What does Congress want from the National Science Foundation? A content analysis of remarks from 1995 to 2018.

The U.S. Congress writes the legislation that funds the National Science Foundation (NSF). Researchers who seek NSF support may benefit by understanding how Congress views the agency. To this end, we use text analysis to examine every statement in the Congressional Record made by any member of Congress about the NSF over a 22-year period. While we find broad bipartisan support for the NSF, there are notable changes over time. Republicans have become more likely to express concerns about accountability in how the NSF spends its funds. Democrats are more likely to focus on how NSF-funded activities affect education, technology, and students. We use these findings to articulate how researchers and scientific organizations can more effectively conduct transformative science that corresponds to long-term and broadly held Congressional priorities.

Automated data collection with a Tecnai 12 electron microscope: applications for molecular imaging by cryomicroscopy.

In high-resolution biological electron microscopy, the speed of collection of large numbers of high-quality micrographs is a rate-limiting step in the overall process of structure determination. Approaches to speed up data collection can be very useful, especially in "single-molecule" microscopy of large multiprotein and protein-nucleic acid complexes, where many thousands of individual molecular images need to be averaged to determine the three-dimensional structure. Toward this end, we report the development of automated low-dose image acquisition procedures on a Tecnai 12 electron microscope using the scripting functionality available on the microscope computer. At the lowest level of automation, the user is required to select regions of interest that are to be imaged. All subsequent steps of image acquisition are then carried out automatically to record high-resolution images on either film or CCD, at desired defocus values, under conditions that satisfy user-specified limits for drift rates of the specimen stage. At the highest level of automation, determination of the best grid squares and the best regions suitable for imaging are carried out automatically. A medium level of automation is also available in which the user can designate the most promising grid squares manually and leave the process of finding the best holes in those grid squares to the microscope computer. We also show that all steps subsequent to insertion of the specimen in the microscope can be carried out remotely by connecting to the microscope computer via the Internet. Both features are implemented using Windows NT and Web-based tools and provide tools for automated data collection on any Tecnai microscope from any location.

Using pentafluorophenyl as a Lewis acid to stabilize a cis secondary amide conformation.

[reaction: see text]. N-(pyrimidin-2-yl)pentafluorobenzamide adopts a cis amide bond in the solid state with a pyrimidyl nitrogen pointing toward the center of the perfluorophenyl ring. In solution, the compound is a mixture of cis and trans rotamers. The conformational equilibrium is strongly solvent dependent, and the cis rotamer is entropically favored. It is proposed that the entropic driving force is decreased solvation of the two aryl groups when in the cis conformation.

Hydrogen bonding isosteres: bimolecular carboxylic acid and amine-N-oxide interactions mediated via CH...O hydrogen bonds.

The X-ray structures of cocrystals between 2,2'-dipyridyl-N,N'-dioxide (1) with fumaric acid (2), itaconic acid (3), succinic acid (4), and oxalic acid (5) were solved to determine if concurrent CH...O interactions were capable of orienting the bimolecular association of the two molecules. Cocrystals 1.2, 1.3 and 1.4 produce cyclic hydrogen bonded motifs employing pair-wise OH...O and CH...O hydrogen bonds, whereas cocrystal 1.5 forms analogous OH...O hydrogen bonds with a different set of intermolecular CH...O hydrogen bonds. Evidence of cocrystal formation was also observed for these complexes by differential scanning calorimetry and FT-IR spectroscopy. The structures of 1.2, 1.3 and 1.4 demonstrate the potential of the pair-wise OH...O and CH...O hydrogen bonding interactions and serve to illustrate their use as hydrogen bonding isosteres in crystal engineering, molecular recognition, and drug design.

Novel gallium(III) complexes transported by MDR1 P-glycoprotein: potential PET imaging agents for probing P-glycoprotein-mediated transport activity in vivo.

BACKGROUND: Multidrug resistance (MDR) mediated by expression of MDR1 P-glycoprotein (Pgp) represents one of the best characterized barriers to chemotherapy in cancer patients. Positron emission tomography (PET) agents for analysis of Pgp-mediated drug transport activity in vivo would enable noninvasive assessment of chemotherapeutic regimens and MDR gene therapy. RESULTS: Candidate Schiff-base phenolic gallium(III) complexes were synthesized from their heptadentate precursors and gallium(III)acetylacetonate. Crystal structures demonstrated a hexacoordinated central gallium with overall trans-pseudo-octahedral geometry. Radiolabeled (67)Ga-complexes were obtained in high purity and screened in drug-sensitive (Pgp(-)) and MDR (Pgp(+)) tumor cells. Compared with control, lead compound 6. demonstrated antagonist-reversible 55-fold lower accumulation in Pgp-expressing MDR cells. Futhermore, compared with wild-type control, quantitative pharmacokinetic analysis showed markedly increased penetration and retention of 6. in brain and liver tissues of mdr1a/b((-/-)) gene disrupted mice, correctly mapping Pgp-mediated transport activity at the capillary blood-brain barrier and hepatocellular biliary cannalicular surface in vivo. CONCLUSIONS: These results indicate that gallium(III) complex 6. is recognized by MDR1 Pgp as an avid transport substrate, thereby providing a useful scaffold to generate (68)Ga radiopharmaceuticals for molecular imaging of Pgp transport activity in tumors and tissues in vivo using PET.

Design, synthesis, and activity of 2,6-diphenoxypyridine-derived factor Xa inhibitors.

A novel series of 2,6-diphenoxypyridines has been designed to inhibit factor Xa, a serine protease strategically located in the coagulation cascade. The evolution from the photochemically unstable bisamidine (Z,Z)-BABCH to potent bisamidine compounds with a pyridine heterocycle as the core scaffold has been achieved. The most potent compound in the series, 6h, has a Ki for human factor Xa of 12 nM. The selectivity of 6h against bovine trypsin and human thrombin was greater than 90- and 1000-fold, respectively. Two proposed modes of binding of 6h to factor Xa are made based on the crystal structures of 6h by itself and of 6h bound to bovine trypsin.

Relevance of oral intake and necessity to void as ambulatory surgical discharge criteria.

Discharge criteria used in the outpatient setting of a 500-bed academic medical center were evaluated by nursing staff in two ambulatory units to determine validity in identifying patient readiness for discharge. Criteria categories include temperature, circulation, activity and mental status, pain, bleeding, voiding, and oral intake. The hospital course and post-discharge course of a convenience sample of 248 ambulatory subjects was drawn from consecutive patients. Post-discharge recovery outcomes identified by the telephone assessment included recovery, complications, necessity of further medical treatment, and the need to return to a medical facility. The descriptive results showed the safety of the seven discharge criteria. Voiding and oral intake were related to prolonged stays in the ambulatory units. Approval was granted by the Hospital Policy Board to relax discharge criteria, and make voiding and oral intake optional for patients. A stage II follow-up study of 1,582 patient subjects was conducted using the new criteria of voluntary voiding and oral intake. The average ambulatory stay was reduced 50 minutes after voiding and oral intake were made optional.

The gene of chicken axonin-1. Complete structure and analysis of the promoter.

We have isolated and characterised the gene encoding the chicken axonal cell adhesion molecule axonin-1. This gene comprises 23 exons distributed over approximately 40 kb. Each of the six immunoglobulin-like domains and the four fibronectin-type-III-like domains of axonin-1 is encoded by two exons. The introns between two domains are exclusively phase I. Their exon/intron borders correspond to the domain borders of the protein, suggesting that the gene of axonin-1 had been generated by exon shuffling. Three transcripts with a length of 4.3 kb, 5 kb, and 8 kb are found, and we provide evidence that they result from alternative use of polyadenylation signals. In situ hybridization revealed co-localisation of these transcripts in time and space in the developing chicken retina. Several identical transcription initiation sites were found in retina, brain, and cerebellum by RNase protection assay and anchored polymerase chain reaction. By transfection of HeLa cells, rat PC-12 phaeochromocytoma cells, and chicken embryonic fibroblasts with serially truncated segments of the 5'-flanking region linked to a luciferase reporter gene, we have found that the sequence from -91 to +56 relative to the transcription initiation site is sufficient to promote efficient gene expression. Tissue-specific expression of the axonin-1 gene seems to be regulated in part by sequences more than 1 kb upstream of the transcription initiation site. As revealed by computer analysis, the sequence immediately upstream of exon 1 contains an AP-2 binding site, a tumor phorbol-ester-responsive element, and a homeodomain protein binding site, but no canonical TATA box. A second AP-2 binding site and a homeodomain protein binding site are located within exon 1.

Distribution of TAG-1/axonin-1 in fibre tracts and migratory streams of the developing mouse nervous system.

The axonal cell adhesion molecule, TAG-1/axonin-1, stimulates axonal growth and supports neurite fasciculation in vitro. Using a polyclonal antiserum raised against chick axonin-1, which shares 75% of its sequence with TAG-1 of the rat, we have mapped the distribution of TAG-1/axonin-1 throughout the developing nervous system of the mouse. Although absent from proliferating neuroepithelia and from non-neuronal cells, immunoreactivity for TAG-1/axonin-1 is expressed by stage-specific subpopulations of differentiating neurons from embryonic day 10 to postnatal day 15. It stains their axons and the surface of their parent somata during the early phases of axogenesis. In agreement with a putative role of TAG-1/axonin-1 as an axon-bound growth substrate, immunoreactivity is found in developing spinal and cranial nerves, in corticothalamic projections, as well as in subsets of fasciculating long projecting tracts of the central nervous system, such as the dorsal funiculi of the spinal cord, the lateral olfactory and optic tracts, the fasciculus retroflexus, and the predorsal bundle. High levels of immunoreactivity characterise the development of the cerebellar molecular layer, the corpus callosum, anterior and hippocampal commissure, and of crossed projections in the spinal cord and at several levels of the brainstem. Intense immunoreactivity in fine collaterals of cutaneous afferents, including their growth cones that are in contact with the embryonic skin, suggests a role of TAG-1/axonin-1 in target recognition. While staining is weak on the somata of radially migrating neurons such as cortical neurons and cerebellar granule cells, strong immunoreactivity is associated with neural somata and processes of the three tangential migrations that form the precerebellar nuclei, indicating a possible involvement of TAG-1/axonin-1 in contacts between these neurons and the processes they migrate upon.

Demonstration of species-specific and cross-reactive components of the adult microsomal antigens from Schistosoma mansoni and S. japonicum (MAMA and JAMA).

Analysis of human serum reactivities to the Schistosoma mansoni adult microsomal antigens (MAMA) showed that S. japonicum and S. haematobium infection sera, as a rule, did not react as well to MAMA as did the homologous S. mansoni infection sera. The degree of species specificity, although not absolute, was quite pronounced. Purification of the corresponding microsomal antigens from S. japonicum adults (JAMA) and subsequent assays with both homologous and heterologous infection sera show a distinct and reciprocating species specificity between S. mansoni and S. japonicum microsomal antigens. The specificities of these antigens were quantitated by k-ELISA. Qualitative analysis of active antigenic components for both JAMA and MAMA involved assay by the "Western blot" or enzyme-linked immunoelectrotransfer blot (EITB). The EITB patterns of both antigens, after resolution by SDS-PAGE, show species-specific reactive bands at the 16,000 to 35,000 m.w. region. S. japonicum-specific antigens are located at the 18,000 to 35,000 m.w. region whereas S. mansoni-specific antigens were associated with m.w. components of 16,000 to 29,000. High m.w. antigen components (greater than 40,000) of both JAMA and MAMA are recognized by both heterologous and homologous infection sera and are thus not species specific. The demonstration of the clear separation of species-specific antigen bands of JAMA and MAMA by physical size offers a unique opportunity to isolate and characterize the species specificities of antibody-antigen reactions in these parasitic infections.