Electrolyte disorders

Electrolyte disorders can result in life-threatening complications. The kidneys are tasked with maintaining electrolyte homoeostasis, yet the low glomerular filtration rate of neonatal kidneys, tubular immaturity, and high extrarenal fluid losses contribute to increased occurrence of electrolyte disorders in neonates. Understanding the physiologic basis of renal electrolyte handling is crucial in identifying underlying causes and initiation of proper treatment. This article reviews key aspects of renal physiology, the diagnostic workup of disorders of plasma sodium and potassium, and the appropriate treatment, in addition to inherited disorders associated with neonatal electrolyte disturbances that illuminate the physiology of renal electrolyte handling

Syn-sedimentary to diagenetic Cu ± Co mineralization in Mesoproterozoic pyritic shale driven by magmatic-hydrothermal activity on the edge of the Great Falls tectonic zone – Black Butte, Helena Embayment, Belt-Purcell Basin, USA: Evidence from sulfide Re-Os isotope geochemistry

The ca. 1,500 to 1,325 Ma Mesoproterozoic Belt-Purcell Basin is an exceptionally preserved archive of Mesoproterozoic Earth and its paleo-environmental conditions. The Belt-Purcell Basin is also host to world-class base metal sediment-hosted mineralization produced in a variety of settings from the rift stage of basin evolution through to the subsequent influence of East Kootenay and Grenvillian orogenies. The mineral potential of this basin has not been fully realized yet. New rhenium-osmium (Re-Os) data presented here for chalcopyrite, pyrite and black shale contribute to refine a robust genetic model for the origin of the Black Butte copper ± cobalt ± silver (Cu ± Co ± Ag) deposit hosted by the ca. >1,475 Ma Newland Formation in the Helena Embayment of the Belt-Purcell Basin in Montana, USA. Chalcopyrite Re-Os data yield an isochron age (1,488 ± 34 Ma, unradiogenic initial 187Os/188 Os composition Osi-chalcopyrite = 0.13 ± 0.11) that overlaps with the geological age of the Newland Formation. Further, the Re-Os data of syn-sedimentary to diagenetic massive pyrite yield evidence of resetting with an isochron age (1,358 ± 42 Ma) coincident with the timing of the East Kootenay Orogeny. The unradiogenic Osi-chalcopyrite at ca. 1,488 Ma (0.13 ± 0.11) argues for derivation of Os from a magmatic source with a 187Os/188 Os isotopic composition inherited from the upper mantle in the Mesoproterozoic (Osmantle 1,475 Ma= 0.12 ± 0.02). The unradiogenic Osi-chalcopyrite also suggests limited contamination from a continental crustal source. This source of Os and our new sulfur isotopic signatures of chalcopyrite [–4.1 to +2.1 ‰ - VCDT] implies a dominantly magmatic source for metals. We integrate our new results and previously published geological and geochemical evidence to conceptualize a genetic model in which Cu and metals were largely contributed by moderate-temperature, reduced magmatic-hydrothermal fluids carrying reduced sulfur species with a magmatic origin and flowing as highly metalliferous fluids within the shale sequence. A subsidiary derivation of metals during thermally forced shale diagenesis is possible. Chalcopyrite mineralization replaced locally massive syn-3 sedimentary to diagenetic pyrite units close to the sediment-water interface, i.e., an ideal locus where magmatic-hydrothermal fluids could cool and the solubility of chalcopyrite would fall. We suggest that Cu mineralization was coeval with the timing of an enhanced thermal gradient in the Helena Embayment triggered until ca. 1,455 Ma by tholeiitic dike swarm that intruded into Archean basement rocks and intersected the NE–SW-trending Great Falls Tectonic Zone

A Chemical Genetic Approach Reveals Distinct Mechanisms of EphB Signaling During Brain Development

EphB receptor tyrosine kinases control multiple steps in nervous system development. However, it remains unclear whether EphBs regulate these different developmental processes directly or indirectly. In addition, as EphBs signal through multiple mechanisms, it has been challenging to define which signaling functions of EphBs regulate particular developmental events. To address these issues, we engineered triple knockin mice in which the kinase activity of three neuronally expressed EphBs can be rapidly, reversibly, and specifically blocked. Using these mice we demonstrate that the tyrosine kinase activity of EphBs is required for axon guidance in vivo. By contrast, EphB-mediated synaptogenesis occurs normally when the kinase activity of EphBs is inhibited suggesting that EphBs mediate synapse development by an EphB tyrosine kinase-independent mechanism. Taken together, these experiments reveal that EphBs control axon guidance and synaptogenesis by distinct mechanisms, and provide a new mouse model for dissecting EphB function in development and disease

Phenotypic Variation and Bistable Switching in Bacteria

Microbial research generally focuses on clonal populations. However, bacterial cells with identical genotypes frequently display different phenotypes under identical conditions. This microbial cell individuality is receiving increasing attention in the literature because of its impact on cellular differentiation, survival under selective conditions, and the interaction of pathogens with their hosts. It is becoming clear that stochasticity in gene expression in conjunction with the architecture of the gene network that underlies the cellular processes can generate phenotypic variation. An important regulatory mechanism is the so-called positive feedback, in which a system reinforces its own response, for instance by stimulating the production of an activator. Bistability is an interesting and relevant phenomenon, in which two distinct subpopulations of cells showing discrete levels of gene expression coexist in a single culture. In this chapter, we address techniques and approaches used to establish phenotypic variation, and relate three well-characterized examples of bistability to the molecular mechanisms that govern these processes, with a focus on positive feedback.

A Simple Screen to Identify Promoters Conferring High Levels of Phenotypic Noise

Genetically identical populations of unicellular organisms often show marked variation in some phenotypic traits. To investigate the molecular causes and possible biological functions of this phenotypic noise, it would be useful to have a method to identify genes whose expression varies stochastically on a certain time scale. Here, we developed such a method and used it for identifying genes with high levels of phenotypic noise in Salmonella enterica ssp. I serovar Typhimurium (S. Typhimurium). We created a genomic plasmid library fused to a green fluorescent protein (GFP) reporter and subjected replicate populations harboring this library to fluctuating selection for GFP expression using fluorescent-activated cell sorting (FACS). After seven rounds of fluctuating selection, the populations were strongly enriched for promoters that showed a high amount of noise in gene expression. Our results indicate that the activity of some promoters of S. Typhimurium varies on such a short time scale that these promoters can absorb rapid fluctuations in the direction of selection, as imposed during our experiment. The genomic fragments that conferred the highest levels of phenotypic variation were promoters controlling the synthesis of flagella, which are associated with virulence and host–pathogen interactions. This confirms earlier reports that phenotypic noise may play a role in pathogenesis and indicates that these promoters have among the highest levels of noise in the S. Typhimurium genome. This approach can be applied to many other bacterial and eukaryotic systems as a simple method for identifying genes with noisy expression

Sensory Experience Differentially Modulates the mRNA Expression of the Polysialyltransferases ST8SiaII and ST8SiaIV in Postnatal Mouse Visual Cortex

Polysialic acid (PSA) is a unique carbohydrate composed of a linear homopolymer of α-2,8 linked sialic acid, and is mainly attached to the fifth immunoglobulin-like domain of the neural cell adhesion molecule (NCAM) in vertebrate neural system. In the brain, PSA is exclusively synthesized by the two polysialyltransferases ST8SiaII (also known as STX) and ST8SiaIV (also known as PST). By modulating adhesive property of NCAM, PSA plays a critical role in several neural development processes such as cell migration, neurite outgrowth, axon pathfinding, synaptogenesis and activity-dependent plasticity. The expression of PSA is temporally and spatially regulated during neural development and a tight regulation of PSA expression is essential to its biological function. In mouse visual cortex, PSA is downregulated following eye opening and its decrease allows the maturation of GABAergic synapses and the opening of the critical period for ocular dominance plasticity. Relatively little is known about how PSA levels are regulated by sensory experience and neuronal activity. Here, we demonstrate that while both ST8SiaII and ST8SiaIV mRNA levels decrease around the time of eye opening in mouse visual cortex, only ST8SiaII mRNA level reduction is regulated by sensory experience. Using an organotypic culture system from mouse visual cortex, we further show that ST8SiaII gene expression is regulated by spiking activity and NMDA-mediated excitation. Further, we show that both ST8SiaII and ST8SiaIV mRNA levels are positively regulated by PKC-mediated signaling. Therefore, sensory experience-dependent ST8SiaII gene expression regulates PSA levels in postnatal visual cortex, thus acting as molecular link between visual activity and PSA expression

Differential Requirements of Two recA Mutants for Constitutive SOS Expression in Escherichia coli K-12

Background Repairing DNA damage begins with its detection and is often followed by elicitation of a cellular response. In E. coli, RecA polymerizes on ssDNA produced after DNA damage and induces the SOS Response. The RecA-DNA filament is an allosteric effector of LexA auto-proteolysis. LexA is the repressor of the SOS Response. Not all RecA-DNA filaments, however, lead to an SOS Response. Certain recA mutants express the SOS Response (recAC) in the absence of external DNA damage in log phase cells. Methodology/Principal Findings Genetic analysis of two recAC mutants was used to determine the mechanism of constitutive SOS (SOSC) expression in a population of log phase cells using fluorescence of single cells carrying an SOS reporter system (sulAp-gfp). SOSC expression in recA4142 mutants was dependent on its initial level of transcription, recBCD, recFOR, recX, dinI, xthA and the type of medium in which the cells were grown. SOSC expression in recA730 mutants was affected by none of the mutations or conditions tested above. Conclusions/Significance It is concluded that not all recAC alleles cause SOSC expression by the same mechanism. It is hypothesized that RecA4142 is loaded on to a double-strand end of DNA and that the RecA filament is stabilized by the presence of DinI and destabilized by RecX. RecFOR regulate the activity of RecX to destabilize the RecA filament. RecA730 causes SOSC expression by binding to ssDNA in a mechanism yet to be determined

Genomic correlates of glatiramer acetate adverse cardiovascular effects lead to a novel locus mediating coronary risk

Glatiramer acetate is used therapeutically in multiple sclerosis but also known for adverse effects including elevated coronary artery disease (CAD) risk. The mechanisms underlying the cardiovascular side effects of the medication are unclear. Here, we made use of the chromosomal variation in the genes that are known to be affected by glatiramer treatment. Focusing on genes and gene products reported by drug-gene interaction database to interact with glatiramer acetate we explored a large meta-analysis on CAD genome-wide association studies aiming firstly, to investigate whether variants in these genes also affect cardiovascular risk and secondly, to identify new CAD risk genes. We traced association signals in a 200-kb region around genomic positions of genes interacting with glatiramer in up to 60 801 CAD cases and 123 504 controls. We validated the identified association in additional 21 934 CAD cases and 76 087 controls. We identified three new CAD risk alleles within the TGFB1 region on chromosome 19 that independently affect CAD risk. The lead SNP rs12459996 was genome-wide significantly associated with CAD in the extended meta-analysis (odds ratio 1.09, p = 1.58×10-12). The other two SNPs at the locus were not in linkage disequilibrium with the lead SNP and by a conditional analysis showed p-values of 4.05 × 10-10 and 2.21 × 10-6. Thus, studying genes reported to interact with glatiramer acetate we identified genetic variants that concordantly with the drug increase the risk of CAD. Of these, TGFB1 displayed signal for association. Indeed, the gene has been associated with CAD previously in both in vivo and in vitro studies. Here we establish genome-wide significant association with CAD in large human samples.This work was supported by grants from the Fondation Leducq (CADgenomics: Understanding CAD Genes, 12CVD02), the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (e:AtheroSysMed, grant 01ZX1313A-2014 and SysInflame, grant 01ZX1306A), and the European Union Seventh Framework Programme FP7/2007-2013 under grant agreement no HEALTH-F2-2013-601456 (CVgenes-at-target). Further grants were received from the DFG as part of the Sonderforschungsbereich CRC 1123 (B2). T.K. was supported by a DZHK Rotation Grant. I.B. was supported by the Deutsche Forschungsgemeinschaft (DFG) cluster of excellence ‘Inflammation at Interfaces’. F.W.A. is supported by a Dekker scholarship-Junior Staff Member 2014T001 - Netherlands Heart Foundation and UCL Hospitals NIHR Biomedical Research Centre

Textural and geochemical constraints on andesitic plug emplacement prior to the 2004–2010 vulcanian explosions at Galeras volcano, Colombia

Hazardous sequences of vulcanian explosions are thought to result from the repeated emplacement and destruction of degassed, highly crystalline magma plugs in the shallow conduit of arc volcanoes. The processes governing the timing and magnitude of these explosions are thought to be related to magma ascent rate and efficiency of degassing and crystallisation. We study a rare suite of time-constrained ballistic bombs from the 2004–2010 period of activity of Galeras volcano to reconstruct magma plug architecture prior to six individual vulcanian explosions. We find that each plug was vertically stratified with respect to crystallinity, vesicularity and melt volatile content, melt composition and viscosity. We interpret this structure as resulting from multiple bubble nucleation events and degassing-driven crystallisation during multi-step ascent of the magma forming the plug, followed by spatially variable crystallisation within the plug under contrasting conditions of effective undercooling created by degassing. We propose that the shallow conduit evolved from more open degassing conditions during 2004–2008 to more closed conditions during 2009–2010. This resulted in explosions becoming smaller and less frequent over time during 2004–2008, then larger and more frequent over time during 2009–2010. This evolution was controlled by changing average ascent rates and is recorded by systematic changes in plagioclase microlite textures. Our results suggest that small volume vulcanian explosions (~ 105 m3) should generally be associated with longer repose times (hundreds of days) and produce ballistics characterised by small numbers of large, prismatic plagioclase microlites. Larger volume vulcanian explosions (~ 106 m3) should be associated with shorter repose times (tens of days) and produce ballistics characterised by high numbers of small, more tabular plagioclase microlites