ISSN:0892-6638    

DOI:10.1096/fasebj.7.14.8224603

出版商:Wiley    

年代:1993

数据来源: WILEY

摘要:

Triage of grant application at the National Institutes of Health (NIH) is a process whereby an initial screening of applications by a scientific peer review group eliminates applications that are not competitive for awards. The process of application triage has been limited to those applications submitted to the NIH in response to an RFA (Request for Applications). A hypergeometric model was developed to determine the extent to which five, six, seven, or eight member triage teams or subsets of 12‐to‐20 member full committees could provide a statistically defensible triage decision. Although the intent of triage is to remove from review those applications that are noncompetitive, the model was weighted in favor of the applicant to minimize the likelihood that highly competitive applications would be eliminated. Within the assumptions and rules developed, it was determined that there was little likelihood that the latter would occur. For example, in the worst case scenario, the greatest probability that a highly competitive application would be knocked out of competition isP≤ 0.014 in the case of a five‐member triage subset of a 20‐member committee. Using the latter case, the model was tested on a set of 73 applications that were submitted to the National Cancer Institute for action at the February 1993 National Cancer Advisory Board. The model selected for triage required that each application be assigned to five reviewers, that each reviewer be blinded to the review assignments of the other reviewers, and that four noncompetitive votes be registered to triage out an application. Each of 19 applications received four to five noncompetitive votes, and were triaged out of the review process. The remaining 54 applications were then reviewed according to the usual NIH review process. Four of the applications received three noncompetitive triage votes each and were either rated as not recommended for further consideration (NRF,n= 2)) or received priority scores e 250 (n= 2) (The smaller the priority score the better the technical merit). Thirteen of the53applications received two noncompetitive votes. Of the latter, two were not recommended for further consideration and the remaining 11 received priority scores between in excess of 200. The distribution of competitive applications was such that funding was limited to those applications with priority scores of less than 190. Thus, the data suggest that the conservative model is valid such that the likelihood of eliminating a highly competitive application from consideration for funding is remotely small. With this model, the process of triage is fair to applicants on the one hand and is also effective in reducing consultant workloads on the other. The model could be applied to many different types of review situations (private sponsors as well as federal), especially when few awards are to be issued relative to the number of competing applications.—Vener, K. J., Feuer, E. J., Gorelic, L. A statistical model validating triage for the peer review process: keeping the competitive applications in the review pipeline.FASEB J.7: 1312‐1319; 1993.

ISSN:0892-6638    

DOI:10.1096/fasebj.7.14.8224604

出版商:Wiley    

年代:1993

数据来源: WILEY

摘要:

Normal morphogenesis and differentiation depend heavily on the coordination of cell‐cell and cell‐extracellular matrix interactions. During early mammalian development, the first cell lineages to be established are extraembryonic (trophoblast and extraembryonic endoderm), which are essential for satisfying the nutritional requirements of the developing embryo. This review emphasizes the importance of the cadherin family of cell‐cell adhesion molecules and the integrin family of extracellular matrix receptors in mediating interactions between cells and their environment during early development. The review first discusses the critical role of cell‐cell interactions in fertilization and early lineage decisions that occur during pre‐ and peri‐implantation development in the mouse, using the calcium‐dependent cell adhesion molecule E‐cadherin as the primary example. The remainder of the review discusses the importance of cell‐ECM interactions in the further morphogenesis and differentiation of the newly segregated lineages. The critical roles of integrine in differentiation, migration, and invasion of trophoblast in both mouse and human are emphasized.—Damsky, C., Sutherland, A., Fisher, S. Adhesive interactions in early mammalian embryogenesis, implantation, and placentation.FASEB J.7: 1320‐1329; 1993.

ISSN:0892-6638    

DOI:10.1096/fasebj.7.14.8224605

出版商:Wiley    

年代:1993

数据来源: WILEY

摘要:

In biological systems oligosaccharides are normally conjugated to proteins or lipids. The heterogeneity and branching of oligosaccharides allow glycoconjugates to display a further level of structural and functional diversity compared with linear proteins and nucleic acids or with lipids. This review summarizes some general principles that are emerging from the new field of glycobiology which, by addressing the molecular interactions of glycoconjugates in biological systems, spans the classical physicochemical, biological, and biochemical sciences. We discuss the genesis of glycoforms, the functional roles for glycosylation, and some general aspects of structure/function relationships with reference to N‐glycosylated animal glycoproteins including the enzymes ribonuclease and tissue plasminogen activator, IgG, the family of C‐type lectins, and receptor ligands.—Opdenakker, G., Rudd, P. M., Ponting, C. P., Dwek, R. A. Concepts and principles of glycobiology.FASEB J.7: 1330‐1337; 1993.

ISSN:0892-6638    

DOI:10.1096/fasebj.7.14.8224606

出版商:Wiley    

年代:1993

数据来源: WILEY

摘要:

Several bacterial species are able to catalyse ice formation at temperatures as warm as –2°C. These microorganisms efficiently catalyze ice formation at temperatures much higher than most organic or inorganic substances. Because of their ubiquity on the surfaces of frost‐sensitive plants, they are responsible for initiating ice formation, which results in frost injury. The high temperature of ice catalysis conferred by bacterial ice nuclei makes them useful in ice nucleation‐limited processes such as artificial snow production, the freezing of some food products, and possibly in future weather modification schemes. The rarity of other ice nuclei active at high subfreezing temperature, and the ease and sensitivity with which ice nuclei can be quantified, have made the use of a promoterless bacterial ice nucleation gene valuable as a reporter of transcription. Target genes to which this promoter is fused can be used in cells in natural habitats. Warm‐temperature ice nucleation sites have also been extensively studied at a molecular level. Nucleation sites active at high temperatures (above –5°C) are probably composed of bacterial ice nucleation protein molecules that form functionally aligned aggregates. Models of ice nucleation proteins predict that they form a planar array of hydrogen binding groups that closely complement that of an ice crystal face. Moreover, interdigitation of these molecules may produce a large contiguous template for ice formation.—Gurian‐Sherman, D., Lindow, S. E. Bacterial ice nucleation: significance and molecular basis.FASEB J.7: 1338‐1343; 1993.

ISSN:0892-6638    

DOI:10.1096/fasebj.7.14.8224607

出版商:Wiley    

年代:1993

数据来源: WILEY

摘要:

Mammalian cells contain two Cbl‐dependent enzymes,l‐methylmalonyl‐CoA mutase and methionine synthase. The former requires adenosyl‐Cbl and catalyzes the conversion ofl‐methylmalonyl‐CoA to succinyl‐CoA. The latter requires CH3‐Cbl and catalyzes the conversion of 5‐CH3‐tetrahydrofolate and homocysteine to tetrahydrofolate and methionine, respectively. Biochemical abnormalities related to a decrease in the activity of methionine synthase are thought to be responsible for the indistinguishable hematologic abnormalities seen in both Cbl and folate deficiency. The biochemical basis for the neuropsychiatric abnormalities seen in Cbl deficiency, but not in folate deficiency, is not known although hypotheses have been proposed that implicate one or the other of the two Cbl‐dependent enzymes. Recent studies have shown that levels of serum methylmalonic acid, 2‐methylcitric acids I and II, total homocysteine, and cystathionine are elevated in most patients with Cbl deficiency and that total homocysteine, cystathionine, N,N‐dimethylglycine, and N‐methylglycine are elevated in most patients with folate deficiency. Analysis of these metabolic abnormalities in various patient groups fails to support hypotheses that eitherl‐methylmalonyl‐CoA mutase or methionine synthase alone are responsible for the neuropsychiatric abnormalities. We suggest that they may result from a third, unknown mammalian Cbl‐dependent enzyme or from a combined deficiency of both Cbl‐dependent enzymes together with an unknown genetic or environmental factor.—Allen, R. H., Stabler, S. P., Savage, D. G., Lindenbaum, J. Metabolic abnormalities in cobalamin (vitamin B12) and folate deficiency.FASEB J.7: 1344‐1353; 1993.

ISSN:0892-6638    

DOI:10.1096/fasebj.7.14.7901104

出版商:Wiley    

年代:1993

数据来源: WILEY

摘要:

Cholinesterases (acetylcholinesterase and butyrylcholinesterase) exhibit additional catalytic activities apart from their well‐known action in hydrolyzing choline esters. An amine‐sensitive aryl acylamidase activity is exhibited by both acetyl‐ and butyrylcholinesterases. A metallocarboxypeptidase‐like activity is found associated with both acetyl‐ and butyrylcholinesterases. The peptidase activity exhibited by butyrylcholinesterase was located in a 50‐kDa COOH‐terminal fragment. Acetylcholinesterase is implicated in noncholinergic functions in the substantia nigra. A relationship between tumorigenesis, cell differentiation, and cholinesterases has been speculated. The sequence similarities between different esterases, lipases, thyroglobulin, cell adhesion proteins, and cholinesterases would make it appear that cholinesterases are capable of exhibiting more than one biological activity and their functions are wider than what is hitherto known.—Balasubramanian, A. S., Bhanumathy, C. D. Noncholinergic functions of cholinesterases.FASEB J.7: 1354‐1358; 1993.

ISSN:0892-6638    

DOI:10.1096/fasebj.7.14.8224608

出版商:Wiley    

年代:1993

数据来源: WILEY

摘要:

The inception of experimentally induced atherogenesis is marked by subtle biochemical and ultrastructural changes of the arterial intima, modifications that precede the monocytes migration within the vessel wall. Long before any recognizable endothelial denudation, hypercholesterolemia induces a sequence of prelesional events that start with the enhanced transport of excess plasma lipoproteins especially by transcytosis, followed by intima accumulation of chemically (oxidatively) modified and reassembled lipoproteins (MRLp). Exposure of endothelial cells concomitantly to hypercholesterolemia on the luminal side, and to the MRLp cytotoxic effects on the abluminal side, generates endothelial dysfunctions with altered biosynthetic activities. The latter are manifested initially by the hyperplasia of basal lamina and its disjunction from endothelium, and by the proliferation and reorganization of a modified extracellular matrix that traps MRLp. The cytotoxic effects of MRLp contribute to the endothelial production of chemoattractants and adhesion molecules that are instrumental in monocyte recruitment and migration in the subendothelium, where activated and differentiated as macrophages, they avidly ingest MRLp and their complexes to form foam cells. The latter are the hallmark of fatty streaks that marks the transition from the prelesional to the lesionai stage of atherogenesis. Understanding the earliest biochemical alterations of the artery wall is a prerequisite for designing more successful means of prevention and treatment of atherosclerosis.—Simionescu, M., Simionescu, N. Proatherosclerotic events: pathobiochemical changes occurring in the arterial wall before monocyte migration.FASEB J.7: 1359‐1366; 1993.

ISSN:0892-6638    

DOI:10.1096/fasebj.7.14.8224609

出版商:Wiley    

年代:1993

数据来源: WILEY

摘要:

Metal complexes that cleave nucleic acids provide a new means to study RNA structure and RNA‐protein interactions. Methods that use these chemical nucleases help compensate for the limitations of other techniques used to determine structure. Because the ligands that coordinate the metal generally control the cleavage selectivity of these complexes, it has become possible to design nucleolytic reagents that target specific higher‐order structures. In combination with site‐directed mutagenesis these conformation‐specific probes can be used to delineate long‐range interactions. Alternatively, complexes that cut irrespective of sequence and secondary structure have been used in protection (foot‐printing) experiments to locate protein binding sites. Because each position of the nucleic acid is susceptible to cleavage, the protection pattern yields a highly resolved definition of the contact site between the protein and RNA. In other applications, metal complexes have been conjugated to functional moieties such as oligonucleotides, peptides, or substrate analogs to direct their binding to a distinct site on a specific RNA molecule. This latter strategy holds significant therapeutic promise for the destruction of pathogenic RNAs.—Huber, P. W. Chemical nucleases: their use in studying RNA structure and RNA‐protein interactions.FASEB J.7: 1367‐1375; 1993.

ISSN:0892-6638    

DOI:10.1096/fasebj.7.14.7693534

出版商:Wiley    

年代:1993

数据来源: WILEY

摘要:

Pretreatment of 1321N1 human astrocytoma cells with serum induces a pronounced increase in subsequent stimulation by forskolin and other agents of intracellular cyclic AMP accumulation, a phenomenon referred to as sensitization (Mol. Pharmacol.39, 399–406, 1991). Pretreatment of these cells with lysophosphatidic acid induced sensitization to a similar extent as that with serum (approximately fivefold for forskolin stimulation and twofold for isoproterenol and prostaglandin E1stimulation), with half‐maximal effects at approximately 30 nM lysophosphatidic acid. Phosphatidic acid was effective but less potent whereas other lipids were ineffective. Sensitization by serum and by lysophosphatidic acid were almost completely inhibited by pertussis toxin pretreatment and partially inhibited by prolonged phorbol ester exposure to induce protein kinase C down‐regulation. Among nine cell lines tested, those that exhibited sensitization with serum showed comparable sensitization with lysophosphatidic acid. The effects of both lysophosphatidic acid and serum were markedly inhibited by treatment with phospholipase B but only minimally altered with phospholipases A2, D, and C. Exposure of cells to phospholipase C alone induced approximately threefold sensitization, but both serum and lysophosphatidic acid were able to induce further three‐ to fourfold sensitization above that induced by phospholipase C alone. In contrast, the effects of serum and lysophosphatidic acid were not additive with each other. Together these results suggest that lysophosphatidic acid or a closely related compound present in serum is the factor responsible for sensitization of the cyclic AMP pathway.—Kreps, D. M., Whittle, S. M., Hoffman, J. M., Toews, M. L. Lysophosphatidic acid mimics serum‐induced sensitization of cyclic AMP accumulation.FASEB J.7: 1376‐1380; 1993.

ISSN:0892-6638    

DOI:10.1096/fasebj.7.14.8224610

出版商:Wiley    

年代:1993

数据来源: WILEY