Pre-existing Pathways Research Articles

Coherent pathway enrichment estimation by modeling inter-pathway dependencies using regularized regression.

Gene set enrichment methods are a common tool to improve the interpretability of gene lists as obtained, for example, from differential gene expression analyses. They are based on computing whether dysregulated genes are located in certain biological pathways more often than expected by chance. Gene set enrichment tools rely on pre-existing pathway databases such as KEGG, Reactome, or the Gene Ontology. These databases are increasing in size and in the number of redundancies between pathways, which complicates the statistical enrichment computation. We address this problem and develop a novel gene set enrichment method, called pareg, which is based on a regularized generalized linear model and directly incorporates dependencies between gene sets related to certain biological functions, for example, due to shared genes, in the enrichment computation. We show that pareg is more robust to noise than competing methods. Additionally, we demonstrate the ability of our method to recover known pathways as well as to suggest novel treatment targets in an exploratory analysis using breast cancer samples from TCGA. pareg is freely available as an R package on Bioconductor (https://bioconductor.org/packages/release/bioc/html/pareg.html) as well as on https://github.com/cbg-ethz/pareg. The GitHub repository also contains the Snakemake workflows needed to reproduce all results presented here.

Molecular Basis and Evolutionary Origin of 1-Nitronaphthalene Catabolism in Sphingobium sp. Strain JS3065.

Nitrated polycyclic aromatic hydrocarbons (nitro-PAHs) enter the environment from natural sources and anthropogenic activities. To date, microorganisms able to mineralize nitro-PAHs have not been reported. Here, Sphingobium sp. strain JS3065 was isolated by selective enrichment for its ability to grow on 1-nitronaphthalene as the sole carbon, nitrogen, and energy source. Analysis of the complete genome of strain JS3065 indicated that the gene cluster encoding 1-nitronaphthalene catabolism (nin) is located on a plasmid. Based on the genetic and biochemical evidence, the nin genes share an origin with the nag-like genes encoding naphthalene degradation in Ralstonia sp. strain U2. The initial step in degradation of 1-nitronaphthalene is catalyzed by a three-component dioxygenase, NinAaAbAcAd, resulting in formation of 1,2-dihydroxynaphthalene which is also an early intermediate in the naphthalene degradation pathway. Introduction of the ninAaAbAcAd genes into strain U2 enabled its growth on 1-nitronaphthalene. Phylogenic analysis of NinAc suggested that an ancestral 1-nitronaphthalene dioxygenase was an early step in the evolution of nitroarene dioxygenases. Based on bioinformatic analysis and enzyme assays, the subsequent assimilation of 1,2-dihydroxynaphthalene seems to follow the well-established pathway for naphthalene degradation by Ralstonia sp. strain U2. This is the first report of catabolic pathway for 1-nitronaphthalene and is another example of how expanding the substrate range of Rieske type dioxygenase enables bacteria to grow on recalcitrant nitroaromatic compounds. IMPORTANCE Nitrated polycyclic aromatic hydrocarbons (nitro-PAHs) have been widely detected in the environment and they are more toxic than their corresponding parent PAHs. Although biodegradation of many PAHs has been extensively described at genetic and biochemical levels, little is known about the microbial degradation of nitro-PAHs. This work reports the isolation of a Sphingobium strain growing on 1-nitronaphthalene and the genetic basis for the catabolic pathway. The pathway evolved from an ancestral naphthalene catabolic pathway by a remarkably small modification in the specificity of the initial dioxygenase. Data presented here not only shed light on the biochemical processes involved in the microbial degradation of globally important nitrated polycyclic aromatic hydrocarbons, but also provide an evolutionary paradigm for how bacteria evolve a novel catabolic pathway with minimal alteration of preexisting pathways for natural organic compounds.

The impact of an enhanced recovery programme on length of stay and post-discharge resource usage following hip and knee arthroplasty : a service evaluation and cost analysis.

AimsThe aim of this study is to assess the impact of a pilot enhanced recovery after surgery (ERAS) programme on length of stay (LOS) and post-discharge resource usage via service evaluation and cost analysis.MethodsBetween May and December 2019, 100 patients requiring hip or knee arthroplasty were enrolled with the intention that each would have a preadmission discharge plan, a preoperative education class with nominated helper, a day of surgery admission and mobilization, a day one discharge, and access to a 24/7 dedicated helpline. Each was matched with a patient under the pre-existing pathway from the previous year.ResultsMean LOS for ERAS patients was 1.59 days (95% confidence interval (CI) 1.14 to 2.04), significantly less than that of the matched cohort (3.01 days; 95% CI 2.56 to 3.46). There were no significant differences in readmission rates for ERAS patients at both 30 and 90 days (six vs four readmissions at 30 days, and nine vs four at 90 days). Despite matching, there were significantly more American Society of Anesthesiologists (ASA) grade 3 patients in the ERAS cohort. There was a mean cost saving of £757.26 (95% CI £-1,200.96 to £-313.56) per patient. This is despite small increases in postoperative resource usage in the ERAS patients.ConclusionERAS represents a safe and effective means of reducing LOS in primary joint arthroplasty patients. Implementation of ERAS principles has potential financial savings and could increase patient throughput without compromising care. In elective care, a preadmission discharge plan is key.Cite this article: Bone Jt Open 2021;2(11):966–973.

Walking the forest imaginary: A breath between us

Walking the forest imaginary: a breath between us is a site-specific audio artwork that invites the audience to walk into the forest imaginary populated by things magical and unseen. Crafted uniquely in response to Alingsås Nolhaga Park, and using cues in the landscape as guides to research and poetic inscription, the artwork consists of an approximately one-hour walk with audio listening points throughout the park. Audio is accessed digitally through QR codes posted on pre-existing pathways and listened to with individual headphones. Wandering pathways through the woods, participants listen to a hybrid essay that explores the alternate spaces and time scales of the miniature worlds of moss. Focusing on the ancient and present role of bryophytes in creating oxygen and storing carbon, and helping to keep our ecosystem in balance, the work considers this ancient exchange as a form of dialogue.

Synchronous and Asynchronous Response in Dynamically Perturbed Proteins.

We present a dynamic perturbation-response model of proteins based on the Gaussian Network Model, where a residue is perturbed periodically, and the dynamic response of other residues is determined. The model shows that periodic perturbation causes a synchronous response in phase with the perturbation and an asynchronous response that is out of phase. The asynchronous component results from the viscous effects of the solvent and other dispersive factors in the system. The model is based on the solution of the Langevin equation in the presence of solvent, noise, and perturbation. We introduce several novel ideas: The concept of storage and loss compliance of the protein and their dependence on structure and frequency; the amount of work lost and the residues that contribute significantly to the lost work; new dynamic correlations that result from perturbation; causality, that is, the response of j when i is perturbed is not equal to the response of i when j is perturbed. As examples, we study two systems, namely, bovine rhodopsin and the class of nanobodies. The general results obtained are (i) synchronous and asynchronous correlations depend strongly on the frequency of perturbation, their magnitude decreases with increasing frequency, (ii) time-delayed mean-squared fluctuations of residues have only synchronous components. Asynchronicity is present only in cross correlations, that is, correlations between different residues, (iii) perturbation of loop residues leads to a large dissipation of work, (iv) correlations satisfy the hypothesis of pre-existing pathways according to which information transfer by perturbation rides on already existing equilibrium correlations in the system, (v) dynamic perturbation can introduce a selective response in the system, where the perturbation of each residue excites different sets of responding residues, and (vi) it is possible to identify nondissipative residues whose perturbation does not lead to dissipation in the protein. Despite its simplicity, the model explains several features of allosteric manipulation.

A systematic pipeline for classifying bacterial operons reveals the evolutionary landscape of biofilm machineries.

In bacteria functionally related genes comprising metabolic pathways and protein complexes are frequently encoded in operons and are widely conserved across phylogenetically diverse species. The evolution of these operon-encoded processes is affected by diverse mechanisms such as gene duplication, loss, rearrangement, and horizontal transfer. These mechanisms can result in functional diversification, increasing the potential evolution of novel biological pathways, and enabling pre-existing pathways to adapt to the requirements of particular environments. Despite the fundamental importance that these mechanisms play in bacterial environmental adaptation, a systematic approach for studying the evolution of operon organization is lacking. Herein, we present a novel method to study the evolution of operons based on phylogenetic clustering of operon-encoded protein families and genomic-proximity network visualizations of operon architectures. We applied this approach to study the evolution of the synthase dependent exopolysaccharide (EPS) biosynthetic systems: cellulose, acetylated cellulose, poly-β-1,6-N-acetyl-D-glucosamine (PNAG), Pel, and alginate. These polymers have important roles in biofilm formation, antibiotic tolerance, and as virulence factors in opportunistic pathogens. Our approach revealed the complex evolutionary landscape of EPS machineries, and enabled operons to be classified into evolutionarily distinct lineages. Cellulose operons show phyla-specific operon lineages resulting from gene loss, rearrangement, and the acquisition of accessory loci, and the occurrence of whole-operon duplications arising through horizonal gene transfer. Our evolution-based classification also distinguishes between PNAG production from Gram-negative and Gram-positive bacteria on the basis of structural and functional evolution of the acetylation modification domains shared by PgaB and IcaB loci, respectively. We also predict several pel-like operon lineages in Gram-positive bacteria and demonstrate in our companion paper (Whitfield et al PLoS Pathogens, in press) that Bacillus cereus produces a Pel-dependent biofilm that is regulated by cyclic-3',5'-dimeric guanosine monophosphate (c-di-GMP).

A Comparative Study of All-atom Molecular Dynamics Simulation and Coarse-grained Normal Mode Analysis in Identifying Pre-existing Residue Interaction Networks that Promote Coupled-Domain Dynamics in Escherichia coli Methionyl-tRNA Synthetase

Inter-domain communication plays a key role in the function of modular proteins. Earlier studies have demonstrated that the coupling of domain motions is important in mediating site-to-site communications in modular proteins. In the present study, bioinformatics and molecular simulations were usedto trace “pre-existing” residue-residue interaction networks that mediate coupled-domain dynamics in multi-domain Escherichia coli methionyl-tRNA synthetase (Ec MetRS). In particular, a comparative study was carried out to evaluate the effectiveness of coarse-grained normal mode analysis and all-atom molecular dynamic simulation in predicting pre-existing pathways of inter-domain communications in this enzyme. Integration of dynamic information of residues with their evolutionary features (conserved and coevolved) demonstrated that multiple residue-residue interaction networks exist in Ec MetRS that promote dynamic coupling between the anticodon binding domain and the connective polypeptide I domain, which are > 50Å apart, through correlated motions. Mutation of residues on these pathways have distinct impact on the dynamics and function of this enzyme. Moreover, the present study revealed that the dynamic information obtained from the coarse-grained normal mode analysis is comparable to the atomistic molecular dynamics simulations in predicting the interaction networks that are essential for promoting coupled-domain dynamics in Ec MetRS. KEYWORDS: Domain-domain Communication; Molecular Dynamics; Methionyl-tRNA Synthetase; Normal Mode Analysis; Coupled-domain Dynamics; Course-grained Normal Mode Analysis; Aminoacyl tRNA Synthetases; Statistical Coupling Analysis

Reliable and Elastic Propagation of Cortical Seizures In Vivo

Mapping the fine-scale neural activity that underlies epilepsy is key to identifying potential control targets of this frequently intractable disease. Yet, the detailed invivo dynamics of seizure progression in cortical microcircuits remain poorly understood. We combine fast (30-Hz) two-photon calcium imaging with local field potential (LFP) recordings to map, cell by cell, the spread of locally induced (4-AP orpicrotoxin) seizures in anesthetized and awake mice. Using single-layer and microprism-assisted multilayer imaging in different cortical areas, we uncover reliable recruitment of local neural populations within and across cortical layers, and we find layer-specific temporal delays, suggesting an initial supra-granular invasion followed by deep-layer recruitment during lateral seizure spread. Intriguingly, despite consistent progression pathways, successive seizures show pronounced temporal variability that critically depends on GABAergic inhibition. We propose an epilepsy circuit model resembling an elastic meshwork, wherein ictal progression faithfully follows preexistent pathways but varies flexibly in time, depending on the local inhibitory restraint.

Commentary: Conservation of AtTZF1, AtTZF2, and AtTZF3 homolog gene regulation by salt stress in evolutionarily distant plant species.

Commentary: Conservation of AtTZF1, AtTZF2, and AtTZF3 homolog gene regulation by salt stress in evolutionarily distant plant species.

The non-genomic effects of endocrine-disrupting chemicals on mammalian sperm.

Exposure to toxicants present in the environment, especially the so-called endocrine-disrupting chemicals (EDCs), has been associated with decreased sperm quality and increased anomalies in male reproductive organs over the past decades. Both human and animal populations are continuously exposed to ubiquitous synthetic and natural-occurring EDCs through diet, dermal contact and/or inhalation, therefore potentially compromising male reproductive health. Although the effects of EDC are likely induced via multiple genomic-based pathways, their non-genomic effects may also be relevant. Furthermore, spermatozoa are transcriptionally inactive cells that can come in direct contact with EDCs in reproductive fluids and secretions and are therefore a good model to address non-genomic effects. This review thus focuses on the non-genomic effects of several important EDCs relevant to mammalian exposure. Notably, EDCs were found to interfere with pre-existing pathways inducing a panoply of deleterious effects to sperm function that included altered intracellular Ca(2) (+) oscillations, induction of oxidative stress, mitochondrial dysfunction, increased DNA damage and decreased sperm motility and viability, among others, potentially jeopardizing male fertility. Although many studies have used non-environmentally relevant concentrations of only one compound for mechanistic studies, it is important to remember that mammals are not exposed to one, but rather to a multitude of environmental EDCs, and synergistic effects may occur. Furthermore, some effects have been detected with single compounds at environmentally relevant concentrations.

Application of the proximity-dependent assay and fluorescence imaging approaches to study viral entry pathways.

Virus entry into cells is a complex, multistep process that requires the coordinated activities of a large number of cellular factors and multiple membrane compartments. Because viruses can enter cells via one or more of a large number of preexisting pathways, understanding the mechanism of virus entry and transport between various intracellular compartments is a challenging task. The arrival of "omics" technologies such as genome-wide RNA interference screens has greatly advanced our ability to study the molecular intricacies of viral entry. Bioinformatics analyses of high-throughput screen data can identify enriched gene categories and specific individual genes required for infection, which can yield important insights into the cellular compartments that viruses traverse during infection. Although there are a variety of well-established genetic and biochemical approaches to validate genome-wide screen findings, confirmation of phenotypes obtained from RNA interference studies remains an important challenge. Imaging techniques commonly used to visualize virus localization to cellular organelles are often prone to artifacts that result from the necessity of using a high multiplicity of infection. Fortunately, recent advances in microscopy-based methods for studying protein location have improved our ability to accurately pinpoint virus localization within its host cell. Here we describe in detail one such technique-the proximity ligation assay (PLA)-as a tool to validate findings from a genome-wide loss-of-function genetic screen. In addition, we discuss a number of important considerations for the utilization of immunofluorescence microscopy and RNA interference to investigate the molecular mechanisms of virus entry.

484 Treatment of advanced solid tumors with golvatinib (E7050) in combination with lenvatinib (E7080)

Background: Lenvatinib (L) is an oral multi-targeted tyrosine kinase inhibitor of VEGFR 1−3, FGFR 1−4, PDGFRa, RET and KIT (Phase 1 single-agent MTD 24mg QD). Golvatinib (G) is a highly potent, small molecule ATP-competitive inhibitor of the MET receptor tyrosine kinase and multiple members of the Eph receptor family as well as KIT and RON, based on isolated kinase assays (Phase 1 single-agent MTD 400mg QD). Combination therapy with agents that block MET, VEGF, FGF, PDGFa and ephrin signaling constitutes a promising approach to circumvent adaptive or pre-existing tumor resistance pathways, and preclinical models indicate that the combination of L and G could overcome some intrinsic resistance to each agent. This Phase 1b study assessed safety, MTD, and preliminary antitumor activity of L plus G in patients (pts) with advanced solid tumors. Methods: Pts with advanced solid tumors, ECOG PS 0−1, 18 years (yrs) and adequate organ function were eligible. Starting dose was 12mg/day L and 200mg/day G once daily administered continuously in 28-day cycles in a conventional 3+3 dose escalation design (dose range 12−20mg/day L and 200–400mg/day G). An expansion cohort confirmed the MTD and established the recommended Phase 2 (RP2) dose. Results: 28 pts (M/F: 15/13; median age 61.5 yrs [range 34−75]) received combination dosing (median exposure 2.5 cycles [range 1−13], 8 pts ongoing at data cut) of L plus G in escalation cohorts (12mg + 200mg [n = 3]; 20mg + 200mg [n = 3]; 20mg +300mg [n = 6]; 20mg + 400mg [n = 8]) and in the expansion cohort 20mg +300mg [n = 8]. Two DLTs (at 20mg + 400mg) were observed during dose escalation: elevated AST and hyponatremia (1 pt) and inability to achieve at least 75% of planned dose in cycle 1 due to fatigue. The MTD/RP2 dose was determined to be 20mg L + 300mg G (4 DLTs in 14 evaluable pts [6 pts escalation cohort and 8 pts expansion cohort] at this dosing level). Frequently (>30%) occurring AEs of any grade and irrespective of relationship were fatigue, diarrhoea, nausea, vomiting, decreased appetite and dehydration. One fatal event of dyspnea, 21 days after discontinuing study drug for progressive disease, was observed. There was 1 possibly related G4 event of bowel perforation in the expansion cohort. Confirmed partial responses were seen in 5 (28%) pts [prostate (2 pts), endometrial (2 pts) and nasopharyngeal cancer]. Stable disease for at least 8 weeks was seen in an additional 13 pts. Conclusions: The MTD and RP2 dose was lenvatinib 20mg combined with golvatinib 300mg. This dose combination toxicity was consistent with the individual agents’ toxicity profiles, and there were no new safety signals identified. The observed activity warrants further evaluation of the combination in patients with advanced solid tumors.

Trigemino-cervical-spinal reflexes after traumatic spinal cord injury

ObjectiveAfter spinal cord injury (SCI) reorganization of spinal cord circuits occur both above and below the spinal lesion. These functional changes can be determined by assessing electrophysiological recording. We aimed at investigating the trigemino-cervical reflex (TCR) and trigemino-spinal reflex (TSR) responses after traumatic SCI. MethodsTCR and TSR were registered after stimulation of the infraorbital nerve from the sternocleidomastoid, splenius, deltoid, biceps and first dorsal interosseous muscles in 10 healthy subjects and 10 subjects with incomplete cervical SCI. ResultsIn the control subjects reflex responses were registered from the sternocleidomastoid, and splenium muscles, while no responses were obtained from upper limb muscles. In contrast, smaller but clear short latency EMG potentials were recorded from deltoid and biceps muscles in about half of the SCI patients. Moreover, the amplitudes of the EMG responses in the neck muscles were significantly higher in patients than in control subjects. ConclusionThe reflex responses are likely to propagate up the brainstem and down the spinal cord along the reticulospinal tracts and the propriospinal system. Despite the loss of corticospinal axons, synaptic plasticity in pre-existing pathways and/or formation of new circuits through sprouting processes above the injury site may contribute to the findings of this preliminary study and may be involved in the functional recovery. SignificanceTrigemino-cervical-spinal reflexes can be used to demonstrate and quantify plastic changes at brainstem and cervical level following SCI.

B-cell receptor signalling and its crosstalk with other pathways in normal and malignant cells.

The physiology of B cells is intimately connected with the function of their B-cell receptor (BCR). B-cell lymphomas frequently (dys)regulate BCR signalling and thus take advantage of this pre-existing pathway for B-cell proliferation and survival. This has recently been underscored by clinical trials demonstrating that small molecules (fosfamatinib, ibrutinib, idelalisib) inhibiting BCR-associated kinases (SYK, BTK, PI3K) have an encouraging clinical effect. Here we describe the current knowledge of the specific aspects of BCR signalling in diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukaemia (CLL) and normal B cells. Multiple factors can contribute to BCR pathway (dys)regulation in these malignancies and the activation of 'chronic' or 'tonic' BCR signalling. In lymphoma B cells, the balance of initiation, amplitude and duration of BCR activation can be influenced by a specific immunoglobulin structure, the expression and mutations of adaptor molecules (like GAB1, BLNK, GRB2, CARD11), the activity of kinases (like LYN, SYK, PI3K) or phosphatases (like SHIP-1, SHP-1 and PTEN) and levels of microRNAs. We also discuss the crosstalk of BCR with other signalling pathways (NF-κB, adhesion through integrins, migration and chemokine signalling) to emphasise that the 'BCR inhibitors' target multiple pathways interconnected with BCR, which might explain some of their clinical activity.

Engaging novel cell types, protein targets and efficacy biomarkers in the treatment of diabetic nephropathy.

EDITORIAL article Front. Pharmacol., 07 August 2014Sec. Experimental Pharmacology and Drug Discovery https://doi.org/10.3389/fphar.2014.00185

Morphometry of subaerial shield volcanoes and glaciovolcanoes from Reykjanes Peninsula, Iceland: Effects of eruption environment

We present a morphometric study of 33 basaltic volcanic edifices from the Reykjanes Peninsula, Iceland, using a 20m resolution digital elevation model (DEM). Slope values distinguish subaerial from intraglacial eruption environments, with glaciovolcanic edifices having average slope values that are >5° higher than subaerial shields. The 26 analyzed glaciovolcanic edifices are separated into 3 groups based on size, and are also categorized following the new classification scheme of tuyas by Russell et al. (2014), into 15 tindars, 1 conical tuya, 3 flat-topped tuyas and 7 complex tuyas.The glaciovolcanic edifices show a continuum of landforms ranging from small elongated tindars to large equidimensional flat-topped tuyas. The smaller edifices (<0.01km3) are all tindars and the larger edifices (>0.1km3) are flat-topped tuyas. The mid-sized edifices (0.01–0.1km3) show a wide variety of shapes and classify either as tindars or as complex tuyas, with only one edifice classifying as a conical tuya. Edifice elongation tends to decrease with volume, suggesting that small edifices are primarily fissure controlled, whereas larger edifices are mainly controlled by a central vent. The mid-sized complex tuyas are transitional edifices, suggesting that some intraglacial eruptions start as fissure eruptions that subsequently concentrate into one or more central vents, whereas the mid-sized tindars suggest a sustained fissure eruption.There is a tectonic control on the orientation of the edifices evidenced by a strong correlation between edifice elongation azimuth and mapped faults and fractures. Most edifice elongations cluster between 020° and 080°, coinciding with the strike of normal faults within and at the boundary of regional volcanic systems, but some edifices have elongations that correlate with N–S striking book-shelf faults. This implies that intraglacial eruptions are controlled by pre-existing pathways in the crust, as has been previously observed for subaerial fissure eruptions.In terms of classification, quantification of the limits between the four tuya types proposed by Russell et al. (2014) is difficult because of the transitional nature shown by several edifices. A threshold of 1.8 in ellipticity index (E.I.) values can be used to distinguish tindars from the other three types. Flat-topped tuyas are distinguished by their greater overall size, their large and relatively flat summit regions, reflected in bimodal slope distributions, and their low E.I. and low to intermediate irregularity index (I.I.) values. The only analyzed conical tuya has very low E.I. and I.I. values, very small summit regions and very steep flank slopes. The complex tuyas have variable morphometries, but are in general characterized by high I.I. values and very irregular slope distributions. No correlation is observed between edifice-scale morphology and lithology (e.g. pillow dominated or hyaloclastite dominated).

Evolution of the insect terminal patterning system—Insights from the milkweed bug, Oncopeltus fasciatus

The anterior and posterior ends of the insect embryo are patterned through the terminal patterning system, which is best known from the fruitfly Drosophila melanogaster. In Drosophila, the RTK receptor Torso and its presumed co-activator Torso-like initiate a signaling cascade, which activates two terminal gap genes, tailless and huckebein. These in turn interact with various patterning genes to define terminal structures. Work on other insect species has shown that this system is poorly conserved, and not all of its components have been found in all cases studied. We place the variability of the system within a broader phylogenetic framework. We describe the expression and knock-down phenotypes of the homologues of terminal patterning genes in the hemimetabolous Oncopeltus fasciatus. We have examined the interactions among these genes and between them and other patterning genes. We demonstrate that all of these genes have different roles in Oncopeltus relative to Drosophila; torso-like is expressed in follicle cells during oogenesis and is involved in the invagination of the blastoderm to form the germ band, and possibly also in defining the growth zone; tailless is regulated by orthodenticle and has a role only in anterior determination; huckebein is expressed only in the middle of the blastoderm; finally, torso was not found in Oncopeltus and its role in terminal patterning seems novel within holometabolous insects. We then use our data, together with published data on other insects, to reconstruct the evolution of the terminal patterning gene network in insects. We suggest that the Drosophila terminal patterning network evolved recently in the lineage leading to the Diptera, and represents an example of evolutionary “tinkering”, where pre-existing pathways are co-opted for a new function.

Fluid transport properties and estimation of overpressure at the Lusi mud volcano, East Java Basin (Tanikawa et al., 2010)

1. IntroductionThe Lusi mud volcano in Sidoarjo, East Java, started to erupt onMay 29th 2006 and has displaced 13,000 families. Controversysurrounds whether the mud volcano was caused by drilling of theBanjar Panji 1 gas exploration well (Davies et al., 2007; Manga, 2007;Davies et al., 2008; Tingay et al., 2008) or due to the Yogyakartaearthquake that occurredat 05:54 amon the27th May2006(Mazziniet al., 2007; Sawolo et al., 2009). Constraining (a) pore pressure insedimentary strata prior to drilling; (b) changes in pore pressure thatoccurred due to drilling the Banjar Panji 1 well and the earthquake,and; (c) potential routes for fluid to the surface are critical forresolving this debate. These areas are tackled in the recent paper byTanikawaetal.(2010),whomodelporepressuredevelopmentduringburial of sedimentary strata at the site of the eruption and measurethe permeability and porosity of outcrop samples of formations ofequivalent age and lithology as those penetrated by the well. Fromthis analysis, they conclude that overpressure developed withinspecific successions, in particular the Upper Kalibeng clays and a deepcarbonate formation. They go on to argue that the overpressure madethe clay-rich unit susceptible to liquefaction as a result of cyclicdeformation duringtheYogyakartaearthquake,and thatthisinitiatedthe mud volcano. In this discussion we begin by summarising themain conclusions made by Tanikawa et al. (2010) and then considerthe validity of their most important conclusion that Lusi is a naturaldisaster. Lastly, we reiterate the compelling evidence (Davies et al.,2008;Tingayetal.,2008)thatLusiisman-madeandwascausedbyanunderground blowout at the Banjar Panji 1 well.2. Main conclusions of Tanikawa et al. (2010)The main conclusions of the Tanikawa et al. (2010) paper werethat overpressure developed within the bluish grey clay, termed theUpper Kalibeng Formation Unit 2, and therefore, these strata wereundercompacted and susceptible to remobilisation. They consideredthe deeper carbonates (termed the Upper Kujung Formation) as themost likely source of fluids. (Note: earlier papers on Lusi (e.g. Davieset al., 2007; Mazzini et al., 2007) referred to the carbonates as theKujung Formation however, strontium isotope ratios from themindicate they are 16–18 Ma (Kusumastuti et al., 2002), and thus arenottheOligioceneKujungFormation, butrathershouldbetermedthePrupuh or Tuban Formations (Tingay, 2010) and are thus termed thePrupuh Formation for the remainder of this discussion.) The authorshypothesized that the elevated pressure within the Upper KalibengFormation Unit 2, made the sediment more susceptible to the smallamplitude static or dynamic stresses caused by the Yogyakartaearthquake, so that small changes in pressure were sufficient toinduce liquefaction. The rapid influx of gas and liquid from the deepcarbonates flowed through pre-existing pathways formed by naturalhydraulic fractures, and this explains the continuous mud eruption atLusi. In summary, Tanikawa et al. (2010) hypothesize that pore fluidpressure changes caused by the Yogyakarta earthquake causedliquefaction of undercompacted shales and fluid flow occurredthrough natural fractures.3. DiscussionThe paper provides key new information on the hydrodynamics ofLusi, and we indeed agree with several important points made by theauthors. For instance data from Banjar Panji 1 corroborates themodelling by Tanikawa et al. (2010) that the Upper Kalibeng Unit 2 isa fine grained lithology that is overpressured and undercompacted.We also agree that the most likely source of fluid is the deepcarbonates. Furthermore, we agree with the model results suggestingthat significant overpressures exist in and below the PrupahFormation carbonates. Very high magnitude overpressures wereobserved in the same section in the Porong 1 well, 6 km away fromLusi.Although we are in agreement in these areas, there are severalconclusions on how the mud volcano was triggered which are at oddswith our published research (Davieset al., 2007; Manga, 2007; Davieset al., 2008; Tingay et al., 2008) and given the scale of thishumanitarian disaster it is important that these are challenged. Themost important of these, is their reasoning that the Yogyakartaearthquake triggered the eruption rather than drilling of the BanjarPanji 1 well. Tanikawa et al. (2010) propose that stress fluctuationsinduced by the M6.3 Yogyakarta earthquake (2 days prior to theeruption) caused the mud in the Upper Kalibeng Unit 2 to losestrength and liquefy (their abstract and section 7.1). Others have also

Synaptic pathways and inhibitory gates in the spinal cord dorsal horn

Disinhibition in the dorsal horn accompanies peripheral nerve injury and causes the development of hypersensitivity to mild stimuli. This demonstrates the critical importance of inhibition in the dorsal horn for maintaining normal sensory signaling. Here we show that disinhibition induces a novel polysynaptic low-threshold input onto lamina I output neurons, suggesting that inhibition normally suppresses a preexisting pathway that probably contributes to abnormal pain sensations such as allodynia. In addition, we show that a significant proportion of superficial dorsal horn inhibitory neurons are activated by low-threshold input. These neurons are well situated to contribute to suppressing low-threshold activation of pain output neurons in lamina I. We further discuss several aspects of inhibition in the dorsal horn that might contribute to suppressing pathological signaling.

Visual Cortical Activation During Auditory Word Categorization: Evidence for Multiple Sensory Interaction From Normal Sighted Participants*

Sensory substitution has been reported in recent brain imaging studies with blind people and others with sensory deficits so that sensory cortical regions traditionally considered unimodal respond to stimulation from other sensory modalities. Similar effects are also found for normal sighted people with sensory deprivation (blindfolded), indicative of pre-existing neuronal pathways for multiple sensory interactions. Such pathways are considered latent in that they only become unmasked or potentiated in the event of sensory deafferentation, although whether sensory deprivation is necessary to expose these pathways is unclear due to inconclusive evidence. With a relatively strong power in experimental design, visual cortical activation was observed when normal sighted participants (not blindfolded) judged whether auditorily-presented nouns referred to artificial or natural objects. The results suggest the above mentioned pathways can be exposed without sensory deafferentation and therefore are not totally latent. This establishes a boundary condition constraining theoretical models for the neural basis of multiple sensory interactions.