Ultrafast diffraction and structural dynamics: The nature of complex molecules far from equilibrium

Studies of molecular structures at or near their equilibrium configurations have long provided information on their geometry in terms of bond distances and angles. Far-from-equilibrium structures are relatively unknown—especially for complex systems—and generally, neither their dynamics nor their average geometries can be extrapolated from equilibrium values. For such nonequilibrium structures, vibrational amplitudes and bond distances play a central role in phenomena such as energy redistribution and chemical reactivity. Ultrafast electron diffraction, which was developed to study transient molecular structures, provides a direct method for probing the nature of complex molecules far from equilibrium. Here we present our ultrafast electron diffraction observations of transient structures for two cyclic hydrocarbons. At high internal energies of ≈4 eV, these molecules display markedly different behavior. For 1,3,5-cycloheptatriene, excitation results in the formation of hot ground-state structures with bond distances similar to those of the initial structure, but with nearly three times the average vibrational amplitude. Energy is redistributed within 5 ps, but with a negative temperature characterizing the nonequilibrium population. In contrast, the ring-opening reaction of 1,3-cyclohexadiene is shown to result in hot structures with a C—C bond distance of over 1.7 Å, which is 0.2 Å away from any expected equilibrium value. Even up to 400 ps, energy remains trapped in large-amplitude motions comprised of torsion and asymmetric stretching. These studies promise a new direction for studying structural dynamics in nonequilibrium complex systems.

High affinity type I interleukin 1 receptor antagonists discovered by screening recombinant peptide libraries.

Two families of peptides that specifically bind the extracellular domain of the human type I interleukin I (IL-1) receptor were identified from recombinant peptide display libraries. Peptides from one of these families blocked binding of IL-lalpha to the type I IL-1 receptor with IC50 values of 45-140 microM. Affinity-selective screening of variants of these peptides produced ligands of much higher affinity (IC50 approximately 2 nM). These peptides block IL-1-driven responses in human and monkey cells; they do not bind the human type II IL-1 receptor or the murine type I IL-1 receptor. This is the first example (that we know of) of a high affinity peptide that binds to a cytokine receptor and acts as a cytokine antagonist.

Identification of a Drosophila G protein alpha subunit (dGq alpha-3) expressed in chemosensory cells and central neurons.

We have identified another Drosophila GTP-binding protein (G protein) alpha subunit, dGq alpha-3. Transcripts encoding dGq alpha-3 are derived from alternative splicing of the dGq alpha locus previously shown to encode two visual-system-specific transcripts [Lee, Y.-J., Dobbs, M.B., Verardi, M.L. & Hyde, D.R. (1990) Neuron 5, 889-898]. Immunolocalization studies using dGq alpha-3 isoform-specific antibodies and LacZ fusion genes show that dGq alpha-3 is expressed in chemosensory cells of the olfactory and taste structures, including a subset of olfactory and gustatory neurons, and in cells of the central nervous system, including neurons in the lamina ganglionaris. These data are consistent with a variety of roles for dGq alpha-3, including mediating a subset of olfactory and gustatory responses in Drosophila, and supports the idea that some chemosensory responses use G protein-coupled receptors and the second messenger inositol 1,4,5-trisphosphate.

Gene therapy for long-term expression of erythropoietin in rats.

The injection of recombinant erythropoietin (Epo) is now widely used for long-term treatment of anemia associated with chronic renal failure, cancer, and human immunodeficiency virus infections. The ability to deliver this hormone by gene therapy rather than by repeated injections could provide substantial clinical and economic benefits. As a preliminary approach, we investigated in rats the expression and biological effects of transplanting autologous vascular smooth muscle cells transduced with a retroviral vector encoding rat Epo cDNA. Vector-derived Epo secretion caused increases in reticulocytes, with peak levels of 7.8-9.6% around day 10 after implantation. The initial elevation in reticulocytes was followed by clinically significant increases in hematocrit and hemoglobin for up to 11 weeks. Ten control and treated animals showed mean hematocrits of 44.9 +/- 0.4% and 58.7 +/- 3.1%, respectively (P < 0.001), and hemoglobin values of 15.6 +/- 0.1 g/dl and 19.8 +/- 0.9 g/dl, respectively (P < 0.001). There were no significant differences between control and treated animals in the number of white blood cells and platelets. Kidney and to a lesser extent liver are specific organs that synthesize Epo in response to tissue oxygenation. In the treated animals, endogenous Epo mRNA was largely down regulated in kidney and absent from liver. These results indicate that vascular smooth muscle cells can be genetically modified to provide treatment of anemias due to Epo deficiency and suggest that this cell type may be targeted in the treatment of other diseases requiring systemic therapeutic protein delivery.

Expression at the Imprinted Dlk1-Gtl2 Locus Is Regulated by Proneural Genes in the Developing Telencephalon

Imprinting is an epigenetic mechanism that restrains the expression of about 100 genes to one allele depending on its parental origin. Several imprinted genes are implicated in neurodevelopmental brain disorders, such as autism, Angelman, and Prader-Willi syndromes. However, how expression of these imprinted genes is regulated during neural development is poorly understood. Here, using single and double KO animals for the transcription factors Neurogenin2 (Ngn2) and Achaete-scute homolog 1 (Ascl1), we found that the expression of a specific subset of imprinted genes is controlled by these proneural genes. Using in situ hybridization and quantitative PCR, we determined that five imprinted transcripts situated at the Dlk1-Gtl2 locus (Dlk1, Gtl2, Mirg, Rian, Rtl1) are upregulated in the dorsal telencephalon of Ngn2 KO mice. This suggests that Ngn2 influences the expression of the entire Dlk1-Gtl2 locus, independently of the parental origin of the transcripts. Interestingly 14 other imprinted genes situated at other imprinted loci were not affected by the loss of Ngn2. Finally, using Ngn2/Ascl1 double KO mice, we show that the upregulation of genes at the Dlk1-Gtl2 locus in Ngn2 KO animals requires a functional copy of Ascl1. Our data suggest a complex interplay between proneural genes in the developing forebrain that control the level of expression at the imprinted Dlk1-Gtl2 locus (but not of other imprinted genes). This raises the possibility that the transcripts of this selective locus participate in the biological effects of proneural genes in the developing telencephalon.

Plant species, biomass and environmental characteristics of relevés along the North America Arctic bioclimate gradient

Question: How do interactions between the physical environment and biotic properties of vegetation influence the formation of small patterned-ground features along the Arctic bioclimate gradient? Location: At 68° to 78°N: six locations along the Dalton Highway in arctic Alaska and three in Canada (Banks Island, Prince Patrick Island and Ellef Ringnes Island). Methods: We analysed floristic and structural vegetation, biomass and abiotic data (soil chemical and physical parameters, the n-factor [a soil thermal index] and spectral information [NDVI, LAI]) on 147 microhabitat releves of zonalpatterned-ground features. Using mapping, table analysis (JUICE) and ordination techniques (NMDS). Results: Table analysis using JUICE and the phi-coefficient to identify diagnostic species revealed clear groups of diagnostic plant taxa in four of the five zonal vegetation complexes. Plant communities and zonal complexes were generally well separated in the NMDS ordination. The Alaska and Canada communities were spatially separated in the ordination because of different glacial histories and location in separate floristic provinces, but there was no single controlling environmental gradient. Vegetation structure, particularly that of bryophytes and total biomass, strongly affected thermal properties of the soils. Patterned-ground complexes with the largest thermal differential between the patterned-ground features and the surrounding vegetation exhibited the clearest patterned-ground morphologies.

An assessment of travel demand management approaches at suburban activity centers. Final report.

Transportation Systems Center, Cambridge, Mass.

Pathogens and microbial control of North American forest insect pests /

"August 1998" -- Cover.

Longwall and room-and-pillar productivity : a review of the U.S. coal mines /

Includes bibliographical references.

Propofol infusion syndrome in a super morbidly obese patient (BMI = 75)

Propofol infusion syndrome (PRIS) is a rare but often fatal complication as a result of large doses of propofol infusion (4–5 mg/kg/hr) for a prolonged period (>48 h). It has been reported in both children and adults. Besides large doses of propofol infusion, the risk factors include young age, acute neurological injury, low carbohydrate and high fat intake, exogenous administration of corticosteroid and catecholamine, critical illness, and inborn errors of mitochondrial fatty acid oxidation. PRIS manifestation include presence of metabolic acidosis with a base deficit of more than 10 mmol/l at least on one occasion, rhabdomyolysis or myoglobinuria, acute renal failure, sudden onset of bradycardia resistant to treatment, myocardial failure, and lipemic plasma. The pathophysiology of PRIS may be either direct mitochondrial respiratory chain inhibition or impaired mitochondrial fatty acid metabolism mediated by propofol. We report a case of supermorbidly obese patient who received propofol infusion by total body weight instead of actual body weight and developed PRIS.

Cognitive fit between conceptual schemas and internal problem representations: The case of geospatio-temporal conceptual schema comprehension

Geospatio-temporal conceptual models provide a mechanism to explicitly represent geospatial and temporal aspects of applications. Such models, which focus on both what and when/where, need to be more expressive than conventional conceptual models (e.g., the ER model), which primarily focus on what is important for a given application. In this study, we view conceptual schema comprehension of geospatio-temporal data semantics in terms of matching the external problem representation (that is, the conceptual schema) to the problem-solving task (that is, syntactic and semantic comprehension tasks), an argument based on the theory of cognitive fit. Our theory suggests that an external problem representation that matches the problem solver's internal task representation will enhance performance, for example, in comprehending such schemas. To assess performance on geospatio-temporal schema comprehension tasks, we conducted a laboratory experiment using two semantically identical conceptual schemas, one of which mapped closely to the internal task representation while the other did not. As expected, we found that the geospatio-temporal conceptual schema that corresponded to the internal representation of the task enhanced the accuracy of schema comprehension; comprehension time was equivalent for both. Cognitive fit between the internal representation of the task and conceptual schemas with geospatio-temporal annotations was, therefore, manifested in accuracy of schema comprehension and not in time for problem solution. Our findings suggest that the annotated schemas facilitate understanding of data semantics represented on the schema.

Understanding conceptual schemas: exploring the role of application and IS domain knowledge

Although information systems (IS) problem solving involves knowledge of both the IS and application domains, little attention has been paid to the role of application domain knowledge. In this study, which is set in the context of conceptual modeling, we examine the effects of both IS and application domain knowledge on different types of schema understanding tasks: syntactic and semantic comprehension tasks and schema-based problem-solving tasks. Our thesis was that while IS domain knowledge is important in solving all such tasks, the role of application domain knowledge is contingent upon the type of understanding task under investigation. We use the theory of cognitive fit to establish theoretical differences in the role of application domain knowledge among the different types of schema understanding tasks. We hypothesize that application domain knowledge does not influence the solution of syntactic and semantic comprehension tasks for which cognitive fit exists, but does influence the solution of schema-based problem-solving tasks for which cognitive fit does not exist. To assess performance on different types of conceptual schema understanding tasks, we conducted a laboratory experiment in which participants with high- and low-IS domain knowledge responded to two equivalent conceptual schemas that represented high and low levels of application knowledge (familiar and unfamiliar application domains). As expected, we found that IS domain knowledge is important in the solution of all types of conceptual schema understanding tasks in both familiar and unfamiliar applications domains, and that the effect of application domain knowledge is contingent on task type. Our findings for the EER model were similar to those for the ER model. Given the differential effects of application domain knowledge on different types of tasks, this study highlights the importance of considering more than one application domain in designing future studies on conceptual modeling.