residues specific to the acetophenone or TMT receptors, and developed models to predict receptor activation by acetophenone. This study provides a means to understand the combinatorial coding of odors in vivo.

Differential Function of Arabidopsis SERK Family Receptor-like Kinases in Stomatal Patterning

Plants use cell-surface-resident receptor-like kinases (RLKs) to sense diverse extrinsic and intrinsic cues and elicit distinct biological responses. In Arabidopsis, ERECTA family RLKs recognize EPIDERMAL PATTERNING FACTORS (EPFs) to specify stomatal patterning. However, little is known about the molecular link between ERECTA activation and intracellular signaling. We report here thatthe SOMATIC EMBRYOGENESIS RECEPTOR KINASE (SERK) family RLKs regulate stomatal patterning downstream of EPF ligands and upstream of a MAP kinase cascade. EPF ligands induce the heteromerization of ERECTA and SERK family RLKs. SERK and ERECTA family RLKs transphosphorylate each other. In addition, SERKs associate with the receptor-like protein (RLP) TMM, a signal modulator of stomata development, in a ligand-independent manner, suggesting that ERECTA, SERKs, and TMM form a multiprotein receptorsome consisting of different RLKs and RLP perceiving peptide ligands to regulate stomatalpatterning. In contrast to the differential requirement of individual SERK members in plant immunity, cell-death control, and brassinosteroid (BR) signaling, all four functional SERKs are essential but have unequal genetic contributions to stomatal patterning, with descending order of importance from SERK3/BAK1 to SERK2 to SERK1 to SERK4. Although BR signaling connects stomataldevelopment via multiple components, the function of SERKs in stomatal patterning is uncoupled from their involvement in BR signaling. Our results reveal that the SERK family is a sharedkey module in diverse Arabidopsis signaling receptorsomes and that different combinatorial codes of individual SERK members regulate distinct functions.

The study of the Bithorax-complex genes in patterning CCAP neurons reveals a temporal control of neuronal differentiation by Abd-B.

ABSTRACTDuring development, HOX genes play critical roles in the establishment of segmental differences. In the Drosophila central nervous system, these differences are manifested in the number and type of neurons generated by each neuroblast in each segment. HOX genes can act either in neuroblasts or in postmitotic cells, and either early or late in a lineage. Additionally, they can be continuously required during development or just at a specific stage. Moreover, these features are generally segment-specific. Lately, it has been shown that contrary to what happens in other tissues, where HOX genes define domains of expression, these genes are expressed in individual cells as part of the combinatorial codes involved in cell type specification. In this report we analyse the role of the Bithorax-complex genes – Ultrabithorax, abdominal-A and Abdominal-B – in sculpting the pattern of crustacean cardioactive peptide (CCAP)-expressing neurons. These neurons are widespread in invertebrates, express CCAP, Bursicon and MIP neuropeptides and play major roles in controlling ecdysis. There are two types of CCAP neuron: interneurons and efferent neurons. Our results indicate that Ultrabithorax and Abdominal-A are not necessary for specification of the CCAP-interneurons, but are absolutely required to prevent the death by apoptosis of the CCAP-efferent neurons. Furthermore, Abdominal-B controls by repression the temporal onset of neuropeptide expression in a subset of CCAP-efferent neurons, and a peak of ecdysone hormone at the end of larval life counteracts this repression. Thus, Bithorax complex genes control the developmental appearance of these neuropeptides both temporally and spatially.

Using Grid Cells for Navigation

SummaryMammals are able to navigate to hidden goal locations by direct routes that may traverse previously unvisited terrain. Empirical evidence suggests that this “vector navigation” relies on an internal representation of space provided by the hippocampal formation. The periodic spatial firing patterns of grid cells in the hippocampal formation offer a compact combinatorial code for location within large-scale space. Here, we consider the computational problem of how to determine the vector between start and goal locations encoded by the firing of grid cells when this vector may be much longer than the largest grid scale. First, we present an algorithmic solution to the problem, inspired by the Fourier shift theorem. Second, we describe several potential neural network implementations of this solution that combine efficiency of search and biological plausibility. Finally, we discuss the empirical predictions of these implementations and their relationship to the anatomy and electrophysiology of the hippocampal formation.

Gene Expression Data from the Moon Jelly, Aurelia, Provide Insights into the Evolution of the Combinatorial Code Controlling Animal Sense Organ Development.

In Bilateria, Pax6, Six, Eya and Dach families of transcription factors underlie the development and evolution of morphologically and phyletically distinct eyes, including the compound eyes in Drosophila and the camera-type eyes in vertebrates, indicating that bilaterian eyes evolved under the strong influence of ancestral developmental gene regulation. However the conservation in eye developmental genetics deeper in the Eumetazoa, and the origin of the conserved gene regulatory apparatus controlling eye development remain unclear due to limited comparative developmental data from Cnidaria. Here we show in the eye-bearing scyphozoan cnidarian Aurelia that the ectodermal photosensory domain of the developing medusa sensory structure known as the rhopalium expresses sine oculis (so)/six1/2 and eyes absent/eya, but not optix/six3/6 or pax (A&B). In addition, the so and eya co-expression domain encompasses the region of active cell proliferation, neurogenesis, and mechanoreceptor development in rhopalia. Consistent with the role of so and eya in rhopalial development, developmental transcriptome data across Aurelia life cycle stages show upregulation of so and eya, but not optix or pax (A&B), during medusa formation. Moreover, pax6 and dach are absent in the Aurelia genome, and thus are not required for eye development in Aurelia. Our data are consistent with so and eya, but not optix, pax or dach, having conserved functions in sensory structure specification across Eumetazoa. The lability of developmental components including Pax genes relative to so-eya is consistent with a model of sense organ development and evolution that involved the lineage specific modification of a combinatorial code that specifies animal sense organs.

What the fly’s nose tells the fly’s brain

The fly olfactory system has a three-layer architecture: The fly's olfactory receptor neurons send odor information to the first layer (the encoder) where this information is formatted as combinatorial odor code, one which is maximally informative, with the most informative neurons firing fastest. This first layer then sends the encoded odor information to the second layer (decoder), which consists of about 2,000 neurons that receive the odor information and "break" the code. For each odor, the amplitude of the synaptic odor input to the 2,000 second-layer neurons is approximately normally distributed across the population, which means that only a very small fraction of neurons receive a large input. Each odor, however, activates its own population of large-input neurons and so a small subset of the 2,000 neurons serves as a unique tag for the odor. Strong inhibition prevents most of the second-stage neurons from firing spikes, and therefore spikes from only the small population of large-input neurons is relayed to the third stage. This selected population provides the third stage (the user) with an odor label that can be used to direct behavior based on what odor is present.

Enteric glia express proteolipid protein 1 and are a transcriptionally unique population of glia in the mammalian nervous system.

In the enteric nervous system (ENS), glia outnumber neurons by 4-fold and form an extensive network throughout the gastrointestinal tract. Growing evidence for the essential role of enteric glia in bowel function makes it imperative to understand better their molecular marker expression and how they relate to glia in the rest of the nervous system. We analyzed expression of markers of astrocytes and oligodendrocytes in the ENS and found, unexpectedly, that proteolipid protein 1 (PLP1) is specifically expressed by glia in adult mouse intestine. PLP1 and S100β are the markers most widely expressed by enteric glia, while glial fibrillary acidic protein expression is more restricted. Marker expression in addition to cellular location and morphology distinguishes a specific subpopulation of intramuscular enteric glia, suggesting that a combinatorial code of molecular markers can be used to identify distinct subtypes. To assess the similarity between enteric and extraenteric glia, we performed RNA sequencing analysis on PLP1-expressing cells in the mouse intestine and compared their gene expression pattern to that of other types of glia. This analysis shows that enteric glia are transcriptionally unique and distinct from other cell types in the nervous system. Enteric glia express many genes characteristic of the myelinating glia, Schwann cells and oligodendrocytes, although there is no evidence of myelination in the murine ENS. GLIA 2015;63:2040-2057.

Gray codes and lexicographical combinatorial generation for nonnesting and sparse nonnesting set partitions

We present combinatorial Gray codes and explicit designs of efficient algorithms for lexicographical combinatorial generation of the sets of nonnesting and sparse nonnesting set partitions of length n.

Insect olfaction and the evolution of receptor tuning

Insects detect odorants primarily using odorant receptors (OR) housed in the dendritic membrane of olfactory sensory neurons (OSN). Pioneering studies indicated that insects, like mammals, detect odorants in a combinatorial fashion with a specific odor ligand activating several broadly tuned ORs, and each OR being activated by several ligands. Several recent studies, however, challenge this view by providing examples where ecologically relevant odorants are detected by high-specificity ORs activating dedicated neuronal circuits. Here we review these contrasting findings on the ligand selectivity of insect ORs and their neuronal wiring, and outline scenarios describing how adaptive and neutral evolution might shape both narrow and broad receptor tuning. The fact that not all ORs display narrow tuning might partly be due to key ligands having been missed from screens or too high stimuli concentrations being used. However, the birth-and-death model of OR evolution, involving both adaptive and neutral events, could also explain the evolution of broad tuning in certain receptors due to positive selection or relaxed constraint. If the insect olfactory system indeed contains both narrowly and broadly tuned ORs, this suggests that it is a hybrid between dedicated channels and combinatorial coding. The relative extent of the two coding modes is then likely to differ between species, depending on requirements of perceived chemical space and the size of the OR repertoire. We address this by outlining scenarios where certain insect groups may be more likely to have evolved combinatorial coding as their dominant coding strategy. Combinatorial coding may have evolved predominantly in insects that benefit from the ability to discriminate between a larger number of odorants and odor objects, such as polyphagous or social species. Alternatively, combinatorial coding may have evolved simply as a mechanism to increase perceived odor space in species with small OR repertoires.

Evolution of retinoic acid receptors in chordates: insights from three lamprey species, Lampetra fluviatilis, Petromyzon marinus, and Lethenteron japonicum

BackgroundRetinoic acid (RA) signaling controls many developmental processes in chordates, from early axis specification to late organogenesis. The functions of RA are chiefly mediated by a subfamily of nuclear hormone receptors, the retinoic acid receptors (RARs), that act as ligand-activated transcription factors. While RARs have been extensively studied in jawed vertebrates (that is, gnathostomes) and invertebrate chordates, very little is known about the repertoire and developmental roles of RARs in cyclostomes, which are extant jawless vertebrates. Here, we present the first extensive study of cyclostome RARs focusing on three different lamprey species: the European freshwater lamprey, Lampetra fluviatilis, the sea lamprey, Petromyzon marinus, and the Japanese lamprey, Lethenteron japonicum.ResultsWe identified four rar paralogs (rar1, rar2, rar3, and rar4) in each of the three lamprey species, and phylogenetic analyses indicate a complex evolutionary history of lamprey rar genes including the origin of rar1 and rar4 by lineage-specific duplication after the lamprey-hagfish split. We further assessed their expression patterns during embryonic development by in situ hybridization. The results show that lamprey rar genes are generally characterized by dynamic and highly specific expression domains in different embryonic tissues. In particular, lamprey rar genes exhibit combinatorial expression domains in the anterior central nervous system (CNS) and the pharyngeal region.ConclusionsOur results indicate that the genome of lampreys encodes at least four rar genes and suggest that the lamprey rar complement arose from vertebrate-specific whole genome duplications followed by a lamprey-specific duplication event. Moreover, we describe a combinatorial code of lamprey rar expression in both anterior CNS and pharynx resulting from dynamic and highly specific expression patterns during embryonic development. This ‘RAR code’ might function in regionalization and patterning of these two tissues by differentially modulating the expression of downstream effector genes during development.Electronic supplementary materialThe online version of this article (doi:10.1186/s13227-015-0016-4) contains supplementary material, which is available to authorized users.