Time Course Of Emergence Research Articles

Temporal Dynamics and Neuronal Specificity of Grin3a Expression in the Mouse Forebrain.

GluN3A subunits endow N-Methyl-D-Aspartate receptors (NMDARs) with unique biophysical, trafficking, and signaling properties. GluN3A-NMDARs are typically expressed during postnatal development, when they are thought to gate the refinement of neural circuits by inhibiting synapse maturation, and stabilization. Recent work suggests that GluN3A also operates in adult brains to control a variety of behaviors, yet a full spatiotemporal characterization of GluN3A expression is lacking. Here, we conducted a systematic analysis of Grin3a (gene encoding mouse GluN3A) mRNA expression in the mouse brain by combining high-sensitivity colorimetric and fluorescence in situ hybridization with labeling for neuronal subtypes. We find that, while Grin3a mRNA expression peaks postnatally, significant levels are retained into adulthood in specific brain regions such as the amygdala, medial habenula, association cortices, and high-order thalamic nuclei. The time-course of emergence and down-regulation of Grin3a expression varies across brain region, cortical layer of residence, and sensory modality, in a pattern that correlates with previously reported hierarchical gradients of brain maturation and functional specialization. Grin3a is expressed in both excitatory and inhibitory neurons, with strong mRNA levels being a distinguishing feature of somatostatin interneurons. Our study provides a comprehensive map of Grin3a distribution across the murine lifespan and paves the way for dissecting the diverse functions of GluN3A in health and disease.

Constructing Complexity in a Young Sign Language

A universally acknowledged, core property of language is its complexity, at each level of structure – sounds, words, phrases, clauses, utterances, and higher levels of discourse. How does this complexity originate and develop in a language? We cannot fully answer this question from spoken languages, since they are all thousands of years old or descended from old languages. However, sign languages of deaf communities can arise at any time and provide empirical data for testing hypotheses related to the emergence of language complexity. An added advantage of the signed modality is a correspondence between visible physical articulations and linguistic structures, providing a more transparent view of linguistic complexity and its emergence (Sandler, 2012). These essential characteristics of sign languages allow us to address the issue of emerging complexity by documenting the use of the body for linguistic purposes. We look at three types of discourse relations of increasing complexity motivated by research on spoken languages – additive, symmetric, and asymmetric (Mann and Thompson, 1988; Sanders et al., 1992). Each relation type can connect units at two different levels: within propositions (simpler) and across propositions (more complex).1 We hypothesized that these relations provide a measure for charting the time course of emergence of complexity, from simplest to most complex, in a new sign language. We test this hypothesis on Israeli Sign Language (ISL), a young language, some of whose earliest users are still available for recording. Taking advantage of the unique relation in sign languages between bodily articulations and linguistic form, we study fifteen ISL signers from three generations, and demonstrate that the predictions indeed hold. We also find that younger signers tend to converge on more systematic marking of relations, that they use fewer articulators for a given linguistic function than older signers, and that the form of articulations becomes reduced, as the language matures. Mapping discourse relations to the bodily expression of linguistic components across age groups reveals how simpler, less constrained, and more gesture-like expressions, become language.

Understanding the emergence of collective motion of microtubules driven by kinesins: role of concentration of microtubules and depletion force

We investigated the role of the concentration of microtubules and depletion force in the emergence of collective motion of microtubules driven by kinesins. Critical concentrations were found for both microtubules and the depletant to demonstrate the collective motion of microtubules. More importantly, the kinetics of the collective motion were found to be significantly dependent on the concentration of microtubules and the depletant. Substantial variations in the time course of emergence of the collective motion of microtubules were observed in response to the changes in concentration of the microtubules and the depletant. This study provides new insights into the kinetics of the collective motion of microtubules driven by kinesins, which might also be useful in understanding the coordinated behavior of other self-propelled systems.

A pharmacokinetic-pharmacodynamic model characterizing the emergence of resistant Escherichia coli subpopulations during ertapenem exposure.

Resistant subpopulations with reduced expression of outer membrane porins have been observed in ESBL-producing Escherichia coli during exposure to ertapenem. The aim of this work was to develop a pharmacokinetic-pharmacodynamic (PKPD) model to characterize the emergence of resistant E. coli during exposure to ertapenem and to predict bacterial killing following different dosing regimens of ertapenem. Data from in vitro time-kill experiments were used to develop a mechanism-based PKPD model for three E. coli strains: a native strain, an ESBL-producing strain, and an ESBL-producing strain with reduced expression of porins OmpF and OmpC. Each strain was exposed to static ertapenem concentrations (1-512 × MIC) for 24 h using starting inocula of ∼10(6) and 10(8) cfu/mL. The developed PKPD model consisted of three bacterial states: susceptible growing, less susceptible non-growing, and non-susceptible non-growing bacteria. A pre-existing bacterial subpopulation was used to describe the emergence of resistance. The PKPD model adequately characterized the data of the three E. coli strains investigated. Results from predictions suggest that the conventional dosage (1 g intravenously once daily) might result in regrowth of resistant subpopulations when used to treat infection caused by ESBL-producing strains. Resistant subpopulations frequently emerged in E. coli when exposed to ertapenem, supporting that the time course of emergence of resistance should be taken into consideration when selecting dosing regimens.

Signaling perturbations induced by invading H. pylori proteins in the host epithelial cells: A mathematical modeling approach

Helicobacter pylori ( H. pylori), a gram-negative bacterium, infects the stomach of approximately 50% of the world population. H. pylori infection is a risk factor for developing chronic gastric ulcers and gastric cancer. The bacteria produce two main cytotoxic proteins: Vacuolating cytotoxin A ( VacA) and Cytotoxin-Associated gene A ( CagA). When these proteins enter the host cell they interfere with the host MAP Kinase and Apoptosis signaling pathways leading to aberrant cell growth and premature apoptosis. The present study expanded existing quantitative models of the MAP Kinase and Apoptosis signaling pathways to take into account the protein interactions across species using the CellDesigner tool. The resulting network contained hundreds of differential equations in which the coefficients for the biochemical rate constants were estimated from previously published studies. The effect of VacA and CagA on the function of this network were simulated by increasing levels of bacterial load. Simulations showed that increasing bacterial load affected the MAP Kinase signaling in a dose dependant manner. The introduction of CagA decreased the activation time of mapK signaling and extended activation indefinitely despite normal cellular activity to deactivate the protein. Introduction of VacA produced a similar response in the apoptosis pathway. Bacterial load activated both pathways even in the absence of external stimulation. Time course of emergence of transcription factors associated with cell division and cell death predicted by our simulation showed close agreement with that determined from a publicly accessible microarray data set of H. pylori infected stomach epithelium. The quantitative model presented in this study lays the foundation for investigating the affects of single nucleotide polymorphisms (SNPs) on the efficiency of drug treatment.

Acoustic trauma induces reemergence of the growth- and plasticity-associated protein GAP-43 in the rat auditory brainstem.

We explored the consequences of unilateral acoustic trauma to intracochlear and central nervous system structures in rats. An acoustic trauma, induced by applying click stimuli of 130 dB (sound pressure level; SPL) for 30 minutes, resulted in an instant and permanent threshold shift of 95.92 +/- 1.08 dB (SEM) in the affected ear. We observed, as a consequence, a structural deterioration of the organ of Corti. Deprivation-dependent changes of neurons of the auditory brainstem were determined using antibodies against neurofilament and the growth-associated protein GAP-43 and compared with those following cochleotomy, studied earlier. By 231 days posttrauma, spiral ganglion cell bodies and their processes were almost entirely lost from all cochlear regions with destroyed organ of Corti. In the lateral superior olive (LSO) ipsilateral to the trauma, cell bodies of lateral olivocochlear neurons turned transiently GAP-43 positive within the first 1.5 years posttrauma. The time course of emergence and disappearance of this population of neurons was similar to that found after cochleotomy. Additionally, after noise trauma, principal cells in contralateral LSO and in medial superior olive (MSO) on both sides of the brainstem developed an expression of GAP-43 that began 3 and 16 days posttrauma, respectively, and lasted for at least 1 year. Such cells were rarely observed after cochleotomy. An unequivocal rise in GAP-43 immunoreactivity was also found in the neuropil of the inferior colliculus and the ventral cochlear nucleus, both preferentially on the acoustically damaged side. We conclude that the degree and specific cause of sudden unilateral deafness entail specific patterns of plasticity responses in the auditory brainstem, possibly to prevent the neural network dedicated to locate sounds in the environment from delivering erroneous signals centralward.

Epidemiology and clinical outcomes of patients with multiresistant Pseudomonas aeruginosa.

We conducted a case-series study of multiresistant Pseudomonas aeruginosa in patients who did not have cystic fibrosis. Patient characteristics, antibiotic exposures, time course of emergence of resistance, and clinical outcomes were examined. Twenty-two patients were identified from whom P. aeruginosa resistant to ciprofloxacin, imipenem, ceftazidime, and piperacillin was isolated. Nineteen (86%) had clinical infection. Patients received prolonged courses of antipseudomonal antibiotics before isolation of multiresistant P. aeruginosa. Nine of 11 patients with soft-tissue infection exhibited resolution of clinical infection but usually required surgical removal of infected tissue with or without revascularization. Overall, three patients died. In two instances in which multiple isolates with different susceptibility profiles from the same patient were available, pulsed-field gel electrophoresis profiles of serial isolates were indistinguishable or closely related. This study illustrates that multiresistant P. aeruginosa emerges in a stepwise manner after exposure to antipseudomonal antibiotics and results in adverse outcomes.

Consequences of Reduced Cerebral Blood Flow in Brain Development: II. Retardation of Neurological Outcome and Phosphorus Metabolism

We investigated the temporal relationship of the emergence of biochemical abnormalities to the development of behavioral dysfunction to identify the central factors of ischemic neurological disorders in developing brains. To induce early ischemia, bilateral carotid artery occlusion (BCAO) was surgically performed on 21 cats at the second week of age. BCAO produces histopathological damage, including neuronal loss and thinning of white matter. 31P magnetic resonance spectroscopy was used to monitor brain oxidative metabolism, neuronal membrane growth, and myelination of the prefrontal cortex in the first 3 months. Neurological development was monitored by conducting 25 tests of reflex, motor, sensory, and integrated behavioral function. At 1 month, phosphodiester (PDE) levels, a component of membranes and myelin, were low in animals showing complete ligation. At 2 months, the growth of PDE was low (14 to 12 of normal) in BCAO animals, whereas normal animals demonstrated a 23% increase. Phosphocreatine (PCr) levels, indicated by PCr/ATP and PCr/inorganic phosphate ratios, were retarded at 2 months in completely ligated animals (14 of normal). Neurologically, the completely ligated animals showed retardation of general development. The retardation was most pronounced for integrative functions, including visual function, and became more pronounced later in development. The time course of emergence of the retardation generally coincided with emergence of abnormalities in phosphorous compounds. The simultaneous occurrence of several biochemical and functional abnormalities in development following early ischemic insult suggests a causal relationship between membrane and mitochondrial development and neurological function.

Differing time course of emergence of psychotic symptoms and dyskinesia after neuroleptic withdrawal

Differing time course of emergence of psychotic symptoms and dyskinesia after neuroleptic withdrawal

The growth-related 28-kilodalton protein in germinating wheat. Use of peptide mapping to identify cryptic forms in cell-free extracts and protein-synthesizing systems

Characteristic peptide maps have been prepared and used to identify cryptic forms of the methionine-labeled 28-kilodalton (28-kd) protein (the G protein) which marks onset of growth in germinating wheat embryos. Peptide mapping of material eluted from areas detected as "bands" in autoradiograms of one-dimensional Laemmli-type gels and from areas detected as "spots" in autoradiograms of two-dimensional O'Farrell-type gels has led to identification of a counterpart to G among methionine-labeled products of cell-free synthesis. Identification of its cell-free counterpart has made it possible to show that translatable mRNA for the G protein, like G itself, only begins to appear between 5 and 10 h after onset of water uptake by dry wheat embryos. Peptide mapping of methionine- or proline-labeled material eluted from an area detected as a conspicuous "band" in autoradiograms of one-dimensional Laemmli-type gels has uncovered the existence of an unusual (apparently complexed) form of G in extracts of germinating but not dry wheat embryos. Unique among the hundreds of prominent proteins made by germinating wheat embryos, G exists as part of a thermolabile "150-kd complex" which is refractory to dismutation in a reducing environment containing sodium dodecyl sulphate (SDS). Presence or absence of the G complex constitutes the only conspicuous difference between SDS–polyacrylamide distributions of newly synthesized proteins derived from unheated as opposed to heated extracts of germinating embryos. Analysis of extracts prepared at different times after onset of water imbibition by dry wheat embryos shows that time course of emergence of the G complex, detected in unheated extracts, and of the G protein, detected in heated extracts, is the same. By fractional electroelution and silver staining of protein, it has been possible to show that G may be the principal if not the only protein component of the G complex.

Synthesis and turnover of proteins and mRNA in germinating wheat embryos.

The most prominent methionine-labeled protein made when cell-free systems are programmed with bulk mRNA from dry wheat embryos has been identified with what may be the most abundant protein in dry wheat embryos. The protein has been brought to purity and has a distinctive amino acid composition, Gly and Glx accounting for almost 40% of the total amino acids. Designated E because of its conspicuous association with early inhibition of dry wheat embryos, the protein and its mRNA are abundant during the "early" phase (0--1 h) of postimbibition development, and easily detected during "lag" phase (1--5 h), but they are almost totally degraded soon after entry into the "growth" phase of development, by about 10 h postimbibition. The most prominent methionine-labeled protein peculiar to the cell-free translational capacity of bulk mRNA from "growth" phase embryos is not detected as a product of in vivo synthesis. Its electrophoretic properties and its time course of emergence, after 5 h postimbibition development, suggest that this major product of cell-free synthesis may be an in vitro counterpart to a prominent methionine-labeled protein made only in vivo, by "growth" phase embryos. Designated G because of its conspicuous association with "growth" phase development, the cell-free product does not comigrate with any prominent dye-stained band in electrophoretic distributions of wheat proteins. The suspected cellular counterpart to G, also, does not comigrate with a prominent dye-stained wheat protein during electrophoresis, and although found in particulate as well as soluble fractions of wheat embryo homogenates it is not concentrated in either nuclei or mitochondria, as isolated.

Kinetics of DNA replication in bacteria with heterogeneous generation times

Kinetics of DNA synthesis in bacteria which exhibit dispersion in the generation times of individual cells are calculated for a model in which each cell synthesizes DNA during its entire life-cycle. These kinetics are expressed as the amounts of DNA in each of three categories as a function of time. The categories represent original material, synthesized before a hypothetical transfer to medium in which newly synthesized DNA can be identified; hybrid material, representing the first stage of semiconservative replication, and fully new material, in which neither strand contains original material. The problem is solved by computer simulation of a cell population in exponential growth, with generation times distributed to produce varying amounts of heterogeneity. In addition we calculate the time course of emergence of transforming markers into hybrid and new DNA when a culture with all chromosomes initially aligned at the origin of replication is permitted to replicate in new medium.